Apotex Pty Ltd v ICOS Corporation

WITNESSES 17 Apotex adduced evidence (both written and oral) from Dr Denis Cherry, Dr Phillip Reece and Dr Brett Mooney. In addition, it tendered affidavits of Mr Rodney Cruise and Ms Catherine Halmagyi respectively. Neither Mr Cruise nor Ms Halmagyi were required for cross-examination. It is convenient to refer to the evidence of those witnesses first. 18 Mr Cruise is a patent attorney. He is a partner of Phillip Ormonde Fitzpatrick, an intellectual property services firm. He was engaged by Apotex to carry out a search of material available on 29 April 1999. Mr Cruise affirmed two affidavits in this proceeding. Those affidavits were tendered in evidence. Mr Cruise's evidence establishes (and ICOS does not dispute) that Daugan 1997 satisfies the requirements of s 7(3) of the Act. 19 Ms Halmagyi is an employee of Apotex. She is a Regulatory Affairs Team Leader and has held this position since June 2015. She joined the Regulatory Affairs Department of Apotex in June 2013. Her evidence establishes that the Apotex products will be manufactured by third party entities located outside of Australia, with different entities (located in different countries) approved for the manufacture of the active ingredient in the drug and the manufacture of the finished dosage form. 20 ICOS adduced evidence (both written and oral) from Professor Boddy, Dr Christopher McMahon, Professor Gerald Brock, Dr Malcolm Mitchell, Professor Allan Evans and Professor James Polli. It tendered an affidavit of Dr Alan Robertson. Dr Robertson was not required for cross-examination. Again, it is convenient to refer to his evidence first. 21 Dr Robertson described his technical expertise as being in medicinal chemistry. A medicinal chemist is a scientist with expertise in chemistry who conceives new molecules with a view to achieving a given therapeutic effect. Dr Robertson's qualifications are set out in his affidavit and I will not repeat them. I am satisfied that he has specialised knowledge and experience in the field of medicinal chemistry. Dr Robertson expresses the opinion that, as at 3 August 1999 and 1 August 2000, the relevant compound or active pharmaceutical ingredient (API) (tadalafil) was capable of forming salts and it would not necessarily be difficult to form a salt of tadalafil. I will return to his evidence later in these reasons. 22 With respect to three of the relevant scientific disciplines in this case, the experts conferred before the trial and prepared a joint experts' report. They then gave evidence in a joint session. The joint sessions were as follows: (1) Dr Cherry, Dr McMahon and Professor Brock. Dr Mitchell was involved in part of the joint experts' report and in part of the joint session. These experts were referred to as the clinicians; (2) Dr Reece, Professor Evans and Professor Brock. These experts were referred to as the pharmacologists; and (3) Dr Mooney and Professor Polli. These experts were referred to as the formulators. 23 A summary of the qualifications and experience of each of the experts is set out below. Generally speaking, I find that each expert was well qualified to give evidence on the matters which they addressed and I find that each did his best to assist the Court. There was one area where I thought that Professor Brock gave more emphasis to a point than was warranted, and this is discussed below. Otherwise, he was well-qualified and his evidence was satisfactory. Dr Reece gave some evidence relevant to obviousness which was based on information which went beyond common general knowledge. Apotex did not rely on this aspect of his evidence and I do not think that it affected the balance of his evidence. Of the most significance was Dr Mooney's lack of experience in formulating new chemical entities (NCEs) and, in my opinion, that lack of experience does affect the weight to be accorded to his evidence.

Dr Cherry 24 Dr Cherry is a consultant and, formerly, he was the Medical Director of the Perth Human Sexuality Centre (PHSC). The PHSC was, and remains, an organisation that specialises in the assessment and management of all areas of male and female sexuality, with a special interest in the treatment of male ED. Dr Cherry graduated in 1970 with a Bachelor of Medicine and Surgery from the University of Western Australia. 25 From 1970 to 1981, Dr Cherry worked in various positions across public hospitals in Western Australia, including as a resident medical officer, senior resident medical officer and registrar. Between 1974 and 1980, he worked as a registrar in the Department of Clinical Biochemistry at the Royal Perth Hospital, and later, the Princess Margaret Hospital. During that time, he became interested in many aspects of endocrinology, human biochemistry and the fundamental role of pharmacology in developing new treatments in the management of human disease. He also became a member of the Australian Association of Clinical Biochemistry. 26 From 1981 to 1989, Dr Cherry worked as a general medical practitioner in Western Australia and maintained a large clinical practice. He also held the position of chief medical officer for the Shires of Donnybrook and Capel, and was responsible for local hospital management and public health issues. During this time, Dr Cherry developed an interest in sexual medicine, particularly treatments for ED. He would regularly refer patients to the late Professor Ted Keogh, who specialised in the treatment of ED. Dr Cherry would generally be responsible for the patients' treatment. 27 In 1989, Dr Cherry was offered a part-time position as a clinical fellow at the Reproductive Medicine Research Institute (RMRI) that had been set up by Professor Keogh (now known as the Keogh Institute for Reproductive Medicine). RMRI was, and remains, a clinical institute with specialised expertise in the field of sexual medicine. As a clinical fellow, Dr Cherry was responsible for the assessment, management and treatment of male patients with ED. 28 In 1992, Dr Cherry set up the PHSC, together with Dr Alistair Tulloch (a urologist who had also previously worked with Professor Keogh at RMRI). From 1992 to 2011, Dr Cherry was the medical director of the PHSC. 29 At the PHSC, the treatment of ED constituted about 75% of the male sexual disorders that were treated by the practice. The majority of those patients were males aged over 50 years old. The remainder of the PHSC's practice involved the treatment of ejaculatory and libido disorders, and, more rarely, transgender cases. During his time at PHSC, Dr Cherry would treat upwards of around 15 to 20 patients per day. 30 During his time as Medical Director of PHSC, Dr Cherry also served as a member of the Australian Advisory Boards of Pfizer (in relation to Viagra), Eli Lilly (in relation to Cialis), and GSK-Bayer (in relation to Levitra). As I will explain later in these reasons, all of these drugs are used in the treatment of ED. As I have said, tadalafil is the compound which is the subject of the two patents in suit in this proceeding. He also undertook clinical research on behalf of Pfizer, Eli Lilly and GSK-Bayer in relation to each of those drugs, which was part of the clinical trials for obtaining regulatory approval for those drugs from the Therapeutic Goods Administration (TGA). 31 While the Medical Director of PHSC, Dr Cherry was also a lecturer at a number of institutions. From 1997 to 2011, he was a lecturer in the Royal Australian College of General Practitioners Training Program in Western Australia, where he delivered a series of lectures to general practitioners concerning the management and treatment of ED. From 2005 to present, he has held the position of visiting lecturer at the Notre Dame University, where he lectures year one to three students in the Medical Faculty. 32 Between 1995 and 2014, Dr Cherry was also a consultant with the Urology Out Patient Sexual Dysfunction Clinic at the Royal Perth Rehabilitation Hospital, where he advised on the sexual issues associated with spinal cord injuries. 33 Over the course of his career, Dr Cherry has been a member of the following professional organisations: Australian Urological Association, Australian Society for Impotence Medicine and European Society for Impotence Research. He has also served as a board or committee member for the following organisations at various dates: Centre for Sexual Health (Curtin University of Technology), Impotence Australia, Asian EDACT (Advisory Council), Pfizer (Australian Advisory Board), Eli Lilly (Australian Advisory Board), GSK-Bayer (Australian Advisory Board), and the Men's Health Journal Asia Pacific (Editorial Board).

Dr McMahon 34 Dr McMahon is an Australian physician, who has specialised in sexual medicine since 1982. In 1976, he was awarded a Bachelor of Medicine and Bachelor of Surgery from Monash University. 35 Between 1976 and 1981, Dr McMahon held positions in Melbourne hospitals as an intern, then a junior resident, before becoming a surgical registrar. In 1981, he commenced working as a general practitioner. Later in 1981, he commenced his genito-urinary/sexual health practice in Sydney. 36 Since 1991, Dr McMahon has been the Director of the Australian Centre for Sexual Health. He is the founding and past president of the Australasian Society of Impotence Medicine, which he himself founded in 1995. He is the current committee chairman of the World Health Organisation (WHO) Consultation on ED, and a committee member of the International Society of Impotence Research. 37 He is a member of the Australian ED medical advisory boards for various pharmaceutical companies, including Eli Lilly, Bayer and Pfizer. He gave evidence as an independent expert witness in relation to Pfizer's application to have Viagra listed on the Australian Schedule of Pharmaceutical Benefits. He has also conducted clinical trials for new drug companies, including Eli Lilly, Pfizer, Bayer, and Pharmacia & Upjohn. 38 Dr McMahon has also been a clinical investigator on multiple clinical trials in Australia, including trials conducted with respect to Viagra, Cialis and Levitra for each of Pfizer Australia, Eli Lilly Australia and Bayer Australia/GSK Singapore respectively, which were, in each case, the sponsor of trials in Australia. Those trials were run in 1996, 1998 and 2000, respectively. 39 Between 2001 and 2006, Dr McMahon was the chairman of Eli Lilly's Australian Medical Advisory Board for Cialis. During that time, in 2002, Cialis was approved in Australia by the TGA. 40 Dr McMahon is a member of the editorial board of the Journal of Sexual Medicine and Sexual Medicine Reviews, and he has acted as a referee for multiple international peer-reviewed medical journals. He is a member of several local, regional and international medical associations, and he is the past international president of the International Society of Sexual Medicine. He is the vice chairman of the WHO Second and Third International Consultation on Erectile and Sexual Dysfunction. 41 Dr McMahon has been invited to lecture on sexual medicine worldwide, and has published extensively on sexual health. He has published over 90 articles in peer reviewed international medical journals and 22 book chapters. His current research focuses on drug treatment for patients with refractory ED and drug treatment of premature ejaculation.

Professor Brock 42 Professor Brock is a Professor of Urology at the University of Western Ontario, Canada, where he manages a research team in ED. He was awarded a Bachelor of Science in physiology in 1981 and a Doctor of Medicine (MD) in 1986, both from McGill University. From 1986 to 1991, he trained as a urology resident at McGill University. In 1991, he passed his Urology Royal College board exams. 43 From 1991 to 1993, Professor Brock was a research fellow at the University of California in San Francisco. His research was conducted under the direction of Drs Tom Lue and Emil Tanagho, both of whom are leading researchers in the area of ED, focussing on neuro-urology. 44 From 1993, Professor Brock was Assistant Professor at McGill University in Montreal, Quebec, before being promoted to Associate Professor and receiving tenure in 1998. 45 In 1998, he left McGill University to join the Division of Urology at the Schulich School of Medicine and Dentistry at the University of Western Ontario as an Associate Professor. In 2000, he also joined the Obstetrics and Gynaecology Department of the Schulich School of Medicine and Dentistry. Since 2006, he has held the title of Professor of Urology at the University of Western Ontario. In 2009, he became the Program Director of the Division of Urology at the University of Western Ontario. 46 Professor Brock is also a practising clinical urologist Ontario where he treats patients with urological issues, including ED. Since 1991, he has practised as a clinical urologist at the various institutions at which he was employed. In 1999, on average, he treated approximately 50 new patients, and in the range of approximately 100 patients in total, per week, who were suffering from ED. Today, he continues to treat the same number of patients suffering from ED. 47 Since 1991, Professor Brock has both taught and carried out research in relation to the cause of ED and its treatments. Since 1993, he has also managed his own research team. He is widely published and has written over 200 peer-reviewed publications, of which at least 150 concern the field of male sexual dysfunction. His research from 1991 until present continues to focus on the causes and treatments of ED. 48 Professor Brock has also had significant experience with various animal models for ED, performing such work in his various laboratories since 1993. He has published over 30 peer reviewed articles and many more abstracts concerning the use or development of animal models. 49 Professor Brock has extensive experience in the role of principal or lead investigator in clinical trials that are directed to ED treatments. For example, in 1997, he was the principal investigator in at least five clinical studies concerning sildenafil. He was also principal investigator of other studies that investigated the effect of sildenafil in patients with mild ED and patients who were hypersensitive. 50 Professor Brock was also the chair of the Viagra Advisory Board for Canada from about 1997. In the period from around 1997 and 1998, he served on Eli Lilly/ICOS's international and Canadian Advisory Boards for the development of tadalafil, noting that once Eli Lilly purchased ICOS, the advisory boards became an Eli Lilly Advisory Board. 51 In around 1998, Professor Brock was the principal investigator for a ten site multi-centre Phase II study for tadalafil in Canada. His involvement with tadalafil has continued until the present day through his role as an investigator in various clinical trials as well as in his practice as a clinical urologist. 52 At the same time as conducting the Cialis Phase II study, he was the lead investigator in one of Bayer's clinical trials for vardenafil. The brand name for vardenafil is Levitra. In around 2009 and 2010, Professor Brock was chair of Johnson & Johnson's Drug Safety Monitoring Board for their clinical trials relating to dapoxetine (marketed as Priligy), a treatment for premature ejaculation. 53 Professor Brock has received multiple awards for his research in the field of urology, and in particular, relating to investigations into ED. He is currently the president-elect and a member of the Canadian Urology Association, chair of the Canadian Male Sexual Health Council and secretary-general of the International Society for Sexual Medicine. He was previously the secretary of the Sexual Medicine Society of North America, and is also a member of various other associations relating to the field of urology. 54 Professor Brock has also held seats on national and international committees relating to ED and its treatments, including as chair of the Canadian Urological Association's Office of Education, the Heart and Stroke Foundation's Cariovascular Safety - Viagra Panel, and the WHO Consensus Panel on Impotence. In 2003, at the Second WHO Consensus Conference on Impotence in Paris, he served as a member on the pharmacologic therapeutics committee that evaluated inhibitors. In 2009, he was co-chair of the Penile Rehabilitation Committee at the Third WHO meeting, and meeting chair of the 2015 Fourth ISSM Consensus Meeting on Sexual Medicine, held in Madrid, where more than 200 of the world's experts met to arrive at a consensus on current and future therapies in the field. 55 Professor Brock consults with and sits on the medical advisory boards of a number of pharmaceutical companies and routinely advises these companies about various issues relating to the causes and clinical treatments of urological conditions, including ED. These companies include Pfizer, Eli Lilly/ICOS, Bayer, Janssen-Ortho, Pharmacia and American Medical Systems. 56 Professor Brock gives lectures to physicians and pharmacists on behalf of various pharmaceutical companies, including Eli Lilly. 57 Since 1993, Professor Brock has also taught and supervised undergraduate and graduate medical students, post-doctoral research fellows, and urology residents. His teaching has focused on infertility and ED, including the causes, known and established treatments, and research regarding new theories of treatment. Between 2009 and 2014, he was the urology residency Program Director at Western University. From 2000 to 2004, he was a corresponding member of the test committee for the Royal College of Physicians and Surgeons of Canada for urology and, from 2005 to 2010, he served as a core examiner for the test committee. 58 Professor Brock sits on the editorial boards of the Canadian Journal of Urology, Journal of Andrology, and Asian Journal of Urology and Translational Urology and Andrology. He is also a peer reviewer for the Journal of Urology, Urology, American Journal of Physiology, American Society of Hospital Medicine, Pharmacists AHFS Drug Information, Canadian Medical Association Journal and the Journal of Sexual Medicine. He has authored over 200 peer-reviewed publications and book chapters and hundreds of additional presentation abstracts, most relating to ED. He has also been an invited speaker at many institutions around the world, again mostly relating to ED. 59 Finally, he has presented expert advice to the Health Protection Branch (the Canadian pharmaceutical regulatory authority) on behalf of Johnson & Johnson for a premature ejaculation treatment and Sanofi-Aventis for an over-the-counter ED treatment containing tadalafil (on licence from Eli Lilly).

Dr Mitchell 60 Dr Mitchell is a former clinical pharmacologist, who has now retired. He was previously the Medical Director at Eli Lilly. In that role, he was responsible for overseeing the clinical pharmacology studies that were brought into existence and deployed to support the registration of Cialis. He was also one of the co-authors of the "Kloner Papers" which were the subject of evidence from the clinicians and which are referred to later in these reasons. 61 In 1973, Dr Mitchell graduated from Newcastle Medical School in the United Kingdom with a Bachelor of Medicine and Bachelor of Surgery. Between 1973 and 1977, he undertook junior doctor medical rotations. Between 1978 and 1979, he held the position of research registrar at various hospitals. 62 In 1979, Dr Mitchell moved to Glasgow and commenced practising in the area of radiotherapy and oncology, which involved working with cancer patients receiving treatment for their disease. Between 1979 and 1982, he was the radiotherapy registrar at two hospitals in Glasgow. 63 In 1982, Dr Mitchell joined Pfizer UK as a medical advisor. In that role, he took on responsibility for a compound called prazosin, which is an "alpha-blocker" used to treat high blood pressure (amongst other diseases). He was also responsible for Phase III clinical trial work relating to follow-up alpha-blocker compounds. 64 Under the supervision of the Medical Director at Pfizer UK, Dr Mitchell also explored the use of alpha-blockers in diseases such as asthma and prostatic hyperplasia (enlargement of the prostate). During that time, Dr Mitchell also worked on high-dose cytarabine (a chemotherapy medication used for the treatment of certain blood cancers). 65 Between 1986 and 1987, Dr Mitchell then moved to Napp Pharmaceutical Holdings Limited in Cambridge, where he held the position of Medical Director. During that time, he worked on the development of slow-release compounds, and in particular, morphine. 66 In 1987, Dr Mitchell moved to Eli Lilly. He was initially involved in Phase II and Phase III clinical trial work, relating to respiratory compounds, as well as the H2 blocker, nizatidine. In 1990, Dr Mitchell then moved to Cardiac Pacemakers Inc, which was then a part of Eli Lilly, for around three years. In that role, he was involved in applying pharmaceutical development strategies to cardiac implantation devices. 67 In 1993, Dr Mitchell moved to Eli Lilly's clinical pharmacology group, where he was involved in ongoing drug development work for all aspects of clinical pharmacology across Eli Lilly's portfolio, including conducting many first in human studies, through to bioequivalence studies for formulation changes. A large part of that work included developing clinical pharmacology regulatory packages for compounds (small molecules and biologics) that Eli Lilly was intending to register as medicines. This process involved designing the package of clinical pharmacology studies that would need to be conducted and included in the regulatory dossier in order to obtain marketing approval for the compound, as well as overseeing the implementation of the study protocols, discussing them with investigators, and analysing the resulting data (on a study-by-study basis as well as across multiple studies). For example, Dr Mitchell was responsible for developing the clinical pharmacology regulatory package for tadalafil, in all the indications registered to date, with the largest pharmacology package being for the original ED indication. I will refer to his work in relation to tadalafil again later in these reasons. 68 Dr Mitchell was also in charge of the clinical pharmacology package for olanzapine (an atypical antipsychotic medication used in the treatment of schizophrenia and other psychoses) for all formulations registered after the original launch of that product (namely, the oral rapidly dissolving formulation and both intramuscular preparations). 69 In around 2006, Dr Mitchell became Medical Director for Eli Lilly for late phase compounds. While this was more of a managerial role, given his extensive experience in clinical pharmacology at Eli Lilly, the clinical pharmacologists continued to consult him in relation to the regulatory packages they were designing. As such, he has advised in relation to clinical pharmacology packages for almost all the approvals obtained by Eli Lilly in the last twenty years. 70 In addition to his experience in creating pharmacology packages for small and large molecules, Dr Mitchell also has particular knowledge of the Thorough QT (TQT) study, which is designed to assess whether new drugs have the potential to cause cardiac arrhythmia. Since 2002, he has conducted TQT studies, and became a member of the Eli Lilly cardiovascular safety committee at around the same time. That committee had responsibility for reviewing all molecules in development from a cardiovascular safety perspective. 71 Since his retirement in 2016, Dr Mitchell has acted as a consultant for Eli Lilly in relation to its ongoing application (made in conjunction with its licensee, Sanofi) for regulatory approval to supply Cialis without a prescription, as well as in connection with patent litigation relating to tadalafil.

Dr Reece 72 Dr Reece has been an independent consultant to the biotechnology and pharmaceutical industries, both in Australia and overseas, since May 2003. In 1971, he was awarded a Bachelor of Science from the University of Adelaide, and, in 1973, First Class Honours in organic chemistry also from the University of Adelaide. In 1976, he was awarded his PhD in medical chemistry from the Australian National University. 73 Immediately after completing his doctoral studies, Dr Reece was employed initially as a hospital scientist, and later, as a principal hospital scientist, in the Department of Clinical Pharmacology at the Queen Elizabeth Hospital in Adelaide (QEH). 74 Dr Reece worked at the QEH for a number of years and he was promoted to various positions. In February 1983, he was promoted to Chief Hospital Scientist, and in 1985, to the 'excellence' category of Chief Hospital Scientist. He remained in that position until September 1987. In these roles, Dr Reece had both service-related and research-related duties. 75 In 1977, Dr Reece completed a postgraduate course in pharmacokinetics presented by Dr William O'Reilly in the School of Pharmacy at the South Australian Institute of Technology in Adelaide (now part of the University of South Australia). 76 In 1978, Dr Reece took three months' study leave from the QEH to train under the guidance of Professor Sidney Riegelman at the School of Pharmacy, Medical Centre at the University of California in San Francisco. During this time, he undertook a three-month intensive postgraduate course in advanced pharmacokinetics at the University of California. 77 Following Professor Riegelman's death in 1982, Dr Reece attended and presented at a symposium held in his honour. This symposium covered a broad range of drugs, pharmacokinetic principles and delivery mechanisms. It involved a number of presentations given by Professor Riegelman's former colleagues and students. Dr Reece attended each of these lectures and also presented a lecture on his work on hydrallazine and endralazine pharmacokinetics. 78 Dr Reece's research interests at the QEH evolved to include oncology research, in which he specialised after he was awarded a Churchill Fellowship in 1983. The Churchill Fellowship provided support for Dr Reece to undertake a six month project with Dr Garth Powis at the prestigious Mayo Clinic in Rochester, Minnesota in the United States, to study the pharmacokinetics of anticancer drugs. 79 On his return to the QEH, Dr Reece applied for and was awarded Anticancer Foundation and National Health & Medical Research Council grants to support his research projects. 80 By the time Dr Reece left the QEH, he had completed several clinical research projects with various groups both within and outside the hospital. The projects were mainly focused on oncology, but also included other therapeutic areas, such as neurology, cardiology and renal disease. Dr Reece had a small team of researchers working on these different projects. In general terms, that work related to investigating the relationship between the plasma concentrations of the drug or drug dosage and pharmacological effect. 81 In addition to his duties as Chief Hospital Scientist at the QEH, between January 1986 and September 1987, Dr Reece was also an evaluator for the Australian Department of Health. In this capacity, he evaluated the pharmacokinetic component of applications for the regulatory approval of drugs. He reviewed approximately six different approval applications over that time. 82 The Department of Clinical Pharmacology at the QEH was part of what was known as the Adelaide Pharmacology Group (APG), which was a group that also included the Departments of Clinical Pharmacology of the University of Adelaide and Flinders University and the Pharmacy School of the South Australian Institute of Technology. At that time, the APG was considered the pre-eminent group in Australia for its expertise in clinical pharmacology and pharmacokinetics. 83 In September 1987, Dr Reece moved to Sydney to become the Clinical Trials Manager at Astra Pharmaceuticals (Astra). As Clinical Trials Manager, he was responsible for six clinical research associates, each of whom had responsibility for conducting and monitoring human clinical trials of Astra's new pharmaceuticals in Australia and New Zealand for the purpose of obtaining regulatory approval of those products. These trials were generally Phase III trials. Dr Reece's group had responsibility for ensuring that the clinical trial data that was generated met international regulatory requirements suitable for submission in support of a new drug application. 84 After 12 months, Dr Reece left Astra to take up the position of Associate Regional Director of Clinical Research at Parke Davis Ltd (Parke Davis) in Sydney. In this role, he was responsible for the clinical trial research activities of the international group in the Asia Pacific region. 85 In August 1990, Dr Reece transferred to the United States office of Parke Davis in Ann Arbor, Michigan, as Director of Clinical Pharmacology. In that role, he served as the clinical pharmacology representative on several multi-disciplinary project teams, each of which was responsible for the development of a new pharmaceutical product. Each of the drug development project teams of which he was a member included representatives from multiple departments across Parke Davis. In general, those teams included personnel with expertise in medicinal chemistry, toxicology and non-clinical pharmacology, formulation chemistry, clinical pharmacology, clinical medicine, regulatory affairs and marketing. In a majority of the drug development projects that he was involved in at Parke Davis, Dr Reece participated in the transition from pre-clinical studies (involving studies conducted in vitro and in laboratory animals) to Phase I clinical trials in human subjects. He remained a member of the team as the drug proceeded through clinical development. As the clinical pharmacology representative on those teams, Dr Reece was responsible for designing and monitoring studies of each new drug in human subjects (primarily healthy volunteers, and occasionally patients) and analysing and interpreting the results obtained in those studies, including all of the associated pharmacokinetic and toxicology data. 86 In his role at Parke Davis, Dr Reece was also responsible for designing the protocols for Phase I trials of new pharmaceutical products and for conducting the trials which he designed with the assistance of medical practitioners in the clinical pharmacology group at Parke Davis. He also provided advice on the design and conduct of Phase II and Phase III trials. 87 Dr Reece was also responsible for preparing the clinical pharmacology reports for investigational new drugs (IND) and new drug applications, and reviewed pre-clinical data for suitability for IND applications and Phase I trials. 88 In October 1993, Dr Reece returned to Australia to take up the position of Director of Research and Development at Biota Holdings (Biota) in Melbourne. He worked for Biota in a number of different roles for the next nine years, including, between July 1994 and May 1995, acting as Biota's Chief Executive Officer, and, between May 2001 and March 2002, as a non-executive director of Biota's United States subsidiary, Biota Inc. In December 2001, Dr Reece was promoted to general manager of the Australian operations of Biota. 89 In all of his roles at Biota, Dr Reece was responsible for the company's research and development activities. 90 In March 2002, Dr Reece left Biota to become Chief Executive Officer and Managing Director of Boron Molecular Ltd in Melbourne. In May 2003, Dr Reece left Boron Molecular Ltd and became an independent consultant. 91 Since 2003, Dr Reece has been an Honorary Senior Fellow in the Department of Pharmacology, University of Melbourne and each year he has presented a series of lectures on drug discovery and development. He has also held the following positions: from December 2000 to February 2009, non-executive director of EnGeneiC Pty Ltd in Sydney; from December 2003 to April 2008, non-executive chairman of Cryptopharma Pty Ltd in Melbourne; and from February 2004 to November 2008, consultant to Biota.

Professor Brock 92 As mentioned above at [22], Professor Brock was also a part of the joint session of pharmacologists.

Professor Evans 93 Professor Evans is the Provost and Chief Academic Officer at the University of South Australia. His expertise is in the areas of pharmacology, pharmacokinetics and formulation science of medicines. Professor Evans also has extensive experience in the design, conduct and analysis of clinical trials in the context of drug development projects. 94 Apart from his academic duties at the University of South Australia, he has conducted training programs for Australian members of the pharmaceutical industry and the TGA on the process of drug development spanning pre-clinical through to the point where the drug is marketed. He also has extensive experience working with pharmaceutical companies in developing new drug treatments spanning a 10 year period. Professor Evans has also acted as a primary investigator or consultant in at least 50 clinical trials studying the pharmacokinetics and efficacy of APIs. 95 In 1982, Professor Evans was awarded a Bachelor of Pharmacy from the South Australian Institute of Technology. From 1983 to 1984, he worked full time as a pharmacist in community pharmacies and in a hospital pharmacy. He continued to work part time in community pharmacies until 1989. 96 Between 1985 and 1989, Professor Evans also completed his PhD at the Department of Clinical & Experimental Pharmacology at the University of Adelaide. His PhD research investigated the pharmacokinetics of enantiomers of ibuprofen. 97 Between 1985 and 1989, he was also involved in teaching undergraduate courses in pharmaceutics at the South Australian Institute of Technology. 98 From 1989 and 1991, Professor Evans lived in Manchester in the United Kingdom, where he worked as a postdoctoral research associate under the supervision of Professor Malcolm Rowland at the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester. In 1990, he attended a residential Advanced Course in Pharmacokinetics and Pharmacodynamics in Switzerland. 99 In 1991, Professor Evans returned to Australia and spent a brief period as a research associate at the Department of Clinical & Experimental Pharmacology at the University of Adelaide. In August 1992, he joined the School of Pharmacy and Medical Sciences at the University of South Australia as a lecturer. In January 1995, he became a senior lecturer and associate professor in January 2000. He was promoted to Professor of Pharmaceutics in January 2003, and then Head of School in September 2004. 100 In August 2009, Professor Evans became Pro Vice Chancellor & Vice-President of the Division of Health Sciences of the University of South Australia. He held this position until June 2013. As Pro Vice Chancellor, he had responsibility for the teaching, research, human resources, financial and engagement activity of all health science activity at the University. He was also responsible for the management of the University's City East campus. He continued to teach undergraduate and postgraduate students in the Division of Health Sciences, although to a far lesser extent than in the 1990s through to 2004. 101 In 2013, Professor Evans became Provost and Chief Academic Officer at the University of South Australia; a position that he currently holds. He has lectured in pharmacokinetics, biopharmaceutics, clinical pharmacology, and pharmacy practice. In particular, he taught students how drugs were discovered, how they were developed and the process of taking a drug from discovery through to marketing, which required him to keep up-to-date with new developments within the pharmacology and pharmaceutical field. 102 From 1992 to 2001, Professor Evans was also a faculty member of the APG Drug Disposition Workshop Faculty (Workshop Faculty), which ran intensive five-day training programs for Australian members of the pharmaceutical industry and the TGA. In 1996, Professor Evans became convenor of the Workshop Faculty and was the main organiser of the 1998 program, held in Canberra. 103 Professor Evans has also held a variety of consulting roles. During his time living in Manchester in the early 1990s, he consulted for an Italian pharmaceutical company, Zambon Company S. p. A, providing it with advice on pharmacological issues and, in particular, pharmacokinetics. 104 In 1992, after returning to Australia, Professor Evans also began consulting for FH Faulding & Co Ltd (Faulding), advising it in relation to new drug delivery systems and formulations. In around 1995, Faulding set up a clinical trial facility conducted at the Royal Adelaide Hospital. At the time, Faulding employed Professor Evans as their main consultant, so he was responsible for liaising with industry representatives, providing advice around the design and conduct of clinical trials and assisting with the quality control and analytical systems. He held this role for nearly ten years and only stopped consulting in 2004, when he was promoted to Head of School. 105 From 1994 until 2009, Professor Evans also worked extensively with Gebro Pharma during which time he assisted with (among other things) investigating whether or not there were any advantages of (S)-ibuprofen over racemic ibuprofen, for the purposes of European regulatory approval of (S)-ibuprofen. This product was successfully registered and is currently marketed as Seractil. 106 Beginning in 1993, Professor Evans also worked (and still currently works) with the Italian company Sigma Tau S. p. A and its United States subsidiary Sigma Tau Pharmaceuticals, based in Washington (Sigma Tau). His role at this company with respect to clinical trials was similar to the role held for Faulding, which included responsibility for work concerning propionyl-L-carnitine. Propionyl-L-carnitine is an endogenous compound (meaning that it is already naturally present in the body), which shows some evidence that it is a useful energy source. 107 In 1997, Professor Evans moved to Italy for approximately six months, so that he could assist Sigma Tau in preparing the dossier that was to be submitted for regulatory approval across Europe. He worked primarily with the pharmacokinetics and metabolism team (which comprised three or four other scientists), but was required to integrate the reports we drafted into the dossier as a whole. 108 In 1993, Professor Evans became involved with the Drug Metabolism and Disposition Group (later to become the Centre for Pharmaceutical Research) at the University of South Australia, and was the Director of the Centre between 2001 and 2004. He remains a non-executive director of this company, now known as CPR Pharma Services, which is one of Australia's largest contract research organisations. 109 Between 1993 and up to 30 April 1999 (the priority date for the 946 Patent), Professor Evans provided consultancy for 10 to 20 pharmaceutical companies through the Centre. After that priority date, he consulted directly with at least 20 to 30 pharmaceutical companies. His consultancy work involved assisting these companies with evaluating the pharmacological properties of dosage forms and with designing new dosage forms. In this role, he consulted extensively with Faulding to design novel drug delivery systems and improve existing drugs. In particular, he assisted with formulation work by analysing the results of various pre-clinical and clinical trials and advising Faulding about how to modify their formulations to obtain improved plasma drug concentration versus time profiles. 110 Throughout his career, Professor Evans has acted as a primary investigator, investigator or consultant in what he estimates to be at least 50 clinical trials studying the pharmacokinetics and efficacy of APIs. 111 Professor Evans has also been involved, both before and after the priority date of the 946 Patent, in designing and analysing the results of pre-clinical studies. His work before that priority date in this area included designing animal models (primarily in rats) to address absorption, distribution (including protein binding modelling), metabolism and excretion. After that priority date he formed a company called PharmaQuest to commercialise intellectual property in the cancer prevention area. 112 Between 1998 and 2001, Professor Evans was a member of the Human Research Ethics Committee and chair of the Divisional Human Research Ethics Committee, Division of Health Sciences (Divisional), at the University of South Australia. During the same period, he assisted the National Health and Medical Research Council in reviewing grant proposals for both human and non-human research. His role as a reviewer was to consider matters such as scientific rationale, statistical factors, human ethics issues, researcher track record and project feasibility. 113 Professor Evans has also been named as an inventor on a number of international patent applications and Australian patents and patent applications. 114 Between 1995 and 2004, Professor Evans worked for the TGA evaluating pharmacokinetic studies and advising on the accuracy of the results and indications set out in the product information. In this role, he considered approximately 25 submissions for entry onto the Australian Register of Therapeutic Goods, including submissions dealing with antidepressant, immune-suppressant, cardiovascular and non-steroidal anti-inflammatory drugs. This work, combined with his teaching roles, allowed him to gain experience in a wide range of drugs and keep up-to-date with developments in relation to both specific drugs as well as the general therapeutic markets. In 1999, he became the Assistant Editor for Sansom Lloyd N (ed), Australian Pharmaceutical Formulary and Handbook (17th ed, Pharmaceutical Society of Australia, 2000). This reference source was mandatory for all pharmacies in Australia. 115 During the period leading up to the priority date of the 946 Patent, Professor Evans attended various academic conferences in his field, including the Australian Pharmaceutical Science Association. Between 1998 and 2002, he was the president of that body, and has been involved in various organising committees for these conferences.

Dr Mooney 116 Dr Mooney is a consultant and director at BM Pharma Consulting Pty Ltd, and has been in this position since 14 December 2012. His expertise is in pharmaceutical sciences, including in the areas of pharmaceutics and pharmaceutical formulation (including oral formulations). He holds a Bachelor of Science (Honours) in organic chemistry, which was awarded to him in 1976 by the University of Adelaide, and a PhD in synthetic organic chemistry, which was awarded to him in 1980 by the University of Adelaide. 117 Dr Mooney is the co-inventor of about 27 Australian patent applications, including in relation to composition, processes for manufacture and formulation of solid dosage forms. The majority of those patent applications have lapsed, and Alphapharm is the applicant on 25 of them. Two of the patent applications have joint applicants, being Alphapharm and Generics (UK) Limited. 118 Over the course of Dr Mooney's career he has been involved in the formulation of about 140 oral solid dosage forms involving about 160 drug substances. This work includes drug substances used in immediate and modified-release tablets and capsules, formulations with cosmetic and functional coatings, orally dispersible tablets and oral contraceptives manufactured under current good manufacturing practice. The majority of this experience occurred throughout the course of his employment with Alphapharm. 119 Between 1985 and 2009, during Dr Mooney's employment with Alphapharm, the company grew in size from about 50 to about 500 local employees and became one of Australia's leading generic pharmaceutical companies. Alphapharm also went through a number of corporate restructures during his employment. Throughout Dr Mooney's employment, Alphapharm had a focus on developing, manufacturing and registering solid oral dosage forms for domestic and foreign export markets. 120 From 1985 to 1988, Dr Mooney was employed as a research and development chemist at Alphapharm. During this period he was engaged in, and responsible for the supervision of about 12 employees involved in product formulation and manufacture, analytical method development and method validation, finished product and stability testing and process validation. 121 Between 1988 and 1999, Dr Mooney was employed as Manager of Research and Development at Alphapharm. In this role, he was responsible for supervising approximately 50 employees working in Alphapharm's research and development program and managing the associated budget for the research and development program. His role included responsibility for overseeing the research and development product formulation team, the research and development laboratory team and the research and development regulatory affairs team. 122 The research and development product formulation team was responsible for formulation development and manufacture from small scale trials (involving batch sizes of about 0.5 to 1 kilogram) through scale-up (involving batch sizes of about 3 to 8 kilograms) to pilot batch manufacture (involving at least 100,000 tablets or 10% of the proposed commercial batch size, whichever was greater). The team was also involved in technology transfer (manufacturing) for commercialisation (i.e., the passing on of know-how relating to manufacturing processes for production on a commercial scale). 123 The research and development laboratory team was responsible for the evaluation and testing of the drug substance (physical and chemical properties), testing of in-process products and final formulations of trial batches including small scale batches to pilot batches and bioequivalence batches and stability testing of development batches. The team was also engaged in analytical method development and validation, cleaning validation and the analytical work required for process validation. 124 The research and development regulatory affairs team coordinated the distribution of chemistry and manufacturing documentation of new products to overseas and local affiliates for dossier compilation and the filing of necessary documentation for new product registration with the relevant regulatory bodies in Australia and overseas. The team supervised by Dr Mooney was responsible for preparing the relevant dossiers. The team was also involved with post-approval product compliance. In his work with this team he regularly liaised with colleagues regarding bioequivalence study (also referred to as biostudy) requirements for filing product applications in Australia, Europe, Canada and the United States, supervised the preparation of chemistry manufacturing controls for foreign regulatory filings and was involved in pre and post approval of regulatory files and responses to questions for product registrations into Europe, Australia, Canada, New Zealand and the United States. 125 As Manager of Research and Development Dr Mooney was also responsible for provision of relevant information and product samples to overseas and local biostudy teams. Each biostudy team in a particular jurisdiction was responsible for designing and supervising the bioequivalence studies that were included in the regulatory materials submitted to the relevant authorities in Australia or overseas for product approval. 126 In addition to having direct contact with the members of the teams described in the preceding paragraphs which included chemists, formulators and pharmacokineticists, as Manager of Research and Development, Dr Mooney also had regular contact with Alphapharm's patents group. The patents group was responsible for obtaining and providing information on existing patents in relation to a particular molecule to help guide product development work within Alphapharm. The patents group was also responsible for monitoring patent activities of products of interest. 127 Between 1999 and 2005, Dr Mooney was employed as Senior Manager of Research and Development at Alphapharm. In this role, he was responsible for supervising approximately 70 employees and managing the associated budget. He also continued to have responsibility for, and supervise, the research and development program covering the research and development product formulation team, the research and development laboratory team and the research and development regulatory affairs team. His responsibilities during this period included being involved in decisions regarding bioequivalence studies and in particular, making decisions whether or not to conduct pilot studies or full clinical bioequivalence trials. Pilot studies involve a reduced number of subjects compared to a full study, which have an increased number of participants as necessary to meet statistical needs of the regulatory requirements. He also continued to coordinate with related Alphapharm Group companies on bioequivalence studies for their markets. 128 From 2005 to 2009, Dr Mooney was employed as Director of Research and Development for the Asia Pacific Region at Alphapharm. In this role, he was responsible for the coordination of Alphapharm's research and development programs in Australia and at Merck Seiyaku in Japan. The research and development programs involved product development steps from formulation through to registration of a product. This role included managing the budget for and supervision of approximately 80 employees in Australia and approximately 40 employees in Japan engaged in the research and development product formulation, research and development laboratory and research and development regulatory affairs teams. 129 As Director of Research and Development for the Asia Pacific Region Dr Mooney continued to be involved in decisions regarding the conduct of bioequivalence studies. He also reviewed regulatory submission documents for various global markets and supported the research and development regulatory affairs team in response to any questions from those regulatory bodies regarding the registration of products. 130 During his time as Director of Research and Development for the Asia Pacific Region Dr Mooney was responsible for the successful integration of the Merck Seiyaku research and development team (of approximately 40 employees) into the global Merck Generics research and development group through regular visits to Japan, coordination of staff exchange and the conduct of intra-company training programs on formulation and analytics for senior research and development people. 131 From September 2009 to October 2010, Dr Mooney was a Senior Manager at KPMG in the research and development tax group. His role included developing new business opportunities across various disciplines including biotechnology, oil and gas, electrical, manufacturing, construction engineering and mining. 132 From November 2010 to November 2012, Dr Mooney was employed by CHEMO at their Leon Farma pharmaceutical manufacturing facility in Spain, initially as a private consultant and, from March 2011 onwards, as Research and Development Manager of women's health care. In both roles, he provided advice and guidance to the Leon Farma research and development team on the development of solid dosage oral contraceptives, including formulation, analytics and regulatory affairs in Europe, the United States and Canada. He was also involved in project management of the development of a medical device. The Leon Farma research and development team consisted of approximately 35 employees. 133 In December 2012, Dr Mooney started his own consulting firm, BM Pharma Consulting. He has been providing consultancy services to companies in Bangladesh, China, Australia, New Zealand, Europe, the United States and South Africa concerning solid oral dosage formulation of tablets and capsules (both immediate-release and modified release) and the analytical development, validation and testing of drug substances and finished dosage forms. As part of his consulting, Dr Mooney also provides pharmaceutical expertise on drug substance evaluation in terms of its drug master file and physical property characterisation, processes to optimise the efficiencies in product development, bioequivalence studies, regulatory guidance with review of dossiers and expertise on manufacturing scale up of oral dosage forms from small scale through pilot to commercial scale production with accompanying validation protocol review.

Professor Polli 134 Professor Polli is a Professor of Pharmaceutical Sciences and the Ralph F Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics at the University of Maryland in Baltimore. He has been a member of the Department of Pharmaceutical Sciences at the University of Maryland since 1993. He has over 25 years of academic industry experience in the field of pharmaceuticals, including formulation, oral absorption and biopharmaceutics. Professor Polli has had an extensive engagement with industry which I will explain below. 135 In 1989, Professor Polli was awarded a Bachelor of Science in pharmacy from the Philadelphia College of Pharmacy and Science. In 1993, he was awarded his PhD in pharmaceutics from the University of Michigan. On completion of his PhD, he joined the Department of Pharmaceutical Sciences at the University of Maryland, where he has remained since. 136 Professor Polli's primary interest, and the continued focus of his research, is the study of orally administered drugs, including the improvement of oral bioavailability through formulation and chemical approaches. He has published widely in peer-reviewed journals in his field, having published approximately 100 articles in the areas of dissolution, drug intestinal permeability, transporter substrate requirements, prodrug design, oral bioavailability, in vitro-in vivo correlation and bioequivalence. 137 Since 2008 Professor Polli has been a Fellow (and from 2012 and 2013 was a member-at-large) of the American Association of Pharmaceutical Scientists. From 2005 to 2010, he was the Vice Chair of the USP Expert Committee on Biopharmaceutics. From 2011, he has been a member of the FDA Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology. 138 From 1989 to 2016, Professor Polli was also a licensed pharmacist. Since 1993, he has taught professional pharmacy students and graduate students at the University of Maryland. 139 Since 2011, he has been the co-director of the University of Maryland Centre of Excellence in Regulatory Science and Innovation and since 2013, he has been the director of the University of Maryland MS in Regulatory Science degree program. 140 Professor Polli is on the editorial boards of several academic journals in the field of pharmaceutical sciences. In particular, he is associate editor of Pharmaceutical Research. 141 Professor Polli's collaboration with industry began in the late 1980s during his undergraduate studies. He was invited to join an industrial pharmaceutical laboratory operated by Dr Joseph Schwartz, a renowned pharmaceutical scientist. The purpose of this laboratory was to solve problems associated with the formulation and dissolution of drugs identified by the pharmaceutical industry. During that time, one of the projects Professor Polli was involved in was a project concerning the formulation of an immediate release oral dosage form for a poorly-soluble API. 142 During his undergraduate studies, Professor Polli also had the opportunity to work in the manufacturing group at Merck & Company Inc. The role of the manufacturing group was to translate the drug formulations developed in a laboratory environment to manufacturing on a large scale. 143 In 2004, Professor Polli worked with Sanofi-Aventis in relation to formulation, in vitro dissolution and in vitro-in vivo correlation work. More recently, in 2010, he worked with Novartis to develop a formulation approach to increase the bioavailability of a poorly soluble, weakly basic drug. 144 One of Professor Polli's current research projects, funded by the United States Food and Drug Administration (FDA), involves the poorly soluble, weakly basic drug, itraconazole. Given the low solubility of itraconazole, the project involves making spray-dried amorphous solid dispersions of the drug, resulting in a more soluble form of the drug in order to increase drug dissolution and absorption. The project also aims to develop a clinically-relevant in vitro dissolution test for itraconazole spray-dried amorphous solid dispersions.

Professor Boddy 145 Professor Boddy gave evidence in the usual way. He is a Professor of Pharmacy at the University of Sydney. His expertise is in the fields of pharmacology and pharmacokinetics. Pharmacokinetics is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. Professor Boddy's primary area of expertise is in the application of pharmacokinetic principles to the dosing of anti-cancer drugs, in the context of both adult and paediatric cancers. Professor Boddy's qualifications are set out in his affidavit. They were not challenged and there is no need for me to set them out. I am satisfied that he has specialised knowledge and experience in the fields of pharmacology and pharmacokinetics.

THE 946 PATENT 146 I will address the 946 Patent in its amended form. I will discuss the patent in its original form and the amendments made to it in the section of these reasons dealing with Apotex's claim of false suggestion. 147 The 946 Specification describes the "Field of the Invention" as follows: The present invention relates to a highly selective phosphodiesterase (PDE) enzyme inhibitor and to its use in a pharmaceutical unit dosage form. In particular, the present invention relates to a potent inhibitor of cyclic guanosine 3ꞌ ,5ꞌ - mono-phosphate specific phosphodiesterase type 5 (PDE5) that when incorporated into a pharmaceutical product is useful for the treatment of sexual dysfunction. The unit dosage form described herein is characterized by selective PDE5 inhibition, and accordingly, provides a benefit in therapeutic areas where inhibition of PDE5 is desired, with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes. 148 The 946 Specification then refers to a pharmaceutical product, which was currently on the market and which is a PDE5 inhibitor, namely, VIAGRA® (Viagra) and states that the active ingredient in Viagra is sildenafil. The 946 Specification contains statements as to the potency and selectivity of sildenafil, as well as its potential to cause side effects, such as vision abnormalities and facial flushing. It also refers to the risks involved in taking sildenafil and organic nitrates at the same time. There is then a reference to the disclosures in Daugan 1995 about the selectivity, dosages and side effects of tadalafil. 149 The 946 Specification states that the applicants have discovered that one of the compounds disclosed in Daugan 1995 (i.e., tadalafil) can be administered in a unit dose which is effective and without all the side effects associated with sildenafil. There is then a discussion of the benefits of tadalafil in terms of reduced or lessened side effects and, in that context, the side effects which are discussed are facial flushing and vision abnormalities. 150 The 946 Specification contains a detailed summary of the invention and a diagram showing the structural formula for tadalafil. The invention is said to provide for a pharmaceutical dosage form for human pharmaceutical use, comprising 1 to about 20 mg of tadalafil in a unit dosage form suitable for oral administration. Further, the invention is said to provide a method of treating conditions where inhibition of PDE5 is desired, which comprises administering to a patient in need thereof, an oral dosage form containing about 1 to about 20 mg of a selective PDE5 inhibitor, as needed, up to a total dose of 20 mg per day. Conditions that can be treated include male ED. The invention is also said to provide the use of a unit dose containing about 1 to about 20 mg of a compound having the structure set out for the manufacture of a medicament for administration up to a total maximum dose of 20 mg of the compound per day for the treatment of sexual dysfunction in a patient in need thereof. 151 There is then a detailed description of the invention. Certain terms are defined in this section of the 946 Specification and it is important to note the following definitions: The term "IC5o" is the measure of potency of a compound to inhibit a particular PDE enzyme (e.g., PDE1c, PDE5, or PDE6). The IC50 is the concentration of a compound that results in 50% enzyme inhibition in a single dose-response experiment. Determining the IC50 value for a compound is readily carried out by a known in vitro methodology generally described in Y. Cheng et al., Biochem. Pharmacol., 22, pp. 3099-3108 (1973). … The term "oral dosage form" is used in a general sense to reference pharmaceutical products administered orally. Oral dosage forms are recognized by those skilled in the art to include such forms as liquid formulations, tablets, capsules, and gelcaps. The term "vision abnormalities" means abnormal vision characterized by blue-green vision believed to be caused by PDE6 inhibition. The term "flushing" means an episodic redness of the face and neck attributed to vaso-dilation caused by ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration. The term "free drug" means solid particles of drug not intimately embedded in a polymeric coprecipitate. 152 The 946 Specification refers to Butler US Patent No 5,985,326 (Butler) which will be discussed later in these reasons in the context of the 666 Patent. 153 The 946 Specification states that the invention is based on detailed experiments and clinical trials and the unexpected observations that some side effects previously believed to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels by the selection of a compound and unit dose. The unexpected observation enabled the development of a unit dosage form that incorporated tadalafil in about 1 to about 20 mg per unit dosage forms that, when orally administered, minimised some undesirable side effects previously believed unavoidable. 154 The 946 Specification set out IC50 values for tadalafil for PDE5 and PDE6. This is followed by examples showing the preparation of the claimed invention (Examples 1-4 inclusive). 155 Examples 5, 6 and 7 each contain a discussion of the results of studies carried out. Example 5 describes a study involving healthy male volunteers designed to evaluate the hemodynamic effects of the concomitant administration of tadalafil and short-acting nitrates. This Example will be particularly relevant when I come to consider the allegation of false suggestion. It is convenient to set out the discussion in Example 5 in full: Example 5 This study was a randomized, double-blind, placebo-controlled, two-way crossover design clinical pharmacology drug interaction study that evaluated the hemodynamic effects of concomitant administration of a selective PDE5 inhibitor (i.e., Compound (I)) and short-acting nitrates on healthy male volunteers. In this study, the subjects received either Compound (I) at a dose of 10 mg or a placebo, daily for seven days. On the sixth or seventh day, the subjects received sublingual nitroglycerin (0.4 mg) while supine on a tilt table. The nitroglycerin was administered 3 hours after Compound (I) dosing, and all subjects kept the nitroglycerine tablet under their tongue until it completely dissolved. The subjects were tilted to 70° head-up every 5 minutes for a total of 30 minutes with measurement of blood pressure and heart rate. There were no discontinuations among the twenty-two healthy male subjects (ages 19 to 60 years old) that entered this study. In a preliminary analysis of this study, Compound (I) was well tolerated and there were no serious adverse events. There were no Compound (I) changes in laboratory safety assessments or 12-lead ECGs. The most common adverse events were headache, dyspepsia, and back pain. Compound (I) demonstrated minimal effect on mean systolic blood pressure, and mean maximal nitroglycerin-induced decrease in systolic blood pressure. 156 Example 6 describes a study involving patients with ED designed to ascertain efficacy and to record side effects. The measurement tools used to determine efficacy were the International Index of Erectile Function (IIEF), diaries of sexual attempts and a global satisfaction question. These measurement tools are discussed below. 157 Example 7 describes a "third clinical study" and it involved "on demand" administration of tadalafil in the case of 212 men with mild to severe ED. Different doses were administered (2 mg, 5 mg, 10 mg and 25 mg). The measurement tools used were the IIEF, a Sexual Encounter Profile Diary and a global assessment question. These measurement tools are discussed later in these reasons (at [414]-[419]). 158 The two most important questions in the IIEF are said to be, first, the ability of the patient to penetrate his partner and, secondly, the ability of the patient to maintain an erection during intercourse. Those functions or abilities improved as the dose of tadalafil increased. 159 The Specification then sets out a Table showing combined results relating to efficacy and dose from clinical studies. It can be seen from the number of subjects which are referred to in this Table, that it is based on more studies than the third clinical study referred to in Example 7 which, as I have said, involved 212 male volunteers. The Table is as follows: 160 There is also a Table showing adverse events called "Treatment-Emergent Adverse Events" which illustrates the point made in the 946 Specification that treatment-emergent adverse events increase with an increasing unit dose of tadalafil. This Table also includes results in relation to doses of 50 mg and 100 mg. The Table is as follows: 161 Finally, Apotex relied on the following statement in the 946 Specification in connection with its novelty argument based on Stoner: Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

THE 666 PATENT 162 As with the 946 Patent, I will address the 666 Patent in its amended form, that is to say, including claims 25-38. 163 As I have said, the filing date of the application for the 666 Patent was 3 August 2000. The 666 Patent claims a priority date of 3 August 1999 by reference to US 60/147048 (US 048). 164 The 666 Specification describes the invention as relating to the fields of pharmaceutical and organic chemistry and to a β-carboline compound which is useful for the treatment of various medical indications where the inhibition of type 5 cGMP-specific phosphodiesterase (PDE5) is desired. The invention is described as providing a free drug form of β-carboline particles in a size range allowing for the uniform formulation of stable pharmaceutical compositions, especially compositions providing desired bioavailability properties not provided previously. 165 The 666 Specification refers to Daugan 1995 and to Daugan 1997. It states that Daugan 1995 discloses a class of β-carboline compounds, and pharmaceutical compositions containing the β-carbolines, useful in the treatment of conditions wherein inhibition of PDE5 is desired and that Daugan 1997 discloses the use of the compounds in the treatment of sexual dysfunction. 166 The 666 Specification refers to the fact that the poor solubility of many β-carboline compounds useful in the inhibition of PDE5 led to the development of co-precipitate preparations as disclosed in, among others, Butler. Studies revealed that there were difficulties in generating precisely reproducible lots of co-precipitate product. Another problem with co-precipitate tablets is said to be that maximum blood concentration of the β-carboline compound was achieved in three to four hours. That was in a context where a more rapid achievement of maximum blood concentration and therapeutic effect was desired. The 666 Specification states that there was a need in the art for orally administrable beta-carboline compounds and beta-carboline-containing pharmaceutical compositions with the ability to provide a therapeutic effect within a desirable, or at least acceptable, timeframe. 167 The 666 Specification provides a summary of the invention. The invention is said to provide particulate preparations of a free drug form of a β-carboline compound having specific and defined particle size characteristics. The defined particle size is said to permit a uniform formulation of stable pharmaceutical compositions. In particular, it is said that the invention provides compositions that exhibit a rapid achievement of the maximum blood concentration of the PDE5 inhibitor or a rapid onset of a therapeutic PDE5 inhibitory effect or both. 168 The invention relates to tadalafil and pharmaceutically acceptable salts and solvates thereof. 169 The 666 Specification contains consistory clauses for claims 1-4 inclusive. There is a reference to particle size. It states that the invention provides for a free form of a β-carboline compound which can be used in an effective therapy for conditions where inhibition of PDE5 provides a benefit. The free form of tadalafil has a particle size such that the onset of beneficial effects of PDE5 inhibition are exhibited in a relatively short time after oral administration. 170 An aspect of the invention is a free drug form of tadalafil and pharmaceutically-acceptable carriers, diluents, or excipients with certain pharmacokinetic parameters, namely: (1) a Cmax of about 180 to about 280 micrograms/litre; or (2) an AUC (0-24) of about 2280 to about 3560 micrograms hour/litre measured using a 10 mg dose of the compound. 171 Professor Boddy, whose evidence I accept, described the meaning of these terms. The term "Cmax" is a standard technical term that is used in pharmacokinetics to denote the observed or predicted maximum concentration of API in the plasma following a single dose of the API. AUC is an acronym for "area under curve" and the curve refers to a plot of the concentration of the API in the plasma over time. The AUCt represents the aggregate amount of API present in the plasma over a given amount of time. "AUC (0-24)" represents the amount of API present in the plasma in the 24 hour period following administration of the API. 172 The 666 Specification then states that Daugan 1995 teaches that processing tadalafil to bring the particle size within a particular narrow range enhances manufacturing capability and pharmaceutical compositions can be prepared that exhibit an improved bioavailability of the tadalafil. The Specification states that a typical daily dose of tadalafil is about 1 to about 20 mg per day. It states that preferred daily doses generally are about 1 to 20 mg per day, particularly 5 mg, 10 mg and 20 mg tablets administered as needed. 173 The 666 Specification contains definitions of various terms used in it and the following should be noted: The term "free drug" refers to solid particles of compound (I) not intimately embedded in a polymeric coprecipitate. … The nomenclature describing the particle size of compound (I) is commonly referred to, and is herein, as the "d90". For example, a d90 of 40 (or d90=40) means that at least 90% of the particles have a particle size of less than 40 microns. 174 The 666 Specification states that a co-precipitate, including tadalafil was manufactured in accordance with the method set out in Butler. The inventors found that on controlled dissolution, the co-precipitate contained a portion of the free drug form of tadalafil that was not embedded in the co-precipitate polymer and that the blood levels of tadalafil within 30 minutes of administration were attributable to the free drug present in the co-precipitate compositions. Those results are described as surprising in view of Butler, and that Butler was attempting to provide a solid dispersion of a poorly water-soluble drug which had enhanced bioavailability compared to free particles of the poorly water-soluble drug. Butler was attempting to avoid the free form of the drug. The 666 Specification states that, based on these observations, bimodal delivery of tadalafil could be achieved, that is, partly free drug in particulate form and partly embedded drug form. 175 The 666 Specification then states that the pharmacokinetic parameters of Cmax and AUC (0-24) in plasma are dose dependent and that there should be a linear relationship between the parameters for a 10 mg dose and the parameters of a 20 mg dose such that the parameters of a 20 mg dose should be about twice that of a 10 mg dose. A 5 mg dose will produce parameters about half that of a 10 mg dose. 176 There are five examples in the 666 Specification. 177 Example 1 involved in vitro dissolution tests where the raw state particulate form of tadalafil (d90 = 75-200 microns) were processed to sizes of d90 = 4, d90 = 22, d90 = 55, d90 = 65, d90 = 73 and d90 = 116. The results illustrated in Figure 1 to the 666 Specification show improved in vitro dissolution occurs with smaller particle sizes of tadalafil. 178 Example 2 states that the pharmaceutical composition with which it deals was prepared as in Examples 4 and 5. It sets out results in terms of Tmax, of a comparison between a particulate free drug form of tadalafil having a d90 of 8.4 microns and a compound incorporating the co-precipitate of tadalafil. Tmax is said to be a measure of the time to achieve peak blood levels of a drug and to be indicative of an improved onset of action. 179 Example 3 was a particle size comparison of tadalafil in terms of its pharmacokinetic properties and involved particle sizes of d90 = 8.4 microns, d90 = 20 microns and d90 = 52 microns. Unlike Example 2, Example 3 does not state that the pharmaceutical compositions used were prepared as in Examples 4 and 5. The study which was carried out and which is the subject of the report in Example 3 shows, according to the Specification, that reducing the particle size of tadalafil improved the in vivo absorption of the drug from a solid dosage form and hence the bioavailability of the drug. The significance of Example 3 and the results referred to in it will become apparent when I address Apotex's novelty challenge to claims in the 666 Patent based on Oren. 180 Example 4 sets out the formula used to prepare the finished dosage form of a tablet providing 10 mg of tadalafil, and Example 5 does the same in relation to a tablet providing 5 mg and 20 mg respectively of tadalafil.

THE COMMON GENERAL KNOWLEDGE RELEVANT TO THE ISSUES IN THIS CASE 181 In Minnesota Mining & Manufacturing Company v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 (Minnesota Mining), Aickin J described common general knowledge in the following terms (at 292): …The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge… 182 In Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411 (AB Hässle v Alphapharm), Gleeson CJ, Gaudron, Gummow and Hayne JJ said (at [31]) that information that was not shown by evidence to be generally accepted and assimilated by, in that case the formulating community, was not part of common general knowledge. 183 In ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [2000] FCA 1349; (2000) 106 FCR 214 (ICI Chemicals) at [57], the Full Court of this Court endorsed observations of the trial judge in that case to the effect that common general knowledge is not limited to material which might be memorised and retained at the front of the skilled worker's mind, but also includes material in the field in which he is working which he knows exists and to which he would refer to as a matter of course. 184 In Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559; (2008) 76 IPR 618 (Alphapharm v H Lundbeck A/S), Lindgren J, after referring to Minnesota Mining, said (at [221]): … The question is whether it is "generally accepted without question" or "generally regarded as a good basis for further action" by the bulk of those in the art: Minnesota Mining and Manufacturing Co v Tyco Electronics Pty Ltd (2002) 56 IPR 248 at [100], quoting Blanco White TA, Patents for Inventions and the Protection of Industrial Design (5th ed, Stephens, London, 1983) at [4-207]. (See also Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11 (Ranbaxy v AstraZeneca) at [214]-[218] per Middleton J.) 185 There is no dispute that in this case the skilled person in the relevant art for the purposes of s 7(2) of the Act would comprise a multidisciplinary team of professionals with different fields of expertise who were typically involved in the drug discovery and development process. I describe the composition of the team later in these reasons (at [334]). 186 The subject matter of the two patents in suit is the formulation and use of a PDE5 inhibitor for the treatment of ED. The asserted priority dates are 30 April 1999 in the case of the 946 Patent, and 3 August 1999 in the case of the 666 Patent. The alternative dates (i.e., the filing dates) of 26 April 2000 and 1 August 2000 respectively were also the subject of evidence. The experts did not give any evidence which suggested that there was any material difference in the relevant common general knowledge between the dates in 1999 and the dates in 2000. 187 There was a good deal of common ground between the experts as to the knowledge and information which comprised the common general knowledge. I set out below my findings as to common general knowledge. Where there was a dispute, I will identify it and the way in which I resolve it. 188 ED is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. It is a condition that is particularly common among males over 50 years of age. It is also referred to as impotence and that term was used more frequently prior to April 1999 than it is today. 189 It was understood prior to April 1999, and this understanding continues to the present day, that ED can be caused by patho-physiological diseases and conditions (organic ED) or by psychological problems (psychogenic ED) and sometimes by a combination of both. It was understood that depending on the underlying causes, certain treatment options would be more suitable than others. Furthermore, it was understood that the condition itself can have psychological effects, such as strong feelings of inadequacy. A clinical guide referred to by Dr Cherry in his evidence stated that almost all men with ED will be affected psychologically even if the cause is organic (Erectile Dysfunction European Society for Impotence Research, Physicians Guide (Annexure DJC-6)). 190 Sildenafil, or Viagra as it is commonly known, was released in Australia in September 1998. It revolutionised the treatment of ED and was effective and resulted in manageable side effects for most patients. In addition, sildenafil was far more convenient to administer than the other ED treatment options that were available prior to its release. However, there were disadvantages associated with sildenafil. The first was that it did not have spontaneous effects. Typically, a patient would need to wait about 30 minutes to one hour after ingestion of the tablet before the drug took effect and longer if the tablet was ingested with food. The second disadvantage was that it was a relatively expensive drug that was also relatively short acting. Sildenafil had a short half-life, that is to say, it was cleared and excreted from the body quickly. The third disadvantage was that sildenafil had known side effects, which include the risk of cardiovascular events, facial flushing, reflux and vision abnormalities. 191 The clinicians were persons skilled in the field of the treatment of ED before 30 April 1999. In their joint experts' report, they said that a person skilled in the field would have known and understood the following matters about sildenafil or Viagra: (1) it was the first approved oral treatment for ED; (2) it is a PDE5; (3) it is effective, well tolerated and safe; (4) the commonest side effects of Viagra are facial flushing, headache and dyspepsia; (5) vision abnormalities resulted from PDE6 inhibition; and (6) the co-administration of Viagra and a nitrate is contraindicated. 192 PDEs are enzymes that are diffusely found in many parts of the body. 193 One of the clinical guides referred to by Dr Cherry provides the following relatively simple explanation of how sildenafil or Viagra works: Viagra works by inhibiting an enzyme called phosphodiesterase (PDE), in particular, one member of this class of enzymes called PDE5. This enzyme is found within the penis and this accounts for the relatively selective action of Viagra on ED. By inhibiting PDE5, Viagra increases the level of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels result in relaxation of the cavernosal smooth muscle, which in turn results in engorgement of the tissue and erection. In patients with ED, cGMP levels may be low and would therefore be raised by Viagra. (Erectile Dysfunction: A Clinical Guide (Annexure DJC-6)) 194 The potency of a drug is an important feature of the drug and may be is measured by an IC50 value which is the amount of the drug needed to reduce the enzymes' activity by 50%. I have already referred to the description of an IC50 value in the 946 Patent. The lower the IC value, the more potent the drug. If a lot of the drug is needed to be effective, then its potency is not very good. 195 The selectivity of a drug is also important. There are a number of PDEs in the body and it is important that the drug be as selective as possible for PDE5 in order to avoid undesirable side effects. One difficulty in the area of selectivity is that, as at 30 April 1999, scientists were not aware of all the PDEs in the body. Those skilled in the field were aware of approximately six different subtypes of PDEs. Furthermore, those skilled in the field were not aware of which PDEs were responsible for the side effects associated with a PDE5 inhibitor. 196 Potency and selectivity may point in opposite directions in terms of the usefulness of a drug. A potent drug may not be selective and may cause side effects that patients are not prepared to tolerate. Selectivity can be measured as a ratio between the IC50 for a given PDE and the IC50 for PDE5. In order to establish the selectivity of a PDE inhibitor to the extent it could be done, it was necessary to determine the IC50 for a given PDE and the IC50 for PDE5. 197 A Product Information (PI) Statement for Viagra was issued when the drug came onto the market and such a statement has been reissued from time to time. The PI Statements for Viagra for 1998, 1999 and 2016 respectively, were tendered in evidence. A PI Statement contains information about the product and that will include a description of the product, its pharmacodynamics properties, details of clinical trials of the product, its pharmacokinetic properties, indications, contraindications, precautions, details of adverse reactions and details of dosage, administration and presentation. The purpose of contraindications is identified later in these reasons (at [703]-[707]). 198 The clinicians were asked to consider the 1999 Viagra PI Statement and identify the information in the Statement which was part of the generally accepted background knowledge and understanding of a person skilled in their field. As I understand it, that was done simply because it was a convenient way for them to proceed. They agreed that the following information fell into that category: (1) Sildenafil is an orally active selective inhibitor of a cGMP-specific PDE5. (2) Nitrates and sildenafil (Viagra) must not be used concomitantly and Viagra is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors. (3) Viagra is an oral therapy for ED which restores blood flow to the penis resulting in a natural response to sexual stimulation. (4) Sildenafil is a potent and selective inhibitor of PDE5 which is responsible for degradation of cGMP in the corpus cavernosum. Inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore, sexual stimulation is required in order for Viagra to produce its beneficial pharmacological effects. (5) Mild and transient differences in colour discrimination (blue/green) are detected in some patients following a 100 mg dose and at lower doses. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6. In vitro studies show that sildenafil is 10-fold less potent against PDE6 than PDE5. (6) The IIEF can be used to measure efficacy of an ED treatment. (7) A 100 mg dose of Viagra provides better therapeutic efficacy than a 50 mg dose, a 50 mg dose provides better therapeutic efficacy than a 25 mg dose. All three doses provide better therapeutic efficacy than placebo. (8) Viagra improves erectile function, orgasm, satisfaction with intercourse and overall satisfaction. (9) A therapeutic effect is ordinarily observed within about an hour after administration of Viagra. (10) Viagra is indicated for the treatment of ED in adult males. (11) Use of Viagra is contraindicated in patients with known hypersensitivity to any component of the tablet. (12) Viagra potentiates the hypotensive effects of organic nitrates and its co-administration with nitric oxide (NO) donors or organic nitrates in any form is therefore contraindicated. Drugs which must not be used concomitantly include glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite or organic nitrates in any form. (13) Viagra is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors (e.g., patients with severe cardiovascular disease such as established cardiac failure and unstable angina pectoris). The possibility of undiagnosed cardiovascular disorders in men with ED should be considered before prescribing Viagra. (14) The use of sildenafil is contraindicated in patients with severe hepatic impairment, hypotension, uncontrolled hypertension (at higher risk of heart attack or stroke), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa. (15) A thorough medical history and physical examination should be undertaken to diagnose ED, determine potential underlying causes and identify appropriate treatment. (16) Prior to initiating any treatment for ED, physicians should consider the cardiovascular status of their patients, including those with recent onset angina, since there is a degree of cardiovascular risk associated with sexual intercourse. (17) Viagra has vasodilator properties, resulting in mild transient decreases in blood pressure and, as such, potentiates the hypotensive effect of nitrates. (18) The incidents of adverse events may be greater in those patients who require the maximum recommended dose of 100 mg (e.g., some diabetic and spinal cord injury patients). (19) Patients with cardiovascular disease who have not engaged in sexual intercourse for a number of years should have their cardiovascular status carefully assessed prior to initiating treatment with Viagra. (20) Viagra is not indicated for use in women. (21) As transient visual disturbances have been reported in some patients taking Viagra, particularly at the 100 mg dose, patients should be aware of how they react to Viagra before driving or operating machinery, and the doctor should advise accordingly (visual disturbances are also reported in some patients taking 50 mg doses). (22) When Viagra is taken as recommended (on an as needed basis in flexible dose placebo controlled clinical trials) the following adverse events were reported: headache, flushing, dyspepsia and abnormal vision. (23) In fixed dose studies, the incidents of adverse events increased with dose. (24) In fixed dose studies, dyspepsia and abnormal vision were more common at 100 mg than at lower doses. Priapism is rare with sildenafil. Single doses of more than 100 mg cause adverse events similar to those seen at lower doses, but incidents are increased. (25) Viagra tablets are for oral administration. (26) The recommended dose of Viagra is 50 mg taken as needed approximately one hour before sexual activity. Based on the efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg, although the most commonly prescribed dose was 100 mg, with the 25 mg dose only prescribed in limited cases. (27) The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day. Since sildenafil clearance is reduced in elderly patients, a first dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg. (28) The dosing recommendations for use in adults should be followed for patients with mild to moderate renal impairment. Since sildenafil clearance is reduced in patients with severe renal impairment, a 25 mg starting dose may be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg. (29) Viagra is not indicated for use in children. 199 The clinicians also addressed the issue of the extent to which, in their clinical practice, they would consult the 1999 Viagra PI Statement. Dr McMahon and Professor Brock said that they would have read the 1999 Viagra PI Statement at about the time Viagra received regulatory approval, but would rarely consult the Statement and it would have little or no role as a source of information in their clinical practice. Dr Cherry, on the other hand, said he read it initially and thereafter regularly consulted the Viagra PI Statement in his clinical practice. After discussion between the clinicians, they agreed that in the vast majority of cases, the Viagra PI Statement was rarely reviewed by physicians. In an addendum to the joint experts' report, Dr Cherry corrected his answer by saying that he was uncertain about the use of the specific Viagra and Cialis PI Statements by doctors (i.e., specialists and general practitioners). He provided some information about the availability of PI Statements on MIMS digital platforms and by way of printed versions. However, as ICOS pointed out, Dr Cherry's research as to those matters was carried out on 1 and 2 June 2017. 200 Dr Cherry gave evidence that his ongoing use of PI Statements was mainly for drug interactions, impact upon the elderly, impact upon diabetics and, say, kidney and liver failure. He said: Those sort of clinical situations rather than the actual pharmacological situations. 201 He said that he did not consult the 1999 Viagra PI Statement in respect of the molar mass of sildenafil or plasma concentrations of sildenafil associated with any dose or the pharmacokinetics of sildenafil being absorption (bioavailability), distribution, metabolism and excretion (clearance). Dr Cherry said he rarely consulted the Viagra PI Statement for pharmacological information, including information about PDE potency. The significance of whether this type of information was part of common general knowledge will become clear when I come to consider the evidence of the pharmacologists and, in particular, Dr Reece. 202 I am not satisfied on the evidence that information in the 1999 Viagra PI Statement (other than that agreed between the clinicians and set out above) was generally accepted and assimilated by the skilled person in the field in the sense identified in the authorities to which I have referred. It is therefore not part of the common general knowledge. 203 The contraindication of Viagra with the concomitant use of nitrates which are a common ingredient in medications to treat angina, limited in a not insignificant way, the number of patients who were able to take Viagra. That was the case because the primary group of males with ED were males over 50 years old and many of that group suffered from heart disease and needed to take medications to treat angina. 204 Viagra was available in 25 mg, 50 mg and 100 mg tablet doses. Although not all patients responded in the same way, it was generally the case that efficacy and the severity of side effects increased with dose. 205 The clinicians were asked to describe their dosing practices in relation to Viagra. 206 Dr Cherry's dosing practice with respect to Viagra as at 30 April 1999 was to start at a low dose and titrate up to minimise side effects, but eventually achieve a successful dose. His practice was to start with a dose of 25 mg and raise the dose until a satisfactory outcome for the patient had been achieved. He gave evidence that he had done a small survey in relation to patients in his practice which indicated that within a week, or two at most, he had settled on a dose for his patients. Almost three-quarters of his patients were taking doses of 100 mg. 207 In contrast to the dosing practice of Dr Cherry, the dosing practice of Dr McMahon and Professor Brock was to start the vast majority of patients seeking treatment for ED on doses of 100 mg of Viagra. Their dosing practice differed from the recommended 50 mg dose in the 1999 Viagra PI Statement. They explained their reasons for their practice in the following way: The rationale for our dosing practice was predominantly based upon the fact that the majority of patients seeking treatment for erectile dysfunction are aged ˃50 years and have vasculogenic erectile dysfunction. Many of these men have vascular risk factors including diabetes, hypertension, hyperlipidaemia, a history of coronary artery disease or peripheral vascular disease or smoke cigarettes. This population of men is a more challenging population to treat and the majority will require a dose of 100 mg. Furthermore, there are recognised links between erectile dysfunction, depression and a reduced quality of life. Many of these men have suffered erectile dysfunction for several years and or may have failed to respond to previous treatments. The psychological burden of erectile dysfunction is substantial and many men who fail to respond to treatment made [sic] choose to suspend treatment-seeking, further reducing the quality of life. On this basis we regard that it is vital to achieve the best possible outcome from treatment and regard a 100 mg dose of Viagra as most likely to achieve that outcome. In Goldstein's 1998 landmark article published in the New England Journal of Medicine only 2% of patients selected 25 mg of Viagra at the end of dose titration. We would occasionally vary this dosing practice in younger men with psychogenic erectile dysfunction and use a commencing dose of 50 mg. Although the prescribed information recommends a commencing dose of 25 mg in men with impaired renal or hepatic function and in men prescribed CYP 3A4 inhibitor drugs, these are uncommon clinical scenarios which were only occasionally seen in our practices. 208 The Goldstein article to which this evidence refers stated the following: In the flexible dose-escalation study, 329 different men were randomly assigned to take placebo or 50 mg of sildenafil approximately one hour before sexual activity for 12 weeks. At each follow-up visit, the dose could be doubled or reduced by 50 percent on the basis of the therapeutic response and adverse effects. Each man completed the International Index of Erectile Function at 0 and 12 weeks and was asked about global efficacy at week 12. The event logs were reviewed at 0, 2, 4 8 and 12 weeks. The men who completed the study and who did not have any serious adverse effects were eligible to receive open-label sildenafil for an additional 32 weeks. (Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD and Wicker PA, "Oral Sildenafil in the Treatment of Erectile Dysfunction" (1998) 338 The New England Journal of Medicine 1397 (Goldstein et al (1998) (Annexure GBB-9).) 209 As I have said, the clinicians agree that, as at 30 April 1999, the most efficacious dose of Viagra was 100 mg and that was the most commonly prescribed dose (see 198 and (26)). 210 Although Dr Cherry was an impressive witness, I find that his dosing practice did not represent the norm. I find that the dosing practice of Dr McMahon and Professor Brock represented the norm among clinicians. I reach that conclusion for the following reasons. 211 First, most of those patients taking Viagra as at 30 April 1999 were taking doses of 100 mg and doses in that quantity were known to have the greatest therapeutic effect. Secondly, it is likely that the majority of Dr Cherry's patients were, after a short period of time, taking doses of 100 mg. Thirdly, Dr Cherry conceded that his dosing practice was influenced by his experience with intracavernosal injections which could cause priapism. Priapism is a prolonged, rock-hard, painful erection lasting for greater than four hours. The clinicians agree that priapism is rare with sildenafil (see 198). Finally, various scientific publications provide strong support for the reasons which Dr McMahon and Professor Brock gave for their dosing practices. 212 Professor Brock said, and I accept, that his clinical experience at and since 30 April 1999 is consistent with findings reported in Tomlinson & Wright, "Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study"; British Medical Journal, doi.org/10.1136/bmj.38044.662176.EE (published 29 March 2004) (Annexure GBB-12) concerning the following matters: the psychological effects of ED, the psychological effects of treatment for ED, treatment failure even the first time and the high expectations generated by Viagra. I will not set out all of the details. It is sufficient to say that patient interviews revealed that ED had a significant effect on a patient's confidence, morale and relationship with their partner, that most patients had high expectations of sildenafil and that an initial failure, and certainly a second failure, could have devastating consequences. 213 Professor Brock's approach (and that of Dr McMahon) aligns with the findings set out in Ströberg P, Kaminetsky JC, Park NC, Goldfischer ER, Creanga DL and Stecher VJ, "Hardness, Function, Emotional Well-being, Satisfaction and the Overall Sexual Experience in Men using 100-mg Fixed-dose or Flexible-dose Sildenafil Nitrate" (2010) 22 International Journal of Impotence Research 284 (Annexure GBB-11). The following appears in that article: Given that almost 90% of the men who initiated treatment with flexible-dose sildenafil titrated to a dose of 100 mg after 2 weeks, initiating treatment with 100-mg sildenafil should greatly decrease the need for dose titration and, in those men for whom a dose of 50 mg might prove ineffective, may decrease the risk of discouragement and treatment abandonment because of inadequate dosing. The high proportion of men titrating to a dose of 100 mg supports earlier results, which showed that 100-mg sildenafil produced optimal erection hardness (fully hard and rigid) in a substantial proportion of men with ED and that 100 mg was the dose used by most men in dose-optimization studies. Several studies reported that titration to the highest well-tolerated approved dose and/or early dose optimization contributed to treatment success. … In conclusion, sildenafil in doses of 50 and 100 mg is effective for the treatment of ED, and both doses are generally well tolerated. An initial dose of sildenafil 100 mg appears to be at least as efficacious and well tolerated as an initial dose of 50 mg with the option to titrate to the optimal dose. Furthermore, an initial dose of 100 mg may reduce the need for dose titration and may prevent discouragement and treatment abandonment in men for whom a dose of 50 mg is insufficient. This suggests prescription of an initial dose of 100 mg, except in those for whom it is inappropriate. 214 Viagra was the only oral drug treatment for ED on the market prior to 30 April 1999 where the active ingredient, sildenafil, acted as a PDE5 inhibitor. As at 30 April 1999, it was expected by those skilled in the field that Viagra would eventually be followed by other oral drug treatments for ED which acted in the same way as sildenafil. The person skilled in the field expected that other pharmaceutical companies would have been keen to develop other oral drug treatments for ED to compete with Viagra. Viagra was a first generation drug because it acted in a unique way that was different to all previous drugs for the treatment of a particular condition, that is, it was the first oral drug treatment for ED where the active ingredient (sildenafil) acted as a PDE5 inhibitor. Drugs which follow a first generation drug and act in the same way to treat the same condition are referred to as second generation drugs. The first and second generation drugs are part of the same therapeutic class. Typically, each new drug in a therapeutic class has improved features which distinguish it from the existing drugs in that class on the market, such as better efficacy or reduced side effects. 215 The clinicians agreed that as at 30 April 1999, the desirable properties of a treatment for ED were as follows: (1) oral administration; (2) on-demand prior to sexual activity; (3) rapid onset; (4) effective; (5) minimal side effects; (6) safe; (7) tolerable; and (8) low cost. 216 There was evidence directed to the form of administration. Viagra was a tablet and Daugan 1997 referred to tablets and capsules. Generally speaking, tablets and capsules were the preferred form of administration. Dr Reece described tablets and capsules as the most common and convenient form of administration of drugs, and Professor Boddy said that it was the most common route of administration. On the other hand, Dr Cherry (with the concurrence of Dr McMahon and Professor Brock) said that forms of administration, other than oral administration, such as nasal, buccal and sublingual, would be avenues to be explored by a skilled team developing an ED treatment in April 1999. In fact, Dr Cherry said that in his practice he would often advise his patients to grind their Viagra tablet into a powder in order to aid absorption. I will return to the issue of the form of administration later in these reasons. 217 ICOS submitted that in giving his opinion in his affidavit affirmed on 18 November 2016 as to how he would proceed with drug development in light of Daugan 1997, Dr Reece has relied on information in the 1999 Viagra PI Statement which was not part of common general knowledge First, Dr Reece has given an opinion as to the increased selectivity of Compound A (tadalafil) over sildenafil (see paragraphs 318(b) and (c) of his first affidavit) and, in doing so, has used the selectivity figures in the 1999 Viagra PI Statement in relation to PDE6 and in relation to PDE1, PDE2, PDE3 and PDE4 (see paragraph 306 of his first affidavit). Secondly, Dr Reece has used information in the 1999 Viagra PI Statement as to the absorption and half-life of sildenafil when expressing opinions concerning Compound A (see paragraphs 309, 318(d) and 325 of his first affidavit). Thirdly, Dr Reece has expressed opinions about the relative potency of Compounds A and B compared with sildenafil based on (among other things) the molecular weight of sildenafil contained in the 1999 Viagra PI Statement (see paragraphs 312, 314, 316-318 of his first affidavit). He uses that information to express an opinion as to the range of doses at which he would expect efficacy would be observed for Compound A (see paragraph 322 of his first affidavit). The matters which have been taken from the 1999 Viagra PI Statement were not part of common general knowledge. I address Dr Reece's evidence and the extent to which I accept it later in these reasons. 218 With an eye to Apotex's obviousness challenge, ICOS emphasised two matters about common general knowledge as at 30 April 1999 and 3 August 1999 which it is convenient to identify at this point. 219 First, ICOS emphasised the fact that on-demand treatment was desired, not chronic dosing. Chronic dosing means lower dosing and the fact that it was not desired supports (so ICOS's submission goes) the inventiveness of the lower doses of less than 10 mg. Professor Brock said, and I accept, that patients and physicians expected on-demand treatment. In 1999/2000, he had recommended against a daily dosing regimen for tadalafil. He could not be more precise about the date. Professor Brock had taken this view for two reasons. First, the paradigm of on-demand treatment had been set by Viagra. Secondly, there was also the consideration that, in light of the likely limited sexual activity of the target group, the risk of chronic exposure to side effects was not justified. Dr Cherry had given advice as to chronic dosing, but he could not recall whether that was before or after the priority dates in 1999. ICOS submitted, and I accept, that, in any event, to investigate chronic dosing was not a matter of routine. I will return to this issue. 220 Secondly, ICOS emphasised that the nature of ED and the way in which any improvement is measured means that identifying a minimum clinically relevant dose is difficult. There are difficulties and complexities in interpreting the data produced by the measurement tools which are available and judgment calls have to be made. I will return to this issue. The identification of the minimum clinically relevant dose does not mean that it will be used in Phase III trials where a balance must be struck between safety and efficacy. I accept that, unlike some other drugs, most of the patients with ED have a combination of organic and psychogenic ED and it is important that a treatment for ED succeed on the first occasion, otherwise there could be further psychological harm or the patient will not return for further treatment. 221 It is not in dispute that tadalafil and its physiochemical, pharmacokinetic and pharmacodynamics properties were not part of common general knowledge at the priority dates in 1999. 222 I turn now to summarise common general knowledge at the priority dates in 1999 as to the process of drug discovery and drug development. This summary is given at a high level of generality and is not specific to developing a new drug for the treatment of ED. 223 The pharmacologists described the steps involved in drug discovery and drug development prior to April 1999. They are not in dispute. Dr Reece said that drug discovery covers the period from the first identification of a target, the identification of compounds that are active against the target, and then the identification of a compound to take into development. He said that drug development covers the processes of pre-clinical and clinical development of a drug candidate, the object of which is to establish the safety and efficacy of the drug for approval by a regulator. The process includes determining the doses intended to be marketed. Dr Reece said that drug development also includes formulation development, both for the purposes of early human studies and also for use in late stage clinical trials. Professor Evans gave evidence to similar effect. More particularly, the drug development process involves the following. First, there are pre-clinical trials involving in vitro tests and tests with animal models and these trials may include an assessment of efficacy if one or more appropriate and validated animal models are available. Secondly, Phase I clinical trials will be conducted and these trials will involve healthy volunteers. The primary purpose of the Phase I clinical trials is to identify and characterise the pharmacokinetics and safety of the API. Thirdly, Phase II clinical trials will be conducted and these will involve patients (i.e., persons with the condition to be treated). The primary purpose of Phase II clinical trials is to obtain an indication of whether certain doses show efficacy and safety in patients. Pharmacokinetics are also measured in Phase II clinical trials. Phase II clinical trials may be divided into Phase IIA and Phase IIB, with Phase IIA involving fewer patients and a shorter time to complete, for example, up to 20 patients over a few weeks, and Phase IIB involving a larger number of patients and longer time to complete, for example, up to a few hundred patients for up to several months, depending on the indication. Phase III clinical trials are conducted over a longer period of time than Phase II clinical trials and involve a larger number of patients. Such trials can involve hundreds or thousands of patients over many months. The primary purpose of Phase III clinical trials is to demonstrate the clinical efficacy and safety of the API. Phase IV clinical development occurs after marketing approval has been given and involves the surveillance of patients who are taking the commercial product. Phase IV clinical development commonly involves thousands of patients. 224 The pharmacologists were agreed as to the type of pre-clinical tests which would be carried out in the course of developing a new drug for the treatment of ED. The in vitro and animal studies that would be carried out and the significance of the data that would be obtained from such studies was summarised by the pharmacologists in the following table: Type of Test Specific Examples Significance of data In vitro tests PDE-5 inhibition Tells you whether the compound is active against the target site. Allows you to test activity of metabolites. Inhibition of other PDE enzymes Tells you about the selectivity of the compound with respect to PDE-5 over the other PDE enzymes. Allows you to test the activity of metabolites. Binding to other enzymes, receptors and/or other potential targets Tells you what other activities the compound might have against non-PDE targets and hence potential for unexpected toxicity arising from binding to these targets. Animal and human Microsomal enzyme systems Provides an indication of the extent of the metabolism, what metabolites will be formed and what enzymes are involved and provides a possible signal as to whether there will be differences between animals and humans in how the compound is metabolised. Genotoxicity including Ames and other toxicity tests Provides an indication of the potential to cause genetic injury and would include tests on sperm parameters. Physicochemical properties Includes solubility testing, stability testing, crystalline form assessment. Provides information on the suitability of the compound for pharmaceutical development. Chemical properties Includes chemical stability, salt formation, ease of synthesis. Provides information on the raw material (API) relevant to pharmaceutical development. Cell permeability Provides an indication about whether the drug will have difficulty being absorbed after oral dosing. Plasma protein binding Provides an indication of potential drug interactions via competition for specific binding sites, linearity of binding and gives information that can be useful for understanding relationships between plasma levels and efficacy (which will become important in later stages of drug development). Animal models Safety studies Acute and chronic toxicology and safety pharmacology studies will give an indication of what safety issues need to be investigated in any future clinical studies. Provides information on the maximum tolerated dose and plasma concentrations in animals. Provides information to guide initial dosing in humans. Might provide information that arrests the development programme. Pharmacokinetics Can be used to understand absorption, distribution, metabolism and excretion which can provide useful information for Phase I clinical studies in humans. Efficacy in erectile dysfunction Models exist in rabbit, dog and monkey all require use of an anaesthetic, surgical interventions (placing of the pressure monitoring catheter in the penis) and methods to induce and measure the erectile response which are artificial in nature. Given these requirements, the resulting data is often of limited use for drug development. Specifically, use of an animal model for erectile dysfunction in predicting drug efficacy, or tolerability is lacking. GB informs us

"GB" is Professor Brock. 225 The design and conduct of clinical trials are established in accordance with well-established protocols and procedures. The conduct of clinical trials is governed by the Declaration of Helsinki which can be considered as a general set of principles for the conduct of clinical trials in order to respect the human rights of the subjects participating. The objective of clinical trials is to establish the safety and efficacy of a drug. The doses, dose regimes and dosage forms are determined during the clinical trials. 226 At the in vitro stage when testing for the IC50 result, the question of the doses to be tried in the Phase II clinical trials has not yet arisen. 227 Professor Evans gave evidence about how the doses for use in clinical trials are formulated. I accept this evidence which may be summarised as follows. First, the tests for the IC50 value are carried out at the very start of the in vitro tests. The result is not particularly useful in determining the dose to be used in humans. Secondly, the first Phase I study is carried out primarily to assess the safety and tolerability of the drug in humans in most cases, and generally, the drug development team would start at doses well below the doses which caused dangerous effects in the animal models. In Phase I studies, the development team is working towards determining the maximum tolerated dose and proceeds by increasing the dose having regard to previous results. In Phase I studies, the development team is not only observing side effects, but (usually) conducting pharmacokinetic studies. Thirdly, the results of the Phase I studies will inform the doses the development team will experiment with in the Phase II study. The development team do not go above what has been determined as the maximum tolerated dose. Fourthly, it may be that a Phase IIA study is used to test safety because the drug is for the first time administered to patients suffering from the condition to be treated. One might then progress to efficacy studies in Phase II. Fifthly, Professor Evans considered that the study which is described in Example 7 in the 946 Patent "looks like" a "Phase 2B type study". I will return to this issue. Sixthly, Professor Evans said that even in the case of a Phase II efficacy study, the team would be cautious and often start off with a low dose. Finally, as each study informs the next, the team may start with quite a wide range which is then narrowed down or refined as the studies progress. 228 Dr Reece said that, where possible, efficacy is also determined in animal models. However, there are cases where there are no predicative animal models for determining the dose at which a drug will achieve efficacy in humans. An example is a drug to treat Alzheimer's disease. In such a case, the in vitro potency and selectivity may provide a guide to predicting efficacy in human studies. 229 The pharmacologists were asked to comment on the extent of judgment involved in the selection of an API(s) and dosage(s) in the course of a drug discovery and drug development process and its different stages, including any specific issues that arise in relation to a new drug to be used for the treatment of ED. In their joint experts' report, they provided the following answer: Judgement is needed at all stages of drug development from preclinical through Phase 4. The selection of the API and dosage form requires a series of judgements early in the discovery process. The degree of uncertainty or certainty (in other words the extent of judgement) will be determined by the extent and quality of the data at hand and the clarity of the signals it sends in terms of the judgements or the decisions that need to be made. At one extreme the in vitro and animal data collected (refer to our previous table) might signal a standout candidate from a group of possibilities (it may be most potent and safe and has suitable chemical properties) and tested animal models of efficacy point to the compound being an obvious choice. In this case, the degree of uncertainty at each judgement point would be relatively low. At the other extreme, data may be lacking or unreliable, experience with previous similar compounds in that therapeutic class may be limited and what data is available suggests there will be problems during development (ie. early signs of toxicity, stability problems). In this case, the degree of uncertainty at each judgement point will be relatively high. 230 Professors Brock and Evans also pointed out that as at 30 April 1999, the dosage forms that existed for the treatment of ED include intracavernosal, topical, nasal, oral dispersible and oral. 231 The pharmacologists were also asked to comment on the extent of judgment involved in the design and conduct of clinical trials in the course of a drug discovery and drug development process, including any specific issues that arise in relation to a new drug to be used for the treatment of ED in relation to the following: (1) plasma concentrations; (2) the selection of doses and dosage regimens; (3) the relevance of the minimum clinically relevant dose; (4) the methods of measuring efficacy; (5) an acceptable side effect profile; and (6) the relevance of information about a first generation drug when the NCE is a second generation drug, including in respect of the issues referred to in (1) to (5) above. 232 The answers they gave, including additional comments made by one of the clinicians were as follows: PR & AE (i) plasma concentrations; Judgement related to plasma concentrations will depend on having a thorough knowledge of the relationship between plasma concentration and efficacy, safety and tolerability. To obtain this information, plasma concentrations and end points that relate efficacy, safety and tolerability need to be simultaneously measured. If a suitable animal model is available, this relationship might be defined ahead of a Phase 1 study. For safety and tolerability, this is usually the case. In terms of efficacy related to erectile dysfunction, GB makes a comment below. If a drug is second in class, it may be possible to use learnings from the first in class compound to make some judgements about a new compound. For example, if the plasma concentrations for the new compound in Phase 1 exceed the IC-50 for that compound and if this had been shown for sildenafil to be efficacious, then this may make for an easier or earlier judgement in deciding on whether to proceed to Phase 2. GB In the case of erectile dysfunction, reliable animal models do not exist to predict efficacy in humans. Furthermore, Phase 1 pharmacokinetic studies will not allow assessment of erectile efficacy given the lack of sexual stimulation. (ii) the selection of doses and dosage regimens; PR, GB & AE Judgements concerning the selection of doses and dosage regimes in any phase of clinical development will be determined by evidence collected in the preceding phases. This evidence would be used to select the optimal dose range that achieves a chosen balance between efficacy and side effect. GB In the case of erectile dysfunction with a new PDE-5 inhibitor, information from the clinical use of sildenafil would also be of use in some aspects. However, sildenafil had been used exclusively as on-demand therapy, which defined the treatment paradigm at that time. This would have needed to be taken into account in the selection of doses and dosage regimens, as would issues around patient preferences. (iii) the relevance of the minimum clinically relevant dose; PR & AE During Phase 2 of drug development you may determine a dose that may produce a partial or full clinical response in a proportion of patients and this might be considered to be a minimum clinically relevant dose at that time. More information collected in Phase 3 and in special populations might refine what is considered to be the minimum clinically relevant dose. In terms of its relevance for clinical study design it would depend on tolerability as well as efficacy. If the drug was well tolerated at higher doses where efficacy was better, we believe that a Phase 3 study would not necessarily utilise a minimum clinically relevant dose. However, up and until the point of drug registration a company might decide, or be called upon by the regulatory body, to lower the dose range. GB Specifically with respect to defining a minimum clinically relevant dose in erectile dysfunction, researchers would face challenges in terms of reproducibility of their efficacy measures, the intra-individual variation, the effect of the partner on efficacy measures and given that questions 3 and 4 of the IIEF were used as primary efficacy measures. Recall bias may further dilute the veracity of the findings, as this questionnaire captures erectile function that occurred over the previous four weeks. (iv) the methods of measuring efficacy; PR, GB & AE The extent of a judgement in the design of a trial is improved when researchers have access to a reliable method of measuring efficacy (eg. that is objective rather than subjective, it is reproducible and shows minimal bias). GB informs us that there was a range of efficacy measures that were available at the priority date (30 April 1999) that provided an insight into the dose-response relationships. Included in this list are the IIEF, GAQ, EDITS, Rigiscan, EHS and SEP period. All of these efficacy measures have strengths and weaknesses with variable reliability. (v) an acceptable side effect profile; and PR, GB & AE In general terms a compound that shows an acceptable side effect profile (that might mean side effects are primarily tolerated by individuals, that they are not serious and they are predictable from the known pharmacological profile of the drug) allows for more certainty in terms of the judgements required for the design and conduct of clinical trials. Patients are less likely to tolerate side effects when the therapeutic area involves a lifestyle or non-life threatening condition, and this needs to be taken into account when making judgements around what is an acceptable side effect profile for any new drug. GB Specifically when dealing with erectile dysfunction treatments, a wide variability in toleration of side effects between individuals is frequently encountered. Some side effects may be interpreted as being ominous whereas others may simply negatively impact treatment efficacy. (vi) the relevance of information about a first generation drug when the new chemical entity is a second generation drug, including in respect of each of the issues referred to in paragraphs (i)-(v) above. PR, GB & AE Some of the judgements involved in the design and conduct of clinical trials are assisted by knowledge of, and learnings from, the process that was undertaken for development and registration of the first generation drug. "PR" is Dr Reece and "AE" is Professor Evans. 233 I turn now to the evidence of common general knowledge which was directly relevant to issues of drug formulation. Most of the evidence on this topic was given by Dr Mooney and Professor Polli. 234 The process for formulating NCEs was well-established before August 1999, being the earliest priority date for the 666 Patent. An NCE is a compound that has not been approved by a recognised health regulatory body, such as the FDA, TGA or Medicines and Healthcare Products Regulatory Agency (MHRA) for use for medicinal purposes. 235 In their joint experts' report, Dr Mooney and Professor Polli said that a common requirement for a generic product and an NCE in terms of developing and formulating a product for commercial approval by the regulatory authorities was that they have to meet the same quality control standards for the raw material and the finished product as detailed in various guidances and pharmacopeia, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances, FDA guidances, United States Pharmacopeia (USP), European Pharmacopeia (Ph Eur) and British Pharmacopeia (BP). The quality standards for NCE formulations and generic formulations are the same in terms of the chemistry and manufacturing control requirements. 236 The formulators agreed that there were differences between the formulation development process for a generic product and that for an NCE. 237 As to the former, they said: Generics: 1. The dose is known, including the form of the API (at least salt form), route of administration, target pharmacokinetic profile in terms of bioequivalence requirements, qualitative composition of the reference formulation and the fact that the reference formulation is safe and effective. 2. The method of manufacture of the referenced drug product is unknown, but a qualitative composition will provide guidance as to compatible excipients with the active and possibly method of manufacture such as direct compression but no details further than that. 3. For the API not all of its physico-chemical characteristics used in the formulation would be known (for example: polymorph or particle size of the material). 4. In the case of the raw material the unknown physico-chemical characteristics that are not already disclosed in the drug master file/technical package can be established through experimental studies. 5. The method of manufacture is dependent on the experience of the formulator and the equipment at their disposal and may be very different to what can be surmised from what's in the public domain. The qualitative composition of the reference product may have limited application for selection of the excipients with the alternative method of manufacture. 238 As to the latter, they said: New Chemical Entity (NCE) NCE: a compound that has not been approved by a recognised health regulatory body (such as FDA, MHRA, TGA) for use for medicinal purposes. 1. Dose is unknown 2. Route of administration is unknown 3. Excipients are unknown and dependent on the final dosage form 4. Method of manufacture is unknown and there is further uncertainty on the grounds that the method or route of administration are unknown 5. There is no target pharmacokinetic profile at least initially. A target pharmacokinetic profile evolves during drug discovery (eg. from in-vitro and animal studies) and drug development (eg. clinical study phases 1- 3). 6. There is a larger volume of information available prior to generic drug development compared to NCE development. This information is relevant to the likelihood of being able to successfully develop a formulation of the API that produces a pharmacokinetic profile that is safe and effective. 239 Dr Mooney described the development brief he would expect to receive had he been asked on 3 August 1999 to develop a formulation for an NCE for which there is no reference product. Dr Mooney was provided with a development brief by Apotex's solicitors. The development brief identified certain matters which were known about the treatment of ED by August 1999, patient considerations and identified the task which Dr Mooney was asked to perform. Dr Mooney agreed that he did not have any actual experience before 3 August 1999 of formulating any product for administration to a patient or a volunteer with so little information as was set out in his development brief. Apotex submitted that, to the extent that information was missing, Dr Mooney would obtain that information by conducting routine tests or from other members of the drug development team. 240 One of the most important chemical properties of a drug is its solubility. This is particularly important for immediate release oral formulations where rapid absorption of the drug into the blood stream is desired. One of the responsibilities of the formulator is to optimise the drug's absorption characteristics to achieve the desired therapeutic effect. 241 Apotex submitted that both of the formulators acknowledged that solubility can be defined quantitatively, as describing its absolute (or saturation) solubility and that used in this way the absolute solubility is distinct from its dissolution rate. The formulators also referred to qualitative descriptions of solubility that provide semi-quantitative characteristics, for example, the solubility tables in the BP and the USP. 242 Professor Polli gave evidence of common general knowledge relevant to the formulation of a solid dosage form for oral administration of an API as at 3 August 1999. I accept that evidence, and the following is largely a summary of Professor Polli's evidence. 243 An API is rarely administered to a patient alone. It is typically combined with other compounds, known as excipients, in a "dosage form". The combination is also known as a "formulation". 244 Dosage forms may be administered by various "routes", such as oral or intravenous. Dosage forms for oral administration include solid oral dosage forms, such as tablets and capsules, and non-solid dosage forms, such as solutions and suspensions. 245 An excipient is a compound that is not directly responsible for the pharmaceutical activity of the dosage form. Some excipients do influence the therapeutic effect of the API by affecting the manner in which the API is absorbed from the dosage form into the patient. Other excipients may be used to assist in the manufacture of the API, or to enhance the stability of the API, or the palatability of the dosage form. 246 The gastrointestinal tract is a continuous passageway between the mouth and the anus that includes the main organs of digestion, being the stomach which feeds into the small intestine which, in turn, feeds into the large intestine (GI tract). Orally administered APIs are typically absorbed into the body from the GI tract. 247 Upon the oral dosage form reaching the stomach, it disintegrates unless protected by "enteric coating", thereby exposing particles of the API in the tablet to the gastric fluid. The stomach empties into the small intestine periodically and this is known as gastric emptying. There is considerable variation in gastric emptying times between individuals. Furthermore, the gastric emptying times vary according to whether the person has ingested a meal and the nature of the meal (solid or liquid). 248 The pH of the small intestine is substantially higher than that of the stomach. The stomach is very acidic (the pH varies between about 1.5 and 3.5), whereas the small intestine is closer to neutral. Some compounds that are soluble in the much lower pH of the gastric fluid of the stomach are less soluble in the higher pH of the small intestine. This can cause re-precipitation in the small intestine. Other compounds may be soluble in the higher pH of the small intestine and poorly soluble in the stomach. 249 Most orally administered APIs are intended to be absorbed from the small intestine. The features of the stomach are that it has a relatively small surface area and absorption is limited by its thick mucus layer and short transit time. On the other hand, the small intestine has the largest surface area for drug absorption in the GI tract and its membranes are more permeable than those of the stomach. The residence time in the small intestine is approximately three to five hours. 250 The process of absorption of the API from the GI tract involves two steps. First, the API must be solubilised into the fluid in the GI tract. Secondly, the solubilised API must permeate through the epithelial cells that line the GI tract into the bloodstream. Thus, absorption from the GI tract is affected by both the solubility characteristics of the API into the fluid in the GI tract and the permeability of the dissolved API across the epithelial cells of the GI tract into the hepatic portal vein which carries it to the liver, from which it enters the systemic circulation. An illustration of this process is set out in the evidence of Professor Polli and is reproduced below. (Chan OH and Stewart BH, "Physicochemical and Drug-delivery Considerations for Oral Drug Bioavailability" (1996) 1 Drug Discovery Today 461, Figure 2, p 462.) 251 The solubility of an API refers to the maximum amount of API that will dissolve in a given volume of solvent at a certain temperature. A solution that contains the maximum amount of API that can dissolve is a "saturated" solution. There was debate between the experts as to whether solubility could include dissolution rate. Dr Mooney considered that it did, whereas Professor Polli considered that it did not. Professor Polli said that pharmaceutical scientists are very aware of the difference between the concepts of solubility on the one hand, and dissolution rate on the other. He teaches the difference to his students. The difference is reflected in the standard texts. The following appears in Smith BT, Remington Education: Physical Pharmacy (Pharmaceutical Press, 2015) (Smith (2015) at pp 31-32: Solubility and dissolution are different concepts, but are related. Solubility is the capacity of a solute to dissolve in a pure solvent. This means the maximum amount of solute that the pure solvent can hold in solution, at specified environmental conditions. Beyond this saturation concentration, a solute cannot further dissolve in the amount of solvent provided. It can exist tenuously in a supersaturated condition but will eventually revert to the solvent's true capacity. But what occurs between solutes and solvents that bestows the variability observed in solubilities in a given solvent? Solubility is a thermodynamic process: the system will tend to arrive at a point of lowest potential energy (PE) (Gibbs free energy), which is most thermodynamically stable. When we speak of solubility, it is understood to mean the ultimate outcome, without regard to how fast it occurs. Solubility provides us with important information, but it only tells us the endpoint, not how long it takes to get there. Solutes vary not only in the extent to which they will dissolve, but also how quickly they will reach their respective solubility limits. Solubility and dissolution rate are two distinct phenomena. Dissolution rate is a kinetic process. A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. Conversely, a solute can be very soluble, yet require a protracted amount of time to arrive at the final, saturation concentration. Some solutes dissolve very rapidly in appropriate solvents, while others can take an inordinate amount of time to reach a desired concentration, or saturation. 252 Dr Mooney, on the other hand, referred to "solubility" as the tendency of a drug substance to go from a solid phase into solution in a specific aqueous and organic media (e.g., water). Apotex submitted that Dr Mooney's approach encompassed both the amount of a drug that is capable of being dissolved, that is to say, its absolute solubility as well as the rate at which it dissolves in a particular solvent, that is to say, its rate of dissolution. As I will explain, absolute solubility and the rate of dissolution of a drug are distinct concepts. 253 ICOS submitted that, in the end, the so-called dispute was one of form rather than substance. Apotex took a similar approach and it submitted that nothing turned on the difference. Apotex submitted that what was important was that the experts agreed that both absolute solubility and dissolution would be measured as part of routine in vitro pre-formulation tests, and the methods for determining absolute solubility and dissolution were well-established as at August 1999. 254 Compounds are generally more soluble in solvents at higher temperatures. The solubility of an API in a given solvent is generally expressed in terms of mass of API per unit volume of the solution. Professor Polli gave the following example. At a temperature of 37 degrees centigrade, 1 g of aspirin dissolves in 100 mL of water. This corresponds to 10 g of aspirin per litre of water (10 g/L or 10 gL-1) or, using units commonly used in the pharmaceutical field, 10 mg per millilitre (mg/mL) or 10,000 micrograms per millilitre (ug/mL). Upon the maximum amount of API being dissolved in a given amount of solvent at a given temperature, any further API present will remain in a solid state. In the aspirin example, if 50 g of aspirin is present in a litre of water, 10 g will be dissolved in the water and 40 g will remain in a solid state. 255 The solubility of compounds, including APIs, can be vastly different in different solvents. The solubility of an API in a solvent may be altered by adding other compounds to the solvent. The GI tract contains two solvents, being gastric fluid and intestinal fluid. Both are described as aqueous solvents, although both contain other compounds which may affect the solubility of the API relative to pure water. Another factor which may affect the solubility of some compounds, including APIs in aqueous solutions, is the pH of the solvent. For example, a compound that is basic will be more soluble in aqueous solutions with a low (acidic) pH than in neutral solutions or solutions with high (basic) pH. Gastric fluid has a much lower (more acidic) pH than intestinal fluid. As a result, some APIs are more soluble in gastric fluid than intestinal fluid, and vice versa. 256 The process by which a solid dissolves into a solvent involves breaking the intermolecular forces which hold the molecules of solute together and the intermolecular forces that hold the molecules of solvent together, and the forming of forces between the solute and the solvent. 257 It is and was well-known that high melting points are a useful indicator of poor solubility in aqueous solutions because they correspond with strong bonds between the molecules within a solid which must be overcome for the solid to dissolve. Dr Mooney expressly agreed with Professor Polli on this issue. 258 Solubility refers to "equilibrium solubility", that is to say, the solubility that is observed after the solute/solvent system has had sufficient time to reach thermodynamic equilibrium. A given solute has a given equilibrium solubility in a given solvent at a given temperature. Professor Polli referred to the fact that it may be possible to exceed that equilibrium solubility ("apparent solubility"), but this is temporary only and the solubility will return to equilibrium solubility. 259 Whilst solubility refers to the amount of API that is able to be dissolved in a given amount of solvent, such as GI fluid, dissolution rate refers to something different. It refers to the speed at which the API dissolves in that fluid. It does not affect the API's solubility. Irrespective of any increase or decrease in the rate at which the API dissolves, the amount of API that is able to be dissolved in a given volume at a given temperature will remain constant. By contrast, the solubility of an API does affect the dissolution rate. 260 The Noyes-Whitney equation is as follows: dm/dt - kA (Cs - Ct) in which: A = the effective surface area of the undissolved API, which is the surface area available for contact with the surrounding dissolution medium being the GI tract fluid (solvent); Cs = the saturated concentration (i.e. solubility) of the API at the interface of the solid particle surface and the liquid dissolution medium (i.e. the diffusion layer which surrounds the undissolved drug); Ct = the concentration of the dissolved API in the bulk of the dissolution fluid (where convectional mixing occurs) at time t; and K = the dissolution rate constant, calculated by dividing the API diffusion coefficient by the thickness of the "diffusion layer" around the particle (being the stagnant liquid layer adjacent to the solid-liquid interface into which the particle's molecules dissolve). 261 As shown by the Noyes-Whitney equation, the dissolution rate of an API is a function of the following: the difference between the saturation concentration of API at the surface of the API particles and the concentration of the API in the bulk solution of API in the solvent; the surface area of the API particles which is exposed to the solvent; and the dissolution rate constant for the API. The variables within the Noyes-Whitney equation which may be modified by the pharmaceutical scientists are the surface area of the API exposed to the solvent and/or the solubility of the API. A higher surface area of API exposed to the solvent means a higher dissolution rate. A higher solubility of the API (Cs) means the difference between the solubility and the API concentration in the bulk solution is higher, meaning a higher dissolution rate. As I have said, solubility cannot be improved by increasing the dissolution rate, but the dissolution rate can be increased by modifying an API's solubility. 262 The dissolution rate can also be improved by altering the surface area of the API that is exposed to the solvent. As at 3 August 1999, a technique that could be used to achieve this result was called "micronisation". Professor Polli described this as a process where the mean particle size of the API is reduced to, at the smallest, single digit micron sizes. I accept that description of "micronisation". It was generally accepted among pharmaceutical scientists as at 3 August 1999 that solubility was independent of surface area and particle size. It was also understood that the Noyes-Whitney equation did not mean that a drug with a low solubility reached that low solubility slowly. The rate of dissolution defined by the Noyes-Whitney equation relates to the absolute amount of API that dissolves per unit time (for example, milligrams per second), not the amount of API relative to the total solubility. In other words, as Professor Polli put it, "all else being equal, although a poorly soluble drug may have a small dissolution rate measured in mg s -1, it will nevertheless reach its Cs just as quickly as a highly soluble drug". The other matter demonstrated by the Noyes-Whitney equation is that the rate of dissolution slows as the concentration of the API in the bulk solution (Ct) increases (as the difference between Cs and Ct becomes smaller). 263 The dissolution rate and the solubility of an API are dependent on the identity of the API itself and are very likely to be dependent on the dosage form into which the API has been formulated and from which the API dissolves. Formulating an API into a dosage form may affect the apparent solubility and thus (as expressed in the Noyes-Whitney equation), the dissolution rate. The dissolution rate may be affected by the apparent surface area of the API exposed to the solvent, even though this will not impact the apparent solubility of micron sizes. Frequently, the purpose of formulating the API is to affect the apparent solubility of the API, the dissolution rate of the API, or both. 264 Permeation of dissolved API from the GI tract may occur by one or more different mechanisms. This is shown by a diagram which was part of Professor Polli's evidence and which is reproduced below. (Boroujerdi M, Pharmacokinetics: Principles and Applications (McGraw-Hill/Appleton & Lange, 2001) p 61.) 265 Most APIs pass through the epithelial lining of the GI tract by passive diffusion from an area of high concentration of API, such as the fluid in the small intestine, to an area of low concentration of API, such as the intestinal cell membrane. 266 The rate at which the dissolved API will permeate across the epithelial lining of the GI tract depends on the following factors: (1) the surface area of the GI tract exposed to the API; (2) the concentration "gradient" being the difference between the concentration of the API in the gastrointestinal fluid and the concentration of the API across the cell membranes. Drugs diffuse across the cell membrane from a region of high concentration (e.g., GI fluids) to one of low concentration (e.g., across the cell membranes and into the hepatic portal vein). Drugs having higher solubility in the gastrointestinal fluid are capable of existing at higher concentration in the gastrointestinal fluid; (3) the epithelial cells lining the gastrointestinal tract comprises a cell wall that is formed from a layer of lipids. Accordingly, solubility of the API and lipids will affect the rate at which the dissolved API will permeate. Lipids are fatty compounds and, generally speaking, a compound that is highly soluble in aqueous solvents, such as the fluids of the GI tract, will be poorly soluble in lipids. Highly lipid-soluble drugs tend to diffuse more rapidly through the cell walls; (4) the size of the API. Smaller molecules tend to permeate membranes more rapidly than larger ones; and (5) where the drug is a weak acid or weak base, the proportion of unionised API present. Many drugs are weak organic acids or bases, capable of existing in charged (ionised) and neutral (unionised) forms in an aqueous environment, depending on the pH of that environment. The neutral form is usually more lipid-soluble and thus more capable of permeating into the lipid bi-layer of cell walls than the charged form. 267 Permeable compounds are simply not those that are lipophilic. A compound must be lipophilic enough to partition into the lipid bi-layer, but not so lipophilic (i.e., not so hydrophobic) that it will not partition out again, which it must do to be absorbed into the bloodstream. 268 The following matters affect the total amount of API that may be absorbed from the GI tract into the hepatic portal vein from a given dosage form of an API: (1) the amount of API in the dosage form; (2) the apparent solubility of the API from the dosage form; (3) the volume of the gastrointestinal fluid into which the API may dissolve; (4) the rate at which the API dissolves from the dosage form into the gastrointestinal fluid; (5) the rate at which the dissolved API permeates through the membranes of the GI tract into the hepatic portal vein; (6) the time for which the API remains in the region of the GI tract from which it may be absorbed, usually the small intestine; and (7) the stability (including metabolism) of the API in the gastrointestinal fluids prior to the hepatic portal vein. 269 The volume of the gastrointestinal fluid and the time for which the API remains in the region of the GI from which it may be absorbed (i.e., (3) and (6) directly above) are independent of the identity of the API and the dose form in which it is formulated. 270 The amount of API in the dosage form provides an upper limit to the amount of API than can be absorbed. However, more often, because the API only remains in the relevant region of the GI tract for a limited time, a portion of the API in the dosage form is absorbed. If there was an infinite amount of time available, then all API would be absorbed from any dosage form, although that API would be subject to metabolism. 271 The total amount of API that is absorbed from a given dosage form of the API is limited by one of the following three mechanisms: (1) the rate at which the API dissolves ("dissolution rate-limited absorption"); (2) the rate at which the dissolved API permeates from the solution through the relevant gastrointestinal membrane, into the hepatic portal vein ("permeability-limited absorption"); and (3) the apparent solubility of the API ("solubility-limited absorption"). 272 Apotex accepts the absorption of a drug may be limited by the dissolution rate, the permeation and absolute solubility. It is clear that as at 3 August 1999, Dr Mooney had not come across an absolute solubility limitation. 273 Professor Polli produced a diagram which illustrates the three absorption limiting factors. The diagram is reproduced below: Scenario (A) represents dissolution rate-limited absorption and the top tank represents the amount of API in solid form, the middle tank represents the amount of API dissolved in the fluid of the GI tract and the bottom tank represents the amount of dissolved API absorbed in the hepatic portal vein. Scenario (B) represents permeability-limited absorption and Scenario (C) represents solubility-limited absorption. 274 Professor Polli explained that dissolution rate-limited absorption occurs where the in vivo dissolution rate of the API is slower than its permeation through the intestinal membrane, such that the limiting step is represented by the top tank. If the absorption of API from the dosage form is dissolution rate-limited, increasing the surface area of the API exposed to the gastrointestinal fluid, for example, by decreasing the size of the API particles, can increase the amount of API absorbed, as can increasing the dose. The dissolution rate of an API is related to the solubility (as I described in the context of discussing the Noyes-Whitney equation), so improving the solubility will also increase the amount of API absorbed if the absorption is dissolution rate-limited. 275 Permeability-limited absorption occurs where the API dissolves rapidly from the dosage form, but the dissolved API permeates slowly across the GI tract into the hepatic portal vein. Since the API is only present in the GI tract for a finite period of time (approximately three to five hours), permeation rate can limit the amount of API absorbed. If absorption is permeability-limited, then modifying solubility may increase absorption by increasing the concentration gradient (the difference between the concentration of the API in the gastrointestinal fluid and the concentration of the API in the blood). 276 Solubility-limited absorption occurs when the total dose of the API exceeds the amount of API that is able to be dissolved in the GI fluids, limiting overall absorption of the API. In this scenario, the API may dissolve quickly, and therefore reach the maximum (saturated) concentration quickly. It may also permeate quickly. However, the saturated concentration at the site of drug absorption is low relative to the total dose of the API. This limits the amount of API that can be absorbed in the time frame when the API is in the small intestine. This is reflected in the drawing by the smaller tank in Scenario C relative to the other scenarios. If absorption is solubility-limited, the extent of absorption of the API can only be improved by improving the solubility of the API. Increasing the rate of dissolution will have no effect on the amount of API that is absorbed. 277 The key to understanding solubility-limited absorption is to appreciate that it depends entirely on the relationship between the measured solubility and the size of the dose. The problem of solubility-limited absorption is that even if permeability is good and the dissolution rate is instant, the measured solubility value is so low relative to the dose size that the full amount of drug will never dissolve in the limited amount of gastric fluid that is available for the purpose. This is because the gastric fluid will become saturated at a concentration that is too low for even good permeation to result in the full dose dissolving in the limited 3-5 hour period for absorption. This is a basic application of a fundamental principle, being that for every solute there is a maximum amount that is capable of dissolving in a given volume of solvent in particular environmental conditions. 278 The Cialis 2002 PI Statement describes tadalafil as a crystalline solid that is practically insoluble in water. The BP and USP contain a threshold point of "practically insoluble" as meaning above 1:10,000. In that circumstance, a 50 mg dose of API would require more than 10 L of solvent to dissolve. Dr Mooney accepted in his evidence that it would have been apparent to him that a 50 mg dose would not have been capable of dissolving in the gastric fluid, even assuming instant dissolution and good permeability. He accepted that other pharmaceutical scientists would have recognised the problem immediately. At the same time, it would not have deterred Dr Mooney from trying to find a way around it. Nevertheless, Dr Mooney accepted in his oral evidence that micronising could not solve this particular problem. The BP and USP provide a calculation for practically insoluble or insoluble of 10,000 and over parts of a solvent required for one part of the solute. ICOS put a series of examples to Dr Mooney, including this formula, an assumption that tadalafil was 20 times less soluble than the BP threshold point, and an assumption that tadalafil was 50 times less soluble than the BP threshold point. The USP sets out the meaning of various terms used to describe the solubility of a compound. It is as follows: Descriptive Parts of Solvent Required for 1 Part of Solute Term Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 Very slightly soluble From 1,000 to 10,000 Practically insoluble, or Insoluble 10,000 and over

The BP is in similar terms. 279 Professor Polli said that in drug development, the BP and USP solubility classification has very limited relevance because any one descriptor encompasses a broad range of solubilities and does not factor in anticipated dose, so cannot even contribute to differentiating permeability-limited absorption from either solubility-limited absorption or dissolution rate-limited absorption. The BP and USP solubility classifications which do not consider dose is less useful than the Biopharmaceutical Classification System (BCS) solubility classification which does consider dose. This difference is dramatically accentuated when doses are known. Professor Polli considered that the BP and USP solubility classifications are of little practical assistance. By contrast, actual solubility and permeability values are the most relevant and can be applied to calculations of the maximum absorbable dose. 280 Dr Mooney described the BP and USP solubility classifications as a semi-quantitative value, which classifies qualitatively the tendency of a drug to dissolve in different media, but particularly water. Where the drug substance is very slightly soluble or practically insoluble or insoluble, it is classified as poorly soluble. Development proceeds assuming the drug substance is a poorly soluble drug and ways are considered to improve its solubility and thus dissolution rate. 281 Professor Polli referred to a paper by Amidon GL, Lennernäs H, Shah VP, Crison JR, "A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability" (1995) 12 Pharmaceutical Research 413 (Annexure JEP-17). The paper acknowledged that "sink" (i.e., non saturated) conditions will not prevail if the dose is very high relative to measured solubility. In that case, the gastric fluid will be saturated. This does not necessarily mean the dose must be high. 282 The following passage also appears in this paper: …If the drug is a case 2 drug (high permeability, low solubility) then absorption from solution is faster than dissolution and sink conditions are likely to prevail in vivo. As a general rule one should maintain sink conditions in the dissolution media if possible, such that the drug dissolves in less than 20-30% of the dissolution media. Other factors which need to be considered, especially for case 2 drugs, are particle aggregation and the effective particle size in vivo. Quite often the first approach to increasing the dissolution rate of drugs in this class is micronization. This, however, also increases the surface energy and hence potential for particle aggregation… 283 The Amidon paper led to the adoption by the FDA by no later than 1997 of the BCS. The classification system takes into account the size of the highest unit dose for a drug which has been approved by the relevant regulator. Both the solubility and permeability determinations are made with reference to the dose of the API in the dosage form. As a result, two drugs with equivalent solubility can be classified as having either "high" or "low" solubility under the BCS depending on the size of the highest marketed dose for the drug. The BCS classification system is a further recognition of the relevance of the relationship between solubility and dose size. Professor Polli states that depending on the relationship between the dose of the API and the dosage form, and the solubility of the API from the dosage form, for BCS Class II dosage forms, dissolution rate may be the absorption limiting step, or where the solubility is low and the dose is high, solubility may be the absorption limiting step. If absorption of the intended dose of API is solubility-limited, micronising the API will not assist to increase the amount of drug absorbed. 284 The BCS is set out in the United States "Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms, August 1997". The following classes are identified based on drug solubility and permeability: Case 1: High solubility - high permeability drugs Case 2: Low solubility - high permeability drugs Case 3: High solubility - low permeability drugs Case 4: Low solubility - low permeability drugs 285 The Guidance provides that the classification can be used as a basis for setting in vivo dissolution specifications and can also provide a basis for predicting the likelihood of achieving a successful in vivo in vitro correlation (IVIVC). The Guidance states that the solubility of a drug is determined by dissolving the highest unit dose of the drug in 250 mL of buffer adjusted between pH 1.0 and 8.0. The Guidance states that a drug substance is considered highly soluble when the dose/solubility volume of solution are less than or equal to 250 mL. 286 Dr Mooney and Professor Polli agreed that if a poorly water soluble drug had a high permeability across the GI membranes, as with BCS class 2 drugs, the rate of dissolution of the drug in the aqueous environment of the GI tract is likely to be the rate-limiting step in drug absorption and so attempting to improve the aqueous solubility of the drug is likely to lead to an increase in the rate of absorption. BCS class 3 drugs, that is, drugs with high solubility and low permeability, with very rapid dissolution are expected to have permeability-limited absorption. 287 Professor Polli said that a poorly water soluble drug with a high permeability as with BCS class 2 drugs, can exhibit solubility-limited absorption or dissolution rate-limited absorption. He said that he would want to understand both the aqueous solubility of the drug substance and the permeability of the drug substance across the GI membranes. If a poorly water soluble drug had poor permeability across the GI membranes, as with BCS class 4 drugs, attempting to improve the aqueous solubility of the drug may not lead to an increase in the rate of absorption. 288 Professor Polli considered that the BCS categories have "some relevance". Solubility and permeability values will contribute to the maximum absorbable dose calculation and they will also contribute to assessing if the compound is poorly soluble or not. In addition, they will contribute to assessing if absorption can be expected to be permeability-limited absorption. Professor Polli said that although solubility and permeability allow for an API to be categorised into one of the four BCS classes, the BCS is primarily a regulatory framework for biowaivers. BCS categories themselves do not differentiate between solubility limited absorption and dissolution rate-limited absorption as low solubility drugs are not eligible for biowaivers. I accept his evidence. 289 Dr Mooney said that he had been developing products since 1985 and his decisions in terms of the influence of solubility was based on the Pharmacopeia characteristic definition. The BCS provides a definition of highly soluble to which I have already referred. The limiting feature in initial product development is that the dose is not known and further, there is no indication of how long you use to establish whether the material dissolves in that volume. In those circumstances, there is no characteristic to base development decisions on. 290 Lieberman H, Lachman L and Schwartz JB (eds) Pharmaceutical Dosage Forms: Tablets (2nd ed revised and expanded, Taylor & Francis, 1989) (Lieberman et al (1989)) is a standard pharmaceutical textbook well-known in this field. The following appears in the edition available as at 3 August 1999: When dissolution is considered to be slow, a means of enhancing it may be sought. In the absence of a more soluble, physical or chemical form of the drug, particle size reduction is the most commonly employed practice. Enhanced surface area, with a concomitant increase in the dissolution, can also be accomplished by adsorbing the drug on an inert excipient with a high surface area, such as a fumed silicone dioxide. … (at p 23) (Annexure BAM-4) … It is now generally recognized that poorly soluble drugs showing a dissolution rate-limiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state than as a coarse material. … Because of these significant roles, it is important to decide on a desired size range, and thence to maintain and control it. It is probably safest to grind most new drugs having particles that are above approximately 100 µm in diameter. If the material consists of particles 30 µm or less in diameter, then grinding is unnecessary except if the material exists as needles - where grinding may improve flow and handling properties or if the material is poorly water-soluble where grinding increases dissolution rate. Grinding should reduce coarse material to, preferably, the 10-40 µm range. Once this is accomplished, controlled testing can be performed both for subsequent in vivo studies and for in depth preformulation studies. As the studies proceed, it may become apparent that grinding is not required and that coarser materials are acceptable. At that time, it is conceptually simpler to omit that step without jeopardizing the information already developed. The governing concept is to stage the material so that challenges are maximised. (at p 5) (Annexure BAM-18) 291 Dr Mooney said that he understood that the above textbook was widely read and routinely consulted by other people in his profession in Australia and overseas prior to 3 August 1999. He said that he himself routinely consulted Lieberman et al (1989) before 3 August 1999 when developing pharmaceutical formulations. There is a dispute between the parties as to the proper interpretation of the above passage. Professor Polli said that the passage quoted was limited to poorly soluble drugs. Apotex submitted that, read in context, that is not the case. 292 As at April 1999, particle size distribution and size distributions by mass and by volume were well understood by pharmaceutical scientists. 293 ICOS's contention is that the fact that a marketed product is classified BCS Class II, indicating that absorption is likely to be dissolution rate-limited, does not mean that the absorption of a higher dose of the very same API will not be solubility-limited. A marketed dose is unlikely to be affected by solubility-limited absorption as, by definition, an effective amount of the drug can be absorbed. Any issue of solubility-limited absorption has already been solved. 294 The distinction between solubility-limited absorption and dissolution rate-limited absorption is of little consequence to the purpose for which the BCS is used by the FDA, as no BCS Class II formulations are eligible for a waiver of the need to perform a human bioequivalence experiment. Professor Polli's evidence is that Daugan 1997 does not contain information concerning the permeability of the claimed compounds. It is not possible to categorise tadalafil into a BCS class without conducting experiments to determine the permeability classification of the compound. 295 Dr Mooney did not give consideration to the issue of solubility-limited absorption in his affidavit or in the joint experts' report. Dr Mooney was a formulator of generic drugs before the priority date. He had no knowledge or experience with the problem of solubility-limited absorption because it never arose (or arises) in the context of generic drug formulation. He did agree that the relationship between the measured solubility value and dose size was a potential limitation to absorption that was relevant to the development of NCEs before August 1999. He also agreed that the concept of solubility-limited absorption was documented in the literature and readily recognisable having regard only to the general background knowledge that was available to all pharmaceutical scientists interested in formulation as at August 1999. 296 The relationship between the three scenarios (i.e., those illustrated by the tanks diagram prepared by Professor Polli) is as follows. Where absorption is dissolution rate-limited and where absorption is permeability-limited absorption, the rate at which API dissolves or permeates determines the amount of API in the dosage form that is absorbed. Where absorption is solubility-limited, it is the extent to which the API in the dosage form is able to dissolve that determines the amount of API in the dosage form that is absorbed. Where absorption of the API from the dosage form is permeability-limited, increasing the amount of API in the dosage form (the dose) proportionately increases the concentration of dissolved API and proportionately increases the amount of API absorbed. However, where the extent of the absorption of the API from the dosage form is solubility-limited, increasing the dose of API will simply result in more undissolved API in the gastrointestinal tract, and it will not increase the extent of absorption. The only mechanism by which the extent of absorption can be increased is by increasing the solubility of the API. 297 Which of the three mechanisms limits absorption of the API from the dosage form may depend on either the API or the dosage form within which the API is formulated. For example, for a given formulation of a given API, the dissolution of the API may be slow and limit the amount of API absorbed within the available time. The dissolution rate of the API from the dosage form may be improved by changing the formulation, for example, by adding excipients such as disintegrants, or by increasing the effective surface area of the API such as by reducing particle size. The improvement may be such that dissolution rate no longer limits the amount of API absorbed. If dissolution rate does not limit the extent of absorption, then either permeability or solubility will. If permeability or solubility limits the extent of absorption, further improvements to the dissolution rate will not improve the extent of absorption. The dissolution rate may be improved to the point that it is practically instantaneous. However, if the saturated concentration of the API in the gastrointestinal fluid is too low relative to the size of the dose for the entire amount of the API to be absorbed within the limited time available, the extent of absorption from that dosage will be solubility-limited. As the Noyse-Whitney equation shows, increasing the solubility (the saturated condition of the API) in the solution (Cs) will also increase the dissolution rate of the API. It is possible to improve the extent of absorption of API from a dosage form from which absorption of the API is dissolution rate-limited by improving the solubility of the API from the dosage form. However, improvements to the dissolution rate of the API will not affect the solubility of the API so will not improve the extent of absorption from a dosage form from which the absorption of the API is solubility-limited. 298 The distinction between solubility and dissolution rate is of real practical importance because different formulation techniques may be used to address the problem. A drug development team is able to use calculations to assess whether or not there might be a solubility-limited absorption problem, including the maximum absorbable dose (MAD calculation). Professor Polli said that the maximum absorbable dose can be calculated using the following formula: MAD = S x Ka x SIWV x SITT where: S is the solubility of the API at pH6.5 (in mg mL-1) Ka is the transintestinal absorption rate constant (in min-1); SIWV is the volume of fluid in the small intestine (in mL); and SITT is the small intestine transit time (in minutes). 299 The amount of fluid available in the small intestine to dissolve the API is effectively constant at 250 mL. The residence time in the small intestine is also effectively constant and for the purpose of the calculation is assumed to be 4.5 hours. The solubility and permeability can be measured enabling the calculation of the maximum absorbable dose. The maximum absorbable dose is the maximum amount of the compound that could be absorbed if the small intestine was saturated with a compound for the entire period of time in which the compound transited through the small intestine. It assumes that the dissolution rate of the API in the intestinal fluid is instant because the purpose of the calculation is to test whether, even if dissolution is perfect, there will still be a problem with absorbing the anticipated dose due to solubility. The maximum absorbable dose describes the maximum amount of drug that can be absorbed into the hepatic portal blood. The oral bioavailability of an API is a function of the amount of drug absorbed into the hepatic portal blood, and of the amount of that API that survives first pass metabolism by the liver and thus enters the systemic circulation. The maximum absorbable dose model takes no account of first pass metabolism which can result in still less API being absorbed in plasma concentration. If the maximum absorbable dose is lower than the anticipated dose, the pharmaceutical scientists would be concerned that the anticipated dose would not be absorbed (and therefore the target pharmacokinetic profile could not be attained) without improving the solubility of the API. This is a simple way of ascertaining, early in a drug development project, whether or not solubility-limited absorption is likely to be a problem. 300 Another available approach is to consider the volume of gastrointestinal fluid required to dissolve a full dose of the API. If the volume required to deliver a full dose is much higher than the volume of gastrointestinal fluid in the small intestine (250 mL), then it is unlikely that the dose will be absorbed. This approach allows for the fact that permeation of dissolved API from the GI tract will mean that more API can be dissolved by considering multiples of the actual volume of GI fluid. At the priority date, if an API had a solubility that required more than 10 times the volume of gastrointestinal fluid (10 x 250 mL = 2.5 L) to dissolve a full dose that would be an API where permeation would not be adequate to overcome the poor solubility and the full dose would not be absorbed. 301 Professor Polli said, and I accept, that as at August 1999, it was common general knowledge that the following techniques could be adopted to improve the solubility of an API: (1) the formation of salts of acidic or basic APIs; (2) the formation of polymorphs (different crystalline forms) of the API; (3) the formation of amorphous forms of the API (where the API is solid, but not crystalline); (4) the use of co-precipitates (solid dispersions), where the solid API is dispersed through another solid compound; (5) the use of solvates (and other co-crystals), where the API is crystallised together with a fixed ratio of the solvent, such as water, (6) the use of lipid-based formulations where the API is dissolved in a lipid; (7) the use of liposomes where the API is dissolved in a lipid bi-layer; (8) the use of surfactants and pH modifiers; and (9) the use of pro-drugs, where a different API is produced, the different API being metabolised into the original API after absorption has occurred. 302 Dr Mooney said that there were a number of well-known approaches employed by formulators to improve the solubility of a poorly water soluble drug, including particle size reduction or micronisation, use of different polymorphs, use of different salts, use of a solid dispersion and use of pro-drugs. He did accept that the choice may depend on whether absolute solubility or dissolution rate is the rate-limiting step in drug absorption. Dr Mooney accepted that micronisation is not a technique that can improve the solubility (absolute solubility) of an API. 303 The experts were agreed that the formulator uses the same formulation strategy for all doses tested. When formulating for a study of a range of doses, such as a Phase II study by which the dose is established, the formulator must formulate the drug so as to ensure that none of the doses tested will be solubility-limited. 304 Micronising can increase the surface area of the API exposed to the GI fluid and may therefore increase dissolution rate. However, there are certain disadvantages associated with micronising. They are as follows: (1) a reduction in particle size can also cause a decrease in drug stability by increasing the total particle surface area exposed to the external environment. Formulations with the micronised drug substance (i.e., reduced particle size) may therefore be more susceptible to degradation caused by heat, light, oxygen and moisture as compared to formulations with the unmicronised drug substance (i.e., unreduced particle size); (2) micronisation can also affect the compressibility and flow properties of the drug substance. Compressibility refers to the ability of the blend to be subjected to a compressional force so that the blend compressed volume can be decreased to provide a tablet or capsule with appropriate physical characteristics. Flowability refers to the ability of the blend to flow through the compression or encapsulation process and afford consistent tablet and capsule weight respectively; (3) where the drug particle size is very fine, this can cause drug substance particles to aggregate due to electrostatic changes. Particle aggregation can occur during manufacture of the dosage form when blending the drug substance with excipients to create a blend for direct compression, or when mixing prior to dry/wet granulation. This can lead to poor tablet (capsule drug substance) uniformity of content (especially for low dose formulations) and poor compressibility and flowability of the blend (especially for high dose formulations); and (4) powder segregation can occur. This is a process where particles of different sizes that are mixed together (such as a mixture of API and excipient particles intended for tableting) will separate based on size under agitation (such as during transport). This is undesirable as it is important that tablets are homogenous. 305 A further disadvantage is that making increasingly smaller particles is likely to be associated with increased cost. 306 Professor Polli said, and I accept, that the extent of any improvement in in vitro dissolution rate in any given solvent produced by a given reduction in particle size was not predictable. As a result, any effect on in vivo absorption is even more unpredictable in the sense that correlations between in vitro dissolution rate and in vivo absorption are difficult to establish.

INVENTIVE STEP AND THE 946 PATENT 307 As I have said, it is not in dispute that Daugan falls within the terms of s 7(3) of the Act. GB 464 is the priority document for Daugan 1997 and it and Daugan 1995, which was said to be unpublished at the time of the application for Daugan 1997, are both referred to in Daugan 1997. Daugan 1997 refers to GB 464 as describing the synthesis of the compounds of the invention and their utility in the treatment of impotence, and Daugan 1995 as describing the synthesis of the compounds of the invention and their utility in the treatment of other diseases associated with inhibition of cGMP PDEs. ICOS did not dispute that the development team could also have reference to GB 464 and Daugan 1995 to the extent that they may be relevant.

Daugan 1997 308 It is convenient to deal with all of the teachings in Daugan at the same time and, in the analysis which follows, I will also identify matters that are particularly relevant to the inventive step challenge to the claims in suit in the 666 Patent. 309 The Daugan 1997 Specification describes the invention as relating to the use of tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3ꞌ,5ꞌ-monophosphate specific phosphodiesterase (cGMP-specific PDE) in the treatment of impotence. A description of impotence and its prevalence in the community is set out. The existing treatments for impotence are described, including direct injections of vasoactive substances into the penis, or patches applied to the penis, or the use of a penile prosthesis. 310 The Daugan 1997 Specification provides the general formula for the compounds which are the subject of the invention and "salts and solvates (e.g. hydrates) thereof" and then it identifies by chemical formula what it describes as 13 suitable individual compounds of the invention for use in the treatment of ED and "physiologically acceptable salts and solvates (e.g. hydrates) thereof". The list of compounds includes Compound A which is tadalafil, but it does not include what is later described as Compound B. 311 The Daugan 1997 Specification then refers to Compound A and Compound B and "physiologically acceptable salts and solvates (hydrates) thereof" as the specific compounds of the invention. 312 The Daugan 1997 Specification states that the compounds of the general formula "and in particular Compounds A and B" have unexpectedly been found to be useful in the treatment of ED and to be capable of being administered orally. The Daugan 1997 Specification refers to pharmaceutically acceptable salts of Compounds A and B. There are statements to the effect that acid addition or base addition salts can be formed and examples of such salts are given. 313 The Daugan 1997 Specification states that the compounds of the invention have been found to be potent and selective inhibitors of cGMP specific PDE. 314 The Daugan 1997 Specification contains a statement about the administration of the compounds of the invention as follows: Generally, in man, oral administration of the compounds of the invention is the preferred route, being the most convenient and avoiding the disadvantages associated with i.c. administration. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, e.g. sublingually or buccally. 315 The Daugan 1997 Specification refers to daily dosages of the compounds of the invention generally being in the range of 0.5-800 mg for an average adult patient (70 kg). Professor Evans said, and I accept, that this is a very wide range and most drugs on the market would fall somewhere within this range. The Specification goes on to say that for a typical adult patient, individual tablets contain 0.2-400 mg of active compound for administration in single or multiple doses, once or several times per day. The Specification also refers to doses for buccal or sublingual administration. 316 The Daugan 1997 Specification states that the invention may be prepared by any suitable method in the art or by a process thereafter described and previously substantially described in GB 464 and Daugan 1995. 317 The Daugan 1997 Specification describes the making or preparation of salts of the compounds of the invention as follows: The pharmaceutically acceptable acid addition salts of a compound of formula (l), and in particular compound A or B which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound A or B with a suitable base. Both types of salt may be formed or interconverted using ion-exchange resin techniques. 318 The Daugan 1997 Specification then sets out in a number of Examples, details of the synthesis of Compounds A and B. As I will explain, it is significant that in the Example for Compound A, the compound is said to have a melting point of 302-303°C and in the Example for Compound B, the compound is said to have a melting point of 307-309°C. These are very high melting points. 319 The Daugan 1997 Specification shows pharmacy formulations for making tablets (by direct compression or wet granulation) for Compounds A and B comprising 50 mg of the active ingredient. It is not in dispute that some of the excipients identified in the formulations, such as sodium lauryl sulphate, polyvinyl pyrollidone, polyethylene glycol and polysorbate 80, are excipients which assist in solubility. The Specification also sets out pharmacy formulations for the preparation of capsules. 320 The Daugan 1997 Specification states that the inhibitory effect of the compounds of the invention was measured using a one-step assay and the process is described in the Daugan 1997 Specification. The Specification states that the results show that compounds of the invention were highly selective for the cGMP specific PDE enzyme. The Specification states that tests were conducted against other PDE enzymes using standard methodology. The results are not set out or summarised in the Specification. As Dr Reece said, there is no supporting data for the statements made in Daugan 1997 about selectivity. 321 The Daugan 1997 Specification goes on to say that the compounds, according to the present invention, were typically found to exhibit an IC50 value of less than 500 nM, and an EC50 value of less than 5. An EC50 value shows the concentration of the compound that results in 50% of its maximum biological effect and, more particularly in relation to PDE5, the concentration of a compound which results in 50% of the maximum increase in cGMP levels. The results, which are set out in the following table, are said to show the ability of the "subject compounds" of the invention to inhibit cGMP PDE, and hence their utility in the treatment of ED. Example No. IC50 nM EC50 µM 1 2 0.2 2 2 0.2

322 The Daugan 1997 Specification does not contain the results of any animal studies or in vivo studies or any statements to the effect that such tests have been carried out. Dr Reece considered that one could infer from the pharmacy formulation of tablets that some testing in animals and possibly humans had been carried out, but it seems to me that one cannot be reasonably certain of that either way. I note that animal studies and in vivo tests are described in Daugan 1995. 323 Both GB 464 and Daugan 1995 list 11 compounds (including Compound A) and refer to Compound A as a specific compound of the invention. Compound B is not referred to as a specific compound of the invention. Although not in the list of 11 compounds, Compound B is the subject of an Example in both the GB 464 Specification and the Daugan 1995 Specification. It seems then that at some point after Daugan 1995, but before Daugan 1997, the inventors considered that Compound B was sufficiently promising to be identified as a specific compound of the invention identified in Daugan 1997. 324 The results of tests for IC50 values and EC50 values for 11 compounds, including Compound A, are set out in Daugan 1995 and GB 464 as follows: Example No. IC50 nM EC50 µM 12 10 0.15 36 ˂10 0.5 52 20 0.8 63 30 0.35 79 ˂10 0.15 82 20 0.5 84 10 0.4 89 10 ˂0.1 95 2 0.2 101 10 0.3 115 ˂10 0.4

Compound A is Example 95. 325 The formulators gave evidence of what Daugan 1997 taught them in particular. 326 First, because of the matters about which there is no information, the Daugan 1997 Specification refers to an NCE development problem at the early development stage. That was Professor Polli's evidence which was, to some extent, accepted by Dr Mooney. In any event, I accept the evidence of Professor Polli. Dr Mooney considered that the fact that Daugan 1997 referred to a dose range of 0.5-800 mg and set out pharmacy formulations involving 50 mg of the active ingredient suggest that some animal studies had taken place. As I have said, in the context of discussing evidence from Dr Reece to similar effect, I do not think one can be reasonably certain either way. Certainly, no results of animal studies or studies in humans are disclosed. I accept Dr Mooney's evidence that there is some instruction in Daugan 1997 about pharmacy formulations and manufacturing that would not ordinarily be available to a company making a generic (copy) drug. 327 Secondly, the concepts of solubility, dissolution and permeability are not mentioned in the Daugan 1997 Specification, and there is no data about these matters. Nor is there in vitro, pre-clinical or in vivo data about these matters. There is information about the melting point of each of Compound A and Compound B and, as I have said, there are the pharmacy formulations involving tablets and capsules. The melting points stated in Daugan 1997 for Compound A and Compound B respectively are extremely high and suggest poor solubility to the point that the solubility of the compound prevents absorption of the necessary dose. 328 Thirdly, there is no express statement in the Daugan 1997 Specification that the compounds are expected to be very poorly soluble. There are a number of references to salts, as well as solvates. I have already noted that the excipients in some of the example pharmacy formulations show that those preparing the formulations were attempting to address perceived solubility problems with the active ingredient. In addition, Dr Mooney considered that one of the formulations suggests the use of a co-precipitate to deal with solubility problems. There is no reference in Daugan 1997 to particle size, particle size reduction or micronisation. 329 Fourthly, the Daugan 1997 Specification identifies a very large number of compounds and a broad range of doses. Compounds A and B are identified and highlighted equally. There is no indication in the Specification of whether the 50 mg dose in the pharmacy formulations has been identified as safe and effective from animal safety studies or animal models of the disease. 330 Fifthly, the Daugan 1997 Specification makes no reference to Cmax or target pharmacokinetic profiles. 331 Sixthly, the Daugan 1997 Specification makes no reference to the onset of action or to the minimum effective concentration of the compound. Having said that, I accept Dr Mooney's evidence that a number of the pharmacy formulations are of immediate release dosage forms suggesting that they are for a rapid dissolution profile. 332 Seventhly, the Daugan 1997 Specification makes no reference to minimising dose through formulation. 333 Finally, the Daugan 1997 Specification makes no reference to the BCS or BP or USP solubility classifications or to Lieberman et al (1989).

Relevant Principles 334 An invention as claimed in each asserted claim is deemed to involve an inventive step when compared with the prior art base unless the party challenging the patent establishes that the invention as claimed would have been obvious to the person skilled in the art, having regard to the common general knowledge and any available s 7(3) information (AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; (2014) 226 FCR 324 (AstraZeneca Full Court) at [200] and [458]; AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30; (2015) 257 CLR 356 (AstraZeneca High Court) at [18] per French CJ). The question is not whether the claimed invention would have been obvious to the inventor or some other particular worker in the field (Minnesota Mining at 293-295 per Aickin J; Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262 (Wellcome Foundation) at 270 and 286 per Aickin J). The person skilled in the art postulated in this test is a legal construct, a hypothetical skilled but non-inventive person in the field. There was no dispute that in this case, the "person" is, in fact, a team of highly skilled scientists, including pharmacologists, clinicians, formulators, as well as organic chemists, toxicologists, statisticians, analytical chemists and persons with expertise in obtaining regulatory and marketing approvals. I will refer to this group as the development team, although, as I will make clear a little later, it is to be borne in mind that the evidence in this case makes it clear that there is an element of drug discovery in what the team will be required to do. 335 I have already referred to the principles relevant to the identification of common general knowledge and I have set out the common general knowledge which is relevant in this case. I will not repeat what I have said. 336 In Wellcome Foundation, Aickin J (with whom the other members of the Court agreed) said (at 286): The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not. 337 In Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 235 CLR 173 (Lockwood (No 2)), the High Court said (at [52]) that obviousness and inventiveness are antitheses and that there is no distinction between obviousness and a lack of inventive step. The Court said that a "scintilla of invention" remains sufficient in Australian law to support the validity of a patent. The Court referred to various phrases which had been used in the authorities to describe an inventive step, including "some difficulty overcome, some barrier crossed" (R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 13 IPR 513; (1989) 25 FCR 565 at 574 per Lockhart J) or "beyond the skill of calling" (Graham v John Deere Co of Kansas City (1966) 383 US 1 at 15 and to the authorities of this Court which are referred to in footnote (94)). The High Court also said at [56]: Whether a patent is obvious under the Act is still to be determined by reference to the hypothetical non-inventive worker in the field (now a "person skilled in the relevant art" (s 7(2) and (3)) equipped with common general knowledge, as stated by Aickin J in Minnesota Mining and followed since. Therefore it is irrelevant whether the invention was arrived at as a matter of chance or luck or the result of long experiment or great intellectual effort. However, reference to and use of prior disclosures, in existence but not part of the common general knowledge, has now been extended. This has the result that the limitation in Aickin J's statement of principle, emphasised above, no longer applies, a topic about which more will be said later. The objective approach to determining obviousness is equally applicable to a combination patent. (Citations omitted.) 338 A test of obviousness or lack of inventive step often applied in pharmaceutical patent cases is the reformulated Cripps question which asks whether the skilled person or team at the priority date armed, only with the common general knowledge and any available s 7(3) information, would "directly be led as a matter of course to try the [claimed invention] in the expectation that the [claimed invention] might well produce a useful alternative to or better drug than [the existing common general knowledge treatments] or a body useful for any other purpose" (AB Hässle v Alphapharm at [53]; AstraZeneca Full Court at [533]; AstraZeneca High Court at [15] per French CJ; at [67] per Kiefel J (as her Honour then was)). ICOS submitted that this was the test of obviousness or lack of inventive step which was to be applied in this case. It also submitted that the test involved two limbs namely, whether the skilled team would directly be led as a matter of course to try the claimed invention and, separately, whether that would be done with an expectation of success. In the case of the latter requirement, the test is one of might well or a reasonable expectation of success. As to the fact that there are two limbs to the test, ICOS relied on the observations of Lindgren J in Alphapharm v H Lundbeck A/S at [180] as follows: The High Court also held in Astra (at [50]-[53]) that obviousness was to be determined by asking whether a hypothetical non-inventive skilled addressee, equipped with the common general knowledge as at the priority date, would have taken steps towards the invention "as a matter of routine" in the expectation that they might well produce the invention or some other useful result (endorsing statements in Wellcome Foundation Ltd v V.R. Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 (Wellcome) at 286 and Olin Mathieson Chemical Corporation v Biorex Laboratories Limited [1970] RPC 157 (Olin) at 187-188). The High Court has therefore insisted on the two elements: (1) being led as a matter of routine to the desired result; and (2) having a reasonable expectation of achieving that result. 339 The essential point made by ICOS was that the test of obviousness or lack of inventive step was not simply whether the steps from the starting point to the claimed invention could properly be described or characterised as routine, but also that it must be shown that those steps would be carried out with a reasonable expectation of success. ICOS, in making that point, did not concede that the steps in this case were routine. Quite the contrary, it submitted that the steps from common general knowledge and Daugan 1997 to the claimed invention were far from routine. Its point was that, in addition, Apotex was required to (but could not) show that such steps would be carried out with an expectation of success. ICOS submitted that that is an additional requirement and it is not met in this case. 340 For its part, Apotex submitted that the reformulated Cripps question is not always the "appropriate" test. By way of example, it submitted that it would not be the appropriate test if it was applied in a way which excluded the possibility of two things being obvious because two things may be obvious. Apotex submitted that the Court should apply the test formulated by Aickin J in Wellcome Foundation and set out above (at [336]). It put its submission in this way: …this formulation [i.e., the reformulated Cripps question] does not exclude the possibility that routine experiments - whose results can test a hypothesis and advance a process of drug development, but cannot be expected with any certainty - come within the statutory question posed by s7(2). (Emphasis in original.) 341 Apotex sought to support its submission by reference to the following matters and considerations. First, it submitted that the High Court in AB Hässle v Alphapharm referred to the test stated by Aickin J in Wellcome Foundation with approval (at [51]-[53]). Secondly, it submitted that there is nothing in Lockwood (No 2) which suggests that the reformulated Cripps question is the sole or exclusive test of obviousness. In fact (so the submission proceeds), the High Court referred to other descriptions of the test with approval. Lockwood (No 2) was decided after AB Hässle v Alphapharm. Thirdly, it submitted that in the recent AstraZeneca litigation, the Courts applied the test formulated by Aickin J in Wellcome Foundation, rather than the reformulated Cripps question. The AstraZeneca litigation concerned a claim for a method of treatment for a patient suffering from hypercholesterolemia. The method of treatment involved a single daily dose of 5 to 10 mg of rosuvastatin or an acceptable salt thereof. The Full Court applied the reformulated Cripps question (AstraZeneca Full Court at [533] per Jessup J with whom Besanko, Foster, Nicholas and Yates JJ agreed at [229]). Apotex submitted that the reasons of the High Court in AstraZeneca High Court show that Jessup J also applied the approach taken by Aickin J in Wellcome Foundation and that the High Court approved of this approach. Apotex referred to various passages in the reasons of members of the High Court which refer to clinical trials or tests being warranted or conventionally carried out. To fully appreciate the argument, it is necessary to set those passages out. 342 Chief Justice French said (at [42]-[44]): Jessup J concluded that the primary judge had not erred in concluding that a person skilled in the art would have been led directly and as a matter of course to try rosuvastatin at a dosage of 5-10 mg/daily in the expectation that it might well be an efficacious treatment for a patient suffering from hypercholesterolemia. The evidence of Professor O'Brien and of Dr Reece was sufficient to sustain the conclusion that the skilled person, having read the Watanabe Article in the light of the common general knowledge, would have entertained the expectation that rosuvastatin might well be at least as efficacious a treatment as atorvastatin. No error was involved in that reasoning. In the light of the evidence it would be a routine step to test rosuvastatin at the lowest efficacious dose. Jessup J rejected a submission by AstraZeneca that the primary judge's conclusion that the skilled person would have proceeded to try rosuvastatin at any dose, let alone a 5 or 10 mg dose, with any reasonable expectation of success was not open on the evidence before her. That rejection was plainly correct. As his Honour said (91): "Whether an invention is obvious is a question to be answered by the Court." The question posed by this Court in Wellcome Foundation Ltd and AB Hässle does not require that, in order to sustain an obviousness case, a party has to lead evidence which echoes the terms of that question. A similar conclusion was open, as the primary judge found, on Patent 471. AstraZeneca submitted in this Court that the "claimed invention" is a treatment using a once daily, 5-10 mg dosage of rosuvastatin. The only dosage expert, Dr Reece, confirmed that neither the Watanabe Article nor Patent 471 contained animal or human trial safety data. He had given evidence that such data were essential to determining what dosage should be tested in clinical trials. The person skilled in the art would never have chosen the dose to be tested simply by trying the doses that worked for other statins. That evidence was referred to by Jessup J, who said (92): "But that evidence also made it quite clear that such trials would conventionally be carried out. They would fall within the concept of working towards the invention with an expectation of success referred to in AB Hässle." No error is disclosed in that reasoning. (Footnotes omitted.) 343 Justice Kiefel said (at [93]-[95]): The final submission was that, armed with the Watanabe article and the common general knowledge, the skilled person would not have been led directly to the invention because the starting dosages are an essential element of the invention and were not revealed by that article or by any other prior art document. This may be accepted. The dosages were revealed to AstraZeneca by clinical trials on humans, as inevitably they would be if undertaken. The point is that the Watanabe article contained sufficient information, including as to the results of the pre-clinical trials on animals, for Professor O'Brien to consider that clinical trials were warranted. Dr Reece was of the same view. Professor O'Brien's evidence about what the right dosages might be, although accurate, was largely speculative and this was not his area of expertise. However, Dr Reece, who has a background in clinical pharmacology and research, gave evidence that dose sizes which would be trialled could be expected to start from 5 mg, 10 mg and 20 mg. I do not understand AstraZeneca to contend that the starting dosages disclosed in the Patent would not be identified by normal clinical trials, which utilise certain standards and procedures. The evidence therefore shows that the skilled person would be led to the invention. 344 Justices Gageler and Keane said (at [116]): It is also wrong to suggest, as AstraZeneca did, that the need for further testing of human subjects was an obstacle to a conclusion that rosuvastatin would have been tried as a matter of course in the expectation of a solution to the problem in the common general knowledge. Section 7(2) does not invite a consideration of the notional addressee's motivation to carry out any tests that would need to be done. In particular, it does not contemplate consideration of whether the skilled addressee would be sufficiently encouraged by the available information to undertake the expense and inconvenience of further tests necessary to bring the solution to the stage of implementation. 345 Justice Nettle said (at [123]): In fact, however, there is no basis in the objection. Both the primary judge and the Full Court approached the matter in accordance with that requirement. As Jessup J said, although Dr Reece's evidence was that the Watanabe article contained no safety data the result of either animal or human trials, the evidence also disclosed that trials of that kind would conventionally be carried out. Accordingly, carrying out the trials fell within the concept of working towards an invention with an expectation of success and that was consistent with the conclusion that the invention was obvious. (Footnote omitted.) 346 Apotex's argument seemed to include the proposition that, providing one could characterise a particular trial, test or experiment as routine or conventional, then it satisfied the "requirement" that it be carried out with an expectation of success. 347 It is not easy to grasp the full extent of Apotex's argument. It cannot be that all the Court is required to do is to identify the test or experiment which led to the invention and then ask whether a test or experiment of that nature has been carried out many times before and is, in that sense, routine. A dose ranging study involving amounts of 1-20 mg of a compound might be a study that is carried out in the case of many clinical trials involving pharmaceutical compounds, but that does not make it routine in this case. Put another way, the fact that such a study is carried out in many cases may be relevant to obviousness or lack of inventive step, but it cannot be decisive. The step must be one that the development team is directly led to and would carry out as a matter of course. It is at least implicit that that step would be taken because it may well succeed. 348 In this context, it is important to remember that in this country the fact that the development team would consider a step or series of steps worthwhile to try or worth a try does not mean that the resulting invention is obvious or lacks an inventive step. In the course of rejecting the test of worthwhile to try or worth a try, the plurality in AB Hässle v Alphapharm referred to the following passage in the reasons of judgment of Buckley LJ in Beecham Group Ltd's (Amoxycillin) Application (1980) 97 RCP 261 at 296 describing it as the vital passage: I am fully prepared to assume on the evidence before the court that [prior patent] 978,178 should be regarded as having made clear to one skilled in the field of penicillins that the epimers of the para-hydroxy and the meta-hydroxy compounds were likely to prove fruitful avenues of research, possibly the most promising avenues known to exist. I accept that the lines which that research would follow would be what [the opponent's] witnesses described as 'routine', ie well-known. I accept that anyone experienced in penicillin research who pursued research along those avenues would probably have found what Beecham found. But with great deference to the learned judge, I do not agree that this is enough to constitute the claim to Amoxycillin as a penicillin for administration to humans obvious for the purposes of section 14(1)(e) of the [1949 UK Act]. To reach the discovery of the particular characteristics of Amoxycillin and its suitability for treating humans the research worker would have had to embark upon a voyage of discovery. It is possible now to see that his voyage would have been short and perhaps uneventfully straightforward, but where each of his two, or possibly more, vessels would make landfall and what those places would be like would not have been obvious to him at the outset. The voyage might have been clearly worth trying but not as a means of reaching a specific hoped-for destination. 349 In my respectful opinion, the High Court in AB Hässle v Alphapharm endorsed a requirement that the step or series of steps be carried out with an expectation of success. After referring to Wellcome Foundation and the reformulated Cripps question, the plurality said (at [54]): Lehane J did not treat "routine" in that way. He erred by giving it an operation more favourable to Alphapharm's case. What his Honour did was in line with the position which now apparently obtains in England, that "all of the courses of action which present themselves without the exercise of invention are obvious". His Honour did not assess what was said by the expert witnesses concerning the procedures they would have followed by making findings whether they would have been led directly as a matter of course to pursue one avenue in the expectation that it might well produce the claimed compound. (Citation omitted, emphasis added.) 350 I respectfully adhere to what the Full Court of this Court (of which I was a member) said in Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; (2014) 222 FCR 336 (Generic Health) said at [71]: We do not think that the plurality in Alphapharm were saying that the reformulated Cripps question was the test to be applied in every case. Rather, it is a formulation of the test which will be of assistance in cases, particularly those of a similar nature to Alphapharm. The plurality did not reject as an alternative expression of the test the question whether experiments were of a routine character to be tried as a matter of course (Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at 280-281, 286 per Aickin J). We do not think there is a divide here in terms of whether an expectation of success is relevant between a test which refers to routine steps to be tried as a matter of course and the reformulated Cripps question. It is difficult to think of a case where an expectation that an experiment might well succeed is not implicit in the characterisation of steps as routine and to be tried as a matter of course. On the other hand, we think a test formulated in terms of worthwhile to try was firmly rejected by the High Court in Alphapharm (see also Pfizer [287] per French and Lindgren JJ). The fact (if it be the fact) that the position in the United States may have shifted does not affect the binding nature of what the plurality said in Alphapharm. 351 After considering the circumstances of this case, I will return to consider the parties' respective submissions as to the effect of the High Court's decision in AstraZeneca High Court. 352 Before leaving the principles relevant to obviousness or lack of inventive step, it should be noted that in AB Hässle v Alphapharm, the plurality (at [58]) said that the tracing of a course of action which was complex and detailed, as well as laborious, "with a good deal of trial and error, with dead ends and the retracing of steps" is not the taking of routine steps to which the hypothetical formulator was taken as a matter of course.

Analysis 353 It is convenient to arrange my analysis of the issues around particular topics. However, I bear in mind throughout the analysis that the relevant question - whether the development team would, as a matter of course, be directly led to try tadalafil at the claimed doses with an expectation of success - relates to the whole process of drug discovery and drug development.

The general submissions of the parties 354 Apotex submitted that from Daugan 1997, the development team would identify Compounds A and B as the most promising candidates for drug development. In due course, Compound A would be identified as the preferred candidate. Apotex submitted that, in any event, two compounds may be obvious. After the selection of the appropriate compound, the drug development process would be carried out in accordance with a well-understood and well-established series of steps which would include a dose-escalation or dose-ranging study. The development team would, as counsel for Apotex put it, "do the tests". The development team would, in the course of pre-clinical tests and clinical trials, formulate hypotheses, carry out experiments, learn from the results and then move forward. This would be done as issues arose. Apotex submitted that this is no more than the normal scientific method and that the pharmacologists who gave evidence in this case agreed with that proposition. 355 The well-understood and well-established steps, including a dose-escalation or dose-ranging study, were no more than routine steps. The dose-escalation or dose-ranging study would identify the doses which are the subject of the claims in the 946 Patent. The studies referred to in Example 7 of the 946 Patent are no more than standard dose-ranging studies carried out as part of Phase II clinical trials. The results are of tests involving 2 mg, 5 mg, 10 mg, 25 mg, 50 mg and 100 mg doses of tadalafil. Apotex submitted that the evidence in this case established that the development team would balance efficacy and side effects and conclude that there was little point in pursuing doses of 50 mg and 100 mg respectively. 356 Although the pharmacologists were agreed that they could not select or predict doses for use in human clinical trials based on the information in Daugan 1997 because of a lack of information about the pharmaceutical, pharmacokinetic, pharmacodynamic, safety, efficacy and tolerability characteristics of tadalafil, Apotex submitted that this was not fatal to its obviousness or lack of inventive step case because the tests, experiments and trials leading to the invention and, in particular, the doses claimed, are routine. 357 Finally, Apotex submitted that this case was similar to AstraZeneca in which both this Court and the High Court held that the low doses of rosuvastatin identified in the claims were obvious. 358 ICOS, on the other hand, submitted that Apotex, which bore the onus, had failed to establish that the claimed invention was obvious or lacked an inventive step. Apotex had not established that the development team would, as a matter of course, be directly led with the required expectation of success to select Compound A for drug development. At best for Apotex, it had established that the development team would consider Compound A was worth a try. In any event, ICOS submitted that the development team would not, as a matter of course, be directly led with the required expectation of success, to the doses claimed in the 946 Patent. In elaborating on this submission, ICOS submitted that the steps to the claimed invention involved a number of "judgment calls" or steps which, if carried out, would be carried out in the hope of a successful, or at least useful result, rather than an expectation of a successful result. ICOS's reference to "judgment calls" was a reference to decisions which were "often complex, and involved trial and error about which reasonable minds might differ". I note at this point that Apotex made the general submission in relation to ICOS's repeated reference to "judgment calls" that it tended to obscure, rather than illuminate the statutory question involving the notional skilled team.

The information available to the development team 359 The matters to be addressed in this section are as follows: the information available by way of common general knowledge, including the desirable properties of a second generation drug for the treatment of ED, the properties of the first generation drug, sildenafil; and the information that is, and is not, contained in Daugan 1997. 360 I have already identified the common general knowledge which is relevant. 361 It is convenient to address, in more detail, the desirable properties of a second generation drug for the treatment of ED because that provides the context in which the development team operates. 362 As previously stated, the clinicians agreed that the desirable properties of a treatment for ED as at 30 April 1999 were oral administration, on-demand prior to sexual activity, rapid onset, effectiveness, minimal side effects, safety, tolerability and availability at a low cost. 363 With respect to the first matter, the experts gave evidence that there were also nasal, buccal and sublingual forms of administration and that these were desirable forms of treatment because they facilitated or could facilitate a fast onset of action. I have already referred to Dr Cherry's evidence that he advises his patients to manipulate their Viagra tablets into powder to hasten absorption of the drug. 364 As to dosage form, it was not obvious that tadalafil should be administered as a tablet, that is, in a solid oral dosage form, as distinct from sublingual, buccal or nasal, particularly in light of doubts or concerns about tadalafil's onset of action. These other forms of administration had the potential to increase the rate of onset of action. It is true the use of tablets is ubiquitous and that sildenafil, which was very successful, was provided in tablet form. Nevertheless, other forms of administration would be investigated because of the desire for a rapid onset of action. Each of the clinicians agreed that it would be reasonable to investigate sublingual, buccal and nasal administration as at 30 April 1999. 365 I note that Dr Reece's development brief instructed him to proceed on the basis that patients preferred oral treatments for ED. 366 The formulators also addressed this issue. It is fair to say that a very important consideration in the decision as to the appropriate dosage form would be the need to achieve a rapid onset of action. The dosage forms which would be considered for a rapid onset of action are the following: intravenous injection; nasal administration; oral buccal; oral sublingual; and a solid dose tablet or capsule. 367 Dr Mooney said that each dosage form had their own constraints, including development challenges, commercial manufacturing costs and patient compliance. He considered that the fact that the drug substance was poorly soluble presented another level of demand. Dr Mooney said that for an intravenous injection, it is necessary to identify a system that provides for a solution. The system is more costly to manufacture because it is sterile and is not patient friendly. From a commercial point of view, it would be considered to be a low likelihood option. Dr Mooney said that nasal administration would face the development challenge of delivering the appropriate quantity of a poorly soluble drug in solution. The finished goods costs would be compounded because it is a delivery device and the product needs to be made as sterile as possible. In the circumstances, there are significant downsides in this dosage form. In addition, dose may be limiting. Dr Mooney considered this a less favoured option. Dr Mooney said that oral buccal and oral sublingual provide potential advantages of rapid absorption. However, they are potentially affected if the drug substance has a bitter taste which would require some form of taste masking. That adds to the manufacturing costs. Furthermore, if a co-precipitate is required, this can lead to a much larger dosage form and that limits patient compliance. Dr Mooney considered that the most appropriate presentation would be a tablet or capsule formula. It would be an appropriate and market accepted product and achieve the required rapid onset of action. It would meet therapeutic needs. 368 Professor Polli said that without pre-clinical, that is animal data, and without human data, it is difficult to categorise the approach to develop a dosage form for a rapid onset of action. This was because major contributors are minimum effective concentration (MEC) and the ability of sufficient drug to be absorbed for MEC via the route of administration together with the need for the drug to be safe and effective in the patient population if MEC is achieved. It is preferable to have Phase II data about relations between dose versus plasma concentration versus drug action data. Professor Polli said that assuming blood plasma levels reach MEC, he expected earlier Tmax will result in an earlier onset of action, although it is not known if this would be of any practical importance. He said that he would consider nasal sprays over oral solid dosage forms if he was instructed to develop a dosage form that had the fastest possible onset of action. He said that he would also consider oral sublingual. 369 There was not a significant difference between Dr Mooney and Professor Polli as to dosage forms and the appropriate route of administration. Dr Mooney correctly identified challenges with various options, but as to whether the development team would consider options other than oral administration of tablets, I prefer the evidence of Professor Polli that other options would be considered. A decision as to the appropriate dosage form adds another layer of complexity to the testing and decision-making in the drug development process. 370 With respect to the second matter, Viagra was an on-demand form of treatment, that is, the medication is taken when the patient wishes to utilise it for the purposes of having sexual intercourse. It set the example or created the precedent. Chronic dosing, on the other hand, involved taking a drug one or more times a day with a view to (in the case of this drug) a constant inhibition of PDE5. The significance of this issue is that it relates to whether the development team would consider chronic dosing of tadalafil and, therefore, almost certainly lower doses as at 30 April 1999. Professor Brock said the team would not have done that and he said that, in fact, in the period of 1999-2000 he served on an Eli Lilly/ICOS advisory board which considered tadalafil's development and that the board was asked to consider chronic dosing. The advisory board advised against it. The reasons were first, that sildenafil was the paradigm and it was an on-demand form of treatment and secondly, that chronic dosing involved the risk of prolonged side effects in a patient population where the predominant group had sex between four to six times a month. Dr Cherry said that he attended a different advisory board meeting and that that board considered that chronic dosing was an option. However, it seems that that meeting and advice was after 30 April 1999 and the option was not taken up. In any event, the fact of the matter is that while on-demand doses of 10 mg and 20 mg respectively of tadalafil were launched in 2004, chronic dosing options of 2.5 mg and 5 mg respectively of tadalafil were not launched until 2008. Dr Reece suggested that the longer Tmax and biological half-life might lead to chronic dosing, that is, daily dosing or taking tadalafil in the morning in anticipation of sexual intercourse later that day. He did agree that in terms of patient preferences, he would defer to what the clinicians said about those preferences. 371 I accept the evidence of Professor Brock to the effect that the development team would not have pursued chronic administration or dosing as at 30 April 1999. First, sildenafil, which had been hugely successful, had set the paradigm as on-demand dosing. In addition, sildenafil's biological half-life of 3-5 hours meant that chronic or daily dosing was not considered realistic. Secondly, the drug was only required for sexual intercourse approximately once per week and, in those circumstances, the clinician is unlikely to consider daily dosing as appropriate. Thirdly, there was a risk of non-compliance and reduced efficacy in the case of a drug which is not being taken to treat a life-threatening condition. Fourthly, there was a risk of continuous adverse side effects associated with a continuous therapeutic benefit. Fifthly, there was the risk of tachyphylaxis, that is, a reduction in the benefit provided by the drug due to chronic administration. To overcome this problem by increasing the dose would give rise to the risk of increasing the side effects. Finally, daily dosing would have costs implications for individuals having sexual intercourse no more frequently than approximately once a week. 372 With respect to the third matter, it was common general knowledge as at 30 April 1999 that the median time for the onset of action of sildenafil was one hour. There would be little utility in developing a second generation drug for the treatment of ED which had a significantly longer period for the onset of action and improving the onset of action of a treatment for ED would have been considered by patients as an advantage. That was the evidence of Professor Brock which I accept. It is important to bear in mind in considering the significance of this factor, that desirable properties of a treatment for ED included other matters, such as minimal side effects, and it may be a matter of weighing improvements in some areas with no improvement in other areas. That is what the development team would do. 373 With respect to efficacy and side effects, the regulatory authorities, such as the FDA and TGA, often require a drug development company to establish a minimum clinically relevant dose for a drug. As I will discuss below, in the case of an API for the treatment of ED as at 30 April 1999, this task involved a number of complexities and difficulties. The clinicians agreed that the development team would have to devise studies for a diverse range of patients and it would have to assess efficacy on the basis of scores from questionnaires, such as the IIEF, and the tolerability of side effects from patient responses. As I explain below, there is an additional complication in that although information from a patient's partner is usually a good source of information, it is often difficult to obtain. Furthermore, even if a minimum clinically relevant dose is identified, it will not necessarily be included in Phase III Studies. Professor Evans said, and I accept, that the doses which will be selected for Phase III Studies will be those doses which provide the best balance between efficacy and side effects. Frequently, doses that are higher than the minimum clinically relevant dose meet that description. In this context, I refer to my earlier discussion concerning the nature of ED and its effects, dosing practices with respect to sildenafil and the importance of achieving early success. 374 Finally, with respect to tolerability, the clinicians described the concept as one where a side effect is present, but is acceptable to the patient, that is to say, the side effects are clinically insignificant. 375 Although tadalafil and sildenafil are in the same therapeutic class (i.e., they are both PDE5 inhibitors useful in the treatment of ED) they are not in the same chemical class. The chemical structure of the two compounds is quite different. I accept Professor Evans' evidence that because the two compounds are in different chemical classes, it would not be expected that they would have the same or similar pharmacokinetic properties. 376 Daugan 1997 provides no information as to the following matters: (1) The pharmacokinetic characteristics of Compound A (tadalafil); (2) The data which forms the basis of the claims as to selectivity; (3) The results of any tests in animals or humans; (4) Although the IC50 results for Compound A were described by Professor Polli as "promising", it is well-known that IC50 results can vary significantly, not only between different laboratories, but between tests in the same laboratory; (5) The preferred drug candidate and, in those circumstances, there must be a process of drug discovery as to the preferred drug candidate as well as drug development; and (6) Although it is true that the example pharmacy formulations involved 50 mg of active ingredient, the range of doses in the specification is so broad as to provide virtually no guidance as to the appropriate doses. 377 In addition, as I will make clear in my discussion in the context of obviousness and the 666 Patent, Daugan 1997 suggests that the compounds of the invention would be poorly soluble.

The choice of Compound A 378 The matters to be addressed in this section are the choice of Compound A and Compound B from the other compounds identified in Daugan 1997, whether two compounds can be obvious and whether Compound A would proceed to drug development. 379 It is convenient to recall that Daugan 1997 discloses Compounds A and B as the "specific compounds of the invention" and 13 suitable compounds are listed, including Compound A, but not Compound B. Furthermore, it discloses manufacturing methods for Compounds A and B, and Compounds A and B are identified as the active ingredients in the example pharmacy formulations. Finally, it discloses the results of potency tests for Compounds A and B which Professor Polli described as "promising". 380 Apotex pointed out that pre-clinical studies would be carried out in relation to Compounds A and B (at least) and these studies would provide the following information about these compounds: (1) their relative potency against PDE5 and relative selectivity in relation to other PDEs as compared with sildenafil; and (2) any difference in their pharmacokinetics (including the rate and extent of oral absorption, half-life and the extent of inter-individual variability) and safety or efficacy profiles as compared to sildenafil. 381 Apotex submitted that these studies are of a standard and conventional type and would be carried out as a matter of course. These pre-clinical studies are described by the pharmacologists in their joint experts report (i.e., the in vitro tests and animal studies). Matters which would be determined are tadalafil's long half-life and its greater selectivity and these would be seen as advantages for the reasons given by Dr Mitchell (longer therapeutic benefit and gentler side effect profile) and Professor Brock (half-life and selectivity constant therapeutic effect and favourable side effect profile). 382 Apotex submitted that although preliminary pre-clinical studies may be undertaken in relation to the other compounds identified in Daugan 1997, Compound A (tadalafil) would be selected as the preferred compound for the reasons which follow. 383 First, the fact of the matter is that ICOS pursued tadalafil to development and registration. There is force in this submission. 384 Secondly, the results of potency tests suggest that Compound A would be chosen. Daugan 1995 and GB 464 are referred to in Daugan 1997 and there is no dispute that the cross references mean that reference may be made to these documents. In Daugan 1995, the potency results of 11 compounds, including Compound A, but not Compound B, indicate that Compound A is the outstanding compound. Compound A is identified as the only "specific compound of the invention". Apotex submitted that the course of events (Daugan 1995 and GB 464 followed by Daugan 1997) suggest that Compound A was the primary candidate and then Compound B was identified as a compound of interest (or "back-up" compound) with the other compounds "having fallen away from consideration". I do not accept this argument. Compounds A and B are described as the specific compounds of the invention in Daugan 1997 and I see no reason the development team would treat Compound B as the back-up compound, having regard only to the information and statements in Daugan 1997 (and Daugan 1995 and GB 464). 385 The drug discovery process, which the pharmacologists agreed would be necessary for the purpose of selecting a candidate(s) for drug development, would include a range of in vitro and animal studies. Professor Evans said that he would not necessarily exclude from consideration compounds in Daugan 1995 and GB 464 with an IC50 value described as less than 10 nM because the inventors may not have conducted tests on these compounds to determine the precise value less than 10 nM. In any event, the potency of a drug is only one of its desirable features. At the same time as he made these observations, which I accept, Professor Evans said that "the development team would be more interested in investigating Compounds A and B (including their physiologically acceptable salts and solvates)". More particularly, he put the matter thus in his first affidavit: I understand Compounds A and B, and their salts and solvates, to be identified in Daugan 1997 as the preferred compounds of the invention. As such, if I was asked whether or not I was able to recommend an API disclosed in Daugan 1997 for further study in clinical trials, I would be more interested in investigating Compounds A and B (including their physiologically acceptable salts and solvates) than any of the other compounds disclosed in Daugan 1997. 386 With respect to drug discovery, Professor Evans said, and I accept, that the tests to be carried out would provide data on a whole range of matters relevant to the selection of the API or APIs to be taken forward for clinical trials, including potency for PDE5 of each API; selectivity for other PDE enzymes and possibly other non-PDE enzymes; the results of pre-clinical animal studies demonstrating the relative adverse event profiles of each API; the physiochemical properties of the API; the pharmacokinetics observed in pre-clinical trials; the ease of manufacture of the APIs; the APIs' chemical and physical stability; the ease of formulation of each API and the results of any clinical studies conducted demonstrating the relative pharmacokinetics, efficacy and safety of the APIs. 387 With respect to potency, that is one, but only one, factor in the decision as to which API to take forward to drug development. Potency is primarily relevant to dose, and I accept the evidence of Professors Evans and Brock that there are other important factors such as selectivity which is relevant to side effects. There is also the consideration that even as to potency, there are difficulties in extrapolating predictions as to a drug's potency in the human body from results of in vitro tests. 388 With respect to selectivity for PDE5, this was important to the issue of side effects and could be tested in vitro to some extent. However, there were significant limitations on the extent to which it can be concluded that in vitro results will be reflected in humans. These limitations as at 30 April 1999 included the following: (1) One cannot be sure of side effects until a drug is tested in humans; (2) Not all of the PDEs were known at the Priority Date and not all PDEs or receptors could be tested in vitro; (3) There was an incomplete understanding of which PDEs caused which particular side effects. An example is the PDE or PDEs which cause facial flushing; (4) Related to (2), not all sites which might cause side effects or mechanisms which might cause side effects could be tested in vitro, not only because not all PDEs were known at the Priority Date, but also because tadalafil may affect other receptors or because it may be metabolites of tadalafil which cause side effects, or because of what was described as cross-talk and back regulation; and (5) Related to (3), selectivity for PDE5 did not mean an absence of side effects because there was no clear understanding as to which side effects were inherent in the inhibition of PDE5. 389 Finally, there are significant pharmacokinetic and physiochemical properties of tadalafil which might dissuade the development team from taking tadalafil forward into clinical trials, or at least, from having any expectation that it could be successfully developed as a useful treatment for ED. The pharmacokinetic properties are the drug's Tmax of a median time of 2 hours after dosing and a half-life of 17.5 hours. The physiochemical property is that tadalafil is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. As I have previously said, this might lead the development team away from tadalafil to one of the other compounds or to pursue a salt form of tadalafil. As ICOS pointed out, a salt form of tadalafil is not within the claims of the 946 Patent. 390 In Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634; (2015) 113 IPR 191, Yates J said (at [467]): The applicants submitted that the person skilled in the art would not choose aripiprazole over any other atypical antipsychotic, such as ziprasidone which was also disclosed in Serper. Relatedly, they said Professor McGorry's evidence was that Serper does not disclose that aripiprazole will be superior to other atypical antipsychotics in treating cognitive impairment in schizophrenia. These considerations are irrelevant to the question of whether the person skilled in the art would be directly led as a matter of course to try aripiprazole as a method of treatment. It does not matter that the person skilled in the art might be led by Serper to try other atypical antipsychotics as well. The only question is whether the person skilled in the art would be directly led as a matter of course to try aripiprazole.

Difficulties associated with the development of Compound A, both generally and as to the appropriate doses 391 In my opinion, although compounds other than Compounds A (tadalafil) and B may be the subject of pre-clinical trials, these two compounds would emerge as the preferred candidates. I note that two compounds may be obvious. It is important to note, as general contextual matters in considering decisions to carry out pre-clinical and clinical trials, the low incidence of drugs proceeding past pre-clinical trials and the even lower incidence of drugs proceeding all the way through clinical trials and the very substantial costs associated with such trials. Professor Evans gave evidence as to these matters. For every 11.8 APIs that enter pre-clinical trials, only one API receives regulatory approval. Clinical trials can involve costs in the hundreds of millions of dollars. The average or usual costs are identified by Professor Rang and Mr Vasella in their publication, Drug Discovery and Development: Technology in Transition (Chapter 18) (Annexure AME-16). 392 The matters to be addressed in this section are the general difficulties which would attend the drug development of Compound A and then particular matters that are relevant to the selection of the appropriate doses for Compound A. These matters overlap as an obstacle to the drug development of Compound A at all may also be a reason that the development team would have no expectation of success of its development at particular doses. 393 In the former category, I will address the results likely to be generated as to Tmax and half-life, and the likely effect of those results, formulation and dosage form issues to be addressed and the difficulties in assessing efficacy and side effects. 394 In the latter category, I address the uncontested evidence of the pharmacologists about the selection and prediction of doses, the relevance of the doses at which sildenafil is marketed and most commonly sold, the evidence about the studies identified in Example 7 in the 946 Patent, the lack of results about efficacy until Phase II clinical trials, and the difficulties in assessing efficacy and side effects in the case of particular doses. 395 ICOS submitted that Phase I Studies involving the administration of tadalafil to healthy volunteers would reveal (if these matters had not been already revealed by the animal studies) the following: (1) When formulated in accordance with ICOS's finalised commercial tablets, tadalafil has a Tmax of a median time of at least 2 hours and significant variability amongst individuals (0.5-12 hours). When formulated as a co-precipitate tadalafil has a Tmax of 3.5 hours; and (2) Tadalafil has a half-life of 17.5 hours compared to a half-life of sildenafil of 3 to 5 hours. 396 These matters would teach away from pursuing tadalafil further or at least from doing so with any expectation of success. 397 With respect to the onset of action, I am satisfied on the evidence of the following: (1) It was understood by those skilled in the field at the Priority Date that a desirable property of a treatment for ED was a rapid onset of action. (2) That Tmax is a reasonable indicator of the onset of action. Dr Reece agreed with this proposition and it is otherwise established by the evidence. (3) A new treatment for ED would need to have an onset of action that is at least similar to that of sildenafil. Although onset of action is not the only consideration, it is an important one. (4) The variability in the onset of action (0.5-12 hours) would also be of concern to the development team. (5) Although the development team would understand that the onset of action can occur at a different time to Tmax, it would be very difficult to discover this before preferred doses had been identified in Phase II Studies. The team could not measure that in Phase I Studies with healthy volunteers and it would be difficult to do it as part of Phase II Studies where the team has not yet determined the right dose. As Professor Brock said, it does not make sense that the team would want to discover the time of onset with an inferior dose. 398 With respect to the biological half-life of tadalafil, I am satisfied on the evidence of the following: (1) The biological half-life of tadalafil is 17.5 hours and it is not possible to change that. (2) The longer biological half-life could mean that side effects last longer or are worse in the circumstances where tadalafil accumulates in the body. 399 The formulation problems are identified in the context of my discussion concerning the 666 Patent. 400 As to dosage form, I have already expressed my conclusion in relation to that matter. 401 In terms of the difficulties in assessing efficacy and side effects, it is convenient to discuss those matters in detail in the context of my discussion concerning the selection of doses. 402 The pharmacologists were agreed that Daugan 1997 provides no information on whether Compounds A or B or any other compound referred to therein has the properties to make it suitable for drug development and that the first step would be to select a preferred candidate. As I have already said, this would require a process of drug discovery prior to drug development. In the context of their approach to drug development in light of Daugan 1997, the pharmacologists were also agreed that, in the absence of data, they would not be able to select or predict dosages for use in human clinical trials. The data to which they referred included data concerning pharmaceutical, pharmacokinetic and pharmacodynamic properties and matters concerning safety, efficacy and tolerability. The pharmacologists further agreed that in the absence of such data, they would not hold any expectation that any of the compounds identified in Daugan 1997 would be associated with a lower incidence or severity of side effects, compared with sildenafil. Finally, and significantly, the pharmacologists agreed that, in light of their opinions about drug discovery, drug development and Daugan 1997, they would not hold any expectation that unit doses incorporating between 1 - 20 mg (up to a maximum daily dose of 20 mg) could be developed into a dosage form for treating ED. In other words, it is not in dispute that the development team starts the process without any expectation as to the appropriate doses. 403 ICOS submitted that the development team would regard the prospects of tadalafil being developed into a treatment for ED at any dose to be low and in the order of 5% or less based on the common general knowledge and Daugan 1997. 404 It seems to me that the dosing practice in relation to sildenafil and the reasons therefore suggest that the development team would lean towards testing higher doses of tadalafil. 405 Professor Brock gave some important evidence about the "judgment call" (as he described it) which he would have made about the dose carried forward into Phase III Studies and those studies designed to form the basis for a grant of marketing approval, had he had available to him, the results of the studies outlined in Example 7 of the 946 Patent. He said that, in those circumstances, he would have recommended studies involving a 25 mg dose as representing the best balance between efficacy and side effects. In other words, if he had been presented with the results of the efficacy of tadalafil and its side effects as set out in Example 7, he would have recommended carrying forward for testing purposes a dose of 25 mg, not 10 mg or 5 mg which together with 2 mg, 50 mg and 100 mg were the other doses tested. Putting the matter somewhat broadly, Professor Brock's opinion is based on a number of matters, including the significance he places on the need for the drug to be effective and the relatively significant improvement in efficacy between a 10 mg dose on the one hand, and a 25 mg dose on the other, compared with the increase in side effects and the relatively small improvement in efficacy between a 25 mg dose on the one hand, and a 50 mg dose on the other, compared with the increase in side effects. ICOS's point is not that Professor Brock's opinion is necessarily correct, but that it is a bona fide reasonable opinion that could be held by members of the development team. ICOS submitted that if that is correct, then testing at the doses claimed in the 946 Patent was not a routine step. As Professor Brock put it: [T]he clinician's recommendation will depend to a great extent on whether the clinician's personal view as to whether it more is important [sic] to achieve a high degree of efficacy or keep side effects to a minimum, and reasonable minds may well differ on this point. 406 I should say that Professor Brock was careful to acknowledge the limitations in the data in Example 7 upon which he based his opinion. First, the results in Example 7 of the 946 Patent do not identify the duration and severity of the side effects and that is a relevant consideration. Secondly, the tests did not include 15 mg or 20 mg doses and Professor Brock said that there was not enough data disclosed in the 946 Patent for him to make a recommendation with respect to excluding a 15 mg or 20 mg dose in the study. 407 ICOS makes a further significant point in connection with pre-clinical studies. Unlike many other drugs, there are no predictive animal models for ED. Professor Brock gave evidence to this effect and I accept his evidence. He explained the reasons why this is the case. First, at the Priority Date, there were no animal models which accurately simulated "the organic aspect of erectile dysfunction" or what Professor Brock described as the psychogenic aspects of ED. Secondly, the means by which an animal can be sexually stimulated for the purposes of pre-clinical tests differ very substantially from sexual stimulation in human males. Thirdly, the means by which the efficacy of a drug can be tested differs very substantially in the case of animals from the means by which it can be tested in humans. Intracavernous pressure is measured in the case of animals which Professor Brock described as an indirect surrogate for penile rigidity and penile rigidity is not the determinative factor in an improvement in the ability to have sexual intercourse. In humans, the most widely used efficacy tools at the Priority Date were subjective questionnaires, most notably the IIEF. 408 ICOS submitted that the absence of animal models which are predictive of efficacy has two consequences. First, the development team will need to decide whether or not to advance a particular API to clinical trials in the absence of important information, being the information obtained from predictive animal efficacy models. The absence of such information makes the decision whether or not to proceed more difficult, and one requiring a judgment. Secondly, animal models for ED could not be used for the purpose of (as Professor Brock said) "developing a target plasma concentration or range of doses for Phase II clinical trials investigating a new erectile dysfunction drug". 409 I accept these two submissions made by ICOS, but, like many points made in the context of inventive step and the 946 Patent, they are either not decisive or require some qualification. 410 Apotex accepted that predictive animal models for efficacy were not available in the case of drugs for the treatment of ED. However, it made the following points, all of which are correct. Animal studies for safety and toxicology purposes remained a routine part of the drug development process. The absence of predictive animal models for efficacy was not without precedent and, as an example, Dr Reece gave evidence of his work with developing drug treatments for central nervous system diseases, such as Alzheimer's disease. Furthermore, Professor Evans did not regard the absence of predictive animal models as a matter which would prevent a drug development team from proceeding with clinical trials. 411 ICOS submitted, correctly in my view, that the development team would have no indication following Phase I Studies as to whether any of the doses administered were useful in the treatment of ED because efficacy is not measured in Phase I Studies. 412 ICOS submitted, again correctly in my view, that at the commencement of Phase II Studies, there will be no real data available to the development team which would enable the development team to select particular doses to test during the Phase II Studies. The results of the in vitro potency tests (IC50 values) will not assist the development team to do so. That was the evidence of Professors Evans and Brock which I accept. Furthermore, there were no predictive animal efficacy models for ED which would assist the development team to select doses for Phase II trials with any degree of confidence. This means that there is a greater degree of judgment in selecting doses for Phase II Studies and a greater likelihood of error and the retracing of steps. 413 ICOS's general submission concerning the doses which would be selected by the development team for Phase II Studies is that the evidence shows there is so much uncertainty and subjectivity about assessing the efficacy of the drug to be developed for the treatment of ED, its side effects and the appropriate balance between efficacy and side effects that it cannot be concluded that the development team would be led to the invention as a matter of course or, at least, it cannot be concluded that any particular dose would be chosen by the development team with the necessary expectation of success. The difficulties in measuring efficacy were also the difficulties in measuring what would be correctly described as a clinically meaningful improvement. Ultimately, I accept that submission. The matters said to support the submission are as follows. 414 As at 30 April 1999, there was no single tool for measuring the efficacy of a drug to be used in treating ED and a variety of tools were used and would be used. In the case of sildenafil, efficacy was measured using the IIEF, a patient log and a global-efficacy question. 415 The IIEF contains 15 questions. The two most important are questions 3 and 4. Question 3 asks by reference to six possible replies, how often the patient is able to penetrate (enter) his partner when attempting sexual intercourse, and question 4 asks, again by reference to six possible replies, how often during sexual intercourse the patient is able to maintain his erection after he has penetrated (entered) his partner. The most favourable reply in terms of efficacy is "Always or Nearly Always". Apotex submitted that ICOS has exaggerated the difficulties associated with the use of the IIEF. In my opinion, the evidence establishes that at the Priority Date, the IIEF was at least one of the best available tools to measure the efficacy of ED treatments during clinical trials. 416 Another measurement tool is the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). This is a questionnaire consisting of two parts, one to be completed by the patient and the other to be completed by the patient's partner. The questionnaire was described in the evidence as a Pfizer initiative which was first published in April 1999. Professor Brock's evidence, which I accept, is that it would have been found by a clinician conducting clinical trials. Although the IIEF has since been shown to be the superior questionnaire in terms of reliability, that was not known as at 30 April 1999. ICOS submitted that as at 30 April 1999, the question of which questionnaire to use or place the greater weight on was another matter in respect of which the development team would be required to make a "judgment call". 417 A third measurement tool is Sexual Encounter Profile Diaries. The diaries contain the patient's answers to questions formulated by the drug development company. A difficulty with the reliability of this measurement tool is that some patients complete them shortly after the sexual encounter as contemplated, while others complete them shortly before handing them to the clinician and at a time when their memory of events is not fresh. 418 A fourth measurement tool is questionnaires answered by the partners of patient. These are, if completed and provided, a valuable source of information. However, as Professor Brock put it, the amount of partner data was a small fraction of the actual number of participants as it was difficult to convince the partners to complete the forms. 419 Finally, there was a measurement tool known as the Global Assessment Question (GAQ). This was a single question to be answered "yes" or "no" four weeks after the administration of the drug and which asked whether the drug had improved their erections. 420 There are significant limitations on the ability of the measurement tools in measuring the efficacy of a drug designed to treat ED. They were clearly identified in the evidence and I need to do no more than summarise them. 421 First, the answers, unlike other measurement tools which measure an objective fact such as the amount of cholesterol in the blood, are based on the subjective responses of the patient. 422 Secondly, some of the questions purport to measure matters which are affected not only by the efficacy of an erection, but also by other matters which are not measured. An example are those questions directed to the patient's ability to engage in sexual intercourse. In addition, the answers may also be affected by the characteristics and physiology of the patient's partner. 423 Thirdly, some of the questions require the patient to recall events over a period of four weeks. Unless the patient is a careful and diligent recorder of events, there is the distinct prospect of reconstruction and inaccurate answers. 424 Fourthly, the scores of a questionnaire like the IIEF may be affected by matters other than the therapeutic effects of the drug such as the patient's mental state and his relationship with his partner, including the partner's state of arousal. 425 Fifthly, organic or other factors unrelated to the therapeutic effects of the drug may affect the patient's answers. The matters identified in the evidence were neurological conditions, vascular conditions, curvature of the penis, premature ejaculation and age. 426 Sixthly, and this is partly reflected in the previous matters, the answers will not reflect the differences in the experience of a patient, the patient's expectations and those of his partner. 427 Finally, the IIEF is not a primary measurement tool. The document itself contains the following statement: IIEF assessment is limited by the superficial assessment of psychosexual background and the very limited assessment of partner relationship, both important factors in the presentation of male sexual dysfunction. Analysis of the questionnaire should, therefore, be viewed as an adjunct to, rather than a substitute for, a detailed sexual history and examination. 428 None of the measurement tools I have identified define what is a clinically meaningful improvement for the purposes of determining the minimum clinically relevant dose. This was not done in the case of the IIEF until 2011. The development team as at 30 April 1999 would need to make a judgment about this matter in the sense that there would be no one answer to this issue. It was not known as at 30 April 1999 whether the improvement in terms of an increased score was clinically meaningful depending on the base from which the improvement was calculated, for example, a severe case as compared with a moderate case. 429 The nature of the measurement tools and their shortcomings as set out above were clearly identified on the evidence. Nevertheless, there were matters to be said on the other side. Apotex identified them. 430 First, the inventors of the claims in the 946 Patent themselves used the IIEF. Secondly, the clinicians were agreed that the IIEF questionnaire was the best available technique for measuring efficacy for ED in clinical trials as at 30 April 1999. Professor Brock regarded it as the "gold standard" as at 30 April 1999. Thirdly, in a paper co-authored by Dr McMahon and Professor Brock in 2000, they had no difficulty in using the IIEF questionnaire and other standard tools for measuring efficacy to reach conclusions about the efficacy of tadalafil at doses of 2.5 mg, 5 mg, 10 mg and 20 mg. Finally, as Apotex submitted, subjective measurement tools are used by drug development companies in a number of areas, including pain relief, depression and chronic fatigue syndrome. It referred to Apotex Pty Ltd v Warner-Lambert Company LLC (No 2) [2016] FCA 1238; (2016) 122 IPR 17 (Apotex v Warner-Lambert). 431 Significantly, the clinicians agreed that interpreting the results of a questionnaire such as the IIEF was not a matter of routine and called for the exercise of judgment. Judgment calls have to be made as to "what scores for which questions indicate efficacy or non-efficacy in a clinical trial". This was powerfully illustrated by an example given by Professor Brock. As I have previously stated, it was a matter of common general knowledge at the Priority Date that a 100 mg dose of Viagra provided better therapeutic efficacy than a 50 mg dose. In the study involving sildenafil referred to in Goldstein et al (1998), 100 mg doses of sildenafil elicited a better response to question 3 in the IIEF than 50 mg doses, whereas 50 mg doses elicited a better response to question 4 than 100 mg doses. 432 I find that significant judgment is also required in selecting those doses to be tested in Phase III Studies or for the purpose of seeking marketing approval, bearing in mind the need to balance efficacy and side effects. I have already mentioned the relevant factors bar one. A matter where judgment must be exercised is the proportion of patients (and in the case of an individual patient the number of times) where there needs to be a clinically meaningful improvement and, in the case of side effects, the proportion of patients that "need" to tolerate side effects. No doubt these are matters that must be addressed in the case of clinical trials of a number of drugs. The point is that the nature of the condition and the limitations on the tools available to measure any change means that the extent of judgment required is likely to be particularly significant. 433 Furthermore, judgment also has to be exercised in assessing the extent to which patients suffering from ED are likely to tolerate side effects. The severity of side effects may vary and the extent to which patients are prepared to tolerate the side effects is likely to vary. The latter will include the importance a particular patient places on the treatment of his condition. It is not a life-threatening condition and I accept that there is likely to be a considerable variation between patients as to the importance they place on being able to engage successfully in sexual intercourse and, therefore, the extent to which they are prepared to tolerate side effects. Determining the level of side effects and the extent to which they are likely to be tolerated is not a matter of routine.

Other important matters 434 The matters to be addressed in this section are Dr Reece's assumptions, matters not pursued by Apotex and the relevance to this case of the High Court's decision in AstraZeneca. 435 Apotex submitted that, in truth, there was no dispute between Dr Reece and Professor Evans about the former's assumptions. They were agreed as to the tests to be carried out. Furthermore, the development team conducts the tests and assumptions are not made about any features of similarity (and in the case of the last matter, greater selectivity in tadalafil) between tadalafil and sildenafil (i.e., pharmacokinetics, unbound fractions in blood plasma, the pharmacokinetic and pharmacodynamic properties of metabolites of the two drugs, potency for PDE enzymes other than PDE1-4 and PDE6 and non-PDE active sites and selectivity for PDE5 and PDE1-4 and PDE6). Having regard to the Cialis PI Statement, assumptions about similarities would have been incorrect. Apotex submitted that Dr Reece's assumptions were made for the purpose of illustrating the process involved and what might flow from the results of the experiments. He did not assume that the matters he identified would be the actual results of the experiments and he said that the experiments would need to be carried out. 436 ICOS submitted that certain opinions expressed by Dr Reece about the doses which would be selected for testing should be rejected because the assumptions upon which they were based were not established. Although I do not think that Apotex relied on this aspect of Dr Reece's opinions in its final submissions, I will address the issue so that there is no uncertainty. 437 The background to the issue is as follows. Dr Reece was given a development brief by Herbert Smith Freehills (HSF) (Apotex's solicitors) and he was asked to address the matters raised by the brief in his affidavit. The development brief set out matters known about ED at the Priority Date for the 946 Patent and considerations which were relevant to patients who sought treatment for ED. Dr Reece was asked to put himself in the position at the Priority Date of a person involved in pharmaceutical drug development in "a commercial setting" and asked to develop a drug treatment for ED that addressed the patient's considerations identified in the brief. He was asked to give his opinion as to what he would have done. 438 Dr Reece's opinion in response to the development brief involved the identification of a number of steps which he would have taken. The early steps which he identifies are not the subject of controversy and it is sufficient to summarise them. 439 First, Dr Reece identifies the searches he would have undertaken or caused to be undertaken and the likely results of those searches, including the discovery of Daugan 1997. As I have said, it is not in dispute that Daugan 1997 is part of the prior art base and falls within the terms of s 7(3) of the Act. In addition, ICOS accepts that Daugan 1997 refers to Daugan 1995 and GB 464 and that it is open to Apotex to rely on these publications as well. 440 Secondly, Dr Reece conducts a review of Daugan 1997 and sets out his opinions as to certain matters. Significantly, he sets out the matters he would seek to ascertain about Compounds A and B as part of pre-clinical studies and ultimately as part of Phase I and Phase II Studies. Those matters include the comparative potency, selectivity and half-life of Compounds A and B on the one hand, and sildenafil on the other. 441 Thirdly, Dr Reece conducts a review of Daugan 1995 and GB 464 respectively and sets out his opinion as to certain matters. I do not need to summarise those matters. 442 Fourthly, Dr Reece states that, as part of his approach, he would seek to obtain such information about Viagra (sildenafil) as was publicly available and that that approach would lead him to obtain the 1999 Viagra PI Statement. Dr Reece outlines the information which he would have gleaned from the 1999 Viagra PI Statement. Significantly, he states that he would have discovered the empirical formula for sildenafil citrate and its molecular weight. 443 At this point, Dr Reece states that HSF provided him with specific information about the matters he said that he would seek to establish as part of pre-clinical trials and ultimately in Phase I and Phase II Studies. The information which HSF provided to Dr Reece included the following: (1) that the IC50 values for sildenafil against PDE5 had been reported as 3 nM and as 3.9 nM; (2) that Compound A is ˃10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE3 and PDE4; (3) that Compound A is approximately 700-fold more potent for PDE5 than for PDE6; and (4) that the mean half-life of Compound A is 17.5 hours in healthy subjects. 444 The above information and two further assumptions led Dr Reece to draw certain conclusions about tadalafil's greater potency, selectivity and half-life such that he would have recommended to the development team that tadalafil be taken forward into clinical trials. The two further assumptions were that tadalafil was shown in pre-clinical trials to be safe and that pre-clinical trials did not show that Compound B was a safer and more efficacious drug than Compound A. 445 Dr Reece was then asked to identify how the information he was given might affect the design of trials in the Phase I and Phase II Studies and, in particular, the design in relation to doses, dosage regimens and dosage forms. In response, Dr Reece makes it clear that he is not able to answer the question definitively because ultimately the answer will depend on the results of pre-clinical trials and, in the case of Phase II Studies, the results of the Phase I Studies. Nevertheless, Dr Reece states that the marketed doses of sildenafil and the relative potency of tadalafil compared with sildenafil gave him an indication of the range of doses at which he "expected efficacy would be observed for compound A". As tadalafil is twice as potent as sildenafil, Dr Reece reasoned that efficacy would be observed at approximately half the doses for sildenafil, that is, at 12.5 mg (which he reduces to 10 mg because round numbers are easier to work with in the context of drug development), 25 mg and 50 mg. Dr Reece said that he expected, based on Compound A's greater potency and selectivity for PDE5, that tadalafil would produce fewer side effects than sildenafil, at least in terms of vision abnormalities. 446 Dr Reece also gave evidence of the various dosing regimens he would examine. I do not need to set out the details. 447 ICOS submitted that Dr Reece's conclusions as to the likely potency of tadalafil as against sildenafil were based on a comparison of IC50 values and that this is not a legitimate process of reasoning because of the following: (1) different assays cannot be compared without using a standard to account for the differences between assays. I can indicate at this point that I accept the evidence of Professor Evans to this effect; (2) there was significant variability in IC50 values for tadalafil reported in the literature; (3) there was significant variability in IC50 values for sildenafil reported in the literature; and (4) there was no information about the assay conditions under which the relevant IC50 values for tadalafil and sildenafil were obtained. 448 In expressing his views, Dr Reece assumed that the pharmacokinetic properties of tadalafil and sildenafil were the same. That was, ICOS submitted, an unreasonable assumption to make at the Priority Date. No weight can be placed on the fact that tadalafil and sildenafil are part of the same therapeutic class. The position might be different if they were part of the same chemical class, but they are not. Furthermore, the assumption that tadalafil and sildenafil have similar pharmacokinetic properties is, in fact, incorrect. 449 ICOS also submitted that Dr Reece's expectation that tadalafil was likely to produce few side effects that sildenafil at least in terms of vision abnormalities was without foundation. Finally, ICOS pointed to the fact that Dr Reece agreed in cross-examination that his estimates as to dose were not confident estimates. 450 In reply, Apotex submitted that ICOS's continued attack on Dr Reece's assumptions misstates Apotex's case. It does not rely on an expected dosage of 10 mg or on the pharmacokinetic data in the Viagra PI Statement. Apotex relies on what has been agreed by the pharmacologists, namely, the drug development process. There are no assumptions in relation to that process. 451 The common general knowledge as at 30 April 1999 did not include information concerning the molar mass of sildenafil, the pharmacokinetic properties of sildenafil, that is, those features of a drug which relate to its absorption, distribution, metabolism and excretion, and the selectivity data for sildenafil with respect to PDEs1-4 and PDE6. I place no reliance on Dr Reece's opinion insofar as it is based on matters which were not common general knowledge at the Priority Date. As I have said, and in fairness to Dr Reece, he made it clear that his opinions were subject to the results of clinical tests. 452 There was a dispute between Dr Reece and Professor Brock about whether the development team would carry out a direct comparison study between tadalafil and sildenafil. I will address this dispute for the sake of completeness, even though by the end of the case, Apotex had abandoned reliance on this aspect of Dr Reece's opinion. 453 Dr Reece said in response to his development brief that he would recommend a direct comparison study between tadalafil and sildenafil as part of Phase II Studies for tadalafil and that the results of that study would "provide an indication of the doses of tadalafil that 'provide the best balance between efficacy and side effects' (to use Professor Brock's words), including based on what doses of tadalafil provide a similar or improved level of efficacy and/or fewer adverse events as compared to the marketed doses of sildenafil". This was said to support the conclusion that the doses which are the subject of the claims in the 946 Patent would have been the subject of testing in the Phase II Studies. 454 Professor Brock on the other hand, expressed the opinion that a direct comparison study between tadalafil and sildenafil would not be carried out as part of Phase II Studies. He said that if such a study was carried out, it would occur after appropriate doses of tadalafil had been selected and would be part of Phase III or Phase IV Studies and designed to determine whether the new drug is commercially viable or patient preference. 455 Professor Brock gave three reasons for his opinion. First, he identified the substantial costs involved in a direct comparison study as part of Phase II Studies. In this case, the Phase II Studies would be carried out to determine whether tadalafil was effective and to identify the doses which best balanced safety and efficacy. The development team would select the appropriate dose or doses first, otherwise any direct comparison study could well prove a waste of time. The alternative would involve the cost of testing a whole range of doses. Furthermore, the comparison would be a complex task, having regard to the subjectivity involved in the measurement tools and the possibility of different types of side effects. Secondly, he identified the difficulties involved in a direct comparison study where the drugs have different pharmacokinetic properties producing different results (e.g., time of onset of action, post-administration efficacy, whether the drug can be taken with food). Finally, Professor Brock was not aware of any direct comparison studies of tadalafil and sildenafil carried out as part of Phase II Studies. In my opinion, Professor Brock's first two reasons are sound and I consider it unlikely the development team would carry out a direct comparison study between tadalafil and sildenafil as part of Phase II Studies or before the doses to be carried forward had been selected. 456 Apotex submitted that the facts of this case are similar to those in the AstraZeneca litigation and that this Court should follow the same approach as that taken by the High Court in that litigation which leads to the conclusion that the claimed invention was obvious. The passages in the High Court judgment upon which Apotex relies are set out above (at [342]-[345]). 457 ICOS submitted that AstraZeneca is distinguishable in terms of whether at the Priority Date the development team would be directly led to the invention, that is, the ability of the development team to select tadalafil in the claimed dose range before conducting any experiments and the expectation of success, that is, the confidence that the development team would have had at the Priority Date, based on the common general knowledge and the prior art, that tadalafil would be useful for treating ED. 458 First, ICOS submitted that in AstraZeneca, the prior art (i.e., the 471 Patent and Watanabe) disclosed animal data involving rosuvastatin and comparative compounds which would give the development team a reasonable expectation that rosuvastatin would be useful in the treatment of hypercholesterolemia. By contrast, the development team in this case would have no expectation from reading Daugan 1997 that tadalafil would be useful in the treatment of ED in view of the absence of any data comparing the potency of tadalafil with sildenafil and the absence of animal data, even assuming for present purposes that there are predictive animal models for the treatment of ED. 459 Secondly, ICOS submitted that Daugan 1997 discloses Compound A (tadalafil), Compound B and 12 other "suitable compounds", but the development team could not choose between them without undertaking a process drug discovery, pre-clinical and clinical development. By contrast, the prior art in AstraZeneca clearly revealed rosuvastatin as the preferred compound. 460 Thirdly, ICOS submitted that statins as a class of drugs were well-established and well-known at the relevant priority date. They had "known side effects" and had "a known dose-efficacy-side effect relationship". The prior art showed that rosuvastatin was a potent drug for reducing cholesterol. ICOS submitted that statins were a chemical class and predictions could be made safely about the safety and efficacy of rosuvastatin. By contrast in this case, only one PDE5 inhibitor (sildenafil) had been marketed before the relevant priority date and it was not in the same chemical class as tadalafil. 461 Fourthly, ICOS submitted that the standard practice in treating hypercholesterolemia at the relevant priority date was to start with a low dose to avoid side effects and to titrate to higher doses if the desired improvement in the condition was not observed at the lower doses. ICOS submitted that this dosing practice was developed in response to the known relationship between dose and efficacy as it existed for all statins. In the case of rosuvastatin, the development team could select a starting dose of 5 or 10 mg based on the prior art and the common general knowledge and without conducting any experiments. ICOS submitted that by contrast, in the present case, nothing in the common general knowledge and relevant prior art information allows the development team to select any doses for tadalafil. Tadalafil's different chemical structure to the chemical structure of sildenafil means that sildenafil's properties do not provide a useful guide in terms of the appropriate doses of tadalafil. 462 Fifthly, ICOS submitted that insofar as the dosing practice with respect to existing APIs is relevant, the practice with respect to sildenafil teaches away from investigating low doses. The practice with respect to sildenafil was to administer the highest dose and titrate down to lower doses in those cases where the side effects caused by the highest dose were unacceptable. 463 Finally, ICOS submitted that in AstraZeneca, the experts were able to predict starting doses for rosuvastatin or doses to be used in the hypothetical Phase II Studies whether by reference to common general knowledge or the relevant prior art information. By contrast, the experts in this case were agreed that in the absence of data (including data concerning pharmaceutical, pharmacokinetic, pharmacodynamic, safety, efficacy and tolerability features or properties) they would not be able to select or predict dosages for use in human clinical trials. 464 I do not accept that the High Court in AstraZeneca did not apply the reformulated Cripps question in favour of the test Apotex advances in this case, or that there are strong similarities between the facts in AstraZeneca, where a lack of an inventive step was found, and the facts in this case. Both French CJ and Kiefel J referred to the reformulated Cripps question (at [15] and [67] respectively and see also at [97] per Gageler and Keane JJ, and at [118] per Nettle J). With respect to the facts, unlike this case, there were a number of existing statins which were administered at around the doses claimed (at [28] per French CJ) and there was a practice of starting at low doses and titrating up depending on the patient's response (at [28] per French CJ; at [50] and [95] per Kiefel J).

Conclusion 465 Although I am satisfied that the development team would, as a matter of course, be directly led to try tadalafil with the required expectation of success, I am not satisfied that the team would, as a matter of course, be directly led to the claimed doses with an expectation of success. Certainly at the start of the drug development process, there would be no expectation as to the dose or range of doses. That is not in issue and was the uncontested evidence of the pharmacologists. The nature of the condition, the nature of measurement tools available and the limits on the information available lead me to conclude that a dose ranging study at the claimed doses would not be undertaken as a matter of course and, even if a decision was made to carry out a study at the claimed doses, it would not be a decision made with the required expectation of success. 466 Apotex's inventive step challenge to the claims in suit in the 946 Patent must be rejected.

Daugan 1997 467 The teachings of Daugan 1997 are set out above (at [308]-[333]).

Relevant Principles 468 The relevant principles are set out above (at [334]-[352]).

Analysis 469 I begin with some general observations and a summary of the submissions of the parties. 470 The following points should be noted at the outset. First, a number of claims in the 666 Patent are combination claims. For example, claim 1 consists of three integers which interact to produce a new result. The integers are (1) tadalafil; (2) in free drug form; and (3) at least 90% of the particles of tadalafil have a particle size of less than about 40 microns. As the inventors of the 666 Patent state, the second integer interacts with the first integer to produce a more rapid absorption of tadalafil into the blood. The third integer interacts with the other two integers to improve the bioavailability of tadalafil by improving the rate and extent of its absorption (Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; (1961) 106 CLR 588 at 612 per Dixon CJ, Kitto and Windeyer JJ). It is well-established that a court must be alert not to apply hindsight to questions of obviousness and the dangers of misusing hindsight can be particularly acute in the case of combination claims where some or all of the integers are old (Minnesota Mining at 266; AB Hässle v Alphapharm at [6], [21] and [41]). Secondly, to the extent that the inventive pathway is described in the 666 Patent, the pathway included, in one of the studies, the use of tablets involving a co-precipitate made in accordance with Butler. Thirdly, the 666 Patent states that a typical daily dose of tadalafil is from about 1 to about 20 mg per day and preferred daily doses generally are about 1 to about 20 mg per day, particularly 5 mg, 10 mg and 20 mg tablets administered as needed. 471 Apotex submits that the fact that tadalafil did not suffer from solubility-limited absorption at doses in the range of 1 - 20 mg would be established early in the drug development process and that the problem which would be identified would be that tadalafil suffered from dissolution rate-limited absorption. I will refer later in these reasons to Dr Mooney's evidence about the tests he considers would be conducted and lead to these conclusions. Apotex submits that the most obvious solution to a problem involving dissolution rate-limited absorption was micronisation and that would be well-known to the development team. Apotex submits that micronisation would be the first approach, or at least one of the first approaches, to be adopted to resolve that problem at the Priority Date of the 666 Patent. Apotex submits that ICOS's contention that on the information in Daugan 1997, it was plausible that tadalafil might be 20 to 50 times less soluble than the "practically insoluble" threshold of 1:10,000 in the BP and USP would be quickly disproved by routine solubility and in vitro dissolution tests such as the test carried out by the inventors of the alleged invention in the 666 Patent and referred to in Example 1 of the patent. The results of that study showed a near-complete dissolution of a 10 mg dose in 1L of the dissolution medium. Apotex submits that the pharmacologists and the clinicians in the development team would, in accordance with well-established criteria for pre-clinical studies and clinical trials, select doses of 1-20 mg. There are no solubility-limited absorption problems with tadalafil at those doses and there is no reason to think that they would arise prior to the selection of those doses. 472 In order to better appreciate the significance of the evidence to which I will refer, it is helpful to note at this point the three major ways in which Apotex put its case. First, Apotex submits that Daugan 1997 teaches that the free base form of tadalafil is the preferable form of tadalafil and that means that the formulation of a salt or the making of a solid dispersion, which are two of the possible solutions to the solubility problem identified by Professor Polli, would be excluded from consideration. Secondly, Apotex submits that the principal possible solutions to the solubility problem identified by Professor Polli, namely, the formulation of a salt of tadalafil, the preparation of a different polymorph or an amorphous form, or the use of a solid dispersion, including co-precipitates, are unrealistic solutions which would be quickly dismissed by the development team. Thirdly, Apotex submits that irrespective of possible solubility-limited absorption problems with tadalafil, a rapid onset of action is a desirable feature of a drug for the treatment of ED. Micronisation can improve the dissolution rate and, therefore, the onset of action, and in the circumstances the development team would be led, as a matter of course, to try micronisation with the required expectation of success. 473 Apotex submits that if micronisation does not involve an inventive step, then the claims which involve pharmacokinetic parameters (i.e., claims 10-12, 18 and later claims which include those parameters) do not involve an inventive step because the pharmacokinetic features inevitably flow from micronisation. I do not need to consider this submission for reasons which will become clear. 474 ICOS made a general submission to the effect that Apotex's approach is flawed because the 1 - 20 mg doses to which Apotex referred are not part of the common general knowledge and they are not part of the teachings in Daugan 1997. The submission was that the formulation issues will be addressed before the doses, which are found to be safe and efficious following multiple clinical studies, have been conducted. The formulator must formulate the dosage forms for use in clinical trials, including Phase I and Phase II clinical trials. The dose escalation studies would include studies to determine the maximum tolerable dose. 475 ICOS submits that Daugan 1997 reveals a clear solubility problem which a development team would address as a priority. There were various possible solutions at the Priority Date, including the formation of a salt of tadalafil, different polymorphs and amorphous forms and solid dispersions, including co-precipitates. Micronisation is not a solution and would not be tried by the development team. Even if that be wrong, micronisation would not be tried with the required expectation of success. 476 ICOS also made particular submissions directed to particular classes of claims: ((1) Claims 7, 8 and 17 Method of Treatment and Swiss Style claims; (2) Claims 10-12 and 18 Pharmacokinetic parameter claims; and (3) Claims 24-38 Incorporating Dosage Regimen Integers). Again, I do not need to consider these submissions for reasons which will become clear. 477 I turn to address the expertise and experience of the formulators. 478 As far as the expert formulators are concerned, I formed a clear preference for the evidence of Professor Polli over that of Dr Mooney. Dr Mooney had a high level of expertise in the formulation of generic drugs and was doing his best to assist the Court. However, he had virtually no experience in the formulation of NCEs. There is an important difference between generic drugs and NCEs when considering "solubility" problems. In my opinion, the development team would include a formulator with knowledge and experience in the formulation of NCEs. If I may put it this way, Professor Polli meets that description. 479 Prior to August 1999, the vast majority of Dr Mooney's experience in the field of pharmaceutical formulation related to formulating generic versions of an existing drug. Dr Mooney said that he did not consider that the underlying scientific principles and product development principles associated with formulation changed because the drug substance is an NCE. He said that the main difference between a generic formulation and a formulation for an NCE is the volume of pre-existing information about the drug substance and the need, in the case of a generic formulation, for certain features to match those of the existing drug. Dr Mooney said that he would expect that in the case of an NCE less would be known about the drug substance, and as a result, some additional basic testing may need to be performed by either himself or others in the team to identify its basic physical and chemical properties. Dr Mooney said that in the defined period of time (i.e., 3 August 1999 - 1 August 2000), he was not familiar with solubility-limited absorption. He was asked to bring his own knowledge and experience to the development brief and that knowledge and experience was limited. Dr Mooney had only ever addressed "solubility" issues by reducing particle size and he had no experience (nor the need) to solve solubility issues by any other means. Dr Mooney agreed that a formulator of a generic pharmaceutical product already knows that the amount of the drug needed to produce the desired therapeutic effect can be absorbed. There may be dissolution rate-limited absorption problems to confront, but not solubility-limited absorption problems. 480 Put another way, Dr Mooney's experience was limited to the formulation of generic or copy drugs where absolute solubility problems do not arise. It is known from the original drug that the marketed doses will be absorbed. Dissolution rate problems did arise in the course of formulating generic drugs and Dr Mooney's first choice in terms of a solution, was micronisation. Dr Mooney used the term "solubility" to include both, what might be called, absolute solubility and dissolution rate. 481 Dr Mooney said that he would recognise at the outset of the formulation process that tadalafil had solubility problems. He said that he would conclude from Daugan 1997 that the free base form of tadalafil was the preferable form. He said that he would undertake two steps or tests involving micronisation. First, he would arrange for a sample of tadalafil at the lowest micron range to be prepared and tested in vitro. He would thereby discover (so he said) that the problem was dissolution rate, not absolute solubility. Secondly, Dr Mooney would then arrange for a study to be undertaken of the compound at different particle sizes to determine the best particle size, or range of sizes. This second study was referred to in the evidence as Dr Mooney's particle evaluation study. 482 Dr Mooney said that there were a number of options to improve solubility. First, particle size reduction could improve solubility. There would be no raw material chemistry change. However, the impact on stability with increased surface area and manufacturing would be addressed as part of the development. Secondly, solubility could be improved by the use of a different polymorph. The chemistry remains the same, but to find a suitable polymorph that is stable in the dosage form and complies with the c-GMP quality requirements would be time impacting. Thirdly, solubility could be improved by the use of solid dispersions. Dr Mooney said that this task requires identification of the appropriate polymer, establishing the active to polymer ratio, establishing that the level of polymer is appropriate from a permitted daily ingestion exposure level and then product development time. Additionally, with a high polymer to active ratio, this could lead to a very large dosage presentation, which may limit patient acceptance. Fourthly, solubility could be improved if the salt of tadalafil could be made. Dr Mooney said that this would involve an NCE. He said that significant time would be taken to develop and manufacture appropriate c-GMP material, then formulation commences. In those circumstances, there is an extensive time lag to human clinical trials. He said the synthesis to make the salt at the purity level required for clinical trials would take longer than micronising the existing material. He also said that new salts still require formulation development and have their own inherent issues. Fifthly, solubility could be improved by the use of pro-drugs. This involves an NCE which requires full NCE development and subsequent evaluation. Dr Mooney did not consider that pro-drugs would be considered as a means of improving the dissolution rate. 483 The difficulty with Dr Mooney's analysis is that micronisation does not improve solubility-limited absorption and the problem revealed by Daugan 1997, which would be apparent to the skilled formulator on the development team considering an NCE, was solubility-limited absorption. Dr Mooney's lack of experience with NCEs would have led to him adopting a dissolution rate-limited absorption problem (i.e., micronisation) to what appeared to be a solubility-limited absorption problem. It is now known that the problem with tadalafil at doses of 1 - 20 mg is a dissolution rate-limited absorption problem. 484 By contrast, Professor Polli had researched, taught and published the science relating to the task of formulating NCEs before the Priority Date. He had worked on between six and 12 projects involving the formulation of NCEs before the Priority Date and that work included formulating poorly soluble drugs and, in one case, overcoming a solubility-limited absorption problem by developing a more soluble polymorph. He has had experience working with poorly soluble NCEs since the Priority Date. He was an impressive witness. 485 Professor Polli said that the approach he would take if he was developing the first formulation of an API would be very different to the approach he would take if he was developing a generic version of a registered formulation of the API. He said that that was so because in the case of the first formulation of an API, he would not have a proven pharmacokinetic target to aim for. 486 Professor Polli said that solubility could not be improved by reducing the particle size of the API by micronising to the "low micron range". He said that he was not familiar with the practice of grinding an API to below 100 microns for pre-formulation testing and that, in his experience, it was not generally accepted by other pharmaceutical scientists before the relevant date (i.e., 3 August 1999 - 1 August 2000). In other words, he was not familiar with Dr Mooney's first step or test involving micronisation. He explained that IVIVC was not common for at least two reasons. First, particle size may not impact on in vivo pharmacokinetics, including situation when not expected. Secondly, clinical development resources are not often applied to investigate the in vivo effects of particle size. Clinical development resources typically prioritise the demonstration of safety and efficacy over investigating potential particle size effects. 487 I turn to state my key conclusions and the reasons I have reached those conclusions. 488 The key conclusions I have reached are as follows. It is of the utmost importance that the formulation of a compound is such as to achieve appropriate absorption at various doses. The evidence supports the conclusion that the formulation task would proceed by reference to doses of 25 mg, 50 mg and 100 mg, and the same formulation technique would be used for each of these doses. I accept Professor Polli's evidence that the skilled non-inventive formulator would detect from Daugan 1997 a solubility-limited absorption problem for which there were various possible solutions. Micronisation was not one of them. Having regard to the whole of the evidence, I accept that some of the solutions identified by Professor Polli were realistic solutions. 489 There is no dispute that the first and most important priority of a formulator faced with an NCE is to ensure absorption into the blood stream of a sufficient quantity of the drug to achieve the desired therapeutic effect. The formulators were agreed that for the purposes of a dose escalation study (or studies), the formulation strategy must ensure that higher doses involve greater absorption of the drug than the lower doses. Dr Mooney agreed that the formulators need to ensure that each dose which is tested is absorbed. Dr Mooney also agreed that the relationship between the size of the dose and measured solubility needed to be considered by the formulator as a matter of priority in developing the oral formulation because of the risk that the desired dose for therapeutic effect will not be absorbed. He also agreed that although dissolution rate was a relevant consideration, it was of no use addressing that issue if the dose for the desired therapeutic effect could not be absorbed. Professor Polli said that he would be concerned if the maximum absorbable dose was less than the dose required to achieve the desired therapeutic effect. He also said that solubility and whether poor solubility may result in the necessary dose being unable to be absorbed must be addressed first and foremost. 490 It is important to recognise that the formulator in the development team in this case would approach the formulation issues by reference to doses of 25 mg, 50 mg and 100 mg for the following reasons. First, a commonly used yardstick for appropriate doses is 1 mg for every kilogram of body weight and this was part of common general knowledge at the Priority Date. This yardstick leads to a 70 mg dose in the case of a normal adult male. Secondly, the example pharmacy formulations in Daugan 1997 used doses of 50 mg. Dr Mooney said that, in addition to doses of 50 mg, different doses would be required for the drug to be provided across the population and therefore, he expected that a dose higher and lower than 50 mg would also be developed. Thirdly, Dr Mooney's development brief contained an instruction that he prepare an immediate-release solid oral dosage form in unit doses of 25 mg, 50 mg and 100 mg for use in clinical trials in humans and Dr Mooney said that he could not detect anything in Daugan 1997 that suggested that that was not an appropriate instruction. 491 The related point to the doses the formulator would use is that it was not suggested that different formulation techniques would be applied to different doses. The same technique would be used whether the dose was 25 mg, 50 mg or 100 mg. 492 I accept ICOS's submission that Daugan 1997 raises a clear and pressing solubility-limited absorption problem at 50 mg and 100 mg doses. It suggests that there is a real risk that tadalafil is so poorly soluble that the amount of drug necessary to achieve a therapeutic effect or escalating doses in Phase I and Phase II trials will not be absorbed. Furthermore, the formulator working in the development team would recognise a likely solubility-limited absorption problem, having regard to common general knowledge and Daugan 1997. There is no dispute that Daugan 1997 indicates that tadalafil will be poorly water soluble, perhaps very poorly water soluble. The high melting point and materials used in the Example pharmacy formulations establish this matter. It follows that doses of 25 mg, 50 mg and 100 mg are likely to be very poorly water soluble, particularly if tadalafil is 20 times less soluble than the BP threshold point, or worse still, is 50 times less soluble. 493 A compound (solute) that is "practically insolvent" requires at least 10,000 parts of solvent for each part of the compound. An allowance of 10 times is made for the fact that part of the compound is absorbed over time and further dissolution then occurs. The volume of solvate in the gastrointestinal tract is 250 mL. This means that if a compound had a solubility that required more than 10 times the volume of gastrointestinal fluid, then permeation will not overcome the poor solubility and not all of the dose will be absorbed. Whether all of the dose is absorbed will depend on dose size. If a compound is at the threshold of 1:10,000, a 25 mg dose will dissolve in 250 mL of fluid. If it is significantly above the threshold, then solubility issues arise. The formulators agreed that it was plausible that the correct ratio in the case of tadalafil was 1:200,000 or even 1:500,000 and those levels would require (for a 50 mg dose) quantities of solvent of 10 L and 25 L respectively compared with 2.5 L available (250 mL x 10). 494 I accept Professor Polli's evidence to the effect that one of the very first properties of a compound which is tested is its melting point and that high melting points are a well-known indicator of poor solubility in aqueous solutions because they correspond to strong bonds between the molecules within the solid that must be overcome for the solid to dissolve. I accept that this was part of common general knowledge at the Priority Date. I also accept Professor Polli's evidence that melting points over 300°C were strongly indicative of very poor solubility. As I have said earlier, the melting point for tadalafil shown in Daugan 1997 is 302-303°C. 495 The formulator reading Daugan 1997 in the context of a project to develop an NCE would have recognised the problem of solubility-limited absorption that Daugan 1997 raises for the exemplified 50 mg dose and other doses that may be tested in Phases I and II. The formulator would seek to improve the solubility of tadalafil. This can be done by formulating the API in a way that increases the amount of tadalafil that is able to dissolve in the gastric fluid at thermodynamic equilibrium, that is, raising equilibrium solubility or enables a "super-saturated" state to be achieved, where the amount of tadalafil that is able to dissolve in the gastric fluid temporarily exceeds thermodynamic equilibrium. 496 Professor Polli said that he expected solubility-limited absorption problems at doses of 25 mg and especially at 50 mg and 100 mg. Although having read the 666 Patent, Professor Polli now recognises that tadalafil in doses of 1-20 mg does not raise solubility-limited absorption problems, he maintains his view that tadalafil at doses of 25 mg and (especially) 50 mg and 100 mg were likely to raise solubility-limited absorption problems. This is because of the relationship between the amount of the dose and measured solubility as the BCS previously discussed makes clear. That has a classification for drugs in terms of solubility and permeability and the solubility is calculated by reference to the highest unit dose in a given volume of fluid. Of course, in the case of an NCE in drug development, such as tadalafil, the highest unit dose is not known. 497 There is one other matter to be identified in this context. The formulator could not assume from Daugan 1997 that there would not be permeability-limited absorption problems with tadalafil. There is simply no information in Daugan 1997 from which one could predict or assume permeability. I accept Professor Polli's evidence that if permeability is poor, the solubility-limited absorption problem is likely to be worse and his evidence that improving the rate, whether by reducing the particle size or increasing solubility, will have no effect on the rate at which the API is absorbed, and thus no effect on the onset of action. I accept ICOS's submission that the absence of information about permeability is a further reason that the skilled person reading Daugan and having regard to common general knowledge could not reasonably expect that micronising tadalafil would result in a successful outcome. 498 Professor Polli said that the first option which he would consider to deal with his concerns about the solubility of Compound A and Compound B would be to use salt and solvate forms, particularly salt forms. There is support for this view in the following passage in Lieberman et al (1989) at p 17: When the drug substance under consideration is not an acidic or basic compound, or where the acidic or basic character of the compound is not amenable to the formation of a stable salt, other means of enhancing the solubility may be explored. 499 There is repeated reference in Daugan 1997 to the compounds of the invention including different salt forms and it broadly describes a process for synthesising salts. 500 Professor Polli gave evidence that his second and third choices to improve the solubility of tadalafil would be to try and make a different solvate, polymorph or amorphous forms. The passage from Lieberman et al (1989) proceeds as follows: The use of a more soluble metastable polymorph to enhance bioavailability of orally administered solids is one way to approach the problem. Other approaches to improve solubility or rate of dissolution include use of complexation and high-energy coprecipitates that are mixtures of solid solutions and dispersions. 501 Professor Polli said that the most common solvate is a hydrate and he described the interactions within the crystalline structure. Daugan 1997 refers to solvates and, in particular (by way of example), hydrates. 502 Professor Polli gave evidence that polymorphic forms are alternative crystalline structures of the same API and that the use of different polymorphic forms was a common technique to improve solubility at the Priority Date. Dr Mooney acknowledged that trying to find a polymorph that had a better solubility value is an option that is worth a try in resolving a solubility problem. 503 The fourth choice that the formulation scientist was likely to try was to formulate tadalafil in the form of a co-precipitate or solid dispersion. Professor Polli described how this works: when the polymer dissolves, the drug will be molecularly dispersed to render it more soluble. The formulators identified particular difficulties with the formulation of co-precipitates. It is clear from the formulators' evidence that all of the techniques have disadvantages in terms of time, cost, difficulty and uncertainty. 504 Micronisation cannot solve the solubility-limited absorption problem that appears in Daugan 1997. Dr Mooney agreed in his evidence that increasing the surface area of a particle to a low micron range does not alter the quantitative definition of solubility as distinct from the rate of dissolution. It seemed to me that he agreed that micronisation will not change the character of the drug as "practically insoluble" under the BP and USP. In the course of his evidence, he said: MR BURGESS: And then in paragraph 131, you say the first approach you would have considered to improve the solubility of a poorly water-soluble drug would be to reduce the particle size of the drug substance. DR MOONEY: Yes. MR BURGESS: So is this right: when you say micronizing is a technique that can be employed to improve the solubility of a poorly water-soluble drug, in both your affidavit and in the joint expert report, what you mean is that micronizing is a step that can be taken to improve the dissolution rate; correct? DR MOONEY: Yes. MR BURGESS: And that's what you refer to in paragraph 132; correct? DR MOONEY: Yes. MR BURGESS: And you do not mean to say that micronizing can be used to improve the measured solubility value. DR MOONEY: Well, as I said, when I wrote this my solubility wasn't defined based on saturation. The solubility was referring to my original characteristic. 505 I turn to address the significance of Daugan 1997 containing formulations of tadalafil in free base form. 506 The formulators were asked the "inventive step" question, if I may use that expression, in another way. They were asked whether, having regard to Daugan 1997, they would consider formulating the compounds in other than their free base form. In one sense, this is really doing no more than asking them to comment on the extent to which Daugan 1997 advocates or teaches the use of tadalafil in its free base form. 507 Professor Polli was not dissuaded from his central thesis and he said that he would turn to salts and solvates as his first choice, especially salts. He did note that an alternative polymorph with higher apparent solubility could be in free base form. Professor Polli said that he would first use salt and solvate forms, particularly salt forms, to increase the solubility of Compounds A and B. Even if it was known or discovered that the problem was one of the dissolution rate as distinct from solubility, he would turn to solubility solutions which improve dissolution rate, or failing that, if he was to consider micronisation, not micronisation to the smallest possible size. 508 Dr Mooney considered that Daugan 1997 supported the use of tadalafil in its free base form. 509 It is true that Daugan 1997 describes pharmacy formulations of tadalafil in its free base form, but there is no real indication that that is the preferred form. Furthermore, there are a number of references in the specification to the formation of salts or solvates of tadalafil. In any event, the overriding problem suggested by Daugan 1997 is one of absolute solubility which the formulators skilled in the formulation of NCEs would know could not be solved by micronisation. 510 I turn to address whether Professor Polli's suggested solutions were realistic. 511 Apotex submits that none of the possible solutions identified by Professor Polli were realistic solutions and that they would be quickly dismissed by the development team. 512 Apotex submitted that making a salt of tadalafil was unlikely to be considered a realistic solution to the solubility problem. Daugan 1997 contains information about the preparation of a salt of tadalafil, both an acid addition salt and a base addition salt. As I have said, Professor Polli's first option to solve the solubility problem was the formation of a salt of tadalafil, although he did not give evidence about the extent to which that would be possible or how the development team would go about it. That was because those matters were not within his expertise. The first option of Dr Mooney (who had a PhD in organic chemistry) to solve the solubility problem - in reality, from his point of view, a dissolution rate problem - was micronisation, but if that did not work, the formation of a salt was one of his other options. Dr Robertson is an experienced medicinal chemist and his evidence (which is discussed below) is that the formation of an effective salt of tadalafil is possible. Having regard to Dr Robertson's expertise, his evidence is decisive. 513 Dr Reece gave evidence in relation to the alleged invention in the 946 Patent. In addition, he gave evidence about whether the formation of a salt of tadalafil was possible. He said that he considered that it would be difficult to form an acid addition salt. Dr Reece agreed that he had only considered an acid addition salt and, even as to that opinion, he acknowledged that he would need to consult a medicinal chemist on the point. He seemed to acknowledge that it would be possible to form a base addition salt, but then qualified his opinion by saying that the formation of a salt would present some challenges because the reagents necessary to do so were "explosive agents to use…". There was also reference in the evidence of the pharmacologists to the possibility of re-precipitation of tadalafil in the low pH environment of the stomach. Professor Evans said that the formation of a salt would not be his first option because of the "extreme conditions", but that it is a matter he would take advice on from a medicinal chemist. 514 Dr Robertson explained that a salt is formed by reacting an acid and base. A salt formed by adding an acid to the API is called an acid addition salt. In an acid addition salt, the API behaves as a base and accepts a proton from the acid. A base addition salt is formed by adding a base to the API. Dr Robertson said that it may be that Compound A was insufficiently basic to form an acid addition salt, even with a strong acid. However, he expected that the indole nitrogen in the structure would be capable of forming a base addition salt of the compound represented by the structure (i.e., the chemical structure of tadalafil) and he said that he was confident that he could make such a salt applying his skills as a medicinal chemist. Dr Robertson's opinion was supported by the standard textbook to which he referred (Smith LR, "Indoles, Part Two", in Houlihan WJ, The Chemistry of Heterocyclic Compounds, (Wiley-Interscience, 1972) (Annexure ADR-4)). Dr Robertson said, and I accept, that Dr Reece did not give consideration to base addition salts. I accept Dr Robertson's opinion that, in the event that an acid addition salt of tadalafil could not be made, there was a good expectation that a base addition salt could be made and, furthermore, other medicinal chemists would have recognised that to be the case at the Priority Date of the 666 Patent. 515 Apotex sought to gain assistance from the decision of Birss J in the counterpart UK proceedings in the Patents Court, Actavis Group Ptc EHF v ICOS Corporation [2016] EWHC 1955 (Pat) (Actavis Group v ICOS) (at [418]) where his Lordship said that the alternative of a salt formation would be ruled out early and that there was nothing suggesting that finding a different polymorph was realistic. I have noted those observations, but clearly I am required to proceed having regard to the evidence before this Court. 516 Apotex submitted that making a different polymorph was unlikely to be considered a realistic solution to the solubility problem. It pointed to the fact that the formulators agreed that all polymorphs and amorphous forms achieve the same absolute solubility. However, Professor Polli considered that a different polymorph was an option and, although his experience with different polymorphs was limited as Apotex submitted, his opinion is supported by the standard texts (Lieberman et al (1989) Vol 1 p 34 (JEP-27)). Furthermore, the formulators agreed that equilibrium solubility may be exceeded on a temporary basis and that this may happen with amorphous and more soluble polymorphs. The period of time over which equilibrium solubility may be exceeded can be minutes or hours. In addition, a process of polymorphism, which can improve solubility, involves lyophilisation of a solution of the compound in p-dioxane to produce a dioxane solvate. Elimination of the dioxane by exhaustive drying can produce a polymorphic form with significantly increased solubility (Lieberman et al (1989) Vol 1 p 60 (BAM-32)). 517 I should make it clear that I have not overlooked the point made in one of the articles tendered in evidence (Curatolo W, "Physical Chemical Properties of Oral Drug Candidates in the Discovery and Exploratory Development Settings" (1998) 1 Pharmaceutical Science & Technology Today 387 (JEP-15)) that the formation of salts and different polymorphs does have the disadvantage that earlier pre-clinical work needs to be repeated. 518 With respect to solid dispersions such as the formulation of co-precipitates, Apotex submitted that this was not a realistic possible solution because of the challenges associated with the formation of solid dispersions and, or because of these challenges, solid dispersions were not commonly used at the Priority Date. Professor Polli agreed that solid dispersions were not commonly used at the Priority Date. The force of these points may be acknowledged, but the development team was facing a pressing and significant solubility-limited absorption problem. It may be noted in this context that the inventors of the alleged invention in the 666 Patent started with a co-precipitate. 519 I find that a salt form of tadalafil was a realistic possible solution to solve the solubility problem as were, albeit less attractive, a different polymorph or amorphous forms and a solid dispersion. 520 Even if the possible solutions involved multiple challenges, this is not a reason to think that the development team would adopt a dissolution rate solution (micronisation) for what presents as a solubility-limited absorption problem. Even if the team considered micronisation, which I note raises its own challenges, was worth a try, it would not undertake micronisation with the required expectation of success. There is another matter. Whilst it is now known that the problem with tadalafil of doses at 1-20 mg is the dissolution rate, there is no evidence about the problem at the doses Dr Mooney was asked to consider (i.e., 25 mg, 50 mg and 100 mg). There is, therefore, no evidence that testing at those doses would have led, as a matter of course, to micronisation. 521 Finally, I turn to address whether the development team would have adopted micronisation, in any event, to improve the onset of action. 522 Apotex submitted that even if absolute solubility as distinct from dissolution rate was seen as a problem, a rapid onset of action was seen as a desirable feature of a drug for the treatment of ED, and therefore, micronisation would be easily recognised as a means of improving the onset of action. 523 I reject this submission. For the reasons I have already given, the development team would focus on solving the solubility-limited absorption problem. The development team would know that improving solubility was also likely to improve the dissolution rate. In any event, a dissolution rate problem is not apparent on the face of Daugan 1997. Finally, it is relevant that there are challenges and disadvantages associated with micronisation, including ongoing manufacturing costs. I turn now to expand on these points. 524 It is correct (as ICOS submitted) that no rate of onset problem appears on the face of Daugan 1997. It is clear from the evidence that a drug substance with poor solubility may nevertheless reach its saturated concentration quickly and a highly soluble drug substance can reach its saturated concentration very slowly. Smith (2015) contains the following passage: Solubility and dissolution are different concepts but are related… Solutes vary not only in the extent to which they dissolve, but also how quickly they will reach their respective solubility limits. Solubility and dissolution rate are two distinct phenomena. Dissolution rate is a kinetic process. A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. Conversely, a solute can be very soluble, yet require a protracted amount of time to arrive at the final, saturated concentration… 525 Dissolution is not mentioned in Daugan 1997, nor is there any pharmacokinetic data in Daugan 1997 and without that data, no skilled person would reasonably expect any problem with the rate of onset of therapeutic effect. The pharmacokinetic data would indicate the therapeutic window for tadalafil, including the minimum effective plasma concentration at which efficacy is first observed, and the time required to reach that minimum plasma concentration. 526 Furthermore, even if the dissolution rate was thought to be a potential problem, this would not be the priority for the formulator. The priority for the formulator would be to address the solubility-limited absorption problem. 527 Dr Mooney agreed that improving solubility will also improve the dissolution rate. In the course of his evidence he said: MR BURGESS: Thank you. Now, you would accept as well that if more soluble forms of compound were identified they may improve not only the measured solubility, but also the dissolution rate; correct? DR MOONEY: Yes. MR BURGESS: And any such improvement in measured solubility of compound A or B may have remedied any problem that might otherwise have existed with the dissolution rate of the freebase form of Compound A; correct? DR MOONEY: I accept that, yes. MR BURGESS: And the same could be said of the other 13 suitable compounds; correct? DR MOONEY: Yes. 528 While taking steps to improve the solubility of the selected compound, the formulator would have no reason to expect the dissolution rate and, still less, the time of onset, was problematic. 529 Dr Mooney accepted that his particle size evaluation study could not have occurred until after Phase I dose escalation studies had been conducted to find the maximum tolerable dose and, in the absence of good efficacy models in animals, "perhaps" would not have occurred until after Phase II studies had been conducted investigating safety and efficacy in patients. I accept ICOS's contention that at that point there would be no reason to consider micronisation. Starting with Daugan 1997 and the common general knowledge only, any need to conduct Dr Mooney's study could not be expected to arise until after Phase I testing and, at the earliest, during Phase II or after, wherein formulations were used in which solubility has been increased to address the problem of solubility-limited absorption and yet Phase II (or potentially Phase I) testing showed that despite such steps being taken to increase solubility, there is a dissolution rate problem. If there was no rate of absorption or rate of onset problem observed as a result of these studies, there would be no motivation to reduce the particle size to micron levels or investigate the benefits of doing so. Micronisation is not carried out as a matter of course and I accept the evidence of both experts that there are disadvantages with micronisation and that a formulator or drug development team will not engage in a process of micronisation unless it is necessary to do so. Dr Mooney made a reference to the fact that the findings of his particle evaluation study could be used "to set appropriate quality control particle limits of the raw material for ensuring batch to batch consistency for future clinical trial batches in terms of the extent and rate of absorption of the drug where differences were seen for different particle sizes". The problem with that approach was identified by Professor Polli. A study carried out for that purpose is quite different from a study carried out to address a dissolution rate-limited absorption problem. 530 Even if the development team considered that micronisation was "worth a try" and it was carried out, it would not be done with any expectation of success, either at all or at particular sizes. Before one carried out micronisation, one would need the pharmacokinetic data for safety and efficacy and that was not part of either common general knowledge or in Daugan 1997. Nor was there any way of knowing the appropriate micron range and there may be some inventiveness in perceiving the best particle size range for a particular drug substance. 531 I am not satisfied that the development team would be directly led, as a matter of course, to try micronisation with the required expectation of success.

Conclusion 532 In my opinion, Apotex's inventive step challenge to the claims in suit in the 666 Patent must be rejected.

Introduction 533 Apotex contends that the claims in suit in the 946 Patent are invalid because of a lack of novelty. Stoner is said to anticipate the claims. Stoner has a filing date of 3 March 2000 and a publication date of 14 September 2000. It claims priority based on US 60/123,244 (US 244) which was filed on 8 March 1999. The 946 Patent was filed on 26 April 2000 and claims priority from 30 April 1999. Apotex contends that Stoner falls within paragraph (b)(ii) of the definition of "prior art base" in Schedule 1 to the Act. Stoner and US 244 are, in material respects, the same. 534 Section 18(1) of the Act provides that a patentable invention is an invention that, so far as claimed in any claim, is novel when compared with the prior art base as it existed before the priority date of the claim. The term "prior art base" is defined in Schedule 1 to the Act as follows: prior art base means: (a) … (b) in relation to deciding whether an invention is or is not novel: (i) … (ii) information contained in a published specification filed in respect of a complete application where: (A) if the information is, or were to be, the subject of a claim of the specification, the claim has, or would have, a priority date earlier than that of the claim under consideration; and (B) the specification was published after the priority date of the claim under consideration; and (C) the information was contained in the specification on its filing date and when it was published. 535 Section 7 of the Act provides that an invention is taken to be novel when compared with the prior art base unless it is not novel in light of, relevantly, prior art information contained in a single specification of the kind mentioned in subparagraph (b)(ii) of the definition of prior art base in Schedule 1. 536 Apotex contends that the Stoner specification is a whole of contents specification and, for the purposes of the analysis, it has proffered four notional claims of the specification. Those notional claims are set out in Annexure D to these reasons.

The Contents of the Stoner Specification 537 The "Field of the Invention" is described in the Stoner specification as follows: The present invention provides for novel methods for the treatment of erectile dysfunction comprising a drug combination. More particularly, the drug combination of the present invention comprises an agonist of the melanocortin receptor with a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist. The present invention also provides for pharmaceutical compositions comprising such drug combinations useful in the methods to treat erectile dysfunction. Moreover, the present invention provides for a method of manufacture of a medicament useful in the treatment of erectile dysfunction. 538 The "Summary of the Invention" is described as follows: The present invention provides for methods of treating erectile dysfunction in a human subject in need of such treatment comprising administration of a therapeutically effective amount of an agonist of the melanocortin receptor in combination with a therapeutically effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist. Further, the present invention provides for pharmaceutical compositions useful in the methods of the present invention, as well as a method of manufacture of a medicament useful to treat erectile dysfunction. 539 The invention is described in the Stoner specification as a drug combination useful in the treatment of ED. The drug combination involves two compounds, namely, a drug acting as an agonist of the melanocortin receptor and either a PDE inhibitor or an alpha-adrenergic receptor antagonist. It is clear from the Stoner specification that the PDE inhibitor is a PDE5 inhibitor. 540 One of at least five PDE5 inhibitors mentioned in the Stoner specification is "IC-351" which is tadalafil. 541 Claims 1, 6, 7, 14, 17 and 20 of the Stoner patent are in the following terms: 1. A method for the treatment of erectile dysfunction which comprises administering to a human subject in need of such treatment an effective amount of an agonist of the melanocortin receptor in combination with an effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist. 6. The method of Claim 1 wherein the inhibitor of the cyclic-GMP-specific phosphodiesterase is an inhibitor of the type V phosphodiesterase (PDE-V) isozyme. 7. The method of Claim 6 wherein the inhibitor of PDE-V is selected from the group consisting of: a) sildenafil citrate, b) IC-351, c) M-54033, d) M-54018, and e) E-4010. 14. A pharmaceutical composition for the treatment of erectile dysfunction which comprises a pharmaceutically acceptable carrier, a therapeutically effective amount of an agonist of the melanocortin receptor and a therapeutically effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist. 17. The pharmaceutical composition of Claim 15 wherein the PDE-V inhibitor is selected from the group consisting of: a) sildenafil citrate, b) IC-351, c) M-54018, d) M-54033, and e) E-4010. 20. The use of an agonist of the melanocortin receptor in combination with a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist for the preparation of a medicament useful to treat erectile dysfunction. 542 The Stoner specification refers to sildenafil citrate. When it first refers to other PDE5 inhibitors, it states that other PDE5 inhibitors are "in clinical trials". The relevant passage in the Stoner specification is as follows: The regulatory approval of Viagra® for the oral treatment of erectile dysfunction has invigorated efforts to discover even more effective methods to treat erectile dysfunction. Several additional selective PDE-V inhibitors are in clinical trials. UK-114542 is a sildenafil backup from Pfizer with supposedly improved properties. IC-351 (ICOS Corp.) is claimed to have greater selectivity for PDE-V over PDE-VI than sildenafil. Other PDE-V inhibitors include M-54033 and M-54018 from Mochida Pharmaceutical Co. and E-4010 from Eisai Co., Ltd. 543 The Stoner specification refers to the particular combination of an agonist of the melanocortin receptor with a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist as a combination which produces "unexpectedly superior pharmacokinetic and pharmacodynamics results…". 544 A combination of drugs may be beneficial because of an addictive effect (1+1=2) or a synergistic effect (1+1=3). There was debate between the pharmacologists in this case as to whether the Stoner specification was claiming an addictive effect or a synergistic effect. The Stoner specification contains the following: The combination of an agonist of the melanocortin receptor and a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist provides an unexpectedly superior effect in the treatment of erectile dysfunction. The combination provides for effective treatment of either psychogenic or organic erectile dysfunction in a greater percentage of the affected population than either element of the combination separately. The combination provides for a shorter onset of action and longer duration of action than either element of the combination separately. The combination also has fewer side effects and contraindications than either member of the combination separately. 545 The word "combination" or the words "in combination" could mean two drugs in the same pharmaceutical composition, or two compositions administered at the same time, or at different times, or all of these alternatives. The Stoner specification provides as follows: In the combination of the present invention, the agonist of the melanocortin receptor may be administered separately or in conjunction with the cyclic-GMP-specific phosphodiesterase inhibitor or the alpha-adrenergic receptor antagonist. In addition, the administration of one element of the combination of the present invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination. 546 The Stoner specification provides that dosage ranges of the active ingredients in the combination for each of the compounds is approximately one tenth to one times the clinically effective ranges required to induce the desired erectogenic effect, respectively, when the compounds are used singly. This statement will have significance when I come to consider Example 5 in the Stoner specification. The Stoner specification also provides that "advantageously" the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. 547 As to dose and dosage levels, the Stoner specification relevantly provides: For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of each of the active ingredients for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of each of the active ingredients, preferably, from about 1 mg to about 100 mg of each of the active ingredients…Dosage levels of the cyclic-GMP-specific phosphodiesterase inhibitor or alpha-adrenergic receptor antagonist of between about 0.001 to 50 mg/kg of body weight, preferably about 0.005 to about 25 mg/kg per day, and more preferably about 0.01 to about 10 mg/kg per day are administered to a patient to obtain effective treatment of erectile dysfunction. An especially preferred combination is that wherein the agonist of the melanocortin receptor is selective for the MC-4R subtype, the cyclic-GMP-specific phosphodiesterase inhibitor is the PDE-V inhibitor sildenafil citrate or IC-351, and the alpha-adrenergic receptor antagonist is the alpha-2 antagonist MK-912. In this especially preferred combination, dosage levels of each component are as noted above; however, it is even more preferred that the agonist of the MC-4R subtype be administered at a dosage rate of about 0.01 to about 10 mg/kg/day, especially about 0.05 to about 5.0 mg/kg/day, and more particularly about 0.1 to about 5 mg/kg/day, and that the PDE-V inhibitor, sildenafil citrate or IC-351, or the alpha-2 antagonist MK-912 be administered at a dosage level of about 0.001 to about 20 mg/kg/day, especially about 0.005 to about 10 mg/kg/day, and more particularly about 0.01 to about 5 mg/kg/day. 548 The Stoner specification refers to tablets, among other dosage forms, and among other statements concerning frequency of administration, a single daily dose. 549 The Stoner specification contains a number of examples and it is Example 5 which is said by Apotex to be relevant to the novelty argument in this case. It is as follows: EXAMPLE 5 As a specific embodiment of an oral composition of a combination of the present invention, 5 mg of a melanocortin agonist and 10 mg of a type V phosphodiesterase (PDE-V) inhibitor are formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule.

Relevant Principles 550 Before the introduction of paragraph (b)(ii) in the definition of prior art base, an invention could be anticipated by a patent specification having an earlier priority date, notwithstanding that at the priority date of the claim in question, the earlier specification was unpublished and its contents were not publicly available, but only insofar as a claim is specifically prior claimed by a claim of the earlier specification. This limitation proved unsatisfactory in practice and was considered too narrow. Paragraph (b)(ii) was introduced so that any disclosure contained in an earlier specification may be relied upon as an anticipation for determining novelty (Industrial Property Advisory Committee 1984 Report "Patents, Innovation and Competition in Australia", paragraphs 7.3 and 14). 551 The circumstances leading to and surrounding the introduction of paragraph (b)(ii) were discussed by Burchett J in Alcatel NV v Commissioner of Patents (1996) AIPC 91-260; (1996) 68 FCR 8 at 10-11. 552 In E I Du Pont de Nemours & Co v ICI Chemicals & Polymers Ltd [2005] FCA 892; (2005) 66 IPR 462 (E I Du Pont de Nemours) (at [81]), Emmett J held that the proper construction of paragraph (b)(ii)(A) in the definition of prior art base required the following analysis: a relevant piece of information is identified and consideration is given to whether that information is the subject of an actual claim. If the information is the subject of an actual claim, then consideration is given to whether the claim would take priority over the claims in question. If the information is not the subject of an actual claim, then consideration is given to whether the information could be the subject of a claim. If the information could be the subject of a notional claim, then consideration is given to whether the notional claim would take priority over the claims under consideration. His Honour also said that there must be some relationship between the notional claims and the specification in which the information is said to be disclosed. He said that the notional claim must be a valid claim of the specification in question and to be a valid claim, the notional claim must be fairly based on the specification in question. 553 A notional claim will be fairly based on a specification where there is a real and reasonably clear disclosure in the body of the specification of what is in the claims so that it can be concluded that the invention as claimed is described (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 at [68]-[69]). 554 A "whole of contents" anticipation was considered by Bennett J in Danisco A/S v Novozymes A/S (No 2) [2011] FCA 282; (2011) IPR 209. Her Honour referred to some issues which might be raised in connection with paragraph (b)(ii)(A) of the definition of prior art base, but which were not in dispute before her because the parties accepted the test formulated in E I Du Pont de Nemours (at [298]-[299]). Her Honour addressed the matter by reference to a number of "notional" claims which had been put before her. Her Honour adopted the same approach as Emmett J in E I Du Pont de Nemours in that she said that the notional claims must be fairly based on the disclosure in the prior specification relied upon. 555 In addition to satisfying a fair basing requirement, the party alleging a lack of novelty must establish a lack of novelty by reference to the well-established principles for determining novelty. Section 7(1) of the Act requires a comparison between the claimed invention and the information in the Stoner specification for the purposes of determining whether it has been shown to be not novel. In DSI Australia (Holdings) Pty Ltd v Garford Pty Ltd [2013] FCA 132; (2013) IPR 19, Yates J considered novelty documents which included a "whole of contents" novelty document. Justice Yates set out the relevant principles for novelty in a way which did not discriminate between the novelty documents and the whole of contents novelty document. 556 In Hill v Evans (1862) 45 ER 1195; (1862) IPR 1A 1, Lord Westbury LC said (at 1199): The question then is, what must be the nature of the antecedent statement? I apprehend that the principle is correctly thus expressed: - the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand, and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful. If something remains to be ascertained which is necessary for the useful application of the discovery, that affords sufficient room for another valid patent… A little later, the Lord Chancellor said (at 1200): There is not, I think, any other general answer that can be given to this question than this: - that the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent. The invention must be shown to have been before made known. Whatever, therefore, is essential to the invention must be read out of the prior publication. If specific details are necessary for the practical working and real utility of the alleged invention, they must be found substantially in the prior publication… 557 The test to be applied when determining a question of novelty is the reverse infringement test. In Meyers Taylor Pty Limited v Vicarr Industries Ltd [1977] HCA 19; (1977) 137 CLR 228 at 235, Aickin J said: The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement (see, e.g., Harwood v. Great Northern Railway Co.). (Citation omitted.) 558 In The General Tire and Rubber Company v The Firestone Tyre and Rubber Company Limited and Others [1972] RPC 457 (General Tire), the Court of Appeal said at 485-486: If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated. If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: Flour Oxidizing Co. Ltd. v. Carr & Co. Ltd. (1908) 25 R.P.C. 428 at 457, line 34, approved in B.T.H. Co. Ltd. v. Metropolitan Vickers Electrical Co. Ltd. (1928) 45 R.P.C. 1 at 24, line 1). A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee. This approach has been followed in this Court (see, for example, Novozymes A/S v Danisco A/S [2013] FCAFC 6; (2013) 99 IPR 417 at [145]; AstraZeneca Full Court at [293]). 559 In Samsung Electronics Co Ltd v Apple Inc [2011] FCAFC 156; (2013) 217 FCR 238, the Full Court of this Court said (at [127]): It is trite law that, if the alleged paper anticipation is to deprive an invention of novelty, it must clearly disclose each and every essential feature of that invention, as claimed. This principle has its genesis in Lord Westbury's seminal statement in Hill v Evans (1862) 4 De GF & J 288; 1A IPR 1 at 7 that "the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent", a statement which Lord Reid described in C Van der Lely NV v Bamfords Ltd [1963] RPC 61 at 72; (1962) 1A IPR 86 at 90 as "universally accepted"… 560 The extent to which there might be an implicit disclosure in an alleged anticipation or a disclosure where a skilled addressee would add missing information to a disclosure as a matter of course has been discussed in a number of authorities in this Court. It is not necessary for me to refer to those authorities other than to note certain observations of the Full Court in AstraZeneca Full Court. In that case, the Full Court said that there were limits to implicit disclosure. For example, although common general knowledge can be used in a limited way to construe a prior art document, it cannot be used in a way which leads to a conclusion that there is an anticipation when that conclusion would not be reached on a consideration of the document standing alone otherwise, novelty would transgress into the field of inventive step (at [345] and [352]). 561 More to the point in the circumstances of this case, are those cases which have considered whether what on any view is a broad disclosure is an anticipation. This is particularly pertinent in this case because of the wide range of compounds, unit doses and daily doses disclosed in the Stoner specification. 562 The cases identify the following principle. Generally speaking, while regard must always be had to the particular circumstances of the case, the fact that the claimed invention is included in, or encompassed by, the alleged invention is not sufficient to establish a lack of novelty. This is because the prior inventor has not planted his flag at the precise destination reached by the patentee (ICI Chemicals at [51]) or because there has not been a particular disclosure of the invention, even though a term in the alleged anticipation encompassed, to any person skilled in the art, not only the device specifically disclosed in the anticipation, but also the inventive device and, in those circumstances, it was at least as likely the teaching in the anticipation would be carried out in a way that did not infringe the claims in the patent (IGT (Australia) Pty Ltd v Aristocrat Technologies Australia Ltd [2008] FCAFC 131; (2008) 77 IPR 482 at [39], [41]-[44] and [56]) or because the evidence of the expert witnesses was not clear that the particular mixture of compounds was taught or disclosed by the alleged anticipation (E I Du Pont de Nemours & Company v Imperial Chemical Industries plc [2007] FCAFC 163; (2007) 163 FCR 381 at [155]) or because the alleged anticipation disclosed a broad range of doses and dosage regimens and absent imputed common general knowledge of the general administration of prior drugs of the type in issue, it could not be said that although the person skilled in the art might possibly use the dosage and dosage regimen of the claims, it was inevitable that that person would do something which would infringe the claims (AstraZeneca Full Court at [295]-[298]).

Analysis 563 Apotex submits that Stoner is an anticipation because one form of the invention in Stoner is a combination of compounds administered separately, being an agonist of the melanocortin receptor and tadalafil and, as to the latter, administered in dosages identified in the relevant claims in the 946 Patent. Apotex submits that that form of the invention in Stoner would constitute an infringement of those claims even though the 946 Patent does not involve a combination. A number of the relevant claims in the 946 Patent refer to a dosage form or method of treatment comprising identified elements and it is clear from the definition of the word comprising in the Specification of the 946 Patent that the claims are not restricted to the identified elements. The definition of the word "comprising" is set out above (at [161]). 564 Apotex submits that the relevant claims in the 946 Patent are not confined to monotherapy. It submits that the 946 Patent "contemplates" the co-administration of tadalafil and nitrates. It further submits, by way of example, that claim 1 would include a composition containing both tadalafil and testosterone and, indeed, the claims would encompass any composition which included the relevant quantity of tadalafil. Apotex referred to Apotex v Warner-Lambert at [131] per Nicholas J as an example of a case where a claim was not restricted to monotherapy. It seems to me that that case turned on the construction of the particular claim in question and that it does provide assistance in terms of the issues in this case. 565 ICOS submits that Stoner does not anticipate the relevant claims in the 946 Patent for a number of reasons. For the same reasons, ICOS submits that there is no real and reasonably clear disclosure in Stoner such as to provide a fair basis for any of the notional claims put forward by Apotex. First, ICOS submits that Stoner is for a combination therapy and one in which the combination of the two drugs has a synergistic effect. By contrast, the 946 Patent is plainly for a monotherapy and the definition of the word "comprising" in the 946 Specification does not alter that fact. Secondly, ICOS submits that Stoner offers a number of choices in terms of the PDE5 inhibitor to be used and the most preferred inhibitor is sildenafil. In those circumstances, Stoner does not disclose tadalafil in the relevant sense. Thirdly, ICOS submits that Stoner does not disclose the particular claimed doses of tadalafil (1-20 mg), but rather it describes a broad range of unit doses. Fourthly, ICOS submits that Stoner does not disclose the particular claimed maximum daily dosage (20 mg), rather it describes broad range of maximum daily doses. Finally, ICOS submits that Example 5 in Stoner teaches a formulation which includes sildenafil, but not tadalafil. 566 ICOS's submissions provide a convenient framework for the analysis.

Monotherapy as against a Combination and Synergistic Effect 567 In their joint experts' report, the pharmacologists addressed the issue of whether Stoner disclosed pharmaceutical compositions for use in monotherapy or combination therapy or both. They express the view that the invention in Stoner relates to combination therapy, that is, the treatment of ED comprising a drug combination, comprised of a centrally-acting agonist of the melanocortin receptor with a peripherally-acting cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist. Stoner does not apply to centrally-acting agonists of the melanocortin receptor, peripherally-acting cyclic-GMP-specific phosphodiesterase inhibitors or an alpha-adrenergic receptor antagonists used as monotherapy, whereby any active component would be used alone. Dr Reece added that he understood that the individual components of drug combinations which are the subject of the invention in Stoner can be administered either separately in two dosage forms or together in a combination product. 568 Examples of cyclic-GMP-specific phosphodiesterase inhibitors include sildenafil and other PDE5 inhibitors identified as IC-351 (tadalafil), M-54018 and M-54033. 569 The pharmacologists were not in agreement as to whether the claims in the 946 Patent construed in the context of the Specification are restricted to monotherapy. Clearly, the question is one for the Court, although the Court can be assisted by evidence from experts. Professor Evans and Professor Brock expressed the opinion that the claims are restricted to monotherapy, that is to say, unit dose forms in which tadalafil is the only active ingredient. Their reasons for taking this view are as follows: the 946 Patent only discusses the use of tadalafil as a monotherapy; all of the data described in the 946 Patent is for tadalafil administered as a monotherapy; developing and administering a combined therapy involves entirely different clinical principles to those disclosed in the 946 Patent; and it is common for a drug to be administered at different doses depending on whether it is used as a monotherapy or in combination with another drug. Furthermore, ICOS made the point that claims 12 to 23 inclusive refer to a method of treating ED that involves administering the unit dosage forms as a monotherapy to patients (not as part of a combination therapy) and claims 24 to 35 refer to the manufacture of a unit dosage form that contains tadalafil and no other active ingredients. ICOS submitted that, at the very least, these claims were not anticipated by Stoner. 570 By contrast, Dr Reece expressed the opinion that the 946 Patent does not exclude a dosage form which also includes a unit dose of a second active ingredient. In taking this view, he relies on the fact that claims 1 to 6 and 8 to 11 of the 946 Patent are for a pharmaceutical unit dosage "comprising" doses of tadalafil and the definition of the word "comprising" in the Specification. Dr Reece interpreted the word "contains" in claims 12 and following as having the same meaning as the word "comprising". 571 There is no dispute between the experts that there are no specific claims to a combination product in the 946 Patent. Furthermore, there is no dispute that the 946 Specification is limited to a discussion about the use of tadalafil as a monotherapy and the data is limited to tadalafil. 572 I accept the evidence of Professors Evans and Brock that there are important substantive differences between monotherapies and combination therapies with each drawing upon different clinical principles and that information disclosed for a monotherapy is not applicable to a combination therapy. It is common for an API to be administered at different doses depending on whether it is used as a monotherapy or in combination and the 946 Patent only refers to doses for use in a monotherapy. The different unit doses and daily doses occur in respect of drugs administered as a monotherapy compared with being part of a combination therapy. Professor Evans explained that this is because of the effects - synergistic or additive - different APIs have on each other. A combination therapy arises where two APIs that have a synergistic or additive effect are used together to treat a disease. A combination of APIs having a synergistic effect will impact on the doses of each API to be used in the combination. It is not a matter of adding two APIs together in doses that would ordinarily be used. Stoner itself refers to the advantage to be obtained by using the APIs in combination as distinct from using them as a monotherapy. I found the evidence of Professors Evans and Brock on these issues to be highly persuasive and I accept it. 573 Professor Evans understood Stoner to be disclosing a combination therapy wherein the two APIs have a synergistic effect. Professor Evans put the matter in this way: … The patent itself is promoting the use of two compounds, which in combination provides superiority in some form, over the use of the individual compounds alone. 574 Professor Evans explained why he construed Stoner as identifying synergistic rather than additive benefits. He considered that in order to get a shorter onset of action than either of the compounds alone "something must be happening earlier after the administration of the compounds than you would get from either component alone". Professor Brock's evidence was to similar effect. He could not see how a shorter onset of action could result unless there was a synergistic rather than an additive effect of the combination. In the circumstances, the description in Stoner of APIs having a synergistic effect do not anticipate the asserted claims of the 946 Patent. I accept that evidence. Again, I found the evidence of Professor Evans and Professor Brock on these issues to be highly persuasive and I accept it. 575 Furthermore, it should be noted that there is no reference in those examples in the 946 Patent where efficacy is measured by the use of the IIEF of the efficacy of any other API than tadalafil. The same point may be made about the discussion of side effects. The only side effects referred to in the 946 Patent are those that result from tadalafil and there is no reference to side effects caused by any other API. 576 I accept ICOS's submission that the argument that the discussion in the 946 Patent about the co-administration of the claimed invention together with a nitrate should be understood as a combination therapy should be rejected. As it was succinctly put, nitrates are administered to treat angina, not ED. 577 I also accept ICOS's submission that to construe the 946 Patent as extending beyond monotherapy by reason of the definition of the word "comprising" would be to impermissibly change the nature of the invention. In Actavis Pty Ltd v Orion Corporation [2016] FCAFC 121, the Full Court of this Court in an infringement context noted the definition of the word "comprise" in a patent specification which is similar to the definition in this case. The specification provided that "comprises" in the description and claims of the specification "is not intended to exclude other additives, components, integers or steps". The Full Court rejected the suggestion that the definition of the word "comprise" was decisive. The Court said at [178]: Undoubtedly, this indication in the specification must be borne in mind when construing claim 17. It cannot, however, contort the claimed process into a substantively different process. Put another way, the indication cannot give the word "comprise" and its variants an unbridled operation, when the relevant description and claims themselves specify, with appropriate precision, the step or steps to be taken that will provide the promised advantage. 578 In my opinion, Stoner describes a combination whereas the 946 Patent describes a monotherapy. This had the additional consequence that the teachings in Stoner concerning unit doses and maximum daily doses relate to a combination therapy, whereas the doses in the 946 Patent relate to monotherapy.

The Choice of PDE5 Inhibitors 579 Stoner refers to a number of PDE5 inhibitors. It teaches that sildenafil has regulatory approval, whereas several additional selective PDE5 inhibitors, including IC-351, are in clinical trials. It notes that tadalafil is claimed to have greater selectivity for PDE5 over PDE6 than sildenafil. Stoner teaches that sildenafil citrate with a selective agonist of the melanocortin-4 receptor (MC-4R) is an especially preferred combination. 580 Professor Brock said that there was nothing in Stoner that would lead him to be interested in tadalafil over the other drugs described therein, and in particular, sildenafil. He took that view because tadalafil had not received regulatory approval at the priority date and Stoner provided no data to suggest that tadalafil would be useful for treating ED; whenever Stoner refers to tadalafil as being part of the preferred combinations, it also refers to sildenafil; and Stoner refers to sildenafil, and not tadalafil, as being part of the especially preferred combination. Professor Evans said that he expected that one of the compounds he would be most likely to try would be sildenafil, given that Stoner reports that it had already received regulatory approval. He considered that sildenafil was the only compound about which there was certainty. 581 I accept that the skilled addressee would be more likely to choose sildenafil as opposed to tadalafil as the PDE5 inhibitor for a combination produced in accordance with Stoner.

The Range of Unit Doses 582 Stoner refers to the large range of unit dosages for each of the active ingredients in the combinations. The most preferred range of doses, which applies to each of the active ingredients is 1-100 mg. Professor Evans and Professor Brock expressed the opinion that Stoner provided virtually no clinical guidance on the dosages of each API to be included in the combination therapy and each dosage form. The dose ranges stated within the specification are extremely wide and encompass the doses of most drugs (excluding vaccines and other biologics) on the market. Significantly, Stoner itself provides no justification of doses, no data on safety or efficacy and no useful clinical guidance. I accept these opinions which are supported by the terms of Stoner. 583 In cross-examination, Dr Reece agreed that Stoner provided "virtually no clinical guidance as to the appropriate dose within the range 1 milligram to 100 milligrams". 584 The broad disclosure of unit doses in Stoner does not anticipate the doses of tadalafil (1-20 mg) claimed in the 946 Patent.

The Range of Maximum Daily Doses 585 Stoner discloses a large range of daily doses. The narrowest range of "about 0.01 to about 5 mg/kg/day" equates to 0.7 to 350 mg per day for a 70 kg man. Professor Evans said that he did not understand the passage in Stoner to suggest that all of the combinations disclosed in Stoner, or indeed any of the combinations, could be administered as a treatment for ED in all doses included within the broad disclosed range. Rather, he understood Stoner to teach that, if any of the combinations are safe and effective, the appropriate dose(s) will be likely to fall somewhere within the broad range. 586 Stoner provides that the dosage regime utilising the combination is selected in accordance with a variety of factors, including "type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed". 587 Dr Reece accepted that Stoner does not disclose any efficacy data that would enable the reader of Stoner to form a view about what dose per day might be appropriate within the broad ranges disclosed. 588 The broad disclosure of a maximum daily dose in Stoner did not anticipate the maximum daily dose of tadalafil of 20 mg claimed in the 946 Patent.

Example 5 589 In their joint experts' report, the pharmacologists agreed that Example 5 in Stoner disclosed the following: (1) a combination therapy; (2) comprising a melanocortin agonist (not specified) and a PDE5 inhibitor (not specified); (3) doses are not given but the composition contains 5 mg of melanocortin agonist and 10 mg of PDE5 inhibitor; and (4) maximum dose is not stated and neither is the frequency of administration. 590 Professor Evans and Professor Brock said that if they were asked to prepare the formulation of Example 5, they would select sildenafil as the PDE inhibitor. They both referred to the fact that Stoner states that doses administered may be 0.1 to 1 of the monotherapy doses. As the monotherapy doses of sildenafil had been established before Stoner was filed (25 mg, 50 mg and 100 mg), a 10 mg dose of sildenafil in the combination fits well within this range. By contrast, no other PDE5 inhibitors had received regulatory approval when Stoner was filed, so the doses (if any) of which they might be effective as monotherapies were not known. In my respectful opinion, that reasoning is sound and I accept it. As far as the PDE5 inhibitor referred to in Example 5 is concerned, the example teaches the use of sildenafil. 591 ICOS submitted that Dr Reece had seen the 946 Patent before he considered the teachings of Stoner and that in expressing his views, he succumbed to the danger of hindsight. There is force in that submission, but I do not need to decide that because I have reached a clear view that Stoner is not an anticipation on the basis of the matters which I have identified.

Conclusion 592 Stoner does not anticipate the claims in suit in the 946 Patent.

Introduction 593 The 666 Patent was filed on 1 August 2000 and it claims a priority date of 3 August 1999 by reference to US 60/147048 which was filed on that day. In this section, I will refer to US 60/147048 as the 666 Priority Document. 594 Apotex alleges that claims 10-12 and 18 of the 666 Patent and each of claims 24-28 insofar as they depend on claims 10-12, and each of claims 34-38 insofar as they depend on claim 18, were anticipated by Oren which was filed on 26 April 2000 and claims a priority date of 3 August 1999. Oren claims that priority date by reference to US 60/146,924 which was filed on 3 August 1999. I will refer to this as the Oren Priority Document. Oren was published on 8 February 2001.

The Submissions of the Parties 595 Apotex alleges that claims 10-12 and 18 in the 666 Patent are not entitled to a priority date of 3 August 1999 and the earliest priority date of those claims is the filing date of 1 August 2000. Apotex makes that claim on the basis that the 666 Priority Document does not provide a real and reasonably clear disclosure of a pharmaceutical composition or use of tadalafil which exhibits a Cmax of about 180 to about 280 micrograms/litre or an AUC (0-24) of about 2280 to about 3560 micrograms hour/litre, measured using a 10 mg dose. Apotex claims that claims 10-12 and 18 of the 666 Patent are not fairly based upon the 666 Priority Document and, therefore, not entitled to the asserted priority date pursuant to regs 3.12(1)(b), (2)(c) and (2A) of the Patents Regulations 1991 (Cth) (Regulations). 596 At the relevant time, regs 3.12(1)(b), (2)(c) and (2A) were in the following terms: 3.12 Priority dates generally (1) Subject to regulations 3.13 ("priority dates: certain persons and applications") and 3.14 ("priority dates: certain amended claims") and subregulation (2), the priority date of a claim of a specification is the earliest of the following dates: … (b) if the claim is fairly based on matter disclosed in 1 or more priority documents, the date of filing the priority document in which the matter was first disclosed; … (2) For the purposes of paragraph (1) (b): (c) if: (i) the application that relates to the specification containing the claim is a PCT application that, under Article 8 of the PCT, claims the priority of an earlier application; and (ii) that earlier application is: (A) an application made in Australia not more than 12 months before the international filing date of the PCT application; or (B) a basic application, made not more than 12 months before the international filing date of the PCT application, that is the first application made in a Convention country in respect of the invention; or (C) a basic application made after a basic application referred to in sub-subparagraph (B); that earlier application, and a specification filed in relation to that earlier application after it was made, are priority documents. (2A) For the purposes of paragraph (1) (b) and subregulation (2), "filed" includes filed with the Patent Office and filed with a corresponding Office of another country. 597 Apotex alleges that claims 10-12 and 18 of the 666 Patent are not a patentable invention within the meaning of s 18(1)(b)(i) of the Act in that, when compared with the prior art base to 1 August 2000, the invention is not novel. Apotex relies on the information in Oren which it alleges is a whole of contents specification. 598 In his evidence, Dr Mooney described various aspects of Oren and then he addressed Example 1 in Oren. Example 1 describes the formula and method of preparing a tablet providing 10 mg of tadalafil. It is in the following terms: EXAMPLE 1 … The following formula was used to prepare the finished dosage form, i.e., a tablet providing 10.0 mg of Compound A from Lot 1 material. Ingredient Quantity (mg) Granulation Compound A (d90 of 4) 10.0 Lactose Monohydrate 153.8 Lactose Monohydrate (spray dried) 25.0 Hydroxypropyl Cellulose 4.0 Croscarmellose Sodium 9.0 Hydroxypropyl Cellulose (EF) 1.75 Sodium Lauryl Sulfate 0.7 Outside Powders Microcrystalline Cellulose (Granular-102) 37.5 Croscarmellose Sodium 7.0 Magnesium Stearate (vegetable) 1.25 Total 250 mg

… The tablets were manufactured using a wet granulation process. A step by step description of the process follows: Compound A and excipients were security sieved. The selective PDE5 inhibitor (i.e., Compound A) was dry blended with lactose monohydrate (spray dried), hydroxypropyl cellulose, croscarmellulose sodium, and lactose monohydrate. The resulting powder blend was granulated with an aqueous solution of hydroxypropyl cellulose and sodium lauryl sulfate using a Powrex or other suitable high shear granulator. Additional water can be added to reach the desired endpoint. A mill can be used to delump the wet granulation and facilitate drying. The wet granulation was dried using either a fluid bed dryer or a drying oven. After the material was dried, it can be sized to eliminate large agglomerates. Microcrystalline cellulose, croscarmellose sodium, and magnesium stearate were security sieved and added to the dry sized granules. These excipients and the dry granulation were mixed until uniform, using a tumble bin, ribbon mixer, or other suitable mixing equipment. The mixing process can be separated into two phases: (a) the microcrystalline cellulose, croscarmellose sodium and the dried granulation are added to the mixer and blended, followed by (b) the addition of the magnesium stearate to this granulation and a second mixing phase. The mixed granulation then was compressed into tablets using a rotary compression machine. The core tablets, if desired, can be film coated with an aqueous suspension of the appropriate color mixture in a coating pan (e.g., Accela Cota). The coated tablets can be lightly dusted with talc to improve tablet handling characteristics. … Dr Mooney notes that Example 4 of the 666 Patent is in materially the same terms as Example 1 in Oren. 599 Dr Mooney expresses the view that the formulation in Example 1 would fall within claims 1-3, 5-8 and 14-17. With respect to claims 10-12 and 18, Dr Mooney expresses the view that the values for Cmax and AUC (0-24) for a particle size of 8.4 µ (used in Example 3 in the 666 Patent) were in the middle of the ranges for claims 10-12 and 18. He expresses the view that if he could produce a particle size of 4 µ, then the values would be greater, although not substantially so, than the values for a particle size of 8.4 µ. This is dependent on the same formulation and manufacturing process as set out in Example 4. In essence, the effect of Dr Mooney's opinion is that if the formulation and manufacturing set out in Example 4 in the 666 Patent was used for Example 3 in the same patent, save for the micron size of 8.4, then the results can be used to predict, with a fair degree of certainty, the results for a tablet made in accordance with Example 4 in the 666 Patent and Example 1 in Oren. Those results (i.e., Cmax and AUC (0-24)) fall within claims 10-12 and 18. Dr Reece expresses a similar opinion. 600 The steps in Apotex's novelty case with respect to Oren are as follows. 601 First, the pharmacokinetic parameters identified in claims 10-12 and 18 are derived from the experiment in Example 3 in the 666 Patent. The study which is described in Example 3 involved the use of 10 mg oral doses in tablet form. 602 Secondly, the tablets were made according to the formula set out in Example 4 of the 666 Patent and were made as described therein. There is a dispute between the parties as to whether that was the case. 603 Thirdly, Oren satisfies the "whole of contents" requirements of the definition of "prior art base" in paragraph (b)(ii). Oren contains information about the formulation and manufacture as per Example 4 in the 666 Patent. 604 Fourthly, in addition to the disclosure of formulations of, and therapeutic uses for, tadalafil (including cGMP-PDE5 inhibition for the treatment of ED), Example 1 in Oren contains the information in Example 4 of the 666 Patent. 605 Fifthly, Example 1 in Oren is, with immaterial exceptions, identical to Example 4 in the 666 Patent. 606 Sixthly, both of the examples (Example 1 in Oren and Example 4 in the 666 Patent) refer to a "d90 of 4". Example 3 in the 666 Patent was intended to determine the bioequivalence of tablets containing different particle sizes and tablets with d90s of 52, 20 and 8.4 microns were tested. 607 Seventhly, Apotex's evidence is that if Example 1 in Oren is followed, that is to say, with a d90 of 4 microns, the Cmax and AUC is likely to be higher than the results in the 666 Patent, but within the ranges of claims 10-12 and 18. ICOS led no evidence to the contrary, the joint expert reports did not deal with this issue, and neither Dr Reece nor Dr Mooney was challenged on their evidence on this question. Apotex submits that this is the inevitable result of following Example 1 in Oren. 608 Finally, it follows that a skilled addressee who follows the teaching of Example 1 of Oren will make or use a pharmaceutical composition with a particle size of d90 of 4 microns whose properties will fall within claims 10-12 and 18 of the 666 Patent. Therefore, those claims and the claims dependent on them are not novel. 609 Apotex points to the fact that in the counterpart UK proceedings in the Patents Court, (Actavis Group v ICOS), claims 8 and 9 of the 092 patent in that case were in equivalent terms to the pharmacokinetic parameter claims of the 666 Patent. The claims were as follows: 8. A pharmaceutical composition comprising: (a) a free drug form of a compound having the formula of [tadalafil] and pharmaceutically-acceptable salts and solvates thereof, in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate; and (b) one or more pharmaceutically-acceptable carriers, diluents, or, excipients. wherein the composition exhibits a Cmax of 180 to 280 micrograms/litre or an AUC (0-24) of 2280 to 3560 microgram hour/litre, measured using a 10 milligram dose of the compound. 9. The composition of claim 8 wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/litre and an AUC (0-24) of 2280 to 3560 microgram.hour/litre. 610 Justice Birss held that all of the claims of the 092 patent were invalid, including the pharmacokinetic claims. His Lordship referred to the law in General Tire and expressed his conclusions as follows (at [408] and [409]): In this case the target is clear. Oren teaches the skilled person to make a formulation with a d90 of 4 microns. That is the inevitable result of Oren. The question is whether a composition with that property necessarily has the claimed pharmacokinetics. This size range means the particles are smaller than the narrowest claimed range in the patent (claim 4 has a d90 of 10 microns). Mr Muirhead's evidence on this was not challenged. In paragraphs 59 to 66 Mr Muirhead analyses data available to him in the proceedings and expresses his opinion as follows: "I consider it highly likely that the formulation accordingly to Example 1 of Oren (which contains tadalafil with a d90 particle size of 4 µm) would exhibit Cmax and AUC values with the ranges […] stated by claims 8 and 9." This is an opinion that it is highly likely that the product will have the claimed property. I accept that evidence and find that the product which would inevitably be produced by a skilled person following Oren would, as a matter of fact decided on the balance of probabilities, be within claims 8 and 9. Those claims therefore lack novelty and the same goes for all the claims dependent on them. Apotex submitted that this Court should adopt similar reasoning. 611 With respect to the competing priorities, the parties are agreed that the same example which is in Oren as Example 1 appears in the 666 Priority Document as Example 3. That is correct and such differences as there may be are immaterial. 612 Apotex submits that the fact that while neither priority document discloses the pharmacokinetic parameters, it has proved that following Example 1 of Oren will have the inevitable result of achieving the pharmacokinetic parameters in claims 10-12 and 18 of the 666 Patent and that, therefore, the General Tire test for a lack of novelty is satisfied. However, Apotex submits that such an inevitable result cannot be a "real and reasonably clear disclosure" for the purposes of concluding that the 666 Patent is fairly based on the 666 Priority Document and, therefore, the priority date is August 2000. Apotex submits that in light of the absence of any factual dispute, the question of priority appears to be ICOS's only answer to the case of a lack of novelty based on Oren. The two priority documents were filed on the same day, neither expressly referring to the pharmacokinetic parameters of AUC and Cmax, but each containing the same example. The 666 Priority Document refers only to Tmax (e.g., at pp 11-12). The 666 Patent made later claims to the AUC and Cmax parameters with appropriate description. They are, however, the inevitable result of following Example 1 in Oren and it follows that they are not novel. 613 Apotex submits that, with respect to the new dependent claims in the 666 Patent, being claims 24-28 and 34-38 inclusive, the same conclusion follows for claims 24, 26, 28, 34, 36 and 38 which encompasses a 10 mg dosage form as in Example 1 of Oren. Claims 25 and 35 are limited to 20 mg dosage forms and claims 27 and 37 are limited to 5 mg dosage forms. The pharmacokinetic parameters in the relevant claims of the 666 Patent are measured according to a 10 mg dose, but encompass dosage forms with other doses that exhibit proportionally adjusted Cmax and AUC (0-24) values. 614 Oren describes a 5 mg tablet of tadalafil in Example 2 made by an analogous formulation and method to Example 1 in Oren. Oren also describes a 20 mg tablet, for example in claim 22. Apotex submits that according to the linear pharmacokinetics described in the 666 Patent, the Cmax and AUC (0-24) values for tadalafil are dose dependent in the 5-20 mg dose range. That is, the Cmax and AUC (0-24) for a 5 mg dosage form is about half that of a 10 mg dosage form, and the Cmax and AUC (0-24) for a 20 mg dosage form is about twice that of a 10 mg dosage form. It follows that 5 mg and 20 mg dosage forms described in Oren also will exhibit Cmax and AUC (0-24) values falling within the pharmacokinetic parameters claims of the 666 Patent and therefore anticipate claims 25, 27, 35 and 37. 615 ICOS advanced two submissions in response to Apotex's submission that Oren anticipates the pharmacokinetic parameters in the 666 Patent. First, it submits that the pharmacokinetic claims in the 666 Patent are entitled to claim a priority date of 3 August 1999 based on the disclosure in Example 3 in the 666 Priority Document. That being so, Oren is not an anticipation. Secondly, it submits that the 666 Patent should not be construed so as to lead to the conclusion that the tablets which were the subject of the study identified in Example 3 were manufactured and formulated in accordance with Example 4. The conclusion is a critical element of Apotex's case because Apotex's case is dependent on showing that a tablet formulated in accordance with Example 4 in the 666 Patent (and Example 1 in Oren) will produce the results set out in Example 3 of the 666 Patent. As I have said, Example 1 in Oren is materially the same as Example 4 in the 666 Patent and to provide the link between the results in Example 3 in the 666 Patent and Example 1 in Oren, Apotex must show that the formulation in Example 4 in the 666 Patent produced the results set out in Example 3 in the 666 Patent.

Relevant Principles 616 I set out the relevant principles as to novelty and a whole of contents publication when considering the novelty challenge to the relevant claims in the 946 Patent. I will not repeat what I have said. 617 In Delnorth Pty Ltd v Dura-Post (Aust) Pty Ltd [2008] FCA 1225; (2008) 78 IPR 463, Gyles J discussed the principles involved in "fair basing" in the context of considering the claims in issue in that case and a provisional specification. His Honour referred with approval to the general approach described by Buckley J in Re Stauffer Chemical Company's Application [1977] RPC 33 at [34]: If a new feature were a development along the same line of thought which constitutes or underlies the invention described in the earlier document, it might be that that development could properly be regarded as fairly based on the matter disclosed in the earlier document, and that the new process described in the later document which incorporates that development could as a whole be regarded as fairly based upon the matter disclosed in the earlier document. If, on the other hand, the additional feature involves a new inventive step or brings something new into the combination which represents a departure from the idea of the invention described in the earlier document, it could not, I think, be properly described as fairly based upon the earlier document. 618 Justice Gyles also referred with approval to the following statement of Fox J in Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1988) AIPC 90-491; (1987) 15 FCR 382 at 389: Where the holder of the provisional specification proceeds with a complete specification with a view to the grant of a patent, it is recognised that greater definition, as a result of further experimentation or otherwise, may be achieved before the later step is taken and the result expressed therein. Some generality of expression in the provisional specification is accepted. 619 A feature which is a development along the same line of thought which constitutes or underlies the invention described in the priority document does negate a conclusion that a later document is fairly based on an earlier document (CCOM Pty Ltd v Jiejing Pty Ltd (1994) AIPC 91-079; (1994) 51 FCR 260). 620 In Anaesthetic Supplies Pty Ltd v Rescare Ltd (1994) AIPC 91-076; (1994) 50 FCR 1 at 20, Lockhart J (with whom Wilcox and Shepherd JJ agreed) said: All that the provisional specification needs to do is described generally and fairly the nature of the invention, and not to enter into all the minute details as to the manner in which the invention is to be carried out. It is a mode of protecting an inventor until the time of filing the final specification. It is not intended to be a complete description of the invention, but simply to disclose the invention fairly, though in its rough state. The interval of time between the provisional and final is intended to provide an opportunity for the development and precise expression of the invention foreshadowed in the provisional. 621 In Sigma Pharmaceuticals (Aust) Pty Ltd v Wyeth [2011] FCAFC 132; (2011) 119 IPR 194 at [78], Bennett J (with whom Yates J agreed) said: …the earlier document must in substance disclose the claimed invention. Even if that invention were further developed in the later document, it must be the same invention. Additionally, a disclaimer of the scope of the invention described in the earlier document cannot be disregarded in assessing the external fair basis of the subsequent claim on that earlier document. 622 In Vehicle Monitoring Systems Pty Limited v Sarb Management Group Pty Ltd (t/as Database Consultants Australia) (No 2) [2013] FCA 395; (2013) 101 IPR 496 (Vehicle Monitoring Systems), Yates J said (at [210]): …But if the disclosures in the parent specification anticipate the invention as claimed (as the respondent contended), the claims must at least pass the threshold of being fairly based on matter disclosed in the parent specification, in the sense that there must be a real and reasonably clear disclosure of the invention as claimed. I reject the respondent's contrary submission. It can be seen, therefore, that the respondent's challenge to validity, based on the prior publication of the parent specification, is self-defeating because that challenge provides an undeniable foundation for finding that the priority date of the claims is not the deferred date.

Analysis 623 The 666 Priority Document does not disclose the specific pharmacokinetic values in claims 10-12 and 18 of the 666 Patent. However, rapid absorption of the API is a claimed feature of the invention. For example, the summary of the invention includes the following: The present invention provides particulate preparations of free drug forms of β-carboline compounds having specific and defined particle size characteristics allowing for uniform formulation of stable pharmaceutical compositions and particularly compositions allowing for rapid achievement of maximum blood concentration and/or rapid onset of PDE5 inhibitory therapeutic effect. 624 The suggestion is that the compositions in the 666 Priority Document will provide desirable pharmacokinetic values for rapid onset, including a desirable Cmax or rapid maximum blood concentration. Furthermore, Example 2 in the 666 Priority Document reports on in vivo studies of pharmaceutical compositions made in accordance with, inter alia, Example 3 compared with a co-precipitate formulation and testing for Tmax and, therefore, improved bioavailability. The results showed, it is asserted, an improved Tmax and, therefore, an improved bioavailability. 625 Example 2 in the 666 Priority Document is the same as Example 2 in the 666 Patent. 626 Dr Reece acknowledged that Example 2 in the 666 Priority Document is the same as Example 2 in the 666 Patent. Dr Reece explained that the Cmax and AUC (0-24) ranges specified in claims 10-12 and 18 of the 666 Patent have been defined by taking the Cmax and AUC (0-24) data that is recorded for the d90 = 8.4 micron formulation in Example 3 of the 666 Patent and applying the lower (80%) to upper (125%) bioequivalent limits to the data reported for that formulation. To establish a lack of novelty on the basis of inevitable result novelty, Apotex asserts that the d90 = 8.4 micron formulation used in Example 3 of the 666 Patent is the same formulation that was used in Example 2 of the 666 Patent. Example 2 states that the pharmaceutical formulations were prepared as set out in Examples 4 and 5. Adopting that approach, the d90 = 8.4 micron formulation of Example 3, from which the pharmacokinetic values in claims 10-12 and 18 of the 666 Patent are derived, were also disclosed as Example 2 of the 666 Patent. ICOS submitted that plainly, it was a development "along the same line of thought" or mere "greater definition" for the inventors of the 666 Patent to take Example 2 of the 666 Priority Document to determine the Cmax and AUC values for that formulation and apply the common general knowledge 80-125 % confidence levels to identify the claimed pharmacokinetic ranges. ICOS submitted that it follows that Example 2 of the 666 Priority Document, together with Example 3 and the statements in the summary of the invention set out above, provides a real and reasonably clear disclosure of the claimed pharmacokinetic (Cmax and AUC (0-24)) values, on Apotex's own case. 627 In my opinion, the submissions advanced by ICOS are correct. The statements in the 666 Priority Document about the rapid achievement of maximum blood concentration and Examples 2 and 3 are a real and reasonably clear disclosure of the claimed pharmacokinetic values. To adapt the words of Yates J in Vehicle Monitory Systems, if Oren anticipates the claims then it must also be the case that the 666 Priority Document is a real and reasonably clear disclosure of the claims. In addition, as ICOS submitted, the case is even stronger here because the novelty document is a "whole of contents" citation which requires the information contained therein to be capable of being made the subject of an actual or notional claim that is, of itself, fairly based, before the information can form part of the prior art base. Another way of putting this argument is that first there is no reference to pharmacokinetic parameters in Oren and it does not anticipate the pharmacokinetic claims in the 666 Patent. Alternatively, if the inevitable result of Example 1 is the pharmacokinetic parameters in the 666 Patent, then the inevitable result of Example 3 in the 666 Priority Document is the same and the pharmacokinetic claims in the 666 Patent are fairly based on the 666 Priority Document. 628 Finally, in my opinion, there is a real and reasonably clear disclosure in the 666 Priority Document of claims 24-28 and 34-38 insofar as those claims add dosage integers. The following statement appears in Example 2 in the 666 Priority Document: …A typical daily dose will contain a nontoxic dosage level from about 1 to 20 mg/day of a particulate compound of the present invention. Preferred daily doses generally will be from about 1 to 10 mg/day, particularly of 5 mg and 10 mg tablets, administered once per day. 629 These conclusions are sufficient to dispose of Apotex's novelty case based on Oren. ICOS did have an alternative argument in answer to Apotex's novelty challenge and I will address it for the sake of completeness. The argument was that it was essential for Apotex to establish that the formulation in Example 4 of the 666 Patent was used to make the composition used in Example 3 subject to different particle sizes. That proposition is correct and is not in dispute. It is the next step which is contentious. Apotex submits that it should be inferred that the formulation in Example 4 was used to make the composition used in Example 3 subject to different particle size because Example 4 is the only example of a formulation in the 666 Patent of a 10 mg dose and a 10 mg dose was the dose used in the study described in Example 3. ICOS's submission is that there is no express statement in Example 3 that the tablets used in the study were formulated in accordance with Example 4 and that was in a context where in Example 2 there is an express statement that the pharmaceutical compositions used were prepared in accordance with Examples 4 and 5. 630 In my opinion, it should be inferred, having regard to all five examples in the 666 Patent, that the formulation of the 10 mg doses described in Example 4 was used, subject to particle sizes, for the preparation of the tablets used in the study described in Example 3. ICOS's alternative argument fails.

Conclusion 631 Oren does not anticipate claims 10-12 and 18 (and the other claims identified insofar as they are dependent on those claims) in the 666 Patent.

The Pleaded Case 632 Apotex's false suggestion case is that each of the claims in suit in the 946 Patent are invalid and liable to be revoked on the ground that they were obtained by false suggestion or misrepresentation within the meaning of s 138(3)(d) of the Act. That section provides that a patent or claims in a patent may be revoked by an order of the Court on the ground that the patent was obtained by fraud, false suggestion or misrepresentation. 633 Although Apotex formally presses its plea of inutility, it accepts that the plea must fail in light of the amendments to the 946 Patent. 634 Apotex's pleaded case is that ICOS made the following suggestion or representation to the Commissioner of Patents prior to the grant of the 946 Patent: The alleged invention as claimed in each of claims 1-6, 8-17, 19-29 and 31-35 of AU 946 provides an effective treatment of erectile dysfunction that eliminates, or reduces to clinically insignificant levels, the side effects associated with sildenafil, including: (i) facial flushing; (ii) vision abnormalities; and (iii) adverse cardiovascular events, including a significant decrease in blood pressure, when tadalafil is administered alone or in combination with an organic nitrate. I will refer to this as the pleaded representation. 635 Apotex alleges that the pleaded representation was made in the Specification of the 946 Patent which was filed on 26 April 2000 and in correspondence from ICOS's patent and trade mark attorneys (Wrays and Associates (Wrays)) to IP Australia in 2003. The exchange of correspondence related to the examination of the application by IP Australia and a consideration by it of whether there were lawful grounds of objection to the application. 636 As I have previously said, a number of the statements in the unamended Specification were deleted as a result of orders I made on the Amendment Application. 637 I turn now to identify the statements made in the unamended Specification and in the Wrays' correspondence with IP Australia which are said by Apotex to give rise to the pleaded representation. 638 The unamended Specification of the 946 Patent contained the following statements: Applicants have discovered that [tadalafil] can be administered in a unit dose that provides an effective treatment without the side effects associated with the presently marketed PDE inhibitor, sildenafil. Prior to the present invention such side effects were considered inherent to the inhibition of PDE5. (pp 3-4) The above passage was amended to read: Applicants have discovered that [tadalafil] can be administered in a unit dose that provides an effective treatment without all of the side effects associated with the presently marketed PDE inhibitor, sildenafil. Prior to the present invention such side effects were considered inherent to the inhibition of PDE5. 639 The unamended Specification contained the following statements: Significantly, applicants' clinical studies also reveal that an effective product having a reduced tendency to cause flushing in susceptible individuals can be provided. Most unexpectedly, the product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when [tadalafil] is administered as a unit dose of about 1 to about 20 mg, as disclosed herein. (p 4) The above passage was amended to read: Significantly, applicants' clinical studies also reveal that an effective product having a reduced tendency to cause flushing in susceptible individuals, relative to sildenafil, can be provided. Most unexpectedly, the product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when [tadalafil] is administered as a unit dose of about 1 to about 20 mg, as disclosed herein. 640 The unamended Specification contained the following statements: Thus, the present invention provides an effective therapy for sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalities. (p 4) The above passage was amended to read: Thus, the present invention also provides an effective therapy for sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, in particular including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalities. 641 The unamended Specification contained the following statements: The present invention is based on detailed experiments and clinical trials, and the unexpected observations that side effects previously believed to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels by the selection of a compound and unit dose. This unexpected observation enabled the development of a unit dosage form that incorporates [tadalafil] in about 1 to about 20 mg per unit dosage forms that, when orally administered, minimizes undesirable side effects previously believed unavoidable. These side effects include facial flushing, vision abnormalities, and a significant decrease in blood pressure, when [tadalafil] is administered alone or in combination with an organic nitrate. (pp 10-11) The above passage was amended to read: The present invention is based on detailed experiments and clinical trials, and the unexpected observations that some side effects previously believed to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels by the selection of a compound and unit dose. This unexpected observation enabled the development of a unit dosage form that incorporates [tadalafil] in about 1 to about 20 mg per unit dosage forms that, when orally administered, minimizes some undesirable side effects previously believed unavoidable. These side effects include facial flushing, vision abnormalities, and a significant decrease in blood pressure, when [tadalafil] is administered alone or in combination with an organic nitrate. 642 I turn now to the Wrays' correspondence with IP Australia in 2003. 643 By letter dated 24 February 2003, an examiner at IP Australia provided a report in relation to ICOS's patent application and in that report, the examiner stated that she believed there were lawful grounds of objection to the application. Those grounds included a lack of novelty and a lack of an inventive step of certain claims having regard to the teachings in Daugan 1995 and Daugan 1997. With respect to a lack of novelty, the examiner relied on a statement in a previous decision of the Patents Office to the effect that if a material or compound is known, then any specified quantity of the material or compound is equally known, and, with respect to a lack of an inventive step, the examiner relied on a proposition that a person skilled in the art would routinely investigate the administration of different quantities of known drugs for a known physiological effect and, in those circumstances, the particular dosages in the claims did not involve an inventive step. 644 ICOS took issue with the examiner's approach and, through Wrays, wrote to IP Australia by letter dated 1 July 2003. The passages in the letter which are said by Apotex to give rise to the pleaded representation are as follows: …In addition, the presently claimed invention provides unexpected benefits and is a substantial advance in the art. In particular, the presently claimed invention (a) effectively treats sexual dysfunction using a low dose of a particular PDE5 inhibitor, (b) eliminates or reduces various adverse side effects associated with current PDE5 inhibitor therapy used to treat sexual dysfunction (eg VIAGRA®) and (c) increases the population treatable for sexual dysfunction using a PDE5 inhibitor. (at p 2) Applicants have further discovered that the compound of the present invention can be administered in a unit dosage composition containing about 1 to 20 mg of the compound to provide an effective sexual dysfunction treatment, while reducing or eliminating various adverse side effects associated with VIAGRA®. The present invention is based on detailed experiments and clinical trials, and the unexpected discovery that various side effects previously believed attributable to PDE5 inhibition can be reduced to clinically insignificant levels by the selection of (a) a particular PDE5 inhibitor and (b) a particular low unit dosage. This unexpected discovery led to the development of a unit dosage composition incorporating about 1 to about 20 mg of Compound (1) that, when orally administered, effectively treats sexual dysfunction and eliminates or reduces various undesirable side effects previously believed attributable to PDE5 inhibition, and, therefore, unavoidable. These adverse effects include facial flushing and vision abnormalities. (at pp 3-4) Clinical studies have shown that the presently claimed unit dosage composition is an effective product having a reduced tendency to cause flushing or visual abnormalities in susceptible individuals. (at p 4) The present invention therefore, is an improvement over the main commercial PDE5 inhibitor treatment for sexual dysfunction, i.e., VIAGRA®. VIAGRA® must be administered orally in a dose of at least 25 mg (the lowest labeled dosage), and can be administered up to 100 mg. Administration of sildenafil citrate also leads to various adverse side effects, as indicated in the VIAGRA® insert (attached). In addition, particular individuals are precluded from using sildenafil, as noted in the warnings and contraindications present on the VIAGRA® insert. The present invention reduces or eliminates some of these adverse side effects, and allows more individuals to use PDE5 inhibitor therapy to treat sexual dysfunction. (at p 4) The present invention also provides an oral PDE5 inhibitor treatment for sexual dysfunction that previously was unavailable to a portion of the population. When administered in about 1 to 20 mg unit dosage forms, the minimal effect of Compound (1) on PDE6 allows the treatment of sexual dysfunction in individuals who also may be suffering from a retinal disease, like diabetic retinopathy or retinitis pigmentosa. Such individuals previously shunned PDE5 inhibitor treatment for sexual dysfunctions because of warnings on the VIAGRA® label, for example. Furthermore, persons prone to flushing and vision abnormalities now can more freely use a PDE5 inhibitor treatment and have little to no concern with respect to these adverse side effects. In addition, persons who were precluded from PDE5 inhibitor treatment now have an available treatment, e.g., persons suffering form [sic] a retinal disease, suffering from class 1 congestive heart failure, or having a myocardial infarction 3 to 6 months prior to onset of PDE5 inhibitor treatment. (at pp 4-5) A person skilled in the art would not have been motivated from '675 and '978 to provide a unit dose composition as recited in the present claims with any expectation that the unit dosage composition would provide such unexpected results in the treatment of sexual dysfunction. From a reading of '675 and '978, it would have been expected that a dose greater than 20 mg of Compound (1) is needed to treat sexual dysfunction effectively, i.e., about 50 mg. Additional unexpected benefits of the present invention are the improvements demonstrated by a claimed unit dosage composition over commercially available VIAGRA®. The present invention, therefore, not only is novel and inventive over '675 and '978, but also satisfies unmet needs in the art. (at p 5) In summary, the presently claimed invention is novel and inventive over '675 and '978, and the invention satisfies a long-felt need in the art. All examples in '675 and '978 teach a 50 mg dose of the active compound. The cited art absolutely fails to suggest that a low dose of any PDE5 inhibitor, let alone the specific PDE5 inhibitor of the present invention, can be used to successfully treat sexual dysfunction, while eliminating or reducing various adverse side effects associated with the current PDE5 inhibitor treatment for sexual dysfunction. (at p 5) The present invention is not directed to optimizing the dosage of PDE5 inhibitor or the route of administration, but is directed to the discovery of an oral dosage composition containing about 1 to 20 mg of a specific PDE5 inhibitor that effectively treats sexual dysfunction. The reduced PDE5 inhibitor dosage not only performs its intended function, but reduces or eliminates various adverse effects associated with administration of sildenafil citrate, and allows a previously precluded segment of the population to undergo PDE5 inhibitor therapy to treat sexual dysfunction. (at pp 5-6) 645 The significant features of these passages are the following: the use of similar phraseology to that used in the unamended Specification, being the invention "eliminates or reduces" side effects, a comparison with the first generation drug, sildenafil, a claim that the invention satisfies unmet needs in the art in the form of the elimination or reduction of side effects (and perhaps a need for a lower dosage), a claim of an ability to treat a wider group and a reference to the side effects of facial flushing and vision abnormalities, but no reference to the side effect of reduced blood pressure when a PDE5 is co-administered with a nitrate. The passages also emphasise the unexpected nature of the benefits of low doses of tadalafil. 646 The examiner was unpersuaded by these statements and, in her second report, she maintained a novelty objection in relation to certain claims based on Daugan 1995 and Daugan 1997. Further correspondence ensued, with Wrays responding by letter dated 15 September 2003 and referring to the General Tire test and asserting that a key integer of the invention, namely, the dosage of 1 to 20 mg was not disclosed in the prior art. In her third report, the examiner maintained her position with respect to a lack of novelty and a lack of an inventive step. She addressed arguments about whether the particular dosages of the claimed invention were disclosed in the prior art in the sense described in the General Tire test. 647 Wrays responded to the examiner's third report by letter dated 6 November 2003. Apotex relies on the following passages in that letter: However, we note that neither specification contains any further reference to the advantages of dosage forms in the 0.1-20 mg range, nor do they provide any examples of dosage forms within this range, and we respectfully submit that the present invention constitutes a selection invention within the criteria listed in I.G. Farbenindustrie AG's Patents (1930) RPC 289. (at p 1) Firstly, as is apparent from the specification, the claimed dosage range has been selected to avoid the disadvantages conventionally understood to be inherently associated with the inhibition of PDE5 (see page 4). We also draw the examiner's attention to the paragraph beginning on line 24, page 10, which expressly states that the present invention constitutes the selection of the defined unit dose of the compound. (at p 1) Further, the selection of the compound and dosage range is based on 'detailed experiments and clinical trials' and it is at least implicit that the selected range represents a lower threshold at the compound is dosage form of treating the relevant disease states, and an upper threshold at which, whilst the compound is obviously capable of treating the desired disease states, the undesired side effects can no longer be considered clinically insignificant. Thus, it can be said that the present invention satisfies the second and third criteria set down in the I.G. Farbenindustrie case in that the whole of the selected members possess the advantages in question, and that the advantages in question are peculiar to the selected group. (at pp 1-2) The letter concludes with an assertion that the prior decision of the Patents Office was inconsistent with "the well established body of law in relation to selection inventions". 648 I note that the criteria for a selection invention were stated by Maughan J in IG Farbenindustrie AG's Patents (1930) 47 RPC 289 and appear in the following passage (at 322-323): Three general propositions may, however, I think, be asserted as true:- First, a selection patent to be valid must be based on some substantial advantage to be secured by the use of the selected members. (The phrase will be understood to include the case of a substantial disadvantage to be thereby avoided.) Secondly, the whole of the selected members must possess the advantage in question. Thirdly, the selection must be in respect of a quality of a special character which can fairly be said to be peculiar to the selected group. 649 Apotex put before the Court the Australian Patent Office Manual of Practice and Procedure of September 2002 and that document contains a detailed description of "Selections" and the advantages which they must describe. 650 The Wrays' letter dated 6 November 2003 was the last letter in the chain of correspondence put before the Court. The 946 Patent was granted some seven months later. The application was advertised as accepted on 12 February 2004 and there was then a three month period allowed for opposition. 651 Apotex's case is that the pleaded representation in the unamended Specification and the correspondence of Wrays which I have identified, was false and misleading. In support of that allegation, Apotex relies on what it describes as the adverse effects, warnings, contraindications and studies described in the current versions, and the versions prior to the date of the grant of the 946 Patent of the following: the PI Statements for the Australian Cialis (tadalafil) products; the Prescribing Information for the US Cialis products; the Product Monograph for the Canadian Cialis products, and the PI Statements for the sildenafil products marketed under the brand name, Viagra in Australia by Pfizer Australia Pty Ltd with ARTG Nos. 64434, 64435 and 64436. In addition, Apotex relies on the results and conclusions of studies which are described in the following documents: Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, "Time Course of the Interaction Between Tadalafil and Nitrates" (2003) 42 Journal of the American College of Cardiology 1855 (Kloner et al (2003)); Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, "Reply" (2004) 43 Journal of the American College of Cardiology 2150 (Kloner et al Reply); and Kloner RA, Mitchell MI and Emmick JT, "Cardiovascular Effects of Tadalafil" (2003) 92 The American Journal of Cardiology 37M (Kloner et al Review). Where appropriate, I will refer to these three papers collectively as the Kloner Papers. 652 Finally, Apotex alleges that the pleaded representation contributed in a material way to the decision of the Commissioner of Patents to grant the 946 Patent and, in support of that allegation, it relies on the chain of correspondence between Wrays and IP Australia.

Relevant Principles 653 For the purposes of this case, the following principles or propositions are relevant. First, a false suggestion can be made by statements in the specification about the nature or utility of the invention. Secondly, it is not necessary in order to make out a false suggestion case to establish that the person making the suggestion had an intention to deceive. The notion of false suggestion is informed by principles akin to those relating to equitable fraud. Thirdly, it is not necessary in order to engage the power to revoke a patent, or claims in a patent, on the ground of false suggestion or misrepresentation to establish that the patent would not have been granted but for the conduct constituting the false suggestion or misrepresentation. It is sufficient if the conduct which constitutes the false suggestion or misrepresentation materially contributed to the decision to grant the patent. Fourthly, where the Commissioner (or her delegate) does not complain about the patentee's conduct and does not give evidence, the question becomes one of whether the Court should infer that the representation played a part in the decision. Nevertheless, in deciding whether to draw the inference, it is relevant that the Commissioner has not complained about being misled or deceived. These propositions are established by the following cases. 654 Re Alsop's Patent (1907) 24 RPC 733 establishes that a false suggestion can be made by statements in the specification about the nature or utility of the invention. 655 The Patents Act 1952 (Cth) contained a provision which provided for the revocation of a patent if it was obtained on a false suggestion or representation (s 100(1)(k)). This section was considered by the Full Court of this Court in Prestige Group (Aust) Pty Ltd v Dart Industries Inc (1990) AIPC 90-715; (1990) 26 FCR 197 (Prestige Group v Dart Industries). It was not suggested by either party that the difference in wording between the 1952 Act and the 1990 Act is material for the purposes of this case. 656 Justice Lockhart made the following observations about s 100(1)(k) (at 198-199 and 201): The words "false suggestion or representation" are of wide import. The statutory ground of revocation and invalidity expressed in s 100(1)(k) is based on equitable notions of good faith, fairness, conscionable conduct and honesty. If an applicant for a patent has misled the Commissioner in a material respect in the course of procedures which led to the grant of the patent, he should not have the benefit of his misleading conduct…It is possible that there is little work for s 100(1)(k) to do; but that it has some work to do is recognised by its presence in the section as a separate ground of revocation. It is a good example of the kind of objection which should not be narrowed or circumscribed by judicial decision, but left to develop in the light of changing circumstances and as each case arises. Indeed, in many cases the material on which a defendant may seek to rely in support of a defence of file wrapper estoppel would be admissible as evidence of false suggestion or representation. … Although s 100(1)(k) uses the words "false suggestion" I derive no principle from the authorities to support the proposition that fraud in the sense of deliberate intent to deceive is necessarily involved. Indeed, quite the contrary, as the cases speak of the relevant conduct in terms akin to equitable fraud… 657 His Honour also identified the conduct which might give rise to a false suggestion or misrepresentation in terms which match the circumstances pleaded by Apotex in this case. His Honour said (at 199): There are, at this stage in the development of the law relating to false suggestion or representation (but the categories must not be regarded as closed), two types of conduct which may fall within s 100(1)(k): first, promises made by the patentee in the specification itself as to the results which he asserts are obtainable by the invention and second, conduct of the patentee during the process of application for grant. 658 In terms of the causative link required, Lockhart J, after referring to a statement in Blanco White TA, Patent for Inventions and the Protection of Industrial Designs (5th ed, Stevens, 1983) at [4-1002], said (at 201): …I would state the test, however, in different terms, namely, whether the conduct constituting the false suggestion or representation materially contributed to the Commissioner's decision to grant the patent even if other circumstances or causes also played a part in the making of that decision. It is sufficient if the conduct is a material inducing factor which led to the grant. It goes too far to say that the false suggestion or representation must be material in the sense that without it the patent would not have proceeded to grant. 659 Justice Gummow (with whom Northrop J agreed) agreed with Lockhart J that it would be sufficient that the false suggestion was a material inducing factor to the grant. His Honour said that he would not accept that the patent will be bad only if it can be shown on the facts that no grant would have been made "but for" the false suggestion (at 218). 660 Section 138(3)(d) was considered by the Full Court of this Court in Ranbaxy Australia v Warner-Lambert Co LLC [2008] FCAFC 82; (2008) 77 IPR 449 (Ranbaxy v Warner-Lambert). That case confirmed the application of the causation test identified by the Court in Prestige Group v Dart Industries. The Court also made the point that as the grant of a patent was a right in rem and the Commissioner could be expected to take a position if a misrepresentation did, in fact, play a part in the decision to grant the patent, it is a relevant circumstance that the Commissioner chooses not to give evidence. In the absence of such evidence, it is for the Court to make a finding based on the evidence before it. If a particular representation was objectively likely to contribute to whether or not a patent is granted and the patent was, in fact, granted, then it is open to the Court to infer that a representation in fact contributed to the decision to grant the patent (at [83]). 661 As I mentioned in the Amendment Reasons (at [30]), the Commissioner was given notice of the amendments sought in relation to both patents. She considered that they met the requirements of s 102 of the Act and indicated that she did not intend to appear at the hearing. 662 The Full Court in Ranbaxy v Warner-Lambert also made it clear that false suggestion was not limited to information in the claims of a specification and could include representations in a letter from an applicant's patent attorney (at [107]). After making the point that it is necessary to prove causation as well as the fact that a statement was false or misleading, the Full Court explained its reasons for finding that causation was established in the case before it. In a passage which in many aspects reflects how Apotex puts its case, the Court said (at [140]): …When the examiner questioned the patentability of a claim to an enantiomer where the racemate had been prior published, the representation was repeated and affirmed. The statements in the patent attorneys' letter were made in response to the examiner's objection, which if not overcome, would have led to rejection of the patent application. The statements sought to overcome the objection. Warner-Lambert succeeded in overcoming the objection based on want of novelty and the Enantiomer Patent was granted. The inference is clearly open, and should be drawn, that the grant of the Enantiomer Patent was made because the examiner accepted the truth of the representation. It follows that the Enantiomer Patent was obtained by false suggestion or misrepresentation. That is the conclusion reached by the primary judge. 663 Finally, it is convenient to note a related matter. In Pracdes Pty Ltd v Stanilite Electronics Pty Ltd (1995) 35 IPR 259, Windeyer J upheld a claim that a patent was obtained on a false representation contained in the specification. The false representation concerned the elimination by the claimed invention of a disadvantage identified in the prior art. His Honour said that one could not call the Commissioner to establish whether the representation substantially influenced his decision, but that was a matter which could be inferred from the way in which the claim for improvements had been made. As noted in the Amendment Reasons, Windeyer J subsequently allowed an amendment to the patent to delete the matter giving rise to the false representation (Pracdes Pty Ltd v Stanilite Electronics Pty Ltd (1995) 35 IPR 277).

Analysis 664 Apotex's false suggestion case raises four issues. First, was the pleaded representation made in the unamended Specification or in Wrays' correspondence or both? Secondly, was the pleaded representation false? Thirdly, if the pleaded representation was made and it was false, did it materially contribute to the decision to grant the patent? Finally, even if all of these questions are answered in favour of Apotex, is there a residual discretion under s 138(3)(d) of the Act to decline to revoke the 946 Patent and should such a discretion be exercised in this case? As will become clear, the critical issue in this case is the nature of the representation(s) which was made. 665 Sildenafil was the first generation drug and it was known to have side effects. Tadalafil is a second generation drug. The pleaded representation relates to claimed advantages of tadalafil in terms of side effects. Although the pleaded representation uses the word "including", the case is limited to the three side effects identified in the pleaded representation, namely, facial flushing, vision abnormalities and the hypotensive effects of the co-administration of the claimed invention and nitrates, or the claimed invention alone. 666 It is convenient at this point to describe, in general terms, the nature of each of these side effects. 667 As mentioned earlier in these reasons, the 946 Patent contains a definition of "flushing" which is sufficient for present purposes. It is as follows: … means an episodic redness of the face and neck attributed to vasodilation caused by ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration. 668 I will examine the evidence of the clinicians concerning facial flushing in due course. The short point at this stage is that a small number of patients suffer facial flushing as a result of taking tadalafil and most of this group tolerate the side effect. A small number of patients within the class who think facial flushing is a sign of a possible heart attack will cease or suspend taking tadalafil. For these patients, it is a relatively serious side effect. 669 As mentioned earlier in these reasons, the 946 Patent also contains a definition of "vision abnormalities". Again, it is sufficient for present purposes. It is as follows: … means abnormal vision characterized by blue-green vision believed to be caused by PDE6 inhibition. 670 Dr Mitchell explained the mechanism whereby a PDE5 inhibitor might augment the hypotensive effect of a nitrate. I accept his explanation which is as follows. 671 Tadalafil belongs to a class of compounds that inhibit an enzyme called phosphodiesterase type-5 (PDE5). While PDE5 is found in many tissues and organs throughout the body, it is the predominant PDE in the corpora cavernosa of the penis, that is, the spongey erectile tissue which fills with blood during an erection. To say that tadalafil is a PDE5 inhibitor means that it is much more highly selective for PDE5 compared with the other PDE isoforms. Other PDE5 inhibitors which have been marketed as pharmaceuticals include sildenafil, marketed by Pfizer under the brand names, Viagra® and Revatoio®, and vardenafil, marketed by Bayer Pharmaceuticals under the brand name, Levitra®. 672 When a male becomes sexually aroused, NO is released by the parasympathetic nerves to the penis and also by the endothelial cells lining the arteries of the penis. The NO diffuses into the smooth muscle in the artery walls where it activates an enzyme called guanylate cyclase, leading to the production of cyclic guanosine monophosphate (cGMP). cGMP activates downstream signalling pathways, ultimately leading to a decrease in intracellular calcium levels and relaxation of the arterial smooth muscle. This allows the arteries to dilute and blood flow into the corpora cavernosa of the penis to increase significantly leading to an erection. cGMP is converted to the inactive form, 5'GMP by PDE5. The breakdown of cGMP ultimately leads to blood vessel constriction and return of the penis to a flaccid state. Molecules such as tadalafil, sildenafil and vardenafil are all competitive reversible inhibitors of PDE5, which means they temporarily block PDE5 from breaking down cGMP by competing with cGMP for the active site of the enzyme. Accordingly, PDE5 inhibitors prevent the conversion of cGMP to the inactive 5'GMP. It follows that, in the presence of a PDE5 inhibitor, cGMP levels remain higher for longer which acts to enhance erectile function by maintaining blood vessel dilation and hence increased blood flow into the penis necessary for an erection to be achieved and maintained. 673 cGMP is produced in multiple tissues throughout the body and similarly, PDE5 has a fairly broad tissue distribution. As a result of the ability of PDE5 inhibitors to enhance blood vessel dilation by maintaining higher concentrations of cGMP in vascular smooth muscle, PDE5 inhibitors have the potential to cause a drop in systemic blood pressure upon administration. The potential to reduce systemic blood pressure following administration of a PDE5 inhibitor also increases as the dose increases, in part because the higher the dose, the greater the likelihood of non-target effects on other PDEs. Nitrates cause vasodilation by donating NO following administration. The NO activates guanylate cyclase in the smooth muscle cells lining the walls of blood vessels which leads to the production of cGMP, a decrease in intracellular calcium levels, relaxation of the vascular smooth muscle and vasodilation and hence, a decrease in systematic blood pressure following nitrate administration. As at the present day, organic nitrate esters, including nitroglycerin, continue to be used in the treatment of angina pectoris and heart failure, although their use is declining as the treatment options for cardiac disease are evolving. For example, as of today, patients suffering angina will often have stents inserted in their coronary arteries rather than being prescribed nitrates. 674 By reason of the fact that PDE5 inhibitors have the potential to cause a drop in systemic blood pressure upon administration, co-administering a PDE5 inhibitor at the same time as a nitrate may, at least theoretically, lead to an even greater drop in blood pressure than administering a nitrate alone. The PDE5 inhibitor potentiates the hypotensive effect of acute and chronic nitrate administration. Dr Mitchell said, and I accept, that most individuals can deal with large falls in their blood pressure by adjusting their pulse rate.

Was the Pleaded Representation Made? 675 Apotex accepts that it has not proved that any vision abnormalities associated with tadalafil are at other than clinically insignificant levels. Put in that way, it accepts that it cannot prove that the pleaded representation, insofar as it relates to vision abnormalities, is false. However, it advances a different case with respect to vision abnormalities. The starting point for its different case is the results in terms of adverse events of the clinical studies described in Example 7 in the 946 Specification (see [160] above). Those results indicate that tadalafil does not cause vision abnormalities, whether the unit dose is 2 mg or is 100 mg, or a dose in between those amounts. Apotex's argument, as I understood it, is that it was false to suggest that a benefit of an invention involving the selection of a compound at particular dosage levels was the elimination of a side effect when, in fact, the side effect is not present at other dosage levels. This is not the pleaded representation and, as ICOS pointed out, the absence of a plea must be considered in the context of a utility plea (i.e., promises in the Specification have not been met), which the Court was told on the Amendment Application meant that it was unnecessary to plead false suggestion (see Amendment Reasons at [78]). Furthermore, it is relevant that, as ICOS submitted, it did not oppose Apotex's application to amend to introduce a plea of false suggestion on the basis that it went no further than Apotex's plea of inutility. 676 Apotex sought to overcome the absence of a plea by submitting, as I understood it, that it was not advancing a different case of false suggestion. It was merely seeking to deploy the argument it now advances in relation to causation. Apotex submits that the argument undermines ICOS's submission that any false suggestion or misrepresentation was not material because the patent may have been granted as a result of the advantages of the claimed invention in terms of vision abnormalities. There are two alternative answers to this way of putting the matter. As these reasons make clear, Apotex's case fails before I reach the point of considering causation. However, the better answer is that to reach the point of considering the statements about vision abnormalities as relevant to causation, it is first necessary to conclude that they involved a false suggestion or misrepresentation and Apotex should not be permitted to raise such an allegation which does not fall within the pleading or Apotex's case as previously articulated. It is too late for Apotex to raise the allegation. This means that, for the purposes of Apotex's false suggestion case, only two side effects are relevant, namely, facial flushing and adverse cardiovascular events, including a significant decrease in blood pressure. The burden of Apotex's case was as to the second of these side effects. 677 In practical terms, there was a further narrowing of Apotex's false suggestion case. There was very little put by Apotex on the pleaded side effect of tadalafil administered alone causing adverse cardiovascular events, including a significant decrease in blood pressure. The weight of Apotex's case and the evidence with respect to that side effect was tadalafil administered with an organic nitrate. In fact, it was not clear to me at the conclusion of the case whether Apotex was pursuing the former case. It matters not because, for reasons I will give, I reject such a case. 678 There are essentially two points of difference between the parties as to the representation(s) made. Apotex's pleaded representation is set out above. ICOS submits that the representation made is that tadalafil can be administered with clinically insignificant side effects (or that side effects can be reduced to clinically insignificant levels) and that this means that the result can be attained in some, not necessarily all, patients. Furthermore, ICOS submits that there is both express and implied throughout the unamended Specification an assertion that tadalafil, in terms of side effects, will compare favourably with sildenafil, that is, that the side effects will be less frequent or less severe in the case of tadalafil. ICOS submits that the unamended Specification does not describe the extent of the benefit, but it accepts that it would be understood as suggesting a meaningful benefit. I will refer to the representation which ICOS submits arose as "the composite representation". 679 The Court is required to construe the statements in the Specification through the eyes of the skilled addressee and the complete specification must be read as a whole (Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; (2001) 207 CLR 1). In this case, the clinicians and Dr Mitchell addressed the meaning of various terms and phrases in the unamended Specification and there was a good deal of agreement between them. I should say in this context that the parties did not suggest that the statements in the correspondence from Wrays added in any significant way to the statements in the unamended Specification and, in my opinion, that approach is correct. 680 Prominent phrases in the relevant passages in the unamended Specification are "clinically insignificant side effects" and side effects reduced to "clinically insignificant levels". The latter phrase is included in the pleaded representation. The clinicians and Dr Mitchell said in their joint experts' report that the phrase "clinical insignificance" meant an absence of practical importance due to a lack of real, genuine and/or noticeable effect upon the daily life of the subject. They said that they also understood that the phrase might suggest that the side effect is minor, tolerable, infrequent and/or of short duration and is acceptable to the subject. They expressed the view that clinical significance or insignificance is a subjective measure, the use of which is limited by the lack of values or a measurement tool as opposed to the concept of "statistically significant" which can be determined by several statistical methods. It is trite to say that the interpretation of the Specification is a matter for the Court. However, accepting a degree of imprecision in meaning, I cannot see any reason (and none was suggested by the parties) not to accept these views as to the meaning of these phrases. 681 A more contentious phrase is the phrase "can be administered" in the phrase "can be administered with clinically insignificant side effects", and the phrase "can be reduced" in the phrase "side effects can be reduced to clinically insignificant levels". In their joint experts' report, the clinicians and Dr Mitchell agreed that this meant that the results could be achieved in some, but not all, subjects or patients. They said that, overall, the word "can" means that "these endpoints can be achieved in some, but not all, patients". The clinicians and Dr Mitchell go on to say in the same context that the unamended Specification makes it clear that a comparison to sildenafil, the only available PDE5 inhibitor at that time, is what "they [i.e., the authors of the unamended Specification] are referencing their side effects to". As I understand these points, they are linked. The statement is not as to all patients, but it does include a statement to the effect that, in terms of side effects, tadalafil is better than sildenafil. 682 Apotex submitted that the Court should not accept the joint view of the clinicians and Dr Mitchell, even though the clinicians included the clinician it called as an expert witness, Dr Cherry. It advanced the following reasons in support of that submission. First, it submitted that whilst there are, no doubt, statements comparing tadalafil and sildenafil in terms of side effects, there are also statements about tadalafil and its side effects standing alone. Secondly, it submitted that it is unlikely that the phrase "can be administered" meant no more than in some patients because that was already the case with sildenafil and such a meaning would not be consistent with the use in the unamended Specification of phrases such as "most unexpectedly" and "unexpected discovery". There is force in these submissions, but ultimately, I consider that the construction advanced by ICOS is the correct one. 683 It is important to appreciate that ICOS's construction involves two representations which are linked. One is that the drug can be administered with clinically insignificant side effects in some patients, and the other is that the drug provides a meaningful advantage over sildenafil. The former without the latter is an unlikely construction, but with the latter it is, in my opinion, the proper construction. 684 It is reasonable to assume that inconsistent claims to benefits are not being made in the unamended Specification. More particularly, it is reasonable to assume that the authors are not claiming benefits in terms of certain side effects in the case of all patients in one part of the Specification, and in the case of only some patients in another part of the Specification. Furthermore, in the case of this specification, I do not think that different claims are being made for different side effects. In other words, in the case of each side effect, the extent of the benefit claimed is the same. 685 It is true that there are statements in the unamended Specification which, standing alone, might suggest that the benefits relate to all patients and not just some patients. I have in mind the statements about previously untreatable patients now being treated and a nitrate contraindication being unnecessary. It is also true that the statements could mean that the side effects are reduced (or eliminated) to clinically insignificant levels in all patients. However, I think that the more likely construction is that the side effects will be reduced (or eliminated) to clinically insignificant levels in some patients in the class. That is the literal meaning of phrases, "can be administered" and "can be reduced". Furthermore, the construction is supported by the fact that it is claimed that the drug has a reduced tendency to cause flushing and will result in an improvement in the incidence of flushing. The letter from Wrays dated 1 July 2003 also refers to a reduced tendency to cause vision abnormalities. The statements about the drug and its side effects are all made in the context of a representation that tadalafil provides a meaningful advantage over sildenafil and it is the theme of comparison that runs throughout the unamended Specification. This may be seen also in other passages in the Specification which were identified by ICOS: (1) "The unit dosage form described herein …with minimization or elimination of adverse side effects resulting from inhibitor of other phosphodiesterase enzymes" (page 1, lines 19-24); (2) page 2, line 9 - page 3, line 19 discusses the side effects experienced by patients taking sildenafil including in respect of blue-green vision abnormalities, facial flushing (10% incidence rate)" and side effects suffered by "individuals who use organic nitrates"; (3) "The incidence rate of flushing demonstrates marked improvement over prior pharmaceutical products containing a PDE5 inhibitor" i.e. sildenafil: page 9, lines 8-11; (4) "The compound of structural formula (1) was demonstrated in human clinical studies to exert a minimal impact of systolic blood pressure when administered in conjunction with organic nitrates. By contrast, sildenafil demonstrates a four-fold greater decrease in systolic blood pressure over a placebo, which leads to contraindications in the VIAGRA insert, an in warnings to certain patients" (page 31, line 24-31); (5) "This study … evaluated the hemodynamic effects of concomitant administration of selective PDE5 inhibitor (i.e. Compound (1)) and short-acting nitrates … . In a preliminary analysis of this study, Compound (1) was well tolerated and there was no serious adverse events. … Compound (1) demonstrated minimal, if any, effect on mean systolic blood pressure, and mean maximal nitroglycerin-induced decrease in systolic blood pressure" (Example 5, page 26, line 23-page 27, line 16); (6) "Doses from 5 to 20 mg Compound (1) were efficacious and demonstrated less than 1% flushing and no reports of vision abnormalities. It was found that a 10mg dose of Compound (1) was fully efficacious and demonstrated minimal side effects (page 27, lines 26-30); (7) "This study also included a safety evaluation. … a condition present at baseline that increased in severity postbaseline. … The incidence of treatment-emergent adverse events appeared related to dose" (page 30, lines 15-23); and (8) "In accordance with the present invention, …both effectively treats ED and minimizes or eliminates the occurrence of adverse side effects. Importantly no vision abnormalities were reported and flushing was essentially eliminated. … individuals undergoing nitrate therapy also can be treated for ED by the method and composition of the present invention" (page 32, lines 23-page 33, line 2). (Emphasis added.) 686 In my opinion, the construction advanced by ICOS is the correct construction and that is that the unamended Specification contains the composite representation. I note that in one part of their joint experts' report, the clinicians seem to suggest that the phrase "can be administered" means in most individuals most of the time, rather than in some patients. As will become clear, even if that is the effect of the statements, they have not been shown to be false. 687 ICOS submit that if Apotex does not establish the pleaded representation, then it must fail at the first hurdle in the same way a plaintiff in a defamation proceeding who fails to establish a pleaded imputation must fail. I do not accept this submission. The first aspect of the composite representation (reduction to clinically insignificant levels) falls within the pleaded representation, and the second aspect (comparison with sildenafil) was well and truly within the scope of the trial as it proceeded. 688 In its written submissions in reply, Apotex seemed to accept that if I adopted the view of the clinicians and Dr Mitchell about the meaning of "can be administered", then its false suggestion case must fail. However, it is not clear to me how far the concession went because at the same time, Apotex contested the other aspect of the composite representation, namely, that the side effects with tadalafil are less frequent and less severe than they are with sildenafil. 689 I now turn to consider whether the composite representation has been shown to be false.

Has the composite representation been shown to be false?

Facial flushing 690 The first question is whether, as far as facial flushing is concerned, tadalafil can be administered to some patients without clinically significant side effects. The evidence which is relevant to this question is as follows. 691 The clinicians said that on 27 May 2004 and thereafter until the present time, they were aware that facial flushing was an adverse effect of Cialis and that they were aware that the reported incidence of facial flushing in the Cialis clinical trial database was 4%. They said that that result accorded in large measure with their experience in clinical practice. For example, Professor Brock said that in his experience, even with 20 mg doses of tadalafil, the incidence of facial flushing was 2%-3%. 692 The 2003 Cialis PI Statement states that for 10 mg and 20 mg doses of Cialis, facial flushing is reported in 4% of patients. The figure in the 2013 Cialis PI Statement is 3.5%. The 2013 Cialis PI Statement also states that, in the case of lower doses of Cialis, the incidence of facial flushing is less than 2% of patients. 693 The evidence of the clinicians is that, of those patients who experience facial flushing, a small percentage who consider they may be suffering a possible heart attack suspend or discontinue treatment. Professor Brock's description of the number of patients who fell into this category was a "small fraction" and Dr McMahon said that it was "really uncommon". 694 The representation that, in terms of facial flushing, tadalafil can be administered in some patients without clinically significant side effects has not been shown to be false. In fact, a representation that it can be administered in the vast majority of cases without clinically significant side effects would not be false. 695 Had I accepted Apotex's submission that the representation extended to all patients, such a representation would be false in the case of facial flushing because there are a small number of patients who suspend or discontinue treatment because of facial flushing. 696 The second aspect of the composite representation is whether facial flushing occurs less frequently with tadalafil administered in accordance with the claimed invention than with sildenafil. I do not think Apotex contested the fact that the answer to this question is in the affirmative. The evidence is clearly to this effect and is as follows. 697 First, it is known that a cause of facial flushing is the inhibition of PDE1. Sildenafil has a higher selectivity for PDE1 than tadalafil, that is to say, tadalafil is more selective than sildenafil for PDE5 over PDE1. 698 Secondly, the 1999 Viagra PI Statement and the 2015 Viagra PI Statement state that facial flushing is reported in 10% of patients. That is to be compared with the results set out in the Cialis PI Statements. 699 Thirdly, the experience of the clinicians is that facial flushing occurs less frequently with tadalafil than it does with sildenafil. The clinicians agreed that as at 27 May 2004 and thereafter to the present time, facial flushing is a well-recognised side effect of Viagra and that it occurs in their patient population at an incidence of approximately 10%. They also said that there were publications reporting the incidence of facial flushing in the case of Viagra as being as high as 33%. In a small number of patients who misconstrue facial flushing as a possible cardiac event, it can lead to a suspension of treatment. Professor Brock said that this was "much, much more common with Viagra than it was with Cialis". Dr McMahon said that the incidence of facial flushing with tadalafil was "substantially less" than it is with sildenafil. Dr Cherry agreed that a lower incidence of facial flushing with tadalafil than with Viagra was reflected in his clinical practice and that this was a benefit because it reduced the number of patients who might misconstrue facial flushing as a possible cardiac event. 700 The representation that facial flushing occurs less frequently with tadalafil administered in accordance with the claimed invention than with sildenafil has not been shown to be false. I classify the benefit as a meaningful one.

The side effects following the co-administration of tadalafil and a nitrate 701 I have already described the mechanism whereby the administration of a PDE5 inhibitor at the same time as a nitrate may lead to an even greater drop in blood pressure than the administration of a nitrate alone. A measurable decrease in blood pressure may or may not cause symptoms. The means of measuring blood pressure include measuring systolic blood pressure (SBP) standing or sitting, which is the pressure in the arteries when the heart beats and measuring diastolic blood pressure (DBP) standing or sitting, which is the pressure in the arteries between beats. A decrease in mmHg below a certain amount or of a certain amount or both may be the focus of tests carried out. Another focus might be the clinical symptoms considered to be caused by a decrease in blood pressure such as light headedness, dizziness, syncope and pallor. The difference between these two methods of measurement assumed significance in this case. The clinicians and Dr Mitchell agreed that measured changes in blood pressure might generate statistically significant values, but this was a different "endpoint" (as they put it) from symptomatic hypotension. They made the point that it needed to be recognised that the statistical significance of predetermined threshold parameters and clinical significance are different endpoints and are not interchangeable. These different endpoints will be significant when I come to consider the Lilly Nitrate Studies. 702 Apotex relied on three matters to establish that the pleaded representation was false. I have found that, in fact, the representation made was the composite representation. Nevertheless, I will consider the truth of the composite representation by reference to, among other matters, the three matters relied on by Apotex. First, Apotex relied on the fact that the Cialis PI Statements contained a contraindication concerning the co-administration of tadalafil and nitrates (nitrate contraindication). Apotex claimed that ICOS knew in August 1999 that a nitrate contraindication would be required. Secondly, Apotex relied on statements, opinions and observations in the Kloner Papers. Thirdly, Apotex relied on some of the results of the Lilly Nitrate Studies. 703 Professor Brock gave a detailed description of the meaning of a contraindication and the circumstances in which it is imposed. I accept his evidence on this matter. 704 A contraindication is a recommendation of a regulatory authority that a drug should not be prescribed because it may be harmful to the patient. Examples of the circumstances in which a drug may be harmful to a patient are where the patient has a particular medical condition or because he is taking another drug which interacts with the proposed drug. A contraindication is noted on the drug label. The drug label is inserted into the product packaging and contains information for clinicians and patients relating to the product, including the administration of the product, its side effects and any contraindications. As part of the approval process, a regulatory authority is given information about the efficacy, safety and tolerability of the drug and, based on that information, the authority may require a contraindication. In many cases, the decision whether to require a contraindication, involves balancing risk and benefit and is not a "black and white" decision. The risk is the risk of harm occurring and the nature of that harm and the benefit is the efficacy of the drug, including the nature of the condition being treated. The efficacy of the drug for a life-saving condition, such as a new cancer treatment, may be given more weight than a drug treating a condition such as ED. The balancing of risk and benefit involves a judgment. 705 Professor Brock also said that regulatory authorities tend to take a conservative approach to the assessment of risk and benefit. Professor Brock said that the decisions of regulatory authorities are not always consistent because the composition of the group within the regulatory authority making the decisions changes over time and knowledge about the drug develops. 706 Professor Brock said that a contraindication does not prevent a clinician from prescribing a drug contrary to a particular contraindication. This comes about because the regulatory authority generally takes a conservative approach and considers the appropriate recommendation for the whole population of patients who may be administered the drug, whereas a clinician considers the particular patient and his or her circumstances in assessing risks and benefits. This evidence was given at a fairly general level. Nevertheless, I accept it and, more particularly, I accept it in the context of PDE5 inhibitors. It is supported by the evidence of the other clinicians and Dr Mitchell. Professor Brock said: …When I am seeing a patient in front of me, it's a different scenario [from the decision of the regulatory authority]. I have to make a decision about what's best, in my view, based on my knowledge and experience, for that particular patient. 707 Dr Mitchell described a contraindication in succinct terms which I accept. His description is as follows: A "contraindication" is a factor or circumstance that may make the use of a particular drug or medical procedure inadvisable. It does not prohibit two drugs being used together. Rather, it provides guidance to prescribing doctors about when they should exercise particular caution. Of course, patient needs always come first, so even if two drugs are contraindicated, there may be circumstances where the prescribing doctor believes it is in the patient's interests to administer them both, and he or she is able to do so. In addition, I am aware from my interactions with the marketing team at Lilly that sales representatives must specifically mention contraindications during their sales visits to medical practitioners and pharmacists. 708 The 1999 Viagra PI Statements contain a contraindication against the co-administration of sildenafil and nitrates. For example, the 1999 Viagra PI Statement contains the following: VIAGRA was shown to potentiate the hypotensive effects of organic nitrates, and its co-administration with nitric oxide donors or organic nitrates in any form is therefore contraindicated. Drugs which must not be used concomitantly include [various nitrates] or organic nitrates in any form. 709 The Cialis PI Statements also contain a contraindication. The 2015 Cialis PI Statement contains the following: Nitrates and tadalafil must not be used concomitantly. Co-administration of tadalafil with nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, [various nitrates] or organic nitrates in any form. In clinical studies, tadalafil was shown to potentiate the hypotensive effects of both acute and chronic nitrate administration. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. In a patient prescribed CIALIS where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours in most patients and 4-5 days in the elderly (approximately 4-5 half lives) should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring. 710 The circumstances in which a contraindication was included in the Cialis PI Statements are described in Annexure E (at [47]-[52]). 711 As I have said, Apotex also relies on certain statements, opinions and observations in the Kloner Papers. The leading author (Dr R Kloner) of the Kloner Papers is a cardiologist and co-authors of the papers include members of the Lilly ICOS team who worked on the Lilly Nitrate Studies (Drs Emmick and Mitchell). The Kloner Papers report on the results of some of the Lilly Nitrate Studies and it is convenient to introduce those studies at this point. 712 During the late 1990s and early 2000s, Eli Lilly and Company collaborated with ICOS to develop tadalafil. A new company was formed for the purpose of the joint development of tadalafil called Lilly ICOS LLC (Lilly ICOS). During the period from 1999 to 2002, Lilly ICOS conducted five clinical pharmacology studies to investigate the potential interaction between tadalafil and nitrates and those studies were designated LVAB, LVBY, LVCM, LVCP and LVCN respectively (the Lilly Nitrate Studies). 713 Dr Mitchell joined the Lilly ICOS team working on the development of tadalafil in July 1998. ICOS had applied to the FDA for tadalafil to receive the IND designation before Dr Mitchell joined the Lilly ICOS team. In 1999, the IND designation for tadalafil was transferred by ICOS to Lilly ICOS. Dr Mitchell was responsible for overseeing the clinical pharmacology studies required to support the registration of tadalafil. He said that one category of such studies examined the interaction of tadalafil with nitrates. He was responsible for the Lilly Nitrate Studies, other than the first one in time (i.e., the LVAB Study). All the other nitrate studies were performed under Dr Mitchell's supervision and the study protocols were devised by him alone or in collaboration with others. 714 Each Lilly Nitrate Study was the subject of a report and I received excerpts of each of the reports. Those reports and the evidence relating to them are the subject of confidentiality orders. I have discussed those reports and the evidence relating to them in Annexure E to these reasons and that Annexure will be made available in accordance with the terms of the confidentiality orders, but not otherwise. 715 I return to the Kloner Papers. 716 Kloner et al (2003) contains a partial representation of the LVDN Study. The main finding reported is that tadalafil augmented the hypotensive effect of sublingual nitroglycerin given from 2 to 24 hours after the last dose of tadalafil. There was no detectable interaction after 48 hours. The co-administration of tadalafil with nitrates was contraindicated. Kloner et al (2003) contains the following statement: As is the case with sildenafil, physicians and paramedics need to be aware of this potentially serious interaction. Thus, if a patient presents with chest pain, it will be imperative to question whether the patient has used a PDE5 inhibitor. If the patient has taken tadalafil within 48 h, then organic nitrates should not be given. 717 The Kloner et al Reply, also reporting on the results of the LVDN Study states: Therefore, if deemed medically necessary, nitrates should be administered only under close medical supervision with hemodynamic monitoring at 48 h and beyond the last dose of tadalafil. … Importantly, nitrates are contraindicated whether a patient has been taking daily or intermittent doses of any PDE5 inhibitor (e.g., tadalafil, sildenafil or vardenafil). 718 The Kloner et al Review reports on a number of clinical studies, including the LVBY and LVCM Studies. The review contains the following statements, opinions and observations: treatment with tadalafil resulted in a modest additive effect of the nitrate induced reductions in mean maximal blood pressure; treatment with tadalafil resulted in a higher number of subjects with potentially clinically significant changes in blood pressure compared to placebo, indicating that in a subset of subjects, tadalafil augments the decrease in blood pressure induced by nitrates; as with sildenafil, tadalafil should not be used in combination with nitrates and both tadalafil and sildenafil modestly augmented the mean maximal blood pressure decrease induced by sublingual nitroglycerin when compared with placebo, suggesting that in a subset of subjects, both tadalafil and sildenafil augment the nitrate induced decrease in blood pressure. It contained no information about the incidence or severity of side effects. 719 Dr Mitchell gave an explanation as to the context in which the Kloner Papers were prepared. I accept that explanation. First, he said that the focus of the Kloner Papers was the statistical significance, as opposed to the clinical significance, of the results of the research. Secondly, he said that by the time of the Kloner et al (2003) Paper and Kloner et al Review, it was clear that the FDA was going to require a contraindication "driven", as Dr Mitchell put it, "by statistical analysis and outlier data". Dr Mitchell and his team could not publish statements or opinions contrary to the views of the regulator and what they knew would be part of the Cialis label, even though they did not consider that a contradiction was necessary. 720 Finally, Apotex relied on certain results in two of the Lilly Nitrate Studies (LVCM and LVDN). Details of the matters upon which it relies are set out in Annexure E (at [4]-[5] and [34]-[40]). 721 ICOS submits that the composite representation has not been shown to be false. It relies heavily on the evidence of the clinicians as to what, in fact, happens in clinical practice. Despite the contraindications, tadalafil and, for that matter, sildenafil, are prescribed for men taking nitrates. The clinicians said that as at 27 May 2004 and through until the present time, there are circumstances where cardiologists or other treating physicians have been consulted and provided agreement to co-administration and they have prescribed the use of PDE5 inhibitors to men who are taking nitrates, notwithstanding the contraindications. Patients are assessed on an individual basis and the questions which are asked include the frequency of the patient's angina, the frequency of the administration of nitrates, the precipitating circumstances of the angina, the presence of exertional angina during prior episodes of sexual intercourse, previous or current treatments for coronary artery disease and whether the patient has been prescribed a short or a long acting organic nitrate. Dr Cherry said that he would always consult the patient's general practitioner or his cardiologist or both to obtain further details of his history of coronary artery disease and seek approval for the co-administration of nitrates with his prescription of Viagra or Cialis. Dr McMahon and Professor Brock said that they would decide on the need for additional consultation with a general practitioner or cardiologist on an individual case basis. 722 The clinicians agreed that they would consider treatment with either Viagra or Cialis in the following situations: (1) in men with medically or surgically stabilised coronary artery disease who no longer experience exertion or angina, but continue to carry a short acting nitrate; (2) in men with infrequent and predictable angina which has never occurred during sexual intercourse and only occurs during exertion at an energy level in excess of that threshold achieved with sexual intercourse; and (3) in men who were not candidates or declined other treatments for ED and were compliant patients who clearly understood the nature of the drug interaction and the approach to the occurrence of angina occurring following treatment with sildenafil or tadalafil. 723 The clinicians said that they were aware of clinical trial data that suggested that the co-administration of Viagra or Cialis to men prescribed organic nitrates may exacerbate the hypotensive response to nitrates and that this exacerbated response may be associated in some men with symptoms of light headedness, dizziness and syncope. 724 The clinicians were asked about their clinical practice and experience as at 27 May 2004 and the present time of symptomatic hypotension in the case of the co-administration of Viagra and nitrates, Cialis and nitrates and then they were asked to compare the two. For present purposes, I focus on their answer with respect to the co-administration of Cialis and nitrates. With respect to that matter, they said: On May 27th 2004 and until today's date, we were aware of clinical trial data that reported a significant reduction in measured systolic and diastolic blood pressure in some patients co-administered organic nitrates and Cialis. We were aware of this clinical trial data from several sources which included attendance at national, regional and international scientific meetings at which this data was discussed, information supplied to us as Cialis clinical trial investigators and Cialis advisory board members and from reading the Kloner et al publications. On May 27th 2004, we had formed the opinion that most of the subjects in whom a statistically significant reduction in measured blood pressure was observed, failed to experience symptoms of light headedness, dizziness or syncope. Among those patients reporting side effects in the studies most were mild in severity as reported in Table 3 Kloner et al JACC Vol. 42, 10, 1855-60 2003. …The occurrence of symptomatic hypotension related to the co-administration of a PDE-5 inhibitor and a nitrate in our clinical experience is a rare event and as such we have limited clinical experience on efficacy. (Emphasis added.) 725 In addition to these matters about which the clinicians were agreed, the following evidence (which I accept) is relevant. 726 Dr McMahon said that in 1999 and thereafter to the present day, he asks the patient, as part of his initial assessment of patients who require treatment for ED, about the patient's use of organic nitrates. With the relevant information, Dr McMahon then makes an informed decision as to the type of treatment he prescribes. As part of the treatment, he provides information to the patient, including the fact that there is a contraindication in respect of PDE5 inhibitors and nitrates because the use of PDE5 inhibitors and nitrates can result in a reduction in blood pressure. Dr McMahon said that if he felt that a patient could appropriately manage the two drugs together, then he would prescribe the patient, as he put it, "preferentially tadalafil or Viagra before tadalafil became available". Dr McMahon said that approximately 20% of his patients who take nitrates would also be on a PDE5 inhibitor, namely Cialis or Viagra. Dr McMahon made the point that a contraindication is not an absolute bar to doctors and that he considers that most patients can safely use both drugs under a careful management regime. Dr McMahon said that an approach that it is preferable not to administer tadalafil with organic nitrates, is a conservative one. 727 Professor Brock said that, in his experience, regulatory authorities take a conservative approach and that their decision is often based on studies that evaluate patients under conditions which maximise the hypotensive response following the co-administration of a nitrate and a PDE5 inhibitor. Professor Brock said that he is aware that many clinicians prescribe a PDE5 inhibitor, including tadalafil, to patients who take nitrates. It is important that the patient understands the potential interaction of PDE5 inhibitors and nitrates, and understands the strategies designed to avoid hypotensive reactions. Professor Brock said that he provides advice to his patients on the strategies available to minimise the potential interaction between nitrates and a PDE5 inhibitor. He will consult with the patient's physician and he will advise the patient to wait for a minimum period, in the case of tadalafil that period is two days, between the taking of the PDE5 inhibitor and the nitrate. Professor Brock was cross-examined about evidence he had given in court proceedings in Canada in which (it was suggested) he had emphasised matters that he now "downplayed" in this proceeding and vice-versa. I have read the evidence carefully. On the face of it, the emphasis given to certain points does appear to be different. However, Professor Brock's evidence was otherwise satisfactory and his evidence on this particular issue was largely supported by the other clinicians and Dr Mitchell. I accept it. 728 None of the clinicians had experience of a patient who had taken both tadalafil and an organic nitrate and thereafter suffered an intolerable side effect. 729 Dr Cherry agreed in cross-examination that a patient could suffer a clinically insignificant decrease in blood pressure and that that would be a case where the decrease was not symptomatic and the patient was not concerned by it. It followed that because he had not seen any occurrence of intolerable side effects in his practice, any decrease in blood pressure caused by the co-administration of tadalafil and organic nitrates was clinically insignificant. 730 The evidence of the clinicians and Dr Mitchell of their practices and observations supported by the results of the Lilly Nitrate Studies (which are discussed in detail in Annexure E) leads to the conclusion that the claimed invention can be administered with an organic nitrate in the case of some patients without clinically significant side effects associated with a decrease in blood pressure. In fact, the evidence goes further and supports the conclusion that that is so in the case of most patients. 731 The more difficult question is whether, in terms of this side effect, tadalafil provides a meaningful benefit compared with sildenafil. 732 As I said earlier, the clinicians were asked about their clinical experience as at 27 May 2004 and the present time of symptomatic hypotension in the case of the co-administration of Viagra and nitrates, Cialis and nitrates and then they were asked to compare the two. I have already set out their views in relation to the co-administration of Cialis and nitrates. 733 As to the co-administration of Viagra and nitrates they said: From 27 May 2004 until the present date based on our clinical practices, experience and understanding of the medical literature a significant decrease in measured blood pressure can occur when Viagra is co-administered with an organic nitrate. As demonstrated in Webb 1999 when a sublingual organic nitrate was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the Sildenafil treatment period than during the placebo treatment. The occurrence of symptomatic hypotension related to the co-administration of a PDE-5 inhibitor and a nitrate in our clinical experience is a rare event and as such we have limited clinical experience on efficacy. (Emphasis added.) 734 As to the comparative effects, the clinicians said: On May 27th 2004 until today's date we were aware that the co-administration of Viagra and organic nitrates was associated with a greater reduction in blood pressure compared to co-administration of Cialis and organic nitrates. This knowledge was predominantly based upon data contained within the Kloner et al review (page 88 Am. J. of Cardol.). A study conducted in healthy men and women aged ˃ or equal to 55 years, examined the haemodynamic effects of sublingual nitroglycerin 0.4 mg administered after tadalafil 10 mg, sildenafil citrate 50 mg or placebo. Both tadalafil 10 mg and sildenafil 50 mg resulted in a most additive effect on the nitrate-induced blood pressure decreases on day 1 when compared with placebo. Additional analysis demonstrated that tadalafil was non-inferior to placebo with respect to all haemodynamic measurements on both day 1 and day 2. Conversely, standing systolic blood pressure on day 1 sildenafil failed the non-inferiority analysis when compared with placebo. Our understanding of the importance of these findings is that there was no reported difference between tadalafil and placebo in their effects on measured systolic blood pressure when exposed to nitroglycerin 0.4 mg, in contrast a measurable difference was found between sildenafil and placebo as described above. In our own clinical experience, reports of symptomatic hypotension in men co-administering nitrates and PDE-5 inhibitors have been rare. (Emphasis added.) 735 As these passages show, the occurrence of a side effect was a rare event whether the PDE5 inhibitor co-administered with a nitrate was sildenafil or tadalafil. This is a matter to take into account. Furthermore, Dr Cherry said in his evidence-in-chief that he did not notice any significant difference in side effects as between sildenafil and tadalafil. 736 ICOS relies on the following matters to establish that the side effects of hypotension are less frequent and less severe in the case of tadalafil compared with sildenafil: (1) The results of the studies involving sildenafil identified in Webb DJ, Freestone S, Allen MJ and Muirhead GJ, "Sildenafil Citrate and Blood-pressure-lowering Drugs: Results of Drug Interaction Studies with an Organic Nitrate and Calcium Antagonist" (1999) 83 American Journal of Cardiology 21C (Webb et al (1999)) compared with the study involving tadalafil discussed in Example 5 in the 946 Patent; (2) The results of the LVCM Study; and (3) The evidence of the clinicians with respect to these matters. 737 The clinicians and Dr Mitchell gave a description of the results of the study as reported on in Webb et al (1999) which was as follows: Webb et al, reports the results of initial studies which investigated the effects on measured blood pressure of co-administering sildenafil with nitrates. In this study, patients were administered 25mg of sildenafil or placebo three times per day for four days and a single morning dose on day 5. On day 4, one hour after the morning dose, the patients were given nitroglycerin (referred to as "glyceryl trinitrate" in Webb) intravenously, starting at an infusion rate of 2.5mcg/min and doubling every 5 minutes to a maximum rate of 40mcg/min or until the subject experienced a decrease in systolic blood pressure of more than 25mmHg or symptomatic hypotension. On day 5, one hour after the morning dose, a glyceryl trinitrate tablet (500mcg) was administered sublingually for a maximum of 15 minutes. Patients were allowed to remove the tablet if they experienced a decrease in systolic blood pressure of more than 25mmHg or symptomatic hypotension. In Part A, two of the 12 subjects completed the infusion of glyceryl trinitrate on placebo while no patients taking sildenafil completed the infusion. In Part B, 11 of the 12 subjects in the sildenafil group removed the sublingual NTG [nitroglycerin] tablet before the 15 minute period (median time 4.5 minutes) because they were symptomatic, while only 4 on placebo removed the tablet prematurely (median time 15 minutes). Furthermore, within 7 minutes of sublingual glyceryl trinitrate administration, there was a greater than 4-fold difference in the mean decrease in systolic blood pressure between subjects in the sildenafil and placebo treatment groups. As the authors note, given the nitrate tablet was removed by 11 of the 12 subject prematurely, the synergistic effect of sildenafil and glyceryl trinitrate may have been greater if this stopping rule had not been part of the study protocol. (Emphasis added.) 738 Professor Brock explained in the course of his evidence that the subjects of the study removed the nitroglycerin tablet as reported where they were experiencing symptoms or where their measured blood pressure was reduced by more than 25 mmHg. Professor Brock expressed the opinion that the results of the study reported in Webb et al (1999) showed that there was a profound interaction between sildenafil and nitroglycerin. He gave the following evidence: So, for me, the take-home message is it's very clear that there was a profound interaction between sildenafil and nitroglycerin that really, in a sense, didn't allow us to fully assess the degree of interaction because the patients exposed to the nitroglycerin tablet - actually, almost all of them spit out the tablet before it was fully absorbed, but they did that because of symptomatic changes in their blood pressure, by and large. 739 Webb et al (1999) also identifies what it described as "severe treatment-related adverse events" in the group of 12 subjects who were administered sildenafil and nitroglycerin. There were eight reports by seven subjects of such events which included headache, nausea, dizziness and hypotension. All the clinicians and Dr Mitchell agreed that this showed poor tolerability of the co-administration of sildenafil and a nitrate and that this was clinically significant. 740 These results as reported in Webb et al (1999) can be compared with the results of the study described in Example 5 in the 946 Patent. The latter is the study comprising Part A in the LVAB Study. That study showed that tadalafil demonstrated nominal, if any, effect on mean systolic blood pressure, and mean maximal nitroglycerin-induced decrease in systolic blood pressure. While the methodology of the two studies was not precisely the same, I accept Professor Brock's evidence that the basic concept was the same and that it is reasonable to compare the results of the two studies. 741 Dr McMahon said that the results of the study described in Example 5 of the 946 Patent demonstrated that the changes in blood pressure with tadalafil even when the subjects are on the tilt table are "extremely low" and certainly lower than is the case with sildenafil. In terms of adverse events, the 946 Patent teaches that tadalafil was well-tolerated and there were no adverse events. 742 I refer to my discussion of the LVAB Study in Annexure E. I also refer to my discussion of the LVCM Study and the evidence of the clinicians and Dr Mitchell with respect to those studies in Annexure E. 743 The question of whether tadalafil provides a meaningful benefit over sildenafil in terms of the side effects resulting from the co-administration of a PDE5 inhibitor and nitrates is not at all easy to resolve. On the one hand, the evidence of the clinicians was that in their respective clinical practices, the occurrence of symptomatic hypotension related to the co-administration of a PDE5 inhibitor and a nitrate was a rare event. Furthermore, it would be inconsistent with the acknowledged difference between statistical significance and clinical significance to place too much weight on the difference in statistical values between tadalafil and sildenafil. Finally, the fact is that if there is a difference then, as Professor Brock's evidence makes clear, the science has not advanced to the point of providing an explanation of the reasons for the difference. On the other hand, Apotex bears the onus of establishing that this aspect of the composite representation is false and there is evidence of both statistical and clinical differences between tadalafil and sildenafil. The evidence of the studies referred to in Webb et al (1999), Example 5 of the 946 Patent (the LVAB Study, Part A) and the LVCM Study, together with the clinicians' evidence in relation to those matters, satisfies me that the second aspect of the composite representation has not been shown to be false. 744 As I said earlier, it is not clear whether Apotex maintains a case that ICOS made a false suggestion or misrepresentation concerning the effect of tadalafil alone in causing a decrease in blood pressure. To the extent that it did, such a case fails. 745 There is no evidence that the administration of tadalafil alone causes a decrease in blood pressure which, in turn, causes clinically significant symptoms. To the extent that ICOS suggested or represented that tadalafil could be administered without clinically significant side effects, that representation is true, or at least not shown to be false. 746 In terms of a comparative position between tadalafil and sildenafil, ICOS submits that I should find that the claimed invention can be administered with less frequent and/or less severe adverse events associated with a decrease in blood pressure. I accept this submission and find accordingly. A comparison of the PI Statements for tadalafil (Cialis) and sildenafil (Viagra) shows a greater fall in supine systolic and diastolic blood pressure in the case of sildenafil than tadalafil, and symptoms of a fall in blood pressure in the case of sildenafil, but not in the case of tadalafil. Furthermore, Dr Cherry, Professor Brock and Dr Mitchell agreed that sildenafil causes a significantly greater fall in blood pressure than tadalafil.

A material cause? 747 Strictly, it is not necessary to consider whether the pleaded representation or the composite representation was a material cause of the decision to grant the 946 Patent. I have decided that the pleaded representation was not made and that the composite representation has not been shown to be false. Had it been necessary to decide causation, I would have been disposed to decide that it had been established, at least in relation to some of the relevant claims. 748 In terms of the arguments advanced by ICOS against causation, I accept that the Commissioner of Patents has chosen not to appear and that that is a matter to be taken into account. I do not think the delay between the last letter from Wrays on 6 November 2003 and the grant in late May 2004 is of any particular significance. The delay is not of such an extraordinary length as to lead to any particular inference and, in addition, the application was advertised as accepted on 12 February 2004 and there was then a three month period for opposition. I also accept that Wrays advanced three arguments in their letter dated 6 November 2003 in opposition to the objections raised by the examiner and that the argument that the invention was a selection invention was only one of those arguments. Furthermore, it is correct to say that the link between the particular benefits in terms of side effects and particular doses had been identified in earlier correspondence. However, the selection invention argument (with the emphasis on benefits in terms of side effects) was clearly identified for the first time in the correspondence of 6 November 2003 and the other two arguments which may be described as conventional novelty arguments had been raised previously. I would be prepared to infer that the statements about the benefits of tadalafil in terms of side effects were a material cause of the grant of the Patent. That includes the statement about facial flushing.

Discretion 749 Apotex submitted that there was no reason not to exercise the discretion to revoke the relevant claims in the 946 Patent. ICOS submitted that there were a number of reasons why, even had Apotex established all other matters, the Court should exercise its discretion not to revoke the relevant claims. It is not necessary for me to consider the exercise of the discretion and I do not propose to do so.

Conclusion 750 I reject Apotex's false suggestion case.

INFRINGEMENT 751 ICOS alleges that Apotex has threatened to infringe the claims in suit in the 946 Patent. Subject to its claims of invalidity, Apotex admits that its products will infringe claims 1-6 and 8-11 (dosages) and claims 12-17 and 19-23 (methods of treatment using the dosages). Apotex denies infringement of claims 24-29 and 31-35 (dosage Swiss claims) on the basis that the importation or sale of medicaments made overseas by a third party cannot be an infringement of these claims. 752 ICOS alleges that Apotex threatens to infringe the claims in suit in the 666 Patent. Subject to its claims of invalidity, Apotex admits that its products will infringe claims 1-3, 5, 6 and 18 (particle size) and claims 7 and 8 (methods of treatment with compositions having the particle size) and claims 24-28 (to the extent those claims follow claims 5-6 and 16) and claims 29-33 (particle size and dosages). Apotex does not formally admit threatened infringement of the pharmacokinetic properties claims (claims 10-12 and 18), but it accepts that the Court will find infringement on the basis of Professor Boddy's evidence. I address Professor Boddy's evidence below and conclude that the position taken by Apotex is correct. Apotex denies infringement of claims 14 and 15 (particle size manufacturing process claims), 17 and 18 (particle size Swiss claims) and 34-38 (particle size and dosages Swiss claims). It does so on the basis that the importation or sale of medicaments made overseas by a third party cannot be an infringement of these claims.

Claims 10-12 and 18 in the 666 Patent and Professor Boddy's Evidence 753 Claim 10 is a pharmaceutical composition comprising a free drug form of a compound having the formula of tadalafil and pharmaceutically-acceptable salts and solvents thereof, and one or more pharmaceutically-accepted carriers, diluents or excipients wherein the composition exhibits the Cmax of about 180 to about 280 micrograms/litre or an AUC (0-24) of about 2280 to about 3560 microgram hour/litre, measured using a 10 mg dose of the compound. 754 Claim 11 contains the elements of claim 10, save and except that the pharmacokinetic parameters are cumulative and not in the alternative. Claim 12 is the same as claim 11, save and except that the compound need not be in a free drug form. Claim 18 is a Swiss claim concerning the manufacture of products exhibiting similar characteristics. 755 The 666 Patent contains a definition of the term, "free drug". It refers to solid particles of tadalafil not intimately embedded in a polymeric co-precipitate. I have already set out Professor Boddy's description of the terms Cmax and AUC. Professor Boddy produced a graph which illustrates the concepts of Cmax and AUC: 756 I have earlier explained those concepts (at [171]). 757 Professor Boddy said that pharmacokinetics is the study of an API's movements into, around and out of the body. The achievement of a sufficient API concentration at the relevant site of action is critical to the efficacy of the API. Professor Boddy said that conversely, all APIs of which he is aware, produce toxic effects if their concentration in the body is too high. He explained that by studying how the body deals with the API through the processes of absorption, distribution and elimination, pharmacologists seek to design dosage regimes that provide therapeutic API concentrations at the site of action whilst avoiding unacceptable levels of toxicity. Professor Boddy said that the processes of absorption and elimination of an API in plasma can usually be characterised by pharmacokinetic parameters. He said that, broadly speaking, these parameters collectively describe how quickly, and how much of, an API is absorbed in the plasma, and characterise the rate of distribution and elimination of the API from the plasma. Each pharmacokinetic parameter describes a particular aspect of the absorption, distribution or elimination of the API. 758 Professor Boddy was provided with copies of the 666 Patent and a number of documents which describe the Apotex products. The documents included Module 2.5, Module 5 (synopsis) and Module 5 (summary) which set out plasma concentration data for the 20 mg Apotex product only. In order to assess whether the Apotex products have the pharmacokinetic parameters that are identified in claims 10-12 and 18, he considered the logical starting point was to calculate the AUC (0-24) of the 20 mg Apotex products. 759 Professor Boddy said that he does not read claim 10 as being limited to 10 mg doses of tadalafil. In his opinion, the Cmax and AUC (0-24) values provide the reader with "a comparative or standardised set of pharmacokinetic values for the composition, being the values that will result for a 10 mg dosage of the claimed composition". Professor Boddy said that his understanding of claim 10 is that the standardised set of parameters define whether or not a composition that utilises a different dosage of tadalafil also falls within the claim because a linear relationship exists between the dose size and the pharmacokinetic parameters. Professor Boddy referred to, among other matters, a reference in the body of the Specification to the ability to compare or standardise to the Cmax or AUC (0-24) of a composition containing a 10 mg dose of tadalafil. Professor Boddy said that a composition that produces Cmax and AUC (0-24) values that are proportional to the amount of API within the dosage form is routinely referred to in pharmacology as a composition that has "linear pharmacokinetics". Professor Boddy said that the passage in the Specification informed him that at least over the dosage range of 5 mg to 20 mg, tadalafil compositions are subject to linear pharmacokinetics. This means that the Cmax and AUC (0-24) values in claim 10 will vary in proportion to the ratio between the dose under consideration and a 10 mg dose. The 666 Specification contains the following statement: It should be understood that Cmax and AUC (0-24) in plasma is dose dependent. For example, a composition containing a 20 mg dose of [tadalafil] will exhibit a Cmax and AUC (0-24) about twice that of a composition containing a 10 mg dosage. Similarly, a composition containing a 5 mg dosage of [tadalafil] will exhibit a Cmax and AUC (0-24) of about one-half that of a composition containing a 10 mg dosage. 760 Professor Boddy was able to conclude that 20 mg Apotex products exhibit pharmacokinetic characteristics that correspond to the Cmax and AUC (0-24) in claim 10. He also concluded that each of the 2.5 mg, 5 mg and 10 mg Apotex products is a composition that exhibits corresponding Cmax and AUC (0-24) values to the Cmax and AUC (0-24) ranges identified in claim 10 of the 666 Patent. 761 Professor Boddy expressed the opinion that the Apotex products had the other features of claim 10 and the features of claims 11 and 12. He also expressed the opinion that the Apotex products were for the treatment of male ED and met the pharmacokinetic parameters identified in claim 18. I accept Professor Boddy's evidence. 762 Apotex has threatened to infringe claims 10-12 and 18 of the 666 Patent.

Manufacturing Process and Swiss Claims 763 Ms Halmagyi's evidence establishes that the Apotex products will be manufactured by third party entities located outside Australia with different entities (located in different countries) approved for the manufacture of the active ingredient, tadalafil, and the manufacture of the finished dosage form. 764 Sections 12 and 13 of the Act provide as follows: 12 Application of Act This Act extends to: (a) each external Territory; and (b) the Australian continental shelf; and (c) the waters above the Australian continental shelf; and (d) the airspace above Australia, each external Territory and the Australian continental shelf. 13. Exclusive rights given by patent (1) Subject to this Act, a patent gives the patentee the exclusive rights, during the term of the patent, to exploit the invention and to authorise another person to exploit the invention. (2) The exclusive rights are personal property and are capable of assignment and of devolution by law. (3) The patent has effect throughout the patent area. The term, "patent area" is defined in the dictionary in the Act as meaning: (a) Australia; and (b) the Australian continental shelf; and (c) the waters above the Australian continental shelf; and (d) the airspace above Australia and the Australian continental shelf. The word, "exploit" is defined in the dictionary as follows: exploit, in relation to an invention, includes: (a) where the invention is a product - make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or (b) where the invention is a method or process - use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from such use. 765 In Alphapharm v H Lundbeck A/S, Lindgren J rejected a submission that "such use" in paragraph (b) meant a use of the type referred to earlier in the paragraph, that is to say, a use in the patent area. Lindgren J said (at [693], [694]): A consequence of the construction supported by Alphapharm is that in the case of an invention which is a method or process, importation is not a form of exploitation unless the product imported had resulted from the use of the method or process in Australia. However, as the Lundbecks submit, where the product results from the use of the method or process in Australia, the very making of the product, having occurred in Australia, would itself be a contravention of the patented method or process (para (a) of the definition of "exploit"). Accordingly, the effect of Alphapharm's submission would be that in the case of an invention of a method or process, the reference to importing is superfluous. I do not think that the construction supported by Alphapharm is correct. There is no suggestion in the express terms of the definition of "exploit" that importation, with nothing more, is not to be a form of exploitation in the case of a patented method or process. The territorial connection with Australia is one that is implied, and the proper construction of the definition of "exploit" has the territorial connection attaching twice, but not three times. The notion of "in Australia" does not follow the expression "from such use" at the end of para (b). The correct construction is, in my view, as follows: exploit, in relation to an invention includes: (a) where the invention is a product - [in Australia, or more accurately, in the patent area] make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or (b) where the invention is a method or process - [in Australia, or more accurately, in the patent area] use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from [the use, anywhere, of the method or process]. 766 Apotex submits that Lindgren J made two errors. First, he read "in the patent area" into each of the numerous verbs in paragraph (a) and (b), including "use the method or process [in the patent area]" but then declined to read it into the last phrase "a product resulting from such use". Secondly, in saying that if "such use" was read as use of the process in the patent area, then import in paragraph (a) was redundant in that that act mentioned in paragraph (a) did not apply to the use, his Honour overlooked that there are "innumerable acts mentioned in paragraph (a)" that have no application to "a product resulting from the use of a process or method". These include, for example, methods of treatment, and methods of measurement, disposal or prevention. 767 The construction adopted by Lindgren J in Alphapharm v H Lundbeck A/S was followed by Yates J in Otsuka Pharmaceutical v Generic Health at [166], although there was no challenge to Lindgren J's approach in the latter case. 768 In Apotex v Warner-Lambert, Nicholas J reached the same result as Lindgren J, but for different reasons. His Honour said (at [297], [298]): Paragraph (b) of the definition of "exploit" refers to the doing of an act referred to in para (a) which includes to make or import a product. The patentee's exclusive rights are infringed (subject to available defences) if another person does any such act within the patent area. The fact that the patented method is performed outside the patent area does not avoid infringement of a method claim (including a Swiss claim) if the product imported and sold in Australia was made using the patented method because the acts of importation and sale occur within the patent area. The relevant act of infringement is not the use of the method outside the patent area but the exploitation (by importation and sale) in Australia of a product made using the patented method. In my respectful opinion, contrary to the approach taken by Lindgren J, the relevant territorial limitation is reflected in the language of s 12 and s 13(3) and there is therefore no justification for importing words of territorial limitation into the definition of "exploit". It follows that I take a somewhat different approach to the construction of the definition of "exploit" to that taken by Lindgren J in Alphapharm, though I do not think the difference has any impact on whether or not Apotex threatens to infringe the Swiss claims in this case. 769 Apotex contended that Nicholas J erred in failing to conclude that only products resulting from the use of the relevant method in the patent area fell within the definition of "exploit". Apotex submitted that a territorial limitation on products resulting from the use of a method or process is evident from the use of the "relational" words "such use" in paragraph (b). 770 Apotex submits that the infringing importation cases that begin with Saccharin Corporation Ltd v Anglo-Continental Chemical Works Ltd (1900) 17 RPC 307 are not the law in Australia. It submits that the conclusion of Buckley J in that case that one may infringe a patent for a process by importing a product made by the claimed process overseas was expressly founded on the words of the grant then conveyed by the letters patent in the United Kingdom. Apotex submits that that was the basis of the decision was confirmed by the House of Lords in Beecham Group Limited v Bristol Laboratories Limited and Another (1978) RPC 153 at 203 per Lord Diplock and Lord Simon. Apotex submits that to find infringement in the present case would represent a significant extension of what the Act expressly defines in s 13 as territorial rights limited to Australia. 771 Apotex submits that the particle size manufacturing process claims in the 666 Patent (claims 14 and 15) rise no higher than the Swiss claims. They are claims 14 and 15. Apotex submits that the Apotex products are manufactured in accordance with a method that includes each of the features of claims 14 and 15 of the 666 Patent. However, Apotex does not, itself, manufacture the Apotex products. They will be manufactured by third party entities which are located outside Australia. Apotex does not, itself, use the processes claimed in claims 14 and 15 of the 666 Patent. 772 Apotex submits that patent law is territorial. Infringements occur by acts done in the patent area with respect to patented products or to products resulting from the use in the patent area of patented methods. The reasoning of Lindgren J in Alphapharm v H Lundbeck A/S should no longer be followed. It follows that none of the Swiss and manufacturing process claims in suit is infringed. 773 ICOS submits that the decision of Nicholas J in Apotex v Warner-Lambert is correct. Section 13 and the definition of "exploit" operate in tandem to delineate the limits of a patentee's exclusive rights and, pursuant to this legislative scheme, the question of territorial limits only arises when one is determining whether an act of exploitation has infringed a patent, not whether an act amounts to an exploitation. It submits that it is clear from the definition of "exploit" that an Australian patent may be "exploited" anywhere in the world. The question of whether a party is exploiting a patent does not depend on where the relevant act took place. It is only if that exploitation occurs within the patent area that the patentee's legal rights may be infringed. ICOS submits that to place "territorial limitations" into the definition of "exploit" would render the territorial limitation in s 13 superfluous. Accordingly, the exploitation in Australia of the Apotex products will infringe Swiss-style claims irrespective of where the products are manufactured. Apotex threatens to infringe the relevant claims in both patents. 774 After I had reserved my decision, the Full Court of this Court delivered its decision in an appeal from the decision of Nicholas J in Warner-Lambert Co LLC v Apotex Pty Ltd (No 2) [2018] FCAFC 26; (2018) 355 ALR 44 (at [156]-[169]). The Full Court held that Nicholas J's construction of s 13 and the definition of "exploit" is correct. I am bound to follow that decision. I would, in any event, have followed the decision because I respectfully consider that the reasoning of Nicholas J is correct. 775 For the above reasons, I conclude that Apotex threatens to infringe all of the claims in suit in the 946 Patent and in the 666 Patent.

CONCLUSION 776 Apotex's challenge to the validity of the 946 Patent and the 666 Patent must be rejected. ICOS has established that Apotex threatens to infringe the claims in suit in the case of each patent. 777 I will hear the parties as to the appropriate orders in light of these reasons. I certify that the preceding seven hundred and seventy-seven (777) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Besanko.

Associate: Dated: 14 August 2018 ANNEXURE A Claims in suit in the 946 Patent

1. A pharmaceutical unit dosage composition comprising about 1 to 20 mg of a compound having the structural formula: said dosage unit form suitable for oral administration up to a maximum total dose of 20 mg per day.
2. The dosage form of claim 1 comprising about 2 to 20 mg of the compound in unit dosage form.
3. The dosage form of claim 1 comprising about 5 to 20 mg of the compound in unit dosage form.
4. The dosage form of claim 2 comprising about 2.5 mg of the compound in unit dosage form.
5. The dosage form of claim 3 comprising about 5 mg of the compound in unit dosage form.
6. The dosage form of claim 3 comprising about 10 mg of the compound in unit dosage form.
7. The dosage form of any one of claims 1 through 7 wherein the unit dose is in a form selected from the group consisting of a liquid, a tablet, a capsule, and a gelcap.
8. The dosage form of any one of claims 1 through 7 wherein the unit dose is in the form of a tablet.
9. The dosage form of any one of claims 1 through 7 when used to treat a condition where inhibition of PDE5 is desirable. 11 The dosage form of claim 10 wherein the condition is male erectile dysfunction.
10. A method of treating male erectile dysfunction in a patient in need thereof comprising orally administering one or more unit dose containing about 1 to 20 mg, up to a maximum total dose of 20 mg per day, of a compound having the structure:
11. The method of claim 12 wherein the unit dose contains about 2 to 20 mg of the compound.
12. The method of claim 12 wherein the unit dose contains about 5 to 20 mg of the compound.
13. The method of claim 13 wherein the unit dose contains about 2.5 mg of the compound.
14. The method of claim 14 wherein the unit dose contains about 5 mg of the compound.
15. The method of claim 14 wherein the unit dose contains about 10 mg of the compound.
16. The method of claim 14 wherein the unit dose contains about 10 mg of the compound and is administered once per day.
17. The method of any one of claims 12 to 19 wherein the unit dose is in a form selected from the group consisting of a liquid, a tablet, a capsule, and a gelcap.
18. The method of any one of claims 12 to 19 wherein the unit dose is in the form of a tablet.
19. The method of any one of claims 12 to 19 when used to treat a condition where inhibition of PDE5 is desirable.
20. The method of claim 22 wherein the condition is male erectile dysfunction.
21. Use of a unit dose containing about 1 to 20 mg of a compound having the structure: for the manufacture of a medicament for administration up to a maximum total dose of 20 mg of said compound per day for the treatment of male erectile dysfunction in a patient in need thereof.
22. The use of claim 24, wherein the unit dose contains about 2 to 20 mg of the compound.
23. The use of claim 24, wherein the unit dose contains about 5 to 20 mg of the compound.
24. The use of claim 25, wherein the unit dose contains about 2.5 mg of the compound.
25. The use of claim 26, wherein the unit dose contains about 5 mg of the compound.
26. The use of claim 26, wherein the unit dose contains about 10 mg of the compound.
27. The use of claim 26, wherein the unit dose contains about 10 mg of the compound and is for administration once per day. 32 The use of any one of claims 24 to 31, wherein the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap.
28. The use of any one of claims 24 to 31, wherein the unit dose is in the form of a tablet.
29. A use according to any one of claims 24 to 31 when used to treat a condition wherein inhibition of PDE5 is desirable.
30. A use according to claim 34 wherein the condition is male erectile dysfunction. ANNEXURE B Claims in suit in the 666 Patent
31. A free drug particulate form of a compound having a formula and pharmaceutically acceptable salts and solvates thereof, comprising particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.
32. The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 25 microns.
33. The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 15 microns
34. A pharmaceutical composition comprising the free drug particulate form of claim 1 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
35. The pharmaceutical composition of claim 5 wherein the free drug is entirely in particulate form.
36. A method of treating sexual dysfunction in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a composition comprising the free drug particulate form of claim 1 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
37. The method of claim 7 wherein the sexual dysfunction is male erectile dysfunction.
38. A pharmaceutical composition comprising: (a) a free drug form of a compound having the formula and pharmaceutically-acceptable salts and solvates thereof, and (b) one or more pharmaceutically-acceptable carriers, diluents, or excipients, wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter on an AUC (0-24) of about 2280 to about 3560 microgram hour/liter, measured using a 10 milligram dose of the compound.
39. The composition of claim 10 wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of about 2280 to about 3560 microgram hour/liter.
40. A pharmaceutical composition comprising: (a) a compound having the formula and pharmaceutically-acceptable salts and solvates thereof, and (b) one or more pharmaceutically-acceptable carriers, diluents, or excipients, wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of about 2280 to about 3560 micrograms hour/liter, measured using a 10 milligram dose of the compound.
41. A method of manufacturing the free drug particulate form of claim 1 comprising: (a) providing a solid, free form of the compound, and (b) comminuting the solid free form of the compound to provide particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.
42. The method of claim 14 further comprising the step of admixing the particles of step (b) with one or more pharmaceutically-acceptable carriers, diluents, or excipients.
43. A pharmaceutical composition prepared by admixing particles of a compound having a formula or a pharmaceutically-acceptable salt or solvate thereof, with one or more pharmaceutically-acceptable carrier, diluent, or excipient, wherein the particles of the compound have a d90=40 or less.
44. Use of particles of a free form of a compound having a formula wherein at least 90% of the particles have a particle size of less than about 40 microns, for the manufacture of a medicament for the treatment of male erectile dysfunction or female sexual arousal disorder.
45. The use of particles of a free form of a compound having a formula which exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of about 2280 to about 3560 micrograms hour/liter, measured using an 10 milligram dose of the compound, for the manufacture of a medicament for the treatment of male erectile dysfunction or female arousal disorder.
46. A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises about 1 to about 20 mg of the compound.
47. A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 20 mg of the compound.
48. A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 10 mg of the compound.
49. A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 5 mg of the compound.
50. A pharmaceutical composition according to any one of claims 24 to 27, wherein the pharmaceutical composition comprises a tablet.
51. A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises about 1 to about 20 mg of the free drug particulate form of claim 1.
52. A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 20 mg of the free drug particulate form of claim 1.
53. A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 10 mg of the free drug particulate form of claim 1.
54. A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 5 mg of the free drug particulate form of claim 1.
55. A method of treating male erectile dysfunction in a patient in need thereof according to any one of claims 29 to 32, wherein the composition comprises a tablet.
56. A use according to any one of claims 17 and 18, wherein the medicament comprises about 1 to about 20 mg of the compound.
57. A use according to any one of claims 17 and 18, wherein the medicament comprises 20 mg of the compound.
58. A use according to any one of claims 17 and 18, wherein the medicament comprises 10 mg of the compound.
59. A use according to any one of claims 17 and 18, wherein the medicament comprises 5 mg of the compound.
60. A use according to any one of claims 17 and 18, wherein the medicament comprises a tablet. ANNEXURE C Glossary of terms Term Description 666 Patent Australian Patent No 773666 946 Patent Australian Patent No 769946 Act Patents Act 1990 (Cth) Amendment Reasons Apotex Pty Ltd v ICOS Corporation [2017] FCA 466 APG Adelaide Pharmacology Group API Active pharmaceutical ingredient Apotex Apotex Pty Ltd Astra Astra Pharmaceuticals AUCt Area under curve, where the curve refers to a plot of the concentration of the API in the plasma over time, which represents the aggregate amount of API present in the plasma over a given amount of time BCS Biopharmaceutical Classification System Biota Biota Holdings BP British Pharmacopeia Butler Butler US Patent No 5,985,326 cGMP Cyclic guanosine monophosphate, noting that Viagra increases the level of cGMP and elevated cGMP levels result in relaxation of the cavernosal smooth muscle, which, in turn, results in engorgement of the tissue and erection cGMP-specific PDE Cyclic guanosine 3',5'-monophosphate specific phosphodiesterase Cialis® Brand name for tadalafil, which is the compound that is the subject of the two patents in suit in this proceeding Cmax Pharmacokinetic parameter used to denote the observed or predicted maximum concentration of API in the plasma following a single dose of the API cytarabine Chemotherapy medication used for the treatment of certain blood cancers Daugan 1995 WO 95/19978, published on 27 July 1995 Daugan 1997 WO 97/03675, published on 6 February 1997 DBP Diastolic blood pressure, which is the pressure in the arteries between beats Declaration of Helsinki General set of principles for the conduct of clinical trials in order to respect the human rights of the subject participating dissolution rate Speed at which the API dissolves in a given amount of solvent ED Erectile dysfunction (also referred to as impotence), which is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance and is a condition that is particularly common among males over 50 years of age EDITS Erectile Dysfunction Inventory of Treatment of Satisfaction, which is a questionnaire consisting of two parts, one to be completed by the patient and the other by the patient's partner equilibrium solubility Solubility that is observed after the solute/solvent system has had sufficient time to reach thermodynamic equilibrium Faulding FH Faulding & Co Ltd FDA United States Food and Drug Administration flushing Defined in the 946 Patent as "… means an episodic redness of the face and neck attributed to vasodilation caused by an ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration" free drug Defined in the 946 Patent as "… means solid particles of drug not intimately embedded in a polymeric coprecipitate" GAQ Global Assessment Question, which is a single question to be answered "yes" or "no" four weeks after the administration of the drug and which asked whether the drug had improved their erections GB 464 GB9514464.8, published on 6 February 1997 GI tract A continuous passageway between the mouth and the anus that includes the main organs of digestion, being the stomach which feeds into the small intestine which, in turn, feeds into the large intestine Goldstein et al (1998) Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD and Wicker PA, "Oral Sildenafil in the Treatment of Erectile Dysfunction" (1998) 338 The New England Journal of Medicine 1397 HSF Herbert Smith Freehills (Apotex's solicitors) IC50 Measure of potency of a compound to inhibit a particular PDE enzyme ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICOS ICOS Corporation IIEF International Index of Erectile Dysfunction IND Investigational new drugs IVIVC In vitro in vivo correlation Kloner Papers A collection of three papers that were the subject of evidence from the clinicians in this proceeding, and which include the following: Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, "Time Course of the Interaction Between Tadalafil and Nitrates" (2003) 42 Journal of the American College of Cardiology 1855 (Kloner et al (2003)); Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, "Reply" (2004) 43 Journal of the American College of Cardiology 2150 (Kloner et al Reply); and Kloner RA, Mitchell MI and Emmick JT, "Cardiovascular Effects of Tadalafil" (2003) 92 The American Journal of Cardiology 37M (Kloner et al Review) Levitra® Brand name for vardenafil, which is a PDE5 inhibitor Lieberman et al (1989) Lieberman H, Lachman L and Schwartz JB (eds), Pharmaceutical Dosage Forms: Tablets (2nd ed revised and expanded, Taylor & Francis, 1989) Lilly ICOS A new company formed for the purpose of the joint development of tadalafil Lilly Nitrate Studies Five pharmacology studies conducted by Lilly ICOS during the period 1999 to 2002 to investigate the potential interaction between tadalafil and nitrates, being LVAB, LVBY, LVCM, LVCP and LVCN, which are discussed in detail in Annexure E MAD calculation Maximum absorbable dose calculation, being MAD = S x Ka x SIWV x SITT, where: S is the solubility of the API at pH6.5 (in mg mL-1) Ka is the transintestinal absorption rate constant (in min-1) SIWV is the volume of fluid in the small intestine (in mL); and SITT is the small intestine transit time (in minutes) MC-4R Melanocortin-4 receptor MD Doctor of Medicine MEC Minimum effective concentration MHRA Medicines and Healthcare Products Regulatory Agency, which regulates medicines, medical devices and blood components for transfusion in the United Kingdom micronisation A process where the mean particle size of the API is reduced to, at the smallest, single digit micron sizes mmHg Millimetre of mercury, which is a manometric unit of pressure, formerly defined as the extra pressure generated by a column of mercury one millimetre high and now defined as precisely 133.322387415 pascals NCE New chemical entity, which is a compound that has not been approved by a recognised health regulatory body for use for medicinal purposes NO Nitric oxide Noyes-Whitney equation dm/dt - kA (Cs - Ct), in which: A = the effective surface area of the undissolved API, which is the surface area available for contact with the surrounding dissolution medium, being the GI tract fluid (solvent); Cs = the saturated concentration (i.e. solubility) of the API at the interface of the solid particle surface and the liquid dissolution medium (i.e. the diffusion layer which surrounds the undissolved drug); Ct = the concentration of the dissolved API in the bulk of the dissolution fluid (where convectional mixing occurs) at time t; and K = the dissolution rate constant, calculated by dividing the API diffusion coefficient by the thickness of the "diffusion layer" around the particle (being the stagnant liquid layer adjacent to the solid-liquid interface into which the particle's molecules dissolve) olanzapine Atypical antipsychotic medication used in the treatment of schizophrenia and other psychoses oral dosage form Defined in the 946 Patent as "… used in a general sense to reference pharmaceutical products administered orally. Oral dosage forms are recognised by those skilled in the art to include such forms as liquid formulations, tablets, capsules and gelcaps" Oren WO 01/08686, published on 8 February 2001 Oren Priority Document US 60/146,924, filed on 3 August 1999 organic ED ED caused by patho-physiological diseases and conditions Parke Davis Parke Davis Ltd PDE Phosphodiesterase, which are enzymes that are diffusely found in many parts of the body PDE5 Phosphodiesterase type 5, which is an enzyme found within the penis pH A figure expressing the acidity or alkalinity of a solution on a logarithmic scale on which 7 is neutral, lower values are more acid and higher values more alkaline Ph Eur European Pharmacopeia PhD Doctor of Philosophy PHSC Perth Human Sexuality Centre PI Statement Product Information Statement prostatic hyperplasia Enlargement of the prostate psychogenic ED ED caused by psychological problems QEH Queen Elizabeth Hospital, which is a teaching hospital affiliated with the University of Adelaide Regulations Patents Regulations 1991 (Cth) RMRI Reproductive Medicine Research Institute (now known as the Keogh Institute for Reproductive Medicine) SBP Systolic blood pressure, which is the pressure in the arteries when the heart beats Sexual Encounter Profile Diaries Diaries containing the patient's answer to questions formulated by the drug development company Smith (2015) Smith BT, Remington Education: Physical Pharmacy (Pharmaceutical Press, 2015) solubility The amount of the API that is able to be dissolved in a given amount of solvent Stoner WO 00/53148 published on 14 September 2000 (noting that Stoner and US 244 are, in all material respects, the same) TGA Australian Therapeutic Goods Association The clinicians Dr Denis Cherry, Dr Christopher McMahon, Professor Gerald Brock and Dr Malcolm Mitchell The formulators Dr Brett Mooney and Professor James Polli The pharmacologists Dr Phillip Reece, Professor Allan Evans and Professor Gerald Brock Tmax Measure of the time to achieve peak blood levels of a drug and to be indicative of an improved onset of action TQT study Thorough QT study, which is designed to assess whether new drugs have the potential to cause cardiac arrhythmia US 048 US 60/147048 (also referred to in the reasons as the "666 Priority Document") US 244 US 60/123,244, filed on 8 March 1999 (noting that US 244 and Stoner are, in all material respects, the same) USP United States Pharmacopeia VIAGRA® Brand name for sildenafil, which is a PDE5 inhibitor vision abnormalities Defined in the 946 Patent as "… means abnormal vision characterised by blue-green vision believed to be caused by PDE6 inhibition" Webb et al (1999) Webb DJ, Freestone S, Allen MJ and Muirhead GJ, "Sildenafil Citrate and Blood-pressure-lowering Drugs: Results of Drug Interaction Studies with an Organic Nitrate and Calcium Antagonist" (1999) 83 American Journal of Cardiology 21C WHO World Health Organisation Workshop Faculty APG Drug Disposition Workshop Faculty Wrays Wrays and Associates (ICOS's patent and trade mark attorneys) β-carboline compound Compound useful for the treatment of various medical indications where the inhibition of PDE5 is desired