Merck & Co Inc v Arrow Pharmaceuticals Limited

The Patent 10 On 28 August 2000 application was made for the grant of the Patent having a priority date of 2 September 1999. The specification described the field of the invention as follows: 'The present invention relates to oral methods for inhibiting bone resorption in a mammal while minimising the occurrence of or potential for adverse gastrointestinal effects. These methods comprise orally administering to a mammal in need thereof a pharmaceutically effective amount of a bisphosphonate as a unit dosage according to a continuous schedule having a dosage interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, bi-weekly dosing, and twice-monthly dosing. The present invention also relates to pharmaceutical compositions and kits useful for carrying out these methods.' 11 Under the heading 'Background of the Invention', the specification discussed the methods then current for treating disorders associated with abnormal bone resorption involving the use of bisphosphonates and the problems associated with those methods. In the course of that discussion a number of disclosures were made including the following. It was known that alendronate monosodium trihydrate on an alendronic acid active basis was effective in preventing and treating osteoporosis in a human. It was known that it could be orally administered, that is, taken by mouth in various amounts and at various time intervals. It was known that oral administration of the compound had the potential to give rise to GI side effects in a small but significant proportion of the population. It was known that there could be problems of compliance with a daily dosage regime of the type described in the specification. A need for development of a dosing regimen to overcome the shortcomings identified in the specification was asserted. 12 The present invention was described as follows: 'In the present invention, it is found that the adverse gastrointestinal effects that can be associated with daily or cyclic dosing regimens can be minimized by administering the bisphosphonate at a relatively high unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, bi-weekly dosing, and twice-monthly dosing. In other words, it is found that the administration of a bisphosphonate at a high relative dosage at a low relative dosing frequency causes less adverse gastrointestinal effects, particularly esophageal effects, compared to the administration of a low relative dosage at a high relative dosing frequency. This result is surprising in view of the teachings suggesting that adverse gastrointestinal effects would be expected to increase as a function of increasing bisphosphonate dosage. Such administration methods of the present invention would be especially beneficial in treating patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e.g. gastrointestinal reflux disease (i.e. "GERD"), esophagitis, dyspepsia (i.e. heartburn), ulcers, and other related disorders. In such patients conventional bisphosphonate therapy could potentially exacerbate or induce such upper gastrointestinal disorders. …' 13 The claims which are the subject of the present appeal are claims 1, 2 and 3, which are as follows: 1. A method of preventing osteoporosis in a human, comprising orally administering to said human a pharmaceutically effective amount comprising about 35 mg of alendronate monosodium trihydrate on an alendronic acid active basis as a unit dosage according to a continuous schedule having a dosage interval which is once weekly. 2. A method of treating osteoporosis in a human, comprising orally administering to said human a pharmaceutically effective amount comprising about 70 mg of alendronate monosodium trihydrate on an alendronic acid active basis as a unit dosage according to a continuous schedule having a dosage interval which is once weekly. 3. A method for treating or preventing osteoporosis in a human, said method comprising orally administering to said human a pharmaceutically effective amount of a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts, as a unit dosage according to a continuous schedule having a dosage interval which is once weekly. 14 These claims are to a method of treatment (or prevention) of a particular disease with an amount (specified in claims 1 and 2 but not in claim 3) of a known chemical or drug (alendronate) already known to treat that disease, with the sole asserted novelty being that the amount of the drug (claims 1 and 2) or the drug per se (claim 3) is taken weekly. An issue arises in relation to claim 3 as to whether on its proper construction the reference to a 'pharmaceutically effective amount' should be read as signifying 35 mg or 70 mg as the case may be, although the primary judge declined to construe claim 3 in that way.

The judgment appealed from 15 The primary judge held (pursuant to ss 138(3)(b) and 18(1)(a) of the Act) that claims 1 - 3 were invalid because they did not claim a manner of new manufacture within the meaning of s 6 of the Statute of Monopolies. A method of medical treatment of the human body is patentable: Anaesthetic Supplies Pty Ltd v Rescare Ltd (1994) 50 FCR 1; Bristol-Myers Squibb Company v F H Faulding & Co Ltd (2000) 97 FCR 524. Arrow accepted that the primary judge was bound by those decisions and that this Court would follow them whilst reserving its right to argue that those decisions are wrong should the matter proceed to the High Court of Australia. However, his Honour held that in substance, each claim relates to the use of a known substance with known properties for a known purpose in a known manner. There is no claim of any new process or method of the administration of such. There is no claim of discovery of new physical properties in the compound. 16 Guided by the decisions of the High Court in Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232, National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252 and N V Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655, and having regard only to the disclosures in the specification itself, the primary judge held that each of the so-called method claims was one way of utilising alendronate and its known qualities for the known purpose of preventing or treating osteoporosis by a known method of oral administration. They are in the nature of directions for use. That does not constitute an invention or a manner of manufacture. 17 The second ground on which his Honour found that claims 1, 2 and 3 were invalid is that the claims were not novel by reason of the prior publication of the Lunar News articles. His Honour found that the information contained in these publications was 'publicly available' and that the April 1996 issue of Lunar News anticipated claim 3, the July 1996 issue anticipated claims 1, 2 and 3, and the April 1997 issue anticipated claims 1 and 3. 18 One of the grounds upon which Arrow asserted the invalidity of the Patent was that when compared with the prior art base as it existed before the priority date, the claims did not involve an inventive step: s 18(1)(b)(ii). In the light of his other conclusions, it was not necessary for the primary judge to deal with this ground, and he did not do so as he said that it would involve grappling with a considerable body of evidence and the exercise would have an air of unreality having regard to his conclusion that the invention lacked subject matter. By its Amended Notice of Contention Arrow asserts that the primary judge should have found that the invention as claimed did not involve an inventive step when compared with the prior art base as it existed before the priority date.

The issues on appeal 19 The appeal was conducted upon the basis that should it become necessary to determine the question of lack of inventive step or 'obviousness' (as it is sometimes called) the matter would need to be remitted to the primary judge for further consideration. The argument on the appeal was thus confined to the questions of whether the primary judge erred in finding that the invention was not a patentable invention as the claims do not constitute an invention or a manner of manufacture or because of lack of novelty having regard to the disclosures in the publications of Lunar News. MANNER OF NEW MANUFACTURE 20 Section 18(1)(a) of the Act relevantly provides: '… an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim: (a) is a manner of manufacture within the meaning of s 6 of the Statute of Monopolies…' 21 'Invention' is defined in sch 1 to mean: '… any manner of new manufacture the subject of letters patent and grant of privilege within section 6 of the Statute of Monopolies, and includes an alleged invention.' 22 The threshold issue is whether an invention appears on the face of the specification: Philips at 664. The critical steps in his Honour's reasoning on this issue were as follows: '81. The relevant claims of this patent will stand or fall by the so-called method claims. The disclosures in the specification include the following. It was known that alendronate monosodium trihydrate on an alendronic acid active basis was effective in preventing and treating osteoporosis in a human. It was known that it could be orally administered, that is, taken by mouth in various amounts and at various time intervals. It was known that oral administration of the compound had the potential to give rise to GI side effects in a small but significant proportion of the population. It was known that there could be problems of compliance with a daily dosage regime of the type described in the specification. Thus, in substance, each claim relates to the use of a known substance with known properties for a known purpose in a known manner. There is no claim of any new process or method of administration as such. There is no claim of discovery of new physical properties in the compound. 82. It is trite law that a mere new use for an old thing is not patentable. However, a discovery that an old substance may be so used as to produce a new result may possibly give rise to a patentable invention. The old substance in that case is treated as if it were new, the previously unknown or unsuspected qualities of it being revealed by the discovery if the discovery in question is a consequence of scientific ingenuity. The principle extends to a process that results in a new and useful effect that is an artificially created state of affairs of economic utility (National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252 (NRDC) at 265, 277; Wellcome Foundation Ltd v Commissioner of Patents (1980) 145 CLR 520 at 528). 83. However, a process claim cannot lead to a monopoly in a substance limited to its use in the process. The process makes no contribution to the substance - it takes advantage of its properties. The substance is merely an ingredient in that process (Wellcome Foundation Ltd v Commissioner of Patents at 529-530). As Parker J said in Adhesive Dry Mounting Co Ltd v Trapp & Co (1910) 27 RPC 341 (at 353): "The idea of using an old material for an entirely new purpose, not being analogous to purposes for which it has theretofore been used, may be good subject matter, but such idea, however ingenious, can hardly justify a claim for the material itself." 84. As was said in Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 (at 249): "Many valid patents are for new uses of old things. But it is not an inventive idea for which a monopoly can be claimed to take a substance which is known and used for the making of various articles, and make out of it an article for which its known properties make it suitable, although it has not in fact been used to make that article before." 85. The authorities which were analysed in Commissioner of Patents v Microcell Ltd at 247-249 including Re B.A.'s Application (1915) 32 RPC 348 in which it was said (at 349): "once a substance is known, its methods of production ascertained, its characteristics and its constituents well defined, you cannot patent the use of that for a purpose which was hitherto unknown." ' 23 After referring to Philips and Advanced Building Systems Pty Ltd at 191-192 his Honour continued: '87. Guided by those authorities, and having regard only to the disclosures in the specification itself, I would hold that each of the so-called method claims was one way of utilising alendronate and its known qualities for the known purpose of preventing or treating osteoporosis by a known method of oral administration. They are in the nature of directions for use. That does not constitute an invention or a manner of manufacture.' 24 At a later stage his Honour considered the decision of the Full Court in Faulding, a case which dealt with a patent for a method of administration of taxol in the treatment of ovarian cancer. After quoting passages from the joint judgment of Black CJ and Lehane J at [31] and [43]-[44] his Honour said: '95. It does seem to follow that it was held that a mere dosage regime of a known chemical compound for a known therapeutic use based upon known properties and involving no new method of administration was patentable. As will be apparent from the foregoing, I regard that conclusion as being difficult to reconcile with prior and binding authority if applied to the present circumstances. My reservations are underlined by considering the decision of the United Kingdom Court of Appeal in relation to taxol - Bristol-Myers Squibb Co v Baker Norton Pharmaceuticals Inc [2001] RPC 1 (Bristol-Myers). As pointed out by the High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411, great care needs to be taken in reading United Kingdom cases in this field because of the significant differences which have developed. However, Aldous LJ analysed the claim (at [34]) as being: "for the use of two known products to produce a medicament with the novelty relied on being provided by the alleged new application." It was clear that, even under the extended European Community rules, novelty could only lie in a new therapeutic use. Aldous LJ said (at [42]): "… I turn to claim 1. The judge was right to conclude there was not a claim for a second therapeutic use. The medicaments in question were known to be suitable for treating cancer. The remainder of the claim relates to the way such a medicament was to be used. A similar conclusion was reached by the Dutch Court of Appeal in Bristol-Myers Squibb v Yew Trew of 25 June 1998." 96. I have been referred to the English decisions corresponding to this case (Merck & Co., Inc's Patents [2003] EWHC 5 (Pat); [2003] FSR 29 at first instance; and Merck & Co., Inc's Patents [2003] EWCA Civ 1545; [2004] FSR 16 in the Court of Appeal) and to the corresponding United States decision (Merck & Co., Inc. v Teva Pharmaceuticals USA, Inc. 288 F. Supp. 2d 601). It is accepted by counsel that the law in each place is sufficiently different from our present law to distinguish those decisions and limit their utility for present purposes. However, a revealing exercise in the decision at first instance in the United Kingdom was counsel's redrafting of some statements from Holman J at para [111] in the English decision in Bristol-Myers substituting alendronate for taxol, osteoporosis for ovarian cancer, adverse GI effects for neutropenia and 'the new and old alendronate dosing regimes' for 'the new and old taxol dosing regimes'. The result is as follows (at 519): "In the present case, however, the drug alendronate is exactly the same; the method of administration, orally, is exactly the same; and the therapeutic application or purpose, namely the attempt to treat osteoporosis, is exactly the same. The only difference is the discovery that if the drug is administered in a unit dosage form of 70mg once weekly rather than 10mg once daily an undesirable side-effect, adverse GI effects, is less than it otherwise would be, whilst the therapeutic effect remains. No previously unrecognized advantageous properties in the chemical compound have been discovered … All that has been discovered … is that if the compound is administered once a week rather than daily, one of its disadvantageous side effects will be less than it otherwise would be." As Jacob J said, counsel for Merck found no answer to that. That analysis is consistent with that of Heerey J at first instance in Faulding (1998) 41 IPR 467 and with my analysis in this case.' 25 His Honour then (at [97]) distinguished Faulding on the grounds that: · Taxol was a naturally occurring substance with known beneficial properties which could not be utilised without the invention. The dosage regime was, in his Honour's words, 'the key that unlocked the door to utility', and was arguably akin to a first therapeutic cure; · Arguably the dosage regime was the result of a newly discovered technical effect, namely the reduction of neutropenia. Neither of these elements was, in his Honour's view, present in the instant case. 26 We consider that the correctness or otherwise of his Honour's reasoning depends upon an examination of the Patent specification in light of the decision of the High Court in Philips to determine whether the subject matter of the claims was a manner of new manufacture for the purposes of s 6 of the Statute of Monopolies 1623 (Imp). That question requires us to construe the specification. 27 The specification describes the 'background'of the invention, including the occurrence of abnormal bone resorption in human beings and various aspects of the treatment thereof. Numerous publications on the subject, including some patents, are incorporated by reference into the body of the specification. The following propositions emerge: · Numerous disorders in human beings and other mammals involve, or are associated with abnormal bone resorption including, in particular, osteoporosis and Paget's Disease. · Osteoporosis most frequently manifests itself in post-menopausal women. · Osteoporosis leads to low bone mass and deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. · Because osteoporosis, as well as other disorders associated with bone loss, are chronic conditions, appropriate therapy will generally require chronic treatment. In this context, 'chronic' seems to mean 'of indefinite duration', 'long term' or, in some cases, 'for the rest of the patient's life'. · Bisphosphonates are selective inhibitors of bone resorption and are therefore important therapeutic agents in the treatment or prevention of such disorder. · One such bisphosphonate is alendronate. · Bisphosphonates may be administered either orally or by subcutaneous or intravenous injection. · Bisphosphonates are poorly absorbed from the gastro-intestinal tract, thus reducing the efficacy of oral administration. · Intravenous administration has been used to overcome this problem. · Intravenous administration is costly and inconvenient. · Oral administration must be in relatively high dosages (compared with intravenous administration) to compensate for low bio-availability. · To achieve the required effect it is generally recommended that a patient take bisphosphonates on an empty stomach and fast for at least thirty minutes afterwards. This is inconvenient for many patients. · Oral administration of bisphosphonates has been associated with adverse GI effects, especially in connection with the oesophagus, apparently because bisphosphonates tend to irritate it, which irritation is possibly exacerbated by the presence of refluxed gastric acid. · Adverse GI effects increase with increases in dosage. · These adverse effects are more prevalent in patients who fail to take the bisphosphonate with adequate amounts of liquid or who lie down shortly after administration. · Oral administration is generally either by a continuous daily treatment regime or a 'cyclic' regimen of treatment involving periods of treatment and rest periods. · Continuous daily treatment normally involves 'chronic administration of relatively low doses', the objective being delivery of the desired cumulative therapeutic dose over the course of the treatment period. · Continuous daily dosing has the potential disadvantage of causing adverse GI effects due to repetitive, continuous and additive irritation to the GI tract. · Daily dosing is burdensome because of the requirements that the medication be taken on an empty stomach and that administration be followed by a period of fasting and maintenance of an upright posture. · Daily dosing of some bisphosphonates has a further disadvantage in that it can cause decline in bone mineralization. It is not suggested that this disadvantage occurs with alendronate. · Cyclic regimens are generally intermittent, as opposed to continuous, having treatment periods during which the medication is administered, and non-treatment periods, to 'permit the systemic level of the bisphosphonate to return to base line'. · Cyclic regimens, as compared to continuous dosing, 'appear to result in a decreased therapeutic antiresorptive efficacy'. It seems that this has not been specifically demonstrated with respect to alendronate. · Cyclic regimens do not eliminate or minimize adverse GI effects because such regimens typically utilize periods of multiple daily dosing. · Cyclic regimes are cumbersome to administer and have the disadvantage of low patient compliance, resulting in compromised therapeutic efficacy. · US Patent No 5,366,956 ('Strein') addresses the problem of adverse GI effects by teaching the administration of a polyphosphonate compound, either orally, subcutaneously or intravenously, according to an intermittent dosing schedule, having both a bone resorption inhibition period and a 'no treatment' rest period. · That regimen has the disadvantage of not being continuous and regular and requiring nontreatment periods ranging from 20 - 120 days. · PCT Application Number WO 95/30421 ('Goodship') discloses methods for preventing prosthesis loosening and migration using various bisphosphonate compounds, including administration of a once-weekly partial dose. However it does not address the issue of adverse GI effects or disclose administration of larger or multiple dosages. 28 Against this background, Merck claims that: 'It is seen from the current teachings that both daily and cyclic treatment regimens have shortcomings, and that there is a need for development of a dosing regimen to overcome these shortcomings.' 29 The specification then continues: 'In the present invention, it is found that the adverse gastrointestinal effects that can be associated with daily or cyclic dosing regimens can be minimized by administering the bisphosphonate at a relatively high unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In other words, it is found that the administration of a bisphosphonate at a high relative dosage at a low relative dosing frequency causes less adverse gastrointestinal effects, particularly esophageal effects, compared to the administration of a low relative dosage at a high relative dosing frequency. This result is surprising in view of the teachings suggesting that adverse gastrointestinal effects would be expected to increase as a function of increasing bisphosphonate dosage. Such administration methods of the present invention would be especially beneficial in treating patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e.g. gastrointestinal reflux disease (i.e. 'GERD'), esophagitis, dyspepsia (i.e. heartburn), ulcers, and other related disorders. In such patients conventional bisphosphonate therapy could potentially exacerbate or induce such upper gastrointestinal disorders. From a patient lifestyle standpoint, the method of the present invention would also be more convenient than daily or cyclic dosing regimens. Patients would be subjected less frequently to the inconvenience of having to take the drug on an empty stomach and having to fast for at least 30 minutes after dosing. Also, patients would not need to keep track of the complex dosing regimen. The methods of the present invention are likely to have the advantage of promoting better patient compliance, which in turn can translate into better therapeutic efficacy.' 30 The specification describes the invention as follows: 'The present invention relates to a method, preferably an oral method, for inhibiting bone resorption in a mammal in need thereof, while minimizing the occurrence of or potential for adverse gastrointestinal effects. The present invention relates to methods of treating or preventing abnormal bone resorption in a mammal in need of such treatment or prevention. The methods of the present invention comprise orally administering to a mammal a pharmaceutically effective amount of a bisphosphonate as a unit dosage, wherein said dosage is administered according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In other embodiments, the present invention relates to methods comprising a continuous dosing schedule having a dosing periodicity ranging from about once every 3 days to about once every 16 days. Typically, the continuous dosing schedule is maintained until the desired therapeutic effect is achieved for the mammal. The present invention utilizes higher unit dosages of the bisphosphonate at each dosing point than has heretofore been typically administered, yet because of the dosing schedule chosen, the potential for adverse gastrointestinal effects are minimized. Moreover, the method is more convenient because the disadvantages associated with daily dosing are minimized.' 31 A number of terms are then defined, including the following: 'The term "pharmaceutically effective amount", as used herein, means that amount of the bisphosphonate compound, that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen. A preferred pharmaceutically effective amount of the bisphosphonate is a bone resorption inhibiting amount.' 'The term "minimize the occurrence of or potential for adverse gastrointestinal effects", as used herein, means reducing, preventing, decreasing or lessening the occurrence of or the potential for incurring unwanted side effects in the gastrointestinal tract … .' 'The terms "continuous schedule" or "continuous dosing schedule", as used herein, mean that the dosing regimen is repeated until the desired therapeutic effect is achieved. The continuous schedule or continuous dosing schedule is distinguished from cyclical or intermittent administration.' 'The term "until the desired therapeutic effect is achieved", as used herein, means that the bisphosphonate compound is continuously administered, according to the dosing schedule chosen, up to the time that the clinical or medical effects sought for the disease or condition is observed by the clinician or researcher. … Nonlimiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can range from about 2 weeks to the remaining lifespan of the human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.' 32 Under the heading 'Methods of the Present Invention', it is said that: 'The methods of the present invention do not have the disadvantages of current methods of treatment which can cause or increase the potential for adverse gastrointestinal effects or which require cumbersome, irregular or complicated dosing regimens.' The present invention comprises a continuous dosing schedule whereby a unit dosage of the bisphosphonate is regularly administered according to a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. By once-weekly dosing is meant that a unit dosage of the bisphosphonate is administered once a week, i.e. one time during a seven day period, preferably on the same day of each week. In the once-weekly dosing regimen, the unit dosage is generally administered about every seven days. A nonlimiting example of a once-weekly dosing regimen would entail the administration of a unit dosage of the bisphosphonate every Sunday. It is preferred that the unit dosage is not administered on consecutive days, but the once-weekly dosing regimen can include a dosing regimen in which unit dosages are administered on two consecutive days falling within two different weekly periods.' 33 This seems to mean that the once-weekly dosing regimen permits administration of weekly doses on, say, the Sunday at the end of one week and the Monday at the commencement of the next. However this is not a preferred method. 34 The specification provides that: 'The methods of the present invention are intended to specifically exclude methods for the treatment and/or prevention of prosthesis loosening and prosthesis migration in mammals as described in …[Goodship], published November 16, 1995, which is incorporated by reference herein in its entirety.' We have previously referred to Goodship and will return to it at a later stage. Under the heading 'Pharmaceutical Compositions' in the specification of the Patent, there is a discussion of available bisphosphonate preparations. There is then a discussion of dosage as follows: 'The precise dosage of the bisphonate will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount cannot be specified in advance and can be readily determined by the caregiver or clinician. Appropriate amounts can be determined by routine experimentation from animal models and human clinical studies. Generally, an appropriate amount of bisphosphonate is chosen to obtain a bone resorption inhibiting effect, i.e. a bone resorption inhibiting amount of the bisphosphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 μg/kg body weight and preferably about 10 to about 2000 μg/kg of body weight. For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 8.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight base, i.e. on the basis of the corresponding acid.' 35 We do not understand the specification to be teaching new information concerning dosing levels but rather reflecting earlier learning. The specification also provides that: 'For once-weekly dosing, an oral unit dosage comprises from about 17.5 mg to about 70 mg of the alendronate compound, on an alendronic acid active weight basis. Examples of weekly oral dosages include a unit dosage which is useful for osteoporosis prevention comprising about 35 mg of the alendronate compound, and a unit dosage which is useful for treating osteoporosis comprising about 70 mg of the alendronate compound.' These are the dosing levels identified in claims 1 and 2. 36 Experiments on dogs are then described, concluding with the following observations: 'These experiments demonstrate that considerably less esophageal irritation … is observed from the administration of a single high concentration dosage of alendronate … versus administration of low concentration dosages on consecutive days … . These experiments also demonstrate considerably less esophageal irritation is observed from the administration of a single high concentration of alendronate on a weekly basis … versus administration of low concentration dosages on consecutive days … .' 37 In effect, the specification teaches weekly, rather than daily administration of the relevant dose of alendronate. The size of the dose will vary, depending upon potency of the drug and age, size, sex and condition of the patient, including severity of the disorder, and "other relevant medical and physical factors". The dosages of 35 mg and 70 mg identified in claims 1 and 2 seem to be examples only. We do not understand there to be any claimed invention in their selection. Each quantity is described in the relevant claim as "a pharmaceutically effective amount", but that will be so only if the identified dosage is that deemed by the "care giver or clinician" to be appropriate for the particular patient. It seems that claim 3 comprehensively identifies the claimed invention, whilst claims 1 and 2 are specific examples of it. (See Patent at p 18 ll 26-31.) 38 We should also say something about the use in the specification of the terms "cyclic" and "intermittent". The specification asserts that the expression "cyclic regimen" generally involves intermittent, rather than continuous treatment regimens. We infer that cyclic regimens involve periods of treatment and periods of rest from treatment, whereas continuous dosing involves administration of fixed dosages at regular intervals. It is said that cyclic regimens do not eliminate or minimize adverse gastro-intestinal effects 'because such regimens typically utilize periods of multiple daily dosing.' The term 'multiple daily dosing' seems to mean dosing on consecutive days. As cyclic regimes are said generally to involve intermittent treatment regimes, it is implied that intermittent regimes involve daily dosing. It is also asserted that Strein involves an intermittent, rather than a continuous, treatment regime, perhaps inviting the inference that Strein teaches multiple daily dosing as opposed to weekly dosing. Such an inference would be incorrect. Strein teaches (amongst other things) weekly administration of alendronate for the treatment of osteoporosis, although with rest periods. Similarly, Goodship teaches weekly administration of alendronate in doses which include those specified in claims 1 and 2 of the Patent (and, by inference, claim 3), but for a different medical condition. However Goodship asserts that such treatment involves dosages similar to those used in treating osteoporosis. Both Strein and Goodship are expressly incorporated into the Patent. As we have observed the primary judge effectively concluded that the claimed invention was merely a use of alendronate which was analogous to known uses and that: 'All that has been discovered … is that if the compound is administered once a week rather than daily, one of its disadvantageous side effects will be less than it otherwise would be.' 39 In construing the specification we will refer in some detail to Strein and Goodship which are incorporated into it. Those documents support his Honour's conclusion.

Strein 40 The application for Strein was filed on 29 January 1993. It was granted on 22 November 1994. Under the heading 'Background of the Invention' the following passage appears: 'Organic bisphosphonate compounds have been found to inhibit bone resorption which is mediated by osteoclasts. The earliest publication describing the administration of diphosphonates for treatment of osteoporosis was in 1979 when Frost described the "Treatment of osteoporosis by manipulation of coherent bone cell populations." … This coherence concept has been modified by several other authors. In principle, it consists of a stimulation of bone turnover with phosphorus or parathyroid hormone, followed by blocking the resorption with intermittent therapy of blocking agents such as calcitonin or diphosphonates. This therapy, although theoretically very attractive, did not find widespread application because of the difficulty in determining a correct dose for an individual patient and the correct period of time required for stimulation and suppression of individual bone remodelling sites (without exerting an effect on formation). It appears that somewhere between three days and three weeks, most resorption sites should be suppressed. However, no exact information is available anywhere to unequivocally prove this hypothesis. Since the work by Frost in 1979, many have conceived of different treatment regimens using different compounds and modes of administration. U.S. Pat. No. 4,761,406 to Flora et. al. represents one such example, and is an example of the well-known coherence therapy …. Flora '406 discloses and claims a treatment regimen which employs compounds (polyphosphonates) known in the prior art for treatment of osteoporosis. According to the regimen …, at least two cycles are performed, each cycle comprising a daily administration period, during which the polyphosphonate is administered every day, and a rest period. … U.S. Pat. Nos. 4,812,304, 4,812,311 and 4,822,609 disclose the use of [numerous named compounds] … . The treatment comprises one or more cycles, wherein each cycle includes a bone activating period of 1 to 5 days during which a bone activating amount of a bone cell activating compound is administered daily. That step is followed by a bone resorption inhibition period of about 10 to 20 days, during which [an identified acid] or salt or ester thereof is administered daily in a relatively low amount, followed by a rest period of 30 to 180 days, during which the patient receives neither a bone cell activating compound nor a bone resorption inhibiting polyphosphonate. Other bone resorption inhibiting polyphosphonates are disclosed but not claimed in these patents. [Alendronate is both disclosed and claimed.]' 41 Strein then identifies various earlier patents which taught so-called intermittent treatment regimens involving periods of administration of a bone resorption inhibiting polyphosphonate on a daily basis followed by rest periods. At the end of the discussion of such 'background', Strein observes that: 'Treatment for osteoporosis typically requires extended, sometimes chronic, treatment, and patient compliance is a major problem. Those who suffer from osteoporosis would benefit significantly from a new treatment regime which is effective, is easy to administer and/or requires fewer administrations, and avoids or minimizes side effects such as gastrointestinal problems (e.g., as caused by bisphosphonates such as clodronate and pamidronate, when administered orally). Such persons would also benefit from a new treatment regime which can be administered by a wider variety of modes.' 42 Under the heading 'Summary of this Invention', Strein states: 'The present invention provides such a new treatment regime. The present invention stems from an experiment conducted by the present inventors, which experiment had a surprising outcome.' 43 Details of experiments on rats are then provided. They involved daily administration of an appropriate medication to two groups, administration every second day to a third group and administration on the first and eighth days of a 14 day period (ie weekly) to a fourth group. Strein reports that: 'Despite the intermittent administration employed in [the third and fourth groups], in each group of rats, bone loss induced by ovariectomy was totally prevented. The present invention thus provides methods for the treatment and/or prophylaxis of osteoporosis, which methods comprise at lease two cycles, each cycle comprising an inhibiting period followed by a rest period. The inhibiting periods last for 4-90 days, and comprise at lease two intermittent periods. The intermittent periods may be of the same or different duration, and last for 2 to about 14 days. The drug is administered on only one day of each intermittent period. The rest periods last for 20-120 days.' Administration on one day of a period of 7 days would constitute weekly administration. 44 The preferred embodiments of the invention are described as follows: 'In accordance with the present invention, there are provided methods which comprise at least two cycles, each cycle comprising an inhibiting period followed by a rest period. The inhibiting periods preferably last for 4-90 days, more preferably 7-50 days, more preferably about 7-21 days, most preferably about 14 days, and comprise at least two intermittent periods. The intermittent periods may be of the same or different duration, and preferably last for 2 to about 14 days, more preferably 2-10 days, more preferably about 5-10 days, most preferably about 7 days. The drug is administered on only one day of each intermittent period.(emphasis added) Representative suitable inhibiting periods are as follows: 2 or 3 intermittent periods, each 7 days long; 2 to 5 intermittent periods, each 5-10 days long; 2 to 10 intermittent periods, each 4-14 days long. The rest periods preferably last for 20-120 days, more preferably 50-100 days, more preferably about 60-84 days, most preferably about 75-80 days. The cycles preferably last for 24-210 days, more preferably 57-150 days, more preferably about 67-105 days, most preferably about 90 days (90 days is approximately the same as a typical bone turnover cycle in an adult human.) For example, a representative suitable cycle might include a 14 day inhibiting period (two 7-day intermittent periods) and a 2˝ month rest period.' 45 Alendronate is identified as a suitable drug for use in such treatment regimens. Oral, intravenous and subcutaneous administration are all contemplated. With respect to oral administration it is said that: 'Oral administration typically provides only about 1-3% bioavailability (bioavailability varies from one patient to another). Much higher bioavailability is provided by subcutaneous and intravenous administration according to the present invention. Suitable polyphosphonate dosages depend on many factors, e.g., the patient's weight, the mode of administration, the type and degree of osteoporosis, etc. Suitable dosages may be determined by those skilled in the art without undue experimentation. Representative suitable dosages for various poly-phosphonates are set forth in U.S. Pat. Nos. 4,812,304, 4,812,311 and 4,822,609, incorporated herein by reference. … The total treatment time (i.e. the number of cycles for treatment) for the method of treatment for the present invention will vary from patient to patient based on sound medical judgment and factors particular to the patient being treated such as, for example, the extent of bone loss prior to starting treatment, the age and physical condition of the patient, and whether the goal of the treatment is to prevent bone loss or build bone mass. For example, if a certain percent increase in bone mass is desired from the method of treatment of the present invention, the total treatment time is as long as it takes to obtain this goal as determined through bone measurement. Those skilled in the art know the factors to be considered, and can easily determine the total treatment time based on these factors on a patient by patient basis.' 46 This passage is of some importance in that it describes the way in which dosage and length of treatment should be determined. Teaching of weekly administration and the use of rest periods must be understood in this context. At column 6, Strein states that: 'The present invention provides numerous advantages. For example the number, frequency and/or dosages of administrations can be significantly reduced. In addition, the present invention does not cause gastrointestinal problems or fever to the extent seen with patients subjected to other osteoporosis treatment regimes.' 47 In reporting the results of experiments performed on rats, Strein discloses, as part of 'Example 2', the results of treating Group F with 'Two injections of 0.021 mg/kg each with an interval of 7 days between these two injections; 4 weeks off; two injections of 0.021 mg/kg each with an interval of 7 days; 4 weeks off; two injections of 0.021 mg/kg each with an interval of 7 weeks, 4 weeks off; total dose = 0.126 mg.kg.' 48 Following such treatment rats in Group F demonstrated totally inhibited bone loss. Commenting on the outcome of the experiments, it is observed that: 'Owing to the new treatment schedule according to the present invention, during a drug-on interval, the patient only has to take the drug for example once a week. (emphasis added) This can increase patients' compliance (treatment of osteoporosis is typically a chronic treatment). Because bisphosphonates have to be taken at least 2 hours after a meal and 1 hour before a meal (if they are taken with a meal absorption is very low), especially for old patients, correct intake every day is difficult. It is easier to concentrate on the correct drug intake for example only once a week. Additionally, bisphosphonates can cause intestinal discomfort. It is important to have these problems as rare as possible. 49 Finally, the Patent claims relevantly as follows: '1. A method for the treatment of osteoporosis in a patient in need of such treatment, while minimizing the occurrence of patient gastrointestinal problems, said method comprising administering to said patient an effective amount of a bone resorption inhibiting polyphosphonate compound, or a physiologically acceptable salt or ester thereof, wherein the polyphosphonate compound is administered according to a schedule comprising at least two cycles, each said cycle comprising: (a) an inhibiting period of from about 4 to about 90 days, during which the said polyphosphonate is administered intermittently to the patient, said inhibiting period being divided into at least two intermittent cycle drug administration periods of 2 days to about 14 days, with the drug being administered on only one day of each intermittent cycle drug administration period; and thereafter, (b) a rest period of from about 20 days to about 120 days. (emphasis added) 2. A method as recited in claim 1, wherein said bone resorption inhibiting polyphosphonate compound comprises a compound selected from the group consisting of: … 4-amino-1-hydroxybutane-1, 1-diphosphononic acid [alendronate] … or a physiologically acceptable salt or ester thereof. 3. … 4. A method as recited in claim 1, 2 or 3, wherein the polyphosphonate is administered orally. … 10. A method as recited in claim 1, 2 or 3 wherein said schedule comprises 2 or 3 cycles, said inhibiting periods are each about 14 days in duration, said intermittent cycle drug administration periods are about 7 days in duration, and said rest period is about 2˝ months in duration.' 50 Clearly, Strein teaches weekly, oral administration of an 'effective amount' of alendronate. The benefits of such treatment over other regimes are reduction of gastrointestinal problems and ease of compliance. Although the expression 'an effective amount' appears not to be defined, it presumably has the same meaning as the expression 'a pharmaceutically effective amount' in the Patent. This is demonstrated by the passages in both patents which describe the factors likely to affect dosage. The only difference between the teachings of the two patents is that Strein teaches the use of extensive rest periods whilst the Patent teaches continuous administration on a weekly basis. In each case, however, it is intended that the dosage administered be at a level identified by the clinician as adequate to bring about the desired outcome. 51 The above analysis demonstrates that although Strein speaks of cyclic treatment and intermittent administration, it teaches, amongst other things, weekly administration during cyclic treatment. It asserts that weekly dosing reduces GI side effects and offers a more convenient dosing regimen. Although it does not expressly address dosing levels, it asserts that they should be fixed to reflect the circumstances of each case and refers to '(r)epresentative suitable dosages' contained in another identified patent. In other words appropriate dosing levels are known. 52 We should make one other point. The dosages per kilogram of body mass administered to the rats were very low. It seems that they were administered by injection. However Strein contemplates oral, intravenous and subcutaneous administration. The Patent recognizes that oral dosing must be at levels higher than those used in intravenous administration. Thus the dosing levels used with the rats in the Strein research are not necessarily appropriate for oral administration, nor does Strein assert that they are appropriate for that purpose.

Goodship 53 Goodship was filed on 24 April 1995. It teaches the use of bisphosphonates in treating patients who have undergone arthroplasty, especially of the hip joint. The purpose of such use is to prevent prosthesis loosening and migration. Goodship discloses that bisphosphonates have previously been used to inhibit excessive bone resorption in diseases such as Paget's disease and osteoporosis. It does not give a detailed description of the mechanism by which prothesis loosening and migration occur, apparently assuming knowledge of this matter. It focuses upon preparation of the relevant medication rather than upon the mechanics of its operation. However it seems clear from the description of the procedures carried out in connection with experiments on sheep that the purpose of the treatment is to minimize bone loss around the implant, to minimize bone resorption and to encourage or facilitate formation of bone tissue. 54 The invention relates to the use of methanebisphosphonic acid derivatives including alendronate in a 'pharmaceutical preparation that contains a therapeutically effective amount of the active ingredient optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration.' 55 Further: 'Preferably, the pharmaceutical compositions are adapted to oral or parenteral (especially intravenous or transdermal) administration before, during or after prosthesis implantation, …. The particular mode of administration and the dosage will be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, activity level, hormonal status (e.g. postmenopausal), bone mineral density and type of prosthesis to be implanted. The dosage of the active ingredient may depend on various factors, such as effectiveness and duration of action of the active ingredient, mode of administration, warm blooded species, and/or sex, age, weight and individual condition of the warm blooded animal. Normally the dosage is such that a single dose of from 0.002-3.40 mg/kg, especially 0.01-2.4 mg/kg, is administered to a warm-blooded animal weighing approximately 75 kg. If desired, this dose may also be taken in several, optionally equal, partial doses. (emphasis added) "mg/km" means mg drug per kg body weight of the mammal - including man - to be treated. The dose mentioned above - either administered as a single dose (which is preferred) or in several partial doses - may be repeated, for example once daily, once weekly, once every month, once every three months, once every six months or once a year. In other words, the pharmaceutical compositions may be administered in regimens ranging from continuous daily therapy to intermittent cyclical therapy. (emphasis added) Preferably, the methanebisphosphonic acid derivatives are administered in doses which are in the same order of magnitude as those used in the treatment of the diseases classically treated with methanebisphosphonic acid derivatives, such as Paget's disease, tumour-induced hypercalcaemia or osteoporosis. In other words, preferably the methanebisphosphonic acid derivatives are administered in doses which would likewise be therapeutically effective in the treatment of Paget's disease, tumour-induced hypercalcaemia or osteoporosis, i.e. preferably they are administered in doses which would likewise effectively inhibit bone resorption. (emphasis added) Formulations in single dose unit form contain preferably from about 1% to about 90%, and formulations not in single dose unit form contain preferably from about 0.1% to about 20% of the active ingredient. Single dose unit forms such as capsules, tablets or dragees contain e.g. from about 1 mg to about 500 mg of the active ingredient. The invention further relates to the use of a composition for the manufacture of a medicament, e.g. in single dose unit form, for the prevention and treatment of prosthesis loosening and prosthesis migration in mammals including man, wherein the composition contains 0.002-3.40 mg/kg especially 0.01-2.40 mg/kg, of a methanebisphosphonate acid derivative as defined above per dosage form. Moreover, the invention relates to the use of a methanebisphosphonic acid derivative as defined above and a dose of 0.002-3.40 mg/kg, especially 0.01-2.40 mg/kg, per dosage form for the manufacture of a medicament for the prevention and treatment of prosthesis loosening and prosthesis migration in mammals including man.' 56 A discussion of the manufacture of preparations, including preparations for oral administration, follows. 57 In summary, Goodship teaches oral administration of alendronate for the prevention and treatment of prosthesis loosening and prosthesis migration in human beings. It teaches both continuous and intermittent cyclical administration including, in both cases, weekly administration. It teaches dosages of the same magnitude as those used in treating osteoporosis. A 'therapeutically effective dose' is, we infer, the same as a 'pharmaceutically effective amount', the term used in the Patent. Dosages between 0.002 and 3.4 mg/kg of body weight are contemplated. Individual single dose units for oral administration might contain up to 500 mg of the relevant active ingredient. This range clearly includes those identified in claims 1 and 2 of the Patent. 58 The importance of Goodship for present purposes is its disclosure of the levels of dosing which are appropriate for its purposes and the assertion that they are the same as those adopted in the treatment of osteoporosis. 59 In the Patent specification, it is said of Goodship that: 'Administration of a once weekly partial dose of the bisphosphonate is disclosed. However, the reference specifically fails to address the issue of adverse gastrointestinal effects or to disclose administration of larger or multiple dosages.' 60 Goodship does not expressly address adverse GI effects, save for the fact that it teaches the use of a '(g)astric juice-resistant outer coating' for oral administration. The Patent specification refers to numerous reports of the adverse GI effect. The earliest seems to have been Strein. 61 As to the assertion that Goodship does not disclose administration of larger or multiple dosages, we have difficulty in understanding this observation. It teaches administration 'in regimens ranging from continuous daily therapy to intermittent cyclical therapy'. This must include multiple dosing. As to the size of the dosage, the range is 1-500 mg in single dose unit form, clearly including the specific doses identified in claims 1 and 2. As we have said, it seems probable that the term 'a therapeutically effective amount' used in Goodship has the same meaning as 'a pharmaceutically effective amount', the term used in claims 1, 2 and 3 of the Patent. Goodship clearly teaches use of the same dosage range as that used in treating osteoporosis.

The Patent specification, including Strein and Goodship 62 When Strein and Goodship are read as part of the Patent specification, the available ground for the currently claimed invention is significantly narrowed. Strein teaches weekly administration of effective amounts of alendronate for the treatment of osteoporosis, an advantage being reduced GI side effects. By analogy to the treatment of osteoporosis, Goodship teaches weekly administration of alendronate in therapeutically effective amounts for treatment of prosthesis loosening and prosthesis migration. The range of dosages includes those identified in the Patent claims. All that can be said of the Patent, as against Strein, is that the former does not teach rest periods. As against Goodship, the Patent additionally teaches use of alendronate for the treatment of osteoporosis (which the Goodship application assumes) and expressly identifies the advantages of weekly, over daily, dosing. The question is whether the Patent specification (including Strein and Goodship), on its proper construction, demonstrates a claim for a manner of new manufacture for the purposes of s 6 of the Statute of Monopolies. The meaning of that expression emerges from the cases. 63 Microcell, NRDC and Philips establish the following propositions: 1. The opening words of s 18(1) (' … a patentable invention is an invention that …') impose a threshold requirement that the 'patentable invention' be an 'invention', that is to say an 'alleged' 'manner of new manufacture' within s 6 of the Statute of Monopolies (Philips at 663). 2. That requirement will not be met if, on the face of the specification, the subject matter (a) lacks the necessary quality of inventiveness under the Statute of Monopolies (Phillips at 664) (b) is not new (NRDC at 262, Philips at 664) 3. A new use of an old substance is not an invention if its known properties make it suitable for that use - in such a case the new purpose is 'no more than analogous to the purposes for which the utility of the substance is already known' (NRDC at 262) 4. But there will be an invention if the new use consists in taking advantage of a hitherto unknown or unsuspected property of the substance (NRDC at 262). 64 Clearly, it is not sufficient that a claimant simply asserts 'newness'. It is necessary that the specification be 'construed and understood'. Technical terms may need explanation, but that is by no means uncommon in cases of this kind. We acknowledge the need to avoid incursion into areas correctly addressed under other sections of the Act. See Bristol-Myers (supra). 65 Pursuant to ss 40(2)(a) and (b), the specification must: · describe the invention fully, including the best method known to the applicant of performing it; and · in the case of a standard patent, end with a claim or claims defining the invention. 66 We assume that Merck has tried to do these things, and that the necessary element of 'newness' lies in the comparison of the information contained in the specification, including Strein and Goodship, with the claimed invention. By including them in the specification, Merck has invited such a comparison. There can be no basis for excluding those documents from a consideration of the proper construction of the specification, whether or not Arrow relies on them for the purpose of disproving novelty or inventiveness as defined in s 7 of the Act. That situation may, however, dictate the need for caution. Finally, the requirement that there be a claimed manner of new manufacture cannot be satisfied by the applicant's own misunderstanding or misrepresentation of the content of documents incorporated into the specification. Philips establishes that: 'it was the legislative intent that the threshold requirement of "an invention" would continue to exclude from a "patentable invention" any claimed process, method or use which was not, on the face of the specification, a proper subject of letters patent according to traditional principles' (at 665). 67 In Morgan & Co v Windover & Co (1890) 7 RPC 131, the House of Lords considered a patent which claimed invention in the use of a certain type of spring at the front of a carriage, as well as at the rear where it had previously been used. Of this claimed invention, Lord Halsbury LC said at 134: 'I am, therefore, of opinion, speaking of it as a question of fact as I believe it to be, that there is no invention in this supposed patent that the man has simply seen the hinder part of the carriage with those springs, … and has applied them to the front of the carriage. When so applied it may very well be, for aught I know to the contrary (indeed, I will assume in favour of the patentee that it is so), that they have the useful effect which is attributed to them in giving greater ease and comfort in the motion of the carriage; but if it is simply the application of well-known and well-understood things to an analogous use, although it may be true that it is accompanied by advantages not thought of or practised before, that will not save him from the fatal objection that there is no invention; because it is then simply the application of well known things to an analogous use, of which a great many instances might be given. If this patent and the ground upon which this patent is supported could stand, it would be very difficult indeed to say what would not be an invention, provided there was any additional advantages gained by the application of any known thing to an analogous use. It is well known and acted upon and must now be considered to be the law, that that does not constitute invention within the meaning of the Patents Laws. Therefore, I am of opinion that on that ground this judgment cannot be supported.' 68 In the same case Lord Herschell said at 137: 'The law has not been disputed that the mere adaptation to a new purpose of a known material or appliance, if that purpose be analogous to a purpose to which it has already been applied, and if the mode of application be also analogous so that no inventive faculty is required and no invention is displayed in the manner in which it is applied, is not the subject matter of a patent.' 69 At 138 Lord Herschell observed: 'Now, my Lords, if it were held that that was enough to constitute a new invention, just consider what consequences would follow. It is common knowledge that when a new mechanical contrivance, such as a new spring (and many other illustrations might be given) is first invented it is often a very considerable time before its advantage are seen and realised. Men are slow to try experiments, however successful they may turn out to be when once tried. But if the argument of the Respondents were well founded, then if there was an invention of a new spring, let us say, for railway engines or carriages, and for some years no one had taken advantage of it in a particular part of an engine or carriage in which a spring was used until some one thought he would use it in that place, the first person who used it in that place could take out a patent for so using it and protect himself against all the rest of the world, and acquire a monopoly if it turned out that there were advantages in its use in that particular place which had not occurred to anyone before. It seems to me, my Lord, that that would be extending the rights which are conferred upon patentees of new inventions beyond anything which preceding cases will justify. 70 The decision in Windover was applied by the Court of Appeal in Elias v Grovesend Tinplate Company (1890) 7 RPC 455, where the Court considered improvement in a particular piece of equipment which involved effectively doubling its size. Lindley LJ said at 467: 'Now, applying the principle of Morgan v Windover …, to this case, I come to this conclusion, that if such a patent as this were granted it would be mischievous to the State; that is to say, that a monopoly for making this trifling alteration, excluding all the world from doing the same, would be a mischief and not a benefit to the public. 71 It may be that considerations such as these prompted the primary judge in the present case to speak of 'evergreening' in the introductory part of his judgment. 72 We consider that the primary judge was correct in concluding that the specification discloses no invention. His Honour's decision was based upon his general understanding of the Patent specification, some aspects of which are a little involved. Our discussion of Strein and Goodship demonstrates that such general understanding was correct. Strein teaches weekly, as opposed to daily, administration of an effective dose of alendronate as a way of minimizing the adverse GI side effects of such treatment and to provide improved convenience to the patient. There is no reason to doubt that the expression 'effective amount' has the same meaning as the expression 'pharmaceutically effective amount' used in the Patent. Whilst Strein does not specify 'effective' dosages, it asserts that they are already known. The state of knowledge concerning that subject appears to some extent from Goodship. The dosages claimed in the Patent fall within the range identified in Goodship. 73 As to the absence from the Patent of any requirement for rest periods, the asserted 'advantage' is said to be that it is 'regular', not being interrupted by rest periods, and that the patient is more likely to comply with it. This assertion seems to be based on perceptions of personal preferences and human nature. We see no invention in asserting that a patient is more likely to comply with a continuous weekly regime than with an intermittent regime involving periods of weekly administration and rest periods. 74 Counsel for Merck submitted that the Patent discloses a new characteristic of alendronate - namely that it can be effectively administered in weekly doses. That characteristic appears from Strein and Goodship. The problem identified in the Patent specification is that daily dosing may cause GI side effects 'due to repetitive, continuous and additive irritation to the GI tract'. This statement, itself, demonstrates that avoidance of repetitive, continuous and additive dosing will reduce the problem. In so doing, it addresses the self-healing capacity of the human body rather than any characteristic of alendronate. In any event, Strein clearly asserts that weekly dosing will reduce GI side effects. 75 At the most, it might be said, in the words of the Lord Chancellor in Windover, that Merck, by applying well-known and well-understood things to an analogous case, achieved advantages not previously thought of or practised. In the words of Lord Herschell in the same case, Merck saw or realized advantages inherent in an existing substance and practice. However this may be too generous, given Strein and Goodship. The claims in the Patent are analogous to the use of alendronate as taught in those documents. The Patent specification discloses no new substance, no new characteristic of a known substance, no new use and no new method. There is, therefore, no manner of new manufacture.

The Lunar News articles 76 As already mentioned, Arrow's case on novelty was based on alleged anticipations contained in issues of Lunar News published in April 1996, July 1996 and April 1997. 77 In the April 1996 issue under the heading 'Update: Bisphosphonate' it was said that research on bisphosphonates for treatment of osteoporosis had increased greatly over the past ten years. Clinical intention had shifted over the past years 'because alendronate (Merck) has received regulatory approval in many countries'. As his Honour noted, this would be taken as a reference to Merck's product Fosamax. There is discussion of osteomalacia, in the course of which it is said that there was no evidence of this consequence with alendronate 'at low doses, and even with high doses (40 mg/day), in Paget's disease'. After further discussion of the advantages of alendronate and aspects of its use the following passage occurs: 'One of the difficulties with alendronate is its low oral bioavailability. When taken with water in a fasting state, only about 0.8% of the oral dose is bio available. Even coffee reduces this by 60 % and a meal reduces it by > 85%. Alendronate must be taken, after an overnight fast, 30-60 minutes before breakfast. Subjects should remain seated or standing; a very small group of patients have reported some upper gastrointestinal distress if this is not done. This regime may be difficult for the elderly to maintain chronically. An intermittent treatment program (for example, one per week, or one week every three months), with higher oral dosing, needs to be tested. A sustained response has been demonstrated to intravenous administration of high dose alendronate.' 78 In the July 1996 issue, again under the heading 'Update: Bisphosphonate', it is said that some US physicians are reluctant to treat with alendronate because of side effects, difficulty of dosing and high cost ($700/year). Merck had recently sent a letter to physicians warning of esophagitis. Some physicians reported that 5-15 per cent of patients experienced gastric and/or oesophageal distresss but most have seen no side effects. The article concludes: 'The difficulties with oral bisphosphonates may favour their episodic once/week), or cyclical (one week each month) administration. Even oral alendronate potentially could be given in a 40 or 80 mg dose once/week to avoid dosing problems and reduce costs.' 79 In the April 1997 issue under the heading 'Update: Bisphosphonate' it is said: 'One way to reduce the relatively high cost, and the potential side effects, of potent oral bisphosphonate may be to dose only two or three times a week rather than daily. In pigs, the bisphosphonate dose can be reduced without adverse effect on skeletal response by giving a standard 'daily dose' every fourth day or for 5 days out of 20. In the human, there is little difference between 5 and 10 mg/day of alendronate, so the 10 mg dose theoretically could be given only 3X a week or the 40 mg dose once per week. Serum biochemical markers could be used to titrate dose downward. If turnover remains low after three months at 3X/week, the dose could be reduced to 2X/week or lower. These new clinical approaches to dosing need to be tested in at least short-term trials.'

Evidence as to publication of Lunar News 80 From the late 1980s until 2000 Dr Mazess was the author and editor of Lunar News. The aim of this publication was to provide a summary of other articles in the bone area and in particular the treatment of bone diseases and bone densitometry and his opinion on various developments in these areas. 81 In the second half of the 1990s Lunar News was published three times a year. There were two main mailing lists, a select mailing list which was sent by first class or airmail to approximately 1000 priority contacts around the world and the conventional mailing list which was distributed as printed matter mail in the United States. International copies were often sent as packages to distributors who in turn mailed copies locally in the countries they represented. In all about 9,000 to 10,000 copies went to US recipients including Lunar Corporation customers, potential customers and libraries and the remainder of about 8,000 went to recipients outside the United States. Lunar News was also available on the Lunar website. 82 Among the recipients of Lunar News were Dr Santora and Dr Yates of Merck. Dr Mazess identified from a mailing list four Australian recipients. 83 Mr Lyndon Davies of West Pennant Hills New South Wales at relevant times provided consultancy services to Lunar Corporation for its activities in the Asia Pacific region. He received copies of Lunar News and a client distribution list for Australia and New Zealand from the international marketing support department of Lunar Corporation. The total number of listed recipients of Lunar News in Australia and New Zealand in about 1996 was approximately 150, of which 100 were associated with clients of Lunar Corporation and the remainder were potential clients including universities and hospitals or other individuals interested in receiving the publication. Mr Davies attended medical conferences dealing with pain research, bone density and bone research in 1996 and 1997 and distributed the current editions of Lunar News to conference attendees. 84 Dr Terrence Diamond is a Senior Consultant at St George's Hospital in Sydney. His evidence was that he did not see the first or second issues of Lunar News in question. He does not discuss the third. As to the general availability of the publication at his hospital he says: 'I did not have the time or opportunity to read every edition of "Lunar News", nor did they all find their way to me from the nuclear medicine department.'

The statutory test for novelty 85 Relevantly for present purposes, s 18(1)(b)(i) of the Act provides that an invention is a patentable invention if the invention, so far as claimed in any claim, when compared with the prior art base as it existed before the priority date of the claim, is novel. 86 By s 7(1) an invention is taken to be novel when compared with the prior art base unless it is not novel in the light of certain 'kinds of information', one of which is prior art information 'made publicly available in a single document or through doing a single act' (s 7(1)(a)). 87 In the dictionary in sch 1 of the Act 'prior art information' is defined for the purposes of s 7(1) as 'information that is part of the prior art base in relation to deciding whether an invention is or is not novel'. 88 'Prior art base' is relevantly defined to mean: '(a) in relation to deciding whether an invention does or does not involve an inventive step …: (i) information in a document that is publicly available, whether in or out of the patent area; and (ii) information made publicly available through doing an act, whether in or out of a patent area; (b) In relation to deciding whether an invention is or is not novel; (i) information of a kind mentioned in paragraph (a) …' The 'patent area' is Australia, the continental shelf and the waters and airspace above.

Judgment of the primary judge on novelty 89 His Honour at [98] found that copies of each of the relevant issues of Lunar News were distributed to persons in both the United States and Australia prior to the priority date, those persons being free in law and equity to make use of the documents and the information in them without restriction. His Honour also found that, leaving aside the Lunar website, there was no evidence that any of the relevant issues were available for inspection by members of the public at any library or could be purchased by members of the public or even supplied on request to members of the public. Further, such distribution as took place was to persons chosen by Lunar Corporation rather than simply to members of the public at random. 90 His Honour concluded at [100] that persons selected for commercial reasons by the publishers were just as much members of the public as were persons who purchased subscriptions to magazines or buy newspapers or who are on a mailing list. His Honour accepted that Mr Davies distributed the copies of Lunar New which he received. 91 His Honour found that the April 1996 issue of Lunar News was available on the website. There was no direct evidence as to the July 1996 and April 1997 issues but on the balance of probabilities he would infer that the system continued and that each was available. His Honour cited a number of authorities on novelty. His Honour observed there was no relevant link between the various Lunar News articles and each had to be viewed individually. 92 His Honour found at [105] that the April 1996 issue was a clear anticipation of claim 3, subject to the effect of the words 'needs to be tested'. The gist of the novelty in claim 3 was a continuous schedule of oral administration having a dosage interval which is once weekly. He rejected the argument of Merck that 35 mg or 75 mg could be read into claim 3. On the 'needs to be tested' point his Honour said: '107. It is submitted for Merck that the decision of the Full Court in Faulding establishes that to suggest that something needs to be tested is not to anticipate that which is suggested. Black CJ and Lehane J said (at [67]): "What all those authorities contemplate, in our view, is that a prior publication, if it is to destroy novelty, must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention." That statement of principle was based upon a review of certain of the authorities. Those authorities stand for the proposition that the claimed invention must be disclosed as such and not simply as a possibility. If the Lunar News article had said 'in view of these problems a continuous dosing schedule with various intervals greater than one day should be tested' it would not anticipate claim 3, even though a weekly dosage interval would be both technically and practically contemplated by that suggestion. On the contrary, here, the disclosure is quite precise and accords with the gist of the claimed invention. I do not accept the submission on behalf of Merck that the passage in question from Faulding adds an additional requirement for anticipation, namely that the publication should recommend the use of the invention as disclosed. That is not what the passage from Faulding says and it does not follow from the authorities analysed in that judgment. The essential difference in the treatment of the prior publications in Faulding lay in the view that one publication pointed clearly to one solution which was the invention rather than other publications which did not so point. That was a factual rather than a legal judgment and cannot be translated to the present circumstances. 108. In my opinion, the mere fact that a test of a defined solution to a problem is suggested does not avoid the disclosure being an anticipation. A drawing of a mechanical device with a caption "should be tested for speed" would be an anticipation of a claim for that mechanical device. This point has particular cogency in relation to the present field. No invention can be used in the treatment of humans without extensive testing. In the present case, the patent was applied for before that testing had even commenced. The same reasoning is an answer to the argument advanced on behalf of Merck that the disclosure could not amount to an anticipation as no sensible medical practitioner would have acted upon it without adequate testing for safety. Even if that were correct (and it is contrary to some of the expert evidence led on behalf of Arrow) it would not affect the fact of disclosure having been made and being publicly available.' 93 As to the July 1996 article, his Honour noted that this was in the context of the discussion of methods for prevention and treatment of osteoporosis by the oral administration of Fosamax. Applying the principles to which he had referred in dealing with the April 1996 issue, his Honour considered this to be a clear anticipation of claims 1 and 2 subject to the difference between 35 mg and 40 mg and between 70 mg and 80 mg. In his Honour's opinion those differences were immaterial. First, the claims were imprecise, being 'about' the identified figure. Secondly, the dosage of 40 mg was equivalent as a matter of substance to 35 mg in these circumstance and 80 mg was equivalent as a matter of substance to 70 mg. On the evidence in terms of both safety and efficacy there was no relevant difference. Many internal Merck documents demonstrated that fact. 94 His Honour at [111] considered claim 3 was also anticipated by the July 1996 article. The context of the article was discussion of a method of preventing or treating osteoporosis in a human; oral administration of Fosamax was identified; the reference to 40 mg or 80 mg doses answered the description as unit dose (however taken) and it was plain that 40 mg and 80 mg respectively were put forward as being pharmaceutically effective amounts if taken orally, the gist of the claim being the weekly interval as expressly identified. 95 As to the April 1977 issue, for the same reasons his Honour considered that disclosure anticipated claims 1 and 3.

Merck's arguments on appeal 96 Merck argued that the information in the Lunar News articles did not form part of the prior art base. Alternatively, the articles did not provide a sufficient disclosure of the alleged invention as claimed in the relevant claims.

Were the Lunar News articles 'publicly available'? 97 The previous legislation, the Patents Act 1952 (Cth), provided as a ground of revocation by s 100(1)(g) that: 'The invention, so far as claimed in any claim of the complete specification … was not novel in Australia on the priority date of that claim.' 98 It was well established that a description in an obscure publication would suffice to destroy novelty, provided that it was a publication, that is to say that the document, whether or not it was read generally by the public, had been available to the public: Sunbeam Corporation v Morphy-Richards (Aust) Pty Ltd (1961) 180 CLR 98 at 111-112. It was sufficient that the document or thing alleged to be the anticipation came into the hands of a person in circumstances which left him or her free at law and in equity to do whatever they liked with it: Fomento Industrial SA v Metmore Manufacturing Co Ltd (1956) RPC 87 at 100; Re Bristol Myers and Co's Application (1969) RPC 146 at 155; Stanway Oyster Cylinders Pty Ltd v Marks (1996) 35 IPR 71 at 74-75. 99 However, senior counsel for Merck contended that the 1990 Act had changed the law. It was now not enough that the anticipation had been disclosed to a person free to use it. The law, he said, looks at the position of somebody who wants to find the alleged anticipation. Thus although there was evidence that Lunar News had been sent to hospitals and universities, there was no evidence that it had been catalogued and identified in a way that would enable anybody to find it. 100 We do not accept this argument. It finds no support in the text of the 1990 Act. Section 7(1)(a) contemplates that prior art information may be made 'publicly available' in a single document, that is to say, literally, one document. 101 There is no hint of the suggested change in the report of the Industrial Property Advisory Committee 'Patents, Competition and Innovation in Australia', 29 August 1984, a report which led to the 1990 Act, nor in the Explanatory Memorandum when the Bill for the Act was introduced (par 13). The Committee did suggest (par 7.2) a major change in relation to the law of novelty, a recommendation which was adopted, namely that prior art should be that existing in the whole world and not just Australia. If Merck's argument is right, there was another equally important change, but one which escaped everybody's notice. The previous law cannot be ignored. As Windeyer J said in a different context in Vallance v The Queen (1961) 108 CLR 56 at 76: '…we cannot determine (the Tasmanian Criminal Code's) basic provisions concerning such general principles as if they were written on a tabula rasa, with all that used to be there removed and forgotten. Rather is ch IV of the Code written on a palimpsest, with the old writing still discernible behind.' 102 The evidence shows that some 18,000 copies of relevant issues of Lunar News were published and that (not that it matters for the purposes of the Act) a significant number were published in Australia. There is no direct evidence on the point, but the inference to be drawn is that publication was gratis. In any event, as his Honour held, whether a copy is received by a recipient as a gift, or pursuant to a contract for the purchase of a subscription or a single copy, the recipient takes the copy without any restraints at law or in equity to do with the information therein as he or she pleases. 103 Novelty is a rule which at times may operate with seeming harshness, particularly now that the relevant prior art is that existing in the whole world. An Australian patent may now be defeated by reason of some publication which in reality nobody in Australia had the remotest possibility of being aware of before the priority date. Nevertheless, since the Statute of Monopolies almost 400 years ago, a fundamental element of the bargain for which the patentee gets the valuable advantage of monopoly is that the invention is one 'which others at the time of making such letters, patents and grants shall not use'.

Was there sufficient disclosure? 104 Senior counsel for Merck placed great emphasis on the words 'needs to be tested' in the first Lunar News article. However, the contemplation of further experiment or testing is not necessarily fatal to a finding of anticipation. 105 In Hill v Evans (1861) 4 De G F & J 288, 45 ER 1195, Lord Westbury LC said at 300, 1199: '…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.' 106 Lord Westbury's reference to further experiments was elucidated by Lord Reid, with whom all the other members of the House of Lords on this point agreed, in C Van Der Lely NV v Bamfords Limited [1963] RPC 61 at 71: 'The appellants maintain that even if the skilled man could perceive in the photograph all the integers in claim 1 he could not apply the discovery without making further experiments. But Lord Westbury must have meant experiments with a view to discovering something not disclosed. He cannot have meant to refer to the ordinary methods of trial and error which involve no inventive step and are generally necessary in applying any discovery to produce a practical result.' 107 Likewise in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at 281 Aikin J, with whom Gibbs, Stephen, Mason and Wilson JJ agreed, said: 'It will always be necessary to distinguish between experiments leading to an invention and subsequent experiments for checking and testing the product or process the subject of the invention. The latter would not be material to obviousness but might be material to the question of utility.' 108 These observations are particularly relevant in the case of pharmaceutical patents like the present one where it is a matter of notoriety that prolonged testing for the purpose of regulatory approval must occur between the stage of patent application and commercial marketing. 109 Merck's argument sought to rely by way of analogy on a detailed examination of the various publications which the Full Court in Faulding held were or were not anticipations. But, as the primary judge in the present case pointed out, these were questions of fact. We do not read Faulding as support for any proposition of law that, in the case of pharmaceutical patents, no publication can amount to an anticipation unless clinical trials have been actually conducted. 110 In any event, Faulding at [67] speaks of a requirement that an alleged anticipation 'teach', in the sense of 'direct, recommend or suggest', that which is claimed. So a characterisation of an alleged anticipation as suggestion is not necessarily fatal to a novelty argument. Nor is it necessary that a reader, or even all readers, agree with the suggestion. Thus the fact that a Merck medical witness said that he would not have followed the Lunar News article for fear of side effects, does not if itself mean that disclosure was insufficient. 111 As Hill v Evans (at 301,1200) long ago established, equality of disclosure, anticipation as against patent, is the essential element: '…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 shewn 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.' 112 In the present case, the claims in question are for a very simple method: oral administration of a known (indeed commercially marketed) drug at a specified dosage over a specified period. Working the invention does not require any special skill. Details of this method are clearly conveyed in the Lunar News articles, as the primary judge explained. Nothing additional is required. 113 The appeal fails insofar as it attacks the findings on novelty. ORDERS 114 The appeal should be dismissed with costs. I certify that the preceding one hundred and fourteen (114) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justices Heerey, Kiefel and Dowsett.

Associate: Dated: 15 June 2006 Counsel for the Appellant: Dr J M L Emmerson QC and K J Howard

Counsel for the Respondent: D K Catterns QC and S C G Burley

Dates of Hearing: 9, 10 and 11 May 2005 and 19 December 2005