3.1 The 051 or low dose patent
6 The 051 or low dose patent nominates Ali Raza as the inventor. The patent claims a priority date of 6 February 1999 based on the filing of UK Patent Application GB 9902590. There is a dispute about the inventor and AZ's entitlement to the invention. The priority date is also in dispute.
7 The specification of the 051 or low dose patent describes the invention as follows:
USE OF CHOLESTEROL-LOWERING AGENT
The present invention relates to the use of a cholesterol-lowering agent, and more particularly to the administration of a particular dose or dosage range of the HMG CoA reductase inhibitor, [the formula for the compound rosuvastatin]… and pharmaceutically acceptable salts thereof, hereinafter referred to as "the Agent" and illustrated (as the calcium salt) in formula I hereinafter. The invention further relates to the dosage range, start dose and dosage forms of the Agent.
The Agent is disclosed in European Patent Application, Publication No. 0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444 as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) which is a major rate-limiting enzyme in cholesterol biosynthesis. The Agent is taught as useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. HMG-CoA reductase inhibitors are the most widely used prescription medication for the treatment of hypercholesterolaemia. A number of HMG-CoA reductase inhibitors are marketed, namely lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin, and are collectively referred to as 'statins'. Despite the benefits of statin therapy, less than optimal results may be achieved in patients, due to the level of efficacy and safety achieved at the recommended dosages of the currently marketed statins. Accordingly it is important to find dosages of alternative statins which beneficially alter lipid levels to a significantly greater extent than similar dosages of currently used statins and which have a similar or improved safety profile.
Surprisingly it has now been found that when dosed orally to patients with hypercholesterolemia at particular dosages or in a particular dosage range the Agent lowers total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) by an unexpected degree, and without any significant adverse side effects. When dosed at the same dosages or in the same dosage range, the Agent also modifies other lipoprotein levels (such as raising high density lipid cholesterol (HDL-C) levels, lowering triglyceride (TG) levels and lowering apolipoprotein B-100 (Apo-B) levels) to an unexpected and beneficial extent, without any significant adverse side effects. Elevations of alanine aminotransferase (ALT) liver enzyme levels are reported for other HMG-CoA reductase inhibitors. Surprisingly it has now been found that when the Agent is dosed at the dosages or in the dosage ranges discussed herein, clinically significant rises in these levels are less frequently observed.
Accordingly, one aspect of the present invention comprises a method of lowering LDL-C levels by 40% or more, and/or lowering total cholesterol levels by 30% or more, and/or lowering triglyceride levels by 10% or more, and/or lowering apolipoprotein B-100 levels by 30% or more, and/or raising HDL-C levels by 5% or more, in a patient in need thereof, by administration of 5 to 80 mg per day of the Agent.
A further aspect of the present invention comprises a method of …
…
A particularly suitable starting dose of the Agent in the methods referred herein is 5 to 10 mg per day, especially 10 mg per day. After initiation and/or upon titration of the Agent, lipid levels may be analysed and the dosage adjusted accordingly. A further aspect of the invention is therefore a method as defined above when the Agent is administered at a starting dose of 5 or 10 mg per day, for example a method of lowering LDL-C levels in a patient in need thereof by 40% or more by administration of 5 or 10 mg per day …A starting dose of 5 or 10 mg per day of the Agent unexpectedly has a superior efficacy and a comparable or better safety profile compared to the starting doses of other statins, and is therefore particularly advantageous.
In carrying out the methods of the invention, the Agent will be administered to a patient in the form of a pharmaceutical composition. A further aspect of the invention is therefore a pharmaceutical composition which comprises 5 to 80 mg of the Agent together with a pharmaceutically acceptable excipient or diluent. Particular pharmaceutical compositions which themselves are further independent aspects of the invention comprise, for example, 5 mg, 10 mg, 20 mg, 40 mg and 80mg of the Agent together with a pharmaceutically acceptable excipient or diluent. The pharmaceutical compositions will be in the form of a conventional dosage unit form, for example, tablets or capsules. Accordingly, a further aspect of the invention comprises, a tablet or capsule containing the Agent in the amounts given above. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Preferably the Agent is administered as a single dose once daily.
…
8 Pages 11A and 11B of the specification, amongst other things, found the argument in respect of the priority date. Extracts from those pages include the following:
In a further aspect of the invention there is provided a pharmaceutical composition adapted for oral administration as a single, once daily dose which comprises 5 mg to 10 mg of [the Agent]… in the form of the free acid or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
…
Pharmaceutical compositions
The following Example illustrates, but is not intended to limit, pharmaceutical dosage forms which are suitable for use in the invention as defined herein:
…
9 The specification includes reference to trial including in these terms:
To illustrate the invention, a randomised, dose response parallel-group study with [the Agent] calcium salt (hereinafter referred to as ZD4522) and atorvastatin (ATORV) in subjects with primary hypercholesterolaemia was carried out.
Primary objectives
The primary objective of this trial was to estimate the dose-response relationship between the dose of ZD4522 and the percentage reduction of LDL-C from the baseline value with respect to placebo.
Secondary objectives
Secondary objectives of this trial included:
to estimate the effect of 10 and 80 mg doses of atorvastatin on LDL-C levels; to estimate the effects of ZD4522 and atorvastatin on HDL-C, TG, TC, apolipoprotein A-1, apolipoprotein Lp(a), apolipoprotein B-100 levels and LDL-C (by indirect method); to assess the pharmacokinetics of oral doses of 1, 2.5, 5, 10, 20, and 40 mg ZD4522 (capsule formulations) over a 6 week treatment period; and to assess the tolerability and safety of ZD4522 in comparison with placebo.
Trial Design
After a 6-week dietary run-in, subjects were randomised to either atorvastatin doses (10 or 80 mg), supplied open labelled, or to placebo or 1 of 6 ZD4522 doses (supplied blinded). Analysis of the blinded portion of the trial addressed the primary objective. The open atorvastatin groups were included to obtain additional data on the starting and high doses, of a proven cholesterol-lowering agent in this patient population.
Trial Plan
…
Number of Subjects
The primary endpoint on which the sample size is based is on percentage reduction from baseline in LDL-C (LDL cholesterol) values. A sample size of 9 in each group will have 90% power to detect a difference in means of 25% between 2 groups, assuming that the common standard deviation is 15%, using a 2 group t-test with a 0.05 two-sided significance level. This has been increased to 12 subjects per group to adjust for multiple comparisons of groups against placebo while preserving a power of at least 90% (based on simulations). This sample size also leads to an estimate of the dose-response curve for percentage decline in LDL-C with a width of the confidence band less than 10% for most of the dose range.
Inclusion Criteria
For inclusion in the dietary run-in period, subjects had to fulfil all of the following criteria:
(1) fasting LDL cholesterol (>4.14 but 220mg/dL.
There is now a large body of evidence obtained from clinical trials demonstrating that pharmacological agents (particularly the statins) that reduce low density lipoprotein-cholesterol LDL-C levels also decrease Chronic Heart Disease (CHD) risk (Lipid Research Clinics Program 1984, Gould et al 1998). Taken together, the trials published to date support the concept that lowering LDL-C levels should be the principal goal of lipid altering therapy (Ansell et al 1999), and that the reduction in coronary risk that occurs during treatment with statins is directly related to these agents' LDL-C lowering effects (Gould et al 1998, Pedersen et al 1998).
Primary hyperlipidemia is a term used to describe a defect in lipoprotein metabolism. The lipoproteins commonly affected are LDL-C, which transports mainly cholesterol, and VLDL-C, which transports mainly TG. Most subjects with hyperlipidemia have a defect in LDL metabolism, characterised by raised cholesterol, LDL-C, levels, with or without raised triglyceride levels; such subjects are termed hypercholesterolemic (Fredrickson Type II). Familial hypercholesterolemia (FH) is caused by any one of a number of genetically-determined defects in the LDL receptor, which is important for the entry of cholesterol into cells. The condition is characterised by a reduced number of functional LDL receptors, and is therefore associated with raised serum LDL-C levels due to an increase in LDL. In its heterozygous form (HeFH) it is one of the commonest genetic diseases, with a frequency of about 1 in 500 in the United Kingdom (US), the United States (US), and Japan (Myant 1981, Mabuchi et al 1979).
LDL and VLDL are known to be atherogenic, and thus subjects with hypercholesterolemia are at increased risk of developing atherosclerosis, a disease process that results in widespread clinical manifestations, including coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral vascular disease (PVD). In subjects with HeFH, the clinical manifestations of heart disease can occur as early as the mid-twenties. Many subjects with hypercholesterolemia die each year as a result, and many have a reduced quality of life; inevitably, this places very heavy demands on health service resources.
One important goal of therapy in these subjects is to reduce blood cholesterol levels, since this may reduce the progression of the disease and may even induce regression (Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults 1993).
Quoting the % of subjects brought within relevant guidelines (NCEP, EAS) targets for LDL-C levels is a useful way of expressing the efficacy of lipid-regulating agents, and is becoming more commonplace in the literature. The guidelines of the National Cholesterol Education Program (NCEP) and European Atherosclerosis Society (EAS) are well recognised and have been accepted internationally.
Therapies available to treat HeFH include resins, such as cholestyramine and colestipol. Resins reduce LDL-C levels by sequestering bile acids (essential for the absorption of dietary lipid) from the gut and preventing their reabsorption; however, their use is limited by unpalatability and poor subject compliance. Fibrates, such as fenobibrate and gemfibrozil, have a complex mechanism of action on LDL-C, and appear to be of more use in reducing blood TG levels than cholesterol levels; these drugs are therefore less useful in subjects with HeFH (who typically do not have significantly elevated triglyceride levels). Fibrate drugs are thought to act through peroxisomal proliferating activator receptor-ɑ (PPAR-ɑ) and affect gene activation at a number of genes involved in atheroma. Patients on fibrate drugs show improved LDL subfraction distribution (reduced VLDL and raised HDL), reduced LDL and reduced triglyceride levels and possible advantages through improving insulin sensitivity. Examples of fibrate drugs include, bezafibrate, ciprofibrate, fenofibrate and gemfibrozol. Nicotinic acid and its derivates have some benefit, but are limited by prostaglandin-mediated side effects, such as flushing and dizziness.
A breakthrough in treating hypercholesterolemia has come from agents known as statins. These drugs, which include atorvastatin, pravastatin and simvastatin, lower LDL-C levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme involved in the rate-limiting step in cholesterol biosynthesis in the liver. Partial inhibition of hepatic cholesterol metabolism is thought to result in an increase in the number of cellular receptors for LDL-C, leading to an increased removal of LDL-C from the circulation.
Despite the benefits of statin therapy less than optimal therapeutic results are achieved by the use of statins in patients suffering from HeFH. Typically the majority of patients suffering from HeFH are treated with at least a statin and a fibrate or a statin and a bile acid sequestrant or possibly all these in an aggressive attempt to reduce the patients LDL-C levels within acceptable guideline limits. Myopathy and rhabdomyolysis have been associated with taking a statin in combination with gemfibrozil and niacin (HMG CoA reductase inhibitors, Hunninghake, Current Opinion in Lipidology (19921) 3, 22-28) as they are all substrates for P450 3A4 and may lead to clinically significant drug interactions.
Therefore, currently there is no single drug treatment which may be used on its own which consistently brings a significant number of patients suffering from HeFH within NCEP or EAS guidelines.
…
We have discovered that [the formula for the compound rosuvastatin]… or a pharmaceutically acceptable salt thereof (hereinafter called ZD4522), the calcium salt of which is shown in Fig.1 below, is particularly good at treating heterozygous familial hypercholesterolemia, in particular severe heterozygous familial hypercholesterolemia (HeFH).
We have conducted a Phase III trial designed to assess the efficacy of ZD4522 in subjects with HeFH. The dose-response of ZD4522 was compared with atorvastatin using the percentage change from baseline in LDL-C levels as the primary end-point. Doses of ZD4522 up to 80 mg per day were used. Atorvastatin was chosen as the comparator statin in this trial because it has the best LDL-C lowering activity of the currently marketed statins.
A larger percentage of patients with heterozygous familial hypercholesterolemia are brought within NCEP or EAS guidelines with treatment of ZD4522 alone than with any other therapy, in particular in high risk patients.
ZD4522 is a statin that demonstrates potent in vitro and in vivo inhibition of HMG-CoA reductase. Early clinical trials have shown that ZD4522 has a beneficial effect on the lipid profile, by reducing LDL-C, total cholesterol (TC) and TG levels. In addition, ZD4522 has been shown to raise high-density lipoprotein cholesterol (HDL-C) levels.
By the use of the term heterozygous familial hypercholesterolemia we mean patients who have been diagnosed with this type of condition such as patients whose genotype has been determined to be indicative of HeFH. Particular HeFH patients who benefit from ZD4522 are those suffering from severe HeFH. By the use of the term "severe HeFH" we mean patients who are high risk category patients, as defined by the NCEP guidelines (as outlined in JAMA 1993; 269:3015-23 which guidelines and charts are incorporated herein by reference), such patients target LDL-C levels being lower, i.e. ≤100mg/dL.
For the purposes of clarity patients who suffer from homozygous familial hypercholesterolemia are excluded from the scope of this invention.
Therefore we present as a first feature of the invention a method for treating heterozygous familial hypercholesterolemia in a patient suffering heterozygous familial hypercholesterolemia, comprising administering to the patient ZD4522.
ZD4522 is disclosed in European Patent Application, Publication No. 0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444 as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase). Preferably the calcium salt is used as illustrated in Figure 1. Preferably the ZD422 is used at a dose of 5 to 80 mg per day, in particular 40 to 80mg per day.
The pharmaceutical compositions of the present invention may be administered in a standard manner for example by oral or parenteral administration, using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, sterile injectable aqueous or oily solutions or suspensions. These dosage forms will include the necessary carrier material, excipient, lubricant, buffer, bulking agent, anti-oxidant, dispersant or the like. In particular, compositions for oral administration are preferred, for example as disclosed in International Patent Application, Publication No. WO 01/54668.
The dose of ZD4522 which can be administered in accordance with the present invention depends on several factors, for example the age, weight and the severity of the condition under treatment, as well as the route of administration, dosage form and regimen and the desired result. In the treatment of severe heterozygous familial hypercholesterolemia the maximum lipid lowering effect is desired and therefore a maximum dose of at least 40 mg a day is recommended, preferably 80 mg a day.
A unit dosage formulation such as a tablet or capsule will usually contain, for example, from 1 mg to 100 mg of ZD4522. Preferably a unit dose formulation will contain 5 to 80 mg ZD4522.
18 The specification describes a trial in these terms:
A clinical protocol testing the effectiveness of ZD4522 in heterozygous familial hypercholesterolemia and results is set out below.
A 24-week, Randomised, Double-blind, Multicentre, Multinational Trial
to Evaluate the Efficacy and Safety of
ZD4522 and Atorvastatin in the Treatment of
Subjects with Heterozygous Familial Hypercholesterolemia
OBJECTIVES
The primary objective was to compare the efficacy of ZD4522 (titrated to 80 mg) with that of atorvastatin (titrated to 80 mg) in reducing low-density lipoprotein cholesterol (LDL-C) levels in subjects with heterozygous familial hypercholesterolemia (HeFH) after 18 weeks of treatment.
The secondary objectives were to compare the efficacy of ZD4522 with that of atorvastatin in relation to the following: reducing LDL-C levels after 2, 6 and 12 weeks of treatment; in modifying other lipids and lipoprotein fractions after 2, 6, 12, and 18 weeks of treatment; in reducing LDL-C levels to within relevant national and international guidelines after 6, 12, and 18 weeks of treatment; in modifying the inflammatory marker C-reactive protein (CRP) after 18 weeks of treatment. A further secondary objective was to determine the safety of ZD4522.
…
In the primary efficacy analysis (LOCF data from the ITT), ZD4522 20/40/80 mg resulted in a significantly (p6%, the difference on which the trial was powered, and was therefore considered to be clinically relevant (mean % reduction in LDL-C was 57.88% in the ZD4522 20/40/80 mg group and 50.41% in the atorvastatin 20/40/80 mg group). ZD4522 resulted in significantly (p0.050 at 2, 6 and 12 weeks for observed data and 18 weeks for LOCF). ZD4522 20/40/80 mg resulted in significantly (p3xULN) or CK (>10xULN).
175 A version of this article was subsequently published in the European Heart Journal in 2000 which contains the additional statement:
ZD4522 - a new HMG-CoA reductase inhibitor - causes rapid and profound reductions in plasma LDL-C levels in patients with primary hypercholesterolaemia
…
…
ZD4522 showed rapid, clinically relevant, dose-related reductions in LDL-C. The safety profile of ZD4522 compared favourably with those of atorvastatin and placebo.
[European Heart Journal 2000;21 Suppl p156 Abs P975].
176 Professor Tonkin said he read the European Heart Journal at that time and continues to do so regarding it as a very credible journal widely read by cardiologists including in Australia.
177 AZ attempted to diminish the significance of this evidence from Professor Tonkin, submitting that "Professor Tonkin did not give evidence that he had such knowledge before 6 February 1999, and was not able to say whether the knowledge he did acquire, when he later acquired it, was publicly available". This submission, however, does not reflect the full effect of Professor Tonkin's evidence as set out above.
178 Dr Colquhoun also attended and presented a paper at the 12th International Symposium on Atherosclerosis in Stockholm in 2000 but it is not clear whether he became aware of rosuvastatin in so doing. Dr Colquhoun did explain that "in Australia and indeed in the world, there is a very small proportion of people who have an interest in lipids and lipid experts are involved in the basic metabolic studies and the treatment of hyperlipidaemia" which I accept. As at 1999 and 2000 Drs Wilson and Hay probably would not have warranted the characterisation of lipid experts although Professors Tonkin and O'Brien, as well as Dr Colquhoun, would have done so. This is relevant because, as noted, I consider that the non-inventive but skilled addressees of the 051 or low dose patent and the 165 or HeFH patent would have had this particular expertise in the treatment of hyperlipidaemia (or hypercholesterolemia) at the asserted priority dates.
179 Dr Colquhoun also gave evidence that during the trials which AZ conducted and in which he was involved as an investigator between July 1999 and June 2000 he and others involved in the trials called the drug being tested a "superstatin". At that time the drug was not called rosuvastatin (it had not yet been named, the earliest public reference to rosuvastatin seeming to be 29 June 2000 in a Heartwire publication referred to below) and was referred to in this period as ZD4522 or, as Dr Colquhoun said, a "superstatin". Dr Colquhoun said the description "superstatin" was used because of the potency of the drug which was perceived as similar to that of atorvastatin which was also called a superstatin at this time.
180 Professor O'Brien gave evidence that:
As at 6 February 1999, I recall that I was aware that there was a new statin in development and that this statin was substantially more effective than anything then on the market. I recall that I first heard this information from colleagues, possibly reporting on presentations that they had heard at scientific meetings, although I cannot be completely sure as to how I first heard about this statin under development. I often hear information about a new drug in this manner several years before the drug comes to market.
Before personally reading any scientific papers on the new statin, I recall considerable excitement amongst colleagues relating to the efficacy of the new statin. I recall hearing that it was described as a "superstatin" or a "turbostatin" and that it was able to achieve much greater LDL-C reductions than could be achieved with atorvastatin, such that it was at least twice as effective as atorvastatin. At that time, I was very hopeful that this would be a major advantage in treating patients with familial hypercholesterolemia, and from discussions with fellow clinical lipidologists, I believe that they were also similarly hopeful. I later learnt that the name of this new statin was rosuvastatin.
181 In that part of his first affidavit describing experience in the field of clinical lipidology, Professor O'Brien said:
I was also asked to and did sit on various lipid advisory boards for pharmaceutical companies that were producing, developing and marketing statins. I was on the advisory board for Merck in relation to simvastatin in the early 1990s. I was also on the lipid advisory board for Parke-Davis (later Pfizer), initially for gemfibrozil and later for atorvastatin, prior to 1998. I was also on an international advisory board for [AZ] for rosuvastatin leading up to the worldwide launch of rosuvastatin. My participation on these advisory boards generally required me to provide answers to specific questions and to provide scientific and educational advice to the company.
182 AZ attacked the credibility of Professor O'Brien because, in AZ's view, the reference to Professor O'Brien's involvement on the AZ advisory board for rosuvastatin leading up to the worldwide launch of the drug was insufficiently detailed. Further, according to AZ Professor O'Brien's involvement in that advisory board (a process which subjected Professor O'Brien to stringent confidentiality obligations) meant that he could not possibly provide evidence about his awareness of rosuvastatin unaffected by the information which he obtained on a confidential basis. In AZ's words Professor O'Brien's "intimate involvement on [AZ]'s national and international advisory boards before the November 2000 priority date hopelessly compromises his ability to provide evidence that is not tainted by hindsight and/or specialist inside knowledge".
183 There is force in AZ's submission that it could not be reasonably expected that Professor O'Brien would now be in a position to identify and separate information he obtained as a result of involvement in the AZ advisory panel for ZD4522 (which was subject to confidentiality obligations meaning such knowledge could not be relevant to the common general knowledge) and information he obtained other than from that source. The fact that at the time he prepared his affidavit Professor O'Brien could not "be completely sure as to how [he] first heard about this statin under development" indicates that, unsurprisingly given the passage of time, his memory of the nature and level of his involvement with the AZ advisory board had diminished over time. I do not accept any part of the attack on Professor O'Brien's credit. I have no doubt that had he recalled more when he prepared his affidavit he would have disclosed more about his involvement in the AZ advisory board. I also see nothing wrong with Professor O'Brien having been on the AZ advisory board and been willing to give expert evidence in these proceedings. The material effect of AZ's disclosure of the nature and extent of Professor O'Brien's involvement on the AZ advisory board (where he would have learnt a great deal about ZD4522 but on a confidential basis) is that weight should not be placed on Professor O'Brien's present recollection of what he knew when or how he knew it about the drug.
184 Dr Oppenheim was aware at the asserted priority dates of the general class of compounds known as statins which lowered cholesterol but was not aware of the compound rosuvastatin. Professor Evans also was not aware of rosuvastatin at the asserted priority dates. Nor were Drs Oppenheim, Pitman, Rowe and Morella or Professors Kibbe and Charman. This is unsurprising as these were all pharmaceutical experts and were not involved in the treatment of hypercholesterolemia and thus had no reason to be aware of rosuvastatin other than in the context of these proceedings. As such I do not find the state of their knowledge material to the identification of the common general knowledge of the skilled addressees of the 051 or low dose patent or the 165 or HeFH patent.
185 Leaving aside material confidential to AZ at the time, it is apparent that before the 12th International Symposium on Atherosclerosis in Stockholm in June 2000 AZ thought it had good reason to describe the drug, then known as ZD4522, as a "superstatin" because of its much greater potential to lower LDL-cholesterol than so-called "first generation" statins at well-tolerated doses. The predecessor of AZ, Zeneca Ltd, publicised its licence with the inventor of ZD4522, Shionogi & Co Ltd (Shionogi), for the "world-wide development, marketing and commercialization of this very promising lipid-lowering agent to be known as ZD4522…with a "superstatin" profile" in April 1998. A year later, in April 1999, AZ was created from a merger between Zeneca Ltd and Astra Ltd. At that time AZ's new Executive Director of research and development gave an interview to Reuters in which he referred to "Zeneca's superstatin used in heart disease". On 6 December 1999 AZ issued its first R&D presentation referring to Phase II trials data for "ZD4522 superstatin confirms better lipid lowering efficacy than any existing product and tolerability equivalent to the best in the class".
186 The very fact that the results of AZ's research into rosuvastatin were presented at the 12th International Symposium on Athersclerosis in Stockholm in 2000 is also relevant evidence that the drug was part of the common general knowledge of the hypothetical addressees of the patents (or, at least, the 051 or low dose patent and the 165 or HeFH patent). This includes that two of three experts who could fairly be characterised as experts in lipids at that time, Professor Tonkin and Dr Colquhoun, attended the symposium. This is consistent with AZ's own records, which show that half of the experts it had on the advisory panel for rosuvastatin (who thus would have been privy to the same confidential information as Professor O'Brien) attended the Stockholm symposium and thus must also be inferred to have obtained the information that AZ permitted to be published by Olsson and others at that time.
187 The presentation of the results at the 12th International Symposium on Atherosclerosis in Stockholm gained attention. One article, published the same day as the presentation on 28 June 2000, referred to AZ's trials showing a 65% reduction in LDL cholesterol. Another, published the following day on 29 June 2000 in Heartwire, was headed "Rosuvastatin - the most potent statin yet". This article referred to Dr Olsson as having reported that the 65% reduction of LDL cholesterol achieved by rosuvastatin "surpasses the maximum responses of all other statins when used as monotherapy". These results were reported under the by-line in bold "Faster than a speeding bullet? More powerful than a locomotive?" The article also reported that the drug showed "adverse events similar to placebo, [with a] lower risk of interactions with other drugs". Another AZ researcher, Dr McTaggert, was reported as saying that rosuvastatin is more lipophilic than any of the other statins and, as it is not metabolised in the liver as with other statins, it should be free of interactions with other drugs. Dr Wilson described Heartwire as a free newsletter containing information of interest to cardiologists and any clinician interested in that area. Dr Wilson could not recall if he subscribed to Heartwire when a cardiology registrar but knew that it used to be issued in print and was now issued electronically. He plainly read it to keep up to date on issues including summaries of important clinical trials in the cardiology area. A similar article appeared on the same day in the UK newspaper The Guardian which was available online. And on 31 July 2000 AZ issued a statement about its decision to spend £28.5m to construct a new plant to manufacture ZD4522 following the "recent publication of clinical data from Phase II trials demonstrating the potential of ZD4522, a HMG-CoA reductase inhibitor, to be a highly effective and well-tolerated alternative to currently available statins".
188 Although AZ objected to all of the material in the form of newspaper articles and AZ's own press releases, the fact is that AZ and its predecessor chose for its own commercial reasons to make public announcements about the drug, its potential and characteristics from 1998 when it obtained the licence from Shionogi and after the merger creating AZ. I am satisfied that AZ itself, or its predecessor, used the term "superstatin" to describe the drug as part and parcel of its commercial objectives at the time which apparently included making the market aware that it had an important new drug under development which appeared to be the best statin yet discovered in terms of efficacy and tolerability and which, by 31 July 2000, was sufficiently well demonstrated to warrant building a new multi-million pound plant for manufacturing purposes.
189 This evidence provides the context for the evidence of Professor Tonkin and Dr Colquhoun, both of whom attended the Stockholm symposium in June 2000. Professor Tonkin believed he would have been aware of rosuvastatin (even if under the name ZD4522) as a result of the symposium and Dr Colquhoun was aware that the drug was called a superstatin. The evidence also provides a context for the evidence of Professor O'Brien. Although Professor O'Brien was privy to confidential information from AZ about rosuvastatin it is highly unlikely that he was not also aware of the information about the drug that AZ had chosen to make public at and after the Stockholm symposium.
190 I am satisfied that clinicians such as Professors Tonkin and O'Brien, and Dr Colquhoun, who had practices focusing on lipid reducing therapies, were aware by the time of the Stockholm symposium that there was a new statin which had been the subject of Phase II clinical trials. They were aware, due to the results presented at the symposium and subsequent publicity, that the trials showed the drug's potential to be the most potent statin yet in terms of capacity to reduce LDL cholesterol at doses which were as well-tolerated as the best of the existing statins. This awareness on and from 30 June 2000 was part of the common general knowledge of the skilled addressee of the 150 or low dose patent and the 165 or HeFH patent.
191 Despite the earlier press releases by AZ and its predecessors I am not satisfied that this awareness formed part of the common general knowledge of the skilled addressees of the 150 or low dose patent and the 165 or HeFH patent before the Stockholm symposium. Apart from Professor O'Brien's evidence there is no proper basis upon which it may be inferred that people otherwise in his position, such as Professor Tonkin and Dr Colquhoun, became aware of the information which AZ and its predecessor disseminated about the drug in 1998 and 1999. Professor O'Brien's evidence that he was aware of the drug as at 6 February 1999 cannot be accepted at face value due to his access to confidential information. In contrast to the Stockholm symposium it is difficult to accept that a person in Professor O'Brien's position would have become aware of the press releases in 1998 and 1999 which appear to be directed more at the pharmaceutical market than clinicians.
192 For these reasons although I am satisfied that the existence of a new statin with a so-called "superstatin" profile (in terms of its potency in reducing LDL cholesterol levels to a materially greater extent than the existing statins and at doses as well tolerated as the best of the existing statins) was part of the common general knowledge of the skilled addressee of the 051 or low dose patent and the 165 or HeFH patent by 30 June 2000, I am not satisfied that this was so at any time before that date. As AZ submitted, in contrast to the evidence about the Stockholm symposium, there is no basis upon which it should be inferred that the earlier press releases and articles "came to the notice of skilled persons in Australia, let alone that the information in them was actually assimilated into common general knowledge".
193 Although the drug was referred to as ZD4522 at the Stockholm symposium and in some articles about the symposium, it was called "rosuvastatin" in the Heartwire article of 29 June 2000. The earliest date by which a skilled addressee could have known of the name "rosuvastatin" is thus 29 June 2000. Given the prevalence of references to ZD4522 at and around this time it is more likely that the new "superstatin" was known by this name as at 30 June 2000.
194 I do not accept the characterisation of this awareness as a mere "buzz" about a possible new statin. It is possible that such a "buzz" existed as a result of the AZ press releases in 1998 and 1999 but, for the reasons given, I am not satisfied that any such "buzz" had become part of the common general knowledge of the skilled addressees of the patents at that time. The information AZ published at the Stockholm symposium was relatively detailed and based on apparently sound science. The skilled addresses would not have treated this information as other than seriously considered and soundly based. Any caution with which people might have approached AZ's own earlier press releases would not have applied to the information published at and as a result of the Stockholm symposium.