Apotex Pty Ltd v AstraZeneca AB (No 4)
[2013] FCA 162
•5 March 2013
FEDERAL COURT OF AUSTRALIA
Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162
Citation: Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 Parties: APOTEX PTY LTD v ASTRAZENECA AB and ASTRAZENECA PTY LIMITED
WATSON PHARMA PTY LTD v ASTRAZENECA AB and ASTRAZENECA PTY LIMITED
ASTRAZENECA AB and ASTRAZENECA PTY LIMITED v ASCENT PHARMA PTY LTD ACN 118 734 795
File number(s): NSD 673 of 2011
NSD 2342 of 2011
NSD 208 of 2012Judge: JAGOT J Date of judgment: 5 March 2013 Corrigendum: 8 March 2013 Catchwords: PATENTS – pharmaceutical patents – invalidity – priority date – novelty – inventive step – entitlement – fair basis – utility – secret use – manner of manufacture – false suggestion – infringement – authorisation Legislation: Patents Act 1990 (Cth)
Patents Amendment Act 2001 (Cth)
Patents Act 1952 (Cth)Cases cited: Advanced Building Systems Pty Ltd v Ramset Fastners (Aust) Pty Ltd (1998) 194 CLR 171; [1998] HCA 19
Allsop Inc v Bintang Pty Ltd (1989) 15 IPR 686
Anaesthetic Supplies Pty Ltd v Rescare Ltd (1994) 50 FCR 1
Aktiebolaget Hassle v Alphapharm Pty Ltd (2000) 51 IPR 375; [2000] FCA 1303
Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411; [2002] HCA 59
Apotex Pty Ltd v Sanofi-Aventis (2009) 82 IPR 416; [2009] FCAFC 134
Apotex Pty Ltd v Sanofi-Aventis (2008) 78 IPR 485 [2008] FCA 1194
Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (No 2) (2012) 204 FCR 494; [2012] FCAFC 102
Apotex Pty Ltd v AstraZeneca AB (No 3) (2012) 95 IPR 581; [2012] FCA 265
Austal Ships Pty Ltd v Stena Rederi Aktiebolag (2005) 66 IPR 420; [2005] FCA 805
Australian Mud Co Pty Ltd v Coretell Pty Ltd (2011) 93 IPR 188; [2011] FCAFC 121
Bristol-Myers Squibb Co v FH Faulding & Co Ltd (2000) 97 FCR 524; [2000] FCA 316
Britax Childcare Pty Ltd v Infa-Secure Pty Ltd (2012) 290 ALR 47; [2012] FCA 467
British Acoustic Films Ltd v Nettlefold Productions (1935) 53 RPC 221
British United Shoe Machinery Co Ltd v A Fussell & Sons Ltd (1908) 25 RPC 631
Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183
Clorox Australia Pty Ltd v International Consolidated Business Pty Ltd (2006) 68 IPR 254; [2006] FCA 261
Danisco A/S v Novozymes A/S (No 2) (2011) 91 IPR 209; [2011] FCA 282
Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385
Ethyl Corp's Patent [1972] RPC 169
Flexible Steel Lacing Co v Beltreco Ltd (2000) 49 IPR 331; [2000] FCA 890
General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] RPC 457
H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151; [2009] FCAFC 70
Insta Image Pty Ltd v KD Kanopy Australasia Pty Ltd (2008) 78 IPR 20; [2008] FCAFC 139
ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc (2000) 106 FCR 214; [2000] FCA 1349
ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc (1999) 45 IPR 577; [1999] FCA 345
IGT (Australia) Pty Ltd v Aristocrat Technologies Australia Ltd (2008) 77 IPR 482; [2008] FCAFC 131
Inverness Medical Switzerland GmbH v MDS Diagnostics Pty Ltd (2010) 85 IPR 525; [2010] FCA 108
Jupiters Ltd v Neurizon Pty Ltd (2005) 222 ALR 155; [2005] FCAFC 90]
JMVB Enterprises Pty Ltd v Camoflag Pty Ltd (2005) 67 IPR 68; [2005] FCA 1474
Kimberly-Clark v Multigate Medical Products (2011) 92 IPR 21; [2011] FCAFC 86
Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCAFC 178
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd (2004) 64 IPR 444 ; [2004] UKHL 46
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 1) (2004) 217 CLR 274; [2004] HCA 58
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [(2007) 235 CLR 173; [2007] HCA 21
Longworth v Emerton (1951) 83 CLR 539
Martin v Scribal Pty Ltd (1954) 92 CLR 17
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) [154 FCR 31; [2006] FCAFC 91
Minnesota Mining & Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd (1980) 144 CLR 253; [1980] HCA 9
Northern Territory v Collins (2008) 235 CLR 619 [2008] HCA 49
Norton & Gregory Ltd v Jacobs (1937) 54 RPC 271
Novozymes A/S v Danisco A/S [2013] FCAFC 6
NSI Dental Pty Ltd v University of Melbourne (2006) 69 IPR 542; [2006] FCA 1216
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655; [1995] HCA 15
PAC Mining Pty Ltd v Esco Corporation (2009) 80 IPR 1; [2009] FCAFC 18
Pfizer Inc v Commissioner of Patents (2005) 141 FCR 413; [2005] FCA 137
Pfizer Overseas Pharmaceuticals v Eli Lilly & Co (2005) 68 IPR 1; [2005] FCAFC 224
Polwood Pty Ltd v Foxworth (2008) 165 FCR 527; [2008] FCAFC 9
Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (2008) 77 IPR 449; [2008] FCAFC 82
Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (No 2) (2006) 71 IPR 46; [2006] FCA 1787
RD Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 25 FCR 565
Root Quality Pty Ltd v Root Control Technologies Pty Ltd (2000) 49 IPR 225; [2000] FCA 980
Sachtler GmbH & Co KG v RE Miller Pty Ltd (2005) 221 ALR 373; 65 IPR 605 ; [2005] FCA 788
Sanofi-Aventis Australia Pty Ltd v Apotex Pty Ltd (No. 3) (2011) 196 FCR 1; [2011] FCA 846
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132
SNF (Australia) Pty Ltd v Ciba Specialty Chemicals Water Treatments Ltd (2011) 92 IPR 46; [2011] FCA 452
Stanway Oyster Cylinders Pty Ltd v Marks (1996) 66 FCR 577
Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346
Wake Forest University Health Sciences v Smith & Nephew Pty Ltd (No 2) (2011) 92 IPR 496; [2011] FCA 1002
Welch Perrin and Co Pty Ltd v Worrel (1961) 106 CLR 588
Welcome Real-Time SA v Catuity Inc (2001) 113 FCR 210; 51 IPR 327 ; [2001] FCA 445
Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262; [1981] HCA 12Fletcher Moulton, The Present Law and Practice Relating to Letters Patent for Inventions, (1913)
Date of hearing: 22-26, 28-31 October 2012; 1-2, 5-9 November 2012 Place: Sydney Division: GENERAL DIVISION Category: Catchwords Number of paragraphs: 523 In NSD 673 of 2011: Counsel for the Applicant: Mr D K Catterns QC with Ms K Howard SC, Mr A J Maryniak and Mr C Smith Solicitor for the Applicant: Herbert Smith Freehills Counsel for the Respondents: Mr A Bannon SC with Mr D Kell, Mr C Dimitriadis and Mr C J Burgess Solicitor for the Respondents: Ashurst Australia In NSD 2342 of 2011: Counsel for the Applicant: Mr A J Ryan SC and Mr I P Horak Solicitor for the Applicant: King & Wood Mallesons Counsel for the Respondents: Mr A Bannon SC with Mr D Kell, Mr C Dimitriadis and Mr C J Burgess Solicitor for the Respondents: Ashurst Australia In NSD 208 of 2012: Counsel for the Applicants: Mr A Bannon SC with Mr D Kell, Mr C Dimitriadis and Mr C J Burgess Solicitor for the Applicants: Ashurst Australia Counsel for the Respondent: Mr A J Ryan SC and Mr I P Horak Solicitor for the Respondent: King & Wood Mallesons FEDERAL COURT OF AUSTRALIA
Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162
CORRIGENDUM
1.In paragraph 361 of the reasons for judgment delete the words “and no manner of manufacture”.
2.In paragraph 483 of the reasons for judgment delete the words “and no manner of manufacture.”
I certify that the preceding two (2) numbered paragraph is a true copy of the Corrigendum to the Reasons for Judgment herein of the Honourable Justice Jagot. Associate:
Dated: 8 March 2013
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 673 of 2011
BETWEEN: APOTEX PTY LTD
Applicant/Cross RespondentAND: ASTRAZENECA AB
First Respondent/Cross ClaimantsASTRAZENECA PTY LIMITED
Second Respondent/Cross-Claimants
JUDGE:
JAGOT J
DATE OF ORDER:
5 MARCH 2013
WHERE MADE:
SYDNEY
THE COURT ORDERS THAT:
1.Order 2 of the orders of 14 December 2011 be dissolved.
2.The parties file agreed or competing proposed orders reflecting the reasons for judgment published today within 7 days.
3.The proceedings be listed on a date within a further 7 days thereafter, the date to be allocated in consultation with the parties.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 2342 of 2011
BETWEEN: WATSON PHARMA PTY LTD
Applicant/Cross Respondent
AND: ASTRAZENECA AB
First Respondent/Cross ClaimantASTRAZENECA PTY LIMITED
Second Respondent/Cross Claimant
JUDGE:
JAGOT J
DATE OF ORDER:
5 MARCH 2013
WHERE MADE:
SYDNEY
THE COURT ORDERS THAT:
1.Order 1 of the orders of 15 March 2012 be dissolved.
2.The parties file agreed or competing proposed orders reflecting the reasons for judgment published today within 7 days.
3.The proceedings be listed on a date within a further 7 days thereafter, the date to be allocated in consultation with the parties.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 208 of 2012
BETWEEN: ASTRAZENECA AB
First Applicant/Cross RespondentASTRAZENECA PTY LIMITED
Second Applicant/Cross RespondentAND: ASCENT PHARMA PTY LTD ACN 118 734 795
Respondent/Cross Claimant
JUDGE:
JAGOT J
DATE OF ORDER:
5 MARCH 2013
WHERE MADE:
SYDNEY
THE COURT ORDERS THAT:
1.Order 1 of the orders of 15 March 2012 be dissolved.
2.The parties file agreed or competing proposed orders reflecting the reasons for judgment published today within 7 days.
3.The proceedings be listed on a date within a further 7 days thereafter, the date to be allocated in consultation with the parties.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 673 of 2011
BETWEEN: APOTEX PTY LTD
Applicant/Cross RespondentAND: ASTRAZENECA AB
First Respondent/Cross ClaimantASTRAZENECA PTY LIMITED
Second Respondent/Cross-Claimant
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 2342 of 2011
BETWEEN: WATSON PHARMA PTY LTD
Applicant/Cross RespondentAND: ASTRAZENECA AB
First Respondent/Cross ClaimantASTRAZENECA PTY LIMITED
Second Respondent/Cross Claimant
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 208 of 2012
BETWEEN: ASTRAZENECA AB
First Applicant/Cross RespondentASTRAZENECA PTY LIMITED
Second Applicant/Cross RespondentAND: ASCENT PHARMA PTY LTD ACN 118 734 795
Respondent/Cross ClaimantJUDGE:
JAGOT J
DATE:
5 MARCH 2013
PLACE:
SYDNEY
REASONS FOR JUDGMENT
1. THE THREE PATENTS
These proceedings involve the construction, validity and, if valid, alleged infringement of three patents. AstraZeneca AB and AstraZeneca Pty Ltd (together referred to as AZ) are the registered proprietor and exclusive licensee of three Australian patents:
(1)Australian Patent No. 200023051 entitled “Use of cholesterol-lowering agent”. This patent is known as the 051 patent or low dose patent by the parties.
(2)Australian Patent No. 2002214165 entitled “Use of rosuvastatin (ZD-4522) in the treatment of heterozygous familial hypercholesterolemia”. This patent is known as the 165 patent or the HeFH patent by the parties (the shorthand for heterozygous familial hypercholesterolemia being HeFH).
(3)Australian Patent No. 200051842 entitled “Pharmaceutical compositions”. This patent is known as the 842 patent or cation patent by the parties.
Watson Pharma Pty Ltd and Ascent Pty Ltd (which had common representation in the proceedings and are referred to as Watson and Ascent) and Apotex Pty Ltd (Apotex) each wish to supply generic versions of rosuvastatin products. Watson, Ascent and Apotex are referred to as the generic parties where convenient to deal with them as a group. The generic parties each wish to supply pharmaceutical products in the form of tablets of 5 mg, 10 mg, 20 mg and 40 mg in which the active ingredient is rosuvastatin. The proposed supply of those products caused AZ to allege infringement of each of the three patents and the generic parties each to allege that the patents (or at least the claims on which AZ relied to assert infringement) were invalid and should be revoked.
Rosuvastatin is a compound which is used to treat hypercholesterolemia (high cholesterol). The three patents in issue relate to rosuvastatin but are not patents for the invention of the compound rosuvastatin. There is not and never has been a patent in Australia for the invention of the compound rosuvastatin.
Each of the generic parties is subject to interlocutory orders restraining them from infringing the patents. One feature of AZ’s submissions is detailed reference to the reasoning used to found the grant of the interlocutory relief. Given the different nature of an interim and final hearing I do not consider it necessary or appropriate to revisit the reasons for the grant of interlocutory relief in these reasons which concern the final resolution of all of the issues in dispute on the basis of the evidence admitted in the final hearing.
2. ABBREVIATED REFERENCES
In these reasons for judgment the following abbreviations are used:
051 or low dose patent means Australian Patent No 200023051 (769897) entitled “Use of cholesterol-lowering agent”.
165 or HeFH patent means Australian Patent No 2002214165 entitled “Use of rosuvastatin (ZD-4522) in the treatment of heterozygous familial hypercholesterolemia”.
841 application means the application for Australian Patent No. 200051841
842 or cation patent means Australian Patent No 200051842 (781269) entitled “Pharmaceutical compositions”.
471 patent means European Patent Application No 0521471.
the Act means the Patents Act 1990 (Cth).
FDA guidelines means the FDA Guidelines for the clinical evaluation of lipid-altering agents in adults and children dated September 1990.
FH means familial hypercholesterolemia, a genetic disorder characterised by high cholesterol levels.
HDL-C means high density lipid cholesterol.
HeFH means heterozygous familial hypercholesterolemia, a form of FH.
HMG-CoA reductase inhibitor means a drug which inhibits the HMG-CoA reductase, thus lowering cholesterol.
IUPAC means International Union of Pure and Applied Chemistry.
Japanese guidelines means the Japanese Guidelines on Clinical Evaluation Methods for Antihyperlipidemia Drugs dated January 1988.
Joshi article means European Patent Application no. 89105625.1 entitled “Pharmaceutical compositions having good stability”.
Kabadi article means UK Patent Application no. 9225659.3 entitled “Stabilized Pharmaceutical Compositions Comprising an HMG-CoA Reductase Inhibitor Compound”.
LDL-C means means low density lipoprotein cholesterol.
Mills article means European Patent Specification EP 0680320 B1.
Olsson article means the article published by Olsson et al in the European Heart Journal 2000 (21) titled “ZD4552- a new HMG-CoA reductase inhibitor – causes rapid and profound reductions in plasma LDL-C levels in patients with primary hypercholesterolaemia”.
Pears article means the article published by Pears et al in the Canadian Journal of Cardiology 2000 (17) titled “Dose-ranging study of the HMG-CoA reductase inhibitor ZD4522 in patients with primary hypercholesterolemia”.
SCRIP article means the article published in SCRIP No 2573 on 8 September 2000 titled “Statin reverses FH athersclerosis”.
Statin means a drug used to lower cholesterol by inhibiting the enzyme HMG-CoA reductase.
Stein article means the article published by Stein et all in the Journal of the American Medical Association 1999 (281)2 titled “Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia”.
TC means total cholesterol.
Watanabe article means the article published by Watanabe et al in Bioorganic & Medicinal Chemistry 1997 (5)2 titled “Synthesis and biological activity of methansulfonamide pyrimidine- and N-methanesufonyl pyrrole-substituted 3,5-dihtyroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors”.
3. OVERVIEW OF THE PATENTS
3.1 The 051 or low dose patent
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.
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.
…
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:
…
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 <6.21 mmol/L);
…
Exclusion Criteria
Any of the following was regarded as a criterion for exclusion from the trial:
(1)Subjects using cholesterol lowering drugs (this therapy must have been discontinued at least 4 weeks before the start of the dietary run-in period. Subjects taking probucol should have discontinued 12 months before inclusion in this study).
(2)History of serious or hypersensitivity reactions to other HMG-CoA reductase 30 inhibitors.
…
(7)Known homozygous familial hypercholesterolaemia or known type III hyperlipoproteinemia (familial dysbetalipoproteinaemia).
Page 21 of the specification contains the following paragraphs:
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
There are three claims, claim 1 of which is as follows:
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1.A method of treating a patient suffering from hypercholesterolemia which comprises administration as a starting dose of a single, once daily, oral dose of 5 to 10 mg of the compound … or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition.
Claim 2 is in these terms:
A method of treating a patient suffering from hypercholesterolemia which comprises administration of a single, once daily, oral dose of 5.2 to 10.4 mg of the calcium salt of the compound [rosuvastatin], in the form of a pharmaceutical composition.
Claim 3 is dependent on claims 1 and 2 and adds limitations relating to the LDL-C (low density lipoprotein cholesterol) levels and other conditions of the patient receiving the treatment. AZ alleges infringement of all of the claims of the 051 or low dose patent.
The issue of construction between the parties about the 051 or low dose patent is the reference to “starting dose” in claim 1.
In addition to the issues concerning the priority date and the inventor and thus entitlement of AZ to the patent, the validity of the 051 or low dose patent is challenged on numerous grounds under s 138(3) of the Patents Act 1990 (Cth) (the Act) including that: - (i) the claimed invention is not novel, (ii) the claimed invention lacked any inventive step, (iii) the claimed invention does not involve a manner of manufacture, (iv) the claims are not fairly based on the matter described in the specification, (v) the claimed invention lacks utility, and (vi) the 051 or low dose patent was obtained on a false suggestion.
3.2 The 165 or HeFH patent
The 165 or HeFH patent nominates Ali Raza and Howard Hutchinson as the inventors. The 165 or HeFH patent claims a priority date of 22 November 2000. There is a dispute about the inventors and AZ’s entitlement to the invention but the priority date is not in dispute.
The specification of the 165 or HeFH patent describes the invention as follows:
USE OF ROSUVASTATIN (ZD-4522) IN THE TREATMENT OF HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
The present invention relates to a new use of a statin drug in the treatment of severe heterozygous familial hypercholesterolemia (HeFH) and in particular patients with baseline LDL-C>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.
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 HypercholesterolemiaOBJECTIVES
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 (p<0.001) greater % reduction in LDL-C levels than did atorvastatin 20/40/80 mg at 18 weeks. The difference between treatments was >6%, 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 (p<0.001) and clinically greater % reduction in LDL-C at Week 2, 6 and 12. ZD4522 20/40/80 mg also resulted in significantly (p<0.001) greater % reductions in TC and significantly (p≤0.003) greater % increase in HDL-C than did atorvastatin 20/40/80 mg at all time points (observed data for Week 2, 6 and 12; observed and LOCF for Week 18). Both ZD4522 20/40/80 mg and atorvastatin 20/40/80 mg reduced TG levels at all time point, but the % reductions were similar in both treatment groups and the differences were not significantly different (p>0.050 at 2, 6 and 12 weeks for observed data and 18 weeks for LOCF). ZD4522 20/40/80 mg resulted in significantly (p<0.001) greater decreases in ApoB and increases in ApoA-I than did atorvastatin 20/40/80 mg at Week 18 (LOCF). In addition ZD4522 20/40/80 mg resulted in significantly (p<0.001) greater reductions in the LDL-C/HDL-C, TC/HDL-C and non-HDL-C/HDL-C ratios at all time points.
…
OVERALL CONCLUSIONS
ZD4522 was significantly more effective than atorvastatin in improving the atherogenic lipid profile (LDL-C, HDL-C and TC); ZD4522 was also clinically superior to atorvastatin with respect to effect on LDL-C levels, the primary lipid of interest. ZD4522 resulted in more subjects achieving guideline targets for LDL-C than did atorvastatin, particularly with those at high-risk of cardiovascular disease. ZD4522 had a satisfactory safety profile, which was comparable to atorvastatin.
…The claims of the 165 or HeFH patent include the following:
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1.A method for treating heterozygous familial hypercholesterolemia in a patient suffering heterozygous familial hypercholesterolemia, comprising administering to the patient [formula for rosuvastatin] or a pharmaceutically acceptable salt thereof.
2.A method as claimed in claim 1 wherein the patient is suffering from severe heterozygous familial hypercholesterolemia.
…
21.A method as claimed in any one of claims 1 to 5 wherein 20-40mg of …[the formula for rosuvastatin] is administered once a day to the patient in the form of the calcium salt.
Claims 3 to 10, which are not reproduced above, are dependent on claims 1 or 2. AZ alleges infringement of claims 1 to 10 and 21 of the 165 or HeFH patent.
There are no issues of construction about the 165 or HeFH patent. In addition to the issue concerning the inventors and thus the entitlement of AZ to the patent, the validity of the 165 or HeFH patent is challenged on the grounds of: - (i) lack of novelty, (ii) lack of inventive step, (iii) secret use, (iv) lack of a manner of manufacture, (v) the claims of the 165 or HeFH patent not being fairly based on the matter described in the specification, and (vi) the 165 or HeFH patent was obtained on a false suggestion.
3.3 The 842 or cation patent
The 842 or cation patent nominates Joseph Creekmore and Norman Wiggins as the inventors. The 842 or cation patent claims a priority date of 26 January 2000. The priority date is in dispute but there is no issue about the inventors and AZ’s entitlement to the invention (if it be an invention).
The specification of the 842 or cation patent describes the invention as follows:
Pharmaceutical compositions
…
The present invention relates to pharmaceutical compositions and more particularly to a pharmaceutical composition containing … or a pharmaceutically-acceptable salt thereof (and referred to hereinafter as “the Agent”). In particular the sodium and calcium salts, and especially the calcium salt … (shown as Formula I below).The Agent is disclosed as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) in European Patent Application, Publication No. 0521471 and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444 and is useful in the treatment of hypercholesterolemia, hyperlipidproteinemia and atherosclerosis.
The problem associated with the Agent is that it is particularly sensitive to degradation under certain conditions. The major degradation products formed are the corresponding (3R, 5S) lactone (hereinafter referred to as “the lactone”) and an oxidation product (hereinafter referred to as “B2”) in which the hydroxy group adjacent to the carbon-carbon double bond is oxidised to a ketone functionality. The potential for significant degradation of the Agent makes it difficult to formulate and provide a pharmaceutical composition with acceptable storage life for a marketed product.
Pharmaceutical formulations of certain 7-substituted-3,5-dihydroxy-6-heptenoic acid salts, which are HMG CoA reductase inhibitors, are disclosed in UK Patent 2 262 229, and that they are sensitive to pH degradation. These formulations require the presence of an alkaline medium (such as a carbonate or bicarbonate) capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition.
However, we have found that for the Agent it is not sufficient to improve stability by solely controlling pH in the formulation. We have found that with the Agent stability is improved by selection of an inorganic salt to be added to the composition which contains one or more multivalent inorganic cations. Whilst not wishing to be bound by theory we believe that the multivalent inorganic cation stabilises the structure of the Agent and makes it less susceptible to oxidation and/or lactonization.
We present as aspects of the invention
(1)A pharmaceutical composition comprising the Agent or a pharmaceutically acceptable salt thereof as the active ingredient and an inorganic salt in which the cation is multivalent, provided that: the inorganic salt is not hydrotalcite or synthetic hydrotalcite and the counter anion to the inorganic salt is not a phosphate.
(2)The use of an inorganic salt in which the cation is multivalent to stabilise the Agent or a pharmaceutically acceptable salt thereof, provided that: the inorganic salt is not hydrotalcite or synthetic hydrotalcite and the counter anion to the inorganic salt is not a phosphate.
Preferred features of the invention are:
(1)wherein the Agent is present in the composition is more than 5 mg, preferably more than 10mg. Excluded compositions are those wherein the Agent is present at 1mg, 2mg, 5mg and 10mg. Preferred compositions are those where the amount of Agent is 20mg, 40mg or 80mg.
(2)wherein the stabilising compound is not hydrotalcite or synthetic hydrotalcite.
(3) the pharmaceutical composition formed is a tablet or powder.
Preferably the pharmaceutical composition of the invention is a tablet.
The multivalent cation found in the inorganic salt may be selected from the following, calcium, magnesium, zinc, aluminium and iron or a mixture thereof. Preferred multivalent cations are calcium, aluminium and magnesium or a mixture thereof. Especially preferred multivalent cations are aluminium and magnesium or a mixture thereof.
The counter anion in the inorganic salt may be selected from a phosphate, a carbonate, a silicate, an oxide and a metasilicate. Preferred counter anions are selected from a carbonate, a silicate, an oxide or a metasilicate. Especially preferred counter anions are selected from a silicate, an oxide or a metasilicate.
Individual aspects of the invention include an inorganic salt comprising a multivalent cation selected from any of the above and a counter anion also selected from any of the above.
Preferred inorganic salts for use in the present invention are; aluminium magnesium metasilicate (NeusolinTM, Fuji Chemical Industry Limited), dibasic or tribasic calcium phosphate, tribasic magnesium phosphate and tribasic aluminium phosphate. Aluminium magnesium metasilicate and tribasic calcium phosphate are especially preferred.
It is also preferable that such a composition has a good flow rate to assist processing into unit dosage forms for oral administration, for example into tablets, and good disintegration and dissolution characteristics when processed into tablets for oral administration, which tablets can be in different dosage strengths.
The ratio of inorganic salt to Agent in the pharmaceutical composition is, for example, within the range of 1:80 to 50:1 by weight, for example 1:50 to 50:1 by weight, such as 1:10 to 10:1 by weight, and more particularly 1:5 to 10:1 by weight.
Preferably the pharmaceutical composition of the invention is formulated into an oral dosage form, such as a tablet. Accordingly a further aspect of the invention comprises a pharmaceutical composition comprising the Agent, an inorganic salt in which the cation is multivalent, and one or more fillers, binders, disintegrants or lubricants. A still further aspect of the invention relates to a pharmaceutical composition for oral administration comprising the Agent, one or more fillers, one or more binders, one or more disintegrants, one or more lubricants and an inorganic salt in which the cation is multivalent.
…
According to the specification:
The pharmaceutical composition of the invention may be prepared, using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components. For example, the Agent and an inorganic salt in which the cation is multivalent, one or more fillers, one or more binders and one or more disintegrants, as well as other additional excipients if desired are blended together. The components of the blend prior to blending, or the blend itself, may be passed through a mesh screen, for example a 400-700 ųm mesh screen. A lubricant, which may also be screened, is then added to the blend and blending continued until a homogeneous mixture is obtained. The mixture is then compressed into tablets. Alternatively, a wet granulation technique can be employed. For example, the Agent and an inorganic salt in which the cation is multivalent, one or more fillers, one or more binders and a portion of a disintegrant, as well as other additional excipients if desired, are blended together, for example by using a granulator, and the powder blend is granulated with a small volume of purified water. The granulate is dried and passed though a mill. The remainder of the disintegrant and a lubricant are added to the milled granulation and after blending the resultant homogeneous mixture is compressed into tablets. It will be appreciated that modifications of the dry blending and wet granulation techniques, including the order of addition of the components and their screening and blending prior to compression into tablets, may be carried out according to principles well known in the art.
A tablet coating may then be applied, for example by spray-coating with a water-based film coating formulation. The coating may comprise, for example, lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide and ferric oxides. Coating ingredient combinations are commercially available, such as those described in the Examples hereinafter. The coating may comprise, for example, 0.5 to 10% by weight of the tablet composition, particularly 1 to 6%, and preferably 2 to 3%. Coatings containing ferric oxides are especially preferred as they reduce the rate of formation of photodegradation products of the Agent.
Accordingly we present as a feature of the invention a pharmaceutical composition comprising the Agent, the composition having a ferric oxide light protective coating.
A further aspect of the present invention comprises a method of preparing a stabilised pharmaceutical composition which comprises admixing the Agent with an inorganic salt in which the cation is multivalent. A further aspect of the present invention comprises a method of producing a stabilised pharmaceutical composition which comprises incorporating a inorganic salt in which the cation is multivalent in a pharmaceutical composition containing the Agent.
Four examples are then given in these terms:
Example 1
The Agent 2.50 mg Tribasic calcium phosphate 20.0 mg Microcrystalline cellulose 47.0 mg Lactose monohydrate 47.0 mg Sodium starch glycollate 3.00 mg Butylated hydroxytoluene 0.05 mg Magnesium stearate 1.00 mg The Agent, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, tribasic calcium phosphate, and butylated hydroxytoluene were blended together for 10 minutes. Magnesium sterate was screened through a #40 mesh (425 µm) screen and added to the blend and blending continued for a further three minutes. The resulting homogeneous mixture was compressed into tablets.
The tablets were stored at 70ºC/80% relative humidity for one week. After one week there was found to be only 0.11%w/w of the oxidation product B2 formed and only 0.50%w/w of the lactone.
Example 2
The Agent 2.50 mg Povidone 2.50 mg Tribasic calcium phosphate 20.0 mg Microcrystalline cellulose 47.0 mg Mannitol 47.0 mg Sodium starch glycollate 3.00 mg Butylated hydroxytoluene 0.05 mg Magnesium stearate 1.00 mg The Agent, povidone, mannitol, microcrystalline cellulose, butylated hydroxytoluene, tribasic calcium phosphate and sodium starch glycollate (in the amounts given below) were blended for 5 to 60 minutes. Magnesium stearate was screened through a #40 mesh (425 µm) screen and added to the blend and blending continued for a further three minutes. The resulting homogeneous mixture was compressed into tablets. The compressed tablets were coated by spraying with a mixture of hydroxpropyl methylcellulose, polyethylene glycol 400, titanium dioxide and ferric oxide (sold as Spectrablend™ by Warner-Jenkinson)) and water in a coating pan. The weight gain provided by the coating was 1 to 6%w/w, and preferably 2 to 3%w/w.
The tablets were stored at 70ºC/80% relative humidity for one week. After one week there was found to be only 0.06%w/w of the oxidation product B2 formed and only 2.22%w/w of the lactone.
Example 3
The Agent 2.60 mg Crospovidone 3.75 mg Tribasic calcium phosphate 5.66 mg Microcrystalline cellulose 15.5 mg Lactose monohydrate 46.5 mg Magnesium stearate 0.94 mg The Agent and crospovidone were blended together for 5 minutes and the blend then passed through a 400-700µm screen. A small portion of the microcrystalline cellulose was passed through the screen afterwards. The screened material was blended with the other ingredients, excluding the lubricant, for 10 minutes. Magnesium stearate was passed through a #40mesh (425 µm) screen and added to the blend and the mixture was blended for a further 3 minutes. The resulting homogeneous mixture was compressed into tablets. The compressed tablets were coated by spraying with a mixture of lactose monohydrate, hydroxypropyl methylcellulose, triacetin and ferric oxide (sold as Opadry II™ by Colorcon) and water in a coating pan. The weight gain provided by the coating is 1 to 6%w/w, and preferably 2 to 3%w/w.
The tablets were stored at 70º/80% relative humidity for one week. After this time only 0.19%w/w of the oxidation product B2 had formed and only 2.71%w/w of the lactone.
Example 4
The Agent 2.50 mg Povidone 2.50 mg Tribasic calcium phosphate 20.0 mg Microcrystalline cellulose 34.5 mg Lactose monohydrate 34.0 mg Sodium starch glycollate 6.00 mg Magnesium stearate 1.00 mg Butylated hydroxytoluene 0.05 mg A portion of the tribasic calcium phosphate and butylated hydroxytoluene were blended for 30 seconds in a bag. The Agent, povidone, remainder of the tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, tribasic calcium phosphate/butylated hydroxytoluene mixture and a portion of the sodium starch glycolate were blended in a granulator for 30 seconds. The powder blend was granulated with purified water for 1 minute at the addition rate of 70 mg/tablet/minute. The granulation is dried in a fluidized bed drier at 50ºC until the loss on drying is less than 2% w/w. The dried granulation is passed through a mill (e.g. Comil™). The milled granulation and the remainder of the sodium starch glycolate was blended for approximately 5 minutes. Magnesium stearate was screened through a #40 mesh (425 µm) screen and added to the blend and blending continued for a further three minutes. The resulting homogeneous mixture was compressed into tablets.
The tablets were stored at 70ºC/80% relative humidity for one week. After this time only 0.23% w/w of the oxidation product B2 had formed and only 0.28%w/w of the lactone.
…
Page 10 of the specification contains the following statement:
Throughout this specification and the claims which follow, unless the context required otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
The claims include the following:
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1.A pharmaceutical composition comprising … or a pharmaceutically acceptable salt thereof as the active ingredient and an inorganic salt in which the cation is multivalent, provided that:
(i)the inorganic salt is not hydrotalcite or synthetic hydrotalcite; and
(ii)the counter anion to the inorganic salt is not a phosphate.
2.A pharmaceutical tablet comprising … or a pharmaceutically acceptable salt thereof as the active ingredient and an inorganic salt in which the cation is multivalent, provided that the counter anion to the inorganic salt is not a phosphate.
3.A pharmaceutical composition according to claim 1 or claim 2 wherein the cation of the inorganic salt is selected from calcium, magnesium, zinc, aluminium and iron.
4.A pharmaceutical composition according to any one of claims 1 to 3 wherein the counter anion of the inorganic salt is selected from a carbonate, a silicate, an oxide and a metasilicate.
5.A pharmaceutical composition according to any one of claims 1 to 3 wherein the counter anion of the inorganic salt is selected from a silicate, an oxide or a metasilicate.
6.A pharmaceutical composition according to claim 1 or claim 2 wherein the inorganic salt is aluminium magnesium metasilicate.
7.A pharmaceutical composition according to claim 1 which is a tablet or powder.
Claim 8 is dependent on claims 1 or 2. Claim 9 is dependent on any of claims 1 to 8. Claims 10 to 18 inclusive are also dependent claims.
There are two main issues of construction about the 842 or cation patent, being the meaning of “pharmaceutical composition” and of “inorganic salt” as each appears in the claims. In addition to the issues concerning the priority date, the validity of the 842 or cation patent is challenged on the grounds of: - (i) lack of novelty, (ii) lack of inventive step, (iii) lack of a manner of manufacture, (iv) lack of utility, (v) secret use, (vi) the claims of the 842 or cation patent not being fairly based on the matter described in the specification, (vii) the 842 or cation patent was obtained on a false suggestion, (viii) lack of clarity, and (ix) failure of the specification to include the best method known to the applicant of performing the invention.
3.4 Relevant version of s 7 of Patents Act
Because the complete application for each patent was made before the day on which the amendments to s 7 of the Act by the Patents Amendment Act 2001 (Cth) commenced (being 1 April 2002) the version of s 7 which applies is that which existed before these amendments. Section 7, as it applies to the three patents in issue, provides as follows:
(1)For the purposes of this Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:
(a)prior art information (other than that mentioned in paragraph (c)) made publicly available in a single document or through doing a single act;
(b)prior art information (other than that mentioned in paragraph (c)) made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;
(c)prior art information contained in a single specification of the kind mentioned in subparagraph (b)(ii) of the definition of prior art base in Schedule 1.
(2)For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.
(3)For the purposes of subsection (2), the kinds of information are:
(a)prior art information made publicly available in a single document or through doing a single act; and
(b)prior art information made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;
being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area.
4. OVERVIEW OF WITNESS EVIDENCE
4.1 AstraZeneca executives
4.1.1Mike Bull
Mike Bull is the Director of Primary Care at AZ in Australia. Mr Bull gave evidence on a range of topics, including the importation and sale in Australia of Crestor by AZ, the use of private prescriptions in Australia and the marketing of Crestor in Australia.
4.1.2Charles Waterfield
Charles Waterfield is the Director of Market Access and External Affairs at AZ. He gave evidence on the regulatory, pricing and reimbursement regimes that apply to the supply of pharmaceutical products in Australia, including the operation of the Australian Register of Therapeutic Goods and the Australian Pharmaceutical Benefits Scheme and prescriptions of Crestor in Australia including for patients with HeFH.
4.2 Data providers
4.2.1John Frost
John Frost is the Chief Executive Officer of Health Communication Network Ltd (HCN). HCN compiles electronic health record data. Mr Frost explained HCN’s procedures and data supplied by HCN to AZ relating to the incidence of general practitioners allowing generic substitution of prescribed medicines.
4.2.2Atul Muchhala
Atul Muchhala is the Director, Strategic Partners Australia and New Zealand at IMS Health. IMS Health provides information in relation to the pharmaceutical industry in Australia and overseas. Mr Muchhala provides an overview of the processes utilised by IMS to create and maintain datasets, some of which are purchased by AZ.
4.2.3Ben Ramsey
Ben Ramsey is the Director of Finance, Australia and New Zealand at IMS Health. In his evidence Mr Ramsey elaborates on certain aspects of Mr Muchhala’s evidence with respect to IMS’s data processing procedures.
4.3 Patent attorneys
4.3.1Rodney Cruise
Rodney Cruise holds a Bachelor of Science degree in Applied Chemistry and qualified as an Australian and New Zealand Patent and Trade Mark Attorney in 1995. Mr Cruise’s evidence concerned patent and non-patent literature searches of databases available prior to 2000.
4.3.2Nicole Watling
Nicole Watling obtained a Doctorate of Philosophy in Organic Chemistry from the University of Western Australia in 2001 and was registered as a patent attorney in Australia and New Zealand in 2005. She has worked at Freehills Patent Attorneys as a registered patent attorney and senior associate for 11 years. Dr Watling’s evidence primarily dealt with the history of the 842 patent and its amendments and the 051 patent.
4.4 Tablet splitting
AZ adduced evidence of the purchase of tablet splitting devices from several pharmacies in the following locations:
·Mt Hawthorn ChemMart, Mt Hawthorn, Western Australia [Leon Firios 18/7/12]
·PharmaSave Maylands Compounding Pharmacy, Maylands, Western Australia [Leon Firios 18/7/12]
·TerryWhite Chemist, Westfield Bondi Junction, New South Wales [Siobhan Murphy 17/7/12]
·PharmaSave Bob’s Chemist, Newtown, New South Wales [Siobhan Murphy 17/7/12]
·PharmaSave Melbourne City Pharmacy, Melbourne, Victoria [Claire Roberts 17/7/12]
·TerryWhite Chemist, Clarendon Centre, South Melbourne, Victoria [Claire Roberts 17/7/12]
·PharmaSave Patrick’s Road Pharmacy, Ferny Hills, Queensland [Katherine Skene 18/7/2012]
·Ashgrove West ChemMart, Ashrove, Queensland [Katherine Skene 18/7/2012]
The tablet splitting devices were in evidence. One, purchased from PharmaSave Melbourne City Pharmacy, states on its packaging that it is “ideal for when half or quarter doses are required”.
4.5 Pharmacist
4.5.1Divesh Sanghvi
Divesh Sanghvi is a registered pharmacist. His evidence primarily covered the regulatory scheme governing pharmacy practice in Australia, including dispensing prescription medicines, tablet splitting, and product information leaflets.
4.6 Medical practitioners
4.6.1Peter Hay
Peter Hay is a general medical practitioner at Castle Hill Medical Centre. He completed a Bachelor of Medicine and Bachelor of Surgery degree in 1980 and became a fellow of the Royal Australian College of General Practitioners in 1989. Dr Hay has worked as a general practitioner since 1984. His research interests include cardiovascular disease, diabetes and influenza. He has been involved in carrying out influenza research and was also involved with a study concerning atorvastatin and the management of cholesterol at the Royal North Shore Hospital.
Dr Hay gave evidence mainly relating to his practice as a GP and his prescription practices, including tablet splitting and the prescription of statins.
4.6.2Andrew Wilson
Professor Wilson is a cardiologist and Associate Professor at St Vincent’s Hospital in Fitzroy, Victoria. He obtained a Bachelor of Medicine and a Bachelor of Surgery degree with first class honours in 1993. Professor Wilson has worked at St Vincent’s Hospital since the completion of his internship there in 1994, eventually working in the position of cardiology registrar from 1999 to 2000. He obtained specialist qualifications in cardiology in 2002 when he became a Fellow of the Royal Australasian College of Physicians. From 2002 to 2005 he was employed as a cardiologist and physician at St Vincent’s Hospital and also acted as consultant to the University of Melbourne Lipid and Cardiovascular Risk Reduction Clinic at St Vincent’s Hospital. Professor Wilson completed a PhD at the University of Melbourne in 2005 on the relationship between obesity, inflammation and insulin resistance. Professor Wilson completed a fellowship as an Interventional Cardiology Fellow in the Cardiovascular Medicine Division at Stanford University Medical Center in the United States in 2006 and a fellowship as a Post Doctoral Research Fellow at the Falk Cardiovascular Institute at Stanford University in 2007. Since returning to Australia in 2007 Professor Wilson has held the positions of cardiologist as St Vincent’s Hospital and Director of the LCR Clinic at the University of Melbourne.
Professor Wilson has a special interest in the vascular and endothelial biology of atherosclerosis and the prevention of atherosclerosis. He was involved in establishing the Translational Cardiovascular Biology Laboratory at the University of Melbourne, Department of Medicine in 2007. Professor Wilson conducts cell-based research in relation to the role of fat cells in diabetes and heart disease. He has also been involved in a number of clinical trials, generally at a pre-clinical stage or at Phase III or IV. Professor Wilson has authored or co-authored over 50 peer-reviewed manuscripts in leading journals in the areas of cardiology and atherosclerosis and has presented at many international scientific meetings and symposiums.
Professor Wilson’s evidence dealt primarily with his prescription practices and tablet splitting (both generally and in the context of statins), his experience in treating and prescribing medications for patients suffering from HeFH and clinical trials.
4.6.3Richard O’Brien
Professor O’Brien obtained a Bachelor of Medicine/Bachelor of Surgery in 1981. He became a member of the Fellowship of the Royal Australasian College of Physicians in 1988 and completed a PhD in 1992 in the area of diabetic nephropathy. In 2009 he obtained a Graduate Certificate in Health Professional Education. Professor O’Brien was employed at Austin Hospital from 1982 to 1992, eventually becoming Honorary Endocrinologist. From 1992 to 2001 he was Head of Diabetes section at Monash Medical Centre. He was also Director, Special Medicine, Renal and Vascular Program, Southern Health from 1998 to 2000. From 2001 to 2004 Professor O’Brien was Director of Diabetes at Monash Medical Centre and went on to be Director of Lipid Services and Deputy Director of Diabetes at Southern Health from 2005 to 2007.
Professor O’Brien is currently Clinical Dean at the Austin Clinical School of the University of Melbourne and Associate Professor, Faculty of Medicine at the University of Melbourne, both positions he has held since 2007. He is also Senior Endocrinologist (since 2007) and Director of Lipid Services (since 2009) at the Austin Hospital, where he specialises in the management of cardiovascular risk, lipid disorders, general endocrinology and diabetes. Since 2004 Professor O’Brien has held the position of Visiting Scientist at the Baker Heart Research Institute. Professor O’Brien is also currently Chair of the Lipid Management in Diabetes Guidelines Committee of the National Health and Medical Research Council (since early 2010) and a Council Member of the Asia Pacific Society of Atherosclerosis and Vascular Diseases (since 2008). Professor O’Brien has written approximately 60 peer-reviewed articles in scholarly journals. A number of these articles have concerned statins, in particular simvastatin and atorvastatin. Professor O’Brien has also been involved in a number of clinical trials involving statins, including trials prior to 2000 involving a number of studies on simvastatin and atorvastatin.
Professor O’Brien gave evidence on a range of topics including the clinical trial process, hypercholesterolaemia and HeFH, statins (including their use in the treatment of hypercholesterolaemia), and the low dose and HeFH patents.
4.6.4David Colquhoun
Dr Colquhoun obtained a Bachelor of Medicine/Bachelor of Surgery degree in 1976. In 1977 he completed an internship at St Vincent’s Hospital in Sydney and went on to become a resident at the Fairfield District Hospital and Lidcombe Hospital in Sydney, holding the position of Medical Registrar at Lidcombe Hospital from 1979 to 1980. He then worked at the Royal Prince Alfred Hospital, first as a Cardiology Registrar (1981-1982) and then as a Research Fellow (1983-1984). In 1984 Dr Colquhoun became a Fellow of the Royal Australian College of Physicians. In that year he also became a clinical tutor at the University of Queensland before becoming a clinical senior lecturer in medicine in 1993 and an Associate Professor in 1994, a position he still holds.
In 1986 Dr Colquhoun set up private rooms at the Wesley Medical Centre as a Consultant Cardiologist and continues to hold this position. He has also held the position of Consultant Cardiologist at the Repatriation Hospital in Brisbane (renamed the Greenslopes Private Hospital in 1995) since 1981. Since 1985 he has been actively involved in clinical trials, with particular interest in lipids and dietary management and the role of psychological factors in coronary heart disease. In 2004 he became a Fellow of the Cardiac Society of Australia and New Zealand.
Dr Colquhoun is currently Chairman of the National Heart Foundation stress working group. Dr Colquhoun has also been a reviewer and assessor for medical publications since 1987 and is currently an assessor for several medical journals. He has been a member of many advisory committees since 1998, including the lipid advisory committees of pharmaceutical companies including AZ, Pfizer, Merck Sharp & Dohme and Bristol-Myers Squibb. He was also a member of the Queensland Government committee on the prevention of heart disease in 2009.
Dr Colquhoun’s evidence primarily dealt with his involvement as an investigator in a clinical trial of the use of rosuvastatin to treat HeFH conducted between July 1999 and June 2000.
4.6.5Andrew Tonkin
Professor Tonkin completed a Bachelor of Medicine/Bachelor of Surgery in 1967 and a Doctor of Medicine in 1975. Following his graduation in 1967 he worked at the Royal Melbourne Hospital, moving to Sydney in 1972 to take up the position of Cardiology Registrar at the Royal Prince Alfred Hospital. In late 1973 he moved to the United States where he worked as a Cardiology Fellow at the Duke University Medical Centre in Durham, North Carolina and then as Research Associate between 1974 and 1975, while also working as visiting physician at Watts Hospital in Durham. In 1975 Professor Tonkin became a Fellow of the Royal Australasian College of Physicians.
Between 1975 and 1976 Professor Tonkin was employed as a Research Associate of the German Heart Centre in Munich, returning to Australia in 1976 to work at Flinders Medical Centre in South Australia as a Senior Specialist in Cardiovascular Medicine. In 1977 he became the Director of Coronary Care at Flinders Medical Centre, a position he held until 1981 when he was appointed the permanent Head and Senior Director of Cardiology. Professor Tonkin was also Senior Visiting Cardiologist at the Repatriation General Hospital in South Australia between 1976 and 1988 and Senior Consultant Specialist at the Royal Adelaide Hospital between 1980 and 1988. Between 1976 and 1988 Professor Tonkin held honorary appointments with Flinders University, including Senior Lecturer and Associate Professor of Medicine.
In 1988 Professor Tonkin took up the position of Director of Cardiology at the Austin Hospital in Melbourne and Visiting Specialist Cardiologist at the Repatriation General Hospital, Heidelberg. Professor Tonkin subsequently became Director of Cardiology of the Austin and Repatriation Medical Centre in January 1996 when the two hospitals were amalgamated. During this time Professor Tonkin was appointed a Professorial Fellow of the University of Melbourne responsible for coordinating cardiology components of both undergraduate and postgraduate teaching.
In May 1997 Professor Tonkin became Director of Health, Medical and Scientific Affairs of the National Heart Foundation of Australia, a position he held until 2006. In July 2012, having been a Sessional Consultant Cardiologist since May 1997, Professor Tonkin was made Honourary Consultant Cardiologist with Austin Health in Victoria. Since 2004 Professor Tonkin has been the Head of the Cardiovascular Research Unit within the Department of Epidemiology and Preventive Medicine at Monash University. He is also currently Adjunct Professor in the Department of Medicine at Flinders University.
Professor Tonkin has been involved in clinical research since 1973 and his major research interests include cardiac electrophysiology, randomised controlled clinical trials, epidemiology, health inequalities and translational research. As part of his research activities Professor Tonkin has been a member of the Steering Committees of major multicentre trials of lipid-modifying therapy and has also been Chairman of a number of Australian Expert Committees on cardiovascular disease and health. Professor Tonkin has also published over 348 articles, editorials and book chapters concerned primarily with various aspects of cardiovascular disease.
Professor Tonkin’s evidence dealt with a range of topics, including the treatment of hypercholesterolaemia prior to November 2000, the clinical trials process, tablet splitting and the HeFH.
4.7 Pharmaceutical formulators and pharmacologists
4.7.1William Charman
Professor Charman obtained a Bachelor of Pharmacy in 1981 and a PhD in pharmaceutical chemistry in 1985. He also received a Doctor of Science degree in 2011. He is currently the Dean, Faculty of Pharmacy and Pharmaceutical Sciences, and Director, Monash Institute of Pharmaceutical Science at Monash University in Melbourne. He has been a Sir John Monash Distinguished Professor since 2011.
Professor Charman describes his research as characterised by a multidisciplinary and collaborative approach to address major issues in drug discovery, drug delivery and the pharmaceutical sciences. Professor Charman has published over 350 scientific papers dealing with drug discovery, drug delivery, pharmaceutical formulation design and drug development, and he has also given over 170 invited national and international presentations. He is a member of four international editorial boards and was previously an Associate Editor of the Journal of Pharmaceutical Sciences.
Professor Charman has received several academic awards and was elected a Fellow of the American Association of Pharmaceutical Scientists in 2002. Professor Charman was Chairman of the Wellcome Trust Seeding Drug Discovery Funding Committee from 2006 to 2010. Other key external appointments include being a member of the Expert Scientific Advisory Committee of the Medicines for Malaria Venture (2005-2011), an advisor to the World Health Organisation, a co-founder of Acrux Limited and a member of various scientific advisory boards.
Professor Charman gave evidence about pharmaceutical formulations and chemistry relevant to the issues in dispute.
4.7.2Angelo Morella
Dr Morella obtained a Bachelor of Science degree with Honours in organic chemistry in 1979. In 1985 he completed a PhD focusing on the synthesis of molecules. In 1985 Dr Morella commenced work as a chemist at Faulding Pharmaceuticals Pty Ltd (Faulding), becoming an analytical scientist later that year. In 1986 he became a Development Scientist in Faulding’s Pellet Production Development Group. Dr Morella remained at Faulding until 2000 in various roles, eventually becoming Product Development Manager in 1999. In these roles Dr Morella was responsible for managing and actively participating as a formulator in Faulding’s research efforts into the development of pharmaceutical products, from initial concepts through to commercial products. Dr Morella assisted in developing a number of tablet and capsule dosage forms and worked on several major formulation projects. Dr Morella was appointed Formulation Development Manager at Faulding in 2001 and Innovation Manager in 2003, eventually becoming General Manager – Research and Development in 2011. Dr Morella retired from Faulding in March 2012 and since then has worked as a self-employed consultant to the pharmaceutical industry.
Dr Morella’s evidence included an overview of the drug development process, formulating new or improved therapies with reference to dosage form and design, identifying formulation issues and other questions of chemistry relevant to the issues in dispute.
4.7.3Allan Evans
Professor Evans obtained a Bachelor of Pharmacy in 1982. From 1983 to 1984 he worked as a pharmacist in Adelaide. Between 1985 and 1989 he completed a PhD. His research investigated the pharmacokinetics of enantiomers of ibuprofen. From 1989 to 1991 Professor Evans lived in the United Kingdom where he worked as a post-doctoral research associate at the University of Manchester in the School of Pharmacy and Pharmaceutical Sciences. He returned to Australia in 1991 and briefly worked as a research associate at the Department of Clinical & Experimental Pharmacology at the University of Adelaide before joining the School of Pharmacy and Medical Sciences at the University of South Australia as a lecturer in August 1992. He became Senior Lecturer in January 1995 and Associate Professor in January 2000, before being promoted to Professor of Pharmaceutics in January 2003 and then Head of School in September 2004. In August 2009 Professor Evans was appointed Pro Vice Chancellor and Vice-President of the Division of Health Sciences of the University of South Australia, a position he still holds. Professor Evans has responsibility for the teaching, research, human resources, financial and engagement activity of all health science activity at the University, and has lectured in pharmokinetics, biopharmaceutics, clinical pharmacology and pharmacy practice.
Professor Evans was also a faculty member of the Adelaide Pharmacology Group Drug Disposition Workshop faculty from 1992 to 2001, which ran seminars for Australian members of the pharmaceutical industry focusing on drug development. Between 1993 and 1995 he worked as a consultant for Faulding in relation to new drug delivery systems and formulations and worked extensively with Gebro Pharma GmBH from 1994 until 2009. Between 2001 and 2004 Professor Evans was Director of the Centre for Pharmaceutical Research at the University of South Australia, which performed research services for the University including preclinical and Phase I research.
AZ also relies on the principles of joint tortfeasorship, on the basis that the generic parties, by the act of supply, would be aiding, inducing or procuring the infringement of the patent by patients who used the products in issue.
Finally, AZ contends that the generic parties threaten to infringe the patents by authorising the use in circumstances where s 13 of the Act gives the patentee the exclusive right to authorise other persons to exploit an invention during the term of a patent.
AZ submitted that:
There can be no real doubt that use of the generic products in accordance with the instructions contained in the respective PI documents of the generic parties (including to administer once daily, oral doses of 5 or 10 mg rosuvastatin as a starting dose for the treatment of hypercholesterolemia) would result in “persons” infringing claims 1 and 2 of the 051 Patent. Indeed, the matter is effectively admitted, at least by Apotex for the 5 and 10 mg doses. Threatened infringement is established pursuant to s 117(1), by force of s 117(2)(c).
Further, there can be no dispute that the generic parties, as suppliers, have reason to believe (and, indeed, know) that the 5 and 10 mg dosage forms of their generic products will be used in methods of treatment having the integers of each claim of the 051 Patent.
…In this respect, the knowledge of the generic parties is established, amongst other matters, by the PI documents for their proposed generic products and the evidence of Drs Hay and Wilson, who each explain that 5 and 10 mg doses of rosuvastatin are prescribed and administered for the purpose of treating hypercholesterolemia in accordance with the methods of treatment in claims 1 to 3 of the 051 Patent.
As to the proposed supply by the generic parties of the 20 and 40 mg dosage forms of rosuvastatin, AZ said:
The same position applies to the 20 and 40 mg dosage forms of the generics' products, which will be split by patients (both at the direction or with the knowledge of their doctors and at their own initiation) to obtain 5 and 10 mg doses for use in the methods of treatment claimed in claims 1 to 3.
…
Indeed, Watson’s PI and its Consumer Medicine Information expressly contemplate, and encourage, the splitting of such tablets [the product information says “The 10, 20 and 40 mg tablets can be divided into equal halves. The 5 mg tablets are NOT intended for 2.5 mg dosing.”].AZ referred to the evidence of Dr Hay and Dr Wilson to the effect that they prescribe AZ’s product, Crestor:
in the knowledge that their patients will split the tablets into smaller doses, and in many cases specifically instruct their patients to do so, including so that patients will save money when purchasing their prescriptions. As each prescription costs patients the same, regardless of the dose, patients can significantly reduce their medication costs by splitting tablets and making each prescription last longer.
AZ referred to the evidence of Mr Divesh Sanghvi, an experienced pharmacist who was not required for cross-examination, who said rosuvastatin is among the medicines for which patients are most likely to engage in pill splitting, as well as the evidence about readily available pill splitting devices, including one for splitting into quarters, and that:
IMS Health (IMS) data further confirms the existence of tablet splitting including in respect of 20 and 40 mg CRESTOR tablets. For the purposes of its business, IMS relevantly collects, stores and utilises data obtained from a rolling panel of general practitioners, which includes information recorded on prescriptions. For the 24 month period ending 30 March 2012, IMS data records some 22,220 prescriptions for 20 mg CRESTOR tablets that included a recorded direction to take “half a tablet”. This equated to 2.75% of total prescriptions for 20 mg CRESTOR. The figure of 22,220 prescriptions is necessarily under-representative of the extent of tablet splitting since, for example, IMS data will not pick up tablet splitting that occurs other than as may be recorded on a written prescription, for example pursuant to oral directions or advice provided by a doctor, or where the tablet splitting occurs at the patient’s own volition.
AZ observed that:
the prevalence of the practice of splitting rosuvastatin tablets will inevitably further increase if 20 and 40 mg generic products are marketed, because such products will be supplied to patients at substantially less cost (in some instances, possibly even at no cost) compared to the price of [AZ]’s 5 and 10 mg CRESTOR product, thereby creating a significantly stronger price incentive to split larger doses.
According to AZ, and contrary to the generic parties’ case, rosuvastatin is not a staple commercial product. It is rather “a specialised product that is used for a specific medical purpose”. As AZ put it:
The reference in s 117(2)(b) to the supply of a "staple commercial product" means a product that is supplied commercially for various uses: Northern Territory v Collins (2008) 235 CLR 619 [[2008] HCA 49;] at [27], [41], [48], [50] and [145]; [Apotex Pty Ltd (No 3)] at [270]. As submitted below, specific pharmaceutical products that are supplied for the purpose of oral administration to treat disease fall outside the scope of the concept of a product that is supplied commercially for various uses.
AZ also noted that:
The product at issue in Collins, unmilled timber, readily fits the description of a “staple”, within the plain English and dictionary definitions noted above. Timber is also clearly a product (being a raw material) that is supplied for a vast multitude of commercial uses. It comfortably fits within the description of a “staple commercial product” within the meaning of s 117(2)(b).
By contrast, the generic rosuvastatin product the subject of the generic parties’ PIs is very far removed from unmilled timber, or any similar raw material. Rather, the generic rosuvastatin product (claiming bioequivalence to the CRESTOR product) is a complex, synthesised pharmaceutical formulation that is relevantly designed for the two medical treatment uses specified in the generic parties’ PIs. To speak about such an article as being a “staple commercial product” runs counter to common sense. Such an article is not within the ordinary meaning of the word “staple”. A "staple" commercial product is something such as timber, iron ore, rice or wheat, each of which has a number of uses and can be used to make a variety of other things.
AZ also submitted that the generic parties cannot properly call in aid alleged uses beyond those contemplated in their respective product information (which is directed in each case to the treatment of hypercholesterolemia). AZ said: - (i) the questions asked in cross-examination of Dr Hay and Dr Wilson were non-specific and related to “statins” generally, rather than to rosuvastatin, (ii) the generic products are not indicated for any conditions additional to those specified in their product information, and (iii) properly viewed, the generic party is (in each instance) the only relevant supplier.
AZ also put an argument in these terms:
[AZ] does not license medical practitioners or the generic parties to practise a method of treatment that involves administering 5 to 10 mg of its CRESTOR product as the “starting dose”, followed by a higher dose of a competitor’s generic product.
…
The instructions given by the generic parties to doctors to administer a 5 or 10 mg starting dose thus constitute an inducement or permission to practise the claimed invention in a way that is not authorised by [AZ]. [AZ] respectfully maintains the submission, not accepted by the Court at the interlocutory level, that such conduct amounts to infringement under s 13 (by authorisation) or by applying the principles of joint tortfeasorship.
11.2 Generic parties’ case
The generic parties submitted that the supply of 20 mg and 40 mg tablets of rosuvastatin would not fall within the scope of the 051 or low dose patent.
As to the factual question of tablet splitting, Watson and Ascent said that is no evidence to suggest that 40 mg tablets will be divided to make 4 x 10 mg doses. Dr Wilson had not heard of this happening for rosuvastatin. Indeed:
The dividing of doses of 40 mg rosuvastatin into 10 mg doses has not been proven as a reality much less to the requisite extent to show the generic parties reason to believe.
In terms of the splitting of the proposed 20 mg tablets of the generic parties into two doses of 10 mg each, The generic parties noted: - (i) it is clear that the vast majority of patients do not split tablets and that patients take the dosage supplied to them by the manufacturer without adulteration by pill splitting, and (ii) it is also clear that while some, a small proportion of patients, split tablets, most practitioners do not encourage the practice due to compliance and degradation concerns. Given these facts, there is an insufficient evidentiary foundation for the generic parties to have reason to believe that a patient prescribed their products will split the 20 mg dose into two 10 mg doses in order to treat their hypercholesterolemia.
Further, the generic parties characterised s 117(2)(b) of the Act as imputing infringement “where a product is supplied in the circumstance of a reason to believe by the supplier about the use to which a particular primary infringer (“the person” in paragraph (b)) would put the product to the infringing use”. AZ’s case, however, involves a general proposition that “some unidentifiable persons within the class of persons supplied with generic rosuvastatin will split tablets of 20 mg (and 40 mg)”. Watson and Ascent submitted:
It is not sufficient that a person supplied the “product” by Watson and Ascent may split the rosuvastatin and put it to an infringing use. To make Watson and Ascent liable for any infringement under section 117 of the Act it must be shown that the reason to believe relates to the fact that the person being supplied would, in fact, put it to that use.
Furthermore, even if the tablet is split, it must still be shown that there is a reason to believe that the split tablet would be used in the treatment of hypercholesterolemia to be within the scope of the claims; a split tablet may just as well be used to treat diabetes or another condition discussed by Drs Wilson and Hay. This provides another reason why it cannot be said the 20 mg tablet would be put to an infringing use.
The generic parties also contended that as they would be supplying a product of 20 and 40 mg of rosuvastatin, the act of a patient in splitting such a tablet so as to create 5 and 10 mg has the effect of creating a new product. They submitted:
Section 117 of the Act does not encompass such a situation where the product supplied is different to the product actually used.
…
The allegation of infringement made against Watson and Ascent does not relate to the use of 20 mg dosage of rosuvastatin - it is clear that such a dosage would not infringe the patent under the clear wording of section 117 of the Act. Section 117 of the Act does not by its wording cover a situation where a product is supplied, modified or adulterated by the person (for example, by pill splitting) to change it into a new dosage and then used in an infringing manner.In any event, the generic parties contend that rosuvastatin is a staple commercial product. Rosuvastatin, on the evidence, is “used to treat various different conditions or for other effects including (i) pleomorphic (anti-inflammatory) effects to reduce the incidence of plaque rupture and heart attacks; (ii) treatment of diabetes; (iii) treatment of stroke; (iv) treatment of chronic renal disease; and (v) coronary artery disease or peripheral vascular disease”. Further, the “most common group of patients seen by Dr Wilson appear not to be hypercholesterolemia patients but those requiring secondary prevention such patients with coronary artery disease or peripheral vascular disease and diabetes independent of their cholesterol level”. As rosuvastatin can be used in various non-infringing ways, it is a staple commercial product by analogy to the reasoning in Northern Territory v Collins (2008) 235 CLR 619; [2008] HCA 49 (Collins).
The generic parties also referred to an observation of Keane CJ in Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (No 2) (2012) 204 FCR 494; [2012] FCAFC 102 at [56] that s 117 of the Act is not engaged where the patent is in respect of a method of treatment. Keane CJ noted that in such a case the medical practitioner may not be doing any act within the meaning of the definition of “exploit” in s 13, “[i]n particular, the medical practitioner would neither be using a product (as opposed to a method) or doing any act in respect of a product “resulting from” the use of the patented method. One attraction of this argument would be that it prevents the effective renewal of the expired patent for the product”. As an argument to this effect was disclaimed in the hearing in Apotex (No 2), the Court did not need to resolve it. In the present case, the argument is pressed on the basis that:
if the Low Dose Patent is valid and there is invention in the administration of 5 to 10 mg dosages that monopoly resides in the method of treating hypercholesterolemia using that dosage. It does not reside in the 5 mg or 10 mg dosages per se and, even further removed, the operation of section 117 of the Act should not be available to restrict the supply of 20 mg and 40 mg dosages.
The generic parties also challenged the legal and factual foundation of the claim of joint tortfeasorship. As the generic parties have proposed measures (in effect, instructions to medical practitioners not to permit tablet splitting) it cannot be said that the generic parties have engaged in an agreed or common action with persons who may choose to split tablets. Finally, the mere supply of a product does not amount to authorisation.
11.3 Discussion
I have found that all of the claims of the 051 or low dose patent are liable to revocation on various grounds. Accordingly, the question of infringement does not arise. It is nevertheless appropriate to deal with the issues in any event, albeit in an abbreviated form in recognition of the conclusions I have reached as to invalidity of this patent.
Apart from the argument based on the observations of Keane CJ in Apotex (No. 2), there is no real question on the evidence that the proposed supply of the 5 and 10 mg doses of the generic rosuvastatin products of each of Apotex, Watson and Ascent would involve exploitation of the method of treatment claimed in the 051 or low dose patent. Apotex effectively admits as such, as AZ said. This is because the product information for each generic rosuvastatin product directs such use, so that s 117(c), at the least, is engaged.
Although I can see the attraction of the argument which was considered by Keane CJ in Apotex (No. 2), in particular that it would ensure that AZ cannot claim a monopoly over rosuvastatin in Australia when there has never been a patent for rosuvastatin in Australia, I have difficulty in reconciling this approach with the words of s 117. The difficulty is that there is still use of the product (being the generic parties’ rosuvastatin products in 5 and 10 mg doses) within the meaning of s 117(1) even though that use is part only of the claimed method of treatment. As such, I do not accept this argument. It follows that, if the 051 or low dose patent were valid, AZ would have proved threatened infringement in respect of the proposed supply of the 5 and 10 mg doses by each of the generic parties.
The 20 and 40 mg doses involve other issues. I will deal with the 40 mg dose first because this can be resolved at the level of fact. I am aware of that the evidence includes one pill splitter that indicates it can be used to cut tablets into quarters. I am aware also of the real economic incentives that a patient might have to make their medication go further because they will pay no more for a 40 mg dose compared to lower doses. Ultimately, however, whether a person would use the product (the 40 mg generic products) within the claims of the 051 or low dose patent which is limited to 5 and 10 mg is an issue for AZ to prove. I am not satisfied on the evidence that any person could, let alone would, attempt to divide a single tablet into four in order to obtain four 10 mg doses irrespective of the size of the economic incentive to do so. I cannot say the same for the 20 mg tablet which I infer could readily be divided into two 10 mg doses using a pill splitter. I am also satisfied given the ease of tablet splitting by using a pill cutter, whether the tablet be scored or unscored, and the economic incentives, that there is a risk that some people will obtain the 20 mg dose of the generic tablets for the purpose of dividing them into two 10 mg doses. I also infer that this risk will exist irrespective of any instructions the generic parties might send to medical practitioners and pharmacists not to endorse tablet splitting in any way because, ultimately, the obligation of medical practitioners and pharmacists is to their patients and not to drug companies who want to try to avoid patent infringements. The risk also remains despite Apotex’s product information directing against tablet splitting.
All of this said, the question of infringement (assuming validity) remains. As to this question, I am not satisfied the generic parties’ products are “capable” of only one reasonable use within the meaning of s 117(2)(a). On the evidence rosuvastatin has a range of medical uses. Whatever the product information of the generic parties, which focuses on hypercholesterolemia, medical practitioners prescribe and thus patients use rosuvastatin for a variety of uses, albeit all uses associated with disease states in humans, either actual or prospective. I do not accept AZ’s submission that the evidence of those other uses should not be inferred to relate to rosuvastatin just as much as any other statin or is irrelevant due to the product information. Hence, s 117(2)(a) is not engaged.
Section 117(2)(c) is also not engaged. Despite the reference to the tablets being able to be divided in the Watson and Ascent product information, on the whole of the evidence, including the proposed communications with medical practitioners and pharmacists, it cannot be said that the generic parties will instruct or induce any person to split a 20 or 40 mg tablet into two or four.
This leaves s 117(2)(b). Despite the fact that I accept that rosuvastatin has a number of medical uses, not just the treatment of hypercholesterolemia, I cannot accept that it should be characterised as a “staple commercial product”. The difficulty I have arises from the word “staple”, which does indicate something more than merely a “commercial product”. The reasoning in Collins does not lead me to the view that the fact that a product can be used in one or even a number of non-infringing ways is itself sufficient to make the product a staple commercial product. While “staple” is not concerned with the economic significance of uses, it is concerned with the variety of uses. The variety of uses in this case is confined by the nature of the product to a limited class, being the treatment of diseases of a particular kind or class (albeit different diseases) in humans. Rosuvastatin, despite its usefulness for a variety of disease conditions, is not able to be compared to timber (as in Collins) or, for example, types of pharmaceutical products which might be useful for many human conditions. It is for these reasons I conclude that the rosuvastatin products proposed to be supplied by the generic parties are not staple commercial products.
I do not accept that s 117(1) and (2)(b) requires AZ to prove that any particular person will split a 20 mg tablet into two 10 mg doses. In the present case the evidence is sufficient to infer that whatever the instructions the generic parties give to medical practitioners and pharmacists there remains a risk that some people will obtain the 20 mg dose of the generic tablets for the purpose of dividing them into two 10 mg doses. Risk, however, is one thing. Proof on the balance of probabilities that any person “would” infringe the 051 or low dose patent is another. Given the steps proposed by the generic parties to instruct medical practitioners and pharmacists not to endorse or encourage tablet splitting, it is a long stretch on the currently available evidence to conclude that any person would split the tablets into 10 mg doses and thereby infringe the patent. I accept that AZ has proved a real risk that it might occur, given the economic incentives. But in terms of proof that is insufficient.
As to the additional arguments, joint tortfeasorhip, authorisation and directions to use AZ’s low dose products and then swap (the last argument), it is sufficient to say that they are not established on the facts. The generic parties propose to do what they can to stop infringement and thus are not joint tortfeasors and do not authorise any infringement. The last argument is one which I cannot grasp. It remains unclear to me how any use of AZ’s own product could ever constitute an infringement of AZ’s patent.
For these reasons, if the 051 or low dose patent is valid (contrary to my view), I am satisfied that AZ has established that the generic parties threaten infringement of the patent to the extent that they propose to supply the 5 and 10 mg doses of their products. I do not accept that AZ has established any threatened infringement in respect of the 20 or 40 mg doses for the reasons given above.
12. INFRINGEMENT OF THE 165 OR HEFH PATENT
It is not in dispute that the rosuvastatin products of the generic parties will be therapeutically appropriate to treat HeFH. As discussed, it is part of the case of the generic parties (which I have accepted) that all statins treat HeFH to some extent and rosuvastatin, as a powerful statin, is particularly well-suited to treat HeFH.
AZ contended that the generic parties threaten to infringe claims 1 to 10 and 21 of the 165 or HeFH patent. The generic parties propose to exclude HeFH from the indications for their products and to notify medical practitioners and pharmacists to this effect. That said, it is also the case that the generic products will remain suitable for use to treat HeFH and medical practitioners do not always, or even often, prescribe by brand name as opposed to compound when different brands of the same compound are on the market.
In respect of this issue (in common with the conclusions I have reached about the 20 and 40 mg doses of the generic products as set out above) I do not in the ultimate analysis find AZ’s case for infringement as persuasive as I did at the interlocutory stage. First, s 117(2)(a) is not engaged as the generic parties’ rosuvastatin products will have more than one reasonable use, as described. Second, s 117(2)(c) is not engaged as the generic parties (or Apotex and Watson in any event) have excluded the treatment of HeFH from the product information for their products and thus can hardly be said to be instructing or inducing infringement. As to s 117(2)(b), I remain of the view that “doctors and pharmacists should not be burdened by court-mandated instructions from a pharmaceutical company that have no therapeutic efficacy or safety purpose and which are intended to do nothing other than to aid the pharmaceutical company to avoid an alleged patent infringement” (Apotex Pty Ltd v AstraZeneca AB (No 3) (2012) 95 IPR 581; [2012] FCA 265 at [20]). But this is a policy view and the question is not whether the generic parties have proved that their will be no infringement, but whether AZ has proved that, in the face of the product information, a generic rosuvastatin product will be used by some person to treat HeFH. In the case of Apotex and Watson that inference cannot be drawn given the terms of their product information.
Ascent’s case may be different in that the product information for the Ascent product includes HeFH. As the question is hypothetical, given my conclusions that the claims of this patent (specifically, claims 1 to 10 and claim 21, but also all claims dependent on claim 1) are invalid, this is an issue where, if necessary, I would seek further clarification from Ascent as to its position, the result of which if Ascent adopted a position common to that of Apotex and Watson) would result in my conclusion of non-infringement also for Ascent. This is unnecessary given my conclusions as to invalidity.
For these reasons I am not satisfied that AZ has proved threatened infringement of the 165 or HeFH patent on any of the bases argued.
13. INFRINGEMENT OF THE 842 OR CATION PATENT
For the reasons already given I have also concluded that claim 1 of the 842 or cation patent and all dependent claims are invalid and liable to be revoked. In the course of reaching this conclusion I preferred AZ’s construction of the integers of claim 1. Accordingly, I did not, and for the purpose of infringement do not, accept the generic parties’ construction of claim 1 of this patent.
On the basis of this preferred construction it is apparent that, if claim 1 and the dependent claims of the 842 or cation patent are valid, then the generic rosuvastatin products, excluding only the alternative product proposed by Apotex which does not use titanium dioxide or ferric oxide in the coating, would infringe claim 1 and the dependent claims.
14. CONCLUSIONS
For the reasons given I consider that all of the claims of the 051 or low dose patent are invalid and that the patent should be revoked. The claims on which AZ relies to assert infringement of the 165 or HeFH patent (claims 1 to 10 and 21) and the 842 or cation patent (claims 1 to 5, 7 to 9 and 10 to 18) are also invalid and liable to be revoked, although there is a question whether any of the claims of these patents can be sustained given the conclusions I have reached as set out above.
The generic parties should immediately be released from any undertakings and interlocutory injunctions that they have given or by which they are bound. AZ’s applications for relief against infringement should be dismissed. The invalid claims of the patents in question should be revoked but it is also appropriate that I hear the parties further on the form of orders for revocation that should be made in all of the circumstances. Costs may be resolved pursuant to other directions that can be made as required.
I certify that the preceding five hundred and twenty three (523) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Jagot. Associate:
Dated: 5 March 2013
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