Laboratoires Servier, Adir, Oril Industries, Servier Canada Inc. v. Apotex Inc.

Laboratoires Servier, Adir, Oril Industries, Servier Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2008-07-02
Neutral citation
2008 FC 825
File numbers
T-1548-06
Notes
Digest
Decision Content
Date: 20080702
Docket: T-1548-06
Citation: 2008 FC 825
Ottawa, Ontario, July 2, 2008
PRESENT: The Honourable Madam Justice Snider
BETWEEN:
LES LABORATOIRES SERVIER,
ADIR, ORIL INDUSTRIES,
SERVIER CANADA INC.,
SERVIER LABORATORIES
(AUSTRALIA) PTY LTD and
SERVIER LABORATORIES LIMITED
Plaintiffs
(Defendants by Counterclaim)
and
APOTEX INC.
and
APOTEX PHARMACHEM INC.
Defendants
(Plaintiffs by Counterclaim)
REASONS FOR JUDGMENT AND JUDGMENT
I. Introduction
A. Overview
[1] The Plaintiffs (described below and collectively referred to as Servier) manufacture, distribute and sell a drug with the trademark of COVERSYL, used primarily in the treatment of
hypertension and cardiac insufficiency. The active ingredient in COVERSYL is perindopril, a compound covered by Canadian Patent No. 1,341,196 (the '196 Patent), which patent is owned by one of the Plaintiffs, ADIR. The other Plaintiffs – all corporate affiliates of ADIR – are engaged in some aspect of the distribution, manufacture or sale of COVERSYL in a number of countries throughout the world, including Canada.
[2] Since at least 2006, one of the Defendants, Apotex Pharmachem Inc. (Pharmachem), has manufactured a generic version of perindopril erbumine tablets at its facility in Brantford, Ontario, in 2 mg, 4 mg and 8 mg strengths, and tablets containing a combination of perindopril erbumine and indapamide (a diuretic). The products are sold to the other Defendant, Apotex Inc., which company, in turn, sells the 8 mg tablets in Canada and exports all dosages and the combination product to affiliated companies and others abroad.
B. Basis of the Claim and Counterclaim
[3] Servier asserts, in this action, that Pharmachem and Apotex Inc. (jointly referred to as Apotex) infringe its '196 Patent by the manufacture of all perindopril products in Canada and by the sale of the 8 mg tablets in Canada. Further, Servier claims that Apotex Inc. has induced others to infringe the '196 Patent.
[4] In its defence and counterclaim, Apotex asserts that all of the Plaintiffs with the exception of Servier Canada Inc. (Servier Canada) and ADIR have no standing to bring this action.
[5] While Apotex does not explicitly deny that its perindopril products fall within the claims of the '196 Patent, it contends that the patent is invalid because:
· the invention disclosed by the '196 Patent is not inventive in light of prior disclosures and the common general knowledge;
· ADIR was not the first inventor of the subject matter of the patent;
· the promised utility of the invention fails; and
· most of the claimed compounds had not been made and tested as of the application date in Canada and there was no sound basis to predict that they could be made and would have the promised utility.
[6] Apotex further argues that the manner in which ADIR obtained the '196 Patent should disentitle it to enforce that monopoly, even if otherwise valid. The '196 Patent was ultimately obtained by ADIR only after conflict proceedings which were ultimately resolved by a court-endorsed agreement among ADIR and two other parties. As a result of the manner in which the patent was obtained, Apotex claims damages pursuant to s. 36 of the Competition Act, R.S.C. 1985, c. C-34 (the Competition Act), in respect of an alleged breach of s. 45 of the Competition Act.
[7] Finally, Apotex argues, even if claim 5 – as it stands today – of the '196 Patent is otherwise valid, the proper scope of the monopoly granted thereby is not that defined in the twice-corrected claim 5. Apotex argues that the twice-corrected claim 5 is invalid because it is the result of the two certificates of correction which were not obtained in accordance with s. 8 of the Patent Act, R.S.C. 1985, c. P-4.
C. Overview of Conclusion
[8] For the reasons expressed in these Reasons for Judgment, and in very general terms, my overall conclusions are that:
· only ADIR, as patentee, and Servier Canada, who claims under the patentee, have standing to bring this action;
· the '196 Patent is valid and infringed by Apotex through the manufacture, in Canada, of the 2 mg, 4 mg and 8 mg strengths and the combination tablets and through the manufacture and sale in Canada of the 8 mg tablets;
· Apotex has not induced others to breach the '196 Patent; and
· Apotex fails in its claim for damages under the Competition Act.
D. Applicable Law
[9] The application leading to the patent in this proceeding was filed in Canada on October 1, 1981. According to s. 78.1-78.2 of the present Patent Act, patent applications filed before October 1, 1989, are to be dealt with under the provisions of the Patent Act as they read immediately before that date. Accordingly, references in these reasons to the Patent Act (referred to as the Patent Act or the Act) will, unless specifically noted otherwise, be to the Act as it stood immediately prior to October 1, 1989.
E. Table of Contents
[10] For assistance to the reader, I have set out a table of contents of these reasons for judgment.
I. Introduction ................................................................................... [1 ] to [10]
A. Overview ....................................................................................... [1]
B. Basis of the Claim and Counterclaim ............................................... [3]
C. Overview of Conclusions................................................................. [8]
D. Applicable Law............................................................................... [9]
E. Table of Contents ......................................................................... [10]
II. Witnesses...................................................................................... [11] to [38]
A. Factual Witnesses ........................................................................ [12]
B. Expert Witnesses.......................................................................... [21]
(1) Servier Expert Witnesses .................................................. [22]
(2) Apotex Expert Witnesses ................................................. [29]
(3) General Comments on the Expert Witnesses...................... [35]
III. Background................................................................................... [39] to [66] .......................................................................................................................
A. Background to ACE Inhibitors, including Perindopril...................... [39]
(1) ACE Inhibitors Generally................................................... [39]
(2) History of ACE Inhibitors.................................................. [43]
(3) Schering’s Work on ACE Inhibitors ................................. [50]
(4) ADIR’s Development of Perindopril.................................. [56]
(5) Conflict Proceedings ........................................................ [63]
IV. Standing ....................................................................................... [67] to [95]
A. Overview...................................................................................... [67]
B. Statutory Provision ....................................................................... [69]
C. Jurisprudence and Principles ......................................................... [70]
D. The Evidence before the Court ..................................................... [78]
E. Conclusion ................................................................................... [95]
V. Claims Construction .................................................................... [96] to [133]
A. The Law of Claims Construction ................................................... [96]
B. Application of Principles to the Case at Bar ................................ [101]
(1) Person Skilled in the Art ................................................. [101]
(2) Construction of the Claims at Issue ................................. [105]
(a) Description......................................................... [108]
(b) The Claims at Issue............................................. [120]
(3) Apotex’s Argument that there is but one “Invention” ........ [125]
VI. Infringement .............................................................................. [134] to [173]
A. Overview ................................................................................... [134]
B. Direct Infringement ..................................................................... [135]
C. Inducement................................................................................. [139]
(1) The Test for Inducement.................................................. [141]
(2) Was the Act of Infringement completed by the
Direct Infringer? ............................................................. [142]
D. Exemptions from Liability ........................................................... [161]
(1) Statutory Provisions ....................................................... [161]
(2) Experimental and Regulatory Use ................................... [162]
(3) Other Exemptions .......................................................... [169]
(4) Conclusion on Exemptions .............................................. [172]
VII. Claim 5 Corrections................................................................... [174] to [222]
A. Overview ................................................................................... [174]
B. Background to the Issue ............................................................. [177]
C. Statutory Authority of the Commissioner ..................................... [186]
D. Must Apotex Proceed by way of Judicial Review?....................... [187]
E. Standard of Review of a Commissioner’s Decision ...................... [199]
F. Was either of the Decisions of the Commissioner
Unreasonable? ........................................................................... [210]
G. Conclusion on this Issue.............................................................. [222]
VIII. Obviousness ............................................................................ [223] to [266]
A. The Law..................................................................................... [223]
B. The State of the Art..................................................................... [229]
C. Position of the Parties ................................................................. [241]
D. Application of the Law to Facts .................................................. [244]
(1) Obviousness of the 6,5 bicyclic ring................................. [244]
(a) The Invention ..................................................... [248]
(b) The Skilled Person ............................................. [251]
(c) Body of Knowledge ........................................... [252]
(d) Climate in the Field ............................................. [253]
(e) Motivation ......................................................... [257]
(f) Time and Effort .................................................. [260]
(g) Commercial Success........................................... [261]
(h) Meritorious Awards............................................ [262]
(2) Obviousness of linear alkyl side chain .............................. [264]
E. Conclusion ................................................................................. [266]
IX. Utility ....................................................................................... [267] to [343]
A. Overview ................................................................................... [267]
B. Promise of the Patent ................................................................. [273]
(1) Position of Apotex ......................................................... [274]
(2) Position of Servier .......................................................... [278]
(3) Analysis ......................................................................... [281]
C. The 1992 Vincent Article ........................................................... [295]
(1) The Context of the 1992 Vincent Article.......................... [296]
(2) Table I in the 1992 Vincent Article.................................. [301]
(3) Dr. Laubie’s Admission .................................................. [304]
(4) The Purpose of the 1992 Vincent Article......................... [311]
(5) The Underlying Data ...................................................... [314]
(6) Dr. Vincent’s Testimony ................................................. [317]
(7) Conclusion in Respect of the 1992 Vincent Paper ........... [319]
D. Dr. Gavras’s Testing Report ....................................................... [320]
(1) Description of the Testing ............................................... [321]
(2) Apotex’s Argument ........................................................ [329]
(3) Apotex’s Underlying Premise.......................................... [330]
(4) Problems with the Testing Methodology .......................... [342]
(5) Conclusion on the Gavras Report ................................... [343]
E. Conclusion on Utility.................................................................. [343]]
X. Sound Prediction....................................................................... [344] to [380]
A. Overview.................................................................................... [344]
B. Prediction of Utility of the (R,R,R) Compounds ........................... [352]
C. The “Trans” Compounds ............................................................ [369]
D. Conclusion ................................................................................. [380]
XI. Inventorship............................................................................... [381] to [456]
A. Overview.................................................................................... [381]
B. Relevant Statutory Framework under the Patent Act .................. [385]
C. Interpretation of s. 61(1)(b) ........................................................ [393]
(1) General Comments and Position of Parties ...................... [393]
(2) The Context of Conflict Proceedings ............................... [399]
(3) Intent of Parliament ........................................................ [404]
(4) The Object of the Patent Act ......................................... [411]
(5) Relevant Jurisprudence ................................................... [417]
(6) Conclusion on this Issue ................................................. [426]
D. Was there a Missed Conflict? ..................................................... [428]
E. Who was the First Inventor of the '196 Patent? ........................... [440]
F. Summary of Inventorship Issue ................................................... [456]
XII. Competition Act Claim............................................................. [457] to [494]
A. Overview ................................................................................... [457]
B. Relevant Statutory Provisions ..................................................... [460]
C. The Existence of the Patent as a Bar ........................................... [463]
D. Limitation Period ........................................................................ [479]
E. Conclusion ................................................................................. [491]
XIII. Remedies.................................................................................. [495] to [517]
A. Overview ................................................................................... [495]
B. The Bifurcation Order................................................................. [497]
C. Permanent Injunction .................................................................. [498]
D. Damages or Profits ..................................................................... [502]
E. Interest....................................................................................... [512]
F. Punitive or Exemplary Damages................................................... [514]
G. Conclusion ................................................................................ [516]
XIV. Overall Conclusion.................................................................................. [518]
II. Witnesses
[11] During 30 days of testimony in this trial, a number of witnesses – both factual and expert – were heard by the Court. In the following paragraphs, I will provide a brief overview of the witnesses and the areas to which they testified. Further particulars of the evidence will be provided as necessary throughout these reasons.
A. Factual Witnesses
[12] Servier presented a number of employees of the Servier group of companies (referred to as Groupe Servier) as fact witnesses:
· Mr. Michael Sumpter is the chief executive officer of Servier Canada. He spoke to the operations of Servier Canada and its relationship with the Groupe Servier entities. Mr. Sumpter also appeared later in the proceedings to discuss marketing strategies of Servier Canada.
· Dr. Sylvie Jaguelin, who now holds the title of « directeur des brevets » in Les Laboratoires Servier (LLS), joined Groupe Servier in 1985. She spoke to her role during the conflict proceedings, the settlement discussions and the subsequent corrections to claim 5 of the '196 Patent.
· Dr. Yves Langourieux is currently the managing director of Servier International and is in charge of Groupe Servier’s operations for a geographic sector covering North America, Northern Europe, Central Europe and Eastern Europe. He has been with Groupe Servier since 1977. In addition to being a trial witness, he was discovered by Apotex during the pre-trial process. He spoke to the corporate structure of Groupe Servier.
· Dr. Guillaume de Nanteuil is the director of the division of medicinal chemistry for Groupe Servier. He presented, as business records, and explained a number of the laboratory and working notes related to the development of perindopril. Dr. de Nanteuil was also a discovery witness.
[13] Servier also produced Dr. Michel Vincent, who is one of the named inventors of the '196 Patent. Dr. Vincent is now retired from Groupe Servier. He testified on his role in the invention, including the laboratory work leading to the application of the patent and his continuing laboratory work post-application.
[14] Apotex presented a number of witnesses who spoke to the development by Apotex of its perindopril generic compounds, the formulation steps in making perindopril and the experimental testing and use of perindopril. They were: Mr. Stephen Horne, vice-president of research and development at Pharmachem; Mr. Donald John Barber, formulation manager of Apotex Inc.; Mr. John Leslie Hems, director of regulatory affairs for Apotex Inc.; and, Mr. Lance Lovelock, vice-president of quality for Apotex Inc.
[15] A number of Apotex officers or employees testified on the subject of Apotex’s corporate structure and operations:
· Dr. Bernard Sherman is the founder of Apotex. He spoke to a number of topics including: Apotex’s product development process; the role of affiliated international companies; Apotex’s production facilities in India; and, markets for perindopril and ACE inhibitors.
· Mr. Colin Darroch is the managing director of Apotex U.K. Ltd. (Apotex UK). He described the contractual arrangements in place with Apotex Inc. for the selling of perindopril in the United Kingdom.
· Mr. Roger Millichamp is the managing director of Apotex Pty Ltd (previously GenRx Pty Ltd. and referred to as GenRx). He described the arrangements in place with Apotex Inc. for the selling of perindopril in Australia, the regulatory process in Australia (including the approvals necessary for the production of perindopril in Apotex’s India facilities) and Australian litigation involving GenRx and Servier.
· Mr. Gordon Fahner is the vice-president finance for Apotex Inc. He was a very helpful and informative witness on the global operations of Apotex Inc. and its affiliates, from a financial perspective. He also provided evidence on the shipping transactions involved in international sales to affiliates.
[16] Under subpoena, Mr. J. Nelson Landry appeared as an Apotex fact witness. Mr. Landry, now of counsel to Ogilvy Renault, was the lawyer of record and patent agent for Servier during the conflict proceedings. He spoke to two related issues: (a) the translation of claim 5 from English to French for purposes of the '196 Patent; and (b) the two corrections made to claim 5 in the '196 Patent. The subpoena for Mr. Landry was the subject of a motion to this Court; that motion was dealt with in Laboratoires Servier v. Apotex Inc., 2008 FC 321.
[17] Dr. Elizabeth Smith was a fact witness who appeared in Newark, New Jersey, under Commission of this Court, made upon application by Apotex. Dr. Smith, who was and is an employee of Schering Corporation (Schering), is one of the named inventors of Canadian Patent No. 1,341,206 (the '206 Patent). The '206 Patent was issued to Schering as a result of the conflict proceedings and a consent order of Justice Nadon (discussed later in these reasons). Her testimony dealt with her involvement with the development of the Schering claims that became part of the conflict proceedings and her role in those proceedings.
[18] Under subpoena, Mr. Joel Patrick Roche appeared as an Apotex fact witness. He was counsel to the plaintiff, Sheila Wilson, in a class action commenced before the Ontario Superior Court of Justice in Court File No. 98-CV-158832. The named defendants in that action included a number of entities who are part of Groupe Servier.
[19] For completeness, I refer to two Apotex fact witnesses whose testimony was not referred to during final argument. Dr. Edward Lee-Ruff, a professor at York University, and Dr. Gabriella Mladenova, a post-doctoral student at York University, conducted certain experiments, at the request of counsel for Apotex. The experiments were intended to recreate the results of the '196 Patent.
[20] Another Apotex witness whose testimony was not explicitly referenced in final argument was Ms. Nadia Corelli-Rennie, the supervisor of special projects at Pharmachem. She produced the samples of compounds that were sent to Dr. Gavras, an Apotex expert, for testing.
B. Expert Witnesses
[21] This being a patent infringement action with counterclaims of invalidity and Competition Act offences, experts produced by both Apotex and Servier were very helpful to the Court. For purposes of this introductory section of the reasons, I will provide a very brief description of the witnesses’ education and experience and the areas for which this Court found them to be qualified.
(1) Servier Expert Witnesses
[22] Dr. Paul Bartlett is a professor emeritus of chemistry at the University of California, Berkeley. Dr. Bartlett was qualified by the Court as an expert in synthetic chemistry and as a medicinal chemist. Of particular relevance to the issues remaining at the end of the trial, he provided evidence on the issues of claims construction, infringement, utility, sound prediction, obviousness and inventorship.
[23] Dr. Barry Trost is a professor of chemistry at Stanford University. He was accepted by the Court as an expert in synthetic organic chemistry, including processes for making compounds having medicinal use. Of particular relevance, Dr. Trost provided evidence on the issues of obviousness and sound prediction.
[24] Dr. Christopher Cimarusti, retired from Bristol-Myers Squibb (Squibb) in 2006 after having worked 37 years in the pharmaceutical industry, has been a consultant to the pharmaceutical and biotech industry since 2006. He was accepted as an expert in synthetic organic chemistry with particular knowledge and experience in medicinal chemistry. Of note, Dr. Cimarusti worked with Drs. Ondetti and Cushman at Squibb at the time when the Squibb scientists invented captopril, the first ACE inhibitor. His opinions and testimony were particularly helpful on the issues of claims construction, utility, obviousness, sound prediction and inventorship.
[25] Dr. Morris Karmazyn was qualified as an expert in the area of cardiovascular pharmacology, including the role of the renin-angiotensin system in cardiac function and the in vivo and in vitro experimental techniques used to assess biological activity of compounds. The main thrust of his expert evidence was directed to the experiments performed by Dr. Gavras (see below). Thus, his testimony is most relevant to the question of utility.
[26] Dr. Zola Horovitz was qualified as an expert in pharmacology with particular experience in the areas of hypertension and ACE inhibition. Since 1994, when he retired after 35 years at Squibb, Dr. Horovitz has been consulting, mostly to the pharmaceutical industry. In 1967, he started up Squibb’s research program that led to the development of captopril. He worked with Drs. Ondetti and Cushman. In addition to commenting on the experiments performed by Dr. Gavras, and thus the question of utility, Dr. Horovitz addressed the issues of obviousness and sound prediction.
[27] Dr. Aslam Anis is a professor of health and economics at the University of British Columbia, within the faculty of medicine. He was qualified as an expert in the field of health economics, with particular expertise in regard to pharmaceutical markets and competition in such markets. He assisted the Court on the issue of the alleged breach of the Competition Act.
[28] Dr. Iain Cockburn was a second economist retained by Servier to address the issue of the alleged breach of the Competition Act. He was qualified as an expert in the field of health economics, with particular expertise in regard to econometrics, pricing, and demand modeling in pharmaceutical markets.
(2) Apotex Expert Witnesses
[29] Dr. Garland Marshall is a professor of biochemistry and molecular biophysics at Washington University. He was accepted as qualified to give expert evidence as a medicinal chemist with expertise in the areas of renin-angiotensin systems, cardiovascular pharmacology and hypertension and, within those areas, particularly with respect to ACE, angiotensin I, angiotensin II, ACE inhibitors and molecular recognition. His main areas of testimony related to the issues in this trial of utility, sound prediction, obviousness and inventorship.
[30] Dr. Eugene Thorsett is an organic synthetic chemist. In 1975, he joined Merck & Co., Inc. (Merck) in their research laboratories in Rahway, New Jersey. Dr. Thorsett was at Merck in 1980 when Merck first disclosed enalapril. He was accepted by the Court as qualified to give expert testimony in respect of organic chemistry, especially organic chemical synthesis and physical organic chemistry as it relates to drug discovery, enzyme inhibitor design, especially proteolytic enzymes of the zinc-metalloprotease class such as ACE. He was also accepted as an expert in pre-clinical drug development. His main areas of testimony were on the issues of utility, sound prediction and obviousness.
[31] Dr. Robert McClelland holds a Ph.D. in chemistry from the University of Toronto, where he was a tenured professor in the chemistry department from 1980 to 2005. He was found to be qualified to provide evidence as an expert in the area of physical organic chemistry, especially reactive intermediates generated in nucleophilic substitution and addition reactions, and in the area of biological and medicinal chemistry, especially the properties of heterocyclic drugs and the syntheses of new analogs. While I accept Dr. McClelland’s qualifications, I note that he has far less experience working within the ACE inhibition field than the other chemistry experts. He spoke to the issues of obviousness, utility, sound prediction and inventorship.
[32] Dr. Haralambos Gavras, a practising physician, is a professor of medicine at the Boston University School of Medicine. He has been intimately involved in the treatment of cardiovascular disease since at least 1972. Dr. Gavras was accepted by the Court as an expert in the treatment of cardiovascular conditions including hypertension and chronic heart failure and the use in pharmacology of ACE inhibitors. He provided the Court with very useful background information on the development of ACE inhibitors and the various treatments of hypertension. However, the main purpose of his testimony was to address the question of utility and to report on his experiments with some of the compounds included in claim 3 of the '196 Patent.
[33] Dr. Hans Brunner, a medical doctor with extensive experience in cardiovascular conditions, was called by Apotex, in reply, to respond to the criticism of Dr. Gavras’s testing methodology. He was accepted as an expert in the treatment of cardiovascular conditions, including hypertension and chronic heart failure, and the use and pharmacology of ACE inhibitors.
[34] Dr. Aidan Hollis is an associate professor of economics at the University of Calgary. Although his Ph.D. thesis work was unrelated to health economics, Dr. Hollis has consulted in and provided advice to the pharmaceutical industry. He was accepted as qualified as an expert in economics with particular expertise in industrial organization and regulatory economics, particularly with reference to pharmaceutical markets and competition therein. As did Drs. Anis and Cockburn, Dr. Hollis provided his expert opinions and testimony on the question of the alleged violation of the Competition Act. He returned after the appearances of Drs. Anis and Dr. Cockburn as part of the reply case of Apotex.
(3) General Comments on the Expert Witnesses
[35] During the course of the trial, comments were made by both sides about the strength of the qualifications or testimony of witnesses for the other side. On the topic of obviousness, for example, each of Apotex and Servier asserted that the other parties’ experts were viewing the question from “hindsight”. The neutrality of more than one witness was impugned. To the extent that I must deal with individual criticisms as I address specific areas of the testimony, I will do so. However, I wish to make a few overall comments.
[36] Expert witnesses are selected by the parties to litigation. It is obvious that a party will not put forward an expert who disagrees with that party’s position in litigation. It frequently happens that an expert who has appeared for a generic company in a litigation matter will not appear as an expert for a pharmaceutical company in the next litigation. The reverse is also true. From this practice, however, it does not follow, in my view, that experts who appear before the Court do so with any inherent bias. The experts that I had the pleasure of seeing in this trial were all eminently qualified in their fields and presented their opinions in a professional manner. That did not prevent any of them from vigorously supporting their own opinions and providing direct criticisms of the experts who came to contrary views.
[37] I wish to comment directly on the general criticisms directed to Dr. Bartlett, Dr. Cimarusti and Dr. Trost. In final argument, counsel for Apotex asserted as follows:
But I am going to submit to My Lady, that if [you] consider my friends' three principal experts, Cimarusti, Bartlett and Trost, you will find, in my submission, that they lacked objectiveness, that they were advocates and that they constantly, constantly volunteered information in defence of their advocated position.
Counsel then passed up a listing of transcript page references for each of these three witnesses that, in his view, showed “Volunteering advocacy, lack of objectiveness, as well as errors, as well as contradictions . . .”.
[38] I disagree with counsel’s characterization of the evidence of these three experts. I will acknowledge that Dr. Bartlett, in his written report, allowed himself to use unprofessional terms in describing the evidence of experts who disagreed with him. He did not need to do that. Further, Dr. Trost appeared, at times, to be evading certain questions during cross-examination; I eventually had to step in to speak to him. For neither witness do I find the problems so significant that I should discount their opinions. I also suspect that, if counsel for Servier had conducted the same exercise of finding instances of advocacy, lack of objectiveness, errors and contradictions for the Apotex experts, their lists would have been just as long.
III. Background
A. Background to ACE Inhibitors including Perindopril
(1) ACE Inhibitors Generally
[39] The experts did not disagree on the organic chemistry and biochemistry applicable to these proceedings. What follows is a very brief outline of that evidence.
[40] Amino acids are the basic building blocks from which living matter is constructed. By combining various numbers and groups of these acids in various configurations, larger structures known as peptides are formed. The bonds between these acids are known as peptide bonds. Still larger groups known as proteins may be formed from such acids.
[41] Enzymes are organisms present in the body that facilitate the conversion of materials such as proteins and peptides into other material. The enzyme that is of interest in this case is the angiotensisn-converting enzyme (ACE). ACE can bind with a compound known as angiotensin I to produce angiotensin II. This conversion increases blood pressure by constricting blood vessels.
[42] The drugs discussed in this case, including perindopril, enalapril, captopril, lisinopril and quinapril are all “ACE inhibitors”. ACE inhibitors, such as perindopril, bind with ACE to prevent the conversion of angiotensin I to angiotensin II; the result is lower blood pressure.
(2) History of ACE Inhibitors
[43] A number of the experts in this trial were present at various critical times during the history of ACE inhibitors and provided very useful evidence. A number of the articles produced in evidence were helpful. I summarize this evidence in the following paragraphs.
[44] Dr. Horovitz, who worked at Squibb from 1967, provided an excellent summary in his report of the early history of ACE inhibitors. The story begins in the late 1960s, when scientists began studying the venom of the Bothrops jararaca, an indigenous Brazilian snake, because it was known to reduce blood pressure. Scientists at Squibb isolated the active compound and synthesized a compound known as teprotide, a peptide. Teprotide was first tested on humans in 1973 and proved to be an effective anti-hypertensive agent in humans. However, teprotide was only effective through intravenous administration.
[45] The transformation of teprotide into an orally-effective ACE inhibitor occurred as a result of work done by a team of scientists working for Squibb, including Drs. Miguel Ondetti and David Cushman. Although the precise structure of ACE was not known at the time, the Squibb scientists were able to make some educated assumptions about a working model in the human body for ACE, relying upon what was known about another enzyme known as carboxypeptidase A. According to Dr. Horovitz, one of the first steps taken by the Squibb scientists was to include a carboxyl group (HO2C) at the terminal of the teprotide molecule based on prior art in relation to carboxypeptidase A. They then added a CH2 to the backbone. Next, the scientists introduced a sulfhydryl (SH) group in the terminal position instead of the carboxyl group. This was captopril, the first small molecule, orally-effective, ACE inhibitor. As stated by Dr. Horovitz, “After almost ten years of work at Squibb, and the testing of thousands of compounds, Squibb finally had a drug that could be used for the treatment of hypertension and was orally active”. The structure of captopril is set out below:
Captopril
[46] While captopril was a tremendous innovation, the presence of the sulphur atom was responsible for serious side effects in some people. One of the experts, Dr. Thorsett, was at Merck from 1975 through the next exciting years and provided his story of what happened next.
[47] In response to the problem of the side effects, Merck scientists (including Dr. Patchett) focussed on removing the sulfhydryl (SH) group (also referred to as a thiol group or thiol moiety). The result was enalapril. According to Dr. Marshall, who provided expert testimony on this point, enalapril “retained the Ala-Pro C-terminal unit while replacing the sufhydryl methylene group (HSCH2-) in captopril with an N-carboxyalkyl moiety”. While enalapril lacked the sulphur moiety present in captopril, what remained consistent from captopril to enalapril was the presence of the proline unit or five-membered ring structure on the right side of the compound. This new ACE inhibitor had three stereocentres, all of which were in the (S) configuration. As of 1980, when the results of the scientists’ work was confirmed, the mood at Merck was described by Dr. Thorsett as “electric”. The structure of enalapril is set out below:
Enalapril
[48] On June 18, 1980, at a medicinal chemistry conference in Troy, New York (the Troy conference), Dr. Patchett presented Merck’s new ACE inhibitor. The disclosure made by Merck at the Troy conference was widely anticipated by the ACE inhibitor community. Scientists at a number of pharmaceutical companies had been carrying out extensive research to develop new ACE inhibitor drugs. Dr. Vincent of Servier and Dr. Smith of Schering were two such scientists. Both of them had carried out some preliminary work that, they hoped, could build on or incorporate the Merck disclosure.
[49] As we will see in greater detail later in these reasons, both Dr. Vincent and Dr. Smith carried out work that led to the molecules that resulted in ramipril (Dr. Smith) and perindopril (Dr. Vincent).
(3) Schering’s Work on ACE Inhibitors
[50] Although more will be said further on in this decision about the development work done by Schering during the late 1970s and early 1980s, it is helpful at this point to have an overview of the nature of the research work that was being done by Schering leading up to the application for what would become the '206 Patent and the compound ramipril. The evidence of Dr. Elizabeth Smith, both in oral testimony and an affidavit, was helpful.
[51] Prior to the Merck announcement at the Troy conference in June of 1980, scientists at Schering, including Dr. Smith, were trying to develop an anti-hypertensive compound that would be more effective than captopril. While Merck’s work involved the removal of the thiol group, Schering’s work focussed on a different aspect of the captopril molecule - that is, the proline unit. By late 1979 or early 1980, Dr. Smith and her colleagues had found that the replacement of the proline in captopril with certain fused ring or spirocyclic moieties resulted in active compounds.
[52] As a result of the Merck disclosure at the Troy conference, the Schering scientists decided to try to create compounds based, in part, upon the Merck work on the thiol end of the molecule, but also using the fused ring moieties that Schering had already been working on in relation to the proline end of the molecule. That is, Schering’s scientists decided to try using various bicyclic ring structures in place of the proline on an enalapril-type molecule. This proposed work was documented in an invention disclosure report dated June 20, 1980. According to Dr. Smith, this report shows the conception of the generalized structure of the compounds in what ultimately became the '206 Patent.
[53] Over the next few months, Dr. Smith and the other scientists at Schering made several of t