Sanofi-Aventis Canada v. Apotex Inc.

Sanofi-Aventis Canada v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2009-06-29
Neutral citation
2009 FC 676
File numbers
T-1161-07, T-161-07
Decision Content
Federal Court
Cour fédérale
Date: 20090629
Docket: T-161-07
Docket: T-1161-07
Citation: 2009 FC 676
BETWEEN:
SANOFI-AVENTIS CANADA INC.,
SANOFI-AVENTIS DEUTSCHLAND GmbH and
SCHERING CORPORATION
Plaintiffs
and
APOTEX INC.
Defendant
AND BETWEEN:
APOTEX INC.
Plaintiff by Counterclaim
and
SANOFI-AVENTIS CANADA INC. and
SCHERING CORPORATION
SANOFI-AVENTIS DEUTSCHLAND GmbH and
RATIOPHARM INC.
Defendants by Counterclaim
Docket: T-1161-07
BETWEEN:
SANOFI-AVENTIS CANADA INC.,
SCHERING CORPORATION and
SANOFI-AVENTIS DEUTSCHLAND GmbH
Plaintiffs
and
NOVOPHARM LIMITED
Defendant
AND BETWEEN:
NOVOPHARM LIMITED
Plaintiff by Counterclaim
and
SANOFI-AVENTIS CANADA INC.,
SCHERING CORPORATION and
SANOFI-AVENTIS DEUTSCHLAND GmbH
Defendants by Counterclaim
REASONS FOR JUDGMENT
SNIDER J.
I. Introduction
[1] Sanofi-Aventis Canada (Sanofi Canada) sells a drug in Canada with the trademark of ALTACE, which is used primarily in the treatment of high blood pressure and cardiac insufficiency. The active ingredient in ALTACE is ramipril. With some exceptions, Sanofi Canada purchases ramipril from its affiliate, Sanofi-Aventis Deutschland GmbH (Sanofi Deutschland) who manufactures ramipril in Germany. Ramipril is included in Canadian Patent No. 1,341,206 (the '206 Patent), a patent that was issued March 20, 2001 and held by Schering Corporation (Schering). Each of Sanofi Canada and Sanofi Deutschland are licensees under the '206 Patent.
[2] In January, 2007, Apotex Inc. (Apotex) commenced sales of a generic version of ALTACE – Apo-Ramipril – in Canada. Similarly, Novopharm Limited (Novopharm) began selling Novo-Ramipril in Canada in May, 2007. Apotex and Novopharm became authorized to sell a ramipril product in face of an existing patent following the conclusion of a series of proceedings brought under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the NOC Regulations) which I will detail later.
[3] In 2007, Sanofi Canada, Sanofi Deutschland and Schering commenced two actions claiming infringement of the '206 Patent. The defendant in the first action (Court File T-161-07) is Apotex and the defendant in the second (Court File T-1161-07) is Novopharm. Each of the two Defendants responded to the Statement of Claim filed against it with a Statement of Defence and Counterclaim, asserting that the '206 Patent was invalid on a number of grounds. The counterclaims of Novopharm and Apotex joined Ratiopharm Inc. (Ratiopharm) as a defendant by counterclaim in each of the actions. The portions of the counterclaims affecting Ratiopharm were stayed under the provisions of s. 50(1) of the Federal Courts Act, R.S.C. 1985, c.F-7 by Order of Justice Roger Hughes dated September 12, 2007. There is no further reference to Ratiopharm in these Reasons.
[4] Since the patent in question, the issues raised by the parties and much of the evidence is common to both actions, the two were heard together. These Reasons for Judgment apply to both actions.
[5] The combination of the two actions in this manner resulted in great efficiencies in the trial process. The 37-day trial, which involved complex issues on both patent validity and damages, took place within two years of the filing of the first Statement of Claim. The efficiencies and timeliness of the trial were only possible due to the great degree of cooperation amongst the four sets of counsel involved and to the effective case management of Prothonotary Milczynski. I thank them all sincerely.
[6] For the reasons expressed in these Reasons for Judgment, I have concluded that Apotex and Novopharm have infringed certain claims of the '206 Patent. However, I have also found that Claims 1, 2, 3, 6 and 12 of the '206 Patent are invalid. In very general terms, the key determination leading to this result is my finding that, on a balance of probabilities, the inventors of the '206 Patent could not soundly predict, as of October 20, 1981, that all of the eight compounds of Claim 12 of the '206 Patent would have the utility promised by the patent. Claims 1, 2, 3 and 6 include the same compounds as are covered by Claim 12. Accordingly, it follows that Claims 1, 2, 3, 6 and 12 of the '206 Patent are invalid and the claims of Schering and Sanofi will be dismissed.
[7] If I am wrong in this conclusion, and the claims were based on a sound prediction, it follows – on the particular facts of this case – that the same prior art that would form the basis of a sound prediction would render the relevant claims of the '206 Patent obvious as of the appropriate date for assessing obviousness.
[8] The Defendants have raised other grounds of invalidity. In light of my finding of invalidity on the basis of lack of utility, it is not strictly necessary for me to rule on these other grounds. However, if I were required to do so, I would conclude that:
· The '206 Patent is not invalid for obviousness double patenting;
· For the '206 Patent, there is no requirement that the patentee disclose the “best mode” for producing the patented compounds;
· The Gillette defence is unavailable to the Defendants on these facts; and
· Apotex’s argument that Schering was not the first to invent the subject matter of the '206 Patent fails.
[9] The application leading to the '206 Patent was filed in Canada on October 20, 1981. According to s. 78.1-78.2 of the present Patent Act (R.S.C. 1985, c.P-4), 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 the Patent Act in these Reasons will, unless specifically noted otherwise, be to the Patent Act as it stood immediately prior to October 1, 1989.
[10] Finally, I note that the trial of these actions was not bifurcated. Sixteen days of evidence and two days of final argument were devoted to the remedies phase of this matter. Because of my dismissal of the actions, there is no need to consider these issues. Nevertheless, I will retain my notes from the second phase of the trial. In the event that it becomes necessary, I could be available to hear further updates to the evidence and submissions and make determinations on the appropriate damages and remedies.
II. Table of Contents
[11] To assist the reader, the following sets out a Table of Contents for these Reasons with paragraph numbers for each heading:
I. Introduction ............................................................................... [1] to [10]
II. Table of Contents................................................................................... [11]
III. Witnesses ............................................................................. [12] to [43]
A. Introduction.................................................................................. [12]
B. Plaintiffs’ Expert Witnesses............................................................ [15]
C. Plaintiffs’ Fact Witnesses............................................................... [29]
D. Defendants’ Expert Witnesses....................................................... [30]
E. Defendants’ Factual Witnesses...................................................... [43]
IV. Background to the '206 Patent................................................... [44] to [64]
A. Introduction.................................................................................. [44]
B. Chemical Principles....................................................................... [45]
(1) Stereochemistry ............................................................... [46]
(2) ACE Inhibitors Generally .................................................. [50]
C. History of ACE Inhibitors.............................................................. [53]
D. Schering's Work on ACE Inhibitors............................................... [58]
E. The Conflict Proceedings............................................................... [63]
V. Prior Litigation............................................................................ [65] to [73]
VI. Validity, Presumption and Burden............................................. [74] to [78]
VII. Claims Construction................................................ [79] to [138]
A. Principles of Claims Construction................................................... [79]
B. Person Skilled in the Art................................................................ [85]
C. Description of the '206 Patent........................................................ [86]
D. Construction of Claims 1, 2, 3 and 6............................. [99]
E. Construction of Claim 12............................................................. [105]
F. The “Promise” of the '206 Patent................................................. [119]
G. Summary on Construction........................................................... [138]
VIII. Infringement ......................................................................... [139] to [141]
IX. Utility ......................................................................... [142] to [231]
A. General Principles....................................................................... [142]
B. Sound Prediction: Factual Basis and Articulable and
Sound Line of Reasoning............................................................. [151]
(1) Importance of Stereochemistry........................................ [156]
(2) The Schering Work......................................................... [164]
(3) The stereochemistry at the carboethoxy position............... [189]
(4) The “space” theory.......................................................... [203]
C. Sound Prediction: Disclosure....................................................... [213]
D. Conclusion on Sound Prediction.................................................. [229]
X. Sound Prediction of Making................................................... [232] to [259]
A. The requirement to soundly predict how to make......................... [233]
B. Alternative Synthesis Methodologies............................................ [238]
C. Example 20................................................................................. [247]
XI. Obviousness ......................................................................... [260] to [320]
A. General Principles....................................................................... [260]
B. The Invention.............................................................................. [267]
C. Date of Invention......................................................................... [269]
D. Application of the Sanofi-Synthelabo Test for Obviousness......... [288]
(1) Identify the “person skilled in the art”............................... [289]
(2) Identify the relevant common general knowledge.............. [290]
(3) Identify the inventive concept........................................... [298]
(4) Identify the Differences Between the “State of the
Art” and the inventive concept......................................... [299]
(5) Would the differences constitute steps that would
have been obvious?......................................................... [301]
E. Conclusion on Obviousness......................................................... [319]
XII. Best Mode ......................................................................... [321] to [333]
XIII. Double Patenting.................................................................... [334] to [343]
XIV. Gillette Defence..................................................................... [344] to [349]
XV. First Inventorship................................................................... [350] to [354]
XVI. Conclusions ......................................................................... [355] to [364]
Postscript ................................................................................. [1] to [2]
III. Witnesses
A. Introduction
[12] During the 31-day evidentiary phase of this trial, many witnesses appeared, both as expert and fact witnesses. Fifteen days of the trial consisted of evidence dealing with the infringement and validity issues. The balance of the trial was spent considering possible remedies should the plaintiffs be successful in their claims. As noted above, I have concluded that the '206 Patent is invalid. Accordingly, there is no need (at this time) to assess the evidence presented by the many capable witnesses who appeared in the damages phase of the trial.
[13] In the following, I will provide a brief overview of the expert and fact witnesses who appeared during the infringement and validity portion of the trial and the areas to which they testified. For the expert witnesses, I have set out a very short description of their education and experience in the areas for which this court found each of them to be qualified. More detailed references to the experts’ evidence are contained in the appropriate sections of these reasons.
[14] The experts produced by both the Plaintiffs and Defendants were very helpful to the Court. I would comment, however, that there was considerable overlap and repetition in their evidence.
B. Plaintiffs’ Expert Witnesses
(1) Dr. Paul A. Bartlett
[15] After completing his Ph.D. studies in Organic Chemistry, Dr. Paul A. Bartlett began an impressive academic career in 1973 with University of California, Berkley. From 1996 to 2000, he was Chair of the Department of Chemistry. Dr. Bartlett is, at present, a Professor Emeritus of Chemistry at the University of California, Berkley. He has extensive consulting and research experience in fields of relevance to the issues before me in this case. I accepted his qualifications as an expert in medicinal chemistry and synthetic organic chemistry. During his appearances and in his expert reports, on behalf of Schering, Dr. Bartlett provided opinions on the issues of claims construction, infringement, utility, sound prediction and obviousness.
(2) Dr. André Charette
[16] Dr. Charette is a professor at the University of Montreal, Department of Chemistry. He holds the Canada Research Chair in Stereoselective Drug Synthesis of Bioactive Molecules as well as the NSERC, Merck Frosst and Boehringer Ingelheim Industrial Chair on the same topic. He was qualified as an expert in the areas of organic chemistry relating to stereochemistry and stereoselective synthesis.
[17] On behalf of Sanofi, Dr. Charette gave opinions directed to the methods of synthesis of the compounds included in Claims 1, 2, 3, 6 and 12 of the '206 Patent. He reviewed and opined on the experimental techniques used by Dr. Bihovsky, Dr. Mariampillai and Dr. Lautens in their attempts to follow the directions of Example 20 of the '206 Patent. His evidence and testimony also touched on whether the compounds covered by Claim 12 could be prepared using methods known in the art, other than that given by Example 20.
(3) Dr. Arthur Patchett
[18] Dr. Patchett has had a lengthy and distinguished career in pharmaceutical chemistry. He joined Merck & Co. (Merck) as a research chemist in 1957, remaining with that company in various capacities until 2002. Dr. Patchett is a co-inventor of the ACE inhibitors enalapril and lisinopril. Of particular relevance to this trial is the role that he played in Merck’s disclosure of its work in the design of enalapril and lisinopril at a lecture at Troy, New York in June 1980. Dr. Patchett was qualified as a medicinal chemist with experience in the design and development of ACE inhibitors. Since his retirement in 2005, Dr. Patchett has been retained as a consultant for Schering-Plough.
[19] On behalf of Schering, Dr. Patchett provided his opinions on the issues of sound prediction and obviousness. Although there was a certain level of repetition between the evidence of Dr. Patchett and Dr. Bartlett, Dr. Patchett’s experience at Merck brought a unique experience to the Court that was very helpful.
(3) Dr. Wendel Nelson
[20] Dr. Nelson is a professor in the Department of Medicinal Chemistry, University of Washington. He has been in academia since 1965 and served for 19 years (from 1989 to 2007) as a senior editor for the Journal of Medicinal Chemistry. He was qualified as an expert in the area of medicinal chemistry.
[21] On behalf of Sanofi, Dr. Nelson provided his opinions on the issues of patent construction, utility, sound prediction and obviousness. To a large degree, his opinions were confirmatory and repetitive of those of Dr. Bartlett.
(4) Dr. James D. Wuest
[22] Dr. James D. Wuest is a Professor of Chemistry at the University of Montreal, where he has been a full professor since 1986. Prior to joining the University of Montreal, he was an Assistant Professor of Chemistry at Harvard University and Harvard Medical School. Since 2001, Dr. Wuest has held the Canada Research Chair in Molecular Materials. He was qualified as an expert in synthetic organic chemistry.
[23] On behalf of Sanofi, Dr. Wuest commented on the experimental work of Dr. Bihovsky, as well as that of Drs. Mariampillai and Lauten, with respect to Example 20. He also provided his opinion on whether the compounds covered by Claim 12 could be prepared using methods known in the art, other than that given by Example 20. There was considerable overlap and repetition between his opinions and those offered by Dr. Charette and Dr. Roach.
(5) Dr. Mark Lautens
[24] Dr. Lautens is the AstraZeneca Professor of Organic Synthesis at the University of Toronto, where he has been a full professor since 1995. Dr. Lautens was qualified as an expert in synthetic organic chemistry.
[25] On behalf of Sanofi, Dr. Lautens carried out the synthesis described in Example 20 of the '206 Patent.
(6) Dr. Zola Horovitz
[26] Dr. Zola Horovitz was qualified as an expert in pharmacology with particular experience in the area of hypertension and ACE inhibition. Dr. Horovitz worked for almost 35 years in pharmacological research at the Squibb Institute for Medical Research (Squibb). Since his retirement from that post in 1994, he has been a consultant to the biotechnology and pharmaceutical industries, including various companies that develop products in the cardiovascular field. Dr. Horovitz gave evidence on obviousness, sound prediction and utility.
[27] As with Dr. Patchett, Dr. Horovitz’s opinions overlapped to some extent with that of other witnesses. However, Dr. Horovitz brought a unique perspective to the trial because of his pharmacological experience in industry.
(7) Dr. Braden Roach
[28] Dr. Braden Roach has been involved in research, for over 20 years, in areas of chemical synthesis research, in both academic and industry settings. Dr. Roach was qualified as an expert in the synthesis of organic compounds. He was asked by counsel for Schering to opine on the work of each of Dr. Lautens and Dr. Bihovsky in their attempts to follow the synthesis of Example 20. There was considerable overlap and repetition between his opinions and those offered by Dr. Charette and Dr. Roach.
C. Plaintiffs’ Fact Witnesses
[29] Schering presented two fact witnesses to the Court. Dr. Bernard Neustadt is employed by Schering as a research fellow serving as a medicinal chemist in the company’s discovery effort. He has been an employee with Schering since 1969. He is one of the inventors of the subject matter of the '206 Patent. The other fact witness was Dr. Elizabeth Smith, who has been an employee at Schering since 1972. She is a one of the inventors of the subject matter of the '206 Patent.
D. Defendants’ Expert Witnesses
(1) Dr. Eugene Thorsett
[30] Dr. Eugene Thorsett is a synthetic organic chemist with 33 years of experience in the pharmaceutical industry. Of particular interest in this case, Dr. Thorsett was a researcher at Merck from 1975 to 1988, including during the early stages of the development of ACE inhibitors, including enalapril and lisinopril. Dr. Thorsett was qualified as an expert in medicinal and synthetic organic chemistry with particular knowledge in pre-clinical drug development, especially those related to pharmacology, such as pharmacokinetics and the absorption, distribution, metabolism and excretion of a pharmaceutical compound within an organism, and in the area of lead drug candidate optimization, and in the design and development of enzyme inhibitors, including ACE inhibitors. His testimony and reports, on behalf of Apotex, were directed to the issues of claims construction, utility, sound prediction and obviousness.
(2) Dr. Mario Ehlers
[31] Dr. Ehlers is a physician-scientist with 11 years of experience in academic research and 8 years of biopharmaceutical industry experience in drug development, diagnostic product development, and central lab services. He was qualified as a biochemist with academic and industry experience in structure function studies on ACE and ACE inhibitors and the design and synthesis of new ACE inhibitors. On behalf of Novopharm, Dr. Ehlers provided his opinion on patent construction and sound prediction.
(3) Dr. Christopher John Moody
[32] Since 1979, Dr. Moody has been in academia. At present, he is the Sir Jesse Boot Professor of Chemistry at the University of Nottingham, United Kingdom. Of particular interest, Dr. Moody was employed, from 1977 to 1979, as a senior research chemist by Roche to work on a project involving the design and synthesis of ACE inhibitors as potential medicines for hypertension. Dr. John Moody was qualified as an expert in organic chemistry with experience in heterocyclic chemistry. He spoke to the issues of claims construction and the process used by Schering and Novopharm to synthesize ramipril.
(4) Dr. Robert Allan McClelland
[33] Dr. McClelland is Professor Emeritus of the University of Toronto. From 1983 to June 2005, he was Professor of Chemistry at the University of Toronto. Dr. McClelland was qualified 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 synthesis of new analogues.
[34] On behalf of Apotex, Dr. McClelland provided his expert opinion and replied to certain opinions of the Plaintiffs’ experts in the following areas: a comparison of the claims of the '087 Patent with those of the '206 Patent; a comparison of the Apotex manufacturing process of ramipril with that claimed in Canadian Patent No. 1,187,087 (the '087 Patent); Example 20 of the '206 Patent; and the Schering research work in respect of the '206 Patent.
(5) Dr. Ian Fleming
[35] Dr. Fleming is a Professor Emeritus of Chemistry at the University of Cambridge and an Emeritus Fellow at Cambridge’s Pembroke College. From 1965 to 2002, he held various academic posts at Cambridge, his last position being that of Chemistry Professor from 1998 to 2002. He was qualified as an expert in synthetic organic chemistry.
[36] On behalf of Apotex, Dr. Fleming provided his expert opinion in the following areas: Example 20; a comparison of the claims in the '087 Patent and the '206 Patent; and, a comparison of the Apotex manufacturing process of ramipril with that claimed in the '087 Patent.
[37] While Dr. Fleming was a highly competent and knowledgeable expert, I question whether his opinions were necessary to the understanding of the Court, given that his mandate was almost identical to that of Dr. McClelland. It seems to me that one or the other of these two experts would have been adequate.
(6) Dr. Timothy J. Ward
[38] Dr. Ward is the Associate Dean of the Sciences and a Professor in the Department of Chemistry at Millsaps College in Jackson, Mississippi. Dr. Ward worked for Dionex Corporation and Syntex Pharmaceuticals between 1987 and 1990, when he entered academia. He was qualified as an expert in separation science, including chromatography. On behalf of Apotex, he provided his expert opinion on the science of chromatography and separation. In particular, Dr. Ward opined on the separation methodology needed for the compounds of Claim 12 of the '206 Patent and on the work done by Schering in separating compounds within the scope of Claim 12.
(7) Dr. Clayton Heathcock
[39] Dr. Heathcock is a chemist with over 45 years of academic experience in organic chemistry and medicinal chemistry. He is currently Professor Emeritus at the University of California at Berkeley and Chief Scientist of the Berkley branch of the California Institute for Quantitative Biosciences. Dr. Heathcock was qualified as a synthetic organic chemist.
[40] On behalf of Novopharm, Dr. Heathcock provided his opinion on whether the subject matter of the '206 Patent would have been obvious to a person skilled in the art. In light of the evidence of Dr. Thorsett, I question whether Dr. Heathcock added materially to the Court’s knowledge in this area.
(8) Dr. Ron Bihovsky
[41] Dr. Bihovsky is a scientist with over 20 years of experience in chemistry, including in academia and private industry. In 2001, he founded Key Synthesis LLC, an organic chemistry lab that performs contract synthetic projects for pharmaceutical and biotechnology companies, process research and consulting work. Dr. Bihovsky was qualified as an expert in organic synthesis.
[42] Dr. Bihovsky was retained on behalf of Apotex to attempt to reproduce the synthesis described in Example 20 of the '206 Patent and to provide his opinion on the ability of a person skilled in the art to carry out the chemical reactions of Example 20.
E. Defendants’ Factual Witnesses
[43] Apotex presented two factual witnesses to the Court. Dr. Stephen Horne is the vice president of research and development at Apotex Pharmachem. His testimony related to a sample of a compound known as “Ram 85” that was provided to Dr. Bihovsky. Dr. Gabriela Mladenova testified as to her laboratory work in or around 2003. At that time, Dr. Mladenova performed some experiments, under the direction of Dr. Lee-Ruff, in which she unsuccessfully attempted to reproduce the synthesis described in Example 20 of the '206 Patent.
IV. Background to the '206 Patent
A. Introduction
[44] The '206 Patent is entitled “Carboxyalkyl Dipeptides, Processes for Their Production and Pharmaceutical Compositions Containing Them”. Some background information on the subject matter and history of the patent and the relevant chemical principles may be helpful.
B. Chemical Principles
[45] 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.
(1) Stereochemistry
[46] An understanding of the basic principles of stereochemistry is necessary to understand the nature of the invention as claimed in the ‘206 Patent.
[47] Stereochemistry is the study of the three dimensional spatial orientation of compounds of atoms in molecules and the consequences of such arrangements. Molecules having exactly the same chemical composition (and molecular formula) as well as the same molecular structure (i.e. the same connectivity of atoms) may differ in their spatial arrangement in three dimensions. Such compounds are referred to as "stereoisomers".
[48] The term "chiral centre" or “stereocentre”, as it appears in stereochemistry, is used to describe carbon atoms that have four different function atoms or groups attached to it. A chiral compound is one that exists in two mirror image forms that are not superimposable—like a person’s hands.
[49] In order to describe the stereochemistry of molecules having chiral centres, chemists have devised a system whereby a chiral centre is described as being in either the R or S configuration, depending on the exact spatial arrangement of atoms around the chiral centre.
(2) ACE Inhibitors Generally
[50] 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. Larger groups known as proteins may be formed from such acids.
[51] 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.
[52] Ramipril, along with other drugs mentioned in these reasons, are all "ACE inhibitors". ACE inhibitors bind with ACE to prevent the conversion of angiotensin I to angiotensin II; the result is lower blood pressure.
C. History of ACE Inhibitors
[53] 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 also helpful. I summarize this evidence in the following paragraphs.
[54] Dr. Horovitz, who became Director of Pharmacology at Squibb in 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 antihypertensive agent in humans. However, teprotide was only effective through intravenous administration.
[55] 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 developed some hypotheses about a 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, "[a]fter 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:
[56] While captopril was a tremendous innovation in the development of ACE inhibitors, the presence of the sulphur atom was responsible for serious side effects in some people. The next major advancement came from Merck. In response to the problem of the side effects, the Merck scientists (including Dr. Thorsett and Dr. Patchett) focused on removing the sulfhydryl (SH) group (also referred to as a thiol group or thiol moiety). The replacement of the thiol group with a carboxylic acid (COOH) moiety resulted in enalapril. While enalapril lacked the sulphur moiety present in captopril, it retained the proline unit or five-membered ring structure at the C-terminus of the compound. This new ACE inhibitor had three stereocentres, all of which were in the S configuration. The structure of enalapril is set out below:
[57] 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. During his appearance at this trial, Dr. Patchett testified that there were at least several hundred – maybe more – attendees for his lecture . Many of those in attendance were scientists at a number of pharmaceutical companies who had been carrying out research to develop new ACE inhibitor drugs. Dr. Elizabeth Smith of Schering was one such scientist. As discussed below, Dr. Smith had carried out some preliminary work that, she hoped, could build on or incorporate the Merck disclosure.
D. Schering's Work on ACE Inhibitors
[58] 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 provide 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. In this respect, the evidence of Dr. Smith and Dr. Neustadt was helpful.
[59] Prior to the Merck announcement at the Troy conference in June of 1980, scientists at Schering, including Dr. Smith, were trying to develop an antihypertensive compound that would be more effective than captopril. While Merck's work involved the removal of the thiol group, Schering's work focused 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.
[60] As a result of the Merck disclosure at the Troy conference, the Schering scientists decided to try to create compounds combining the Merck disclosure with the work that they had already been working on in relation to the proline end of the molecule. That is, Schering's scientists decided to try using various spirocyclic and 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.
[61] On October 23, 1980, Schering filed US Application No. 199,886. The subsequent Canadian patent application claimed priority from this U.S. patent application.
[62] On October 20, 1981, Schering filed Patent Application 388,336 (the '336 Application) in Canada. The Canadian application ultimately resulted in the issuance of the '206 Patent in March of 2001. The '206 Patent Claims 1, 2, 3, 6 and (subject to some disagreement) 12 cover the molecule known as ramipril, a very successful commercialized compound. The structure of ramipril is set out below:
Ramipril
E. The Conflict Proceedings
[63] As noted, Schering filed the '336 Application in Canada on October 20, 1981. Other claimants also applied for the issuance of patents covering certain compounds. Of specific interest, ADIR filed Application 387,093 (the '093 Application) and Hoechst Aktiengesellschaft (Hoechst), a predecessor to Sanofi Deutschland, filed Patent Application 384,787 (the '787 Application). As provided for in the Patent Act, certain of the claims in the '336 Application were placed into conflict with claims in the other applications.
[64] The conflict proceedings continued until December 12, 2000 when the three parties to the conflict consented to an Order of Justice Marc Nadon, which Order provided for an allocation of the claims in conflict. As a result, the '206 Patent finally issued on March 20, 2001.
V. Prior Litigation
[65] These actions are not the first litigation involving the '206 Patent and ramipril. All of the earlier cases involved applications brought pursuant to the NOC Regulations. The legislative scheme of the NOC Regulations is complex. Simply stated and of particular relevance to this litigation, a party such as Apotex or Novopharm (referred to in the NOC Regulations as a “second person”) may seek authorization (in the form of a Notice of Compliance (NOC)) from the Minister of Health to market a drug, in spite of the fact that the drug may be the subject of a patent. Once a party has declared its intentions to seek an NOC, it must address all patents that might affect its proposed product. A patent holder or other “first person” may apply to the Federal Court for an Order of Prohibition preventing the Minister from issuing the necessary authorization to the “second person”.
[66] There is no doubt that the applications brought under the NOC Regulations involve allegations of infringement and invalidity. However, at the end of the proceeding, the judge hearing the application is not tasked with making a final determination of infringement and validity. Rather, the judge must determine whether the allegation by the second person is “justified”. The distinction is a fine one, which is based, to a large degree, on the “summary” nature of the NOC hearing (see, for example, Pharmacia Inc. v. Canada (Minister of Health and Welfare) (1994), 58 C.P.R. (3d) 209 at paras. 13-14 (F.C.A.); AB Hassle v. Apotex Inc., 2006 FCA 51, [2006] 4 F.C.R. 513 at para. 2 [AB Hassle]). An NOC proceeding is conducted on a “paper record” of affidavit evidence and on the limited written and oral submissions of counsel. There is no opportunity for viva voce evidence from the experts who might provide further guidance and clarification to the hearing judge. So, even though these “summary” proceedings involve thousands of pages of affidavit evidence, extensive cross-examination and many hundreds of hours of work by all parties concerned (and the applications Judge), the result does not provide a determinative finding on the patent’s validity. A patent holder who fails to obtain an Order of Prohibition may still commence a patent infringement action. Conversely, a generic company against whom a Prohibition Order has been made may bring an action to impugn the patent. Given this situation, I can sympathize with the frustration expressed by Dr. Bernard Sherman who, during his testimony, expressed the following views:
It may well be that some didn’t turn his mind adequately to what happens afterwards and maybe no one even considered the possibility that there would be subsequent litigation.
But the regime doesn’t make sense if generic manufacturers are going to do the research, litigate for years, win under the regulations and then be unable to launch; particularly if there is no undertaking for damages, the industry can’t survive.
[67] However, until and unless Parliament sees fit to address the scheme of the NOC Regulations, the situation will arise where a party to an NOC proceeding is exposed to the risk of patent infringement or impeachment proceedings, as applicable.
[68] This was the background against which the earlier ramipril litigation was conducted and against which I must consider such jurisprudence.
[69] In the case of Aventis Pharma Inc. v. Pharmascience Inc., 2005 FC, 340, [2005] 4 F.C.R. 301, [referred to as Ramipril I (FC))], Aventis Pharma Inc. (a predecessor to Sanofi Canada) sought an Order of Prohibition, under the NOC Regulations, to prevent the Minister of Health from issuing an NOC to Pharmascience Inc. in respect of ramipril. At that time, three different patents were listed for ALTACE on the register maintained by the Minister pursuant to NOC Regulations: the '206 Patent; Canadian Patent 1,187,087 and Canadian Patent 1,246,457 (the '457 Patent). In the Notice of Allegation served by Pharmascience in relation to its ramipril capsules, Pharmascience alleged that claims 1, 2, 3, 6 and 12 of the '206 Patent were invalid because they covered subject matter that is not patentably distinct from the subject matter of the claims of the '087 Patent and the '457 Patent. In other words, Pharmascience argued that the '206 Patent was invalid on the basis of “doubl