Merck & Co. Inc. v. Apotex Inc.

Merck & Co. Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2006-04-26
Neutral citation
2006 FC 524
File numbers
T-2792-96
Notes
Digest
Decision Content
Date: 20060426
Docket: T-2792-96
Citation: 2006 FC 524
Toronto, Ontario, April 26, 2006
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
MERCK & CO., INC., MERCK FROSST CANADA & CO.,
MERCK FROSST CANADA LTD., SYNGENTA LIMITED,
ASTRAZENECA UK LIMITED AND ASTRAZENECA CANADA INC.
Plaintiffs
(Defendants by Counterclaim)
and
APOTEX INC.
Defendant
(Plaintiff by Counterclaim)
REASONS FOR JUDGMENT
[1] This action concerns the infringement and validity of claims 1, 2 and 5 of Canadian Patent 1,275,350 (‘350 patent). That patent is directed among other things, to a class of chemical compounds stated to be useful in treating hypertension. One such compound is known as lisinopril.
[2] The Plaintiffs include the owner of and licensees under the patent some of whom sell drugs in Canada incorporating lisinopril as an active ingredient. They commenced selling such drugs in the early 1990’s developing a Canadian market estimated to be at least forty million dollars annually by the late 1990’s. The Defendant Apotex Inc. is commonly referred to as a generic drug company. It chose to produce and sell in Canada and elsewhere a generic version of some of the Plaintiffs’ lisinopril drugs. These generic versions were first introduced in the mid 1990’s and by the end of that decade had acquired a major portion of the market in Canada. As of the time of the trial, Apotex’s market for such drugs was estimated to be fifty to sixty million dollars annually.
[3] This action was commenced in 1996. The Plaintiffs alleged infringement, Apotex counterclaimed alleging invalidity of the patent. By the time of trial, Apotex admitted that, if the claims in issue of the patent were valid, then they had infringed those claims subject to certain exemptions as to some quantities of lisinopril obtained from an allegedly licensed source, and certain quantities used for allegedly exempted purposes.
[4] This action is not the first in which these parties have been engaged. Another action dealt with a related patent 1,275,349 pertaining to a compound known as enalapril. After a lengthy trial, an appeal and several related proceedings, that patent was held to be valid and infringed by Apotex. These former proceedings, say the Plaintiffs, preclude Apotex from raising attacks as to the validity of the patent at issue here.
[5] For the reasons that follow, I find that Apotex has infringed each of claims 1, 2 and 5 of the ‘350 patent, subject to certain exemptions, that Apotex is precluded from challenging the validity of those claims and, in any event, those challenges fail. Appropriate remedies are granted.
[6] I propose to deal with the matters considered in the following order:
1. The Parties
2. The Issues
3. The Witnesses
4. Background to the Biochemistry
5. Development of the Particular Compounds of Concern
6. What are Lisinopril, Enalapril and Enalaprilat
7. Combination with Diuretics
8. Commercialization of Lisinopril Products
9. History of the ‘350 Patent and Related Patents and Applications
10. Construction of the ‘340 Application
11. Use of Extrinsic Evidence
12. Construction of the ‘350 Patent Claims
13. Infringement
a) Admission as to Infringement
b) Exemptions from Infringement
i) Section 56
ii) License
iii) Section 55.2(1)
iv) Common Law
v) Dedication
c) Limitation Respecting Exemptions
14. Validity
a) Effect of the Presumption of Validity
b) Estoppel
i) Previous Litigation
ii) Delmar License
c) Divisional Procedure
d) Effective Filing Date of the Divisional Application
e) Double Patenting
f) Wilful Delay
15. Remedies
1. The Parties
[7] The status of the Plaintiffs is no longer in controversy, having been admitted by Apotex. Merck & Co. Inc. is, and at all times has been, the owner of the ‘350 patent. It is the “patentee” as defined by the Patent Act R.S.C. 1985, c.P.4, section 2 (the Act). The remainder of the Plaintiffs are licensees under the ‘350 patent at issue and are “persons claiming under the patentee,” as defined in section 55(1) of that Act.
[8] A pre-trial order of this Court permitted the Plaintiffs to be arranged into two groups. One is the Merck group comprising Merck & Co. Inc, Merck Frosst Canada & Co. and Merck Frosst Canada Ltd. The other is the Astra group comprising Syngenta Limited, AstraZeneca UK Limited and AstraZeneca Canada Inc. Each of Merck and Astra were permitted to be represented at trial by their own, separate, firm of solicitors and counsel.
[9] The Defendant Apotex Inc., is a Canadian company based in the Toronto area. It formulates and sells generic drugs that is, copies of drugs developed by others and permitted to be made and sold in Canada and elsewhere if they are bioequivalent to the satisfaction of the relevant government authorities. Apotex was amalgamated with Torpharm Inc. on April 1, 2004, and continues as Apotex Inc. The benefits and liabilities of each continue with Apotex Inc.
2. The Issues
[10] The parties were invited to submit a set of issues to the Court for determination. They filed separate submissions. From those submissions, which were much in agreement, the following issues emerge for determination:
1. Construction of the Patent and the Claims
2. Infringement
a) Admission as to infringement
b) Exemptions from Infringement
i) Section 56 – Are certain lots exempt?
ii) License – Does Delmar’s license exempt any lots?
iii) Section 55.2 – Are certain lots exempt?
iv) Common Law – Are there common law exemptions and, if so, what is exempt.
v) Dedication – Does the Merck dedication of certain claims of the ‘559 patent exempt any lots from infringement?
3. Validity
a) Effect of the presumption of validity
b) Estoppel
i) Delmar License – Is Apotex estopped or otherwise precluded from challenging validity as a result of the claim to the benefit of the Delmar License?
ii) Prior Litigation - Is Apotex estopped or otherwise precluded from challenging validity of the ‘350 patent having regard to prior litigation, T-2408-91 and A-724-94?
c) Double Patenting – Are the claims at issue of the ‘350 patent invalid having regard to the ‘684 patent?
d) Improper Divisional – Is the ‘350 patent invalid as by improperly divided out of the patent application 341,340 having regard to that application and the other divided out applications?
e) What is the effective filing date of the application for the ‘350 patent? What is the effect of the disclosures in US patent 4,374,829 and European Patent Applicant?
f) Wilful Delay – Did Merck wilfully delay the prosecution of the application for the ‘350 patent and, if so, what is the effect.
4. Remedies
If a valid claim of the ‘350 has been infringed by non-exempt activity of Apotex
a) To what remedies are the Plaintiffs entitled?
b) To what remedies is the Defendant/Counterclaimant entitled?
3. The Witnesses
[11] There were thirteen fact witnesses and nine expert witnesses called by the parties. Except for opinions of the experts as to whether the ‘350 patent comprised one or several inventions, which is a question ultimately for the Court and not witnesses to determine, there was little disagreement between the witnesses. All witnesses were credible. Where it became necessary to choose among the experts, I prefer the evidence of Drs. Marshall, Garvas, Nelson, Wolfenden and Horovitz, who are not only recognized experts in their fields, but persons who were actually involved in relevant events in the critical periods in the 1960’s, 70’s and 80’s. The other experts, while helpful in many respects, were viewing some matters at issue more with the benefit of hindsight.
[12] Called as factual witnesses were:
1. Mr. Philippe Hébert, Vice-President of Marketing for Merck Frosst. He testified as to the marketing of lisinopril products by Merck in Canada and the effect of Apotex’s entry into that market.
2. Ms. Karen Feltmate, Vice-President of Marketing for AstraZeneca Canada. She testified as to the marketing of Astra lisinopril products in Canada and the effect of Apotex’s entry into that market.
3. Dr. Robert Dickinson, President of Delmar Chemicals, subpoenaed by Apotex. Delmar manufactured lisinopril in Canada in the early 1990’s some of which found its way into the hands of Apotex. Delmar was for a period of time licensed under the patent in accordance with the compulsory license scheme provided under the Patent Act until it was repealed. He testified as to the licensing and the manufacturing of batches of lisinopril which ultimately found their way to Apotex.
4. Dr. Bernard (Barry) Sherman, President of Apotex. He testified generally as to the manufacture and sale of lisinopril products by Apotex. He also spoke about lobbying efforts made by various pharmaceutical trade associations as well as Apotex and Merck against and for proposed (and ultimately successful) revisions to the Patent Act to get rid of compulsory licensing.
5. Mr. Jack Kay, Chief Operating Officer of Apotex. He also spoke as to lobbying by Apotex, Merck and trade associations as to amendments to the Patent Act to get rid of compulsory licensing.
6. Mr. James Keon, President of the Canadian Generic Pharmaceutical Association, previously named the Canadian Drug Manufacturers Association. This is a trade association representing generic pharmaceutical companies in Canada including Apotex. He was previously a member of the policy branch of Industry Canada and involved in revision of the Patent Act. He testified as to lobbying efforts made by trade associations and companies such as Apotex and Merck in respect to proposals to remove compulsory licensing from the Patent Act.
7. Dr. George Michaliszyn, Director of Life Sciences at the Federal Department of Industry Canada. He appeared under subpoena from Apotex and testified as to lobbying efforts by interested parties, including Merck, as to amendments to the Patent Act respecting compulsory licensing.
8. Mr. John Hems, Director of Regulatory Affairs for Apotex. He testified as to the preparation by Apotex of substances including lisinopril for submission to United States and Canadian government regulatory bodies for approval to sell products containing lisinopril in those countries.
9. Ms. Bernice Tao, Associate Director of U.S. Regulatory Affairs at Apotex. She testified as to the preparation by Apotex of lisinopril containing products for purposes of submissions to United States regulatory officials for approval for sale in that country.
10. Mr. Lance Lovelock, Vice-President of Quality Assurance at Apotex. He testified as to the sampling by Apotex of lisinopril materials received by it and of lisinopril containing materials formulated by Apotex, and the testing and retention of such samples.
11. Mr. Donald Barber, Formulation Development Manager at Apotex. He testified as to the use of lisinopril by Apotex in the development and testing of various formulations of drugs for research and for submission to regulatory authorities.
12. Mr. Gordon Fahner, Vice-President of Finance at Apotex. He provided summaries of the records kept at Apotex as to sales of lisinopril products and as to lisinopril used in respect of submissions to regulatory authorities, for quality assurance, and for research and development.
13. Ms. Patty De Luca, a Canadian process server. She testified that she delivered a letter into the hands of a person in New Jersey who she believed to be a United States patent attorney, Michael Sudal. That letter invited Sudal to contact Apotex’s lawyers concerning issues in the trial. Sudal never appeared as a witness.
[13] Expert witnesses were called by each of Merck, Astra and Apotex. All of the experts were qualified as such by the Court. All provided reports or affidavits however the parties did not elect to tender the whole of such documents into evidence. Only portions were deemed to have been read in evidence; certain other portions were ruled inadmissible on grounds, for instance, that the witness lacked expertise to address matters such as patent prosecution. Portions addressing ultimate issues for the Court to determine were read in, but have been given no weight. These witnesses, in order of appearance, were:
1. Dr. Paul Bartlett, called by Merck, an Emeritus Professor of Chemistry at the University of California, Berkeley (Exhibits 34 and 35). He testified as to the processes used by Delmar to manufacture lisinopril and the state of the materials during such process at dates critical to provisions of the Patent Act relating to exemptions from infringement. There was no rebuttal to his evidence although he was cross-examined.
2. Dr. Robert McClelland, called by Apotex, retired Professor of Chemistry at the University of Toronto (Exhibit 89). He gave evidence as to chemistry, organic, biological and medicinal, particularly that relating to the compositions at issue. Dr. McClelland’s general understanding of these matters was sound however, his evidence was acquired through knowledge looking in hindsight and not as a person involved at the relevant time.
3. Dr. Garland Marshall, called by Apotex, Professor of Biochemistry and Molecular Biophysics at Washington School of Medicine in St. Louis (Exhibit 144). He is an expert in medical chemistry, resin angiotensin system, cardiovascular pharmacology, and hypertension including ACE inhibitors. He was closely connected with developments in the area during the relevant period.
4. Dr. Alexander Klibanov, called by Apotex, Professor of Chemistry and Bioengineering at Massachusetts Institute of Technology (Exhibit 180). He was qualified as an expert in medicinal and biological chemistry and gave evidence as to the chemistry and biological features of the compounds of interest in these proceedings. His evidence was based on a hindsight review as he was not directly involved in this particular field at the time.
5. Dr. Robert Langer, called by Apotex, a Professor in the Chemical and Bioengineering Department of the Massachusetts Institute of Technology (Exhibit 187). He was qualified as an expert in chemical and biochemical engineering and gave the opinion that the developmental pathway with respect to the conversion of enalaprilat to the prodrug enalapril was clearly taught and thus, obvious to persons skilled in the art as of 1978.
Dr. Langer was not cross-examined and no rebuttal was offered as to his opinion.
6. Dr. Haralambos Gavras, called by Apotex, a Professor of Medicine at Boston University School of Medicine (Exhibit 211). He was qualified as a medical doctor with expertise in the treatment of cardiovascular conditions, including hypertension and chronic heart failure, the use of ACE inhibitors and the pharmacology of ACE inhibitors. He clearly stated that he was not an expert in chemistry. Dr. Gavras was involved in clinical research involving drugs used to treat hypertension, including ACE inhibitors, and treatment of patients with such drugs at the relevant time. His evidence is important in this regard.
The Plaintiffs put in evidence correspondence indicating that, at one time, they had contacted Dr. Gavras with a view to having him present evidence on their behalf. This correspondence indicated a view by one of the counsel for Merck that Dr. Gavras was seeking a large sum of money for doing so. That counsel did not give evidence as to what actually transpired. Dr. Gavras stated that he was seeking funding for his laboratory and heard nothing further from Merck’s counsel after such correspondence. Other evidence indicated that Dr. Gavras’ fees charged to Apotex’s solicitors are not extravagant. Apparently some fuss was made during pre-trial motions as to whether Dr. Gavras should give evidence. He did give evidence and I find that such evidence is in no way compromised or tainted.
7. Dr. Wendel Nelson, called by Astra, Professor of Medicinal Chemistry at the University of Washington, Seattle (Exhibit 239). He was qualified as an expert in the field of medicinal chemistry, particularly as to ACE inhibitors in the late 1970’s and early 1980’s. His involvement in the area was not as direct as that of others such as Wolfenden and Horovitz. He gave evidence as to the evolution of the development of ACE inhibitors in this period.
8. Dr. Richard Wolfenden, called by Astra, Professor of Biochemistry, University of North Carolina, Chapel Hill (Exhibit 253). He was qualified as an expert in the mechanism of enzyme action including the transition state and the development and design of inhibitors. His evidence is of particular relevance since he was, in the period of the 1960’s through 1980’s, involved directly in the fields relevant to this action. He authored major papers influential in the development of the Squibb inhibitor which was the first commercial oral inhibitor on the market.
9. Dr. Zola Horovitz, called by Merck, retired, Doctorate in Pharmacology and Director of Research at Squibb in the 1970’s (Exhibits 261 and 262). He was qualified as a pharmacologist with particular experience in the areas of hypertension and ACE inhibitors. He testified as to the development at Squibb of the first commercially available oral ACE inhibitor, Captopril. He gave evidence as to the effect of the Merck developments once they became known.
[14] In addition, Apotex read in portions of its examination for discovery of Merck’s designated witness Dr. Wryvatt, one of the persons named as inventor in the patent at issue. Astra agreed that it would be equally bound by the Merck discovery. Apotex also put in evidence a request to admit and response from Merck’s solicitors. Merck tendered no discovery or request to admit into evidence. Astra tendered portions of discovery and related documents of Apotex into evidence.
4. Background to the Biochemistry
[15] The experts were in general agreement as to much of the biochemical background useful in understanding the ‘350 patent.
[16] Amino acids are the basic building blocks from which living matter is constructed. There are twenty amino acids commonly found in nature, these have names such as proline, lysine, glutamine, etc. which names are often shortened to pro, lys and glu, etc. 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. Yet larger structures can result in configurations such as deoxyribonucleic acid (DNA) and, ultimately, living matter.
[17] Materials such as proteins and peptides occur in the body and serve various functions beneficial or otherwise. Enzymes are organisms present in the body that facilitate the conversion of such materials into other material usually by cutting off (cleaving) a portion of the molecule. This process is said to be reversible but usually only when rare conditions exist. The study of one such enzyme, the angiotensin converting enzyme, is of interest in this proceeding.
[18] Enzymes attach themselves to proteins or peptides, usually smaller in size, and break those proteins or peptides, often referred to as substrates, down into smaller fragments. Substrates are attached to certain locations on the enzyme, a surface or pocket, which is particularly adapted for that substrate. The terms “lock and key” and “hand in glove” are sometimes used to describe such attachment. The attachment may be due to one or more of the physical size and shape, electro–chemical forces and, the presence of metallic ions such as zinc. Activity during the process of attachment and cleaving of the substrate is called the transition state.
[19] Enzymes can be prevented from performing their function by enzyme inhibitors, which can be molecules having one or more of a particular size, structure and electro-chemistry designed to mimic the target substrate and occupy much of the pocket or site on the enzyme normally attracted to the substrate, so as to prevent the enzyme from doing its work. It is the design of such molecules that is the subject matter of the patent at issue.
5. Development of the Particular Compounds of Concern
[20] The particular compounds of concern are generally known as ACE inhibitors, that is, angiotensin converter enzymes inhibitors, useful in the treatment of hypertension.
[21] The development of the particular compounds of concern has been well documented in scientific publications authored by some of those named as inventors of the patent in suit, for example Trial Exhibit 102 “Evolution of Angiotensin-Converting Enzyme Inhibitors” by Wryvatt published in Clinical Physiology and Biochemistry in 1988 and Trial Exhibit 109 “A New Class of Angiotensin-Converting Enzyme Inhibitors” by Patchett et al. published in Nature in 1989. These publications, however, are not direct proof of the facts recited in them. Neither the inventors nor any of their colleagues appeared as witnesses at trial although one, Wryvatt, was examined for discovery and some portions of that examination were put in evidence at trial.
[22] Three expert witnesses presented at trial had direct experience with the development of antihypertension drugs, one was Dr. Haralambos Gavras, a medical doctor who was, at the relevant time, active in clinical trials and medical treatment of patients with certain drugs used to treat hypertension. Another was Dr. Richard Wolfenden, an expert enzymological chemist whose published scientific papers in the enzyme field, including transition state reactions, provided the basis for much development in this area. The third was Dr. Zola Horowitz an expert in pharmacology, who participated in the development of a commercially successful angiotensin converting enzyme inhibitor at Squibb, sold under the name Captopril. This Squibb product was the most immediate prior art relevant to the compounds of the patent at issue. Dr. Garland Marshall was also active in the field at the time although not as directly as these three.
[23] Dr. Gavras explained that, historically, there was until the middle 1960’s much doubt as to whether hypertensive patients could be treated. He described how, in the late 1960’s, certain hypertensive medications such as diuretics, methyldopa, and beta blockers were available. If one did not do the job, another was added in administration to a patient. In the 1970’s, a derivative of the venom of a poisonous snake, teprotide, was introduced. It was an ACE inhibitor administered intravenously. Teprotide was sometimes used in combination with a diuretic such as hydrochlorochiozide (HCTZ) in patients who did not respond to treatment with just one of them. When the Squibb product, Captopril, became available, it likewise would sometimes be used in combination with a diuretic where patients initially failed to respond.
[24] Dr. Wolfenden described scientific work directly related to ACE inhibitors. He described that in the late 1970’s, work in this area, including work that related to transition state analog inhibitors, was in its infancy. By the late 1970’s, it was known that the system whereby angiotensin, an eleven amino acid substrate was reduced to angiotensin I, a ten amino acid substrate, by a substance called renin, and further reduced to angiotensin II, an eight amino acid substrate, by an angiotensin converting enzyme. It was known that this system had an important role in the regulation of blood pressure in humans. Dr. Ondetti and others at Squibb determined in the early 1970’s that teprotide, an eight amino acid substance derived from snake venom was effective in lowering blood pressure in hypertensive patients. Dr. Wolfenden attributed remarkable insight to Dr. Ondetti and others, in applying principles that were hypothetical at the time, to the development of the ACE inhibitor we now know as Captopril.
[25] Dr. Horowitz was part of the team, including Dr. Ondetti and others, responsible for the Captopril development at Squibb. He explained that in the 1960’s, researchers at Squibb were able to determine some of the characteristics of the angiotensin converting enzyme that served to cut off (cleave) two terminal amino acids of angiotensin I at a peptide bond, so as to leave angiotensin II. At that time, the Squibb researchers came into contact with Dr. Ferreira, who had isolated venom from a Brazilian snake that Squibb believed might inhibit the angiotensin converting enzyme. Working with this venom, the Squibb researchers identified what became known as teprotide. This substance needed to be administered intravenously but proved to be an effective ACE inhibitor. Dr. Gavras, among others did early clinical work with teprotide.
[26] Squibb recognized that intravenous administration was not very desirable and sought a drug that could be administered orally. They come across a publication by Dr. Wolfenden which discussed possible inhibitors for a different enzyme. Squibb believed that sufficient similarities existed such that portions of the structure proposed by Wolfenden could be used, together with other molecular arrangements, to create an ACE inhibitor. Many compounds were tested, some of which were reported in paper by Dr. Ondetti et al. in Science in 1977. One of these compounds was, what is now known as Captopril. This compound could be administered orally and was shown, at the laboratory level, to be effective. Clinical testing went on through the 1970’s ultimately leading to government approval and commercial distribution of that product for use as an ACE inhibitor in the treatment of hypertension.
[27] It is not disputed that Captopril was a known ACE inhibitor useful in treating hypertension at a time before Merck made its discoveries relating to the patent at issue. In short, it is prior art.
[28] Captopril, as described by Dr. Horovitz, is not a standard peptide although it has certain characteristics of a peptide. As a chemical formula it can be stated as (D-2-Methyl-3-mercaptopropanol-L-proline). Diagrammatically it can be shown as:
[29] It is recognized by all parties that Captopril was a significant invention.
[30] Direct evidence as to the development of Merck’s compound is obtained only through the portions of the discovery tendered into evidence at trial by Apotex. From that evidence, it is clear that the persons named as inventors by Merck were aware of the developments at Squibb, including what is now known as Captopril and that they believed that the toxicity of the Squibb compound had yet to be tested. It was acknowledged that the Merck work that led to the patent at issue was done after Captopril was already known. These persons also knew of the structure of the snake venom compounds that preceeded Captopril, such as teprotide.
[31] The first patent application directed to the class of compounds at issue filed by Merck anywhere was United States application 968,249 filed December 11, 1978. The Canadian application 341,340 (‘340 application) which claimed priority from this United States application was filed in Canada on December 6, 1979.
[32] Merck had made some compounds falling within the general description of Formula I of the patents before filing the United States Patent application, but it is not clear from the evidence as to which or how many or to what degree they were tested. Lisinopril was first made by Merck in about May 1979. Enalapril had been made and tested earlier, in about January 1979. In vivo testing of lisinopril and enalapril maleate was reported in October 1979. It was not until about April 1983 that a clinical operational plan was established. Merck received approval to market lisinopril first in the United States later in the 1980’s.
6. What are Lisinopril, Enalapril and Enalaprilat?
[33] A class of compounds of which lisinopril is one, is described in the ‘340 application and claimed in that patent by means of a general formula, Formula I which contains seven locations R plus R1 through R6 at which a choice of several chemicals or molecules may be placed. It is estimated that easily billions of compounds could exist within this class. Sometimes such a claim is referred to as a Markush claim after a United States decision of that name where such a claim was first discussed (ex parte Markush (1925), 240 US OG 835).
[34] Although the experts were in agreement that there is no commonly accepted scientific definition of the terms, Formula I has been referred to as a “backbone” and the resulting structures when various R through R6 components are affixed have been referred to as “analogs”. In general, the ‘340 application and all related patents and applications refer to the compounds generally as carboxyalkyl dipeptides and derivatives thereof and all refer to the same “backbone”, Formula I. Where they differ is in the selection of chemicals and molecules which comprise each R through R6.
[35] The “backbone” Formula I may be depicted as:
Formula I
[36] Some of the patents divided out of the ‘340 application restrict themselves to classes that include compounds commonly known as lisinopril, enalapril and enalaprilat. Each of lisinopril, enalapril and enalaprilat share the common backbone of Formula I, they differ in some of the substituents found at some of the R through R6 positions. They each can be depicted in various ways. The written formula for each is:
Lisinopril: N-a-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline
Enalapril: N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline
Enalaprilat: N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline
[37] The differences between the molecular structure of each of these compounds can be depicted, using conventional stereochemistry illustration where a solid wedge indicates a molecule rising out of the page toward the reader, and a dotted wedge indicating a molecule directed away from the reader:
Lisinopril
Enalapril
Enalaprilat
[38] Using the jargon of some of the experts in this case, enalapril is the prodrug version of enalaprilat and lisinopril differs from enalaprilat in the molecular structure found in the R3 position.
[39] The concept of a prodrug, according to the evidence, was known to a person skilled in the art as of 1978. Some medicines, if taken orally, will pass through the intestinal wall reasonably well, so that they enter the bloodstream in the desired form. Other medicines do not pass through the intestinal wall or do so poorly. In order to facilitate the passage of such medicines through the intestinal wall, additions to the molecular structure are made so as to change the electrochemistry of the overall molecule. Once the molecule passes through the wall, the added portion breaks off, leaving the desired molecule in the bloodstream to do its work. It is the uncontradicted evidence of Dr. Langer that, given the molecular structure of enalaprilat in 1978, a person skilled in the art could readily convert it to the prodrug enalapril.
[40] Enalaprilat was found to be an effective antihypertensive but could only be administered intravenously. The much more desirable route of oral administration was achieved by creating a prodrug version, namely enalapril.
[41] Lisinopril fortunately has a molecular structure of such a nature that it passes through the intestinal wall sufficiently readily such that a prodrug version is unnecessary. It appears from data available at least until very recently that it has characteristics that make it slightly less effective as an oral medication than enalapril. More recent data suggests that it may be equally or more effective in some respects. From a clinical point of view, according to Dr. Gavras, enalapril and lisinopril are equally effective and they are as effective as Captopril, except that Captopril must be taken several times a day whereas the others are taken only once a day as their persistence in the body is better.
[42] Lisinopril, as a molecule, differs from enalaprilat only in the R3 position, although that difference enables it to be taken orally rather than the less desirable intravenous route.
[43] A useful depiction is found at Figure 7 taken from an article entitled “Evolution of Angiotensin-Converting Enzyme Inhibitors” by Wryvatt published in 1988 in Clinical Physiological Biochemistry.
[44] At the top is depicted various pockets or sites designated as S1, S11 and S21 located on the enzyme, to which the molecules enalaprilat, enalapril or lisinopril will attach themselves so as to inhibit angiotensin conversion. Keeping in mind Formula I, the site depicted as S11 is the location at which that part of the molecular structure designated as R3 will fit.
[45] It is Dr. Marshall’s evidence that the S11 site is fairly promiscuous, that it will accept R3 structures of a variety of types without particular discrimination thus, it is not particularly important what R3 is relatively speaking. He says lisinopril is an obvious variant of enalaprilat. Dr. McClelland is of a similar opinion.
[46] On the other hand Dr. Nelson states that, given that enalaprilat was known to be useful only if given intravenously, it would not have been readily apparent that changes in the R3 position could produce a molecule that could be administered orally. Dr. Wolfenden states that even if the differences from a molecular point of view between lisinopril and enalapril and enalaprilat appear relatively small, the substantial changes that result would not have been obvious to a person skilled in the art as of 1978 or 1979.
[47] Given the known prior art of Captopril, these are even greater differences in the molecular structure in comparison with lisinopril, enalapril and enalaprilat. Only the structure as normally depicted at the right hand side (C terminus) is similar to any of enalapril or enalaprilat or lisinopril. Dr. Horowitz, one of the Squibb scientists responsible for the discovery of Captopril, expressed the surprise and chagrin at Squibb when the Merck developments became known as they were unable to make those discoveries. Dr. Marshall, one of Apotex’s experts, described the Merck discovery in arriving at the backbone represented by Formula I in terms of “eureka”. There is no doubt that, in respect of the prior art known as of 1978 or 1979, the backbone of Formula I, enalapril, enalaprilat and lisinopril were new and inventive. Apotex does not challenge the inventiveness of the class or of lisinopril specifically.
[48] I find, on the evidence, favouring that of Drs. Nelson and Wolfenden that each of lisinopril, enalapril and enalaprilat were, as of 1978 or 1979 inventively different from each other. If separate patent applications had been filed, for instance by third parties, for each of lisinopril, enalapril and enalaprilat, they would have been allowed as separate, inventively different, patents.
7. Combination with Diuretics
[49] Diuretics, such as hydrochlorothiazide (HCTZ) were, for at least a decade prior to 1978, known and used in the treatment of hypertension, according to Dr. Gavras. They reduce the amount of fluid, hence pressure, in the circulatory system. Dr. Gavras stated that for several years prior to 1978, a clinician treating hypertensives would, if one medicine was seen not to be sufficiently effective, add a second or even a third. Thus HCTZ could be added to, for instance, a beta blocker. From a clinical point of view, the administration of a diuretic with another antihypertensive was well known before 1978.
[50] The evidence shows that in practice, the commercial drugs produced by the Plaintiffs indicate that the effect of adding a diuretic to lisinopril in tablet form is simply cumulative, not synergistic, nor antagonistic. The effect is just as Dr. Gavras and others had been practicing for years before.
[51] Dr. Horovitz stated that the combination of a diuretic with another antihypertensive such as Captopril had to be approached with caution. One could not always assume that it would work or, more importantly, be safe and effective. He stressed the need for clinical trials.
[52] From a patent point of view, there is little difference between these opinions. Dr. Gavras is saying that combinations with antihypertensives and diuretics have worked well in the past and there is every reason to believe that these combinations would work equally well in the future. Dr. Horowitz’s caution is essentially on the regulatory side: will it pass muster from a regulatory point of view? The government regulatory bodies always require testing. As stated by Lederman J. in Bayer A/G v. Apotex Inc. (1995), 60 C.P.R. (3d) 58 (Ont Gen. Div.) at page 89 (affirmed (1998) 82 C.P.R. (3d) 526 (Ont CA)), testing for regulatory approval relates to commercial acceptability as opposed to whether it is operable as promised by the patent. While I appreciate that Lederman J. was addressing an argument of inutility, this applies equally to obviousness.
[53] While it is unnecessary for me to make a finding as to obviousness in view of my findings as to enalapril and lisinopril being different inventions, I find that there is no inventiveness in the simple addition of a diuretic such as HCTZ to these compounds.
8. Commercialization of Lisinopril Products
[54] The first commercialization of lisinopril products in Canada was made by Merck in the early 1990’s and closely followed by Astra. On October 26, 1990, Merck received a Notice of Compliance from Health Canada giving it permission to market lisinopril containing drugs in Canada in 5, 10, 20 and 40 milligram (mg) strength tablets for oral administration. Merck sold these drugs under the name PRINIVIL. Commencing at the end of 1990, Merck began to sell these drugs in Canada in tablets of 5, 10 and 20 milligram strength. A 40 milligram strength was never sold in Canada. These sales have continued uninterrupted through to the date of trial. At the end of 1999, a further approval was obtained to sell such a drug in the 2.5 milligram strength. Some sales at this strength were made but have stopped.
[55] Merck does not make lisinopril in Canada, it obtains it from elsewhere, however it formulates lisinopril by adding to it other ingredients, expedients, and produces tablets in the 5, 10 and 20 milligram strengths in Canada. The 2.5 milligram strength tablet was acquired from abroad and packaged in Canada for distribution for a short period of time. In addition, Merck formulates in Canada and exports to the United States 5, 10 and 20 milligram versions of lisinopril tablets, and has done so since 1997.
[56] On October 29, 1992, Merck obtained another Notice of Compliance, this one relating to a drug containing both lisinopril and a diuretic known as hydrochlorothiazide (HCTZ) in strengths of 20/12.5 and 20/25 milligrams of lisinopril/HCTZ. Another Notice of Compliance for such a combination in a 10/12.5 strength was received in June of 1994. Since the dates of such Notices, Merck has been selling these combination drugs in Canada under the name PRINZIDE.
[57] Since its entry into the Canadian market, Merck estimates that it has total sales in excess of around two hundred and fifty million dollars for PRINVIL and thirty million dollars for PRINZIDE.
[58] Astra entered into an arrangement with Merck, the details of which were not given, whereby Astra was licensed in respect of lisinopril products in Canada. Astra and its predecessors, ICI and Zeneca, have been selling lisinopril containing tablets in 5, 10 and 20 milligram strengths in Canada since at least as early as 1993, under the name ZESTRIL. It also sells a tablet containing a combination of lisinopril and HCTZ in 10/12.5, 20/12.5 and 20/25 milligram strengths under the name ZESTORETIC. Astra does not make any of these tablets in Canada, it imports them in bulk from related corporations and packages them in Canada for distribution. Peak sales for ZESTRIL occurred in 1996 at the forty million dollar level.
[59] Apotex obtained app