Apotex Inc. v. H. Lunbeck A/S

Apotex Inc. v. H. Lunbeck A/S
Court (s) Database
Federal Court Decisions
Date
2013-02-26
Neutral citation
2013 FC 192
File numbers
T-1407-09
Decision Content
Date: 20130312
Docket: T-1407-09
Citation: 2013 FC 192
BETWEEN:
APOTEX INC.
Plaintiff
and
H. LUNDBECK A/S
Defendant
AND BETWEEN:
H. LUNDBECK A/S
Plaintiff by Counterclaim
and
APOTEX INC. and
APOTEX PHARMACHEM INC.
Defendants by Counterclaim
PUBLIC REASONS FOR JUDGMENT
(Confidential Reasons for Judgment Issued 26 February 2013)
HARRINGTON J.
[1] This action for impeachment of a patent of invention and the counterclaim for its infringement deal with the compound known as Escitalopram or (+)-Citalopram. It belongs to a class of compounds known as SSRIs (Selective Serotonin Reuptake Inhibitors, or 5-HT reuptake inhibitors). It has proved useful in the treatment of clinical depression. It is branded in Canada as Cipralex, in the United States as Lexapro and in the United Kingdom as Cipramil. It was invented in Denmark in 1988, and has been patented in Canada, and in many other countries. The patent claims (+)-Citalopram itself, as well as methods to make it and non-toxic salts thereof.
[2] Apotex Inc. has wanted to market its generic version of (+)-Citalopram for some time. It was first thwarted by Lundbeck who obtained a Court order pursuant to the Patented Medicines (Notice of Compliance) Regulations [PM (NOC) Regulations] the effect of which was to prohibit the Minister of Health from issuing a Notice of Compliance. That Notice would have permitted Apotex market entry. However, the order did not purport to determine whether or not the patent was valid.
[3] In this action Apotex seeks a declaration that Canadian patent 1,339,452 (‘452) is, and has always been, invalid. Lundbeck, for its part, has counterclaimed that Apotex and a related corporation, Apotex Pharmachem Inc., have infringed the patent. It seeks, among other things, an accounting of profits. Apotex admits that if the patent is valid, in whole or in part, it has infringed. Apotex Pharmachem Inc. produced (+)-Citalopram through a method not covered by the patent. Thus, it has infringed only if Lundbeck’s claim for the compound (+)-Citalopram itself is valid.
[4] An invention must be something new. Apotex alleges that (+)-Citalopram is not new so that Lundbeck invented nothing at all. It says (+)-Citalopram was anticipated in the prior literature and, as well, was obvious to those to whom the patent is addressed.
[5] In order to be patentable, an invention must also be useful. In a later patent application, Lundbeck stated that the Pamoic Addition Salt of (+)-Citalopram was toxic. Since that salt figures in the claims for (+)-Citalopram itself the patent is alleged to be invalid for inutility.
[6] The subject matter must also be patentable (Harvard College v Canada (Commissioner of Patents), 2002 SCC 76, [2002] 4 SCR 45, [2002] SCJ No 77 (QL); Monsanto Canada Inc v Schmeiser, 2004 SCC 34, [2004] 1 SCR 902, [2004] SCJ No 29 (QL)). However, this is not in issue in the present case.
[7] A patent represents a bargain between the inventor and the state. In consideration of the grant of a monopoly, the inventor must fully and properly disclose the invention so that when the monopoly expires, others may reproduce the product or process involved without undue difficulty. The Patent Act requires the applicant to provide a specification which discloses what has been invented and how to replicate it. The specification ends with a claim or series of claims over which a monopoly is asserted. According to Apotex, the specification is fatally defective.
[8] One of the claims of the patent, claim number 7, which on its face is a method or process for preparing (+)-Citalopram, is said to be insufficiently disclosed and is not based on routine techniques which would have been known to the skilled addressee in 1988. The other process claims are also invalid because they are dependent on claim number 7.
[9] The patent is also allegedly insufficient because it states that “[r]esults upon administration to human beings have been very gratifying”. There had actually been no tests on human beings at the time of the application. This constitutes a failure to fully disclose the invention.
[10] There need not be proof positive to back up statements, or promises, in a specification. The statement may be premised on a prediction, as long as there is a sound basis therefor. As shall be seen, (+)-Citalopram is an enantiomer of the racemate Citalopram, which together with precursors thereof was covered by earlier patents. By 1988, Citalopram had proved useful in the treatment of depression. According to Apotex, the ‘452 patent promises that (+)-Citalopram is therapeutically more potent than Citalopram. There was no sound basis for making that prediction as (+)-Citalopram had not as then been tested in human beings. The fact that the prediction later turned out to be true is irrelevant.
[11] I shall deal with both invalidity and infringement. As I stated at trial, no matter my holding on validity, I would deal with infringement. If I were to hold that the patent is invalid, and be reversed in appeal, the likelihood is that the matter would be referred back to me to deal with the counterclaim for infringement. Hence, it is better to cover all aspects of the litigation now.
[12] These reasons are broken down as follows:
PARAGRAPHS
I. PATENT CONSTRUCTION
13-19
II. THE SKILLED ADDRESSEE
20-23
III. AN ORGANIC CHEMISTRY PRIMER
24-33
IV. THE EXPERTS
34-52
V. PATENT ‘452
53-59
VI. HISTORY OF THE PROCEEDINGS
60-68
VII. INVALIDITY
A. Anticipation
B. Obviousness
i. Motivation
ii. Resolution
iii. Chiral HPLC
iv. The Experiments
v. Lundbeck’s Efforts
vi. Mosaic of Prior Art
C. Inutility
D. Insufficient Disclosure
E. Sound Prediction
69-254
69-78
79-218
99-119
120-161
162-195
196-202
203-207
208-218
219-224
225-240
241-254
VIII. INFRINGEMENT
A. Punitive Damages
B. Accounting of Profits
C. The Profits
D. Delivery-Up or Destruction
E. Permanent Injunction
F. Interest
255-311
257-266
267-272
273-304
305
306
307-311
IX. COSTS
312
X. CONFIDENTIALITY
313-314
XI. DRAFTING OF JUDGMENT
315
I. PATENT CONSTRUCTION
[13] The starting point of any inquiry into either invalidity or infringement is the language and meaning of the patent within the context of the Patent Act (Free World Trust v Électro Santé Inc, 2000 SCC 66, [2000] 2 SCR 1024, 9 CPR (4th) 168, [2000] SCJ No 67 (QL); Whirlpool Corp v Camco Inc, 2000 SCC 67, [2000] 2 SCR 1067, 9 CPR (4th) 129, [2000] SCJ No 68 (QL)).
[14] Patents are a creature of statute, in this case the Patent Act, as it was immediately prior to 1 October 1989.
[15] Section 34 thereof required that the patent application contain a specification cumulating with a claim or claims “defining distinctly and in explicit terms the subject-matter of the invention for which an exclusive privilege or property is claimed.” It must be sufficiently full, clear, concise and exact “as to enable any person skilled in the art or science to which it pertains, or to which it is most closely connected, to make, construct, compound or use it.”
[16] The claims are to be read in an informed and purposive way so as to permit fairness and predictability and to define the limits of the monopoly. One way of doing this is to separate the essential from the non-essential. As Mr. Justice Binnie stated in Whirlpool at paragraph 45:
The key to purposive construction is therefore the identification by the Court, with the assistance of the skilled reader, of the particular words or phrases in the claim that describe what the inventor considered to be the “essential” elements of his invention.
[17] However, ultimately, it is not for the skilled reader to tell the Court what the patent means; it is for the Court to tell the parties what it means. A patent is not an ordinary document. It meets the definition of a “regulation” in the Interpretation Act, and must be read to assure the attainment of its objects. “[C]laims construction is a matter of law for the judge, and he was quite entitled to adopt a construction of the claims that differed from that put forward by the parties.” (Whirlpool at para 61.)
[18] Pursuant to section 27 of the Patent Act, as it was, an inventor or legal representative thereof was entitled to obtain a patent for:
…an invention that was
(a) not known or used by any other person before he invented it,
(b) not described in any patent or in any publication printed in Canada or in any other country more than two years before presentation of the petition hereunder mentioned, and
(c) not in public use or on sale in Canada for more than two years prior to his application in Canada
…une invention qui
a) n'était pas connue ou utilisée par une autre personne avant que lui‑même l'ait faite,
b) n'était pas décrite dans quelque brevet ou dans quelque publication imprimée au Canada ou dans tout autre pays plus de deux ans avant la présentation de la pétition ci‑après mentionnée, et
c) n'était pas en usage public ou en vente au Canada plus de deux ans avant le dépôt de sa demande au Canada
[19] An invention was defined at section 2 as meaning:
[…] any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture or composition of matter
[…] Toute réalisation, tout procédé, toute machine, fabrication ou composition de matières, ainsi que tout perfectionnement de l'un d'eux, présentant le caractère de la nouveauté et de l'utilité.
II. THE SKILLED ADDRESSEE
[20] According to the abstract in the patent specification, the invention relates to the two novel enantiomers of Citalopram and to their use as antidepressant compounds as well as to possible use as geriatrics or in the cure of obesity and alcoholism.
[21] Citalopram is stated to be 1-(3-Dimethylaminopropyl)-1,-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, and is accompanied by a diagram of the chemical formula.
[22] It goes without saying that the patent is not addressed to this Court as presently constituted. The Court needs the assistance of experts in order to understand its technical aspects. The patent is notionally addressed to a person skilled in the art or science to which the subject matter relates and is to be read as such a person would have read it when it first became public, which was in June 1988. The parties have called a great array of experts to assist the Court in this regard. There is no significant disagreement as to the identity of this hypothetical skilled addressee. He or she is a medicinal chemist, probably with a doctorate, and has spent at least a few years in a laboratory. The addressee is either part of or has access to a team, which includes analytical chemists, familiar with the principles of organic chemistry and techniques then available which could be used in an effort to separate racemic mixtures into their two enantiomers. Access would also be had to pharmacologists, psychiatrists and to drug formulators.
[23] More shall be said about this skilled addressee under the topic of Obviousness.
III. AN ORGANIC CHEMISTRY PRIMER
[24] This case deals with the element “carbon”, which is essential to human life. Indeed carbon is the very subject of organic chemistry. There is no disagreement among the experts as to the basic principles involved.
[25] Drawing upon the opinion of Dr. Martin Semmelhack, a professor of chemistry at Princeton University, called by Apotex, organic chemistry concerns the study of molecules containing carbon atoms. Molecules are collections of atoms arranged in a particular order. Carbon atoms can form bonds both with other carbon atoms and with other atoms. These bonds may take the form of long chains or cyclic structures. They are three-dimensional.
[26] Atoms bond to each other in various ways. Covalent bonds arise from atoms sharing electrons, while ionic bonds (common in salts) are bonds between charged atoms.
[27] Turning now to stereochemistry, isomers are molecules which have the same molecular formula but either have different connectivities among the atoms (known as constitutional isomers), or have the same connectivity but different orientation in space (known as stereoisomers).
[28] Stereoisomers are molecules with the same atoms and the same chemical bonds but different in how they are oriented in space. Two varieties are enantiomers and diastereomers. Enantiomers are non-superimposable mirror images of one another. The word chiral, Greek for handedness, is often used because the two human hands are non-superimposable mirror images of each other. Diastereomers are stereoisomers that are not enantiomers.
[29] Enantiomers share all the same physical and chemical characteristic such as boiling point, melting point and solubility.
[30] Because enzymes and protein receptors in the body are chiral, they may react differently with one or the other enantiomer of the same compound.
[31] When natural substances are recreated in a laboratory, the result is often a 50/50 mixture of the two enantiomers. This mixture is known as a racemate. The two enantiomers within may be identified by whether they rotate a plane of polarized light to the right, identified as the (+) enantiomer, or to the left, identified as the (-) enantiomer. Another method of identifying them is based on the sizing of atoms attached to the carbon centre, in accordance with what are known as the Cahn-Ingold-Prelog rules. In a molecule with a single stereogenic centre, one will be known as the S-enantiomer and the other as the R-enantiomer. There is no direct correlation between the (+) and (-) and the R and the S nomenclatures. Citalopram is S- and (+).
[32] Because enantiomers have the same physical and chemical characteristics, it may be difficult, if not impossible, to separate them. However, unlike enantiomers, diastereomers have different chemical and physical properties, such as different solubility and melting points. This difference plays an important role in techniques which can be used to resolve a racemate in order to isolate enantiomers. This is one of the fundamental challenges of this case.
[33] All agree it was common general knowledge in 1988 that racemates could be easily identified by their chemical structure, and that there might well be differences between the two enantiomers, and between each of the enantiomers and the racemate. In terms of medicine, it was also common general knowledge that since one enantiomer might react better than the other with enzymes and protein receptors within the body, one might have more therapeutic effect than the other. The other might even have most unfortunate side effects. However, knowledge of the characteristics of the enantiomers could only be had by resolving the racemate in sufficient quantity to allow for testing.
IV. THE EXPERTS
[34] As part of its impeachment case, Apotex called Dr. Martin F. Semmelhack, Dr. Rick Lane Dannheiser, Dr. Peter Jenner, Mr. Thomas Beesley, Dr. John Caldwell and Dr. René Levy. Apotex’s factual witnesses were also experts in their own right. Unless ordered otherwise, a party is limited to five experts. However, on consent, I ordered that both parties could call more than five expert witnesses.
[35] For its part, Lundbeck called Dr. Stephen Graham Davies, Dr. Daniel Wayne Armstrong, Dr. Peter Myers, Dr. Pierre Blier and Dr. Gerd Bode. Lundbeck’s factual witnesses were also experts in their own right.
[36] Then in reply to the evidence of Dr. Davies, Apotex called Sir Jack Baldwin and recalled Dr. Dannheiser.
[37] Each side called one expert witness with respect to the calculation of profits in the event of infringement.
Dr. Martin Semmelhack
[38] Dr. Semmelhack is currently the Associate Chair of the Chemistry Department at Princeton University. The focus of his early independent research in the late 1960s at Cornell University was organic synthesis. He is an organic chemist well aware of stereochemistry, racemates and enantiomers. Since the 1970s, he has taught concepts, including the resolution of racemic mixtures and the impact of stereochemistry on biological systems. He is well respected in academia and is a noted author. His career has been spent in academia, except in 1988 and 1989 when he served as Department Head of Medical Chemistry and then as Consulting Director at the Medical Research Division of American Cyanamid. He was qualified as an expert in organic chemistry and organic synthesis. His evidence focused on ways and means Citalopram, or a precursor thereof, could be resolved into its two enantiomers, based on the common general knowledge, literature and techniques readily available to the addressee of the ‘452 patent in 1988.
Dr. Rick Lane Dannheiser
[39] Dr. Dannheiser obtained his Ph.D in Organic Chemistry from Harvard University in 1978, the same year in which he joined the Massachusetts Institute of Technology. He is their Arthur C. Cope Professor of Chemistry. His laboratory currently deals with the development of new strategies for the synthesis of complex molecules. He too is well published, and was qualified as an expert in organic chemistry and synthetic organic chemistry. Like Dr. Semmelhack, his opinion related to ways and means to arrive at (+)-Citalopram, without recourse to the ‘452 patent.
Mr. Thomas Beesley
[40] Mr. Beesley has a master of science degree from St. John’s University. His career has been in industry. He was at the forefront of the development of some of the analytical tools for separating racemates, including High Performance Liquid Chromatography (HPLC), which was cutting-edge technology in the 1980s. In 1983, he came across Dr. Armstrong, called by Lundbeck. Dr. Armstrong was on the lecture circuit promoting molecules known as Cyclodextrins which could facilitate the resolution of various isomers. To that end, he and Dr. Armstrong formed Advanced Separation Technologies Inc (Astec). He was qualified as an expert in chromatography, one of the techniques available to resolve racemates, and, in particular, by the use of chiral HPLC.
Dr. Peter Jenner
[41] Dr. Jenner is emeritus professor of pharmacology at King’s College, London. He began his training as a pharmacist. His doctorate at the University of London was in the area of drug metabolism and pharmacokinetics. He has worked throughout his career with medical chemists, clinical neurologists and psychiatrists. He was qualified as an expert in pharmacology, drug metabolism and pharmacokinetics, particularly with respect to centrally active drugs used to treat psychiatric and neurological disorders. His testimony did not relate to ways and means to resolve racemates but rather as to reasons to resolve them. In other words, he dealt with what would have motivated the skilled addressee at the time to arrive at (+)-Citalopram.
Dr. John Caldwell
[42] Dr. Caldwell served as Dean of the Faculty of Medicine of the University of Liverpool from 2002 to 2010 and Pro-Vice Chancellor of that University from 2007 until his retirement last year. He is currently professor emeritus. He has a Ph.D in Biochemistry from St Mary’s Hospital Medical School and in 1987 received his doctorate of science in Pharmacology from the University of London for distinction in drug metabolism. The focus of his work has been upon, among other things, the importance of stereochemistry in drug development. He is an author and editor and serves or has served on the editorial boards of a number of scientific publications. In 1989, he co-founded the journal Chirality to address a diverse range of issues relating to stereochemistry, including drug development, pharmacology, synthesis and analysis. He has consulted both with government regulators and industry. Consequently, he qualified to give expert advice as a pharmacologist with expertise in drug metabolism and pharmacokinetics and as to the significance of stereochemistry in drug development, including regulatory policy and practice referable thereto. He testified as to the importance of stereochemistry to pharmaceutical companies and government regulators in the 1980s.
Dr. René Levy
[43] Dr. Levy is professor emeritus at the Department of Pharmaceutics at the University of Washington, and advisor to the Metabolism and Transport Drug Interaction Database which he founded in 2002. He obtained his Ph.D in Pharmaceutical Chemistry from the University of California in 1970. In 1977, he became a full professor of pharmaceutical sciences and adjunct professor of neurological surgery at the University of Washington, and served as Chairman of the Department of Pharmaceutics in its School of Pharmacy from its inception in 1980 until 2006. He has specialized in drug metabolism and like the other experts, is a noted author. He was qualified as an expert in metabolism, pharmacokinetics and pharmacodynamics of drug products and their metabolites, including the consequences of stereoselectivity therein. He dealt with statements, or implications, in the patent about the use of (+)-Citalopram as an antidepressant in humans, whether it was predicted that it had more therapeutic benefits than Citalopram itself, and whether there was a sound basis for making such a prediction.
Dr. Stephen Graham Davies
[44] For its part, Lundbeck called Dr. Davies. He has been teaching at the University of Oxford since 1980, where he is the Waynflete Professor of Chemistry. From 2006 to 2011, he was also chairman of its Department of Chemistry. He obtained his Ph.D in Chemistry from Oxford in 1975 and his doctorate of science degree in Chemistry from the University of Paris in 1980. In 1989, he founded and is still editor-in-chief of Tetrahedron Asymmetry, a journal which reports advances in knowledge of stereochemistry. In 1991, he founded and is the Director of Oxford Asymmetry International PLC. He has received various awards and has acted as a consultant to a number of pharmaceutical companies. He has given evidence in affidavit form or viva voce on behalf of Lundbeck in a number of jurisdictions in which the (+)-Citalopram invention has been challenged.
[45] There was some debate as to whether he should have been qualified, as proposed by Lundbeck, in medicinal chemistry. In the end, I qualified him as an expert in medicinal chemistry and organic chemistry, including resolution techniques, and stereochemistry. His testimony covered a broad range of topics, including obviousness and insufficiency. He also commented on the expert reports of Drs. Semmelhack, Dannheiser, Caldwell and Jenner.
Dr. Daniel Armstrong
[46] Dr. Armstrong is the Robert A. Welch Professor of Chemistry at the University of Texas at Arlington. He teaches courses in separation science and directs research at the undergraduate and graduate levels in bio-analytical chemistry, separation science, colloid science and organic chemistry. He has expertise in separation of racemic mixtures by various methods, including fractional recrystallization, kinetic resolutions, direct crystallization of enantiomers and chiral HPLC. He is a named inventor on 14 United States patents, mainly related to the separation of racemic mixtures by HPLC and other separation techniques. As aforesaid, together with Mr. Beesley, he helped found Astec, a company specializing in enantiomeric separations, mainly using Cyclodextrin chiral HPLC columns. He was frequently retained by scientists and clients to attempt to separate enantiomers, and has regularly consulted with both brand name and generic pharmaceutical companies on issues related to the separation of enantiomers. Again, as with the other experts, his credentials, his expertise, his publications and his role on editorial boards are most impressive. He was qualified as an expert in resolution techniques, including chiral HPLC.
Dr. Peter Myers
[47] Dr. Myers is a professor of separation science in the Department of Chemistry at the University of Liverpool. His career has been split between industry and academia. He has been very much involved in the study and synthesis of silica microparticles for HPLC. Beginning in 1979, he worked with Phase Separations, a United Kingdom company involved in the manufacture and distribution of chromatography products. After its purchase by Waters Corporation, an American company, in 1995, he continued as a consultant. He has been involved in the development of silica products, including products used by Astec, the company established by Dr. Amstrong and Mr. Beesley. He was qualified as an expert in separation science, including chromatography and the manufacture of chromatographic silica. He testified as to the feasibility of arriving at (+)-Citalopram in 1988 by means of chromatography.
Dr. Pierre Blier
[48] Dr. Blier is currently a full professor at the Department of Psychiatry in cellular and molecular medicine, Faculty of Medicine, University of Ottawa; adjunct professor, Department of Psychiatry, McGill University; adjunct professor, Department of Neuroscience, Carleton University; and Director of the Mood Disorders Research Program at the University of Ottawa’s Institute of Mental Heath Research. He obtained his Ph.D in Neuroscience from the Université de Montréal in 1985. He has obtained many peer reviewed research grants and has written extensively. He was qualified as an expert in neuropsychology including pharmacokinetics and pharmacodynamics with respect to SSRIs. He is also a physician specializing in the treatment of mental health illnesses, more particularly depression. He testified with respect to the therapeutic benefits of (+)-Citalopram and the promises, if any, in the patent, with respect to its benefits in the treatment of depression in humans in comparison with Citalopram.
Dr. Gerd Bode
[49] Dr. Bode’s expert report was taken as read. He was not cross-examined by Apotex. He has an M.D. and Ph.D and is an expert in pathology, neuropathology, pharmacology and toxicology. His evidence related to the alleged toxicity of (+)-Citalopram Pamoate.
Sir Jack Baldwin
[50] Apotex called Sir Jack Baldwin to reply to the opinion of Dr. Davies with respect to the “Baldwin Rules”, so called, which he had developed in the 1970s. He was Dr. Davies’ predecessor as the Waynflete Professor of Chemistry at Oxford, and has been the recipient of many awards. A knighthood was conferred upon him in 1997 for his contributions in organic chemistry. He was qualified as an expert in organic, synthetic and biological chemistry. Like Dr. Davies, he has given evidence in other jurisdictions with respect to (+)-Citalopram, however always on the side that submitted the patent should be held to be invalid.
[51] Finally, Dr. Dannheiser was re-called to take issue with some of Professor Davies’ opinions.
[52] I say, without hesitation, that not only were all these witnesses superbly qualified to offer expert opinion to the Court, but they were, each and every one, over qualified. They are not ordinary medicinal chemists, ordinary analytical chemists, ordinary pharmacologists and what have you. Each and every one is a superstar. The challenge they faced, and the challenge facing the Court, is whether they were able, in a sense, to reduce their expertise to that of the skilled addressee in 1988.
V. PATENT ‘452
[53] The application was filed 13 June 1989. The patent was issued 9 September 1997, good for 17 years. Its priority date is stated to be 14 June 1988, the date of the first patent application which was filed in the United Kingdom. Lundbeck has suggested an April priority date, on the grounds that that was when (+)-Citalopram was invented. However, it did not pursue that point with vigour and, in any event, the experts agree that the situation did not change between April and June 1988.
[54] Its inventors were two Lundbeck employees: Dr. Klaus Peter Bøgesø and Jens Perregaard.
[55] To expand upon the abstract, according to Dr. Jenner, the patent is addressed to chemists and pharmacologists with knowledge of antidepressant drugs. It relates to the enantiomers of Citalopram and their use in the treatment of depression in humans. It also relates to methods for obtaining those enantiomers.
[56] Claims 1 through 5 relate to (+)-Citalopram itself, including in salt form and composition, while claims 6 through 11 relate to an intermediate compound and methods of using that compound to make (+)-Citalopram. These comments are not controversial. What is more controversial is the view of some that there is a prediction that (+)-Citalopram is more potent in humans than Citalopram.
[57] Dr. Davies notes that the specification states that it had now (in 1988) proved possible to resolve the intermediate diol of Citalopram into its enantiomers and in a stereoselective way to convert those enantiomers to the corresponding Citalopram enantiomers. A “diol” is an alcohol containing two hydroxyl groups in its molecule.
[58] The patent then sets out two methods of resolution, called “A” and “B”-“C”, described in chemical reaction schemes. These reactions involve resolution of the intermediate diol or an ester thereof followed by conversion of the resultant precursor molecules into the enantiomers of Citalopram by the use of specific reagents and conditions. I shall expand upon this later on in these reasons.
[59] The specification ends with 11 claims:
i. Claim 1 is for Citalopram and non-toxic acid addition salts thereof.
ii. Claim 2 covers the Pamoic Acid Salt of (+)-Citalopram.
iii. Claim 3 covers an antidepressant pharmaceutical composition containing an effective amount of (+)-Citalopram, accompanied by a pharmaceutically acceptable diluent or adjuvant.
iv. Claim 4 is identical to claim 3, except that the composition is of the Pamoic Acid Salt of (+)-Citalopram as the active ingredient.
v. Claim 5 is dependent on claims 3 and 4, and is a pharmaceutical composition in unit dosage form.
vi. Claim 6 is directed to the (-) enantiomer of the intermediate diol, and an ester thereof.
vii. Claim 7 refers to a method of producing (+)-Citalopram.
viii. Claims 8 through 11 are methods dependent on claim 7.
VI. HISTORY OF THE PROCEEDINGS
[60] It all began with the PM (NOC) Regulations. They have been the subject of numerous decisions, including those of the Supreme Court in Merck Frosst Canada Inc v Canada (Minister of National Health and Welfare), [1998] 2 SCR 193, 80 CPR (3d) 368, [1998] SCJ No 58 (QL); Bristol-Myers Squibb Co v Canada (Attorney General), 2005 SCC 26, [2005] 1 SCR 533, [2005] SCJ No 26 (QL), at paragraphs 5-24; and Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61, [2008] 3 SCR 265, [2008] SCJ No 63 (QL) (Plavix), at paragraphs 7 and 12-17.
[61] In accordance with those Regulations, in April 2007 Apotex served a Notice of Allegation upon Lundbeck Canada Inc., the licensee of the patent. The notice asserted that patent ‘452 was invalid on various grounds. One of those grounds, an invalid selection patent, was not pursued in this trial. In turn, Lundbeck filed a Notice of Application in this Court, court docket number T-991-07 the following month, in which it sought an order in accordance with the Regulations that the Minister of Health be prohibited from issuing a Notice of Compliance until the expiration of the patent.
[62] In February 2009, in Lundbeck Canada Inc v Canada (Minister of Health), 2009 FC 146, 343 FTR 53, [2009] FCJ No 249 (QL), I upheld the application and so prohibited the Minister from issuing Apotex a Notice of Compliance. This decision was affirmed by the Federal Court of Appeal, 2010 FCA 320, 88 CPR (4th) 325, [2010] FCJ No 1504 (QL). Application for leave to appeal to the Supreme Court was dismissed, SCC Case Information 34066.
[63] The PM (NOC) Regulations are, in theory, summary in nature. They were not thought binding upon the parties either as to validity or infringement. The issue was simply whether the Minister should have been prohibited from, in effect, licensing Apotex. The parties are entitled to litigate validity and infringement in an action, as opposed to an application. Lundbeck only had to meet the allegations set out in the Notice of Allegation, which did not even raise the issue of non-infringement.
[64] As I mentioned in those proceedings, a trial is much more to be desired from the judge’s point of view, and indeed from the parties’ point of view. Unlike in an action, in an application there is no full discovery of documents and examination for discovery. There is no live testimony in court. The evidence is limited to affidavits and cross-examinations thereon. The Court is unable to ask clarifying questions of the expert witnesses. In this trial most of the experts are new and much of the evidence is different.
[65] It is not all that uncommon that a patent be held invalid at trial, even though the Minister had earlier been prohibited from issuing a Notice of Compliance. In Plavix, above, the Supreme Court upheld this Court’s issuance of a prohibition order. However, at the subsequent trial on the merits, the patent was held to be invalid (Apotex Inc v Sanofi-Aventis, 2011 FC 1486, 101 CPR (4th) 1, [2011] FCJ No 1813 (QL), currently in appeal).
[66] This Court has developed the practice, where possible and practicable, to assign the trial to the judge who heard the Notice of Compliance application. The theory is that these pharmaceutical patents have a long learning curve, and so it is better to assign the trial to a judge who has already looked at the patent. This, without more, does not give rise to a conflict of interest, or to an apprehension of bias (Sanofi-Aventis Canada Inc v Apotex Inc, 2008 FCA 394, [2008] FCJ No 1692 (QL)).
[67] I raised this point fairly early on at a trial management conference. The parties were agreeable that I be the trial judge. Indeed, they, Apotex in particular, shaped their evidence to deal with a concern I had had, which was that the experts benefited from hindsight and were not looking at (+)-Citalopram with 1988 eyes.
[68] I shall now deal with the allegations of invalidity.
VII. INVALIDITY
A. Anticipation
[69] The leading Canadian case is the decision of the Supreme Court in Plavix, above. Section 27 of the Patent Act as it was at the relevant time required, among other things, that the patent be “not described in any patent or in any publication printed in Canada or in any other country more than two years before presentation of the petition hereunder mentioned…”
[70] According to Apotex, the claims for (+)-Citalopram itself as a compound, namely claims 1 through 5, are invalid as they were anticipated by the prior disclosure of (+)-Citalopram as a component of Citalopram.
[71] There were previous patents, issued more than two years before the application, which disclosed Citalopram, for instance US Patent 4,136,193. It was common general knowledge that Citalopram was a racemate, containing equal amounts of (+)-Citalopram and (-)-Citalopram. It was also common general knowledge that the enantiomers might have different therapeutic effects one from the other, and from the racemate itself.
[72] However, the working of patent ‘193 or of the intermediate diol disclosed in US Patent 4,650,884 would inevitably result in a racemic mixture, not in separate enantiomers. This is fatal to Apotex’s submission.
[73] The test for anticipation was set out by Mr. Justice Hugessen speaking for the Federal Court of Appeal in Beloit Canada Ltd v Valmet Oy (1986), 8 CPR (3d) 289, [1986] FCJ No 87 (QL), as follows, at page 297:
One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention.
[74] This test was approved by the Supreme Court in Free World Trust, above.
[75] In Plavix, Mr. Justice Rothstein, after referring to recent English authority, held that there are two aspects to anticipation: prior disclosure and enablement. Prior disclosure means that working the prior patent would necessarily result in infringement thereof.
[76] He held that the Beloit decision only dealt with prior disclosure. Mr. Justice Hugessen had no need to consider whether the working of the invention was also enabled by that disclosure.
[77] In this case, there was no prior disclosure in that the prior patents did not teach how to resolve Citalopram and did not disclose the therapeutic effects of (+)-Citalopram.
[78] Apart from the patents, D.F. Smith of the Psychopharmacology Research Unit, Psychiatric Hospital, Risskov, Denmark, had published two articles: “Stereochemical Considerations of the Actions of Some Psychotropic Drugs” in 1985 in Pharmacopsychiat and “The Stereoselectivity of Serotonin Uptake in Brain Tissue and Blood Platelets: the Topography of the Serotonin Uptake Area” in 1986 in Neuroscience & Biobehavorial Reviews. However, these papers do not explain in any way how to obtain the enantiomers of Citalopram. Furthermore, he predicted that the activity would be concentrated in the R enantiomer while it turns out most of the activity is in the S enantiomer.
B. Obviousness
[79] Unlike section 28.3 of the Patent Act currently in force, the Act at the time did not specifically provide that the subject matter of a claim must not be obvious “to a person skilled in the art or science to which it pertains…” However, it has always been accepted that section 28.3 is merely declaratory in that by its very definition, an invention must be new (Plavix, above, at para 51).
[80] Who then is this skilled addressee? In Whirlpool Corp v Camco Inc, 2000 SCC 67, [2000] 2 SCR 1067, 9 CPR (4th) 129, [2000] SCJ No 68 (QL), above, at paragraph 42, Mr. Justice Binnie quoted Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1 SCR 504, at page 517, to say that the patent must describe the invention “with sufficiently complete and accurate details as will enable a workman, skilled in the art to which the invention relates, to construct or use that invention when the period of the monopoly has expired.”
[81] If the “invention” is obvious to such a person, it is not patentable.
[82] The skilled addressee in patent law does not exist. He or she is a judicial creation. When applied to the concept of obviousness, Mr. Justice Hugessen stated in Beloit Canada Ltd v Valmet Oy, above, as quoted by Mr. Justice Rothstein in Plavix (Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61, [2008] 3 SCR 265, [2008] SCJ No 63 (QL)) at para 52:
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
[83] Another useful commentary is found in the decision of Mr. Justice Laddie in Lilly Icos LLC v Pfizer Ltd, [2000] EWHC Patents 49 at para 62:
The question of obviousness has to be assessed through the eyes of the skilled but non-inventive man in the art. This is not a real person. He is a legal creation. He is supposed to offer an objective test of whether a particular development can be protected by a patent. He is deemed to have looked at and read publicly available documents and to know o