Eli Lilly Canada Inc. v. Apotex Inc.

Eli Lilly Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2018-07-13
Neutral citation
2018 FC 736
File numbers
T-1734-16
Decision Content
Date: 20180713
Docket: T-1734-16
Citation: 2018 FC 736
Ottawa, Ontario, July 13, 2018
PRESENT: The Honourable Mr. Justice Manson
BETWEEN:
ELI LILLY CANADA INC.,
UBE INDUSTRIES, LTD. AND
DAIICHI SANKYO COMPANY, LIMITED
Applicants
and
APOTEX INC. AND
THE MINISTER OF HEALTH
Respondents
PUBLIC JUDGMENT AND REASONS
I. Pleadings 2
II. Issues 3
III. Results 5
IV. Background 5
A. The Patent 5
V. Applicants’ Fact Witnesses 7
A. Dr. Atsuhiro Sugidachi 7
B. Dr. Taketoshi Ogawa 10
C. Ms. Mary Mutchler 11
VI. Applicants’ Expert Witness 11
A. Dr. Robert Falotico 11
VII. Respondents’ Fact Witness 13
A. Ms. Lisa Ebdon 13
VIII. Respondents’ Expert Witnesses 13
A. Dr. Randall Zusman 13
B. Dr. Timothy Warner 14
IX. State of the Art 15
A. Person of Ordinary Skill in the Art 15
B. Common General Knowledge 16
C. Prior Art 21
(1) Applicants’ Position 21
(2) Apotex’s Position 22
X. Claim Construction 26
XI. Validity 28
A. Burden 28
B. Patentable Subject Matter 29
C. Obviousness 36
(1) Claim date, POSITA, common general knowledge and state of the art 40
(2) Inventive concept of claims 22 and 29 40
(3) Differences between the prior art and the inventive concept 42
(4) Whether those differences constitute steps that would have been obvious 43
D. Sufficiency 48
E. Claims broader than the invention made or disclosed 50
XII. Costs 50
I.
Pleadings
[1] The Applicants are Eli Lilly Canada Inc. (“Eli Lilly”), Ube Industries Ltd. (“Ube Industries”) and Daiichi Sankyo Company Ltd. (“Daiichi”). Eli Lilly is a pharmaceutical manufacturer that distributes and sells, among other things, the pharmaceutical EFFIENT® (prasugrel hydrochloride). Ube Industries and Daiichi are the owners of Canadian Patent No. 2,432,644 (the “‘644 Patent”). The ‘644 Patent is listed by Eli Lilly in respect of EFFIENT® on the Patent Registrar maintained by the Minister of Health (the “Minister”) pursuant to the PM(NOC) Regulations, SOR/93-133 [PM(NOC) Regulations].
[2] The Respondent Apotex Inc. (“Apotex”) is a generic pharmaceutical manufacturer. On August 18, 2016, Apotex filed an abbreviated new drug submission (“ANDS”) with the Minister seeking a notice of compliance (“NOC”) for apo-prasugrel, using EFFIENT® as the Canadian reference product. On August 30, 2016, Apotex served a notice of allegation (“NOA”) in which it alleged that the ‘644 Patent is invalid and not infringed by apo-prasugrel.
[3] The Applicants responded to the NOA by commencing this application on October 14, 2016, pursuant to section 6 of the PM(NOC) Regulations, seeking an order that it is not a proper NOA and detailed statement for the purposes of the PM(NOC) Regulations, or in the alternative, an order prohibiting the Minister from issuing a NOC to Apotex for apo-prasugrel until after the expiry of the ‘644 Patent.
II. Issues
[4] Apotex’s allegations in its NOA are as follows:
claims 1-58 of the ‘644 Patent fail to contain a claim for the medicinal ingredient, the formulation, the dosage form or the use of the medicinal ingredient that was approved through the issuance of the NOC;
Apotex will not infringe any of the claims of the ‘644 Patent by the making, constructing, using or selling of apo-prasugrel in Canada; and
the ‘644 Patent is invalid because:
a) each of the claims defines subject matter that would have been obvious to a skilled person;
b) utility had not been demonstrated prior to the filing date and the inventors did not comply with the doctrine of sound prediction;
c) the claims are broader than any invention made or disclosed;
d) it does not make a correct and full disclosure;
e) claims 11 (and dependent claims 12-16), 18, 19, 23 (and dependent claims 24-28), 41 (and dependent claims 44-49) and 50 (and dependent claims 53-58) are ambiguous; and
f) the claims are for a mere aggregate and not a patentable combination.
[5] In their written submissions and at the hearing, the parties narrowed the claims at issue to two claims (the “Asserted Claims”):
claim 22, as it depends from claims 20 and 18 (the use of prasugrel in the preparation of a medicament for simultaneous administration with aspirin, in separate dosage forms, for the prevention or treatment of a disease caused by thrombus or embolus); and
claim 29 (prasugrel for use in combination with aspirin in preventing or treating a disease caused by thrombus or embolus, administered simultaneously or sequentially).
[6] As well, the issues were narrowed to the following validity attacks:
the claims of the ‘644 Patent do not relate to patentable subject matter;
the Asserted Claims are invalid for obviousness;
the ‘644 Patent does not make a correct and full disclosure; and
claim 29 is overbroad.
III. Results
[7] The Court’s finding on the four issues is as follows:
the claims of the ‘644 Patent do relate to patentable subject matter;
the Asserted Claims are invalid for obviousness;
the ‘644 Patent makes a correct and full disclosure; and
claim 29 is not overbroad.
IV. Background
A. The Patent
[8] The ‘644 Patent is entitled “Pharmaceutical Composition Comprising AspirinTM and CS-747”, has an international filing date of December 20, 2001, a publication date of July 4, 2002, and was issued on July 23, 2013. It has a Japanese priority date of December 25, 2000, and its national entry into Canada was on June 19, 2003.
[9] The ‘644 Patent relates to pharmaceutical compositions comprising 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (“prasugrel”) or a pharmaceutically acceptable salt thereof, and aspirin, as active ingredients, which possess inhibitory activity against platelet aggregation and thrombogenesis and are useful for preventing or treating diseases caused by thrombus or embolus.
[10] More specifically, the section of the ‘644 Patent entitled “Technical Field” states that the invention relates to: pharmaceutical compositions containing prasugrel and aspirin as active ingredients for prevention or treatment of diseases caused by thrombus or embolus; the use of pharmaceutical compositions comprising prasugrel and aspirin for the manufacture of pharmaceutical compositions for prevention or treatment of diseases caused by thrombus or embolus; and methods for the prevention or treatment of diseases caused by thrombus or embolus by administration of an effective amount of prasugrel and aspirin to warm-blooded animals (particularly humans).
[11] At page 1 of the ‘644 Patent, under “Background Art”, it explains that prasugrel is a known compound that has been described in a previous Japanese patent application and possesses potent inhibitory activity against platelet aggregation. Furthermore, aspirin is a well-known compound that is known to have an inhibiting activity against platelet aggregation. However, pharmaceutical compositions containing both compounds have not been known.
[12] At pages 3b and following of the ‘644 Patent, under “Industrial Applicability”, it states that the use of prasugrel and aspirin in combination results in more potent effectiveness than the use of each component alone. Furthermore, plasma levels of these two agents do not have to be maintained at a certain level and higher during the same period in order to produce their effects; therefore, they can be administered separately and sequentially.
[13] Asserted Claims claim 22 (as it depends from claims 20 and 18) and claim 29 provide:
18. Use of [prasugrel] or a pharmaceutically acceptable salt thereof in the preparation of a medicament for simultaneous or sequential administration with aspirin, for the prevention or treatment of a disease caused by thrombus or embolus.
20. A use according to claim 18 or 19, where the medicament is for simultaneous administration.
22. A use according to claim 20, wherein the simultaneous administration is by separate administration of said aspirin and said [prasugrel] or a pharmaceutically acceptable salt thereof.
29. A compound which is [prasugrel], or a pharmaceutically acceptable salt thereof, for use in combination with aspirin in preventing or treating a disease caused by thrombus or embolus.
V. Applicants’ Fact Witnesses
A. Dr. Atsuhiro Sugidachi
[14] Dr. Sugidachi is a named inventor on the ‘644 Patent and currently a senior director/chief scientist at Daiichi. He obtained a degree in pharmaceutical sciences in 1987, a master’s degree in 1989 and a PhD in pharmaceutical sciences in 1996. He joined Sankyo Company Ltd. (“Sankyo”), a precursor to Daiichi, in 1989 to work in their biological research laboratories as a member of the thrombosis drug development research group (the “Thrombosis Group”).
[15] Dr. Sugidachi was asked to describe his work at Sankyo that led to the subject matter of the ‘644 Patent, in particular, his research on any prasugrel and aspirin combinations that were conducted before December 20, 2001, the filing date of the ‘644 Patent.
[16] He stated that his first project involved trying to find a new ADP-receptor antagonist compound with antiplatelet activity that could be developed into a drug for clinical use. The Thrombosis Group sought a compound with an improved profile (stronger antiplatelet activity and fewer side effects) compared to ticlopidine, which was an antiplatelet drug that was approved for sale in Japan at that time. Sankyo collaborated with Ube Industries to synthesize hundreds of compounds, including prasugrel.
[17] Dr. Sugidachi explained that by the early 1990s, prasugrel had been selected as a candidate for development as an antiplatelet drug. Many studies on prasugrel were conducted and published during the mid to late-1990s. It was found to be a potent antiplatelet/antithrombotic agent – more potent than ticlopidine in various experimental animals with minimum activity in general toxicological studies. It was well-tolerated by humans in clinical trials.
[18] In or around 1996, Dr. Sugidachi started investigating the effects of prasugrel in combination with aspirin. Four internal Sankyo reports that relate to those studies were attached to his affidavit.
[19] The first report, |||||||||||||||||||||||||| (“Sankyo Report 1”), contained results from an ex vivo platelet aggregation study on the combination of prasugrel and aspirin in rats. Dr. Sugidachi helped to design this study and was responsible for conducting the experiments. The report stated that prasugrel in combination with aspirin showed |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[20] The second report, |||||||||||||||||||||| (“Sankyo Report 2”) described the antithrombotic effect of prasugrel in combination with aspirin in rats, as well as the effect of the combination of prasugrel and aspirin on bleeding time in rats. Dr. Sugidachi wrote this report and was responsible for performing the work with a lab technician. Antithrombotic effects were studied using an arterio-venous shunt (“AV-shunt”) model of thrombosis. He stated that the combination of prasugrel and aspirin resulted in a |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||| Table 1 on page 8 of the ‘644 Patent contains some of the data that were produced in this study.
[21] Dr. Sugidachi noted other internal Sankyo reports involving aspirin-prasugrel combination studies. One report, |||||||||||||||||||||||| (“Sankyo Report 3”), confirmed |||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| in beagle dogs. Another report, |||||||||||||||||||||||||| (“Sankyo Report 4”) compared the antiplatelet effects of aspirin with prasugrel versus aspirin with clopidogrel in rats, and showed |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[22] He explained that prior to these studies, it was uncertain if there would be a benefit to using prasugrel and aspirin together. He was concerned the combination would cause too much bleeding. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Based on the data, he concluded that there would be a benefit to using a combination of prasugrel and aspirin in humans for the treatment or prevention of diseases caused by thrombus or embolus.
B. Dr. Taketoshi Ogawa
[23] Dr. Ogawa is a named inventor on the ‘644 Patent and a senior director at Daiichi. He has a Master’s degree in pharmacy and obtained a PhD in pharmaceutical sciences in 2001. He joined Daiichi (then Sankyo) in 1993 to work with the Thrombosis Group. At that time, he reported directly to Dr. Sugidachi.
[24] Dr. Ogawa was asked to describe his research on any prasugrel and aspirin combination studies performed before December 20, 2001. His affidavit contains the same four Sankyo Reports that were discussed by Dr. Sugidachi.
[25] Sankyo Report 3, of which he was the author, described research on the effects of prasugrel, aspirin and their combination on platelet aggregation in dogs. He concluded in that report that the combined use of prasugrel and aspirin showed |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
[26] Sankyo Report 4 described a study that Dr. Ogawa was involved in, which compared the combined ex vivo antiplatelet effect of prasugrel and aspirin in rats, to that of clopidogrel and aspirin, 30 minutes after oral administration. The author of that report concluded that the combination of prasugrel and aspirin, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[27] The other two reports also involved studies on the combination of prasugrel and aspirin, and were conducted before the ‘644 Patent was filed (Sankyo Reports 1 and 2).
[28] Based on all of these reports, Dr. Ogawa believed that aspirin and prasugrel in combination would be a useful antithrombotic therapy in animals and humans.
C. Ms. Mary Mutchler
[29] Ms. Mutchler is a law clerk at Belmore Neidrauer LLP. Her affidavit attaches a certified copy of the ‘644 Patent, the Apotex NOA and documents cited therein, extracts from the Apotex ANDS, and court filings and orders relating to this proceeding.
VI. Applicants’ Expert Witness
A. Dr. Robert Falotico
[30] Dr. Falotico is currently a private consultant to the medical device and pharmaceutical industry. He obtained a Bachelor’s degree in Biomedical Sciences in 1974 from Brown University in Providence, Rhode Island and a PhD in Pharmacology in 1980 from the University of Minnesota, School of Medicine.
[31] In 2013, Dr. Falotico retired from Johnson & Johnson, where he had been engaged in pharmaceutical and medical device research and development for 34 years. He began working at Johnson & Johnson in 1980 in Cardiovascular Drug Discovery. From 1991 to 1995, he was the Assistant Director of Drug Discovery Research, the Head of Cardiovascular Pharmacology and Co-leader of the Thrombosis Research Team. After 1995, he continued to be involved with the Thrombosis Research Team, but was also focused on finding new treatments for stent-related thrombosis and restenosis (major complications of stent placement) and led a research team that developed the first drug-eluting stent for the treatment of restenosis.
[32] Dr. Falotico has extensive expertise in the field of cardiovascular pharmacology and drug discovery, including developing treatments for cardiovascular diseases. He has authored approximately 45 peer-reviewed publications, over 90 published abstracts and is an inventor or co-inventor on 27 issued US patents. He received numerous awards and honours throughout his career at Johnson & Johnson.
[33] Dr. Falotico submitted an expert report on issues directly related to validity and infringement of the ‘644 Patent. Portions of his submissions are provided throughout these reasons where they are relevant to the Court’s analysis.
VII. Respondents’ Fact Witness
A. Ms. Lisa Ebdon
[34] Ms. Ebdon is a law clerk at Goodmans LLP. Her affidavit attaches copies of certain documents listed in Schedule B of the NOA.
VIII. Respondents’ Expert Witnesses
A. Dr. Randall Zusman
[35] Dr. Zusman is an Associate Professor in Medicine at Harvard Medical School and a physician at Massachusetts General Hospital (“MGH”) in Boston, Massachusetts. He obtained a BSc in chemistry from the University of Michigan in 1969 and a MD from the Yale University School of Medicine in 1973.
[36] Dr. Zusman is a practicing physician with over 44 years of experience in medicine generally, and over 42 years in cardiology, both as a physician and clinical researcher. He has held major administrative positions as a Director at the MGH Cardiac Unit and at the Cardiac Rehabilitation Program at Spaulding Rehabilitation Hospital in Boston, Massachusetts. Since 1982, he has been the Director of the Hypertension Section, Cardiac Division, MGH Medical Services.
[37] Dr. Zusman became an Associate Professor in Medicine at Harvard Medical School in 1994. He is the author or co-author of 50 peer-reviewed publications that are classified as original reports relevant to the study of cardiology, 83 peer-reviewed research publications that are classified as clinical communications, 31 review articles related to cardiology and hypertension and 14 book chapters on cardiology-related topics. As a clinical scientist, he has participated in many landmark clinical trials that have established standard of care principles in the treatment of patients with cardiovascular disease, including pharmacological antiplatelet therapies. He has been recognized with many awards throughout his career.
[38] Dr. Zusman submitted an expert report on issues directly related to validity and infringement of the ‘644 Patent. Portions of his submissions are provided throughout these reasons where they are relevant to the Court’s analysis.
B. Dr. Timothy Warner
[39] Dr. Warner is a Professor of Vascular Inflammation and Director of the Blizard Institute at Queen Mary University of London in the United Kingdom. He obtained a BSc in Pharmacology at Chelsea College (later King’s College London) in 1986, and a PhD at the William Harvey Research Institute at the University of London in 1989. He then pursued post-doctoral studies with a leading biochemical pharmacologist at Northwestern University and Abbott Laboratories in Chicago.
[40] In 1992, Dr. Warner returned to the William Harvey Research Institute, becoming a British Heart Foundation basic science lecturer in 1995 and Professor of Vascular Inflammation in 2000. He also served as Deputy Dean for Postgraduate Research in the School of Medicine & Dentistry (2014-2017) and Deputy Director (Research and Innovation) for the Life Science Initiative of Queen Mary University of London (2015-2017).
[41] His current research involves the interaction between local formed vasoactive mediators (biochemical mediators that cause blood vessels to dilate or constrict), platelets and anti-thrombotic therapies, especially aspirin and ADP-receptor blockers. He has published more than 250 research papers, reviews, articles and abstracts, and is the principal editor of the journal Platelets.
[42] Dr. Warner submitted an expert report on issues directly related to validity and infringement of the ‘644 Patent. Portions of his submissions are provided throughout these reasons where they are relevant to the Court’s analysis.
IX. State of the Art
A. Person of Ordinary Skill in the Art
[43] The parties’ experts agreed that the person of ordinary skill in the art (“POSITA”) includes a pre-clinical pharmacologist in the area of antithrombotic and antiplatelet drugs; however, they disagreed on whether the POSITA also includes clinicians. Specifically, Dr. Falotico opined that a clinician would not be an ideal person to review the ‘644 Patent because it relates to pre-clinical experiments and data.
[44] I agree with Drs. Warner and Zusman that the POSITA also includes a clinician who treats patients suffering from diseases caused by thrombus and embolus. The focus of the ‘644 Patent is the use of prasugrel and aspirin to prevent and treat diseases caused by thrombus and embolus. Moreover, the ‘644 Patent provides dose ratios for prasugrel and aspirin, as well as upper and lower limit doses based on the symptoms of the patient, and these aspects of the ‘644 Patent are directed at a clinician who is trained to determine the appropriate doses of medicaments for his or her patients.
B. Common General Knowledge
[45] Common general knowledge is the knowledge generally known by the POSITA at the claim date (December 25, 2000) when addressing obviousness, or the publication date (July 4, 2002) of the patent when construing the patent’s claims.
[46] What comprises common general knowledge has been articulated by this court in Eli Lilly v Apotex, 2009 FC 991 at paragraph 97, aff’d 2010 FCA 240 [Eli Lilly] (adopted from General Tire & Rubber Co v Firestone Tyre & Rubber Co, [1972] RPC 457, [1971] FSR 417 (UKCA) at 482-483):
1) Common general knowledge is distinct from what in patent law is regarded as public knowledge. Public knowledge is theoretical and includes each and every patent specification published, however unlikely to be looked at and in whatever language it is written. Common general knowledge, in contrast, is derived from a common sense approach to the question of what would be known, in fact, to an appropriately skilled person that could be found in real life, who is good at his or her job.
2) Common general knowledge will include patent specifications that are well known amongst those versed in the art. In particular industries, the evidence may show that all patent specifications form part of the relevant knowledge.
3) Common general knowledge does not necessarily include scientific papers, no matter how wide the circulation of the relevant journal or how widely read the paper. A disclosure in a scientific paper only becomes common general knowledge when it is generally known and accepted without question by the bulk of those engaged in the particular art.
4) Common general knowledge does not include what has only been written about and never, in fact, been used in a particular art.
[47] With regard to how to prove what comprises common general knowledge, this Court in Eli Lilly at paragraph 100, quoted Simon Thorley et al, Terrell on the Law of Patents, 16th ed (London: Sweet & Maxwell, 2006):
Proof of common knowledge is given by witnesses competent to speak upon the matter, who, to supplement their own recollections, may refer to standard works upon the subject which were published at the time and which were known to them. In order to establish whether something is common general knowledge, the first and most important step is to look at the sources from where the skilled addressee could acquire his information.
The publication at or before the relevant date of other documents such as patent specifications may be to some extent prima facie evidence tending to show that the statements contained in them were part of the common knowledge, but is far from complete proof, as the statements may well have been discredited or forgotten or merely ignored. Evidence may, however, be given to prove that such statements did become part of the common knowledge.
[48] The parties’ experts agreed that several features of blood clot formation and treatment constituted common general knowledge as of the claim date:
Blood clotting (thrombus formation or thrombogenesis) prevents excessive bleeding when a blood vessel is injured. A thrombus is a clot that forms in an artery or vein and an embolism is a clot that moves in the bloodstream. Thrombus and embolus formation can lead to undesirable and even fatal conditions including unstable angina, myocardial infarction, stroke and transient ischemic attacks.
Blood platelets provide a foundation for clotting by binding together to form an initial plug. Once the initial plug is made, blood-borne materials (fibrin) stick together and seal the inside of the wound. This traps more platelets and red blood cells within the plug and starts the healing process.
As of the claim date, several physiological pathways of this process were being investigated as potential targets for preventing blood clotting:
the enzyme thrombin converts the protein fibrinogen into fibrin;
a) thrombin also binds to platelets and activates a receptor on the platelet surface known as glycoprotein IIb/IIIa (“GPIIb/IIIa”);
b) when an artery is injured, platelets and injured red blood cells release adenosine diphosphate (“ADP”), which binds to platelets and activates their GPIIb/IIIa receptors;
c) injury to an artery also causes arachidonic acid to be released from platelets. Arachidonic acid is converted by the enzymes cyclooxygenase 1 (COX-1) and thromboxane synthetase into thromboxane A2. Thromboxane A2 binds to platelets and activates their GPIIb/IIIa receptors;
d) once activated by thrombin, ADP or thromboxane A2, the GPIIb/IIIa receptor binds fibrinogen to form a platelet aggregate.
[49] These pathways are illustrated in the diagrams below, as set out on pages 29 and 30 of Dr. Falotico’s affidavit:
a) The drug acetylsalicylic acid (aspirin) was known to inhibit the thromboxane A2 pathway through its inhibition of the enzyme COX-1. It was a standard anti-thrombotic treatment by the claim date; however, it was known to cause allergic reactions and gastrointestinal bleeding in some patients.
b) As well, a number of agents were known to irreversibly block the ADP-receptor on platelets. Two of these agents, ticlopidine and clopidogrel, had been approved for sale as monotherapies. Ticlopidine had a delayed onset of action and potentially severe side effects. Clopidogrel was more potent and had a shorter onset and less-severe side effects. The third agent, prasugrel, was described in the literature as having a better profile than clopidogrel but it had not yet been approved for sale. Ticlopidine, clopidogrel and prasugrel are structurally related and known as “thienopyridines” because of their fused thiophene and tetrahydropyridine rings:
[50] I agree that all the information in (a) to (e) above formed part of the common general knowledge at the relevant date. There was some disagreement with respect to interpreting the scientific literature that existed at the claim date, involving the relationship between these three thienopyridines as well as the results of their use in combination with aspirin. The key pieces of prior art relied on by the parties are described below.
C. Prior Art
(1) Applicants’ Position
[51] The Applicants state that the following articles showed there was no “class effect” among thienopyridines for the treatment of thrombotic diseases:
Asai et al, “CS-747, a New Platelet ADP Receptor Antagonist” (Annu Rep Sankyo Res Lab 1999; 51:1-44) (“Asai et al (1999) #1”); and
Sugidachi et al, “The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties” (Br J Pharmacol 2000; 129:1439-1446).
[52] The Applicants also state that the following paper showed that an ideal treatment for thrombotic diseases would bind reversibly, unlike ticlopidine, clopidogrel and prasugrel:
Smallheer et al, “Chapter 10: Antiplatelet Therapies” (Annu Rep Med Chem 2000; 35:103-122).
[53] The Applicants as well state that the following article showed that the combination of clopidogrel and aspirin had shown synergistic potency in clinical studies:
Herbert et al “The Antiaggregating and Antithrombotic Activity of Clopidogrel Is Potentiated by Aspirin in Several Experimental Models in the Rabbit” (Thromb Haemost 1998; 80:512-8).
[54] The Applicants further state that the following prior art showed that the combination of ticlopidine and aspirin did not have a synergistic, anti-thrombotic effect:
US Patent No. 5,989,578, dated November 23, 1999, entitled “Associations of Active Principles Containing Clopidogrel and an Antithrombotic Agent”;
Canadian Patent No. 1,066,193, dated November 13, 1979, entitled “Therapeutic Composition Having an Inhibiting Activity on Blood Plate Aggregation”;
Farrell et al, “The Lack of Augmentation by Aspirin of Inhibition of Platelet Reactivity by Ticlopidine” (Am J Cardiol 1999; 83:770-774);
Uchiyama et al, “Combination Therapy With Low-Dose Aspirin and Ticlopidine in Cerebral Ischemia” (Stroke 1989; 20:1643-1647); and
Rupprecht et al, “Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation” (Circulation 1998; 97:1046-1052).
(2) Apotex’s Position
[55] Apotex states that the following articles showed that combination therapy comprising ticlopidine and aspirin, or clopidogrel and aspirin, had become the standard of care in the treatment of diseases caused by thrombus or embolus:
Jarvis and Simpson, “Clopidogrel: A Review of its Use in the Prevention of Atherothrombosis” (Drugs 2000; 60:347-377); and
Mishkel et al, “Clopidogrel as Adjunctive Antiplatelet Therapy During Coronary Stenting” (J Am Coll Cardiol 1999; 34:1884-90).
[56] Apotex further states that the following articles showed that combination therapy of aspirin with ticlopidine or clopidogrel, took advantage of the complimentary mechanisms of action of thienopyridines and aspirin:
Uchiyama et al (1989), noted above; and
Gorelick et al, “Therapeutic Benefit: Aspirin Revisited in Light of Introduction of Clopidogrel” (Stroke 1999; 30:1716-1721).
[57] Moreover, Apotex takes the position that the following articles showed that the combination of a thienopyridine with aspirin was safe and effective in the prevention and treatment of diseases caused by thrombus or embolus, and was more effective than each agent alone:
Uchiyama et al (1989), noted above;
Van Belle et al, “Two-pronged antiplatelet therapy with aspirin and ticlopidine without systematic anticoagulation: an alternative therapeutic strategy after bailout stent implantation” (Coron Artery Dis 1995; 6:341-345);
Schömig et al, “A Randomized Comparison of Antiplatelet and Anticoagulant Therapy after the Placement of Coronary-Artery Stents” (N Engl J Med 1996; 334:1084-9);
Goods et al, “Comparison of Aspirin Alone Versus Aspirin Plus Ticlopidine After Coronary Artery Stenting” (Am J Cardiol 1996; 78:1042-1044);
Lecompte et al, “Antiplatelet Effects of the Addition of Acetylsalicylic Acid 40 Mg Daily to Ticlopidine in Human Healthy Volunteers” (Clin Appl Thromb Hemost 1997; 3:245-250);
Neumann et al, “Antiplatelet Effect of Ticlopidine After Coronary Stenting” (J Am Coll Cardiol 1997; 29:1515-9);
Leon et al, “A Clinical Trial Comparing Three Antithrombotic-Drug Regimes After Coronary Artery Stenting” (N Engl J Med 1998; 339:1665-71);
Urban et al, “Randomized Evaluation of Anticoagulation Versus Antiplatelet Therapy After Coronary Stent Implantation in High-Risk Patients” (Circulation 1998; 98:2126-2132);
Moussa et al, “Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin in Preventing Stent Thrombosis After Coronary Stent Implantation” (Circulation 1999; 99:2364-2366);
Mishkel et al (1999), noted above;
Muller et al, “A Randomized Comparison of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin After the Placement of Coronary-Artery Stents” (Circulation 2000; 101:590-593);
Moshfegh et al, “Anitplatelet Effects of Clopidogrel Compared With Aspirin After Myocardial Infarction: Enhanced Inhibitory Effects of Combination Therapy” (J Am Coll Cardiol 2000; 36: 699-705);
Betrand et al, “Double-Blind Study of the Safety of Clopidogrel With and Without a Loading Dose in Combination With Aspirin Compared With Ticlopidine in Combination With Aspirin After Coronary Stenting” (Circulation 2000; 102:624-629); and
Bossavy et al, “A Double-Blind Randomized Comparison of Combined Aspirin and Ticlopidine Therapy Versus Aspirin or Ticlopidine Alone on Experimental Arterial Thrombogenesis in Humans” (Blood 1998; 92:1518-1525).
[58] Apotex also states that the following articles showed that the combination of a thienopyridine with aspirin produced a synergistic antiplatelet/antithrombotic effect:
Canadian Patent No. 1,066,193, noted above;
US Patent No. 5,989,578, noted above;
Rupprecht et al (1998), noted above;
Moshfegh et al (1998), noted above;
Herbert et al (1998), noted above;
Harker et al, “Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates” (Circulation 1998; 98:2461-2469);
Quinn and Fitzgerald, “Ticlopidine and Clopidogrel” (Circulation 1999; 100:1667-1672); and
Cadroy et al, “Early Potent Antithrombotic Effect With Combined Aspirin and a Loading Dose of Clopidogrel on Experimental Arterial Thrombogenesis in Humans” (Circulation 2000; 101:2823-2828).
[59] Finally, Apotex states that the following prior art showed that prasugrel was the third generation thienopyridine developed, exhibiting certain advantages over clopidogrel and ticlopidine, and that prasugrel was expected to be useful for the prevention of thrombotic diseases and to have a similar ratio of benefit/bleeding risk as clopidogrel:
Canadian Patent No. 2,077,695, filed on September 8, 1992, entitled “Hydropyridine Derivatives Having Antithrombotic Activity”;
Asai et al, “Antithrombotic and Antiplatelet Effects of CS-747, a Novel P2T Antagonist” (J Thromb Haemost, 1999 (Supp) p 829) (“Asai et al (1999) #2”);
Asai et al (1999) #1, noted above; and
Sugidachi et al (2000), noted above.
X. Claim Construction
[60] The relevant date for construing the claims of the ‘644 Patent is the date of publication: July 4, 2002.
[61] Construction is a question of law for the Court and should be done before considering infringement or validity. The Supreme Court determined the canons of claim construction in a trilogy of cases: Whirlpool Corp v Camco Inc, 2000 SCC 67 [Whirlpool] at paras 49-55; Free World Trust v Électro Santé Inc, 2000 SCC 66 at paras 44-54; and Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1 SCR 504 at para 27.
[62] Those decisions state that:
a) claims are to be read in an informed and purposive way, with a mind willing to understand and viewed through the eyes of the POSITA, as of the date of publication, having regard to the common general knowledge;
b) adherence to the language of the claims allows them to be read in the manner in which the inventor is presumed to have intended, and in a way that is sympathetic to accomplishing the inventor’s purpose, which promotes both fairness and predictability; and
c) the whole of the specification should be considered, in order to ascertain the nature of the invention, and the construction of the claims must be neither benevolent nor harsh, but instead should be reasonable and fair to both the patentee and the public.
[63] While experts may aid the Court in construing terms or elements of the claims, that assistance is only necessary when the Court deems it helpful or useful to do so – if the meaning of terms is evident from the patent specification, the Court does not need the advice of experts.
[64] The parties are in general agreement on the construction of the Asserted Claims.
[65] Claim 22, as it depends from claims 18 and 20, comprises the following elements:
use of prasugrel or a pharmaceutically acceptable salt thereof;
in the preparation of a medicament;
for simultaneous, but separate, administration with aspirin;
for the prevention of treatment of a disease caused by thrombus or embolus.
[66] Claim 29 comprises the following elements:
prasugrel or a pharmaceutically acceptable salt thereof;
for use in combination with aspirin;
in preventing or treating disease caused by thrombus or embolus.
[67] Claim 29 does not specify whether the administration of prasugrel and aspirin must be simultaneous or sequential; therefore, both possibilities may purposively be included. While the parties agree that “sequential” means that one agent must be given before or after the other, there is a dispute as to whether the POSITA would understand the appropriate time interval between the administrations of the two agents. That issue is discussed in more detail below with respect to insufficiency and claims broader than the invention made or disclosed.
[68] As well, the parties and their experts disagree on whether claims 22 and 29 incorporate the notion that prasugrel combined with aspirin produces a synergistic effect with respect to the prevention and treatment of thrombosis. This is also discussed in more detail below, in relation to patentable subject matter and obviousness.
XI. Validity
A. Burden
[69] The presumption of validity in subsection 43(2) of the Patent Act, RSC 1985, c P-4 [Patent Act] is weak and once Apotex adduces evidence that has an “air of reality” to rebut that presumption, the legal burden shifts to the Applicants to establish on a balance of probabilities that each of the allegations of invalidity asserted are not justified (Meda AB v Canada (Health), 2016 FC 1362 at para 52).
[70] The parties agree that the Applicants must prove on a balance of probabilities that Apotex’s allegation of invalidity is not justified.
B. Patentable Subject Matter
[71] Combinations of compositions of matter and their use are patentable if the claimed subject matter is new, useful and non-obvious (Bridgeview Manufacturing Inc v 931409 Alberta Ltd (Central Alberta Hay Centre), 2010 FCA 188 [Bridgeview] at paras 6-12, 51).
[72] However, it is essential to the validity of a patent for a combination that the combination should lead to a unitary result, and that such result should be different from the sum of the results of the elements (R v American Optical Co (1950), 13 CPR 87 at 98-99 (Ex CR)).
[73] Apotex alleges that the claims of the ‘644 Patent are invalid, void and of no force or effect as they claim a “mere aggregate and not a patentable combination”, thus failing to meet the definition of an invention under section 2 of the Patent Act. The “purported invention” relates to an additive combination of prasugrel plus aspirin – the use of prasugrel plus aspirin does not produce a new or different result as compared to their separate uses.
[74] Apotex also states that the Asserted Claims are not restricted to combinations of prasugrel and aspirin that exhibit a synergistic effect. Nowhere in the disclosure of the ‘644 Pa