Bristol-Myers Squibb Canada Co v. Teva Canada Limited

Bristol-Myers Squibb Canada Co v. Teva Canada Limited
Court (s) Database
Federal Court Decisions
Date
2016-06-08
Neutral citation
2016 FC 580
File numbers
T-1364-14
Notes
A correction was made on September 18, 2017
Decision Content
Date: 20160608
Docket: T-1364-14
Citation: 2016 FC 580
Ottawa, Ontario, June 8, 2016
PRESENT: The Honourable Madam Justice Mactavish
BETWEEN:
BRISTOL-MYERS SQUIBB CANADA CO., BRISTOL-MYERS SQUIBB HOLDINGS IRELAND AND NOVARTIS AG
Applicants
and
TEVA CANADA LIMITED AND
THE MINISTER OF HEALTH
Respondents
PUBLIC JUDGMENT AND REASONS
(Confidential Judgment and Reasons released May 27, 2016)
TABLE OF CONTENTS
[Blank/ En blanc]
Para.
I. Introduction………………………………………………………………………
1
II. Background………………………………………………………………………
9
III. The Development of Atazanavir…………………………………………………
27
IV. The ’840 Patent……………………………………………………………………
51
A) The Burden and Standard of Proof………………………………………
54
B) The Test for Obviousness………………………………………………
58
C) Is Teva’s Allegation of Obviousness Justified?…………………………
62
(i) The Identity of the Person Skilled in the Art ……………………
63
(ii) The Relevant Common General Knowledge……………………
64
(iii) Were pages 200 and 201 of the AU ’479 Patent Application Publically Available as of April 22, 1996?………………………
72
(iv) Was the European Patent Office Letter Publically Available as of April 22, 1996?…………………………………………………
95
(v) The Inventive Concept of the ’840 Patent………………………
104
(a) Legal Principles Relating to the Identification of a Patent’s Inventive Concept…………………………………………
107
(b) Findings Regarding the Inventive Concept of the ’840 Patent………………………………………………………
120
(vi) Were the Differences between the State of the Art and the Inventive Concept of the ’840 Patent Obvious?…………………
147
(a) Was it Obvious to Start with Example 22B of the ’AU 479 Patent? ……………………………………………………
149
(b) Was it Obvious to Start with the Azapeptide Backbone?…
183
(vii) Were the Modifications to the Azapeptide Backbone More or Less Self-evident?…………………………………………………
189
(viii) Conclusion on Obviousness………………………………………
214
D) Anticipation………………………………………………………………
222
(i) Legal Principles Relating to Anticipation…………………………
225
(ii) The Test for Anticipation…………………………………………
229
(iii) Is Teva’s Allegation of Anticipation Justified?…………………
238
(iv) Conclusion Regarding Anticipation………………………………
264
E) Conclusion Regarding the ’840 Patent……………………………………
265
V. The ’736 Patent……………………………………………………………………
266
A) Claims Construction………………………………………………………
266
(i) Legal Principles Governing the Construction of a Patent and its Claims……………………………………………………………
282
(ii) The Applicants’ Position on Construction……………………
285
(iii) Teva’s Position on Construction………………………………
306
(iv) Construction Analysis…………………………………………
339
(v) Conclusion on the Proper Construction of the ’736 patent……
374
B) Is Teva’s Allegation of Obviousness Justified?………………………
375
(i) The Development of the Type-I Atazanavir Bisulfate Salt……
389
(ii) The Identity of the Person Skilled in the Art…………………
403
(iii) The Relevant Common General Knowledge…………………
405
(iv) The Inventive Concept of the ’736 Patent……………………
413
(a) Bioavailability…………………………………………
418
(b) Crystallinity……………………………………………
427
(c) Stability…………………………………………………
431
(d) The In Situ Transformation Behaviour…………………
435
(e) Conclusion Regarding the Inventive Concept of the ’736 Patent……………………………………………………
446
(v) Were the Differences Between the State of the Art and the Inventive Concept of the ’736 Patent Obvious?…………………
448
(a) The Extent to Which an Inventor has to be Able to Predict the Advantageous Properties of a Compound for the Invention of the Compound to be Obvious………………
449
(b) The Application of these Principles to this Case…………
481
(vi) Conclusion on Obviousness………………………………………
509
C) Conclusion Regarding the ’736 Patent……………………………………
511
VI. Costs………………………………………………………………………………
512
I. Introduction [1] Since its effects on the human population were recognized nearly 40 years ago, the Human Immunodeficiency Virus has proved to be a scourge of unimaginable proportions. The virus, and the Acquired Immunodeficiency Syndrome that it causes, have claimed more than 34 million lives, and there are nearly 40 million others living with the virus.
[2] Left untreated, the HIV virus causes a deterioration of the patient’s immune system, which in turn leads to the development of the opportunistic infections that are associated with full-blown AIDS, a condition that was, for many years, almost invariably fatal.
[3] The scientific community has searched long and hard to find treatments that can either cure HIV/AIDS, or allow the virus to be managed. The discovery of protease inhibitors in the 1990s marked a breakthrough in the treatment of patients infected with HIV.
[4] One example of this class of medications is a “second generation” protease inhibitor called atazanavir. The applicants say atazanavir is one of the most important HIV drugs ever developed, and that it was the preferred protease inhibitor-based HIV treatment for nearly a decade.
[5] There are two patents involving atazanavir listed by the applicants on the Register maintained by Health Canada under section 4 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended (PM(NOC) Regulations), which are the patents at issue in this proceeding. Canadian Letters Patent No. 2,250,840 (the ’840 patent) is owned by Novartis AG, whereas Patent No. 2,317,736 (the ’736 patent) is owned by Bristol-Myers Squibb. Atazanavir is sold in Canada by Bristol-Myers Squibb Canada Co. under the brand name “REYATAZ®”, in accordance with a Notice of Compliance received from the Minister of Health.
[6] The ’840 patent pertains to the invention of atazanavir and expires on April 14, 2017. The ’736 patent pertains to the invention of atazanavir bisulfate. It expires on December 22, 2018.
[7] Teva Canada Limited wants to sell atazanavir in Canada, and is seeking to obtain a Notice of Compliance from the Minister of Health to allow it to do so. On April 22, 2014, Teva served a Notice of Allegation (NOA) on Bristol-Myers Squibb Canada Co., alleging, amongst other things that both the ’840 patent and the ’736 patent are invalid on a number of bases, including anticipation, obviousness, and lack of utility. Infringement is not an issue in this case.
[8] By this proceeding, the applicants seek to prohibit the Minister from issuing a Notice of Compliance to Teva until the expiration of both the ’840 and ’736 patents. I have concluded that Teva’s allegations of invalidity are not justified as they relate to the ’840 patent. An order pursuant to section 6 of the PM(NOC) Regulations prohibiting the respondent Minister of Health from issuing a Notice of Compliance to Teva for its atazanavir product until after the expiry of the ’840 patent will therefore be granted. I have, however, concluded that Teva’s allegation of obviousness has been justified insofar as the ’736 patent is concerned. Consequently, the application for a prohibition order in relation to the ’736 patent will be dismissed.
II. Background [9] In the early 1980s, physicians observed that members of certain patient populations (such as homosexual men, hemophiliacs and intravenous drug users) were presenting suffering from unusual infections and severely compromised immune systems. Given the similarity in the patients’ symptoms, it was hypothesized that the underlying cause of the patients’ symptoms was a transmissible agent.
[10] Shortly thereafter, the HIV retrovirus was identified. There are two strains of HIV – HIV type 1 and HIV type 2. The more common virus, and the one that predominates in the North American population, is HIV-1. HIV-2 infection is concentrated in Africa.
[11] It was determined that HIV attacks certain cells of the immune system, leading to an inability to fight infection. Left untreated, the virus ultimately compromises the immune system to the point that the patient develops AIDS, a condition that leads to the patient’s death. Death is usually the result of an opportunistic infection, that is, a secondary infection that thrives because of the body’s weakened immune system.
[12] Research in the mid-1980s determined the virus’ mechanism of replication, and much of the ensuing research focussed on developing drugs that would interrupt the virus’ replication process, thereby preventing further infection.
[13] The first class of anti-HIV drugs emerged in 1987. These drugs were known as nucleotide reverse transcriptase inhibitors (or NRTIs). NRTIs impede viral reverse transcriptase from converting viral RNA to DNA, and were initially administered as a monotherapy using a single NRTI.
[14] Although NRTIs have potent initial activity against HIV in cell cultures, they had little impact on patient survival rates when used as a monotherapy because of poor patient compliance with medication regimens, and the development of drug resistance. The HIV virus replicates very quickly, with billions of copies of the virus being made in a single day. This rapid replication leads to mutations of the viral genome, which can lead to the development of drug resistance. Drug resistance has presented a significant challenge in the development of HIV drugs.
[15] By the mid-1990s, the Federal Drug Administration in the United States had approved five different NRTIs for use in the treatment of HIV infection. Each of these drugs caused unpleasant side-effects, however, and each failed to provide any long-term benefit as a stand‑alone treatment. Indeed, by 1992, it was becoming apparent that HIV treatment with NRTIs alone was not advancing, and that other forms of treatment needed to be developed.
[16] In 1995, a new class of HIV medication was introduced, known as protease inhibitors. The first protease inhibitors to reach the market were saquinavir, ritonavir and indinavir.
[17] Unlike NRTIs, protease inhibitors target HIV protease, a protein that plays an essential role in the viral replication process. Proteases are enzymes that break down other proteins by hydrolysis of the amide (peptide) bond that links amino acids together. Since HIV protease is required for the replication of HIV, it had been a target for the development of anti-HIV drugs.
[18] HIV protease contains several pockets into which the side chains of its peptide substrates bind. By binding to the active site of protease, protease inhibitors prevent it from binding to amino acid chains, inhibiting viral maturation, thereby interfering with viral replication.
[19] According to a well-known nomenclature system, peptidic side chains that bind to a protease are characterized as …P3-P2-P1*P1’-P2’-P3’… where * denotes the location of the scissile bond. The scissile bond is the amide bond that is cleaved or hydrolyzed by the HIV protease.
[20] The binding of a compound to an enzyme is often analogized to a lock and key, where the active site of the protein is the lock into which the specific substrate (the key) fits and binds. Upon binding, each “P” sidechain fits into a complimentary “S” pocket of the protease. This binding mechanism is depicted below:
Peptide
Backbone
[21] The goal of protease inhibitor design was, therefore, to develop a molecule that looks enough like the protein to which protease would naturally cleave that it can attach itself to the protease enzyme and stop it from acting on its usual target. By mimicking peptide substrates, protease inhibitors bind to HIV, thereby preventing hydrolysis and arresting HIV infection. Inhibitors that mimic peptide substrates but are modified such that they are unable to be cleaved are referred to as peptidomimetics.
[22] Protease inhibitors are considered to be some of the most potent anti-retroviral drugs that have been developed to date, and they have had had a major impact on patient survival rates. There were difficulties, however, with first-generation protease inhibitors such as saquinavir, ritonavir and indinavir. Amongst other problems, the drugs had to be taken in large quantities, due to the fact that little of the medication made its way into the patient’s blood, a problem known as poor bioavailability. The medications also had to be taken multiple times daily, on a precise schedule, making strict compliance with the medication regime difficult for patients. Moreover, the failure of a patient to adhere to the dosing schedule allowed the HIV protease genome to mutate, resulting in the development of resistance to the medication, often after only a few months of use.
[23] As a consequence, there was a strong motivation in the scientific community to develop improved “second generation” protease inhibitors in the late 1980s and early 1990s, and many academic institutions and more than a dozen research-based pharmaceutical companies were working on the problem. One such company was Ciba-Geigy Ltd. (which subsequently became Novartis). It was Ciba-Geigy’s research that led to the discovery of atazanavir or REYATAZ®.
[24] REYATAZ® came on the market in 2003, and it has been one of the recommended treatments for HIV since then. According to the evidence of Dr. Jay Dobkin, an infectious disease specialist with decades of clinical experience treating patients infected with HIV, the introduction of REYATAZ® responded to an unmet need by providing an effective treatment with a high barrier to resistance. REYATAZ® encouraged significant patient compliance because it could be administered once a day, as a result of its inherent bioavailability. In Dr. Dobkin’s view, REYATAZ®’s better toxicity and side-effect profiles also gave it a significant advantage over first-generation protease inhibitors.
[25] Based upon his years of clinical experience, Dr. Dobkin states that with proper adherence, a drug regimen including REYATAZ® can supress viral replication indefinitely, dramatically improving the life expectancy of individuals infected with HIV. Dr. Dobkin is of the opinion that REYATAZ® is more effective than the first-generation protease inhibitors, and that it remains one of the best of the second-generation protease inhibitors. The applicants also provided evidence from Mr. Tom Brogan, an economist with experience in the pharmaceutical industry, attesting to the successful commercial performance of REYATAZ®.
[26] Indeed, Dr. Richard Ogden - one of Teva’s own experts - acknowledged that the development of atazanavir involved “a fine effort” and that it “met an unmet need”.
III. The Development of Atazanavir [27] Evidence regarding the development of atazanavir was provided by Dr. Alexander Fässler. Dr. Fässler is a research scientist at Ciba-Geigy, and is one of the inventors named in the ’840 patent.
[28] In 1989, Dr. Fässler joined a project at Ciba-Geigy which was focussing on potential new treatments for HIV. This project led to the development of atazanavir some six years later.
[29] Dr. Fässler’s team employed a medicinal-chemistry strategy based on analyzing the structure and activity of candidate compounds. This involved the iterative synthesis and testing of numerous compounds. The team then tried to understand how the structural features of the compounds that they had studied affected the compounds’ properties, and used these results to try to design improved compounds.
[30] The first stage of the project focussed on identifying inhibitors that bound well to HIV protease. The team at Ciba-Geigy spent the years between 1989 and 1993 developing compounds that showed good enzymatic activity and were selective for the protease enzyme. By 1993, they had identified two classes of protease inhibitors that showed promise, with each class using a different backbone from which various compounds could be made by substituting the side chains. One class used a Phe-C-Phe backbone, and the other was based on an azapeptide backbone. It was from this latter group that atazanavir was eventually developed.
[31] The second stage of the research process involved finding a protease inhibitor that had favourable pharmacological properties such as high cellular activity and good bioavailability. Cellular activity is a measure of a compound’s effectiveness in inhibiting HIV replication in living cells infected with HIV. Due to the complexities of cellular processes, it was impossible to predict prior to 1996 whether a compound that bound tightly to HIV protease - that is, one that had good enzymatic activity - would also have high cellular activity.
[32] Oral bioavailability is a measure of the blood levels (or blood concentration) of a drug following oral administration. Prior to the discovery of atazanavir, it had been difficult to find a protease inhibitor that had good oral bioavailability - one that could provide blood levels in excess of the concentration required to prevent HIV replication in living cells. Indeed, as was noted earlier, one of the problems with first-generation protease inhibitors such as saquinavir, ritonavir and indinavir was their poor bioavailability, which limited their effectiveness as a treatment for HIV infection.
[33] The applicants say that finding a protease inhibitor with favourable pharmacological properties proved to be extremely difficult because of the unpredictable impact of structural changes on properties such as cellular activity and bioavailability. However, because the Phe‑C‑Phe and azapeptide classes of inhibitors were both considered promising, Ciba-Geigy investigated both, in parallel, in an attempt to identify a compound with favourable pharmacological properties.
[34] According to Dr. Fässler, initial research efforts involving the azapeptide group resulted in compounds with good cellular activity, but poor bioavailability. Ciba‑Geigy therefore focussed primarily on the Phe‑C‑Phe series of compounds in 1992 and 1993, paying close attention to a lead candidate and its variants. By 1995, however, the results of clinical trials of the Phe‑C‑Phe compounds were discouraging and work on these compounds was subsequently abandoned.
[35] Although the focus of attention at this time had been primarily on the Phe‑C‑Phe series of compounds, some work was also being done on a completely new and different class of compounds using a different backbone. Based upon Ciba‑Geigy’s experience with the Phe‑C‑Phe series of compounds, Dr. Fässler’s team hypothesized that a nitrogen‑based backbone might provide greater flexibility than compounds with the Phe‑C‑Phe backbone.
[36] Azapeptides, sometimes also known as “hydroxyethyl hydrazines” or “hydrazides”, are peptidomimetics having a nitrogen-nitrogen (-N-N-) bond in the backbone. The azapeptide backbone is illustrated below, as are six locations on the molecule denoted as P3-P2-P1 and P1’-P2’-P3’:
[37] Without making and testing compounds with the azapeptide backbone, however, the Ciba-Geigy team was unable to predict how the cellular activity and bioavailability would be impacted by such a fundamental change in structure. Nor could the team predict the impact that any given substitution would have on a compound’s activity or bioavailability.
[38] The discovery of azapeptides and the results of some of Ciba-Geigy’s initial azapeptide experiments were reported in a 1993 article by Dr. Fässler et al.: “Novel Pseudosymmetric Inhibitors of HIV-1 Protease” (1993) 13(12) Bioorg. Med. Chem. Lett. 2837 [Fässler 1993].
[39] This paper reported that the Ciba-Geigy team had been able to achieve improved enzymatic activity by replacing a phenyl substituent at the P1’ position with a cyclohexyl group and symmetrical substitution with two acetyl-valine residues in the areas marked “amino acid” in the above diagram. This resulted in a new lead compound known as CGP 53820.
[40] CGP 53820 had good binding affinity and it was selective and had good enzymatic test results. It was not, however, a viable drug candidate because it did not possess suitable pharmacological properties. The cellular activity of the compound was only moderate, and in vivo experimentation revealed that it had poor bioavailability. From this, the Ciba-Geigy team understood that high enzymatic activity did not necessarily translate to high cellular activity and bioavailability. It was, moreover, proving difficult to design an azapeptide that had good bioavailability, and it could not be predicted what effect structural changes would have on the pharmacological properties of compounds.
[41] In 1994, the Ciba-Geigy team began working on analogues of CGP 53820 in an attempt to determine which structural changes, if any, would result in improved cellular activity and bioavailability.
[42] One CGP 53820 analogue that did show promise was a compound known as CGP 61783. This compound is central to Teva’s obviousness argument, as it had been disclosed in a 1993 Australian patent application, although the extent of that disclosure is in dispute. CGP 61783 was promising, inasmuch as it had excellent binding affinity and high cellular activity, but it too had poor bioavailability.
[43] Dr. Fässler’s team then modified CGP 61783 to create prodrugs – that is, compounds that are converted within the body into pharmacologically active drugs. However, the prodrugs of CGP 61783 that were made and tested showed only a slight increase in bioavailability, and the team decided to abandon this line of inquiry.
[44] In tandem with its prodrug strategy, the Ciba-Geigy team also experimented with structural modifications to CGP 61783 in an effort to increase bioavailability without negatively impacting cellular activity. While Dr. Fässler’s team was able to generate compounds with good cellular activity using this approach, the bioavailability of the compounds synthesized remained unacceptably low.
[45] In 1995, however, Dr. Fässler and his team achieved a dramatic increase in bioavailability with a CGP 61783 derivative called CGP 70726. It provided the best combination of cellular activity and bioavailability that had been observed in this series of compounds. As a result, CGP 70726 was promoted for further investigation.
[46] In the period leading up to early 1995, Ciba-Geigy had spent millions of dollars on its protease inhibitor development project, and had 20 chemists, biologists and technicians working full-time on the project. By this point, Dr. Fässler and his team had synthesized and tested a vast number of compounds, and had performed extensive bioavailability testing in mice.
[47] Despite the teams’ recent success with CGP 70726, in early 1995, management at Ciba-Geigy decided to shut down the protease inhibitor program because none of the compounds that had been synthesized to that point had pharmacological properties that would provide a competitive advantage over existing protease inhibitors. Dr. Fässler and his team were given a final six months to come up with a suitable candidate or the program would be terminated.
[48] Ciba-Geigy’s team therefore focussed their attention on developing compound analogues of CGP 70726, spending over a million dollars making and testing approximately 100 derivatives of CGP 70726 as part of the final push that led to the discovery of atazanavir. The CGP 70726 derivative that demonstrated the best profile was identified as CGP 73547, now known as atazanavir.
[49] Dr. Fässler’s team was surprised at the magnitude by which atazanavir’s pharmacological properties exceeded those of saquinavir, as well as the other CGP 70726 analogues they had evaluated. Atazanavir’s cellular activity was three times that of saquinavir, and its bioavailability was 60 times than of saquinavir. Moreover, atazanavir’s plasma concentration was significantly higher than each of the other CGP 70726 analogues that the team had studied, and its cellular activity was also very good. Plasma concentration levels also rose from 30 to 90 minutes after administration, suggesting that atazanavir had a longer half-life in the body than other compounds.
[50] Based upon these results, atazanavir was recommended for clinical development in the spring of 1996. In 2003, following the completion of clinical studies, atazanavir was approved for sale in the United States and Canada as REYATAZ®.
IV. The ’840 Patent [51] Atazanavir is disclosed in the ’840 patent. The patent was filed on April 14, 1997, and claims a priority date of April 22, 1996, which, the parties agree, is the relevant date for the obviousness and anticipation analyses.
[52] The ’840 patent discloses azapeptide derivatives for the inhibition of retroviral aspartate proteases, including that of HIV. Example 46 discloses the synthesis and characterization of atazanavir having the following chemical structure:
[53] The ’840 patent has 36 claims. The only claims being asserted by the applicants are claims 20 and 25. I do not understand there to be any disagreement between the parties as to the proper construction of the claims. Claim 20 is a claim to atazanavir or a salt thereof. Claim 25 is a claim to a pharmaceutical composition comprising atazanavir or a pharmaceutically acceptable salt thereof for treatment of a disease that is responsive to a retroviral protease.
A) The Burden and Standard of Proof [54] Before considering the validity issues raise by Teva, it is first necessary to identify the burden and standard of proof in proceedings under subsection 6(1) of the PM(NOC) Regulations. I do not understand there to be any disagreement between these parties on these points.
[55] Insofar as the validity of the ’840 patent is concerned, the patent will be presumed to be valid, in the absence of evidence to the contrary. If a generic manufacturer fails to adduce any evidence on a ground of invalidity, the presumption is not rebutted.
[56] However, if the generic adduces some evidence which, if accepted, is capable of establishing the invalidity of the patent, thereby putting the allegations of invalidity “in play”, the burden will then be on the applicant to establish on a balance of probabilities that all of the allegations of invalidity are not justified: see Patent Act, R.S.C. 1985, c. P-4, s. 43(2); AstraZeneca Canada Inc. v. Pharmascience Inc., 2014 FCA 133, at paras. 32-34.
[57] Although numerous allegations of invalidity were advanced in Teva’s NOA in relation to the ’840 patent, only two were pursued at the hearing of this matter: obviousness and anticipation. My task is to decide if Teva’s allegations are justified. I will deal first with the issue of obviousness.
B) The Test for Obviousness [58] I understand the parties to agree that the test for obviousness is that identified by the Supreme Court of Canada in in Apotex Inc. v. Sanofi-Synthelabo Canada Inc., 2008 SCC 61 [Plavix #1] at paragraph 67. There, the Court adopted the following four-step approach to an inquiry into whether a claimed invention is obvious:
(1) (a) Identify the notional “person skilled in the art”;
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed; and
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?
[59] In the context of the fourth factor, the Court accepted that it may be appropriate to consider an “obvious to try” analysis. As to when such an analysis will be appropriate, Justice Rothstein stated that:
In areas of endeavour where advances are often won by experimentation, an “obvious to try” test might be appropriate. In such areas, there may be numerous interrelated variables with which to experiment. For example, some inventions in the pharmaceutical industry might warrant an “obvious to try” test since there may be many chemically similar structures that can elicit different biological responses and offer the potential for significant therapeutic advances.
[Plavix #1 at para. 68]
[60] If the Court determines that an “obvious to try” test is warranted, Plavix #1 teaches that, depending upon the evidence in each individual case, the following non-exhaustive list of factors should be taken into consideration at the fourth step of the obviousness inquiry:
1. Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?
2. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?
3. Is there a motive provided in the prior art to find the solution the patent addresses?
[Plavix #1 at para. 69]
[61] Insofar as the degree of effort that was required to achieve the invention is concerned, the Supreme Court stated that where, for example, the inventor and his or her team were able to arrive at their invention “quickly, easily, directly and relatively inexpensively, in light of the prior art and common general knowledge”, this may support a finding of obviousness, unless the inventors were working at a level and their knowledge base was higher than that which should be attributed to person skilled in the art: Plavix #1 at paras. 70-71.
C) Is Teva’s Allegation of Obviousness Justified? [62] Before considering the conflicting evidence on this issue, I would start by noting that although the applicants take issue with the way that certain of Teva’s experts approached their tasks, both sides agree that all of the experts providing evidence in this case are qualified to offer the opinions they have given.
(i) The Identity of the Person Skilled in the Art [63] The parties also agree that for the purpose of the obviousness analysis, the person skilled in the art or “POSITA” is a composite person or multidisciplinary drug development team comprising medicinal or organic chemists, molecular biologists, pharmacologists, biochemists, with a few years of practical experience in aspartyl proteases, including HIV protease.
(ii) The Relevant Common General Knowledge [64] As used in patent law, the term “common general knowledge” refers to “knowledge generally known by persons skilled in the relevant art [skilled persons] at the relevant time”: Plavix #1 at para. 37. Unlike “prior art”, which refers to all previously disclosed information in the field, however obscure, information only becomes common general knowledge if the POSITA would become aware of it and accept it as “a good basis for further action”: Mylan Pharmaceuticals ULC v. Eli Lilly Canada Inc., 2016 FCA 119 at para. 24, citing General Tire& Rubber Co. v. Firestone Tyre & Rubber Co., [1971] F.S.R. 417, (1972) R.P.C. 457 at 483 (C.A.).
[65] I will address the state of the common general knowledge in April of 1996 in greater detail when I examine each of Teva’ allegations of obviousness. I do not, however, understand there to be any dispute that the information described below was part of the common general knowledge at the material date.
[66] In April of 1996, there were many research groups working on identifying novel HIV/AIDS treatments. The protease inhibitors known at that time had drawbacks in terms of their pharmacological properties, which led to problems when they were used as HIV treatments. All of the known protease inhibitors had poor bioavailability, which required patients to take large doses of medication, multiple times each day.
[67] Dosing frequency requirements contributed to patient non-compliance, incomplete response and viral resistance, which was a major problem with first-generation protease inhibitors. Patients also suffered side-effects from their medication caused by its lack of selectivity.
[68] There was a broad selection of compounds that constituted possible starting points in developing an improved protease inhibitor, of which azapeptides were one. While there is a dispute between the parties as to whether a compound identified in an example in an Australian patent would have been a logical starting point in looking for a better protease inhibitor, the POSITA would have known that azapeptides were on the easier end of the scale of synthetic difficulty.
[69] The POSITA would, moreover, have been aware that the development of compounds with both antiviral potency and suitable pharmacokinetic properties had proved difficult, and that finding a protease inhibitor with good bioavailability was presenting a considerable challenge. The POSITA would also have been aware that the properties of newly-made compounds, including bioavailability, are not predictable, and that enzyme activity and cellular activity are not necessarily correlated.
[70] While there is no substantial disagreement between the parties as to the state of the common general knowledge at the material date, there is a real dispute as to what was available as prior art as of April 22, 1996.
[71] Insofar as the state of the art is concerned, Teva relies on an Australian patent application as the starting point in their obviousness analysis. This takes us to the first area of dispute between the parties, which is whether the portion of the Australian patent on which Teva relies was indeed part of the prior art as of April 22, 1996.
(iii) Were pages 200 and 201 of the AU ’479 Patent Application Publically Available as of April 22, 1996? [72] The subject matter defined by a claim in a patent must not have been obvious to the skilled person having regard to the information that was publicly available as of the claim date or one year before the Canadian filing date which, in this case, is April 22, 1996: Patent Act, s. 28.3
[73] Teva’s NOA refers to AU 9352479 (AU ’479), an Australian patent that was originally filed with the Australian Patent Office by Dr. Fässler and his team on December 17, 1993. The patent application was laid open to the public on July 7, 1994, and according to the document produced by Teva, the publication date of the accepted patent application was October 3, 1996.
[74] AU ’479 is entitled “Antiretroviral Hydrazine Derivatives” and it discloses azapeptides suitable as inhibitors of HIV protease having “advantageous pharmacological properties”. The patent describes a genus that includes billions of compounds, and covers two classes of compounds which it identifies as formula I and formula II compounds. The patent states that “compounds of formula II are suitable as inhibitors of retroviral aspartate proteases, especially as inhibitors of the protease of HIV-1 or HIV-2, and are suitable for the treatment of retroviral diseases, such as AIDS or its precursors”.
[75] The disclosure of the AU ’479 patent identifies the “most preferred compounds” as being the compounds mentioned in the examples and their salts. There are some 51 different examples cited in the patent application, some that include many different compounds, with some 240 different compounds ultimately being identified in the examples.
[76] Example 22B is one of seven compounds identified in Example 22. This is the compound that Ciba-Geigy called CGP 61783.
[77] Example 22B has the following structure:
[78] Teva says that Example 22B is a potent inhibitor of HIV-1 protease with excellent antiviral activity and good bioavailability. Teva’s medicinal chemist, Dr. Richard Ogden, submits that in trying to develop a better protease inhibitor, Example 22B would have been a good place to start. This, he says, is because the Example 22B compound was specifically claimed in the AU ’479 patent application, from which the POSITA would have understood that it was an important compound.
[79] The applicants contend that Teva’s argument is based upon a mistaken premise. While accepting that the compound described as Example 22B of the AU ’479 patent was disclosed at the time that the patent application was filed in December of 1993, the applicants say that the Example 22B compound was not specifically claimed in AU ’479 when the patent application was originally filed.
[80] In support of this argument, the applicants note that the first 199 pages of the patent have the December 17th, 1993 filing date of the patent noted in the margin of each page. However, on pages 200 and 201 (which includes the page where Example 22B is specifically claimed as Claim 38), the date in the margin of the page is August 12, 1996, which is after the relevant date for the obviousness analysis. There is also a little stamp at the bottom of each of these two pages that does not appear on other pages of the patent.
[81] The applicants further note that while the application date of the original patent application was December 17, 1993, according to the AU ’479 patent itself, the accepted application was not published in its final form until October 3, 1996.
[82] From this, the applicants submit that it is clear that while Example 22B itself was available when the AU ’479 patent was originally filed, the claim to the compound of Example 22B was added after the original patent application, as part of an amended application. As a consequence, it would not have been available to the POSITA prior to April of 1996, and the POSITA would thus not have been alerted to that example as a particularly good starting point.
[83] Counsel for Teva refused to allow Dr. Ogden to identify the original 1993 AU ’479 patent application or to answer any questions with respect to the document during his cross-examination, and it does not form part of the record in this proceeding. Dr. Ogden did state in cross-examination, however, that it was more likely than not that pages 200 and 201 were added to the AU ’479 patent application on or after August 12, 1996. As Teva points out, however, Dr. Ogden is not an expert in Australian patent law.
[84] There is no question that Example 22B was included as one of many examples disclosed in AU ’479 when the patent application was filed in 1993. The onus is on Teva, however, to prove that page 200 of the AU ’479 specifically claiming the compound described as Example 22B was available to the public prior to April 22, 1996, if they want to rely on the existence of the claim as part of the prior art: Pfizer Canada Inc. v. Apotex Inc., 2007 FC 971, at para. 110, [2007] F.C.J. No. 1271 [Apotex Viagra FC], aff’d 2009 FCA 8. On the evidence before me, I am not persuaded that Teva has satisfied its onus of providing some admissible evidence that the AU ’479 patent application in the form before me was available to the POSITA at the relevant time. On its face, the document provided by Teva suggests otherwise.
[85] The only evidence on which Teva relies to support its assertion that pages 200 and 201 of the AU ’479 patent were available to the public prior to April 22, 1996 is a statement by Dr. Nicholas Hodge. Dr. Hodge is the applicants’ expert in organic and medicinal chemistry and the drug development process.
[86] During Dr. Hodge’s cross-examination, counsel for Teva put the October, 1996 version of AU ’479 to Dr. Hodge, asking him to confirm that the state of the art in April of 1996 included Ciba-Geigy’s ’AU 479 patent, which he did. Teva says that constitutes a sworn statement by Dr. Hodge that unequivocally acknowledges that the October, 1996 version of AU ’479 was part of the state of the art at the relevant time. I am not persuaded that, when read in context, Dr. Hodge’s statement has the significance attributed to it by Teva.
[87] Dr. Hodge was shown the AU ’479 patent by Teva’s counsel, and was asked to confirm, based upon the October, 1996 version of the document, that the state of the art in April of 1996 included the October, 1996 version of AU 479. No one directed Dr. Hodge’s attention to the fact that the document post-dated April, 1996, nor did co