Les Laboratoires Servier v. Apotex Inc.

Les Laboratoires Servier v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2019-05-08
Neutral citation
2019 FC 616
File numbers
T-739-17
Decision Content
Date: 20190508
Docket: T-739-17
Citation: 2019 FC 616
Ottawa, Ontario, May 8, 2019
PRESENT: Mr. Justice Roy
BETWEEN:
LES LABORATOIRES SERVIER
and
SERVIER CANADA INC.
Applicants
and
APOTEX INC.
and
MINISTER OF HEALTH
Respondents
JUDGMENT AND REASONS
I. Overview 2
II. Introduction 4
III. The '825 Patent 6
IV. Issue 11
V. The Witnesses 11
A. Fact witnesses 11
B. The Expert Witnesses 16
(1) Dr. Stephen Robert Byrn, PhD 16
(2) Dr. Allan Mark Evans, PhD 25
(3) Dr. Naïr Rodriguez-Hornedo, PhD 29
(4) Mr. Richard J. Bastin 35
(5) Dr. Michael J. Zaworotko, PhD 43
C. Witnesses: admissibility and weight of evidence 49
VI. Person of skill in the art (POSA or POSITA) 57
VII. Burden of Proof 58
VIII. Claims construction 59
IX. Analysis 75
A. Utility 76
B. Sufficiency 81
C. Overbreadth 91
(1) Arginine salt of perindopril 92
(a) Dr. Byrn 93
(b) Dr. Evans 94
(c) Dr. Rodriguez-Hornedo 95
(2) And its hydrates 100
D. Obviousness 110
(1) The obviousness framework 111
(2) The experts 115
(3) Applying the obviousness framework 122
(a) Servier’s counter to obviousness argument 139
(b) History of the invention 142
(c) Pfizer Canada Inc. v Apotex Inc., 2017 FC 774 [Pfizer] (Brown J.) 144
(d) The Australian case 147
E. Double-Patenting 148
X. Conclusion 151
I.
Overview
[1] This application, pursuant to section 6 of the Patented Medicines (Notice of compliance) Regulations, SOR/93-133 as amended [the NOC Regulations], seeks an order from this Court in the nature of a writ of prohibition for the purpose of preventing the Minister of Health from issuing a Notice of Compliance to Apotex Inc. [Apotex] for its APO-PERINDOPRIL/AMLODIPINE consisting of orally administered tablets containing 3.5/2.5 mg, 7/5 mg and 14/10 mg perindopril/arginine/amlodipine.
[2] Les Laboratoires Servier and Servier Canada [Servier], the applicants, are innovators in the pharmaceutical industry who have obtained regulatory approval from the Minister of Health concerning a pharmaceutical product known as VIACORAM® for an angiotensin-converting enzyme (ACE) inhibitor, a drug used primarily for the treatment of hypertension and heart failure.
[3] The patent which grants a monopoly to the applicant is Canadian Patent No. 2,423,825 [the '825 Patent or '825]. It is with respect to the “Nouveau sel de périndopril et les compositions pharmaceutiques qui le contiennent” ([translation] “New Perindopril salt and pharmaceutical compounds containing it”).
[4] A generic manufacturer, like Apotex Inc., who wishes to market a generic version of a drug must file a submission (here, it is an abbreviated new drug submission) with the Minister of Health; the submission makes specified comparisons between the generic drug and the innovator drug in order to obtain a Notice of Compliance [NOC] for its own generic drug.
[5] In effect, the generic drug manufacturer who wants to market a drug already protected by a patent has two options: either the generic manufacturer waits until the expiration of the patent to obtain the Minister’s approval or it alleges through a Notice of Allegation [NOA] that the patent is invalid and, therefore, would not be infringed if a Notice of Compliance were to be issued. This is the case here. The NOA includes a detailed statement of the legal and factual basis for the allegation (subparagraph 5(3)(b)(ii) of the NOC Regulations, SOR/93-133). The NOA constitutes the framework within which the debate must take place. It frames the proceedings: an allegation not included in the NOA cannot be raised in the proceedings.
[6] Here, the NOA concerns the invalidity of the '825 Patent owned by Servier. There is no allegation of non-infringement.
[7] In its NOA of April 4, 2017, Apotex Inc., a generic manufacturer, alleged invalidity of the '825 Patent on the basis of a number of grounds: double-patenting and improper selection, insufficiency, obviousness, inutility, overbreadth, and anticipation.
II. Introduction
[8] Fundamentally, this case is concerned with a patent relating to perindopril, the active pharmaceutical ingredient (API) that is used in the treatment of hypertension and heart failure. But this case is not about getting a monopoly for perindopril. Servier was successful in obtaining a patent in Canada for a compound, the perindopril molecule, and its pharmaceutically acceptable salts (Patent 1,341,196, referred hereafter as ['196 or '196 Patent]).
[9] The application for what became '196 was dated October 10, 1981, but for reasons that never emerged in this case, the '196 Patent was issued close to 20 years later, on March 6, 2001. As a result, Servier enjoyed a monopoly on the drug used in the treatment of hypertension until March 2018.
[10] The drug was commercialized in Canada since 1994 (obviously well before the '196 Patent was issued) under the name “COVERSYL®”. Servier chose to commercialize the perindopril with one of its pharmaceutically acceptable salts. The said salt is designated as the erbumine salt of perindopril or tert-butylamine salt of perindopril. Erbumine is the accepted abbreviation for the tert-butylamine salt.
[11] Servier sought to patent a different salt than erbumine, in association with perindopril, through its application for a New Perindopril Salt and the Pharmaceutical Compositions containing it. Filed in March 2003, ten years after it started commercializing perindopril in the form of its erbumine salt, the application was successful and was issued on February 21, 2006. If valid, it provides Servier with a monopoly specific to a particular salt, the arginine salt of perindopril, a salt that is different from the erbumine salt of perindopril but which constitutes a subset of the “pharmaceutically acceptable salts” covered by the '196 Patent. In other words, both the erbumine and the arginine salts are said to be subsets of the '196 Patent, but they are different in that the arginine salt is said to provide better stability in environments of higher temperature and humidity. The new patent, the one in suit, bears the number 2,423,825.
[12] In essence, Apotex contends that Servier extends its monopoly illegally by patenting a salt that had been the subject of the '196 Patent as one of the pharmaceutically acceptable salts. The '825 Patent is invalid, says Apotex. Apotex is free to commercialize its version of the tert-butylamine salt of perindopril, and does, as the '196 Patent has expired in Canada. Furthermore, as was confirmed during the hearing of this case, Apotex can certainly develop a different salt of perindopril as the '825 Patent is limited to the arginine salt. Nevertheless, Apotex challenges the arginine salt of perindopril that is commercialized by Servier.
[13] The '825 Patent claims a priority date from French Patent No. 02.04847 filed on April 18, 2002.
III. The '825 Patent
[14] '825 is a short document of merely five pages, the fifth page showing the five claims. It pertains to the invention of the arginine salt of perindopril, its hydrates and pharmaceutical compositions containing it. The '825 Patent is not concerned with perindopril as such but rather with a new salt. Perindopril exists in the overall neutral state as a zwitterion (an overall neutral molecule with acidic and basic components, where these components are negatively and positively charged) where its carboxylic acid is negatively charged and its amine is positively charged. As already indicated, perindopril and its “pharmaceutically acceptable salts” was the subject of Canadian '196 Patent.
[15] The '825 Patent’s disclosure notes that it has proven difficult to find a pharmaceutically acceptable salt that will provide good bioavailability with adequate stability such that it will be suitable for the preparation and storage of pharmaceutical compositions. It was considered that the tert-butylamine salt was not the complete solution to the problems encountered in relatively high heat and humidity environments. Thus, the tert-butylamine salt must be protected with additional packaging in some countries and its shelf-life is limited to two years. Although the tert-butylamine salt was adequate for the development of the product containing perindopril, the '825 Patent is presented as being an improvement.
[16] These constraints are somewhat remedied with the new arginine salt, which has “the entirely unexpected advantage over all the other salts studied and, more specifically, over the tert-butylamine salt of perindopril” ('825 Patent, p. 2).
[17] The problem posed to which the '825 Patent offered a solution was the volatility of the erbumine salt of perindopril, which is susceptible to degradation by the formation of diketopiperazines and by hydrolysis at the ester, triggered by high heat and high humidity. Liquid chromatography tests at Servier confirmed that perindopril is inherently unstable and the erbumine salt did not remedy the chemical stability issues. The '825 Patent refers, at page 2, to the consequences of this instability, namely the necessity for “tropicalized” PVC/foil blister packaging for the perindopril erbumine tablets and the restrictive 2-year shelf-life. The tablets must be stored at a temperature of less than 30 degrees.
[18] The reader is advised that numerous salts customarily used in the pharmaceutical industry were studied and were rejected as being unusable. The disclosure insists that, unexpectedly, the arginine salt of perindopril showed advantages over the other salts studied.
[19] Although the invention is said to relate to the arginine salt of perindopril, its hydrates and to pharmaceutical compositions containing it, the '825 Patent speaks in terms of “the arginine salt of perindopril is preferentially the salt of natural arginine (L‑arginine)” (p. 2). The only other place the reader will find a reference to the L‑arginine salt is to be found at page 4 of the specification where are presented the results of a study comparing the volatility of the new salt to that of the tert-butylamine salt. The Patent states that “(t)he arginine salt used in this study is the L‑arginine salt”. The L‑arginine salt is found in nature, but there also exist other configurations: D-arginine and the racemate D-L.
[20] There are many pharmaceutical compositions that are mentioned, such as nasal administration, suppositories, creams, ointments, and tablets or dragees. The '825 goes on to say that the “pharmaceutical composition according to the invention will preferably1 be immediate release tablet”. As we shall see when the claims are examined, the third claim refers specifically to a pharmaceutical composition claimed, that of an immediate-release tablet.
[21] Similarly, the '825 shows also a preference for a dosage between 1 and 10 mg of the arginine salt of perindopril (p. 3), yet it claims a dosage from .2 to 10 mg at claim 4. Evidently, this time the '825 Patent claims more than the preference expressed in the disclosure. Thus, the disclosure speaks of these preferences:
a) one about the pharmaceutical composition, which translates into claim 3 which is about the preferred composition in the form of an immediate release tablet;
b) another about the preferred dosage of 1 to 10 mg of the arginine salt of perindopril, which does not translate into any claim, as the fourth claim ends being for a dosage from .2 to 10 mg of the arginine salt;
c) finally the preference for the salt of natural arginine, the so-called L‑arginine, is only referenced with respect to the comparative study between the arginine salt and the erbumine salt found in the disclosure. Two things are notable. First, the '825 states that “(t)he arginine salt used in the study is the L‑arginine salt”. Second, the Patent never claims anything other than arginine salt of perindopril and its hydrates; the claims do not specify that only L‑arginine is sought.
[22] The '825 Patent offers little information on how the L‑arginine salt was prepared other than “according to a classical method of salification of organic chemistry” (p. 4). This will be read with the information provided to the reader on how the study was conducted. One reads at the bottom of page 3:
The study was carried out using immediate-release tablets containing either 2.4 mg of the arginine salt of perindopril or 2.0 mg of the tert-butylamine salt of perindopril (each of the two tablets containing 1.7 mg of perindopril). The tablets were assayed 6 months after the start of storage of the tablets at different temperatures and different relative humidities (% R.H.).
The study’s results are reproduced herein. As can be seen, at 40ºC, with relative humidity of 75%, the erbumine salts degrades quite significantly more than the arginine salt in that significantly less perindopril erbumine salt (loss of close to 1/3) remains according to the study in conditions of high humidity and high temperature:
Conditions
6 months
tert-Butylamine
salt of perindopril
Percentage remaining (%)
Arginine salt of
perindopril
Percentage remaining (%)
25ºC
60% HR
101.0
99.5
30ºC
60% HR
94.4
98.1
40ºC
75% HR
67.2
98.6
The '825 clamours the “very great stability of the arginine salt compared to the tert-butylamine salt” (p. 4). Hence, the disclosure declares that the new product requires less constraint with respect to packaging and allows obtaining a shelf-life of at least three years.
[23] The three inventors listed on the '825 Patent are Gérard Damien, who offered an affidavit and was cross-examined, François Lefoulon and Bernard Marchand. Perindopril arginine was first produced in 1984 by Mr. Marchand.
[24] The '825 Patent makes five claims. Claim 1 of the '825 claims an arginine salt of perindopril and its hydrates. Claim 2 claims a pharmaceutical composition containing the arginine salt of perindopril and its hydrates in combination with one or more non-toxic and pharmaceutically acceptable excipients. Claim 3 claims the pharmaceutical composition of claim 2 in the form of an immediate-release tablet. Claim 4 claims a pharmaceutical composition of claims 2 or 3, containing 0.2 to 10 mg of perindopril arginine. Claim 5 refers to the usefulness of the pharmaceutical composition according to any of claims 2 to 4 for the treatment of hypertension and heart failure.
IV. Issue
[25] The issue before this Court is whether Servier has demonstrated that the allegations of invalidity made by Apotex in its Notice of Allegation are unjustified. The grounds of invalidity raised concerning the '825 Patent are:
invalidity;
insufficiency;
overbreadth;
obviousness;
double-patenting;
anticipation.
V. The Witnesses
A. Fact witnesses
[26] The parties have submitted affidavits from four fact witnesses: Denise Pope and Gérard Damien for Servier; and Lisa Ebdon and Duane Terrill for Apotex. Denise Pope is a paralegal at Norton Rose Fulbright LLP, counsel for the applicant. Lisa Ebdon is a paralegal/law clerk at Goodmans LLP, counsel for the defendant. Duane Terrill, is Associate Director, Regulatory Affairs for Apotex Inc. Because the affidavits provided by Denise Pope, Lisa Ebdon and Duane Terrill served the primary purpose of submitting exhibits, these witnesses were not cross-examined.
[27] Gérard Damien was the only fact witness to be cross-examined. Mr. Damien is one of the named inventors on the '825 Patent. He holds a degree in Chemical Engineering from the Institut National des Sciences Appliquées de Lyon. From February 1970 to November 1974, he worked as a researcher in organic chemistry at les Laboratoires Égic. He subsequently began his 34-year career at Les Laboratoires Servier in December 1974 as Manager of the Analytical Development Department at the Centre for Pharmaceutical Development. He remained in this role until 1987, when he became Assistant Director and, subsequently, Director of the Centre in 1992 (Damien affidavit at paras 8-10). He also explored and determined the cause of the instability of the perindopril erbumine tablets, conceived of the arginine salt of perindopril as a solution to the problem, investigated and confirmed its stability as compared to perindopril erbumine.
[28] Mr. Damien provided the history of the Patent. In 1982, Mr. Damien began development work on perindopril in its erbumine salt form, which he had received from the synthesis research team at Servier. Servier’s goal was “to develop a pharmaceutical formulation containing the perindopril erbumine salt that was stable enough to be launched on the market quickly, preferably in tablet form” (Damien affidavit at para 22). Mr. Damien’s specific role was to “put in place appropriate analytical methods to analyze the perindopril erbumine salt, study the purity of batches of the perindopril erbumine salt used in developing the pharmaceutical composition, and undertake stability studies on the active ingredient itself as well as on the pharmaceutical composition of the perindopril erbumine salt” (Damien affidavit at para 25).
[29] At the time, Mr. Damien was “concerned (as was [his] team) about the possibility that the perindopril erbumine salt could lead to stability issues given the initial stability results of the experimental formulations” (Damien affidavit at para 26). Subsequent liquid chromatography studies and structural analyses revealed that perindopril itself could degrade via two different pathways: first, hydrolysis of the ester function at high relative humidity; and second, intramolecular cyclization leading to the formation of lactam-type compounds at high temperatures. Thus, finding a formulation of the perindopril erbumine that limited the rate of degradation of the perindopril proved to be a challenge (Damien affidavit at paras 27-28). The formulation that was achieved, that was marketed as COVERSYL®, was stable at low to moderate temperatures and at low to moderate humidity, but it became less stable at higher temperatures and high relative humidity.
[30] In order to bring perindopril to market quickly, Servier chose to use perindopril erbumine salt and proceed with direct compression instead of its preferred wet granulation to avoid the loss of perindopril.
[31] In his affidavit, Mr. Damien recalled a discussion with his colleague, Bernard Marchand, in the mid-1980’s, during which an arginine salt of perindopril was suggested as an alternative formulation. The issue was that erbumine was understood to be a relatively volatile product when used in the salification of perindopril. The solution became optimal packaging that would be resistant to heat and humidity, what has been referred to as a type of “tropicalized” packaging. That brought Mr. Damien and his team to discuss the possibility of a different salt. The conversation then turned to the use of other amino acids (Damien affidavit at para 44). Mr. Damien recalled his experience at Égic where he worked with lysine, a natural amino acid. No lysine was available at Servier at the time. However, “the natural form of arginine, i.e. L‑arginine” (Damien affidavit at para 46) was available. Neither Mr. Damien nor Mr. Marchand was aware of the L‑arginine salt having been used to form a salt of an active ingredient. However, they did know that the L‑arginine salt had been used on its own in some pharmaceutical preparations (Damien affidavit at para 46).
[32] In 1984, Mr. Damien and Mr. Marchand succeeded in synthesizing the perindopril arginine salt. The process was not optimized to manufacture the perindopril arginine salt. Non-salified perindopril and L‑arginine were brought together in stoichiometric quantities in an aqueous medium. The solution was then vacuum dried. This method was considered a standard procedure at the time (Damien affidavit at para 47). At this stage, substantial progress had already been made in the development of the perindopril erbumine salt tablets and Management at Servier had strong reservations about spreading the research efforts too thin. Further, Management wanted to bring their existing perindopril erbumine product to market as quickly as possible and the instability of the tablets could be alleviated by the use of tropicalized packaging for hot and humid countries (Damien affidavit at para 49).
[33] Between 1990 and 1993, Mr. Damien’s team continued to support Servier’s efforts to bring to market the perindopril erbumine salt. In addition, Mr. Damien conducted a few tests to confirm his hypothesis that the stability problems with perindopril erbumine were linked to the volatility of erbumine. Mr. Damien confirmed this hypothesis, which renewed his interest in finding the most stable salt of perindopril (Damien affidavit at paras 50-54).
[34] Mr. Damien subsequently supervised the comparative stability testing of five perindopril salts: sodium, hydrochloride, maleate, arginine, and erbumine. The active ingredients were tested in powder form. The results demonstrated that perindopril arginine salt and the perindopril erbumine salt were both stable at high temperature (100 degrees Celsius) for 48 hours when the container was sealed. However, when the perindopril erbumine salt was heated to 100 degrees Celsius for 48 hours in an open container, total degradation of the perindopril molecule was observed. In contrast, when perindopril arginine was heated to 100 degrees Celsius for 48 hours in an open container, the arginine salt did not degrade (Damien affidavit at paras 56-59). Hence, perindopril arginine tablets could be packaged in ordinary pill bottles, in contrast to the tropicalized packaging that was required for the perindopril erbumine tablets. However, at that stage, it would have been necessary to manufacture perindopril arginine salt tablets to fully evaluate their stability. That was not a priority for Servier at that time. Servier continued to use different packaging according to the region where the tablets were marketed. However, the tropicalized packaging was more expensive and required new equipment and additional steps.
[35] In 1998, Mr. Damien convinced Management at Servier to reopen the topic of alternative perindopril salts. Further to having conducted more advanced stability testing comparing the stability of perindopril erbumine with that of perindopril arginine, it was concluded that perindopril arginine salt tablets demonstrated greater stability than the perindopril erbumine salt tablets and that they could be packaged in a pill bottle with a desiccant. It also became clear to Mr. Damien during these studies that in the presence of humidity, the arginine salt would be able to form hydrates. Based on Mr. Damien’s results, Servier decided in late 2002 to develop and market the perindopril arginine salt (Damien affidavit at paras 67-74).
B. The Expert Witnesses
[36] The parties have also submitted affidavits from five expert witnesses, all of whom were cross-examined. Servier’s expert witnesses are: Dr. Stephen Byrn, Dr. Allan Mark Evans and Dr. Naïr Rodriguez-Hornedo. Apotex’s expert witnesses are: Mr. Richard J. Bastin and Dr. Michael J. Zaworotko.
(1) Dr. Stephen Robert Byrn, PhD
[37] Dr. Byrn is a renowned expert in pharmaceutical development and, specifically, formulation development, stability and salt selection. He is the Charles B. Jordan Professor of Medicinal Chemistry at Purdue University and holds a PhD in Chemistry from the University of Illinois, with post-doctoral work at UCLA. Dr. Byrn is a prolific author of peer reviewed publications and has co-authored the leading book in the field of solid state chemistry of pharmaceuticals. He also founded SSCI, Inc. (SSCI), a research and information company in 1991, with 100 employees specialized in analytical research with respect to polymorph and salt studies. The company was sold in 2006. Dr. Byrn had conducted, supervised or controlled over 100 salt screens and over 200 polymorph screens as of April 2002.
[38] The expert has testified on numerous occasions in patent cases, including being retained by innovators mainly, but also by generic pharmaceutical companies.
[39] Dr. Byrn was an expert witness retained by Servier in the Australian case Apotex Pty Ltd v Les Laboratoires Servier [2013] FCA 1426 (Justice Rares) in the Federal Court of Australia, a case about a patent quite similar to our patent in suit. In that case, Dr. Byrn set out his opinion regarding (1) how he would attempt to solve the instability problem of tert-butylamine perindopril when exposed to heat and humidity and (2) Apotex Pty Ltd’s allegation of obviousness (Byrn affidavit at para 21).
[40] Dr. Byrn was assigned a number of mandates which he addressed in his affidavit:
a) he provided a scientific background in which he described the knowledge of a researcher in the field and the development of pharmaceutical compounds as of April 2002, with a focus on the stability of the product and the formation of salts;
b) once the first mandate completed, Dr. Byrn was given the English version of the '825 Patent. He was asked to discuss the qualifications of the POSA, the common general knowledge of that person, the understanding such a person would have of the 825 claims and what the inventive concept is;
c) following mandate #2, Dr. Byrn was advised of the allegations of invalidity made concerning the '825 Patent. Responding to questions provided by counsel, he addressed first the issue of obviousness;
d) the fourth mandate related to anticipation. He was provided with two patents for the purpose of examining the allegation of anticipation: United States Patent No. 4,508,729 and Canadian Patent No. 1,341,196, to which reference was made earlier;
e) Dr. Byrn was then asked if the disclosure in '825 was sufficient for a person of skill in the art (POSA) to understand the nature of the invention and how to practice the invention as of October 18, 2003;
f) he was then asked to opine on an allegation of overbreadth, i.e. whether the subject of the invention is broader than the invention described in '825;
g) Dr. Byrn then addressed the issue of the utility of the invention;
h) it is argued that the claims of the '825 Patent and the '196 Patent are for the same invention. The expert was asked whether the claims of '825 are “patentably distinct” from those of the '196 Patent;
i) finally, Dr. Byrn reviewed an Apotex letter of January 19, 2017 which contains allegations about '825; he was asked to comment to the extent the allegations affected or altered his opinion relating to the previous mandates.
[41] With respect to the scientific background, which includes the development and evaluation of stable pharmaceutical compounds and composition, Dr. Byrn provided a description of the knowledge that a researcher in the field of formulation and development of pharmaceutical compounds would have been endowed with as of April 2002. To that end, Dr. Byrn also describes the POSA as being someone with “a bachelor’s or higher degree in Pharmacy (with a focus on chemistry), or in Chemistry, Biochemistry or a related area … and a minimum of 1 to 2 years of experience working in the field” (Byrn affidavit at para 163).
[42] Dr. Byrn insists on the requirement of stability of pharmaceutical compounds because it is one of the most important criteria for safety and efficacy. Chemical and physical stability are evaluated and assessed. Packaging may be a solution in solving stability issues if the method of manufacture of the product (e.g. wet granulation or compression) leaves the issue not adequately addressed. Crystal formation is said to be a potential strategy, but it is unpredictable according to the witness. Dr. Byrn affirms that a scientist “would be aware that salts, like all solids, may absorb water from their surroundings”. However, “there was, and still is, no way to predict which hydration states a salt has, if any” (para 97). The unpredictability, together with the effort and time required to search for crystal forms, make the strategy “secondary”.
[43] As for salts that can be isolated, Dr. Byrn states that “there is no correlation between the properties of salts and the properties of the acids and bases from which they are derived” (para 113). They have unpredictable physical properties (para 118). That results in a process of trial and error in the search for a suitable salt form without being able to predict the result.
[44] The affiant is not leaving the reader under the impression that the wheel must be re-invented every time a scientist seeks to perform a salt screen for a pharmaceutical product. There was, at the time, literature, which would be part of the common general knowledge of the person of skill. That would be consulted to identify what has worked in the past: there are lists of salt formers that have even been approved by regulators. The publications of Berge2 and Bighley3 are referenced. However, “the ability to make a salt with one salt former is not predictive of the ability to make a second salt with the same salt former in conjunction with a different compound” (para 126). Dr. Byrn states that not only are these lists of acids and bases that can be put to contribution, but often variables include different solvents, different temperatures, different cooling rates and different concentrations. Even today, solid form screening and salt screening is done empirically, by hand.
[45] Dr. Byrn summarizes the process of looking for another salt of perindopril as:
a) select salt formers from 10-12 classic salt formers because they have been used with many important and well-known drugs;
b) select solvents, concentrations, temperatures and crystallization conditions;
c) if the products are unstable, the scientist could use other, less common salt formers, already listed in the literature in order to avoid the scrutiny of regulators.
The results are not guaranteed.
[46] Dr. Byrn notes that in April 2002, the state of the art was not very advanced in terms of addressing stability issues, formulation chemistry and solid state chemistry of drugs. As such, the 1977 Berge publication would have been the main foundational document that a POSA would have used to understand salts. Furthermore, at the time, a number of ACE inhibitors were already on the market and the POSA would have had access either to the formulations or the tablets of the drugs. A POSA would also have been aware of the USP 2000 list of common excipients listed in the Handbook of Excipients, 3rd Edition. Finally, the POSA would have been aware of the key documents pertaining to these technologies, including two publications by Berge and Gould4 and other publications co-authored by Dr. Byrn5 himself. He opines that the POSA would readily conclude that it is a difficult exercise to find a suitable salt because it is not predictable and it requires experiments: “the POSA would view the development of a stable product a major issue that the '825 Patent solved” (para 169). As part of the common general knowledge (CGK) of the time, a POSA would have had knowledge in the field of solid chemistry of drugs, including crystallography, analytical methods and ways to determine the stability of drug compounds (paras 165-187).
[47] Dr. Byrn then proceeds to construe the claims of the '825 Patent. Dr. Byrn posits that the POSA would understand that claim 1 pertains to the L‑arginine salt of perindopril. Dr. Byrn also notes that use of the term “and its hydrates” would connote to the POSA that the L‑arginine salt could contain some water. Based on the data in the Patent, the POSA would also know that at high humidity levels, the L‑arginine salt of perindopril is stable and could therefore take on water without degrading. The fundamental inventive concept is similarly the L‑arginine salt of perindopril that may potentially form hydrates. The other claims are dependent on claim 1.
[48] With respect to obviousness, Dr. Byrn observes succinctly that the difference between the “state of the art” in April 2002 and “the inventive concept of the claims of the '825 Patent is the L‑arginine salt of perindopril, which may pick up water” (para 209). Furthermore, Dr. Byrn contends that a POSA would have attempted to improve the stability of perindopril erbumine before considering the search of a new salt form of perindopril (paras 210-217). In searching for a new salt, the POSA would look to numerous other choices before resorting to L‑arginine (para 221) which was not a salt former for a commercial product, much less an ACE inhibitor, at the time. Finally, even if the POSA were to successfully synthesize the arginine salt of perindopril, it would not have been known whether this salt would have been characterized by increased stability. In fact, a POSA would not think that it was more or less self-evident that attempting to form an arginine salt with perindopril would lead to a solid, much less that it would have the stability properties sought (para 230). In view of the state of the art, there would have been many other choices the POSA would have selected before resorting to arginine. A POSA would not have come directly and without difficulty to the arginine salt of perindopril. Moreover, it was not self-evident that what was being tried ought to work: it was not obvious to try to form an arginine salt with perindopril because of the numerous avenues of solution for the stability problem and the properties of salts were, and are, unpredictable. Indeed, “(a) POSA would believe that arginine salt is unlikely to work” (para 233).
[49] With respect to anticipation, Dr. Byrn finds that neither the previous Canadian 1,341,196 Patent claiming perindopril and “pharmaceutically acceptable salts” nor the U.S. Patent No. 4,508,729 disclose the arginine salt (para 255). Dr. Byrn did not discuss enablement in view of his conclusion that the patents did not even satisfy the disclosure requirement.
[50] With respect to sufficiency of disclosure, Dr. Byrn contends that the '825 Patent “discloses everything that the POSA would need to understand what the invention is (the L‑arginine salt of perindopril), make it, and put it into practice” (para 258). Further, “a POSA would also know how to formulate a pharmaceutical composition (and make a tablet) which contains the L‑arginine salt of perindopril” (para 261). It is a simple exercise for a POSA as the patent discloses the use of “a standard method of salification”, with which a POSA would be familiar.
[51] The formulation of a tablet would also be a straight forward exercise for a POSA who would identify the excipients used in the COVERSYL tablets, which are commonly incorporated in immediate release tablets (claim 3).
[52] I note that Dr. Byrn refers to the formation of hydrates which, he explains, would be understood by the POSA as suggesting that the L‑arginine salt of perindopril is not less stable if it picks up water (which may or may not happen) (para 271).
[53] With respect to overbreadth, Dr. Byrn maintains that each of the 5 claims in the '825 Patent pertains to what has been described in the specification. Notably, Dr. Byrn contends that claim 1 is “limited to the L‑arginine salt of perindopril, whether or not it contains water” (Byrn affidavit at para 279), which corresponds to the specification.
[54] With respect to utility, Dr. Byrn finds that the POSA would conclude that the subject matter of each of the claims in the '825 Patent is capable of a practical purpose (paras 285-287). The new salt is more stable to heat and humidity: that allows for a different packaging and less limitation on its shelf-life and storage conditions.
[55] The POSA would find in the data provided at page 4 of the '825 Patent the utility in that the data show that the new salt is more stable than the tert-butylamine. Furthermore, the testing conducted by Mr. Damien and his team confirms the better stability of the L‑arginine salt of perindopril, thus confirming the utility of the new salt.
[56] The expert was critical of the testing conducted by Apotex:
tablets were not tested, but rather the testing was in bulk form;
the packaging used meant that the products were essentially sealed and designed to avoid degradation. This is obviously counter-productive if one seeks to assess instability and hydration;
the testing did not include excipients, which may affect stability.
[57] With respect to double-patenting, Dr. Byrn states in no uncertain terms that the claims of the '825 Patent and the earlier '196 Patent do not pertain to the same invention and, further, that a POSA would find that the claims of the '825 Patent are patentably distinct from the claims of the '196 Patent (paras 301 and 303).
[58] For Dr. Byrn, the '196 Patent includes a very general reference to “pharmaceutically acceptable salts”. “The Patent is directed to the perindopril molecule. It is not a patent directed to salt forms of perindopril” (para 302).
[59] Because the '196 Patent speaks in general terms of “pharmaceutically acceptable salts”, it would not be suggesting of including the arginine salt of perindopril. Arginine salt was not a salt form of an approved product in 2002 and 2003. Claim 1 of the '825 Patent is therefore patentably distinct. In fact, the '196 Patent presents example salts (ammonium, maleate, sodium, acetate, trifluoroacetate and bistie trifluoroacetate), that are not amino acids like the L‑arginine; none of these examples would suggest L‑arginine (para 306).
[60] Finally, Dr. Byrn finds a number of perceived contradictions in Apotex’s Letter of Allegation. Chiefly among them, he sees a tension between allegations of obviousness and the claim that there was insufficient specification in the '825 Patent (paras 313 and 314).
(2) Dr. Allan Mark Evans, PhD
[61] Dr. Evans is an expert in pharmaceutics and pharmaceutical sciences. He holds a PhD in Clinical and Experimental Pharmacology from the University of Adelaide, Australia. Dr. Evans has over 26 years of experience in conducting research in clinical pharmacology including pharmacokinetics and biopharmaceutics. He is presently Provost & Chief Academic Officer at the University of South Australia.
[62] Dr. Evans was also an expert witness for the Servier in Australian case Apotex Pty Ltd v Les Laboratoires Servier, (supra). Dr. Evans supplied two individual affidavits and two joint expert reports with the other expert witnesses retained in the Australian proceeding. He also testified in open court before Justice Rares (Evans affidavit at para 22).
[63] In his affidavit, Dr. Evans was asked to comment on a plethora of issues some of which overlap with the ground covered by Dr. Byrn. First, he provides a general comment on pharmaceutical compounds as well as the '825 Patent. Following the completion of his comment on the '825 Patent, he was advised by counsel for the applicant that there were allegations of insufficiency of disclosure with respect to the '825 Patent. He was then instructed to answer a series of questions regarding the '825 Patent that the applicant’s counsel advised him would allow the Court to come to a finding on whether or not the '825 Patent provided sufficient disclosure. The same process was repeated to enable him to answer questions pertaining to overbreadth and utility. He did not discuss obviousness.
[64] Dr. Evans was then given the English translation of Mr. Damien’s affidavit and asked whether anything therein altered his opinions of the aforementioned allegations of invalidity. The same process was repeated with a series of literature references. Finally, counsel for the applicant gave Dr. Evans a copy of “a letter from Apotex Inc. dated January 19, 2017” which contained allegations about the '825 Patent. Dr. Evans was asked to comment on this letter. (paras 27-46)
[65] First, Dr. Evans comments generally on the criteria to develop an active pharmaceutical ingredient for a commercial drug product, strategies for improving stability and questions pertaini