LES LABORATOIRES SERVIER v. SERVIER CANADA INC., 2019 FC 616

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 preferably 1 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 Berge 2 and Bighley 3 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, 3 rd Edition. Finally, the POSA would have been aware of the key documents pertaining to these technologies, including two publications by Berge and Gould 4 and other publications co-authored by Dr. Byrn 5 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 pertaining to salt synthesis. Stability is at the forefront of the concerns in the development of the active pharmaceutical ingredient (API). Accelerated stability studies (where the product is subjected to extreme conditions of relative humidity and heat) are commonly used. In the end stability improves shelf-life, but also patient safety and therapeutic efficacy.

From a commercial benefits standpoint, the expert identifies a number of advantages: the manufacturing environment need not be as carefully controlled; larger remaining shelf-time; large individual batches can be produced, thus reducing the frequency of production; wider range of packaging options will not be required; different packaging for the same product brings a range of complexities. [ 66 ] Dr. Evans’ evidence is consistent with that of Dr. Byrn as to how a POSA would get to identify a suitable salt, starting with salt forming agents of a limited number.

That is because the task is difficult and time-consuming. Typically, scientists will use formulations most likely to succeed because they have been used commercially with success in the past. There is no guarantee of success: indeed other variables factor in, such as the solvent, concentration and temperature. This is not a straightforward process. [ 67 ] Dr. Evans seems to be in broad agreement with Dr. Byrn in terms of the nature of the skilled person, the POSA.

In his words: " “The POSA to whom the " " 825 Patent is addressed is a scientist in the pharmaceutical field or industry, knowing how medications are made, evaluated and regulated” " (para 126) and the person may " “have at least a bachelor’s degree in industrial/pharmaceutical chemistry or chemical engineering … as well as a minimum of two (2) years of experience working in a pharmaceutical company” " (para 127). Dr. Evans lists a series of journals and textbooks which the POSA would have been familiar with as of April 2002 (paras 130-131). Dr.

Evans notes that in 2002, a POSA would have likely been aware of perindopril as an ACE-inhibitor and also aware that any development program for perindopril would need to take into account premature degradation of the active pharmaceutical ingredient (paras 133-134). In order to resolve stability issues, the POSA would have started by modifying the existing product formulation and exploring changes to the packaging which would be simpler than searching for an alternative salt form of perindopril.

In selecting salts for testing, the POSA would focus on approved commercial drugs in salt form, consulting lists of salts in publications such as those co-authored by Bighley (paras 143-148). [ 68 ] Dr. Evans construed the claims in the '825 in much the same way as Dr. Byrn (paras 150-159). Thus, the " “classical method of salification” " is truly well known by the POSA as leading to salt formation. His understanding of claim 1 is that the POSA would recognize that L-arginine is the naturally occurring form of arginine, making it the form that would be readily approved by regulators as

it is found in the body. Dr. Evans also noted that the salt in claim 1 retains water or not, and was in a hydrate form; it may pick up and incorporate water without degrading. [ 69 ] Dr. Evans acknowledges that there exist L-arginine, D-arginine and a racemic mixture. However, the disclosure of '825 refers to " “(t)he arginine salt of perindopril is preferentially the salt of natural arginine (L-arginine)” " . The data produced at page 4 of '825 deals with the stability of the L-arginine. That would confirm in the mind of the POSA that the invention does not refer to the other forms of arginine.

There is also a technical reason why the racemic mixture cannot be considered. Paragraph 154 reads: Another reason why the POSA would understand that arginine in claim 1 is not referring to a racemic mixture of L-arginine and D-arginine is because perindopril is a chiral molecule having five stereogenic centres with particular configurations. Combining a racemic mixture of arginine with perindopril would result in a mixture of diastereomeric salts with different physical properties such as solubility and melting point.

Such a mixture of salts without uniform properties would be undesirable from both a production and a regulatory perspective. [ 70 ] Claims 2 to 5 are read the same way as read by Dr. Byrn. [ 71 ] With respect to sufficiency of disclosure, Dr. Evans maintains that the specification of the '825 Patent provides sufficient information to the POSA with common general knowledge to prepare the L-arginine salt of perindopril using a classical method of salification, and prepare pharmaceutical compositions thereof as claimed in the Patent (para 161). The POSA would know about the classical method of salification.

In essence, the POSA can’t predict that a stable salt can be produced, but once told that it can in fact be done, the POSA would be able to arrive at the salt. Similarly, the POSA would know how to formulate a tablet of L-arginine perindopril using '825 and the information available in the public domain. Indeed " “the 825 patent does not claim a particular formulation, much less an optimized formulation” " (para 174). [ 72 ] With respect to overbreadth, Dr. Evans maintains that the claims of the '825 Patent are no broader than the invention of the '825 Patent (para 182).

Since claim 1 refers to L-arginine salt of perindopril, which may pick up water, and the tested tablets are tablets of L-arginine perindopril, the inventors made the invention claimed. The other claims follow naturally. [ 73 ] With respect to utility, Dr. Evans concludes that the POSA would know that the L-arginine salt of perindopril is useful because of its increased stability in the face of high heat and humidity. Indeed the subject matter of every claim is capable of practical purpose because of the improved stability. Such utility was demonstrated, as the data displayed at page 4 of '825 shows.

Furthermore, the L-arginine salt of perindopril is a compound known for the treatment of arterial hypertension and heart failure. [ 74 ] Finally, none of Dr. Evans’ opinions changed following his reading of the affidavit of Mr. Damien, various references or Apotex’s Letter of Allegation (paras 52-54).

(3) Dr. Naïr Rodriguez-Hornedo, PhD [ 75 ] Dr. Rodriguez-Hornedo is an expert in pharmaceutical development, pre-formulation science and dosage form optimization, including salts. She teaches pharmaceutical sciences at the University of Michigan, Ann Arbor. She holds a PhD. in Pharmaceutics from the University of Wisconsin-Madison. Dr. Rodriguez-Hornedo has been teaching and researching in the pharmaceutical field for over 30 years, with a focus for the last ten years on pharmaceutical multi-component crystals and cocrystals.

She has published many articles on issues relevant to this case, such as pharmaceutical compounds, pharmaceutical formulations, salts, crystallization and cocrystals. It is the first time she is retained by Servier. [ 76 ] Dr. Rodriguez-Hornedo was given the same nine-point mandate and instructions as Dr. Byrn, although she was asked to comment on anticipation before obviousness and double-patenting before utility. [ 77 ] As with Dr. Byrn and Dr. Evans, the scientific background of the skilled person would essentially be the same as April 2002 and October 2003, according to Dr. Rodriguez-Hornedo.

The expert provided a long scientific tutorial on basic concepts relevant to this case and her affidavit. In particular, Dr. Rodriguez-Hornedo provided explanation about stability, crystallinity, cocrystals, hydratation/hydrates, acids and bases, salts and hygroscopicity. [ 78 ] The affidavit considers basically the same steps a scientist would follow in search of greater stability: packaging, manufacturing process, excipients, chemical structure of the API.

Searching for other solid state forms constitutes another avenue. [ 79 ] The expert identifies a series of textbooks and papers that a scientist would consult, including of course those of Stephen Berge, Lyle Bighley and Donald Monkhouse, which contain a list of salts found in US Food and Drug Administration (FDA) approved, and non-approved, commercially marketed products, as well as a list of salt forms reported to have been made but not commercialized. Dr.

Rodriguez-Hornedo reports that salt screens were done manually at the time, with the various combinations of variables making the process lengthy and the likelihood of success unknown (paras 113 and 116). [ 80 ] Dr. Rodriguez-Hornedo would appear to require marginally higher academic qualifications and experience to be an adequate POSA.

If the person does not hold a PhD or master’s degree in pharmaceutical science (with a chemistry focus) with a year or two of industrial experience in the pharmaceutical industry, a bachelor’s degree in chemistry or biochemistry, together with 3 to 5 years of experience in the field would be acceptable. [ 81 ] As for the claims in '825 , Dr. Rodriguez-Hornedo says that the POSA would expect the arginine in claim 1 to be the one found in nature, the L-arginine: the POSA would expect to be told if the arginine referred to is a non-natural one.

Furthermore, naturally occurring compounds are preferred by regulators as more likely to be safe. The '825 disclosure would confirm that the L-arginine is the one contemplated at claim 1 because page 2 speaks in terms of " “(t)he arginine salt of perindopril is preferentially the salt of natural arginine (L-arginine)” " and the only testing, found at page 4 of the disclosure, compares L-arginine to tert-butylamine salt of perindopril. The reference to " “hydrates” " in claim 1 means " “the L-arginine salt of perindopril which has water molecules associates with the solid.

Moisture uptake can lead to the formation of hydrates” " (para 149). The expert notes that is not possible to know the hydration state until the hydrate has been discovered. [ 82 ] Claim 2, which deals with excipients, simply addresses the L-arginine salt, regardless of water, but with non-toxic and pharmaceutically acceptable excipients. Claim 3 is concerned with a tablet, said tablet having an immediate release rather than a modified or sustained release. Claim 4 covers the same scope as claims 2 and 3, but adds limitations to the amount of arginine salt of perindopril.

Finally, claim 5 adds the element of treating hypertension and heart failure. The invention is therefore the L-arginine salt of perindopril and its hydrates. [ 83 ] Dr. Rodriguez-Hornedo is largely in agreement with Dr. Byrn on the points of anticipation, obviousness, overbreadth and double- patenting. [ 84 ] The expert found that the criteria for anticipation were not met. Considering the '196 Patent and the US ' 729 Patent No. 4,508,729, neither one discloses the arginine salt of perindopril. Dr.

Rodriguez-Hornedo concludes: A POSA would understand the references in the 729 and the 196 Patents to “a pharmaceutically-acceptable inorganic or organic base”, “a pharmaceutically-acceptable inorganic or organic acid” and “their pharmaceutically acceptable addition salts” to do no more than point in a general way to the possibility that either a basic or acidic salt might be formed using an organic or inorganic salt former. The number of possible salt formers covered by the claim is at least in the hundreds. … (Rodriguez-Hornedo affidavit at para 170) [ 85 ] On obviousness, Dr.

Rodriguez-Hornedo states forcefully that " “(p)rior to being retained as an expert in this litigation matter, I had not read any literature on pharmaceutical products using arginine salts” " (para 174). Arginine would not have been a candidate to form a salt with perindopril. The differences between the common general knowledge and the prior art, and the inventive concept involve many steps that would not have been obvious. Inventive skill and effort are needed.

There was no indication that L-arginine salt of perindopril could be made or that it could be more stable than the tert-butylamine salt. [ 86 ] Further references to more prior art did not prove to be more successful. Dr.

Rodriguez-Hornedo classified references in eight categories, none of which would be considered to be of assistance: references describing general approaches; references describing arginine as a potential salt former; references involving ACE inhibitors; references describing perindopril and its salts; references providing examples of arginine salts; references listing arginine as a potential salt of a compound or class of compounds without specific examples; references describing the use of perindopril to treat medical conditions; references describing pharmaceutical products containing hydrates. [ 87 ] Was the invention of '825 obvious to try?

Not according to the expert. There were many avenues of exploration to solve the stability issue, but there were not a finite number of solutions, with the L-arginine salt of perindopril not being a predictable solution. Large amounts of time and effort would be required: it follows that " “skill and judgment is required to narrow down the choices of variables, such as the salt former, concentrations of perindopril and salt formers, solvents, pH, and temperatures” " ( para 230). Stability testing alone could take at least 6 months.

Indeed, nothing in the prior art would have motivated a POSA to try to form an L-arginine salt of perindopril. [ 88 ] With respect to sufficiency of specification, Dr. Rodriguez-Hornedo meticulously details the steps involved in the preparation of perindopril arginine using the specification of the '825 Patent (paras 239-256). Her conclusion is ultimately that the information contained within the '825 Patent is sufficient to allow the POSA to produce the invention using only the instructions contained in the disclosure.

Notably, she mentions that while the '825 Patent does not describe a particular process, it does refer to a classical method of salification. One such classical method of salification would be to " “combine perindopril and the L-arginine in a solvent, and then to collect the salt that precipitates. While a change in solvent, concentration or pH may be required, this would be no more than routine experimentation for a POSA” " (para 243). Essentially, the view expressed by Dr. Rodriguez-Hornedo is consistent with the demonstration made by Dr.

Byrn (Byrn affidavit at paras 259 and 260). [ 89 ] The expert contends that '825 is not overbroad. None of the claims is broader than the invention as invented or as described in the Patent. I note in particular on this reading, that claim 1 would be understood by the POSA as the hydration state not limiting the invention, which is simply the L-arginine salt of perindopril. The invention remains the same. [ 90 ] The expert also addressed the allegation of double-patenting. '825 and '196 are for different inventions.

They are patentably distinct because the arginine salt of perindopril is not included in the scope of the '196 claims, as arginine is neither disclosed nor described in the specification of '196. The claims of '825 are distinct from '196 " “because inventive skill and effort would be required to arrive at the invention in the claims of the 825 patent” " (para 268). [ 91 ] With respect to utility, Dr. Rodriguez-Hornedo is in agreement with Dr. Byrn but also adds that the utility was demonstrated on the basis of the data contained within the '825 Patent itself. The increased stability serves a practical purpose.

The data at page 4 of '825

makes the case. Further, even if the utility had not been demonstrated by the '825 Patent , the data provided therein proves a factual basis to soundly predict the utility of the invention (para 56). The further data provided by Mr. Damien confirm the testing results concerning the invention. Dr. Rodriguez-Hornedo later contends that Apotex was unsuccessful in showing lack of utility in their Letter of Allegation. She identifies two important differences between Apotex’s bulk testing and that which was carried out and reflected in the Patent. First, Apotex used the API as opposed to the pharmaceutical tablets.

Second, the Apotex testing used packaging that was not representative of how perindopril erbumine would have been marketed. (paras 290-291). Hence, the results of the defendant’s testing were skewed and are not useful.

(4) Mr. Richard J. Bastin [ 92 ] Richard J. Bastin is one of two experts retained by Apotex. He is a consultant who worked in the pharmaceutical industry from 1983 to 2013 in the fields of drug formulation and process development. He is less of an academic, and more of a practitioner. He holds a M.Sc. in Chemistry from the University of Manchester and an MBA from Open University. Out of the five experts in this case, he is the only one who does not hold a PhD in the relevant field. He has, however, extensive experience in the industry. [ 93 ] As with the experts retained by Servier, Mr. Bastin was directed to offer his opinion in a series of steps, one following the other:

a) work undertaken by the average pharmaceutical development scientist;

b) review of the '825 Patent ;

c) being provided with some 18 documents, from the Berge, Bighley and Monkhouse paper of 1977 and its 1996 update, to Mr. Bastin’s own Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical entities 6 of 2000, Mr. Bastin was asked if the POSA would have needed ingenuity to arrive at the inventive concepts of the '825 Patent . He also considered the Damien affidavit in answering the question;

d) are the properties of perindopril arginine unique compared to the properties possessed by any other members of the group of pharmaceutically acceptable salts of perindopril;

e) Mr. Bastin then reviewed the '196 Patent in order to opine on whether claim 5 overlaps with the subject matter of the claims in '825 ;

f) the next step concerned the disclosure found in '825 and whether it allows the invention to be put in practice by the skilled person;

g) the expert then opined on a comparison between '825 and the invention made;

h) Mr. Bastin reviewed the

Summary Basis of Decision for COVERSYL to offer views on storage requirements and shelf-life of the product;

i) he also opined on the testing of the arginine salt and the erbumine salt conducted by Apotex;

j) Mr. Bastin commented on the reports supplied by the experts retained by Servier. [ 94 ] Mr. Bastin was asked: " “what work would the average pharmaceutical development scientist have done (and why) in April 2002 if he/she was instructed to overcome a stability issue relating to the marketed perindopril tert-butylamine (erbumine) product?” " (Bastin affidavit at para 10). In providing his answer, Mr. Bastin was asked to assume certain facts that would have been known in April 2002.

He was given the chemical structure of perindopril, access to several foreign patents, and the information that perindopril was marketed in its erbumine salt form. Finally, he was told that the tablets were marketed with additional packaging measures for certain countries and had a two-year shelf-life (Bastin affidavit at para 11). [ 95 ] Mr.

Bastin replied that an average pharmaceutical development scientist would consider 4 approaches to solving the stability issue in respect of perindopril erbumine: alternative packaging, altering the formulation, using a different salt of perindopril or selecting a more stable crystalline form of perindopril erbumine. The preferable path would depend on the source of the instability.

Where the instability is the result of the interaction between the active ingredient and one of the excipients, a change in the formulation, to use a more suitable excipient, would have been a preferred choice (paras 12-16). [ 96 ] The work to be undertaken by the POSA faced with a stability issue is not much different from views offered by the experts retained by Servier. What was significantly different was the insistence Mr. Bastin put on the possibility of discovering a different salt of perindopril, using a structured salt screen, or a different crystalline form of perindopril tert-butylamine. Mr.

Bastin insists on the use of structured salt screens, which he describes in great details. [ 97 ] With respect to the '825 Patent , Mr. Bastin noted, much like the experts for Servier, that the POSA would be someone with experience in chemistry, preformulation, formulation and conducting stability studies. This person would have a PhD in chemistry or a related field with 1-2 years of relevant experience, or a M.Sc. in the same disciplines with 3-5 relevant experience. The POSA would understand as of October 2003, that the " “essence” " (para 40) of the '825 Patent is perindopril arginine and its hydrates.

A POSA would also understand the increased stability of perindopril arginine compared to perindopril erbumine in high heat and relative humidity. It would be understood that the '825 Patent relates to pharmaceutical compositions of perindopril arginine and its hydrates would be useful to the treatment of hypertension and heart failure (para 40). [ 98 ] Mr. Bastin seems to read the '825 Patent in a way similar to the scientists retained by Servier. The Patent is about perindopril arginine and its hydrates; it is useful for the treatment of hypertension and heart failure.

He identifies the utility as being the stability to heat and humidity compared to erbumine perindopril, together with the treatment of hypertension and heart failure.

[ 99 ] There are however some nuances bordering on differences. Having reviewed the '825 Patent , Mr. Bastin opines that " “the salt of the invention also relates to salts prepared with L-arginine and D-arginine, and presumably, racemic (D,

L) arginine” " (para 102). He notes that the excipients are not identified in the specification. He seems to take issue with the stated " “very great stability” " of the new salt as he is not satisfied with the data supplied, which do not include bulk material (only on immediate release tablet). Mr. Bastin claims also that the POSA would not understand the phrase " “classical method of salification of organic chemistry” " , yet he offers a method (para 108). His criticism relates to the contention that the Patent does not offer a particular method.

It is not clear why there should be a method identified as the specification is content to refer to the arginine salt being " “prepared according to a classical method of salification of organic chemistry” " . In fact, Mr. Bastin describes a method very similar to what was offered by the other experts. [ 100 ] Tellingly, the expert retained by Apotex claims that the statement in '825 that the results were unexpected would not be shared by the POSA because the structured salt screen method would have identified a salt with greater stability.

It is noteworthy that the expert limits himself in his paragraph 111 to a general statement that a structured salt screen would have produced, with a very high degree of probability, a salt of perindopril more optimal than the one marketed up to now, i.e. erbumine perindopril. He does go so far as concluding that arginine perindopril would have been produced. [ 101 ] Crucially, Mr. Bastin claims that the POSA would not have required inventive ingenuity to arrive at the subject matter/inventive concept in the '825 Patent .

In his view, the skilled person would have prepared perindopril arginine as part of any structured salt screen that would have been conducted when seeking to identify an optimal salt form of perindopril (para 199). Further, the skilled person would have been able to prepare pharmaceutical compositions of perindopril arginine, including immediate release tablets, without difficulty using standard pharmaceutical excipients and routine methods of preparation (para 200). While the '825 Patent states that numerous salts were studied, it is clear, in the view of Mr.

Bastin, that the inventors studied merely a few salts and they did not even come close to being in a position to determine that all salts customarily used in the pharmaceutical sector were unusable (para 234). After having read the affidavit of Mr. Damien, his mind was unchanged (paras 43-44). [ 102 ] Mr. Bastin’s thesis is that a structured salt screen will produce a better salt. Over a great number of paragraphs, Mr.

Bastin explains in great detail how a structured salt screen would produce the L-arginine salt because he would expect the POSA to include L-arginine as one of the salt formers to be used (para 180). To be sure, the process presented by Mr. Bastin contains many variables to be accounted for. Thus, Mr. Bastin states at paragraph 172 that the only difference between the prior art, which he reviews, and is considerable, and the inventive concept of '825 " “is that there is not a specific description of perindopril arginine or its hydrates having actually been made in the documents I have reviewed.

Likewise, there is not a specific description of a pharmaceutical composition containing perindopril arginine or its hydrates in the treatment of hypertension or heart failure” " . In other words, there is not a significant step between the state of the act, which includes the new techniques of salt screening and the relatively simple arginine salt of perindopril, the inventive concept. [ 103 ] For the expert, it would appear that the method leads to the solution. In fact, he discounts the evidence of Mr.

Damien, who testified that the properties of perindopril arginine and its hydrates are unique among the pharmaceutically acceptable salts of perindopril. He is not satisfied with the demonstration (para 242). He notes that a very limited number of salts were tested by Servier over a period of 20 years: sodium, hydrochloride, maleate and tert-butylamine. Early on, the Servier scientists settled on tert-butylamine, before perindopril arginine was discovered in 1984. [ 104 ] Further, Mr.

Bastin also claims that the content of the '825 Patent overlaps with that of the patent claiming perindopril and pharmaceutically-acceptable salts, the '196 Patent. Mr. Bastin repeats that prior to April 2002, arginine would have been a well-known salt former to the POSA, contrary to the view expressed by the Servier experts, which would make it a pharmaceutically acceptable salt of perindopril (paras 246-247). The expert does not discuss that it is perindopril that is patented in '196. [ 105 ] In addition, Mr.

Bastin is of the view that, assuming the perindopril arginine would not have been found through a structured salt screen, the '825 Patent did not describe its invention in a manner that would have allowed the skilled person to successfully use routine methods to identify suitable conditions to prepare perindopril arginine. Having read the '825 Patent , this skilled person would not know, inter alia , whether the inventors prepared and used hydrated, assuming it could be prepared, or non-hydrated forms of perindopril arginine and the method used by the inventors to prepare perindopril arginine.

The POSA would not know the ingredients used in the immediate release tablets and how to prepare them. Moreover, the expert questions what is meant by " “classical method of salification of organic chemistry” " . The expert seems to acknowledge that the method followed by the inventors could be used, but he prefers another one (para 255-256). In fact, he expressed a preference for a controlled crystallization. [ 106 ] Mr. Bastin also opined on whether the '825 claims are consistent with the invention made and described.

The subject matter of the '825 Patent is of course the arginine salt of perindopril and its hydrates. For the expert, no work done by the inventors was identified to show that they actually prepared a hydrate of perindopril arginine: they could not have known that a hydrate " “could actually be formed” " (para 262). [ 107 ] Quite obviously, the expert takes a view of what a " “hydrate” " is. Thus, he states at paragraph 263 that " “(s)imply because a compound absorbs water, it does not mean that the compound will form a hydrate” " .

He would consider only the " “bound water” " to form part of the compound’s crystal lattice, leading to a change in the crystalline lattice of the perindopril arginine. Mr. Bastin continues by stating that " “if the inventors had identified a change in the crystalline form of perindopril arginine following exposure to increased humidity during the stability studies, this would indicate that the perindopril arginine initially prepared was not physically stable” " (para 263).

Without a hydrate, as defined by the expert, being prepared, the stability of a composition of a hydrate of perindopril arginine could not be ascertained either factually or following a line of reasoning to predict improved stability to heat and humidity. [ 108 ] The expert also notes that the claims refer to arginine, not specifically L-arginine. Mr.

Bastin argues that " “(w)hile it would be reasonable for inventors to expect that D-arginine or racemic arginine would form a salt with perindopril, that the salt would crystallise, and that the salt would not exhibit the same instability issues as perindopril tert-butylamine since these forms of arginine would also be known to be volatile, the skilled person would not be able to predict whether these forms of perindopril arginine would be able to form a hydrate, and whether these forms of perindopril arginine would exhibit very great stability to that and to humidity when compared to perindopril tert -butylamine” " (para 269).

[ 109 ] Finally, the inventive concept of claim 1 is the perindopril arginine (and not only the salt of natural arginine) and hydrates of perindopril arginine, while the pharmaceutical composition is understood to be the inventive concept of claims 2 to 4. Claim 5 is simply that the various compositions of claims 2 to 4 are useful to treat hypertension and heart failure. It does not appear that there is a dispute as to the utility of the invention (if it is an invention): greater stability to heat and humidity.

(5) Dr. Michael J. Zaworotko, PhD [ 110 ] Dr. Zaworotko holds a PhD. in Chemistry from the University of Alabama. He is the Bernal Chair of the Crystal Engineering and Science Foundation of Ireland and Research Professor at the University of Limerick, in Ireland. He has authored some 390 papers, most of which relate to crystallization. He is currently an associate editor of the journal Crystal Growth & Design . Dr. Zaworotko has done some consulting work for pharmaceutical companies in the United States and Europe. [ 111 ] Dr.

Zaworotko was immediately given the '825 Patent and he was not asked to comment on obviousness. Dr. Zaworotko was instructed in much the same way as Mr. Bastin, except that he was given a narrower mandate than that of Mr. Bastin. The expert was asked to opine on the following areas: who is the POSA and what would be understood of the '825 Patent , its subject matter and that of its claims, and its utility; having reviewed the affidavit of Mr. Damien, Dr.

Zaworotko was asked to consider: how was perindopril arginine prepared and what would the POSA consider to be " “a classical method of salification of organic chemistry” " ; what were the solid forms of perindopril arginine prepared by the inventors; was the disclosure in '825 sufficient to arrive at the same perindopril arginine; does the work carried out by the inventors show that bulk perindopril arginine has " “very great stability” " to heat and to humidity compared to the tert-butylamine salt; the nature and amount of effort to arrive at perindopril arginine; whether the claimed invention is consistent with that disclosed in the Patent and made by the inventors. [ 112 ] Although the expert would suggest that the POSA has an advanced degree in Chemistry (he did not allude to the bachelor degree) with two years’ experience, Dr.

Zaworotko is in substantial agreement with the other experts on the definition of the POSA. He also agrees on the subject matter of the '825 Patent . He notes that while the '825 Patent does not expressly identify a utility for perindopril arginine, upon reviewing the description in the patent, a POSA would understand that perindopril arginine, its hydrates and the pharmaceutical compositions containing them would be more stable in the face of high heat and relative humidity, compared to perindopril erbumine.

He notes however that the POSA " “would not know of the solid form of perindopril arginine used, the composition of the tablet or the packaging used to obtain this result” " (para 96). Furthermore, perindopril arginine could be used to treat hypertension and heart failure (para 34). [ 113 ] Dr.

Zaworotko seems to believe that the POSA would understand that the " “classical method of salification of organic chemistry” " to involve the isolation of a salt, but following standard crystallization procedures (para 91) such as cooling the solution, evaporation or adding a solvent in which the salt is not soluble. [ 114 ] It is interesting to note that Dr.

Zaworotko takes issue with the statement in the '825 disclosure that the results of the stability studies (p. 4 of the '825 Patent ) was " “entirely unexpected” " and " “could not have been deduced from, or suggested by, the tracking of the literature of this product” " , but he seems to do so on a rather different basis.

Evidently, the statement refers to perindopril, yet the criticism speaks in terms of " “preparing and identifying salts of a drug molecule to select a salt with acceptable stability (in addition to other properties) was a common, routine practice for pharmaceutical scientists well before 2002” " (para 94). He accepts that it is not possible to precisely predict in advance which salt will be most stable however: he can, at best, say that the POSA would be confident that a salt of perindopril with " “acceptable stability” " would be located. [ 115 ] It is somewhat surprising to read that Dr.

Zaworotko would consider that the reference, at page 4 of '825, to " “less onerous constraints” " with respect to packaging would prove to be a challenge for the POSA (para 95). The original French version speaks of " “ " " contraintes moins lourdes ” " ([ translation ] less weighty constraints) and the disclosure refers to these onerous constraints as relating to packaging, these constraints having to do with organizational complexities and costs.

Indeed, the disclosure refers specifically to the intrinsic fragility of the API, perindopril, which has required protection with additional packaging measures. [ 116 ] Looking at the '825 claims, Dr. Zaworotko reads the word " “and its hydrates” " in claim 1 as being " “hydrated crystal forms of perindopril arginine” " . Furthermore, the claim is not limited to L-arginine, which would make the POSA understand that the salt could be prepared with D-arginine or racemic arginine.

For the expert, " “hydrates” " means that water molecules are part of a crystal lattice; they are absorbed into that crystal lattice (para 101). Claim 2 would be understood to mean that the pharmaceutical composition could be in any common form, while the pharmaceutical composition is an immediate-release tablet according to claim 3. The excipients used would not function to delay or prolong the release of the API.

Claim 4 specifies the dose of arginine salt of perindopril while claim 5 speaks of using the product for treatment of hypertension and heart failure – the POSA would know that the product is useful because of the API, not because of the salt. [ 117 ] Upon reading the affidavit of Mr. Damien, Dr. Zaworotko opined that a POSA would not consider the inventors’ work to be a " “classical method of salification of organic chemistry” " .

In his view, the classical method of salification of organic chemistry is " “the isolation of a salt following standard crystallization procedures, i.e. cooling of the solution, evaporating some of the solvent or adding an anti-solvent to reduce the solubility of the salt” " (para 118). Freeze-drying to isolate a salt would not be considered to be a standard

method. A POSA, following the directions provided in the '825 Patent could not be expected to arrive at the same solid forms of perindopril arginine as prepared by the inventors (paras 122-125). The inventors used freeze-dried an aqueous solution while the skilled person would have isolated a salt by following what he calls the standard crystallization (using a solution of the salt that is cooled, then evaporating some of the solvent and adding an anti-solvent to reduce the solubility of the salt). [ 118 ] Dr. Zaworotko took issue with the testing conducted by Servier to obtain the L-arginine salt of perindopril.

The stability testing is acknowledged to show better stability in favour of perindopril arginine (open flask for 48 hours at 100ºC), yet the expert discounts such result because these conditions are " “irrelevant to real-world conditions and industry regulatory standards for stability testing” " (para 128). Unfortunately, there is no discussion of accelerated testing to which other experts referred.

In the end, it seems that the criticism is limited to the use of the words " “very great stability” " which, presumably, is considered by the expert as unwarranted hyperbole. [ 119 ] The expert notes that the arginine salt absorbs more water under high humidity conditions than perindopril tert-butylamine. He does not discuss the fact that '825 is concerned with finding a remedy to the loss of the API, perindopril, in high heat and high humidity, requiring the " “tropicalized packaging” " . In fact, the Patent addresses degradation of the product in that the API is reduced in various conditions.

Servier was looking for the stability of a compound where there is less of a loss of the API. [ 120 ] In the view of Dr. Zaworotko, there was not a significant effort involved in arriving at the invention. He seeks to dissect the various tests conducted over time to conclude that it consists of the work that would be performed by a POSA (para 145). [ 121 ] Finally, the expert expressed the view that the invention claimed in the '825 Patent is not consistent with the invention disclosed in the Patent. This time, the criticism is centered on the inclusion of hydrates.

The expert notes that the Patent provides no specific information regarding characterisation of the solids that were isolated. The Damien affidavit is not more instructive. Dr. Zaworotko would have liked to be told " “whether any water associated with the material was absorbed surface water or whether the water was absorbed to form part of the crystal lattice” " (para 149). He claims that a change in the crystalline form of the

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