Astrazeneca Canada Inc. v. Mylan Pharmaceuticals ULC

Astrazeneca Canada Inc. v. Mylan Pharmaceuticals ULC
Court (s) Database
Federal Court Decisions
Date
2017-02-07
Neutral citation
2017 FC 142
File numbers
T-336-15
Notes
A correction was made on March 15th, 2017.
Digest
Decision Content
Date: 20170207
Docket: T-336-15
Citation: 2017 FC 142
Toronto, Ontario, February 07, 2017
PRESENT: The Honourable Mr. Justice Diner
BETWEEN:
ASTRAZENECA CANADA INC
AND
POZEN INC
Applicants
And
MYLAN PHARMACEUTICALS ULC
AND
THE MINISTER OF HEALTH
Respondents
JUDGMENT AND REASONS
Table of Contents
I. Introduction. 3
II. Background. 3
III. Expert Evidence. 7
IV. Issue. 8
V. Burden of Proof. 8
VI. Claim Construction. 9
A. The Law.. 9
B. Analysis. 10
VII. Obviousness. 12
A. The Law.. 13
B. Expert Evidence. 17
(1) Summary of the Experts Affidavits. 17
(2) Challenges to Expert Evidence and Credibility. 23
C. Obviousness Analysis. 27
(1) The State of the Art 27
(2) The Inventive Concept 34
(3) Differences Between the State of the Art and Inventive Concept 36
(4) Whether Those Differences Constitute Obvious Steps. 37
(5) Obvious To Try Consideration. 41
(6) Reliance on Mosaics. 53
VIII. Utility and Overbroadness. 55
IX. Conclusion. 55
X. Costs. 56
ANNEX A.. 1
I. Introduction [1] The Applicants seek an order prohibiting the Minister of Health from issuing, pursuant to the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [Regulations], a Notice of Compliance [NOC] to the Respondent Mylan Pharmaceuticals ULC [Mylan] in respect of its generic naproxen-esomeprazole magnesium tablet product, until the expiry of Canadian Patent No. 2,449,098 [098 Patent].
[2] For the reasons that follow, the application is dismissed.
II. Background [3] Nonsteroidal anti-inflammatory drugs [NSAIDs] are commonly used to treat pain, fever, and inflammation through their analgesic (pain-killing), antipyretic (fever-reducing), and anti-inflammatory properties. They are used to treat inflammation and pain associated with chronic, incurable rheumatic and degenerative musculoskeletal disorders, including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. NSAIDs are distinguished from acetaminophen (TYLENOL), steroidal anti-inflammatories (corticosteroids such as cortisone), and other drugs used to treat pain (such as opioids).
[4] NSAIDs are amongst the world’s most widely used medications, having been used for over a century. They include drugs such as acetylsalicylic acid (ASPIRIN, BUFFERIN), ibuprofen (ADVIL, MOTRIN, NUPRIN), diclofenac (VOLTAREN), and naproxen (ALEVE, NAPROSYN).
[5] Unfortunately, NSAIDs can cause gastrointestinal [GI] injuries, including ulcers in the interior surface (mucosa) of the upper GI tract – primarily the stomach and duodenum. Complications arising from ulcers include bleeding and perforations, resulting in thousands of deaths every year around the world including in North America. There currently are no means of entirely eliminating the risk of these side effects, but a number of drugs can help mitigate them.
[6] Approaches to mitigating the side effects have included taking co-therapy drugs such as misoprostol, H2 receptor antagonists, and proton pump inhibitors [PPIs] with NSAIDs. By 2001, accepted risk-reduction therapies included using less injurious NSAIDs (at least with respect to GI injury) such as COX-2 specific inhibitors (CELEBREX), and a co-therapy drug such as misoprostol or a PPI. NSAID co-therapy with other drugs, including misoprostol, a prostaglandin analogue, remained risky due to the side effects of the chosen co-therapy drug.
[7] One of the issues with co-therapy, no matter which of the varieties it came in, was known to be patient non-compliance.
[8] In 2001, commercially available PPIs were formulated as oral solid dosage forms (for simplicity, and consistent with the claims asserted in this case, “Tablets”) with an enteric coating. The enteric coating delayed release of the PPI until the dosage form reached the small intestine, thus avoiding degradation by gastric acid.
[9] Tablets can be formulated for various internal impacts, which include: (a) immediate release in the stomach; (b) delayed release in the small intestine or further down the GI tract; or (c) sustained release through all or part of the GI tract.
[10] Nothing but abstinence from NSAID therapy will eliminate the risk of GI injury. NSAID toxicity may result from both local and systemic effects of the drug. Locally, the NSAID impacts the mucosa of the stomach lumen. Systemically, NSAIDs inhibit cyclooxygenase [COX] enzymes, thereby reducing prostaglandin synthesis throughout the body, including in the GI tract. Prostaglandins help to maintain the integrity of the mucosal lining of the stomach and duodenum, which provides a natural defence against the highly acidic conditions in those lumens. Specifically, prostaglandins inhibit acid secretion, stimulate mucous and bicarbonate secretion, and increase blood flow and healing. Therefore, systemic reduction of prostaglandin production caused by NSAIDs can cause ulcers and related GI damage.
[11] An advent to co-therapy came with the drug ARTHROTEC, first disclosed in 1992, and then launched commercially in 1998. It is a multilayer tablet containing a NSAID (diclofenac) with an enteric coating and immediate-release misoprostol.
[12] This application relates to a formulation of an immediate-release prophylactic (preventative) medication to address the deleterious effects of NSAIDs, namely VIMOVO, marketed by AstraZeneca Canada Inc. [AstraZeneca]. VIMOVO is the brand name of AstraZeneca’s patented naproxen-esomeprazole magnesium tablet, which pairs naproxen (a NSAID) with esomeprazole magnesium (a PPI).
[13] The 098 Patent is owned by Pozen Inc. and is listed on the Health Canada Patent Register against AstraZeneca’s VIMOVO drug. It was filed in Canada on May 31, 2002 [the Filing Date], claiming priority to June 1, 2001 [the Claim Date], and was published on December 12, 2002. Unless found to be invalid, it will expire on May 31, 2022.
[14] The 098 Patent states that a new method of reducing GI risks would ensue from a single unit dosage form that provides a coordinated, sequential release of an acid inhibitor first, and a NSAID second.
[15] The patent provides examples: examples 5 through 8 contain enteric-coated naproxen and immediate release PPI, omeprazole or pantoprazole; examples 9 and 10 set out clinical studies examining the relationship of gastric pH to NSAID-induced gastric ulcers, and whether co-administration of an H2 blocker (famotidine) with a NSAID (naproxen) reduces NSAID-related GI damage.
[16] Mylan filed an Abbreviated New Drug Submission with the Minister of Health for the issuance of a NOC with respect to a generic naproxen-esomeprazole magnesium tablet product. As required by section 5 of the Regulations, on January 20, 2015 Mylan served a Notice of Allegation [NOA] on AstraZeneca. The NOA claimed non-infringement of certain claims of the 098 Patent, as well as invalidity on a number of grounds.
[17] In response to the NOA, the Applicants initiated the present proceeding under subsection 6(1) of the Regulations, asserting claims 26 to 28, 34 to 38, and 39 to 44 where dependent on claims 26 to 28 and 34 to 38 of the 098 Patent. For the purposes of these proceedings, Mylan relied on its allegations of invalidity, which focus primarily on obviousness, but in the alternative that the claims lack utility and are overbroad.
[18] In a pre-hearing conference, AstraZeneca advised that it was narrowing its claims from those asserted in its Application to claim 37 (itself dependent on claim 34, 35, and/or 36) and claims 38 to 44 where dependent on claim 37 [the Asserted Claims, reproduced in Annex A to these Reasons]. AstraZeneca stated that it was focusing its claims in this manner both (a) to reflect the commercial product (a tablet) and (b) because the case did not turn on some of the properties that were the focus of the other claims that had originally been asserted.
III. Expert Evidence [19] The Applicants served affidavits from two expert witnesses:
• Dr. James Polli is a Professor of Pharmaceutical Sciences and the endowed chair in Industrial Pharmacy and Pharmaceutics at the University of Maryland School of Pharmacy.
• Dr. David Armstrong, a gastroenterologist, is a Professor in the Gastroenterology Division of the Department of Medicine at McMaster University.
[20] Mylan served affidavits from three expert witnesses:
• Dr. Leah Appel, an industrial formulator, is a managing partner of Green Ridge Consulting, a company based in Oregon that provides formulation consulting services to the pharmaceutical industry.
• Dr. Ping Lee is a Professor in Pharmaceutics and Drug Delivery at the University of Toronto.
• Dr. Loren Laine, a gastroenterologist, is a Professor of Gastroenterology and Director of Clinical Research at the Yale School of Medicine.
IV. Issue [21] The sole issue in this case is whether the Asserted Claims of the 098 Patent are invalid. The Respondent Mylan relies primarily on obviousness for its invalidity claim, although it raises lack of utility and overbreadth as alternate bases of invalidity. The Applicants strenuously refute all contentions of invalidity.
V. Burden of Proof [22] In terms of the burden of proof for NOC proceedings under the Regulations, subsection 43(2) of the Patent Act, RSC, 1985, c P-4 [Patent Act] creates a presumption that a patent is valid. In order to rebut this presumption, Mylan bears the evidential burden of giving its allegations of invalidity an air of reality, thereby putting the issues in play. If Mylan is successful in doing so, AstraZeneca must establish, on a balance of probabilities, that Mylan’s allegations of invalidity are unjustified (Pfizer Canada Inc v Canada (Minister of Health), 2007 FCA 209 at paras 109-111; Leo Pharma Inc v Teva Canada Ltd, 2015 FC 1237 at paras 62-64).
[23] The bulk of the written and oral submissions in this matter revolved around the first and primary issue of obviousness. An overview of that area of the law follows the next section, which construes the claims at issue.
VI. Claim Construction A. The Law [24] Patents are to be construed purposively, having regard to the whole of the patent, in order to ascertain the particular words or phrases in the claims that describe what the inventor considered to be the "essential" elements of the invention (Whirlpool Corp v Camco Inc, 2000 SCC 67 at paras 44-45 [Whirlpool]). The claims are to be construed as of the date of publication (Whirlpool at para 55).
[25] Claims are to be construed through the eyes of the notional person of ordinary skill in the art [POSITA] (Whirlpool at para 70, quoting Dickson J in Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1 SCR 504 at 523, 56 CPR (2d) 145 (SCC), in turn quoting HG Fox, Canadian Law and Practice Relating to Letter Patent for Invention, 4th ed (Toronto: Carswell, 1969) at 204:
The persons to whom the specification is addressed are "ordinary workmen", ordinarily skilled in the art to which the invention relates and possessing the ordinary amount of knowledge incidental to that particular trade. The true interpretation of the patent is to be arrived at by a consideration of what a competent workman reading the specification at its date would have understood it to have disclosed and claimed.
[26] In sum, a patent is to be construed through the eyes of the POSITA having a mind willing to understand the invention, and the claims are to be approached in a purposive manner and construed in light of both the disclosure and the claims (Eli Lilly Canada Inc v Canada (Attorney General), 2015 FCA 166 at para 52; see also ABB Technology AG v Hyundai Heavy Industries Co Ltd, 2015 FCA 181 at para 36). That said, while it is permissible to read the disclosure in order to assist in understanding the terms used in the claims, the disclosure cannot be used to construe the claims more narrowly or widely than the text of the claims allows (Sanofi-Synthelabo Canada Inc v Apotex Inc, 2008 SCC 61 at para 77 [Sanofi]; see also MediaTube Corp v Bell Canada, 2017 FC 6 at paras 35-37).
[27] As the construction of claims precedes an evaluation of infringement or validity (Whirlpool at para 43), this is where my analysis begins.
B. Analysis [28] As discussed, the claims asserted from the 098 Patent are claims 34 to 38, and 39 to 44 where dependent on claims 34 to 38 (see Annex A). The construction of the claims in this case proved to be straightforward, and was not a source of dispute between the parties. Nonetheless, in an effort to construe the claims purposively and contextually as instructed by the jurisprudence, including Whirlpool, a sequential examination of the Asserted Claims follows.
[29] Claim 34 is the relevant independent claim. Like other independent claims of the 098 Patent not asserted in this case, Claim 34 follows the general structure set out in Claim 1, which does not specify any particular acid inhibitor or NSAID. Specifically, Claim 34 provides as follows:
34. A pharmaceutical composition in unit dosage form comprising therapeutically effective amounts of:
(a) a pharmaceutically acceptable salt of esomeprazole, wherein at least a portion of said pharmaceutically acceptable salt of esomeprazole is not surrounded by an enteric coating; and
(b) naproxen, wherein said naproxen is surrounded by a coating that inhibits its release from said dosage form unless said dosage form is in a medium with a pH of 3.5 or higher;
wherein said unit dosage form provides for release of said pharmaceutically acceptable salt of esomeprazole and said naproxen such that:
i. upon introduction of said unit dosage form into a medium, at least a portion of said pharmaceutically acceptable salt of esomeprazole is released regardless of the pH of the medium; and
ii. said naproxen is released when the pH of said medium is 3.5 or higher. [Emphasis added.]
[30] In light of the whole of the 098 Patent, I construe claim 34 as comprising a pharmaceutical formulation of a PPI (esomeprazole) and a NSAID (naproxen), such that there is a coordinated release of at least a portion of the PPI regardless of the pH of the medium, and a delay of all of the NSAID until the pH of the medium is at least 3.5.
[31] Claims 35 to 38 are cascading dependent claims.
[32] Claim 35 provides an alternative pharmaceutical composition of claim 34 wherein none of the pharmaceutically acceptable salt of esomeprazole is surrounded by an enteric coating, such that upon introduction into a medium, essentially all of it would be immediately released.
[33] In other words, claim 35 limits the pharmaceutical composition in claim 34 such that none of the esomeprazole (the PPI) is surrounded by an enteric coating, as distinct from claim 34, which as I have construed above, instructs that ‘at least a portion of the PPI’ not be enteric coated. This means that whereas in claim 34 anywhere from 1% through 99% of the PPI would have no enteric coating, in claim 35 none (0%) of the PPI would be coated.
[34] Claim 36 provides that the naproxen be present in an amount between 250 and 500 mg. Claim 37 provides that the unit dosage form be a tablet. Claim 38 provides that the pharmaceutically acceptable salt be the magnesium salt of esomeprazole.
[35] Claims 39 to 44 are usage claims. The claimed uses of the pharmaceutical composition include treating a patient for pain or inflammation (claim 39), or in the manufacture of a medicament to treat the same (claim 40), and in particular for use where the said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis (claim 41). Similarly, the other claimed uses include treating osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (claim 42), or in the manufacture of a medicament to treat the same (claim 43), and in particular for use in patients at risk of developing NSAID associated gastric ulcers (claim 44).
VII. Obviousness A. The Law [36] Section 28.3 of the Patent Act provides that the subject-matter defined by a claim of a patent must not have been obvious to the skilled person, having regard to the information that was publicly available as of the claim date or one year before the Canadian filing date:
28.3 The subject-matter defined by a claim in an application for a patent in Canada must be subject-matter that would not have been obvious on the claim date to a person skilled in the art or science to which it pertains, having regard to
28.3 L’objet que définit la revendication d’une demande de brevet ne doit pas, à la date de la revendication, être évident pour une personne versée dans l’art ou la science dont relève l’objet, eu égard à toute communication:
(a) information disclosed more than one year before the filing date by the applicant, or by a person who obtained knowledge, directly or indirectly, from the applicant in such a manner that the information became available to the public in Canada or elsewhere; and
a) qui a été faite, plus d’un an avant la date de dépôt de la demande, par le demandeur ou un tiers ayant obtenu de lui l’information à cet égard de façon directe ou autrement, de manière telle qu’elle est devenue accessible au public au Canada ou ailleurs;
(b) information disclosed before the claim date by a person not mentioned in paragraph (a) in such a manner that the information became available to the public in Canada or elsewhere.
b) qui a été faite par toute autre personne avant la date de la revendication de manière telle qu’elle est devenue accessible au public au Canada ou ailleurs.
[Emphasis added.]
[Non souligné dans l’original.]
[37] In what remains the leading case on obviousness almost a decade later, Sanofi, the Supreme Court of Canada adopted a four-step analytical framework for assessing a claim of obviousness, which culminates in whether the differences between the state of the art and the inventive concept constitute steps that would have been obvious to the POSITA (para 67):
[67] It will be useful in an obviousness inquiry to follow the four-step approach first outlined by Oliver L.J. in Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd., [1985] R.P.C. 59 (C.A.). This approach should bring better structure to the obviousness inquiry and more objectivity and clarity to the analysis. The Windsurfing approach was recently updated by Jacob L.J. in Pozzoli SPA v. BDMO SA, [2007] F.S.R. 37 (p. 872), [2007] EWCA Civ 588, at para. 23:
In the result I would restate the Windsurfing questions thus:
(1)(a) Identify the notional “person skilled in the art”;
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention? [Emphasis added.]
It will be at the fourth step of the Windsurfing/Pozzoli approach to obviousness that the issue of “obvious to try” will arise.
[38] In Beloit Canada Ltd v Valmet Oy (1986), 8 CPR (3d) 289, [1986] FCJ No 87 (Fed CA) [Beloit], Justice Hugessen provided this classic description of the technically knowledgeable yet uninventive POSITA:
The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
[39] While still good law, the Supreme Court cautioned that the Beloit test must neither be treated as a statutory prescription, nor applied in an acontextual manner (Sanofi at paras 61-62).
[40] The Supreme Court also provided that, as part of the fourth step of the obviousness analysis, the “obvious to try” test may be applied to assess obviousness in circumstances such as these (Sanofi at para 68):
i. When Is the “Obvious to Try” Test Appropriate?
[68] In areas of endeavour where advances are often won by experimentation, an “obvious to try” test might be appropriate. In such areas, there may be numerous interrelated variables with which to experiment. For example, some inventions in the pharmaceutical industry might warrant an “obvious to try” test since there may be many chemically similar structures that can elicit different biological responses and offer the potential for significant therapeutic advances.
[41] In order to find that an invention was obvious to try, there must be “evidence to convince a judge on a balance of probabilities that it was more or less self-evident to try to obtain the invention”, but “[m]ere possibility that something might turn up is not enough” (Sanofi at para 66). In Pfizer Canada Inc v Apotex Inc, 2009 FCA 8 at paras 28-29, the Federal Court of Appeal clarified that the “obvious to try” test is not a “worth a try” test and provided the following guidance:
The test recognized is "obvious to try" where the word "obvious" means "very plain". According to this test, an invention is not made obvious because the prior art would have alerted the person skilled in the art to the possibility that something might be worth trying. The invention must be more or less self-evident.
The factors to consider when assessing whether an invention was “obvious to try” include the following (Sanofi at paras 69-70):
1. Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?
2. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?
3. Is there a motive provided in the prior art to find the solution the patent addresses?
[42] Another important factor may arise from considering the actual course of conduct which culminated in the making of the invention. It is true that obviousness is largely concerned with how a skilled worker would have acted in the light of the prior art. But this is no reason to exclude evidence of the history of the invention, particularly where the knowledge of those involved in finding the invention is no lower than what would be expected of the skilled person.
[43] The Supreme Court stipulated in Sanofi that the obvious to try factors enumerated above are not exhaustive, but rather must be (a) applied in accordance with the facts of each case (para 69), and (b) approached cautiously as one consideration in the broader obviousness inquiry, not as a “panacea for alleged infringers” (para 64).
[44] As specified in the Patent Act, the obviousness test is to be considered based on information that was available to the public before the claims date, which is June 1, 2001 in this case (see Mediatube Corp v Bell Canada, 2017 FC 6 at para 119, commenting on s. 28.3 of the Patent Act).
B. Expert Evidence (1) Summary of the Experts Affidavits (a) Dr. Polli (Applicants’ Pharmaceutical Expert) [45] Dr. Polli provided an in-depth analysis of the 098 Patent, reviewing the available treatment options and co-therapies listed, considering its examples, and interpreting its claims. Dr. Polli noted the harmful side effects of NSAIDs on the GI system, and approaches to mitigating this, including combining NSAIDs with a cytoprotective prostaglandin, such as misoprostol, in ARTHROTEC.
[46] After examining the prior art listed by Mylan in its NOA, Dr. Polli stated that it showed that PPIs were well known to be sensitive to acid, and it was clear in teaching that PPIs had to be protected from acids in the abdomen. PPIs were therefore, at the time, always enteric coated.
[47] Dr. Polli wrote that the skilled person would only have been led to the inventive concept with the benefit of the 098 Patent’s teachings and a hindsight analysis, given that the prior art taught away from – and indeed provided absolutely no suggestion of – a coordinated dosage unit containing a PPI and NSAID where the PPI or a portion thereof would be released immediately followed by a delayed NSAID release.
[48] Dr. Polli rejected the obvious to try assertions of Mylan in maintaining that despite significant academic and industry interest in developing alternative co-therapies to traditional NSAID formulations, the skilled person would not have been thinking about trying an oral solid dosage form in which all or a portion of the PPI was not enteric coated or otherwise unprotected from gastric acid. With respect to ARTHROTEC, Dr. Polli concluded that the skilled person would not think that an uncoated PPI could simply be substituted for the misoprostol with immediate release in the stomach.
(b) Dr. Armstrong (Applicants’ Expert Clinician) [49] Dr. Armstrong provided a comprehensive review of the human body’s defences to stomach acids, and the grave dangers of ulcers, lesions and other GI injuries. He examined the least harmful NSAIDs (such as COX-2 selective, and nitrous oxide NSAIDs), along with the various co-therapies available by 2001.
[50] Considering the prior art, Dr. Armstrong found that agents that raised gastric PH, including antacids (such as MAALOX), H2 blockers (such as ranitidine in ZANTAC or famotidine in PEPCID), and PPIs (such as omeprazole in LOSEC), to be the most effective NSAID co-therapies at the relevant time. However, he found that the accepted wisdom was that PPIs required an enteric coat to be effective.
[51] Dr. Armstrong also considered exogenous prostaglandins, such as misoprostol in ARTHROTEC, as an existing co-therapy with NSAIDS in 2001. However, Dr. Armstrong wrote that a skilled clinician would not consider misoprostol and PPIs to be interchangeable, as they are different types of drugs, and have different mechanisms to reduce the risk of NSAID-induced GI injury (i.e., that misoprostol was known to have protective effects on the gastroduodenal mucosa that went beyond inhibition of gastric acid secretion).
[52] Dr. Armstrong concluded in his Affidavit that to the skilled clinician, the 098 Patent provided a novel and rationally-based approach to managing the risk of NSAID-induced GI disorders, as it was contrary to the conventional wisdom that PPIs had to be enteric coated.
(c) Dr. Lane (Respondents’ Expert Clinician) [53] Dr. Laine asserted that because physicians commonly recommended co-administration of a PPI with a NSAID to reduce gastric injury, a skilled person would have found the claimed formulation (such that the PPI would release initially, followed by the NSAID when the pH was 3.5 or higher) obvious in light of the common general knowledge at the time.
[54] Dr. Laine found that the 098 Patent’s “sequential release” approach had already successfully been used for other agents including misoprostol in preventing GI tract injury, and oral formulations of uncoated PPIs in solid dosage forms were in use by the year 2000. He cited various prior art for these conclusions, including MD30 and MD10 (ARTHROTEC), MD7 (PPI/NSAID combination), and MD13 (oral formulation of non-enteric coated PPI).
[55] Dr. Laine, like Dr. Armstrong, identified various approaches to co-therapy, namely, protective agents, agents that raise gastric pH, and exogenous prostaglandins. However, according to Dr. Laine, the fact that PPIs have a different mechanism of action than other agents would not have deterred persons skilled in the art from pursuing the sequential-release approach of the 098 Patent, which he found at the relevant time would have been obvious to an ordinary clinician, and not involved any degree of inventiveness. Dr. Laine also wrote that sequentially releasing the PPI before the NSAID did not provide for any benefit over existing strategies. Dr. Laine noted the shortcomings of the examples used in the 098 Patent (based on the fact that the evidence relied upon did not provide any novel information), and that the patent did not provide any testing results for the claimed formulation.
[56] Ultimately, although acknowledging his expertise as a clinician rather than a formulator, Dr. Laine rejected the claims of Drs. Armstrong and Polli that the skilled person would only have considered enteric coating PPIs. Instead, he opined that there would have been a strong motivation to combine NSAIDs with PPIs in a single dosage form due to (i) co-administration of a NSAID with a PPI being a “standard of care” to reduce NSAID-associated GI injury; (ii) a concern about improving compliance for patients at risk of this type of injury; and (iii) existing and widely-used products that provided NSAID benefit and GI protection in a single dosage form.
(d) Dr. Appel (Respondents’ Pharmaceutical Formulator Expert) [57] Dr. Appel wrote that designing “a specific mechanism of release” and “a specific architecture” are distinct parts in the formulation process. She concluded, after considering the prior art and claimed invention, that the asserted claims would have been obvious to a skilled formulator, as the architecture had been used previously in combination formulations containing NSAIDs and gastroprotective drugs, such as ARTHROTEC.
[58] Dr. Appel found that the architecture described in the 098 Patent could have been used for any combination of NSAID and PPI (i.e. not only naproxen and esomeprazole). She noted in any event that the combination of NSAID and PPI had previously been formulated in prior art. She disagreed with her counterpart expert for the Applicants, Dr. Polli, who opined that the prior art taught away from the patent. Rather, Dr. Appel posited that a formulator would have considered a broader range of approaches than had Dr. Polli, and would have been motivated to arrive at the claimed formulation. Indeed, the prior art demonstrated that there were multiple formulation approaches possible, including a sequential release profile.
[59] Dr. Appel outlined three types of strategies to counter NSAID degradation caused by its acid lability (sensitivity) and provided examples of each of them in the prior art: (i) enteric coating (MD7); (2) time-release coating (MD9 and MD33); and (3) an alkalizing agent (MD13 and MD14). Dr. Appel characterized enteric coating the PPI as one option, but not the only one. Furthermore, Dr. Appel noted that ARTHROTEC has the same formulation strategy and architecture as the proposed invention, namely the sequential release of an acid inhibitor and a NSAID from a unit dosage form.
[60] Dr. Appel concluded that the prior art indicated a consistent motivation to come up with new formulations and products in the area. Indeed, the patent itself covers numerous drugs with different mechanisms, including PPIs and H2 inhibitors. With “acid inhibitors” being broadly defined, there is no reason that misoprostol would not be included, as it had been shown to inhibit gastric acid secretion and raise pH levels.
(e) Dr. Lee (Respondents’ Pharmaceutical Formulator Expert) [61] Dr. Lee concluded that a skilled formulator at the relevant date would have seen the approach set out in the asserted claims as having been similarly pursued previously. He based this on various NOA materials, observing that the prior art showed that the sequential release approach in the asserted claims had been successfully applied to several other products co-formulated with a NSAID for the same GI-protective purpose, such as in ARTHROTEC.
[62] Dr. Lee disagreed with Dr. Polli, who wrote that the inventive concept was to delay the NSAID release until GI acid levels were reduced to non-toxic levels. Rather, Dr. Lee interpreted the claims as simply stipulating the NSAID release would occur in a medium with pH levels above 3.5, regardless of how the PPI behaves. Dr. Lee further opined that the claims in issue do not specify that the PPI (esomeprazole or its pharmaceutically acceptable salt) must achieve any minimum level of acid inhibition. In short, Dr. Lee found that the difference between the state of the art and the inventive concept of the asserted claims appeared to be choosing, in a single dosage form, to sequentially release a PPI – as opposed to another protective agent – prior to a NSAID.
[63] According to Dr. Lee, arriving at this NSAID-PPI tablet with its particular sequential release formulation was not inventive given the prior art, and would have been obvious to try through minimal and routine experimentation. Of the four available formulation options he noted, Dr. Lee explained that the 098 Patent’s ‘tablet-in-tablet’ approach required only a routine formulation exercise using the prior art, which included ARTHROTEC and which did not teach away from the claimed invention. A skilled formulator would have been motivated to (a) combine these agents in a single pill, given the finite number of combinations, and (b) consider a co-formulation that replaced misoprostol with a more efficient (or potent) acid inhibitor. He also critiqued the lack of clinical studies or results provided in the 098 Patent. Dr. Lee pointed to numerous sources where the PPI was not enteric-coated or otherwise protected.
(2) Challenges to Expert Evidence and Credibility [64] Having seen the main thrust of the experts’ evidence, this section will briefly summarize the primary attacks on the experts, and any conclusions drawn.
(a) Partiality [65] Both sides impugned the partiality of the experts.
[66] AstraZeneca made claims impugning the impartiality of Mylan’s experts given certain ties (financial and otherwise). For the reasons below, I reject those arguments.
[67] Mylan’s argument that AstraZeneca’s experts exhibited an unjustified bias towards enteric coating was equally unpersuasive: this was simply a point of disagreement in the interpretation of the prior art, rather than any demonstration of bias in the legal sense.
[68] The Supreme Court of Canada recently revisited the inadmissibility of expert evidence for partiality in White Burgess Langille Inman v Abbott and Haliburton Co, 2015 SCC 23 [White Burgess]. In White Burgess, the Supreme Court found that experts have a duty to the court to provide “fair, objective and non-partisan” assistance (at para 46), and are required to certify that they are aware of and will comply with this duty (at paras 28-29; see also Federal Courts Rules, SOR/98-106, Rule 52.2(1)(c)).
[69] The party opposing the admission of the evidence must show “a realistic concern that the expert's evidence should not be received because the expert is unable and/or unwilling to comply with that duty” (White Burgess at para 48). If successful, the burden switches back to the party supporting the expert to establish, on a balance of probabilities, that the evidence is admissible – a threshold that the Supreme Court states is “not particularly onerous”. The following discussion and scenario provided is illustrative of the relatively low threshold to admit expert evidence (White Burgess at para 49):
The trial judge must determine, having regard to both the particular circumstances of the proposed expert and the substance of the proposed evidence, whether the expert is able and willing to carry out his or her primary duty to the court. For example, it is the nature and extent of the interest or connection with the litigation or a party thereto which matters, not the mere fact of the interest or connection; the existence of some interest or a relationship does not automatically render the evidence of the proposed expert inadmissible. In most cases, a mere employment relationship with the party calling the evidence will be insufficient to do so. On the other hand, a direct financial interest in the outcome of the litigation will be of more concern… I emphasize that exclusion at the threshold stage of the analysis should occur only in very clear cases in which the proposed expert is unable or unwilling to provide the court with fair, objective and non-partisan evidence. Anything less than clear unwillingness or inability to do so should not lead to exclusion, but be taken into account in the overall weighing of costs and benefits of receiving the evidence.
[70] The Supreme Court went on to further explain that the high threshold is breached when the expert is actually unable or unwilling to fulfil this duty to the court, not by a perceived lack of independence (at para 50):
When looking at an expert's interest or relationship with a party, the question is not whether a reasonable observer would think that the expert is not independent. The question is whether the relationship or interest results in the expert being unable or unwilling to carry out his or her primary duty to the court to provide fair, non-partisan and objective assistance.
[71] Of course, prior inconsistent statements or implausible positions may also lead one to question the credibility of that expert. However, there would need to be evidence of such statements and positions (see, for instance, Allergan Inc v Canada (Minister of Health), 2011 FC 1316 at para 32). I find no such evidence in this case.
[72] The Court finds, after having listened to the submissions about the experts, insufficient evidence to sustain any credible presumption of bias. Suffice it to say that pharmaceutical experts often appear before the Court for the same party, and may have even been previously employed by that party. But this does not mean that they lack independence, and it certainly does not mean they are not impartial: to suggest that their opinions have been tainted by prior work or affiliations can only hold water with compelling evidence of the same.
[73] This is far from a clear case where any of the experts were unable or unwilling to provide fair, objective and non-partisan input; no evidence of same was furnished. As a result, none of the five experts who gave evidence for this litigation will be rejected on the basis of bias or credibility. That the experts evidently disagreed on their interpretation of certain aspects of the prior art, common general knowledge, and resulting obviousness conclusions, is common in pharmaceutical litigation. Certain experts’ observations and conclusions are more compelling than others, and as a result, the Court places more weight and greater reliance on some experts’ evidence than others.
(b) Blinding [74] AstraZeneca claims that the Mylan’s experts simply responded to Dr. Polli’s opinions without reviewing the NOA, and that Dr. Polli was the only expert who expressly addressed the allegations raised in the NOA. Mylan’s experts, on the other hand, relied on new factual bases outside of the NOA. Furthermore, Mylan failed to blind their experts to the patent. AstraZeneca’s experts, on the other hand, gave their opinions based on their review of the common general knowledge and prior art, ensuring they had open minds.
[75] Mylan deflected AstraZeneca’s criticisms of the experts, arguing that the latter’s approach was worse, namely blinding to any alternative to enteric coating for PPIs. Mylan also noted that while AstraZeneca’s experts were blinded to the patent, they were given an inventive concept and asked to evaluate it, which is tantamount to receiving the patent without the ability to independently assess it.
[76] For its part, Mylan argued that its experts were respectful of their roles within a clinician-formulator team,