Docket: T-336-15
Citation:
2017 FC 142
Toronto, Ontario, February 07, 2017
PRESENT: The
Honourable Mr. Justice Diner
BETWEEN:
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ASTRAZENECA
CANADA INC
AND
POZEN INC
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Applicants
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And
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MYLAN
PHARMACEUTICALS ULC
AND
THE MINISTER OF
HEALTH
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Respondents
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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
[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.
[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.
[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.
[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.
[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.
[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 S.C.R. 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.
[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).
[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:
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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
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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:
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(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
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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;
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(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.
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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.
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[Emphasis added.]
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[Non souligné dans l’original.]
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[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).
(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.
[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, correctly
instructed on the law, told to avoid using hindsight, and not provided with a
copy of the NOA (which would have revealed Mylan’s position).
[77]
Blinding experts does not necessarily produce a
more reliable outcome. As Justice Locke recently held in Shire Canada Inc v
Apotex Inc, 2016 FC 382 at paras 45-46:
45 …I am mainly interested in the substance
of an expert's opinion and the reasoning that led to that opinion. If it is
well-reasoned, there may be no reason for concern about whether the witness was
blinded to certain facts when giving the opinion. A concern may arise where the
expert's opinion seems tortured or less well-reasoned.
46 I am also conscious that the blinding of
witnesses is no guarantee that the expert evidence before the Court is
reliable. It would not be difficult (though it would be expensive) for an
unscrupulous party to seek opinions from a number of experts, keeping them all
blind to unnecessary information. If one of those many experts provided the
opinion that the party sought and all of the others concluded otherwise, the
party would be able to retain the outlier and present him or her as a blinded
(and therefore reliable) witness.
[78]
In this case, the approach of both sides in the
preparation of their witnesses was acceptable, and as a result neither warrants
exclusion or less weight. Rather, my analysis turns on which of the experts
provided the most compelling evaluations of the common general knowledge held
by the POSITA, the state of the art, and other factors in the obviousness
analysis.
(a)
The POSITA
[79]
The parties and the expert witnesses agree that
the notional POSITA would include a skilled pharmaceutical formulator with
relevant education and experience, working in collaboration with a drug
development and formulation team that includes at least a skilled medical clinician.
(b)
Common General Knowledge
[80]
The parties differ on their positions with
respect to the common general knowledge at the relevant time.
[81]
In short, AstraZeneca posits that the common
general knowledge would have led the POSITA to conclude that a PPI, when
co-administered with a NSAID, had to be protected by an enteric coating in
order to avoid being immediately released. Immediate release would have failed
to protect the PPI from the acidic conditions of the stomach. Mylan refutes
this argument, contending that the skilled person would have known not only of
NSAID-PPI combination formulations and of co-formulations of a NSAID with other
gastroprotective drugs with a sequential release profile, but also of
non-enteric coated PPIs.
[82]
The Court’s task at this stage is simply to
determine the common general knowledge of the POSITA at the relevant date, as
opposed to what the POSITA might have been expected to find and consider from
researching the relevant prior art.
[83]
As discussed in the facts section above, as of
the relevant date the skilled person knew, as common general knowledge, that
alternative treatments to the 098 Patent’s co-therapy of a NSAID with an
uncoated PPI included: (a) less injurious NSAIDs, such as COX-2 specific
inhibitors (CELEBREX); and (b) NSAID co-therapy with drugs such as H2 blockers
(e.g. MD8), misoprostol (as in ARTHROTEC), or enteric coated PPIs (e.g. MD7).
While some of these alternatives were less desirable and prescribed than
others, they were all commonly known. Indeed, the 098 Patent itself mentions
these treatment options.
[84]
Of particular note here is that PPI and NSAID
combinations were well known. Indeed, as Dr. Laine pointed out in his
affidavit, the 1998 American College of Gastroenterology guidelines on the
treatment and prevention of NSAID-induced ulcers, which remained current in
2001, recommended preventative co-therapy with either misoprostol or PPIs (Dr.
Laine Affidavit at para 56). The specific choice of naproxen and esomeprazole
for a NSAID-PPI combination was also not novel (e.g. MD7).
[85]
Further, enteric coated NSAIDs were widely used;
even enteric coated naproxen specifically was commercially available (MD24; Dr.
Laine Affidavit at para 144).
[86]
Finally, there were three other pieces of prior
art that were the focus of significant debate in the obviousness issue: (i)
MD52: a 1985 journal article which AstraZeneca argued ‘taught away’ from
non-enteric coated PPIs; (ii) MD13: a May 2000 patent application for a
medication combining a PPI with a bicarbonate salt; and (iii) ARTHROTEC, e.g.
MD30: a 1992 journal article discussing ARTHROTEC, the co-formulation of
misoprostol and a NSAID in a multi-layer tablet, with the immediate release of
misoprostol followed by a delayed release of the NSAID.
(i)
Non-enteric Coated PPIs (MD52, MD13 and MD14)
[87]
According to AstraZeneca, MD52 shows that the
prior art ‘taught away’ from not fully enteric coating a PPI. AstraZeneca
argued that despite being from 1985, this prior art was not outdated as of the
relevant date, and that the prior art relied upon by Mylan is not relevant. For
example, MD7, which was published many years later in 1997, is consistent with
MD52.
[88]
Nevertheless, I agree with Mylan that MD52 is
dated art. Mylan’s experts (Drs. Laine and Appel) addressed it, and I agree
with them that subsequent art, including MD13, superseded it.
[89]
According to Dr. Laine, by the relevant date,
the administration of PPIs without enteric coating was not merely theoretical;
it was well-described and used in clinical practice (Dr. Laine Affidavit at
para 185). MD13, which was released in 2000 (15 years after MD52), is a patent
directed to the treatment of gastric disorders by administering a
pharmaceutical composition of a PPI with a bicarbonate salt in a dry solid
formulation, prior to dissolution. MD13 acknowledged challenges with existing
PPI-sodium bicarbonate formulations, but taught that the invention therein
overcame these. In particular, its inventors claimed a solid oral
pharmaceutical composition containing a PPI and bicarbonate salt wherein the
dosage form, such as a tablet or capsule, is not enteric coated or time released
(claims 5 and 8 of MD13).
[90]
In reply, AstraZeneca argues that this prior art
is directed only to the administration of PPIs as suspensions or solutions, not
solid dosage forms, and so it is not relevant. In particular, it was for those
who cannot swallow. The solid form is simply for storage.
[91]
These objections are noted. However, it is also
noted that MD13 teaches that the dry formulation need not necessarily be mixed
with water prior to ingestion; it may simply be ingested and then acted upon by
the water utilized to swallow the solid formulation (MD13 at 27).
[92]
Moreover, MD14 is another patent from 2000
directed to a non-enteric coated PPI, and it was published by AstraZeneca. Of
particular note is the comment of its inventors regarding their dosage form
without an enteric coating “which previously [has] been
almost an axiom for dosage forms containing omeprazole or any other proton pump
inhibitor compounds” (MD14 at 2-3). According to the MD14 inventors, any
‘teaching away’ was now in the past. Further, MD14 taught that the alkalizing
agent in the core would neutralize the absorbed acidic fluid and protect the
active ingredient against degradation.
[93]
As a result of the above, I find that the common
general knowledge included several approaches to formulating acid-sensitive
compounds such as PPIs, including the use of an alkalizing agent to reduce
degradation by acid in the stomach.
[94]
I further find that at the relevant date the
common general knowledge was that there were alternatives to enteric coating a
PPI. Stated conversely, it was not common general knowledge that one must
enteric coat a PPI.
(ii)
ARTHROTEC (MD10, MD11, and MD30)
[95]
AstraZeneca argued that ARTHROTEC should not
figure into the obviousness analysis because misoprostol acts differently than
a PPI; it is not an “acid inhibitor”. This is
because it has a different protective mechanism than PPIs: misoprostol is a
prostaglandin analogue, supplementing prostaglandins (which help to protect the
stomach lining). Therefore, the administration of misoprostol is sometimes
referred to as “replacement therapy.” Misoprostol
inhibits prostaglandins throughout the body, rather than targeting just the
stomach lining, which can be contrasted with PPIs, which solely inhibit acid by
inactivating proton pumps (which secrete acid) within the parietal cells of the
stomach lining. Dr. Laine lists the various defensive mechanisms of
prostaglandins as follows:
(a)
inhibition of acid secretion;
(b)
stimulation of mucus (which covers the lining of
the stomach) and bicarbonate (alkaline molecule which counteracts/neutralizes
acid;
(c)
increased blood flow in the stomach lining;
(d)
accelerated restoration and healing of the
stomach lining; and
(e)
prevention of blood cells from sticking to the
walls of blood vessels.
[96]
Mylan argues that while misoprostol may not work
in exactly the same way as other acid inhibitors such as PPIs, and may have
different side effects, arguing that it is not an acid inhibitor equates to
saying a Swiss Army Knife is not a knife. ARTHROTEC was the only
commercially-available fixed dose NSAID co-therapy drug to mitigate GI
side-effects at the relevant time. AstraZeneca’s own expert Dr. Armstrong
appeared to accept this (Dr. Armstrong Cross-Examination at 71:14-22) and
generally noted that misoprostol reduced gastric acid secretion and
NSAID-induced ulcers (Dr. Armstrong Affidavit at para 74).
[97]
MD30, a journal article about ARTHROTEC
published in 1992, showed not only that fixed-dose
combinations of NSAIDs and other gastroprotective drugs were well-known, but
also showed that a sequential-release formulation was commercially available
for such combinations. It depicted ARTHROTEC’s formulation (left), which can
be compared to the 098 Patent’s Fig. 2 (right), below.
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[98]
Both diagrams depict a NSAID core, immediately
surrounded by an enteric coating, with an outer layer of a gastroprotective
drug (misoprostol on the left, and an acid inhibitor – being a PPI in the Asserted
Claims – on the right). Dr. Appel addressed the architectural similarities at
length, which I find to be persuasive evidence.
[99]
After considering the arguments from both
parties, I do not find it necessary to decide whether misoprostol is properly
labeled as an “acid inhibitor”, due to the fact
that I find that misoprostol has a similar purpose and ultimate effect as PPIs
within their respective formulations (ARTHROTEC and the 098 Patent).
[100] I find the distinction made among the two types of effects –
systemic and local – is of no consequence for the purposes of this proceeding,
as ultimately both act on the same receptors and have the same net effect of
limiting GI injury resulting from NSAID use.
[101] The fact that, as conceded by Mylan, misoprostol was not as
desirable a NSAID co-therapy option as PPIs due to its side-effects does not
eliminate it from the state of the art. That art, including MD10, MD11, and
MD30, clearly shows that as part of a multi-layer tablet, misoprostol was
co-formulated using similar architecture to that depicted in the 098 Patent.
[102] Despite the disagreement over misoprostol’s proper classification,
it is not disputed that misoprostol has the effect of inhibiting acid. Further,
there is uncontradicted evidence that misoprostol and PPIs were generally
recommended co-therapy agents to protect against NSAID-associated injury at the
relevant date. For example, as discussed in paragraph 84, the 1998 American
College of Gastroenterology guidelines on the treatment and prevention of
NSAID-induced ulcers, which remained current in 2001, identified misoprostol
and PPIs as the acceptable co-therapy agents (Dr. Laine Affidavit at para 56).
[103] In short, it is unnecessary to determine whether misoprostol is
properly classified as an “acid inhibitor”
because what ultimately impacts the obviousness analysis is whether misoprostol
would have been considered by the POSITA. While misoprostol might not be “interchangeable” with PPIs per se, I find that
the skilled person would have considered it as part of the relevant prior art
as one of the other generally recommended NSAID co-therapy agents.
[104] As discussed in Section II (“Background”)
above, for the purposes of these proceedings, the Applicants asserted claim 37
(itself dependent on claim 34, 35, or 36) and claims 38 to 44 where dependent
on claim 37.
[105] According to AstraZeneca, the inventive concept could be described,
consistent with the experts evidence, as follows: a solid dosage form (such as
a tablet) that provides for the immediate release of at least a portion (or
all) of the esomeprazole regardless of the pH of the medium, and for the
delayed release of all of the naproxen. AstraZeneca claimed that what made the
098 Patent inventive was that it offered “a new method
of reducing the risk of GI side effects in people taking NSAIDs: a single
tablet or capsule that provides for a coordinated (i.e., sequential) release of
acid inhibitor first and NSAID second” (Applicants’ Memorandum at para
17).
[106] According to Mylan, the inventive concept is the use of a
coordinated, sequential-release formulation architecture for a formulation
containing a NSAID and a PPI. Mylan goes on to argue that the inventive concept
neither includes the decision to combine a NSAID and a PPI, nor the specific
choice of naproxen or esomeprazole as the NSAID and PPI in the formulation.
[107] In other words, the parties and their experts were in large measure
agreed as to the inventive concept. However, in light of my findings with
respect to the common general knowledge, as set out above, I agree with Mylan
that there was nothing novel or inventive about combining a NSAID and a PPI,
nor the specific type of each used in the Asserted Claims. Therefore, I find
the inventive concept to be a Tablet formulated for immediate release of a
portion, or all, of the PPI regardless of the pH of the medium, with a delayed
release of the NSAID until the pH of the medium is at least 3.5.
[108] The third determination considers the difference, or delta, between
the state of the art and the inventive concept. It is that delta on which the
obviousness determination will hinge.
[109] A substantial difference between what was known in the art and what
was represented in the 098 Patent normally would not have been obvious to the
POSITA. A small delta, by contrast, might have been relatively easy to bridge
and therefore may satisfy the difficult obviousness threshold – although a mere
scintilla of inventiveness is always sufficient to put the difference beyond
what would have been obvious to the POSITA.
[110] As a result, in an obviousness challenge to a patent’s validity,
determining the knowledge delta is a key inquiry.
[111] The parties differed in describing the delta between the state of
the art and inventive concept. According to AstraZeneca, the major difference between
the inventive concept and the state of the art includes the sequential release
of a PPI followed by a NSAID. AstraZeneca contends that this constituted a
major difference that would not, without the patent, have been self-evident to
the POSITA, because the prior art taught away from the invention.
[112] Mylan disagreed, contending that the difference between the
inventive concept and the state of the art is the application of the well-known
sequential release architecture to the well-known NSAID-PPI combination, using
routine means, to achieve a well-known advantage: reduction of GI side effects
in NSAID co-therapy. In other words, the inventive concept is simply a
combination of the prior art – a minor difference.
[113] Despite Mylan’s ostensible disagreement, I do not believe the
parties are, in substance, far apart on this point. Both focus on the
formulation’s sequential release profile.
[114] As discussed, a NSAID-PPI co-formulation for this purpose was not
new, and neither was the concept of sequential release when co-formulating a
PPI with a gastroprotective drug. What was indeed novel, however, was the
application of this sequential release profile in a NSAID-PPI co-formulation.
Therefore, I find that the difference between the state of the art and the
inventive concept lies in the sequential release profile, which is achieved by
the decision not to fully enteric coat the PPI.
[115] In my view, the divergence between the parties’ position, as
outlined above, properly goes to the fourth step, and so is further considered
in the analysis section below.
[116] The fourth and final section of the obviousness analysis involves a
determination of the steps that the POSITA would have required to bridge the
gap between the state of the art and the inventive concept. The key question to
be answered in this final stage of Sanofi’s four part test is whether
the bridging of this gap required steps which would have been obvious to the
POSITA. Otherwise stated, did the steps require any degree of invention? In my
view, they did not.
[117] AstraZeneca argued that the differences would not have been obvious
to the POSITA at the relevant time: coordinated release, with the PPI releasing
immediately (at least in part) in the stomach followed by a delayed release of
the NSAID in the small intestine, was inventive “because
PPIs were known to be acid sensitive and should not be immediately released in
the acidic stomach from a solid dosage form” (Applicants’ Memorandum at
para 2). AstraZeneca maintained that “all commercial
PPI products were delayed release formulations”, as “[o]nly a delayed release PPI, when used with NSAID therapy,
had been shown to effectively reduce the risks of NSAID-induced GI injury”
(Applicants’ Memorandum at para 2).
[118] According to Mylan, while the 098 Patent’s coordinated release may
not have been previously suggested in the exact combination proposed (i.e.
NSAID-PPI), it was consistent with the common general knowledge at the relevant
time and represented an obvious step.
[119] The obvious to try considerations are examined in a separate section
below. Before looking at those factors, I will address some of the key elements
explaining why bridging the gap between the state of the art and the inventive
concept would have been self-evident to the POSITA at the relevant time.
[120] As discussed, a NSAID-PPI combination was part of the common general
knowledge, as was the sequential delivery profile for combinations with other
co-therapy agents.
[121] All of Mylan’s experts provided compelling evidence that, although
the combination had not yet been tried, applying the sequential release profile
to a NSAID-PPI combination was obvious to try for a tablet-in-tablet
formulation (e.g. Dr. Lee Affidavit at para 158).
[122] Even AstraZeneca’s experts, when pressed, generally agreed that
ARTHROTEC served a similar purpose in that misoprostol is used to help protect
against the negative GI effects of NSAIDs. The fact that the side effects from
misoprostol could be more severe than those from a PPI, making it a less desirable
medication for many, does not detract from the fact that it served as (a) an
option to address the nefarious effects of GI injury, along with some of the
other co-therapies and anti-acidic agents paired with NSAIDs, and (b) a reason
(or motivation) for inventors to try other formulations, including that set out
(but not tested) in the 098 Patent. As already explained, I cannot support
AstraZeneca’s refusal to characterize misoprostol as an acid inhibitor, despite
the acknowledgement that it inhibits acid and addressed the same problem as the
098 Patent.
[123] The prior art included formulations without an enteric coating, such
as a PPI and bicarbonate where, like with the 098 Patent, there was no enteric
coating or time-release (MD13). Further, the architecture was known in the
context of another NSAID co-agent, misoprostol, and its commercial
co-formulation ARTROTEC. What was not known was using a (non-enteric
coated) PPI instead of misoprostol for the outer layer in this architecture,
such that the PPI was subject to immediate release in the stomach, followed by
the delayed release of the NSAID. However, I find this sequential release (via
not enteric coating the PPI) to have been obvious, due in part to the prior art
(such as MD7, MD10, MD13, and MD30). Given the highly competitive nature of the
pharmaceutical market, my conclusion is further supported by the “obvious to try” test, discussed below.
[124] Before proceeding with the obvious to try analysis, I wish to note
that it, and indeed all facets underpinning the obviousness analysis, is
focused on claim 37 as dependent on the other Asserted Claims, as the Applicant
asserted. I have nevertheless considered all of the Asserted Claims individually,
as first addressed in Section VI above. Limited attention has been expressly
given to a number of the individual claims within the Asserted Claims simply
because there was no genuine dispute regarding them in the context of the
obviousness allegation.
[125] For instance, the composition specified in claim 35, as varied from that
in claim 34, did not change the inventive concept for the purposes of the
obviousness analysis. Further, I find that there was nothing inventive – nor
was there any suggestion that there was anything inventive – regarding the
following:
a.
specifying that the dosage amount of naproxen in
the composition be between 250 and 500 mg (claim 36);
b.
specifying that the unit dosage form outlined in
claim 34 (or claims 35 or 36) be a tablet (claim 37); or
c.
using the pharmaceutical composition for any of
the purposes set out in the usage claims (claims 39 to 44), which are
consistent with the existing alternative products already discussed.
[126] Therefore, as with the rest of my analysis, the obvious to try
considerations below will focus on crux of this matter: the application of the
sequential release profile in a NSAID-PPI co-formulation, which was achieved by
not fully enteric coating the PPI – whether it be partially enteric coated
(claim 34), or not at all (claim 35).
[127] The final point to canvass, as an adjunct to the fourth Sanofi
criterion, is the “obvious to try” test. As is
often the case in pharmaceutical patent disputes (Sanofi at para 68),
the “obvious to try” test is warranted here. I
have concluded that the inventive concept in this case was indeed obvious to
try because: (i) there were a limited number of
predictable solutions in managing GI injury that would have been more or less
self-evident to work, (ii) the
invention did not involve an undue amount of effort to achieve, and (iii) there was a strong motive to combine
a NSAID with a PPI in a single dosage combination with the sequential release
profile.
(a)
Is it More or Less Self-Evident That What is
Being Tried Ought to Work?
[128] Here, Mylan’s experts found that there were indeed a limited number
of identified predictable solutions known to the POSITA. Clearly, the options
were limited as to what agents could be used in combination with a NSAID to
lessen the risk of GI injury (see said options above). PPIs were commonly known
to be one of those options, even if they had not been brought to market in a
tablet form with sequential release. PPIs had been brought to market in other
forms (such as co-administered for intravenous, immediate release).
[129] In light of the expert evidence, and given the common general
knowledge as set out above, including the understanding that PPI’s did not
necessarily have to be enteric coated, I find it would have been self-evident
to the POSITA that an ARTHROTEC-type of architecture could be successfully
applied to a NSAID-PPI formulation.
[130] Therefore, it would have been more or less self-evident to the
POSITA that the sequential release profile in the Asserted Claims, achieved in
part by the decision not to fully enteric coat the PPI, would work.
(b)
What is the Extent, Nature, and Amount of Effort
Required to Achieve the Invention?
[131] Dr. Appel described the work that would have gone into the
formulation of the 098 Patent as routine and noted the inventor’s own
observation in the 098 Patent that the invention “can
be made in accordance with methods that are standard in the art” (098
Patent at p 10, lines 21-22).
[132] Drs. Appel, Laine, and Lee also found that the patent provided
incomplete clinical testing data in its examples, with no testing of any
NSAID-PPI formulation (rather, there were only limited trials conducted on
other agents). AstraZeneca’s experts did not counter these observations in
their written testimony, and indeed, under cross-examination Dr. Polli agreed
that the patent did not provide for any testing of the non-enteric coated PPI
formulation in the patent.
[133] On this factor of effort, I am persuaded by Mylan’s conclusion that
only a limited amount of effort was required to achieve the inventive concept.
The only evidence of any trials was of limited use because they were for other
agents (Examples 8 and 9 of the 098 Patent). Nor is there any evidence from the
inventor, apart from what has been set out in the patent which, as mentioned,
is not very much. The fact that there was no evidence of any trials, nor any
evidence of the knowledge of the inventors relative to the notional skilled
person, can also be a relevant factor in considering the actual course of
conduct (AstraZeneca Canada Inc v Teva Canada Ltd, 2013 FC 245 at para
64).
[134] Furthermore, neither the fact that (i) no one knew whether the
claimed invention would provide any additional benefit (i.e. the non-enteric
coated PPI), nor that (ii) there were other options amongst gastroprotective
agents apart from PPIs, render the claims non-obvious. The following words of
Justice Barnes in Janssen Inc v Teva Canada Limited, 2015 FC 184 at para 113, are apposite:
…The fact that the formulator had a few
choices to make and would need to test the formulation to ensure its efficacy
does not render this exercise non-obvious. Here I adopt the point made by
Justice Roger Hughes in Shire Biochem Inc. v. Canada (Minister of Health),
2008 FC 538 (F.C.) at para 80, [2008] F.C.J. No. 690 (F.C.), that the existence
of number of possible routes to solve a problem does not mean that the route
taken was not obvious. In Brugger v. Medicaid Ltd. (No. 2), [1996]
R.P.C. 635 (England P.C.) at p 661, the same point was stated in the following
way:
First a route may still be an obvious
one to try even if it is not possible to be sure that taking it will produce
success, or sufficient success to make it commercially worthwhile. ...
Secondly, if a particular route is an obvious one to take or try, it is not
rendered any less obvious from a technical point of view merely because there
are a number, and perhaps a large number, of other obvious routes as well. If a
number of obvious routes exist it is more or less inevitable that a skilled
worker will try some before others.
(c)
Is There a Motive From the Prior Art to Find the
Solution That the Patent Addressed?
[135] The parties spent a significant amount of time putting forward their
positions on specific versus general motivation, and whether the former alone
could satisfy the “obvious to try” test.
[136] AstraZeneca argued that specific motivation – rather than simply a
general motivation – must be present to satisfy Sanofi’s “obvious to try” test in this case. Here, there
must have been a reason why a skilled person would have tried to specifically
combine a PPI and NSAID with the uncoated PPI released first and the NSAID
second. Otherwise stated, the motivation must be specific to the inventive
concept.
[137] AstraZeneca claimed that Mylan’s experts’ evidence on whether it was
obvious to try was (a) inconsistent, and (b) failed to establish any specific
motivation to try. Drs. Appel and Lee, Mylan’s expert formulators, stated that
skilled clinicians would need to direct a particular release profile of a
NSAID-PPI, and they provided inconsistent testimony as to what a skilled
formulator would have done.
[138] AstraZeneca argued at the hearing that the evidence of Mylan’s
experts showed that there was no motivation to try the claimed sequential
release formulation. AstraZeneca’s argument in this regard was based primarily
on the testimony of Dr. Laine, Mylan’s expert gastroenterologist (clinician),
whose evidence supposedly raised two bases for showing a lack of motivation.
(i)
Alleged lack of motivation on part of clinician
to instruct the formulation
[139] Normally, in the pharmaceutical team process which represents the
POSITA in this case, the clinician’s role is to direct the formulator. Simply
put, the clinician generally identifies a clinical problem and may suggest
approaches to solve it, while the formulator would generally develop the new
drug or formulation that achieves that need, is stable, and can be reliably
manufactured. The clinician directs and the formulator executes in the drug’s
design.
[140] In AstraZeneca’s view, Dr. Laine (as clinician) would not have
directed the formulator to design the sequential-release tablet described in
the disputed claim. Specifically, AstraZeneca points to Dr. Laine’s evidence
that it was not clear that the sequential release of the PPI followed by the
NSAID provides any additional benefit as compared to a formulation not designed
to provide sequential release. This statement, AstraZeneca posits, is
tantamount to admitting that there was no impetus to direct the formulators to
come up with the inventive concept; and therefore there was no motivation to
try.
[141] I do not accept this argument. The comment in question arises from a
portion of Dr. Laine’s Affidavit in which he is supporting his opinion that the
sequential release formulation – the concept of having a protective agent (in
the 098 Patent, the PPI) release before the NSAID – was well-known in clinical
practice, in the medical literature, and in patents.
[142] In particular, just before the impugned comment, Dr. Laine stated
that the knowledge that misoprostol, H2s, and other similar NSAID
co-therapy agents were released before the NSAID with the goal of providing
more effective protection against NSAID-induced GI injury in other
formulations, would “certainly have suggested to the
skilled clinician that he/she could pursue a similar approach with PPI
protective therapy” (Dr. Laine Affidavit at para 204).
[143] While Dr. Laine indeed goes on to say that there is no evidence that
the sequential release provides additional benefits in a NSAID-PPI combination,
he was pointing out the 098 Patent’s lack of evidence to support any additional
benefits, and that it did not provide any inventive advantage, concluding at
paragraph 223 of his Affidavit that:
… sequential-release formulation could have
produced an inventive advantage if the inventor has documented or taught that
sequential release provided greater reduction of NSAID-associated GI injury,
such as ulcers, than coadministration of PPI and NSAID or a combination
formulation without the specified sequential-release pattern. However, this was
not the case.
(ii)
Alleged lack of known benefit
[144] Furthermore, I do not agree with the implicit argument that if there
is no known inventive benefit to something, there would be no reason to try it.
Such a reading would also be inconsistent with the context provided by the rest
of Dr. Laine’s opinion, namely that the existing sequential release
co-formulations of NSAIDs with other gastroprotective agents would suggest to
the skilled clinician that a similar approach could be taken with PPI
protective therapy, and his ultimate conclusion that it was indeed obvious to
try. Dr. Laine acknowledged that not enteric coating the PPI in such a
combination had not previously been formulated, but it was nonetheless obvious.
In other words, just because an idea is new, does not mean it cannot also be
obvious. Mylan pointed to several classic cases that stood for this basic
principle in patent law (e.g. Actavis UK Ltd v Novartis AG, [2010] EWCA
Civ 82 (UK CA) at paras 36-38).
[145] Mylan argued that the skilled clinician would have had the required
motivation to develop a sequential-released NSAID-PPI tablet formulation, and
that the law does not require that motivation to be so specific as to be the
singular pursuit of the exact invention claimed when there were many good
options available. To require otherwise would mean protecting claims without
any inventive step.
[146] I do not read Dr. Laine’s testimony as stating that skilled
formulators would have lacked any motivation. After emphasizing that he was not
a formulator (Dr. Laine Affidavit at para 213), Dr. Laine nonetheless went on
to explain why the inventive concept, and in particular the formulation of
sequential release NSAID with non-enteric coated PPI, was neither novel (paras
213-220) nor advantageous (paras 221-227). Dr. Laine went on to explain
immediately after, “[i]n my view, there was a motive to
combine an NSAID with a PPI in a single dosage combination, because
co-administration of an NSAID with a PPI was a standard of care to reduce
NSAID-associated GI injury such as ulcers…”
(para 229).
[147] Dr. Armstrong acknowledged under cross-examination that a NSAID-PPI
combination would have been of strong interest in 2001 to the clinician, as an
improvement over ARTHROTEC. As discussed, misoprostol has undesirable
side-effects.
(iii)
General vs Specific Motivation
[148] Returning to the basic principles on motivation (general or
specific), Sanofi requires that a contextual analysis be conducted: it
teaches that the importance of motivation as a factor depends wholly on the
facts.
[149] Among other cases, Mylan relied on Janssen-Ortho Inc v Novopharm
Ltd, 2007 FCA 217 [Janssen-Ortho] at subpara 25(5) (quoting from
Justice Hughes’s trial judgment below):
"Motivation" in this context may
mean the reason why the claimed inventor made the claimed invention, or it may
mean the reason why one might reasonably expect the hypothetical person of
ordinary skill in the art to combine elements of the prior art to come up with
the claimed invention. If within the relevant field there is a specific problem
that everyone in the field is trying to solve (a general motivation), it may be
more likely that the solution, once found, required inventive ingenuity. On the
other hand, if there is a problem that only the claimed inventor is trying to
solve (a unique or personal motivation), and no one else has a reason to
address that problem, it may be more likely that the solution required
inventive ingenuity. However, if commonplace thought and techniques can come up
with a solution, there may be a reduced possibility that the solution required
inventive ingenuity.
[150] Mylan argues that specific motivation is not be required in order to
find that it was “obvious”. While acknowledging
that Janssen-Ortho pre-dates Sanofi, Mylan posits this statement
is entirely consistent with Sanofi’s contextual approach to motivation,
and remains consistent with the current state of the law. I agree.
[151] In Sanofi, the Supreme Court recognized specific motivation
as the third of three factors, rather than as an independent requirement. Its
relative importance will depend on the context and factual backdrop of each
case. Other factors may weigh equally or even more so on the outcome of the “obvious to try” test, since Sanofi’s three
enumerated factors are neither determinative, nor exhaustive. When taking into
account the third factor, a general motivation to search for new and improved
medications is generally a given in the intensely competitive pharmaceutical
industry (Sanofi at para 90). The parties discussed several individual
cases at length on this point, with Mylan first contending they were examples
where obviousness had been made out despite only general motivation being
found, while AstraZeneca then countered that in all of those cases specific
motivation had actually been found – even if only implicitly (Ratiopharm Inc
v Pfizer Ltd, 2009 FC 711, aff’d 2010 FCA 204; Janssen-Ortho Inc v
Novopharm Ltd, 2007 FCA 217; AstraZeneca Canada Inc v Teva Canada Ltd,
2013 FC 245; Gilead Sciences Inc v Canada (Health), 2016 FC 856 [Gilead];
Bristol-Myers Squibb Canada Co v Teva Canada Ltd, 2016 FC 580). In my
view, the difficulty here arises from the jurisprudence generally describing
motivation as falling on either side of a dichotomy: general or specific.
[152] It is unclear to me that the Supreme Court, when articulating the Sanofi
test, intended that motivation fall wholly on one side or the other. In many
cases, one could compellingly argue either side of this “motivation” coin. After all, motivation is an
intrinsically difficult measure to take, and even more so when it comes to the
notional POSITA. In short, a “general” versus “specific” motivation distinction, which consumed a
great deal of energy in these proceedings, may be a false dichotomy.
[153] Rather, the measure to be taken is one of difference or degree, not
kind. Like with many subjective measures, the notional skilled person’s motivation
would at best be identified as somewhere along a spectrum. It is a given that
the drive to modernize results in an innate motivation to innovate; science
will always strive to search for new and improved formulations, including with
medications.
[154] Some of the submissions on motivation, which tended to frame
motivation as being an independent requirement – and therefore requiring a
binary determination from the court – only exacerbated the potential for
confusion here.
[155] This is not to say that there will not be cases where motivation
clearly falls on the side of specificity: in certain cases, motivation may
clearly be specific to the invention ultimately claimed.
[156] However, when that motivation falls short of being so specific to
the exact invention, instead falling somewhere in the middle, identifying it
categorically as being general or specific may be an entirely subjective
exercise, akin to evaluating modern art. What one person characterizes as
general motivation could reasonably be described as specific motivation by
another, while in many cases the truth lies somewhere in the gray – between the
black of general motivation, and the white of specific motivation.
[157] The recent decision in Gilead – one of the cases upon which
the parties to this proceeding disagreed on regarding whether general or
specific motivation had been found – provides a useful illustration of what I
have described as the false dichotomy of the motivational split. Justice Brown
put the debate thus in Gilead (at para 119):
Gilead asks the Court to consider whether
there was specific motivation to co-formulate Coviracil and VIREAD®, and
suggests that where these drugs were not yet widely used or prescribed
together, there would not have been a motive for the co-formulation of the
claimed invention. I disagree that this level of specificity was required in
the motivation analysis. I find that the Conference Call establishes general
motivation to develop a single-dose, once-daily co-formulation of VIREAD®
and FTC. This was enough for the skilled formulator to turn his or her
attention to the co-formulation of TDF and FTC. [Emphasis added.]
[158] Despite this pronouncement, Gilead serves as a good example
of the uncertainty caused by the motivational dichotomy in the present
proceeding. Mylan, in its written submissions and then at the hearing, relied
on Gilead (citing paras 117-122) as an example of where general
motivation satisfied the obvious to try test. AstraZeneca, for its part,
acknowledged that general motivation was indeed expressly recognized in
paragraph 119 (see extract above), but nevertheless argued that Justice Brown
then went further in the subsequent paragraphs, adding more specificity, which
was tantamount to a finding of specific motivation (citing the remainder of
para 119 and para 120). This debate occurred despite Justice Brown’s statement
in paragraph 119 (above) that “I disagree that this
level of specificity was required in the motivation analysis.”
[159] Finally, specific motivation arguably cuts both ways. It could be
said that its existence indicates that it was likely obvious that someone would
eventually get there, without inventiveness. On the other hand, it could be
said that the existence of specific motivation before the claimed invention was
patented only reinforces Beloit’s classic question (at para 21): if it
was obvious – and there was specific motivation to try it – why didn’t you?
[160] The third factor in the “obvious to try”
test asks, “is there a motive provided in the prior art
to find the solution the patent addresses?” (Sanofi at para 69).
This does not prescribe the exact nature or degree of the motive needed. The
key question is thus, assuming there is a motive provided in the prior art, “how specific” to the claim was the motivation.
The more specific to the claim, the more weight motivation may have as a factor
in determining whether the claim was obvious to try. Here, I find, like in Gilead,
that the prior art provided to the skilled person the motive to develop the
claimed invention.
[161] It is also important to keep in mind that neither this motivation
factor, nor the larger obvious to try consideration, determines obviousness. Rather,
both are considerations in the decisive obviousness question set out as the
fourth step in the framework: “viewed without any
knowledge of the alleged invention as claimed, do those differences [between
the state of the art and the inventive concept] constitute steps which would
have been obvious to the person skilled in the art or do they require any
degree of invention” (Sanofi at para 68).
[162] Viewed as a whole, I agree with the Respondent’s position on
motivation. Mylan’s experts were consistent in their observations – albeit
based on their individual analyses – of a strong and documented motivation to
improve outcomes for GI injury, which included NSAIDs and PPIs in different
formulations. ARTHROTEC provided the same architecture in the same tablet
format. In arriving at their conclusions, the Mylan experts each conducted
individualized studies of the prior art, and backed their conclusions with
compelling reference sources contained in the NOA, and in particular, MD7, MD8,
MD10, MD12, MD13, MD18, and MD30.
(d)
Conclusion on Obvious to Try Considerations
[163] Even if the prior art would have alerted a skilled person that
something might be “worth trying”, that remains
insufficient to make it obvious to try unless the invention was more or less
self-evident: Alcon Canada Inc v Cobalt Pharmaceuticals Co, 2014 FC 462
at para 129, aff’d 2015 FCA 191. The test is not whether the skilled person had
good reason to pursue solutions that provide a “fair
expectation of success”: Eli Lilly Canada Inc v Mylan Pharmaceuticals
ULC, 2015 FCA 286 at para 4.
[164] In sum, I find that the inventive concept in the Asserted Claims was
obvious to try, given the (a) finite number of identified predictable solutions
known to the POSITA, (b) minimal amount of effort apparently required to
achieve the invention, and (c) strong motivation to arrive at better outcomes
for NSAID-related GI injury and in particular to try the claimed formulation.
It would have been more or less self-evident to the POSITA to try to obtain the
sequential release formulation addressed in the Asserted Claims, and that such
a formulation would work.
[165] AstraZeneca criticized Mylan’s alleged reliance on mosaics to arrive
at its conclusions of obviousness – that is, relying on a series of prior art
that in combination led to the 098 Patent’s invention. Citing Bridgeview
Manufacturing Inc v 931409 Alberta Ltd, 2010 FCA 188 at para 51 [Bridgeview],
AstraZeneca stressed that just because each piece of prior art may have been
known or even in the realm of common general knowledge, does not mean that the
combination is obvious: the mere idea to combine those independent parts can be
inventive, and was in this case. Specifically, the Court of Appeal stated the
following in Bridgeview (at para 51):
It is not fair to a person claiming to have
invented a combination invention to break the combination down into its parts
and find that, because each part is well known, the combination is necessarily
obvious…
[166] Overall on the issue of combinations, AstraZeneca contended that
Mylan’s obviousness arguments consisted of pointing to small excerpts from a
number of pieces of prior art. AstraZeneca argued this was indicative of
hindsight, and that it lacked any specific motivation to combine the art.
[167] In response, Mylan acknowledged that the NOA indeed contained
several mosaics, but asserted that they are all very similar. For instance, the
Mylan pointed to NOA Mosaic 7.2.3.1 in its NOA, which sets out the following
breakdown of prior art:
•
MD18: PPI-NSAID combination;
•
MD07: Esomeprazole-Naproxen combination
specifically;
•
MD65: Esomeprazole is no better than any other
PPI;
•
MD10: ARTHROTEC architecture; and
•
MD13: Non-enteric coated PPI.
[168] Of these pieces of prior art, only MD10 (ARTHROTEC) and MD13
(non-enteric coated PPI) are disputed, according to Mylan.
[169] I agree with Mylan that this combination was an example of
illustrating the prior art. Mylan also gave another example at footnote 140 of
its Memorandum (albeit in response to criticisms that its experts had relied
upon art outside of the NOA):
The crux of the analysis is that a
well-known formulation architecture in the prior art (e.g., in
MD10/MD30) is adapted for use with a PPI (known to be effective, e.g. in
MD18, and formulated in combination, e.g. in MD7/MD12), with no
difficulty in formulating the PPI for immediate release (e.g., as taught
in MD13).
[170] All of the pieces of prior art relied upon in this decision were
asserted in the NOA. Further, for reasons already explained, I have found that
all of the underlying points asserted in the above examples were indeed common
general knowledge at the relevant date.
[171] I am persuaded by Mylan’s arguments. Therefore, consistent with my
obvious to try findings in the section immediately above, I find that it would
have been self-evident to the POSITA to combine the ample common general
knowledge known at the relevant time, with a limited amount of prior art, to
arrive at the inventive concept, expecting it to work.
[172] Given my obviousness findings, there is no need to address the
alternative issues raised by the Respondent.
[173] For the reasons set out above, I find that Mylan’s allegations that
it was obvious to try to obtain a sequential release of
a NSAID-PPI formulation in a
single oral dosage combination has an air of reality.
AstraZeneca failed to convince the Court that Mylan’s allegations of invalidity
on the basis of obviousness are unjustified. The application for an order of
prohibition is dismissed.
[174] AstraZeneca’s application for an order pursuant to section 6 of the Regulations
prohibiting the Minister of Health from issuing a Notice of Compliance to Mylan
for a generic naproxen-esomeprazole magnesium tablet is dismissed. The Minister
of Health may therefore issue a Notice of Compliance to Mylan for the contested
product forthwith.
[175] There was a brief discussion on costs during the Case Management
Conference of October 18, 2016, wherein the parties agreed that they would
attempt to come to an agreement on costs, and report back to the Court on the
outcome of those discussions, within 15 days of receiving the judgment.
[176] If unable to arrive at a mutually agreeable costs order, the parties
will have ten days to provide submissions, of no longer than five pages each,
setting out their positions on costs.