20111117
Docket: T-154-10
Citation: 2011 FC 1316
Ottawa, Ontario, November 17, 2011
PRESENT: The Honourable Mr. Justice Crampton
BETWEEN:
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ALLERGAN INC., ALLERGAN
SALES INC.
AND ALLERGAN, INC.
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Applicants
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and
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THE MINISTER OF HEALTH
AND SANDOZ CANADA INC.
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Respondents
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REASONS FOR JUDGMENT AND JUDGMENT
[1]
The
Applicants, (collectively “Allergan”), seek an order pursuant to subsection 6(1)
of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133
to prevent the Minister of Health from issuing a Notice of Compliance (NOC) to
Sandoz Canada Inc. until the expiry of two patents that Allergan owns, namely,
Canadian Patent No. 2,440,764 (the ‘764 Patent) and Canadian Patent No.
2,225,626 (the ‘626 Patent).
[2]
If
issued, the NOC that Sandoz has requested would permit it to market in Canada a generic
version of a drug which combines two active ingredients, brimonidine tartrate (0.2%)
(“brimonidine”) and timolol maleate (0.5%) (“timolol”), used in the treatment
of glaucoma. Allergan currently markets the branded version of that drug under
the name “COMBIGAN”.
[3]
In
support of its NOC, Sandoz filed an abbreviated new drug submission with the
Minister in which it compared its drug (the “Generic Drug”) to COMBIGAN. Sandoz
then sent a Notice of Allegation (NOA) to Allergan in which it alleged, among
other things, that:
i.
the
invention claimed by the ‘764 Patent was obvious as of the priority date of
April 19, 2002 (the “Priority Date”), such that the ‘764 Patent is invalid;
ii. the Product
Monograph of the Generic Drug will not induce infringement of any of the claims
in the ‘626 Patent;
iii. the Generic
Drug will not infringe any of the claims in the ‘626 Patent; and
iv. the ‘626
Patent is invalid for inutility, on the basis that:
(a) the claims therein cover non-useful
subject matter; and
(b) the
utility of that subject matter could not be soundly predicted as of the
Priority Date and the Canadian filing date of the ‘626 Patent.
[4]
Allergan
submits that Sandoz’s allegations are not justified, as contemplated by
subsection 6(2) of the Regulations. That said, Allergan concedes that Sandoz
has put the invalidity issues raised in its NOA “into play”, such that the
presumption of validity of the ‘764 Patent and the ‘626 Patent has been
rebutted (Novo Nordisk Canada Inc v Cobalt Pharmaceuticals Inc, 2010 FC
746, at paras 68-69 [Novo Nordisk]; Pfizer Canada Inc v Novopharm Ltd,
2009 FC 638, at paras 35-36 [Pfizer (2009 FC 638)]).
[5]
To
obtain the order of prohibition that it seeks in this application, Allergan
must demonstrate, on the balance of probabilities, that Sandoz’s allegations
are not justified, either with respect to:
i.
the
alleged obviousness of the invention claimed by the ‘764 Patent; or
ii. all of the above-mentioned
allegations that have been made in respect of the ‘626 Patent.
[6]
For
the reasons that follow, I have concluded that Allergan has met its burden in
respect of the alleged obviousness of the invention claimed by the ‘764 Patent.
Therefore, I will issue the requested order of prohibition in respect of the
‘764 Patent.
[7]
Given
that the ‘764 Patent was issued more recently than the ‘626 Patent, it is not
strictly necessary, for the purposes of the present application, to consider
the allegations that Sandoz has made in respect of the ‘626 Patent. In brief,
any determinations that may be made in respect of the latter patent cannot
affect the period of time during which Sandoz will be unable to market the
Generic Drug, due to the conclusion I have reached in respect of the ‘764
Patent.
[8]
Nevertheless,
in the event that I am found to have erred in my conclusion that the subject
matter of the ‘764 Patent was not obvious, I have also assessed the issues that
have been raised in respect of the ‘626 Patent. In this regard, the issue of
inducement of infringement is determinative, because the ‘626 Patent is a use
patent, which cannot be directly infringed by Sandoz. I have concluded that Allergan
has not met its burden on this issue. In other words, I have determined that Sandoz’s
allegation that it will not induce infringement of the ‘626 Patent is justified.
[9]
In
the event that my conclusion on the inducement issue is overturned, I have proceeded
to address the various other allegations that Sandoz has made in support of its
position that the Generic Drug will not infringe the ‘626 Patent and that the
‘626 Patent is invalid. I have concluded that Allergan has demonstrated, on a
balance of probabilities, that those allegations are not justified.
[10]
In
short, for the reasons that follow, I have determined that this application
will be allowed with respect to the ‘764 Patent but dismissed with respect to
the ‘626 Patent.
I. Background
A. Glaucoma
[11]
Glaucoma
is a chronic disease of the optic nerve that leads to progressive, irreversible
loss of vision and can lead to blindness.
[12]
The
precise cause of damage to the optic nerve is not entirely understood. However,
it is often, but not always, associated with increased pressure of the aqueous
humor located at the front of the eye. This is usually referred to as increased
intraocular pressure (IOP), or ocular hypertension. If left untreated, IOP can
lead to the development of glaucoma. It is for this reason, and the fact that
IOP lowering drugs seem to prevent further progression of the disease, that IOP
is widely considered to be a major risk factor for glaucoma.
[13]
The
terms “elevated IOP” and glaucoma were once used synonymously. However, it
appears that it is now understood that glaucoma is a complicated disease which
may be associated with high IOP, but can also strike people with statistically
normal IOP.
[14]
Although
there is no cure for glaucoma, several different types of drugs have been
developed for its treatment. For more than 100 years, ophthalmologists have
been using cholinergic drugs to treat glaucoma and IOP. Drugs in this class
mimic and amplify the parasympathetic nervous system, and have the general
effect of relaxing muscle tissue. However, they have been associated with
significant side effects.
[15]
A
second class of drugs that have been used since at least the 1920s to treat
glaucoma are andrenergic agents, such as epinephrine. With the advent of modern
anti-glaucoma drugs beginning in the 1970s, the use of epinephrine has become
progressively less popular, mainly due to its significant side effects.
[16]
A
third class of drugs that are used to lower IOP and treat glaucoma are best
known as beta andrenergic antagonists, or beta (ß) blockers. Beta andrenergic
antagonists block natural epinephrine from having activity at the ß-receptors,
and are thereby thought to allow the same IOP lowering effects as epinephrine,
but with fewer side effects. In addition, beta blockers reduce IOP by
decreasing aqueous humor production. Beta blockers are one of the most commonly
used classes of drugs for treating glaucoma, and include drugs such as timolol,
which was first made available commercially by Merck Frosst Canada Ltd.
in approximately 1978, under the brand name TIMOPTIC. Since that time,
timolol has become one of the mainstays in the treatment of glaucoma and IOP.
[17]
A
fourth class of IOP lowering drugs is comprised of drugs generally known as
alpha-2 agonists. Alpha-2 agonists act by stimulating the alpha andrenergic
receptors, thereby lowering IOP. Drugs in this class first became commercially
available in the 1980s. Brimonidine is a drug in this class that has been
available as an ophthalmic solution since approximately 1996, when Allergan
launched a product containing 0.2% by weight of brimonidine, under the brand
name ALPHAGAN. Sandoz launched a generic version of ALPHAGAN the following
year, after sending an NOA to Allergan which was not challenged.
[18]
Two
additional classes of IOP lowering drugs are prostaglandin analogs, such as
latanoprost, and carbonic anhydrase inhibitors (CAIs), such as dorzolamide and
brinzolamide.
[19]
While
both brimonidine and timolol can be effective in reducing IOP in some patients,
monotherapy involving these medications does not help everyone. For example,
these drugs may not be considered to be useful for certain patients because of
their undesirable side effects or their medical contraindications, or because
they are not effective for a particular individual. In other patients,
additional IOP lowering beyond the level that can be achieved with either of
these drugs administered separately is required. Accordingly, those two drugs
began to be prescribed for concomitant (also known as adjunctive or serial) administration
prior to the filing date of the ‘764 Patent.
B. The
Relevant patents
[20]
Pursuant
to section 4 of the Regulations, Allergan listed four patents in the Patent
Register in respect of COMBIGAN. However, Allergan has chosen to bring this
application only in respect of the allegations that Sandoz has made regarding the
‘764 Patent and the ‘626 Patent.
[21]
The
‘764 Patent was filed on April 9, 2003, published on October 19, 2003 and
issued on October 25, 2005. It claims priority from a U.S. Patent filed
on April 19, 2002.
[22]
The
‘764 Patent makes claims with respect to ophthalmic topical pharmaceutical
compositions for the treatment of glaucoma or ocular hypertension including,
among other things, a composition comprising brimonidine (0.2%), timolol (0.5%)
and the preservative benzalkonium chloride (BAK) (0.001% to 0.01% ) in a
pharmaceutically acceptable carrier. The descriptive section of that patent concludes
by stating that, when administered twice a day (BID) for three months, this
combination of brimonidine and timolol was superior to equivalent
concentrations of timolol administered BID and brimonidine administered three
times a day (TID), in lowering the elevated IOP of patients with glaucoma or
ocular hypertension. It also states that the combination “administered BID
demonstrated a favorable safety profile that was comparable to Timolol BID and
better than Brimonidine TID with regard to the incidence of adverse events and
discontinuation due to adverse events.”
[23]
The
‘626 Patent was filed on June 17, 1996, published on January 16, 1997, issued
on September 3, 2002 and claims priority from U.S. Patent filed on June 28,
1995.
[24]
The
‘626 Patent describes a “new method of protecting the optic nerve and retina of
the mammalian eye from damage by glaucoma and other noxious provocations.” This
neuroprotection is stated to be provided by a new use of an effective amount of
certain compounds, including brimonidine, “to inhibit or prevent nerve cell
injury or death … for protecting the retinal or optic nerve cells in a mammal
suffering a noxious action or at risk of experiencing a noxious action on said
nerve cells.” Prior to the Priority Date, brimonidine had been known to be
effective at lowering IOP and was widely used for that purpose.
C. COMBIGAN
[25]
COMBIGAN
is the brand name of the composition described in the ‘764 Patent. It is sold
in Canada pursuant to
NOCs issued to Allergan on December 9, 2003 (for the control of IOP) and August
24, 2007 (for the reduction in long term fluctuation of IOP). As is the case
with the Generic Drug, the active ingredients in COMBIGAN are brimonidine (0.2%)
and timolol (0.5%), and the preservative is BAK (0.005%).
II.
The Parties’ Experts
[26]
Three
individuals adduced expert evidence on behalf of Allergan and two adduced such
evidence on behalf of Sandoz.
A. Allergan’s experts
[27]
Mr.
Gary J. Beck is one of the inventors of COMBIGAN identified in the ‘764 Patent.
From 1995 to 1999, he held the title of Scientist at Allergan. In that capacity
he had responsibility for, among other things, attempting to develop an
ophthalmic formulation that combined brimonidine and timolol. In 1999, he
became a Global Project Manager and thus remained closely involved in the
development of the combination product. He was also part of the team that
prepared and submitted the successful application for approval of COMBIGAN to
the U.S. Food and Drug Administration (U.S. FDA). Mr. Beck provided affidavit evidence
and was cross-examined with respect to the development of COMBIGAN, its reduced
side effects relative to brimonidine monotherapy and timolol monotherapy, its
efficacy, its commercial success and its development costs.
[28]
Dr.
Robert Fechtner is a Professor of Ophthalmology and Director of the Glaucoma
Division at the New Jersey Medical School of the University
of Medicine
and Dentistry of New Jersey. He is also an attending physician at University Hospital in Newark, New Jersey
and conducts his clinical practice at the New Jersey Medical School,
where he has studied and treated patients with glaucoma. In addition being on
various boards and committees related to glaucoma, he has served on many
editorial boards for publications in the field of ophthalmology. His main
research focus during his career has been the treatment of glaucoma. He has
authored many articles, books and chapters related to glaucoma and the
reduction of IOP. Dr. Fechtner provided affidavit evidence with respect to the subject
matter of the ‘764 Patent, the person of ordinary skill in the art (“POSITA”)
to which that patent relates, Sandoz’s NOA and the evidence provided by Sandoz’s
experts, particularly in respect of the alleged obviousness of the subject
matter of certain of the claims in the patent.
[29]
Dr.
Kevin Parkinson is a practising ophthalmologist in British-Columbia. He also
possesses hospital privileges at the Coquitlam Cataract Centre and at Ridge Meadows Hospital. He
has completed fellowship training in the area of glaucoma, has seen
approximately 50,000 patients with this disease and gives lectures on the topic
of ophthalmology and glaucoma. He swore two affidavits, dated November 13, 2010
and March 15, 2011, with respect to the subject matter of the ‘626 Patent, the
POSITA to which that patent relates, Sandoz’s allegations of non-infringement,
and the evidence provided by Sandoz’s experts.
B. Sandoz’s
experts
[30]
Dr.
Henry Jampel is a professor of Ophthalmology at the John Hopkins University School
of Medicine. He is also a practicing physician who has treated thousands of
patients with glaucoma and related eye diseases. He has been active in research
on glaucoma, has held editorial roles with various ophthalmological journals, and
is the author of numerous papers and book chapters on glaucoma and IOP. He provided
affidavit evidence with respect to the subject matter of both the ‘764 Patent
and the ‘626 Patent, the POSITAs to which those patents relate, the allegations
in Sandoz’s NOA and the evidence provided by each of Allergan’s experts.
[31]
Dr.
Ashim Mitra is the Chairman of the Division of Pharmaceutical Sciences at the University of Missouri. He has conducted
extensive research with respect to various drug delivery technologies,
including ocular drug delivery. He is the Director for Translational Research at
the university’s School of Medicine. In that capacity, he is involved in
selecting new technologies from bench research, particularly in the ophthalmic
area, and co-ordinating pre-clinical studies. His research has focused on the
synthesis and formulation of chemical compounds, including in ophthalmic drugs
and examining their ability to be transported through membranes into the body.
He has published extensively in the field of ophthalmic drugs and has made
hundreds of presentations on the topic for various audiences. He provided affidavit
evidence with respect to the subject matter of the ‘764 Patent, the persons to
whom that patent is directed, certain of the allegations in Sandoz’s NOA and
the evidence provided by Mr. Beck.
[32]
Allergan
raised some serious concerns with respect to the credibility of Dr. Mitra. In
short, Allergan referred to a number of U.S. cases in
which Dr. Mitra’s testimony has been found to be not credible (including Allergan,
Inc v Barr Laboratories, Inc, 2011 US Dist LEXIS 101778, 09333 SLR, at
paras 46-52 (D Del) [Barr Laboratories]; Syntex LLC v Apotex, Inc,
2006 WL 1530101, C01-02214 MJJ, at para 78 (ND Cal)), or misleading (Roche
Palo Alto et al v Apotex Inc et al, 526 F Supp 2d 985, at 994 (ND Cal)).
Included among those cases was a case in which Dr. Mitra took a position before
this Court that was inconsistent, to say the least, with the position he
subsequently took before a court in the U.S. (compare Barr
Laboratories, above, with Pfizer Canada Inc v Canada (Minister of
Health),
2009 FC 1294, at para 154). Allergan also drew the Court’s attention to
inconsistent statements made by Dr. Mitra during cross-examination in the case
at bar concerning the fact that, in six of the seven proceedings in which he
has recently testified, it was his opinion that the patent was invalid
(Applicant’s Record, at 940-943). Given the foregoing, I have serious
reservations regarding Dr. Mitra’s credibility. I have therefore approached his
evidence with a considerable degree of caution (Sanofi-Aventis Canada Inc v
Ratiopharm Inc, 2010 FC 230, at para 17 [Sanofi]) and have generally
found the evidence of Allergan’s witnesses to be more credible and reliable in
instances where their evidence has conflicted with his evidence.
III. Issues
[33]
Although
many issues were raised in Sandoz’s NOA and in Allergan’s Application, the
issues that continue to be pursued by the parties are as follows:
1. Is the
allegation that the ‘764 Patent is invalid on the ground of obviousness
justified?
2. Will the
product monograph (PM) for the Generic Drug induce infringement of any of the
claims in the ‘626 Patent?
3. Are Sandoz’s
allegations of non-infringement of the claims in the ‘626 Patent justified?
4. Is Sandoz’s
allegation that the ‘626 Patent is invalid for inutility justified on the basis
that either:
(a) the claims
therein cover non-useful subject matter; or
(b) the utility
of that subject matter could not be soundly predicted as of the priority date
and the Canadian filing date of the ‘626 Patent?
IV. Analysis
A. Is the allegation that
the ‘764 Patent is invalid on the ground of obviousness justified?
[34]
To
assess this issue, it is necessary to first construe the claims of the patent
and to discern the inventive concept in that patent (Free World Trust v Électro
Santé Inc, 2000 SCC 66, [2000] 2 S.C.R. 1024, at para 19 [Free World Trust]).
[35]
Allergan
has asserted claims 1-6 and 14-25 of the ‘764 Patent. The representative claim
is claim 22, which narrows the fixed combination drug claimed in claim 1 to the
specific fixed combination found in COMBIGAN. Claim 22 refers to claim 6, which
in turn refers to claim 3, which in turn refers to claim 1, as follows:
Claim 22 - Topical use of a therapeutically effective amount of a composition
according to claim 6 in an affected eye for treating glaucoma.
Claim 6 - A composition according to claim 3 further comprising from
0.001% by weight to less than 0.01% by weight of benzalkonium chloride.
Claim 3 - A composition according to claim 1, wherein the amount of
brimonidine is 0.2 percent by weight and the amount of timolol is 0.5 percent
by weight.
Claim 1 - An ophthalmic topical pharmaceutical composition for the
treatment of glaucoma or ocular hypertension comprising an effective amount of
brimonidine and an effective amount of timolol in a pharmaceutically acceptable
carrier therefor.
[36]
There
is no dispute between the parties regarding the construction of the language in
claims 1, 3, 6 and 22 of the ‘764 Patent (the “Representative ‘764 Claims”).
The parties are in general agreement that those claims describe a fixed
combination of brimonidine (0.2%) and timolol (0.5%) in a pharmaceutically
acceptable carrier containing BAK (0.001% to 0.01%) (the “Composition”) and the
use of the Composition for the topical treatment of glaucoma and ocular
hypertension.
[37]
The
test for assessing obviousness comprises the following four steps:
1. Identify the
person skilled in the art and the
relevant common general knowledge;
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; and
4. Without any
knowledge of the alleged invention as claimed, assess whether those differences
(i) constitute steps that would have been obvious to the skilled person, or
(ii) required a degree of invention (Apotex Inc v Sanofi-Synthelabo Canada Inc,
2008 SCC 61, [2008] 3 S.C.R. 265, at para 67 [Sanofi]).
(1) Step One
- The skilled person and the relevant common general knowledge
[38]
Dr.
Fechtner opined that the POSITA to whom the ‘764 Patent is addressed “is a
person engaged in developing pharmaceutical formulations and treatment for
methods for the eye, or is a specialist in treating diseases of the eye
such as an optometrist or an ophthalmologist who also has experience in either
developing ophthalmic pharmaceutical formulations or in designing and running
clinical trials on such formulations” (emphasis added).
[39]
Drs.
Mitra and Jampel took a similar position, when they stated that the ‘764 Patent
is addressed to pharmaceutical formulators and to ophthalmologists. However, Sandoz
subsequently took the position that the POSITA is a composite of a practicing
ophthalmologist and a pharmaceutical formulator. During the oral hearing
of this application, Sandoz characterized this difference between the views
expressed by Dr. Fechtner and its own experts as being a “minor” and as having
no “real effect.”
[40]
That
said, in my view, the POSITA to whom the ‘764 Patent is addressed is someone
who is either a pharmaceutical formulator or a specialist in
treating diseases of the eye, as described by Dr. Fechtner. This would include
persons such as Drs. Jampel (who conceded in cross-examination that he has no
experience with formulations), Fechtner, and Mitra, as well as Mr. Beck. This
is consistent with the position taken by Sandoz in its NOA.
[41]
Dr.
Jampel stated in his affidavit that the common general knowledge of the POSITA as
at the Priority Date included the following:
i.
a
detailed knowledge of ocular hypertension and glaucoma;
ii. a detailed
knowledge of the IOP lowering medications in use at that time, including those
described at paragraphs 14 to 18, above;
iii. the knowledge
that IOP lowering medications were commonly used in combination, either in
concomitant use or combined together, in order to obtain adequate IOP lowering,
and that the use of two IOP lowering medications resulted in greater IOP
reduction in either individual medication alone;
iv. the knowledge
that both brimonidine and timolol were well-established IOP lowering
medications;
v. the knowledge
that brimonidine and timolol had been used in concomitant therapy and that such
therapy resulted in a larger IOP reduction than with brimonidine or timolol
alone;
vi. the knowledge
that commercially available combination products typically included timolol as
one of the active ingredients - such products included COSOPT (combination of
dorzolamide and timolol that had been available in the U.S. since 1998 and in
Canada since 1999), as well as combinations of pilocarpine and timolol and of
latanoprost and timolol (Xalacom) that were commercially available outside the
United States prior to 2002; and
vii. the knowledge
that BAK was a commonly used preservative in ophthalmic solutions.
[42]
At
the oral hearing of this application, Allergan stated that while there might be
some “subtle differences” between its experts and Dr. Jampel, its arguments
would be based upon Dr. Jampel’s above-described position regarding the common
general knowledge of the POSITA as at the Priority Date. Accordingly, I am
prepared to accept the foregoing summary provided by Dr. Jampel for the purposes
of the present analysis, subject to the following observations.
[43]
First,
I am satisfied that the evidentiary record demonstrates that a POSITA at the
time of the Priority Date would also have been familiar with the fact that Allergan’s
second generation brimonidine product, ALPHAGAN P, contained (i) 0.15%
brimonidine, rather than the 0.2% concentration that is used in the Composition,
and (ii) Purite, rather than BAK as a preservative. That person also would have
been aware that, when administering brimonidine and timolol concomitantly, the
state-of-the-art was to administer those drugs separately, 5 minutes apart, to
avoid the “wash-out” effect.
[44]
Second,
the record also demonstrates that the POSITA would have been aware of U.S.
Patent No. 5,502,052, issued March 26, 1996 (the “DeSantis Patent”), which
suggested that anti-glaucoma compositions that comprise a combination of one or
more beta-blockers (such as timolol) with one or more alpha-2 agonists
(brimonidine was not specifically mentioned) achieve a greater reduction in IOP
than that which is achievable with the same concentration of either type of
active ingredient used alone.
[45]
Third,
I am satisfied that the POSITA also would have been aware that the benefits
associated with a fixed composition of two active ingredients for use in the
topical treatment of glaucoma, relative to concomitant therapy involving those same
active ingredients, likely would include: (i) less preservative being
administered to patents, and (ii) greater patient compliance with the combined
administration.
(2) Step Two
- The inventive concept
[46]
Sandoz
submits that “it is the claims that define the invention” in any patent and
that the inventive concept of the ‘764 Patent must be discerned solely from the
language in the claims of the patent.
[47]
It
is settled law that the “fences” and “boundaries” of the “field” of monopoly
conferred by a patent are established by the claims of the patent (Free
World Trust, above, at paras 14, 33, 51, 66). That said, to achieve a “purposive
construction,” is permissible to have regard to other parts of the patent “through
the eyes of a skilled addressee,” to resolve ambiguity and to achieve flexibility
and fairness in differentiating between the essential and the unessential
features of the invention (Whirlpool Corp v Camco Inc, 2000 SCC 67,
[2000] 2 S.C.R. 1067, at para 48 [Whirlpool]). Given that there is no
dispute in the case at bar with respect to the construction of the claims,
there is no need to look beyond the claims of the ‘764 Patent to ascertain the
field of monopoly claimed therein.
[48]
The
same cannot be said with respect to the inventive concept of the claims.
[49]
Generally
speaking, the Representative ‘764 Claims simply claim the Composition for
topical use in an affected eye for treating glaucoma. Sandoz submits that the
inventive concept of those claims must be discerned from this description
alone. Dr. Jampel took the same position.
[50]
I
disagree. If that were the case, it would not be possible in this and similar
cases to fully ascertain the differences between the state-of-the-art and the
inventive concept of the claim, for the purposes of performing the third step
of the obviousness test.
[51]
In
cases such as this, where “the inventive concept of the claims is not readily
discernible from the claims themselves,” it is both necessary and permissible
to look to the balance of the patent “to determine its inventiveness” (Sanofi,
above, at para 77). In other words, “to ascertain the nature of the invention”
that is articulated in the claims, and to understand the extent to which the
claimed invention differs from the prior art, the Court may “look to the whole
of the disclosure” in the patent (Whirlpool, above, at para 49(g),
quoting Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1
SCR 504, at 520-21). That said, it bears underscoring that “it is not permissible
to read the specification in order to construe the claims more narrowly or
widely than the text will allow” (Sanofi, above, at para 77).
[52]
In
Sanofi, above, at paras 77-78, the Supreme Court looked beyond the
claims in question, which were confined to “[a] bare chemical formula,” in
ascertaining the inventive concept of those claims. A similar approach was
adopted in Laboratoires Servier v Apotex Inc, 2009 FCA 222, at paras 58-59.
This was necessarily done after claims construction had been completed,
because the exercise of claim construction is antecedent to the assessment of
issues concerning validity and infringement (Free World Trust, above, at
para 19; Whirlpool, above, at para 43).
[53]
Contrary
to Sandoz’s submissions, I do not read Sanofi as suggesting that, in
determining the inventive concept of the claims in a patent, it is only
permissible to look beyond the claims of the patent when the claims are
confined to a bare chemical formula or to a selection patent. Indeed, the Court
in that case specifically noted that its discussion of anticipation and
obviousness was “applicable to patents generally” (Sanofi, above, at
para 29).
[54]
The
view expressed above is consistent with the approach taken in Eli Lilly
Canada Inc v Novopharm Ltd, 2010 FCA 197 [Eli Lilly], at paras 33,
57, where the Federal Court of Appeal discerned the inventive concept of the
claims from the disclosure section of the patent, after observing: “A selection
patent is the same as any other patent. Its validity is vulnerable to attack on
any of the grounds set out in the Act.”
[55]
The
view expressed above is also consistent with the approach taken by my colleague
Justice Mactavish in Novo Nordisk, above, at para 113. As in the case at
bar, that case concerned a drug patent containing use claims. After concluding
that the alleged advantageous properties of the drug repaglinide were not part
of the claims because they were not referred to anywhere in the claims, Justice
Mactavish observed: “That said, any advantageous properties possessed by repaglinide
would indeed be inherent to the compounds described in those claims, and thus
should be taken into account when examining issues such as anticipation and
obviousness.” Justice Mactavish proceeded to have regard to the alleged
properties set out elsewhere in the patent in concluding that the inventive
concept of the relevant claims of the patent, which were not confined to a bare
chemical formula, included “repaglinide and its surprising pharmacokinetic
properties when used to treat diabetes mellitus” (Novo Nordisk, above,
at paras 186, 308).
[56]
In
the case at bar, Sandoz and Dr. Jampel submitted that the inventive concept of
the claims of the ‘764 Patent is limited to the Composition itself, for use in
treating glaucoma or ocular hypertension. This is essentially what Justice
O’Reilly concluded with respect to the only other fixed combination product (COSOPT)
that has been approved for topical treatment of glaucoma in North America (Merck
& Co v Canada (Minister of Health), 2010 FC 1042, at para 38 [Merck
(2010 FC 1042)]). As discussed, above, the position of Sandoz and Dr.
Jampel on this point was rooted in their view, which I do not share, that the
inventive concept of the claims of the ‘764 Patent must be discerned from the
claims themselves.
[57]
Allergan
submitted that the chemical stability of the Composition was a distinct aspect
of the innovative concept of the ‘764 Patent. In the Background section at the
beginning of the patent, reference was made to the recognized need for a
composition comprising brimonidine and timolol which, among other things, has “increased
stability.” However, as Dr. Jampel noted and as Dr. Fechtner conceded, no
evidence of such increased stability was disclosed in the patent, or by
Allergan’s experts. As to whether chemical stability itself is part of the
innovative concept of the patent, Mr. Beck conceded that a pharmaceutical
product has to have sufficient stability to support its shelf life. Therefore, I
prefer to characterize this aspect of the innovative concept as being the
combination of brimonidine (0.2%), timolol (0.5%) and BAK (0.005%) in single
stable solution with a pharmaceutically acceptable carrier.
[58]
I
am satisfied that the inventive concept of the claims of the ‘764 Patent also
includes (i) the improved safety profile of the Composition, (ii) BID dosing
without an afternoon reduction in efficiency, and (iii) the reduction in the
daily load of preservative administered to patients taking both brimonidine and
timolol. Although Allergan submitted that the inventive concept of the claims
further includes “[i]ncreased IOP lowering of the combination as compared to
monotherapy with individual agents,” this was simply baldly asserted and was not
further developed in Allergan’s written or oral submissions. Accordingly, it
will not be further addressed in these reasons.
[59]
With
respect to the improved safety profile, the Background section at the outset of
the ‘764 Patent noted that “there is a need to increase the efficacy of many
topical ophthalmic agents, without increasing the systemic concentration of
such topical agents, since it is well-known that many of such topically applied
ophthalmic agents cause systemic side effects, e.g., drowsiness, heart effects,
etc.” The patent then states: “Unexpectedly, it has been discovered that
brimonidine in combination with timolol meets these criteria.”
[60]
After
reporting the results of a substantial study comparing the side effect profiles
of brimonidine monotherapy, timolol monotherapy and the fixed combination drug
claimed by the patent, the disclosure section of the patent concludes by
stating:
The Combination administered
BID demonstrated a favorable safety profile that was comparable to Timolol BID
and better than Brimonidine TID with regard to the incidence of adverse events and
discontinuations due to adverse events.
[61]
I
accept Dr. Fechtner’s opinion that “[t]he POSITA would have considered the
improved safety profile [of the fixed combination drug], including the
reduction of incidences of adverse events and discontinuance due to adverse
events, to be part of the invention claimed in the ‘764 Patent.” That is to
say, I accept his view that improved safety profile is part of the inventive
concept of the ‘764 Patent.
[62]
With
respect to BID dosing without an afternoon reduction in efficiency, Dr.
Fechtner reported in his affidavit that the U.S. FDA only approved ALPHAGAN to
be administered TID due to concerns of an afternoon reduction (or “trough”) in
the efficiency of brimonidine when administered BID. Among other things, the
clinical trial that was described in the ‘764 Patent assessed the IOP lowering
of the Composition at times 0, 2, 7 and 9 hours. Dr. Fechtner explained that
the nine hour measurement was significant because it was taken at a time when
it would be expected that patients being administered brimonidine TID would
display a greater IOP lowering, due to the effect of the second daily dose of
brimonidine (taken about an hour prior to the nine hour measurement). Dr.
Fechtner proceeded to observe:
Despite this, the inventors report [in the disclosure of the ‘764
Patent] that the fixed combination drug did not demonstrate a trough in
efficiency in the afternoon when compared with patients receiving ALPHAGAN
administered TID. Surprisingly, the inventors report that mean IOP for patients
administered the fixed combination drug (BID) was statistically significantly lower
at the 9 hour point and for those patients receiving ALPHAGAN (TID) after 6
weeks and after 3 months … The fact that patients that were administered
ALPHAGAN TID did not show lower IOP at the 9 hour time point shows that the
inventors had developed a formulation which eliminated the afternoon IOP trough
despite BID administration.
[63]
With
respect to the reduction in the daily load of preservative administered to patients
taking both brimonidine and timolol, Mr. Beck reported in his affidavit that
his team at Allergan expected that a reduction in the concentration of BAK
might result in a reduction in the efficacy of the Composition. Nevertheless,
due to the side effects associated with BAK, his team conducted experiments to
investigate whether a lower amount of BAK could be used as a preservative in
the Composition. Through their work, the team discovered that a combination of
brimonidine and timolol “could be effectively preserved from microbial
contamination using only 0.005% BAK; less than half the amount of BAK known to
be used by Merck in formulating [COSOPT] and a reduction of 70% from the amount
to which the eye is exposed when both drugs are used in monotherapy.” Once
again, this discovery was described in the disclosure section of the ‘764
Patent.
(3) Step Three
- The differences between the state-of-the-art and the inventive concept
[64]
The
differences between the prior art discussed at paragraphs 41 to 45 above and
the innovative concept of the claims in the ‘764 Patent are the following: (i)
the Composition combines brimonidine and timolol into a single, chemically
stable, formulation - that combination had never previously been made or
reported in the prior art, (ii) the Composition has a superior safety profile,
relative to brimonidine TID, (iii) the Composition permits BID dosing without an
afternoon reduction in efficiency, relative to brimonidine TID treatment, and
(iv) patients who are treated with the Composition receive a significantly
reduced daily load of BAK, relative to concomitant treatment of brimonidine and
timolol.
[65]
With
respect to BID dosing without a reduction in afternoon efficiency, the ‘764
Patent disclosed, among other things, that in the clinical trial mentioned
immediately above, the decreases from baseline diurnal IOP at hour 9 of the
daily testing “were greater for the Combination group than for the Brimonidine
group at all follow-up visits, although the differences were not statistically
significant (p > 0.104).” Mr. Beck’s uncontradicted evidence was that
“[t]he frequency of administration for which a formulation is approved
significantly affects its use and value because of the discomfort, difficulty,
unpleasantness, and risk of infection associated with installation of eyedrops.”
For these reasons, Mr. Beck stated that a formulation approved for BID dosing “is,
all else being equal, much better than a drug that must be administered three
times a day.” Once again, this evidence was not contradicted. With respect to
the Composition in particular, it requires only two administrations per day,
versus the five separate administrations that continue to be required in the
United States for patients being administered brimonidine (TID) and timolol
(BID) concomitantly, and the four separate administrations that are required
elsewhere for that concomitant therapy. For this reason, Mr. Beck stated in
cross-examination that a “combination product that had a dosing regimen of two
times a day would be considered more advantageous, from a compliance
standpoint, than monotherapies dosed” four or five times a day. Again, this
evidence was not contradicted.
[66]
With
respect to the superior safety profile of the Composition, the ‘764 Patent
disclosed, among other things, that in the clinical trial discussed in Example
II of the specification, adverse events leading to the discontinuation of
patients occurred in only 3.6% (7/193) of the patients who were administered
the Composition, versus in 14.3% (28/196) of the patients who were administered
brimonidine alone. In addition, it was disclosed that serious adverse events
were reduced by 50% for the combination product, relative to monotherapy
treatment of brimonidine or timolol. Moreover, it was disclosed that the
composition had what may be described as a statistically significant (p<
0.034) improved allergy profile, compared with brimonidine monotherapy.
[67]
Sandoz
submitted that various articles referred to by Dr. Jampel in his affidavit, and
attached thereto, reported that the efficacy of the Composition was not found
to be statistically significant from the efficacy of concomitant
treatment of brimonidine and timolol. However, those articles were all
published a number of years after the Priority Date, and did not address the
common general knowledge of the POSITA as at the Priority Date. Moreover, those
articles were not attached to Sandoz’s NOA. These important facts distinguish
this “post-art” evidence from the cases relied upon by Sandoz. Sandoz was not
able to identify any case in which such articles were admitted or given any
weight in a proceeding involving an application under the Regulations. In my
view, those articles are not admissible, as they are not “probative of a
question at issue; in this case, the state-of-the-art at the relevant time” (Eli
Lilly Canada Inc v Apotex Inc, 2007 FC 455, at para 339). In short, they are
not relevant to my determination of the differences between the inventive
concept of the ‘764 Patent and the state-of-the-art as understood by the POSITA
as at the Priority Date. As an aside, I would add that even if the Composition
is simply as effective as concomitant administration of brimonidine and
timolol, it would continue to have other demonstrated advantages over that
concomitant therapy, including (i) requiring the administration of only two
drops a day versus five in the U.S. and four elsewhere, and (ii) eliminating an
afternoon trough, relative to BID administration of brimonidine in monotherapy
or concomitant therapy.
[68]
In
addition, Sandoz submitted that since the alleged invention claimed in the ‘764
Patent existed once the combination itself was made, the benefits discovered in
Allergan’s subsequent clinical trials cannot be part of the innovative concept
of the patent. Sandoz added that recognition of the superior safety profile of
the Composition would require this Court to hold that the invention did not
exist until the clinical trial was conducted and the results analyzed.
[69]
I
disagree. The cases relied upon by Sandoz on this point simply stand for the
proposition that the utility of the pharmaceutical patent does not need to be
demonstrated by prior human clinical trials (Apotex Inc v Wellcome
Foundation Ltd, 2002 SCC 77, [2002] 4 S.C.R. 153, at para 77; Pfizer (2009
FC 638), above, at paras 87-88; aff’d 2010 FCA 242). In the case at bar,
the safety data in question was disclosed in the ‘764 Patent and is a
legitimate part of the innovative concept of that patent.
(4) Step
Four - Were the differences between the inventive concept and the state
of
the art obvious?
[70]
In
Sanofi, above, at paragraphs 69 and 70, Justice Rothstein identified a
number of factors that should be taken into consideration in cases where it is
appropriate to assess whether the invention was “obvious to try.” In the case
at bar, Allergan conceded that it is appropriate to engage in this assessment,
because the Composition is a pharmaceutical invention that was achieved by
experimentation (Sanofi, above, at para 68; Bridgeview Manufacturing
Inc v 931409 Alberta Ltd, 2010 FCA 188, at para 42). I agree.
[71]
Accordingly,
it is appropriate to consider the following factors that were identified by Justice
Rothstein:
• Is
it more or less self-evident that what is being tried ought to work? Is there a
finite number of identified predictable solutions known to skilled persons?
• What
is the extent, nature and amount of effort required? Are routine trials carried
out or is the experimentation prolonged and arduous, such that the trials would
not be considered routine?
• Is
there a motive provided in the prior art to find the solution?
• What
was the actual course of conduct that culminated in the invention?
(a) Was it more or less
self-evident that the Composition would work? Were there a finite
number of identified
predictable solutions known to skilled persons?
[72]
Sandoz
submitted that to the extent that there was any recognized need for a product
with the alleged benefits of the Composition, it was well known that a
combination product would offer such benefits. However, the fact that it may
have been known that a combination product such as the Composition would
provide particular benefits is not a sufficient basis upon which to conclude
that it was more or less self-evident that the Composition would work or that
there were any predictable solutions for achieving the Composition known to the
POSITA. It is one thing to have an idea that a potential product would or might
have certain beneficial properties. It is quite another thing to actually
create that product. It is on the latter that this assessment must focus (Pfizer
Canada Inc v Apotex
Inc,
2009 FCA 8, at para 29 [Pfizer (2009 FCA 8)]).
[73]
A
similar response is warranted in respect of Sandoz’s submission that a fixed
combination of an Alpha2 agonist (a class of drugs that includes brimonidine)
and a beta blocker, such as timolol, had been described in the DeSantis Patent.
I accept Dr. Fechtner’s opinion that the POSITA would not have read the
DeSantis Patent as disclosing the combination of brimonidine and timolol. Although
that patent stated that “the alpha-2 agonists which can be employed in the
compositions of the present invention include all pharmaceutically acceptable
compounds which have alpha two agonist activity and are effective in
controlling intraocular pressure,” I accept Dr. Fechner’s position that the
class of compounds described “is indefinite, undefined and unknowable.” As Dr.
Fechtner also pointed out, the DeSantis patent provided no experimental data of
any kind to guide the POSITA in understanding what was included in this broad
language. I note that Dr. Jampel acknowledged in cross-examination that (i) “[t]here
is an almost unlimited number of ways that this patent of combining an Alpha-2
agonists and a beta blocker could be executed”, and (ii) the DeSantis Patent
gave no data with respect to efficacy, side effects or stability.
[74]
Sandoz
observed that the ‘764 Patent recognized that brimonidine and timolol had been
combined in concomitant therapy. Sandoz noted that this is a binding admission as
to what constitutes the state-of-the-art, and submitted that Allergan cannot
argue that there is anything inventive in using brimonidine and timolol
together to treat glaucoma and ocular hypertension. Rather, Sandoz submitted
that the invention (which it denies was achieved by Allergan) is confined to
the making of a fixed combination product with brimonidine and timolol in “the
same bottle.”
[75]
I
do not interpret Allergan to be taking the position that there is anything
inventive in using both brimonidine and timolol to treat glaucoma or ocular
hypertension. Therefore the focus of the assessment below will be upon whether
the differences between the inventive concept and the state- of-the-art
discussed at Step Three of this analysis immediately above were obvious. Within
the specific context of the “obvious to try” analysis, the focus will be upon
whether it was more or less self-evident that the Composition would not only
work, but also offer those differences, and whether the solutions for achieving
the composition were predictable and known to the POSITA.
[76]
In
that context, a series of articles appended at Tabs H, I, K and AA to Dr.
Jampel’s affidavit are of no assistance to Sandoz, because, as Dr. Jampel
acknowledged in cross-examination, those articles (i) did not test a combination
of brimonidine and timolol, (ii) did not explore the potential BAK levels that
could be used in a combination product, and (iii) did not address the allergies
or the kinds of other local side effects that can lead to a discontinuance of
therapy. Indeed, the duration of the first three of those studies was limited
to the administration of a single drop, two days, and three weeks,
respectively, which was too short to test for allergies and other adverse
effects that often take much longer to manifest themselves. As noted by Mr.
Beck in his affidavit, “allergic conditions would typically not appear to be
detectable after a short trial of only a few weeks or less.” This evidence was
not contradicted.
[77]
A
fifth study, appended at Tab Z of Dr. Jampel’s affidavit, was similarly
unhelpful. Although it addressed safety, it did so simply by assessing vital
signs and spontaneously reported adverse events. Dr. Jampel did not suggest
that the study yielded any useful data in that regard, and Dr. Fechtner’s
position that the article did not disclose useful safety data was not
contested.
[78]
Sandoz
submitted that the clinical trial reported in the ‘764 Patent compared the
Composition with the monotherapies of brimonidine TID and timolol BID, rather
than with the concomitant administration of those active ingredients. In
this regard, it noted that the uncontradicted evidence was that (i) the
concomitant administration of two glaucoma drugs was a common practice at the
time of the Priority Date, and (ii) brimonidine and timolol were among the
drugs that were being administered concomitantly at that time. Allergan replied
that it had no obligation to expand its clinical trials to include a comparison
with concomitant administration of those ingredients. Stated alternatively,
while Allergan recognized that it bears the burden of demonstrating the alleged
inventive concepts of the Composition, relative to the state-of-the-art as at
the Priority Date, it submitted that it had no obligation to create data pertaining
to concomitant therapy for the purposes of demonstrating those alleged
inventive concepts. Allergan also noted that the uncontradicted evidence of Dr.
Fechtner was that the state-of-the-art suggested that the side effect profile
of the only other fixed combination drug to have been approved by the U.S. FDA
prior to the Priority Date (COSOPT) was worse than (i) the side effect profile
for concomitant administration of the two active ingredients (dorzolamide and
timolol), with respect to eyelid pain and discomfort (reported in the
Strohmaier study), and (ii) the side effect profile of timolol administered as
monotherapy (reported in the Clineschmidt study).
[79]
On
the particular facts of this case, I agree with Allergan’s position on this
point. Sandoz was not able to identify any jurisprudence to support its
position. In my view, in the absence of any prior art which demonstrated a
safety profile for concomitant therapy comparable to that which was reported
for the Composition in the ‘764 Patent, it is entirely appropriate to recognize
that superior safety profile as being one of the differences that distinguish
the Composition from the prior art.
[80]
Sandoz
raised a similar argument with respect to Allergan’s failure to compare the
Composition with brimonidine dosed BID. In this regard, Sandoz noted that
brimonidine is approved for BID dosing in Canada and elsewhere outside of the United
States.
In my view, this argument ignores the important fact that part of the
innovative concept of the Composition is that it eliminated the afternoon
reduction in efficacy of brimonidine administered BID. As discussed at
paragraph 62 above, according to Dr. Fechtner, whose testimony on this point
was not contested, this was a significant concern of the U.S. FDA. By overcoming
this afternoon reduction in efficiency of brimonidine administered BID, the Composition
achieved an innovation, even if the principal commercial benefit of that
innovation arose in the United States. In short, this discovery, together with
the discovery of a way to formulate brimonidine and timolol together in a
chemically stable formula, and the discovery of surprising safety effects, (i) “added
to the cumulative wisdom on the subject of” these active ingredients, and (ii) provided
a method whereby these discoveries can reduce the incidence of blindness in the
population through practical application (Shell Oil Co v Canada
(Commissioner of Patents), [1982] 2 S.C.R. 536, at 549; Calgon Carbon Corp
v North Bay (City), 2005 FCA 410, at paras 11-13).
[81]
Sandoz
was unable to identify any jurisprudence to support the position, which I do
not accept, that an innovation cannot be recognized in assessing obviousness unless
it has value in Canada. Sandoz also provided no
support for its inference that the innovation was of no benefit in Canada, where
doctors who are concerned about the reduction in afternoon effectiveness of
brimonidine BID therapy now have the option of prescribing COMBIGAN.
[82]
Sandoz
suggested that the Composition was obvious from the prior art because (i) the
concentrations of timolol (0.5%) and brimonidine (0.2%) were the same
concentrations of those ingredients that were included in other drugs being
sold at that time, (ii) the concentration of BAK (0.005%) is the same as in
Allergan’s ALPHAGAN product, which was launched before the Priority Date, and
(iii) the excipients in the Composition are the same as those in Merck’s
TIMOPTIC product, which also was launched before the Priority Date. In this
regard, Sandoz noted that Dr. Fechtner acknowledged in cross-examination that
the most prescribed concentration of timolol in the United States at the time
of the Priority Date was 0.5%. Sandoz added that there is no discussion in the ‘764
Patent with respect to any problems encountered in formulating a combination of
brimonidine and timolol. It proceeded to assert that “[t]he skilled formulator
would be able to easily manufacture such a combination.” However, Sandoz never
offered any explanation whatsoever as to why no one ever did so (Beloit
Canada Ltd v Valmet Oy (1986), 8 CPR (3d) 289, at 295; Janssen-Ortho Inc
v Novopharm Ltd, 2007 FCA 217, at para 24 [Janssen-Ortho]).
[83]
Sandoz
observed that Mr. Beck admitted in cross-examination that it was “not
problematic” to make the combination product. In my view, this seriously mischaracterizes
Mr. Beck’s evidence. In the passages of his cross-examination to which Sandoz
referred, Mr. Beck’s response was confined to what he characterized as being “the
actual physical combining of the various active and inactives.” He explicitly
distinguished between “the simple compounding of the formula in its inaqueous
solution,” which he characterized as being “not difficult to do,” and the
obstacles that he and his team encountered “from a chemical standpoint.” Those
obstacles are discussed at paragraphs 96 to 103 below.
[84]
I
accept Dr. Fechtner’s statement that the improved safety profile of the
Composition is remarkable and could not have been predicted in advance of
creating the Composition and conducting experimentation to ascertain the
results. I note that, in cross-examination, Dr. Jampel could not identify any
prior art which demonstrated that the concomitant administration of brimonidine
in timolol BID reduced side effects. In addition, he ultimately conceded that
the improved side effects disclosed in the ‘764 Patent were “unexpected.” The
unexpected nature of the improved safety profile of the Composition is further
corroborated by Mr. Beck’s statement that he and his colleagues did not predict
the improved allergy profile of the Composition and that they considered the
results of the clinical trial with respect to that improved allergy profile to
have been surprising.
[85]
I
also accept Dr. Fechtner’s statements that the POSITA would have known that (i)
potential problems might be encountered when formulating brimonidine and timolol
into a fixed combination drug, and (ii) “differences in pharmacokinetics, the
additive nature of adverse effects with multiple drugs, and potential drug
interactions were difficulties to be overcome in developing a fixed combination
drug.” The various unexpected difficulties encountered by Mr. Beck and his team
are discussed at paragraphs 96 to 103 below. The significant time and effort
that Mr. Beck and his team spent overcoming those difficulties lend credence to
Dr. Fechtner’s statement that it would not have been self-evident or obvious to
the POSITA that a chemically stable Composition could be achieved. Dr.
Fechtner’s conclusion on this point is further supported by Mr. Beck’s
statement, which I find credible, that each time he and his team began with a
new potential formulation, they believed that it could fail at any stage of the
process.
[86]
In
addition, the significant adverse side effects that were known to exist with
BAK lend credence to Dr. Fechtner’s opinion, which I accept, that the POSITA
would not have initially selected BAK as the preservative for the Composition.
[87]
In
response to all of the foregoing, Sandoz submitted that the POSITA would have
started the testing process with a formulation based on TIMOPTIC, including
timolol with a concentration of 0.5% and BAK as the preservative. In the latter regard, Dr. Mitra stated that BAK
is the preservative in the majority of all ophthalmic products including IOP
lowering products. He also stated that the POSITA would have had no reason to
seek to replace BAK, which is the preservative in TIMOPTIC and in ALPHAGAN,
with another preservative. With respect, this fails to address that BAK was
known to have adverse cytotoxic effects and was replaced by Purite in
Allergan’s second generation ALPHAGAN product, ALPHAGAN P. For that reason, Dr.
Jampel conceded that if the POSITA used ALPHAGAN P as his starting point, he
would have ended up with a formulation that contains Purite, rather than BAK. Dr.
Jampel also acknowledged that, by March 2001, the POSITA would have been aware
that (i) Purite was a preservative in ALPHAGAN P, (ii) Purite had a “gentler
side effect profile than BAK,” and (iii) ALPHAGAN P was formulated at 0.15
percent brimonidine, rather than the 0.2% used in ALPHAGAN.
[88]
Dr.
Mitra also stated that the mechanism of action of Purite would suggest that it
would be an inappropriate preservative for a formulation containing timolol. He
added that the POSITA would have realized that Purite may oxidize the sulfur of
the timolol molecule. I place little weight on this evidence because (i) as
discussed at paragraph 32 above, there have been serious credibility issues
raised with Mr. Mitra as a witness, (ii) I accept Dr. Fechtner’s position that
the prior art (namely, ALPHAGAN P) taught away from the use of BAK, based on
its known adverse side effect profile and Allergan’s successful formulation of
ALPHAGAN P with Purite, and (iii) I find it difficult to accept that Allergan
would have undertaken the time and expense associated with attempting to
formulate a solution with Purite, if it was self-evident that Purite would not
work with timolol. The latter observation also applies to the time and effort
that Allergan spent attempting to (i) formulate a product with other active
ingredients, including the Brimo X and Synergel formulations, and (ii)
determine the appropriate concentration of BAK to use in the Composition.
[89]
Dr.
Mitra suggested that the POSITA would have known that a fixed combination of
timolol and brimonidine could be formulated with a concentration of 0.005% BAK,
because brimonidine may have some anti-bacterial activity, such that the 0.01%
concentration of BAK that is used with timolol alone could be reduced by 50%. However,
in cross-examination, it was apparent that he was simply speculating on this
point, because he stated that brimonidine, “being an active ingredient, maybe
has some antibacterial activity so that you don’t need .02 … 01; half is enough”
(emphasis added). He subsequently acknowledged that he had not investigated
this matter.
[90]
Sandoz
further submitted that the POSITA would not have considered using Purite
because that substance is patented by Allergan. However, this fails to
recognize that the POSITA is a hypothetical person who is able to take into
consideration all prior art, including that which may enjoy patent protection (see,
for example, Eli Lilly Canada Inc v Apotex Inc, 2009 FC 320, at para 50,
and Roger T. Hughes, Hughes and Woodley on Patents, 2ed., loose-leaf
(Markham, Ont.: Lexis Nexis Butterworths, 2005), ch 5 at 166.4).
[91]
In
summary, given all of the foregoing, I find that (i) it would not have been more
or less self-evident to the uninventive POSITA that formulating brimonidine and
timolol into a chemically stable fixed combination drug ought to work, and (ii)
there was not a finite number of identified predictable solutions known to
skilled persons.
(b) What was the extent, nature
and amount of effort required? Were routine trials carried out or is the experimentation
prolonged and arduous, such that the trials would not be considered routine?
[92]
As
has been noted, Sandoz submitted that the skilled formulator would have been
able to easily manufacture the Composition.
[93]
In
addition, Sandoz submitted that the time and effort spent by Mr. Beck and his
team to develop the Composition were “routine.” In this regard, Sandoz asserted
that (i) the inclusion and exclusion criteria for the clinical trial discussed
in the ‘764 Patent were typical of those used in clinical trials for IOP
lowering drugs, (ii) the criteria for evaluation were typical, (iii) the safety
criteria would be included in most, if not all, clinical trials of drugs to
treat glaucoma and ocular hypertension, (iv) the methodology was typical of a
clinical trial of ophthalmic drugs prior to the Priority Date, (v) the study
design was typical, and (vi) the type of data collected was typical. Sandoz
maintained that “there is no invention in doing what is routine, even if
unexpected results occur.”
[94]
I
disagree with Sandoz’s positions that (i) a skilled formulator would have been
able to easily manufacture the Composition, and (ii) the time and effort spent
by Mr. Beck and his team to develop the composition were “routine.”
[95]
In
my view, Mr. Beck described, in a forthright and credible manner, a significant
number of difficulties that he and his team encountered in their development of
the Composition. Based on his evidence, and the supporting evidence of Dr.
Fechtner discussed in the section immediately above, I am satisfied that the
skilled formulator would not have been able to easily manufacture the
Composition, and that the efforts undertaken by Dr. Beck and his team to
develop the Composition were not “routine.”
[96]
Mr.
Beck explained that, at the inception of the development project, his team
considered additional or alternative beta blockers to timolol. They also
considered different salt forms of the beta blocker as well as a formulation
that did not contain an alpha-2 agonist (such as brimonidine). At that point in
time, Mr. Beck stated that he did not know whether or not it would be even
possible to formulate a combination product with 0.5% timolol. While he
acknowledged that a 0.5% solution of timolol had been sold for many years, he
explained that he could not have known in advance whether he could achieve a
safe, stable and effective formulation with that concentration in combination
with another active ingredient. I accept his statement that “regardless of the
fact that timolol was marketed [before the Priority Date] at 0.5 percent, it
had no bearing on what I could do as a formulator formulating a new product.”
[97]
After
initially considering multiple formulation candidates, Mr. Beck and his team
began with a “Brimo X” (ALPHAGAN P) formulation that contained Purite and
perhaps carboxymethyl cellulose (CMC). When they were unable to move forward
with that formulation, they switched to a formulation they called Synergel.
Among other things, one of the benefits that they hoped to achieve with
Synergel was the sustained release of the drug, which was considered to be an
optimal objective. It was only after they abandoned Synergel that they
attempted to work with a formulation that included timolol.
[98]
In
working with timolol, Mr. Beck and his team began by using Purite as a preservative
rather than BAK, because BAK was known to be cytotoxic, i.e., it comprises cell
membranes. Due to those cytotoxic side effects, Allergan developed and launched
ALPHAGAN P with Purite, which was approved by the U.S. FDA in 2001. That said,
Mr. Beck and his team recognized that it is much more difficult to maintain the
stability of Purite in formulations. During initial stability studies with
timolol, they also considered alternate salt forms, including the free base and
a heptahydrate salt form.
[99]
Approximately
two months after beginning their work with a formulation containing Purite and
timolol, it became apparent that the timolol in the formula was degrading
faster than the team expected (due to its interaction with Purite) and would
not meet the minimum 24 month preservative efficacy requirement. Therefore, the
team began to work with a formulation containing BAK, with a phosphate buffer
system that was similar to that in Merck’s TIMOPTIC product.
[100] In attempting
to formulate a product with BAK, the team conducted titration studies with
concentrations of BAK ranging from 0.01% to 0.002%. Notwithstanding the fact
that BAK was used in a 0.005% concentration in ALPHAGAN, the team did not know
what minimum concentration would be safe and effective for the Composition.
After discovering that the formulation passed the preservative efficacy test
with a BAK concentration of 0.002%, the team balanced their objective of having
a margin of safety with their objective of minimizing the concentration of BAK
in the formulation, by settling on a concentration of 0.005% for the
Composition.
[101] However, two
months into their stability studies with that formulation, they once again
discovered degradations. Mr. Beck stated that those degradations were novel and
entirely unexpected and that the team did not know whether they would be toxic
or unsafe for use in humans. Ultimately, they turned out to be harmless.
However, this was another unexpected “obstacle” that was encountered in the
testing process, and that led Allergan to incur additional time and expense in
formulating the Composition.
[102] In addition
to the foregoing, Mr. Beck explained that brimonidine and timolol have optimal
pHs that are significantly different. He stated that the pH of ALPHAGAN
(brimonidine) is most stable at a pH of about 6.3, whereas the pH of timolol is
most stable at a pH of approximately 6.9. His uncontradicted evidence, which I
accept, was that he and his team could not predict whether or not those
two active ingredients would be stable at any pH level.
[103] In summary,
before arriving at the final Composition, Mr. Beck and his team:
i.
considered
other active ingredients;
ii. encountered
failures with their Brimo X and Synergel formulations;
iii. encountered a
failure with the preservative that they considered to be superior to BAK and
had used in their ALPHAGAN P product (that was approved by the U.S. FDA shortly
before the Priority Date); and
iv. encountered
novel degradations when brimonidine and timolol were combined with BAK.
[104] Based on the
foregoing, I find that Mr. Beck and his team (i) engaged in a significant
amount of difficult, non-routine work and overcame several unexpected obstacles
to develop the Composition, and (ii) did not spend any significant amount of
time and effort pursuing possible formulations that would not have been pursued
by the POSITA.
[105] In support of
its position that the time and effort spent by Mr. Beck and his team to develop
the Composition were “routine,” Sandoz relied upon Novo Nordisk, above,
at paragraphs 308 to 319. However, in my view, that case is distinguishable.
The inventive concept there was the drug repaglinide and its “surprising
pharmacokinetic properties” when used to treat diabetes mellitus. Among other
things, there was evidence in that case that “it was more or less self-evident
that repaglinide’s pharmacokinetic properties could well be very different from
those of [the other enantiomer in the racemate compound].” Moreover, Justice
Mactavish determined that “the extent, nature and amount of effort required to
make repaglinide in the first place was neither prolonged nor arduous, and the
methods used in processes followed to test its pharmacokinetic properties were admittedly
routine.” In addition, “both sides agreed that the anti-diabetic field was
intensely competitive at the time, and that there was a strong demand for a
better anti-diabetic medication that did not have some of the drawbacks of the
conventional SFU treatments.” Moreover, it was found that “[a]dditional
motivation to separate and test enantiomers was provided by the impending move
towards increasingly stringent regulatory requirements.” Justice Mactavish
noted that during the relevant period, “there was a strong motivation to find a
better antidiabetic medication, given the intense competition field.” She then
found that (i) “it was self-evident that a person skilled in the art would test
enantiomers for their pharmacokinetic properties,” and (ii) there was evidence
that “the testing of enantiomers for their pharmacokinetic properties have
become a routine part of industry practice as of the relevant date and was not
an inventive step by the [Applicant’s] drug development team.” (Novo Nordisk,
above, at paras 308-322).
[106] By contrast,
in the case at bar, I have found that it would not have been self-evident to
the POSITA that formulating brimonidine and timolol into a chemically stable fixed
combination drug ought to work. While the prior art may well have suggested to
the POSITA that such a drug would be “worthwhile” to pursue, that would not be
a sufficient basis upon which to conclude that the Composition was obvious (Pfizer
(2009 FCA 8), above, at para 45). In addition, there was no evidence that a
POSITA would have had any basis whatsoever for believing that the Composition ought
to (i) have a superior safety profile, relative to brimonidine TID, or (ii)
permit BID dosing without an afternoon reduction in efficiency, relative to
brimonidine TID treatment. These discoveries were made only after the
completion of a large clinical trial involving 586 individuals, which began as
a three-month study and was then expanded to include a nine-month masked
extension. Dr. Fechtner characterized the data collected during that trial as
being “at the high end for a clinical trial.” Moreover, there was no evidence in
the case at bar to suggest the existence of any competition, let alone intense
competition, to develop a fixed combination drug comprising brimonidine and
timolol. There was also no evidence that the type of testing conducted by Mr.
Beck and his team to develop the Composition had become a routine part of
industry practice prior to the Priority Date. Furthermore, as discussed below,
I have determined that there was not a strong motive provided in the prior art
to develop a solution such as the Composition. Finally, I am satisfied that the
nature and amount of effort required by Mr. Beck and his team to develop the
Composition, as described above, was prolonged and arduous. I note that a
similar conclusion was reached in the U.S. proceedings between the parties
involving COMBIGAN (Allergan, Inc v Sandoz, 2:09-cv-00097 TJW, at para
122 (ED Tex 2011)), although I recognize that there are significant differences
in (i) the applicable law in this area in Canada and the U.S., and (ii) the
evidentiary records in that case and the case at bar.
[107] In support of
its position that the trials conducted by Mr. Beck and his team were routine,
Sandoz noted that Mr. Beck acknowledged in cross-examination that the cost of
developing a new chemical entity can be in excess of $100 million. Sandoz
submitted that the $26.4 million which Mr. Beck stated was spent by Allergan
developing the Composition was small by comparison, and suggests that the
nature and amount of effort required to develop the composition was not
prolonged and arduous.
[108] I disagree. In
the context of an assessment of obviousness and the particular factual matrix
of this case, the fact that it may cost in excess of $100 million to develop an
entirely new chemical entity provides little helpful information in determining
whether the $26.4 million that was spent by Allergan to develop the Composition
is indicative of routine, as opposed to prolonged and arduous, work. Sandoz was
unable to identify any jurisprudence to support the proposition that an amount
in the range of $26.4 million is, in itself, indicative of work that is merely
routine.
[109] A fundamental
shortcoming with this particular $100 million benchmark is that it does not provide
a useful measure of what might be considered sufficiently routine to weigh in favour
of a conclusion that the invention of the Composition was obvious to try. It
simply provides a measure of what may be routinely required to invent an
entirely new chemical entity. Moreover, in the absence of additional
information, the utility of any particular monetary benchmark may often be limited.
For example, a level of expenditure that may be indicative of work that is
routine in the presence of a high motivation may well be indicative of work
that is not routine where such motivation is not present.
[110] In response
to my request for jurisprudence that is more helpful in distinguishing between
effort that is routine and effort that is prolonged and arduous, as
contemplated by Sanofi, above, at paragraph 69, Sandoz referred to Schering-Plough
Canada Inc v Pharmascience Inc, 2009 FC 1128 [Schering-Plough].
There, my colleague Justice Snider concluded that the steps that had been taken
by the applicant to develop a new drug were not “overly arduous or complex,”
but rather appeared to have been somewhat “routine pre-formulation experiments.”
She therefore concluded that “this factor would tend to operate in favour of a
finding of obviousness, although not strongly so” (emphasis added) (Schering-Plough,
above, at para 209).
[111] In that case,
the inventive concept of the patent in question consisted of avoiding lactose
and other acidic excipients as the carrier medium and using a basic salt
to stabilize the composition (Schering-Plough, above, at para 200). In
reaching her conclusion regarding the routine nature of the experimentation
that had been undertaken by the applicants, Justice Snider concluded that the
step of identifying the incompatibility between the active ingredient
(descarboethoxyloratadine (DCL)) and lactose “was more or less self-evident”
(para 204). With respect to the use of a basic salt, she was skeptical of the respondents’
position that this was “more or less self-evident” (para 206), but then
proceeded to reach her conclusion regarding the routine nature of the
experimentation in question, after considering certain evidence (para 208).
Among other things, that evidence did not include anything analogous to (i) the
failures that Mr. Beck and his team encountered with their Brimo X and Synergel
formulations, or (ii) the failure that they encountered with Purite.
Accordingly, Schering-Plough is distinguishable. There was also no
evidence to suggest that a trial consisting of over 500 persons was undertaken,
let alone the additional two trials that Mr. Beck stated were undertaken.
[112] In the course
of its arguments regarding the alleged “routine” nature of the work undertaken
by Mr. Beck and his team, Sandoz suggested that I draw an adverse inference
from the fact that Allergan failed to provide more evidence regarding the steps
that were taken to develop the Composition. In this regard, Sandoz suggested
that Allergan should have provided laboratory notebooks, reports and
presentations that were made with respect to the Purite degradation issue,
documents dealing with the accelerated stability tests that were undertaken and
other documentation relating to the testing that was performed. Sandoz asserted
that these documents were being “hidden” from this Court.
[113] I have some
sympathy for Sandoz’s position on this point. Nevertheless, if Sandoz truly
thought that anything in that documentation may have supported its allegation
of obviousness, it should have availed itself of its opportunity to serve a
direction, under Rule 91 of the Federal Courts Rules, SOR/98-106, on Mr.
Beck to attend and produce that documentation for inspection. It could also
have attempted to simply request Allergan’s counsel to provide that
documentation. Given that it did neither of these things, I declined to draw
the requested adverse inference.
(c) Was there a motive provided in
the prior art to combine brimonidine and timolol into
a fixed combination?
[114] Sandoz
submits that the prior art disclosed a motive to develop the Composition
because it was known that patient compliance likely would be better with fewer
daily administrations of drops to the eye, and that the daily preservative load
delivered to a patient would be less with a fixed combination drug. This
position was undermined by the statement in Dr. Jampel’s affidavit that he did
not recall having ever heard of the “long felt need for an effective and safe
ophthalmic pharmaceutical composition including brimonidine and timolol,”
described in the ‘764 Patent. In cross-examination, Sandoz’s position on this
point was virtually negated when Dr. Jampel affirmed that he was not aware of
any particular motivation among person skilled in the art to combine
brimonidine and timolol, although, he speculated that pharmaceutical companies
might have such a motivation.
[115] Dr.
Fechtner’s uncontradicted evidence on this point, which I accept, is that:
(i) the known
difficulty in obtaining U.S. FDA approval for fixed combination drugs for the
treatment of glaucoma was a major disincentive against the development of such
drugs, and the POSITA would not have been motivated to develop a fixed
combination drug containing timolol and brimonidine;
(ii) the extent of
time, effort and resources required to conduct the clinical trials described in
Mr. Beck’s affidavit would have given rise to a disincentive for the POSITA to
pursue the development of the Composition; and
(iii) the cost of
the work required to develop such a drug would have been a further disincentive
for the POSITA.
[116] Another
statement made by Dr. Fechtner that is relevant to this consideration is that
the POSITA would have been well aware that combining two drugs into a fixed combination
may lead to the over-administration or under-administration of one of the
active ingredients, which is apparently what happened with the combination
product of pilocarpine and epinephrine.
(d) Summary of “obvious to try” assessment
[117] It follows
from the conclusions reached under the headings (a) to (c) immediately above
that combining brimonidine and timolol into a fixed combination drug is not something
that would have been “obvious to try” for the POSITA. In short, (i) it was not
more or less self-evident that the steps that were undertaken to achieve a
chemically stable formulation of the Composition ought to work, (ii) the
experimentation undertaken to achieve that formulation was not routine, (iii) Allergan
did not have a strong motivation to pursue that experimentation, and (iv) the
course of conduct undertaken to achieve the Composition does not suggest that
the Composition was obvious.
[118] Sandoz
submitted that the facts of the case at bar are similar to those that were
addressed in Merck (2010 FC 1042), above, where Justice O’Reilly
concluded that the only other fixed combination anti-glaucoma drug that has
been approved for use in Canada (COSOPT) would have been obvious for the POSITA
to formulate.
[119] I disagree. In
my view there are significant differences between the content of the patents
and the evidence adduced in the two cases. The key passages from Merck (2010
FC 1042), are as follows:
[47] There is nothing in the
patent itself that suggests that there was anything inventive about the
co-formulation of a [carbonic anhydrase inhibitor (CAI)] and a beta blocker. No
difficulties are mentioned. The patent sets out 32 different examples of
co-formulation. Nothing suggests that co-formulation was as difficult as Merck’s
experts thought it might have been. I have no evidence before me as to the
steps the inventors took to arrive at the co-formulation. In the circumstances,
all indications seem to be that co-formulation was routine. I have no evidence
from Merck about any difficulties or arduous experimentation being required to
arrive at a co-formulation. Nor do I have any evidence of difficulty in
arriving at an acceptable pH …
…
[49]
While Merck’s experts might have been surprised that dorzolamide could be effective
when dosed twice daily with timolol instead of three times daily, this effect
was clearly disclosed in both Gunning and Nardin. A skilled person would have
expected the same effect in a co-formulation of the two agents.
…
[52]
No evidence of difficult or prolonged experimentation to achieve a
co-formulation was tendered. Indeed, no evidence about the course of conduct
leading to a co-formulation was provided. The prior art and the general common
knowledge in the field would have motivated a skilled person to attempt to
co-formulate dorzolamide and timolol. It was obvious.
[120] By contrast,
the ‘764 Patent included a significant amount of data to support the surprising
findings of safety and of the absence in a reduction of afternoon efficiency
for the Composition, relative to TID dosing of brimonidine. As has been
discussed, these effects were not disclosed in the prior art. Moreover, Mr.
Beck’s uncontested evidence demonstrates that he and his team encountered a
number of unexpected difficulties in developing the Composition, and pursued a
number of unsuccessful formulations before finally arriving at the Composition.
In short, Merck (2010 FC 1042) is distinguishable from the case
at bar in several important ways.
(e) The
Actual course of conduct of the inventors
[121] In Sanofi,
above, at paragraph 70, it was noted that another factor that may be important
in assessing obviousness is the actual course of conduct which culminated in
making the invention. In this regard, the Court observed that “if the inventor
and his or her team reached the invention quickly, easily, directly and
relatively inexpensively, in light of the prior art and common general
knowledge, that maybe evidence supporting a finding of obviousness, unless the
level at which they worked and their knowledge base was above what should be
attributed to the skilled person” (para 71).
[122] Based on the
information discussed paragraphs 96 to 103 above, I find that this factor
weighs in favour of a finding that the Composition was not obvious. In short,
Mr. Beck and his team did not develop the Composition “quickly, easily,
directly and relatively inexpensively, in light of the prior art and common
general knowledge.” On the contrary, they pursued at least three “wild goose
chases” (Sanofi, above, at para 71) and encountered a number of other
obstacles before they finally developed the Composition.
(f)
Commercial success
[123] A secondary
factor that can be relevant in the assessment of obviousness is whether an
invention has achieved commercial success. This factor may be indicative of a
motivation to fill the commercial market, which may in turn suggest inventive
ingenuity (Janssen-Ortho, above, at para 25). Indeed, to the extent that
commercial success may reflect a view of the marketplace, or a segment thereof,
that the invention is superior to previously available products, such success
is suggestive of inventive ingenuity, even in the absence of a motivation to
fill the commercial market. That said, commercial success may also simply
reflect considerations unrelated to the invention, such as marketing skills and
market power. Accordingly, in the absence of evidence indicating that
commercial success is suggestive of inventive ingenuity, rather than the other
factors just mentioned, commercial success may merit little weight in the
overall assessment of obviousness.
[124] In the case at
bar, Mr. Beck stated in his affidavit that Allergan achieved total sales of
COMBIGAN in Canada of
approximately $35 million between January 2005 and November 2010. Among other things,
estimated that in 2009 and 2010, COMBIGAN held approximately 6% of total sales
of anti-glaucoma drugs in Canada.
[125] There is
evidence to suggest that the commercial success of COMBIGAN is at least in part
attributable to the favourable safety dimension of the inventive concept of the
‘764 Patent. In short, Dr. Fechtner’s uncontradicted evidence is that “one of
the reasons why COMBIGAN has been a successful product commercially (and one of
the reasons I prescribed it) is because it has an advantageous side effect
profile when compared to its components and other available treatment options.”
This evidence was not contested by Sandoz’s experts.
[126] It would have
been helpful to have additional information regarding total worldwide sales of
COMBIGAN and regarding the size of the market in which it competes. Nevertheless,
I am satisfied, on the basis of the information discussed above, that the
commercial success of COMBIGAN is a factor that weighs slightly in favour of
concluding that the Composition was not obvious.
(5) Conclusion
on obviousness
[127] Allergan has
met its burden of establishing, on a balance of probabilities, that Sandoz’s
allegation that the ‘764 Patent is invalid on the ground of obviousness is not
justified. For the reasons summarized in paragraph 117 above, this would remain
true even if the inventive concept of the claims of the ‘764 Patent did not
include the uncontested surprising improvement in safety, the elimination of
the afternoon reduction of effectiveness and the reduction in daily load of
BAK, relative to concomitant treatment of brimonidine and timolol. These
additional aspects of the inventive concept simply serve to further strengthen
that the invention claimed by the ‘764 Patent was not obvious.
B. Will the PM for the Generic
Drug induce infringement of any of the claims in the ‘626
Patent?
[128] The ‘626
Patent describes a “new method of protecting the optic nerve and retina of the
mammalian eye from damage by glaucoma and other noxious provocations.” It is
common ground between the parties that this describes a neuroprotective use of
the compounds claimed in the ‘626 Patent, including brimonidine.
[129] In its NOA,
Sandoz alleged that the claims of the ‘626 Patent would not be infringed by the
Generic Product. In response, Allergan submitted in its Application in this
proceeding that Sandoz’s sale of the Generic Product will infringe and/or
induce infringement of at least claims 1, 2, 20 and 21 of the ‘626 Patent. With
respect to inducement, Allergan asserted that the proposed indications in the
PM will induce physicians, pharmacists and/or patients to infringe the claims
of the patent.
[130] In his
November 2010 affidavit, Dr. Parkinson explained Allergan’s position regarding
inducement. In brief, he stated that, Sandoz’s PM identifies two indications
for the Generic Drug, namely, (i) the lowering of IOP to treat open-angle
glaucoma, and (ii) the reduction of long-term fluctuation in IOP, in order to
slow or prevent nerve cell injury or death. Regarding the latter indication, he
stated that the POSITA would have known as of January 1997, the publication
date of the ‘626 Patent, that long-term fluctuation in IOP was a noxious action
that would result in damage to optic nerve cells in some patients. He concluded
by asserting that Sandoz’s PM “will induce ophthalmologists to prescribe and
induce patients to use [the Generic Product] for the treatment of long-term
fluctuation and IOP (a noxious action) to inhibit or prevent new cell injury or
death.”
[131] Allergan has
now abandoned that position. Instead, it has submitted that one of the
sentences in Sandoz’s PM and one of the documents identified in the list of
references at the back of the PM are directed to a neuroprotective use of
brimonidine that is unrelated to the reduction of IOP, and will therefore
induce infringement.
[132] For the
reasons set forth below, I disagree.
[133] Sandoz
objected to Allergan’s new position regarding inducement on the procedural basis
that this theory was not articulated in its Notice of Application. However, I
am satisfied that Allergan’s current position is a response to the position
taken by Dr. Jampel in his affidavit, where he argued that the POSITA would
have known in 1997 that the ‘626 Patent describes and claims protecting the
optic nerve cells by directly fortifying those cells, not by having an effect
on a noxious action. I agree with Allergan that it is now too late for Sandoz
to raise this objection, given that (i) Sandoz did not take the position that
it would be prejudiced if this Court were to allow Allergan to advance its new
theory of inducement at a late stage in these proceedings, and (ii) Sandoz did
not seek leave to adduce additional expert evidence in response (Abbott
Laboratories Ltd v Canada (Minister of Health), 2007 FCA 251, at para 35).
(i) The
asserted claims -‘626 Patent
[134] Allergan is
asserting claims 1, 2 and 14 of the ‘626 Patent (the “Asserted Claims”). Claim
14 is dependent on claims 1 and 2 and limits the compounds claimed to
brimonidine. Taken together, these claims read as follows:
Claim 14 (read with claim 1) - Use of an effective amount of brimonidine to
inhibit or prevent nerve cell injury or death for protecting the retinal or
optic nerve cells in a mammal suffering a noxious action or at risk of
experiencing a noxious action on said nerve cells.
Claim 14 (read with claim 2) - Use of brimonidine to inhibit or prevent
nerve cell injury or death in the manufacture of a medicament for protecting
the retinal or optic nerve cells in a mammal suffering a noxious action or at
risk of experiencing a noxious action on said cells.
(ii) The POSITA - ‘626
Patent
[135] Dr. Parkinson
described the POSITA to which the ‘626 Patent relates as “a resident
ophthalmologist with 2-3 years of experience or a general community
ophthalmologist with 1 year of experience treating patients.” Dr. Jampel
disagreed. He opined that the POSITA “is a researcher with interest, skill and
experience in experimental research of the eye diseases, particularly glaucoma.”
He added: “such a person would have a MD degree or a PhD degree and experience
in conducting and analyzing both animal studies and human clinical trials.”
[136] The basis for
Dr. Jampel’s opinion on this point included the following:
i.
When
the ‘626 Patent was published in 1997, neuroprotection was only the subject of
experimental research.
ii. At that time,
no medication had been approved as a neuroprotective agent for patients with
ocular hypertension or glaucoma.
iii. The ‘626 Patent
does not provide any information with respect to the clinical application of
any invention disclosed in the patent - it simply provided a very large (5000
fold) difference that would be of no use to a practicing ophthalmologist.
iv. Certain data
provided in the patent are only relevant to experimental studies and are not
described in terms used by ophthalmologists.
v. The examples
of the patent relate to testing on cells or in animals and do not provide any
basis upon which the purported invention of the ‘626 Patent could be used
clinically. Indeed, the persons meeting Dr. Parkinson’s definition of the
POSITA would have, at best, limited understanding of these examples and their
results and would not be able to use the results in clinical practice.
[137] Based on the
foregoing, Sandoz submitted that Dr. Parkinson is not a POSITA and that therefore
his opinions should be given little weight.
[138] In response,
Allergan noted that the ‘626 Patent mentions glaucoma and IOP no less than 35
times, and that Sandoz did not refer to a single case to support the
proposition that an expert needs to know how to perform the experiments described
in a patent to provide an opinion regarding the subject matter of the patent. Allergan
further noted that it is now established that “a patent specification is a
unilateral statement by the patentee, in words of his own choosing, addressed
to those likely to have a practical interest in the subject matter of
his invention (i.e., ‘skilled in the art’), by which he informs them what he
claims to be the essential features” (emphasis added) (Whirlpool, above,
at para 44, citing Catnic Components Ltd v Hill & Smith Ltd, [1982]
RPC 183, at 242-43).
[139] Upon further
review of the ‘626 Patent, I am satisfied that it is directed towards persons
fitting the definitions given by both Dr. Parkinson and Dr. Jampel. In my view,
the POSITA is a composite of such persons (Laboratoires Servier v Apotex
Inc, 2008 FC 825, Snider J., at para 103). In short, contrary to Dr.
Jampel’s position, it is readily apparent to me that the ‘626 Patent is also
directed towards ophthalmologists such as Dr. Parkinson who may have a clinical
and practical interest in the invention disclosed by the ‘626 Patent.
For example, I am satisfied that much of the information under the headings “Background
of the Invention,” “Summary of the Invention,” “Drawings,” “Human dosage and
administration” and “Measurement of the effects of drug tests for
neuroprotective properties” would be of potential interest and value to
ophthalmologists.
[140] In the event
that I am found to have erred on this point, I agree with Allergan’s position
that Dr. Parkinson’s evidence (i) is nevertheless material to various issues
that have been raised in respect of the ‘626 Patent, and (ii) goes beyond the
knowledge that this Court is expected to have. Therefore, his evidence should
be admitted and given the weight that I consider to be appropriate (Merck
& Co Inc v Pharmascience Inc, 2010 FC 510, at para 31).
(iii) Claims
construction
[141] There is no
material dispute between the parties with respect to the construction of the
Asserted Claims. In short, although the parties had competing constructions at
the outset of these proceedings, Allergan is now conceding Sandoz’s
construction.
[142] It is now
agreed that the ‘626 Patent relates to a purported new use of certain compounds
identified in the patent as “Formula I,” and that one of the compounds included
in Formula I is brimonidine. The new claimed use is “to inhibit or prevent
nerve cell injury or death … for protecting the retinal or optic nerve cells in
a mammal suffering a noxious action or at risk of experiencing a noxious action
on said nerve cells.”
[143] The patent
states that there “is an unmet need for agents that have neuroprotective
effects in the eye that can stop or retard the progressive damage that occurs
to the nerves as a result of glaucoma or other ocular afflictions.” This need
is said to arise because lowering IOP by administration of drugs or by surgery “is
not always effective in obviating damage to the nerves in glaucomatous
conditions.” Moreover, “[s]ome glaucoma patients never have higher than normal
IOP and others continue to develop optic nerve damage despite maximal lowering
of IOP.”
[144] The promise
of the ‘626 Patent is therefore that the compounds specified in the claims,
including brimonidine, will have this purported neuroprotective effect upon
retinal or optic nerves in humans. As the parties now agree, this effect is
achieved through a mechanism unrelated to IOP, which helps to shield ocular
nerve cells from damage from noxious actions. This use is distinct from the
previously known and practised use of brimonidine to treat elevated IOP, and is
claimed in the patent to be “particularly effective when administered as a
prophylactic treatment, i.e., before damage to the nerve takes place, or before
long-term progression of the disease, such as glaucoma, has taken place.”
(iv)
Inducement of infringement - the legal test
[145] To establish
infringement of a use claim by inducement, it is necessary to demonstrate the
following three things:
i.
an
act of infringement was completed by a direct infringer;
ii. the
infringement was influenced by the inducing party to the point that, without
that influence, the infringement would not have taken place; and
iii. the inducing
party knew that its influence would result in the completion of the act of
infringement.
(See: AB Hassle v Canada (Minister of
National Health and Welfare), [2002] 3 FC 221; Solvay Pharma Inc v
Apotex Inc, 2008 FC 308, at paras 136-137; Sanofi-Aventis Canada
Inc v Novopharm Ltd, 2007 FCA 167, at paras
9-11 [Sanofi (2007)]).
[146] Inducement is
a question of fact (Dableh v Ontario Hydro (1996), 68 CPR (3d) 129, at
149).
[147] In the
context of applications under the Regulations, the mere sale of the
patented product by a second person is not sufficient. “Something more” is
required (Sanofi-Aventis Canada Inc v Apotex Inc, 2006 FCA 357, at para 18
[Sanofi (2006)]). That “something more” is “something active
[that] must be done” by the inducing party (Pfizer Canada Inc v
Apotex Inc, 2005 FC 1421, at para 167). It is not sufficient for the
first person to simply demonstrate that the second person recognized that “off
label” prescription by doctors, dispensation by pharmacists, and subsequent
consumption by patients would occur (Aventis Pharma Inc v Apotex Inc, 2005
FC 1461, at para 32 [Aventis (2005 FC 1461)]; aff’d, Sanofi (2006),
above; Sanofi (2007), above; Sanofi-Aventis Canada Inc v Laboratoire
Riva Inc, 2008 FC 291, at para 31).
(v) Analysis
(a) The first prong
of the tri-partite test
[148] During the
hearing of this application, the initial and principal focus of the parties
with respect to the ‘626 Patent was upon the second prong of the tri-partite
test for inducement, namely, whether the PM for the Generic Drug is likely to
influence physicians or pharmacists to prescribe or dispense the Generic Drug
to patients for neuroprotection. Accordingly, I will only deal briefly with the
first prong of that test now.
[149] In the
context of an NOC proceeding, the first prong of the tri-partite test for
assessing inducement to infringement is whether infringement is likely
to occur if an NOC is issued (Abbott Laboratories Ltd v Canada (Minister of
Health), 2007 FCA 251, at paras 26-27; Aventis Pharma Inc v
Pharmascience Inc, 2006 FCA 229, at para 60); AB Hassle v Canada
(Minister of National Health and Welfare), [2002] 3 FC 221, at para 69). In
cross-examination, Dr. Parkinson stated that the Generic Product will be
prescribed by physicians (and used by patients) for neuroprotection, based on
Sandoz’s PM, the Krupin article and his clinical experience. For the reasons discussed
in Parts IV.C and IV.D of these reasons below, I prefer Dr. Parkinson’s
evidence on this issue and on the related issue of whether brimonidine actually
confers neuroprotection on patients, to the evidence provided by Dr. Jampel and
Dr. Mitra.
[150] Based on Dr.
Parkinson’s evidence, I am satisfied that Allergan has demonstrated, on a
balance of probabilities, that the Generic Drug is likely to be used for
neuroprotection, and therefore is likely to infringe, the ‘626 Patent.
(b) The second
prong of the tri-partite test
[151] Allergan’s
position that Sandoz will induce infringement of the ‘626 Patent is based on
one sentence that appears in Sandoz’s PM and one reference that appears towards
the end of the list of references that are included at the end of that PM. Specifically,
at page 23 of the PM, under the heading Animal Pharmacology, Sandoz
stated the following:
When the action of brimonidine tartrate as a neuroprotective agent
was evaluated in vitro and in vivo pharmacological studies in
rats, no deleterious effects on the optic nerve were observed.
[152] In addition,
the ninth in a list of 13 references at the back of the PM is a reference to an
article by Mr. Lai, one of the named inventors of the ‘626 Patent, and several
other employees of Allergan, entitled “Neuroprotective effect of ocular hypertension
agent brimonidine” (the “Lai Article”).The first sentence in the Summary that
appears at the outset of the Lai Article states: “The ocular hypotensive agent
brimonidine has been shown to be neuroprotective in a mechanical insult model
of the optic nerve.” After briefly discussing certain data obtained from an in
vivo study of rat retinal RNA and from an in vitro study of rat
hippocampal neuronal culture, the Summary states: “These data suggest that
brimonidine is an effective ocular hypotensive agent with neuroprotective
properties.” Under the heading “Results and Conclusions,” the Lai Article
stated: “After 15 days of [BID] topical dosing, mRNA of retinal bFGF increased
50% (0.5% brimonidine) and 200% (1% brimonidine) above control (Fig. 2). Sufficient
amount of brimonidine appeared to have reached the retina to induce retinal
bFGF upregulation.” The Lai Article proceeded to conclude as follows:
Present findings that brimonidine can upregulate bFGF in retina
suggests a mechanistic basis for neuroprotection. Brimonidine is a unique
ocular hypotensive drug since it lowers IOP by both decreasing the aqueous
humor production and increasing uveoscleral outflow. The added neuroprotective
properties of brimonidine in the retina will present a [sic] new opportunities
to explore in neuroprotection in the eye.
[153] Allergan
submitted that if Sandoz receives the NOC that it seeks, it will be permitted
to disseminate its PM to doctors and pharmacists in Canada, who in turn will be
influenced by the above quoted sentence that appears at page 23 of the Sandoz
PM and/or the Lai Reference (collectively the “Neuroprotective Information”) to
prescribe or dispense the Generic Drug to patients for the neuroprotective use
claimed by the ‘626 Patent. Allergan maintained that the presence of the
Neuroprotective Information in Sandoz’s PM is the “something more” contemplated
by the jurisprudence.
[154] For the
reasons set forth below, I disagree. Stated alternatively, I have concluded
that the second prong of the tri-partite test described under the preceding
heading above has not been met.
[155] Accordingly,
the principal question that remains is whether ophthalmologists and pharmacists
will in fact be influenced by the Neuroprotective Information to prescribe or
dispense, respectively, the Generic Drug for neuroprotection, as required by
the second prong of the test.
[156] Sandoz
attempted to minimize the potential significance of the Neuroprotective
Information in its PM by noting that it does not appear in the “Indications and
Clinical Use” section of the PM. Among other things, that section of the PM
describes the indications of the Generic Drug as follows:
Sandoz Brimonidine/ Timolol (brimonidine tartrate 0.2%/timolol
maleate as timolol 0.5%) ophthalmic solution is indicated for the control of
intraocular pressure in patients with chronic open-angle glaucoma or ocular
hypertension who are insufficiently responsive to IOP reducing monotherapy AND
when the use of Sandoz Brimonidine/ Timolol is considered appropriate. Sandoz
Brimonidine/ Timolol is also indicated for reduction of long-term fluctuation
in IOP. In addition to controlling IOP, Sandoz Brimonidine/ Timolol reduces
long-term variability, or fluctuation, in IOP. Together, reductions in IOP and
in IOP fluctuation are expected to slow the progression of visual field loss in
patients with glaucoma.
[157] However,
I agree with Prothonotary Tabib’s conclusion, reached earlier in these
proceedings in connection with a motion for the production of Sandoz’s entire
PM, that “several decisions of this Court support the proposition that in
determining whether an allegation that a second person will not infringe or
induce infringement of a patent directed to the use of the medicine, the
Product Monograph in its entirety is a key document.” See: Allergan Inc v
Sandoz Canada Inc (June 21 2010), Ottawa T-154-10 (Federal Court) (Tabib
P), citing Aventis Pharma Inc v Apotex Inc, 2005 FC 1381; AB Hassle v
Genpharm Inc, 2003 FC 1443; Sanofi (2007), above.
[158] In his
initial affidavit, Dr. Parkinson focused on Allergan’s now abandoned theory of
inducement, described at paragraph 130 above. He did not mention the
theory of inducement now being advanced by Allergan. Nor did he mention the
Neuroprotective Information in Sandoz’s PM. However,
he did state the following:
Canadian ophthalmologists have access to and when they see fit can
access generic product monographs on Health Canada's website or by obtaining paper copies which are available on
demand. Canadian ophthalmologists, including the POSITA, would be able to read,
understand and apply the totality of the reported studies and information
taught in Sandoz’s proposed product monograph, and where they need
information to make prescribing decisions they can and do consider the totality
of the relevant information referred to in the monograph. (Emphasis added.)
[159] In his second
affidavit, Dr. Parkinson focused on replying to various statements made in Dr.
Jampel’s affidavit, particularly with respect to the validity of the ‘626
Patent. Once again, Dr. Parkinson did not mention the theory of inducement now
being advanced by Allergan, or the Neuroprotective Information in Sandoz’s PM.
[160] In
cross-examination, Dr. Parkinson was challenged on his opinion regarding the
manner in which ophthalmologists use PMs. He explained that “when a clinician
uses a drug, it is incumbent upon them [sic] to understand and to have
read the entire monograph, it is not just the first two paragraphs [Indications
and Clinical Use]. And contained elsewhere in [Sandoz’s PM] is evidence that
this drug has neuroprotective qualities, and that’s why we use this section.”
He then referred to the Neuroprotective Information in Sandoz’s PM , and
stated: “and I read that, as a clinician, that as noted deleterious effects
were observed in the optic nerve in these rats that this agent has conferred
some neuroprotective qualities on those nerves.” There was nothing in the
balance of his cross-examination that was particularly helpful in assisting me
to make a determination with respect to Allergan’s position that Sandoz’s PM
will induce infringement of the ‘626 Patent.
[161] On balance, I
am prepared to accept that at least some ophthalmologists read a product’s PM
before prescribing that product. That said, I did not find Dr. Parkinson’s
opinion on this point to be particularly compelling. As a result, I will not
attach determinative weight to that opinion in assessing whether Allergan has
met its burden of demonstrating that Sandoz’s allegation of non-infringement is
not justified.
[162] Turning to
Dr. Jampel, he acknowledged in cross-examination that he did not review the
list of references in Sandoz’s PM, and that therefore he was not aware, when he
prepared his affidavit, that the Lai Article was contained in that list. He
also conceded that (i) he was not aware that the word “neuroprotective”
appeared in Allergan’s PM for COMBIGAN, which was attached as exhibit G to his
affidavit, and (ii) he did not know what COMBIGAN is approved for in the U.S. This
suggests that he is at least one practicing ophthalmologist who does not read
the entire PM filed in respect of a product, before prescribing that product.
[163] Dr. Jampel
also conceded that he had never read a Canadian PM before the case at bar and
that he had no particular knowledge with respect to how Canadian
ophthalmologists use PMs. Nevertheless, I find some of his evidence regarding
how Canadian ophthalmologists are likely to use Sandoz’s PM to be helpful.
[164] In
particular, with respect to the Neuroprotection Information that appears in a
single sentence at page 23 of Sandoz’s PM, he stated: “A physician who read
this cold would have no idea what they're talking about.” When asked if his
opinion on this point would change if the sentence was read in light of Lai
Article, he replied that physicians likely would understand it to be referring
to the experiments described in the Lai Article. However, he also characterized
the “crush model of optic nerve injury” upon which the in vivo
experiment described in the Lai Article was based, to be “a crude and early
relationship to looking at glaucoma.” As to the in vitro experiment
described in the Lai Article, he characterized it as involving “[c]ultured rat
cells in a dish” and stated that it would not be considered to constitute “an
animal study.” In any event, he stated that “the drug reps who come by never
mention animal studies” and suggested that physicians would not be particularly
interested in information from “animal models of neuroprotection.”
[165] In addition,
Dr. Jampel stated that the Lai Article would not be considered to be the type
of study or reference contemplated by section 4.6 of Health Canada’s
publication entitled Guidance For Industry - Product Monograph. Section
4.6 states that the references section of a PM “should include a selection of
the pivotal clinical studies that formed the basis for the evaluation of the
drug and the studies highlighted in the Clinical Trial section … [and] may also
include references to the best published papers containing preclinical data on
the drug and selected, authoritative papers concerning the use of the drug.”
Dr. Jampel stated that the Lai Article is neither such a pivotal clinical study
nor a published paper containing preclinical data on the drug in question. However,
he acknowledged in cross-examination that one of the reasons why the Lai
Article may have been included in the list of references at the back of Sandoz’s
PM is “possibly” to elucidate a mode of action of brimonidine in
neuroprotection. In addition, he acknowledged that one of the reasons why
animal data may be included in a monograph is to provide physicians with extra
information about a particular type of use.
[166] Dr. Jampel
also noted that COMBIGAN is not indicated for neuroprotection and that Sandoz’s
PM does not include neuroprotection as one of the indications for the Generic
Drug. He added that there is nothing in Sandoz’s PM or the COMBIGAN PM that
mentions the use of brimonidine to provide neuroprotection in humans, and
nothing in those documents which states that brimonidine has a neuroprotective
effect. (The sentence on page 23 of Sandoz’s PM simply observes that “no
deleterious effects on the optic nerve [of the rats studied] were observed.”)
[167] After
considering the foregoing and the other evidence and submissions made by the
parties, I have determined that Allergan has not met its burden of
establishing, on a balance of probabilities, that ophthalmologists or
pharmacists likely would be influenced by the Neuroprotective Information in Sandoz’s
PM to prescribe or dispense the generic drug for neuroprotection. Notwithstanding
Dr. Parkinson’s evidence and the adverse inference that I draw from the fact
that Sandoz appears to have consciously chosen to leave the Neuroprotective
Information in its PM, I am not persuaded that the Neuroprotective Information
(i) constitutes the “something more” required by the jurisprudence, or (ii) is
anything more than “a mere reference to the new use” described in the ‘626
Patent (Sanofi (2007), above, at para 9; Aventis (2005 FC 1461),
above, at paras 32-36, aff’d Sanofi (2006), above).
[168] Allergan was
not able to identify any case in which information that was as limited as the
Neuroprotective Information, and that was subject to the various shortcomings
identified by Dr. Jampel, provided the basis for a finding that a generic drug
manufacturer’s allegation of non-infringement was not justified.
[169] Although
Allergan suggested that Sandoz would be free to “market” the Generic Drug for
neuroprotection, I am not persuaded, on a balance of probabilities, that on the
particular facts of this case this is likely to occur, particularly having
regard to (i) Dr. Jampel’s uncontradicted evidence that representatives of drug
companies do not generally mention animal studies and that physicians would not
be particularly interested in information from “animal models of
neuroprotection”, (ii) the Generic Drug is not indicated for neuroprotection,
and (iii) the marketing of a drug for unapproved uses is prohibited (Goodridge
v Pfizer Canada Inc, 2010 ONSC 1095, at para 15).
[170] Based on all
of the foregoing, I am satisfied that Allergan has not met its burden in these
proceedings to establish the second prong of the three-prong test that must be
met to establish infringement of a use claim by inducement.
(c) The third prong
of the tri-partite test
[171] The Neuroprotective
Information in Sandoz’s PM also appeared in the PM that Allergan filed with
respect to COMBIGAN. Indeed, the two PMs are virtually identical. That said,
Sandoz deleted from its PM a small number of passages that appeared in
Allergan’s PM, as well as six of the articles in the list of references that
appeared at the back of Allergan’s PM. Sandoz did not offer any explanation of
why, having taken the trouble to delete certain material from Allergan’s PM, it
retained the Neuroprotective Information. In my view, in the absence of such an
explanation, this raises an inference that Sandoz retained the Neuroprotective
Information in its PM for the purposes of influencing ophthalmologists and
pharmacists to prescribe and dispense, respectively, the Generic Drug for the
neuroprotective use claimed by the ‘626 Patent. Based on this inference, I
conclude that the third prong of the aforementioned tri-partite test for
establishing infringement of a use claim by inducement has been established on
a balance of probabilities.
C.
Are
Sandoz’s allegations of non-infringement of the claims in the ‘626 Patent
justified?
[172] Sandoz is
alleging that the Generic Drug will not infringe any of the claims in the ‘626
Patent for the following two reasons:
i.
COMBIGAN
is not approved for a neuroprotective use; and
ii. the Generic
Drug will not be used for neuroprotection.
[173] With respect
to the first of these two arguments, Sandoz noted that Dr. Parkinson admitted
in cross-examination that there is nothing in the PM for COMBIGAN that mentions
neuroprotection in humans. Based on that acknowledgment on behalf of Allergan,
Sandoz submitted that it cannot be “early-working” the purported invention of
the ‘626 Patent, and that it cannot be infringing the “patented invention” of
the ‘626 Patent. It added that this proceeding as it relates to the ‘626 Patent
ought to be dismissed for this reason alone.
[174] I disagree.
As Allergan noted, Sandoz’s position on this point confuses the safety approval
regime under the Regulations with the law set forth in the Patent Act,
RSC 1985, c P-4. An allegation of
non-infringement cannot be justified solely on the basis that the first
person’s PM for the patented product does not mention a particular use of the
product that the second person has admitted is within the scope of the claims
of the patent. In the case at bar, Sandoz’s own construction of the ‘626 Patent
is that it claims “a purported new use of certain compounds, including
brimonidine … ‘to inhibit or prevent nerve cell injury or death … for
protecting the retinal or optic nerve cells in a mammal suffering a noxious
action or at risk of experiencing a noxious action on said nerve cells.’.” The
fact that COMBIGAN is not yet approved for neuroprotection does not mean that
there is no “quid quo pro,” as suggested by Sandoz. The “quid” that Allergan
provided in exchange for the ‘626 Patent was the disclosure of its invention,
which was set forth in the patent. Biolyse Pharma Corporation v Canada (Attorney
General),
2005 SCC 26, [2005] 1 S.C.R. 533, is distinguishable, as “the Biolyse product was
properly treated as an innovator drug rather than a copy-cat drug” (para 34)
and it “was not approved on the basis of bioequivalence with the BMS
product embodying its inventions” (para 54). Moreover, the Biolyse product was
based on paclitaxel that was extracted from a different species of yew than the
paclitaxel that was the subject of BMS’s patents covering new formulations and
methods of administration of the paclitaxel, but not the paclitaxel itself.
[175] Turning to
the allegation that the Generic Drug will not be used for neuroprotection,
Sandoz stated that: (i) COMBIGAN is not approved for use as a neuroprotective
agent, (ii) the Generic Product will not be approved for use as a
neuroprotective agent, (iii) Allergan did not adduce any “infringement
evidence” that provides any support for its contention that patients would
“use” the Generic Product “for neuroprotection,” and (iv) an article published
earlier this year (the “Krupin Article”) can have no relevance to the approved
uses of COMBIGAN and does not support Allergan’s position that patients will
use the Generic Product for neuroprotection.
[176] I am
satisfied that Allergan has demonstrated, on a balance of probabilities, that
this allegation of non-infringement is not justified.
[177] Sandoz’s
arguments regarding the approved uses of COMBIGAN and the proposed uses of the
Generic Product have already been addressed in my reasons above and do not need
to be revisited.
[178] As to the
suggestion that the Krupin Article was not adduced as part of Allergan’s
“infringement evidence,” it was published after Allergan filed that evidence
and was properly put before the Court as an appendix to Dr. Parkinson’s second
affidavit. That affidavit was filed in accordance with Prothonotary Tabib’s
Order regarding the parties’ evidence with respect to validity. Dr.
Parkinson’s affidavit properly addressed the evidence that Sandoz adduced to
support its allegations of invalidity. One of Sandoz’s allegations of
invalidity is an allegation of lack of utility, which is based on some of the
same arguments that Sandoz is advancing to support this particular claim of
non-infringement. Accordingly, I reject the suggestion that the Krupin Article
is not properly before the Court on this non-infringement issue.
[179] The Krupin
Article reported the results of a four-year double-masked, randomized,
multicenter clinical trial of the efficacy of monotherapy with brimonidine
(0.2%) versus timolol (0.5%) eyedrops in preventing or delaying visual field
progression in patients with low-pressure glaucoma. In his affidavit, Dr.
Parkinson stated that the ophthalmic community had been awaiting the results of
this study, because it was designed to be large enough to address the concerns
that had been identified by Ms. Meredith Saylor in an article published in
April 2009. The latter article (the “Saylor Article”) reported on the research
that had been performed to date, but did not discuss any new research.
[180] Dr. Parkinson
observed that, by limiting their study to patients with low-pressure glaucoma,
the authors of the Krupin Article (collectively, “Krupin”) were able to
separate the effect of lowering high IOP from the neuroprotective effect of
brimonidine. He also noted that, by comparing brimonidine with timolol, which
has a similar IOP lowering effect as brimonidine, Krupin was able to measure
the neuroprotective effect of brimonidine that is separate from any benefit
that may have been achieved by a reduction of IOP in patients with normal IOP.
[181] The Krupin
Article described the results of the study in the following terms:
In summary, in this randomized clinical
trial, twice-daily treatment with topical brimonidine tartrate 0.2% preserves
visual field better than treatment with topical timolol maleate 0.5% in a
subset of open-angle glaucoma patients with statistically normal IOP. Given the
similar IOP-lowering efficacy of the 2 compounds, this finding is consistent
with a non-IOP related mechanism of action favoring brimonidine-treated
patients. The effectiveness of brimonidine in delaying or preventing visual field
progression has to be judged in context of brimonidine’s adverse event profile,
primarily localized external ocular allergy. Validation of a neuroprotective
mechanism of action requires additional basic science and clinical research to
confirm the present results prior to altering current clinical patient care
paradigms. (Emphasis added.)
[182] Dr. Parkinson
stated in his affidavit that the Krupin study “demonstrates that the topical
administration of brimonidine to patients has a neuroprotective effect by a
mechanism unrelated to the effect of brimonidine on IOP.” He proceeded to add:
[I]t is my opinion that brimonidine is
useful as a neuroprotective agent. Brimonidine protects the retinal or optic
nerve cells in a mammal suffering a noxious action or at risk of experiencing a
noxious action. Brimonidine inhibits and prevents nerve cell injury or death.
Dr. Jampel’s statements to the contrary are not correct.
[183] When it was
suggested to him, during cross-examination, that “the best current knowledge is
that it has not yet been proven that brimonidine has a neuroprotective effect,”
Dr. Parkinson said he “totally” disagreed. When further pressed, he stated:
“[t]he word confirm there is very, very potent and very important.”
(Emphasis added.) He elaborated as follows: “I read that as [saying] that
they’re just encouraging others to corroborate their results, as any good
researcher should and would do.” He rejected the suggestion that the conclusion
of the Krupin Article should be interpreted as suggesting that “maybe it’s not
true” that brimonidine has a neuroprotective effect in humans. He also
characterized the results of the Krupin study as being “very positive,” and
observed that “[t]here never stops being a question in medicine.”
[184] Elsewhere
during his cross-examination, Dr. Parkinson was asked what he was relying upon
to support his statement that brimonidine is a neuroprotective agent that is
administered by eyedrops today. He replied: “I’m relying on the [COMBIGAN]
product monograph as well as the Krupin paper as well as my clinical
experience.”
[185] When asked,
during re-examination, how his clinical experience influenced his view that the
Generic Product would be used for neuroprotection, Dr. Parkinson stated that
his clinical experience is often one of the most important considerations for
him. In this regard, he stated:
[My clinical experience] is that when all
else fails and we’ve got the [IOP] at an extremely low level and there is still
progression, that in some patients, and it’s not all, but in some patients,
having that patient exposed to … [brimonidine] seems to give them the benefit,
and enhanced stability.
[186] Dr. Parkinson
proceeded to state that one of the reasons why he and some of his colleagues
were so happy to see the results of the Krupin study is that brimonidine is “a
tool that we use in patients who are losing vision in spite of very low eye
pressure” (emphasis added).
[187] Dr. Parkinson
was also asked to comment on the acknowledgment at page 8 of the Krupin Article
that “it remains possible that another, not yet described timolol or
brimonidine-related vascular (or other) phenomenon could account for the
results of the present study.” He replied as follows:
To me, reading this as a clinician, this
-- personally, that gives me sort of -- allows me to give more credence to this
article because they say that. Because, of course, as I said in the past, this
is just one article. The results show that there is certainly an effect,
but they are – they’re wise enough -- I'm going to use that word -- to say
look, you know, we always have to be on the lookout for other effects, and
let's not discount that. So I respect that. (Emphasis added.)
[188] Dr. Jampel’s
affidavit was written before he had seen the Krupin Article. At paragraph 87 of
his affidavit, Dr. Jampel stated:
Topical administration of brimonidine
does not do what the 626 patent promises - topical brimonidine does not protect
the retinal or optic nerve cells in humans. Topical application of brimonidine
does not confer the neuroprotection promised by the 66 patent.
[189] In cross-examination,
Dr. Jampel was asked whether he would concede, now that he had seen the results
of the Krupin study, that he may not have been correct to assert unequivocally
in his affidavit that brimonidine does not have a neuroprotective effect. He
replied: “I would not write that today.”
[190] Dr. Jampel
also conceded that the design of the Krupin study “seemed acceptable” and that
it passed peer review. That said, he maintained that “this study presents some
highly aberrant results that need to be explained.” In this regard, he referred
to “the absence of an [IOP] lowering effect of either the brimonidine or the
timolol.” He questioned that particular result of the study because
ophthalmologists have prescribed brimonidine and timolol to a large number of
patients for the purpose of lowering eye pressure. That said, he acknowledged
that the Krupin study is “suggestive” of a neuroprotective effect.
[191] On balance, I
prefer Dr. Parkinson’s evidence on this issue of whether the Generic Drug is
likely to be used for neuroprotection. In my view, Dr. Parkinson stood up very
well to his cross-examination. His testimony was very credible and more
persuasive than Dr. Jampel’s. I believe him when he stated that he and other
ophthalmologists do in fact prescribe brimonidine for neuroprotection. His
testimony on this point had an “air of reality” to it, which was reinforced by
the following response that Dr. Parkinson gave earlier in his
cross-examination. When pressed about why an ophthalmologist would prescribe
brimonidine for neuroprotection on the basis of the animal data reported in the
Lai Article, he replied:
Sometimes you do things in medicine to
help patients and to help patients on an individual basis, and that’s how you
treat patients, one patient at a time. And with, specifically, this topic, neuroprotection,
in a horrible disease like glaucoma where we don’t have an agent other than
this drug that can strengthen an optic nerve, we are treating a disease by
lowering eye pressure. This is our only other treatments for glaucoma.
So when patients are worsening or they’re
-- or you see their vision failing, you may do things that as long as they’re
doing no harm to the patient, you may do them. And if you see effects
clinically that possibly are backed up by animal studies, you're going to
continue to do them because that's what's right for the patient. And that's how
medicine is practiced, sir.
[192] Based on all
of the foregoing, I conclude that Allergan has met its burden of demonstrating,
on a balance of probabilities, that Sandoz’s allegations of non-infringement of
the ‘626 Patent are not justified.
D. Sandoz’s allegations of invalidity
of the ‘626 Patent
[193] Sandoz
alleges that the ‘626 Patent is invalid for inutility, on the basis that:
i.
the
claims therein cover non-useful subject matter; and
ii. the utility
of that subject matter could not be soundly predicted as of the priority date
and the Canadian filing date of the ‘626 Patent.
(a)
The Utility of the subject matter of the ‘626 Patent
[194] Some of the
evidence regarding the utility of the subject matter of the ‘626 Patent was
discussed in the immediately preceding section above. It is not necessary to
repeat that evidence in connection with the issue of utility. I will simply
discuss the additional evidence that is relevant to my assessment of that
issue.
[195] In his
affidavit, Dr. Jampel referred to a number of studies that were reported upon
in the Saylor Article, for the purpose of supporting his opinion that the
topical application of brimonidine does not confer the neuroprotection promised
by the ‘626 Patent.
[196] The Saylor
Article was published in April 2009, and reviewed the evidence that existed at
that time with respect to the neuroprotective qualities of brimonidine in optic
nerve and retina injury. It did not report on any new research.
[197] At the outset
of that article, it was noted that “recent experimental and animal models
suggest a neuroprotective effect of brimonidine.” It was observed that “[t]hese
investigations indicate that [brimonidine] might have therapeutic effects if
used clinically to treat optic neuropathies in humans.” Later in the article,
the authors stated: “[s]everal
experimental animal models demonstrated the neuroprotective effects of
topically and systemically administered brimonidine in reducing the effects of
optic nerve injury …”
[198] However,
after reviewing the reports of various clinical trials that had been conducted
to assess brimonidine as a potential treatment in humans, the authors concluded
that “the achievements in animal models regarding the neuroprotective effects
of brimonidine in treating ischemic optic nerve injury have not translated into
effective clinical applications.”
[199] In his
affidavit, Dr. Jampel noted that some of the clinical trials reviewed in the Saylor
Article related to brimonidine as a potential treatment for nonarteritic
anterior ischemic optic neuropathy (NAION), which is a condition thought to be
caused by an acute impairment of the blood supply to the optic nerve. Dr.
Jampel observed that the Saylor Article reported that those trials suggest that
brimonidine treatment has failed to demonstrate neuroprotective efficacy in
humans. Dr. Jampel made a similar observation with respect to certain clinical
trials involving other optic neuropathy conditions, which were reported upon in
the Saylor Article. In addition, he noted that in a more recent review (the
“Chau Article”), the authors reported a similar finding with respect to their
study of brimonidine as a neuroprotective in three small human clinical trials.
[200] In addition
to the foregoing, Dr. Jampel stated in his affidavit that “[t]opical
administration is not identified as a route of administration for the
neuroprotective agents of the 626 Patent.” In support of this opinion, Dr.
Jampel noted that, under the heading Summary of the Invention, the ‘626
Patent describes the new method for protecting the optic nerve and retina of
the mammalian eye, as comprising “administering to the mammal either
systemically or by intrabulbar injection an effective amount” of brimonidine.
He added that “[t]here is nothing in the 626 Patent to indicate that the
inventors considered topical administration of brimonidine to be a method of
administration that confers the purported neuroprotective effects.”
[201] In replying
to Dr. Jampel, Dr. Parkinson noted (in his second affidavit) that, when Dr.
Jampel discussed what the Saylor Article had to say about the aforementioned
clinical trials regarding NAION, he omitted to note the following passage that
immediately preceded the passage to which he referred:
Even in the absence of controlled
clinical trials, physicians prescribed brimonidine and α agonists as
treatment for NAION. This perhaps stems from the substantial experimental
evidence demonstrating the efficacy of brimonidine as a neuroprotective agent
in animal models of ischemia.
[202] Dr. Parkinson
added that this observation is consistent with the practice of Canadian
ophthalmologists, who do in fact prescribed brimonidine for patients for the
treatment of NAION. In this regard, he stated: “I have personally prescribed
brimonidine for the treatment of NAION. In my experience, brimonidine has
helped to stabilize my patients after the initial insult and has prevented some
degree of vision loss that might otherwise have occurred.”
[203] In addition,
Dr. Parkinson noted that the Saylor article reported that, in a 2006 study by
Wilhelm and others, “[t]here seemed to be a slight nonsignificant improvement
in visual fields for the treatment group compared with the control group.” He
further noted that the Saylor Article observed that the results of that study
were inconclusive. With respect to Leber hereditary optic neuropathy, he
observed that the Saylor Article reported that “a non-significant trend was
found, suggesting slower progression of visual field loss in eyes treated with
topical brimonidine (0.2%).” He stated that this suggests that brimonidine is
effective at treating Leber hereditary optic neuropathy, although he
acknowledged that the results of the study are not statistically significant
because only 17 patients were used in the study. He added: “far from reporting
that brimonidine is not effective, Ms. Saylor’s conclusion is that additional
studies are required (but may be difficult to construct).” Despite the
limitations of the studies reviewed in the Saylor Article, he repeated that
brimonidine has been administered to patients for the treatment of NAION, as
well as for Leber hereditary optic neuropathy.
[204] In
cross-examination, Dr. Parkinson conceded that, as of April 2009, when the
Saylor Article was published, the utility of brimonidine as a neuroprotective
agent “was a question mark.” He also agreed that the Saylor Article would be
another piece of evidence that the POSITA would use in determining whether or
not brimonidine has any neuroprotective effects in humans. When asked if he
would agree that the Krupin study is no more than one piece of evidence, he
replied that its significance should not be minimized in that way, because one
has to look at the study’s methods, its results, and how the patients and the
data were treated. He added: “what’s most important in this is you have to
decide if it -- if it makes sense and if it jibes with your clinical
impression, making very -- making sure not to unfairly bias the paper in either
way.”
[205] With respect
to whether the ‘626 Patent includes topical administration of
brimonidine within its scope, Dr. Parkinson made several observations. First,
he noted that Sandoz made no allegation in its NOA that topical administration
of brimonidine is not within the claims of the ‘626 Patent. However, I am
satisfied that this allegation was indeed made in paragraph 96 of the NOA,
which states: “With respect to claims 7-9, 11, 27-29 and 31, Sandoz
additionally does not infringe these claims as Sandoz Brimonidine/Timolol will
be administered as an eye-drop solution. Sandoz Brimonidine/Timolol will not be
administered orally, intramuscularly, or by intrabulbar injection in the eye.”
[206] Dr. Parkinson
then disagreed with Dr. Jampel’s position on this point. In this regard, he
observed that there is no limiting language about the route of administration
in any of claims 1, 2, 14, 20 or 21 of the ‘626 Patent. He added: “The POSITA
reading the ‘626 Patent as of the day it was published (January 16, 1997) would
understand that the inventors did not exclude the topical administration of
brimonidine from the claims in that the topical administration was a possible
route of administration for the invention claimed” in the aforementioned
claims. In addition, he noted that at pages 2 and 3 of the ‘626 Patent, the inventors
discussed a study that showed brimonidine to be effective in reducing
intraocular pressure in rabbits, cats and monkeys after topical administration
to the eye. He further supported his position by observing that (i) the patent
states that the mode of administration and the dosage regimen is left to the
judgment of the treating physician, and (ii) the patent specifically states
that “[c]onventional modes of administration and standard dosage regimens of
protective agents … can be used”, and (iii) the “POSITA would have been well
aware that topical administration was a conventional mode of administering
ophthalmic drugs as of January 16, 1997.”
[207] After
carefully considering all of the foregoing, including the information discussed
in Part IV.C above, I find Dr. Parkinson’s evidence to be more credible and
persuasive than Dr. Jampel’s evidence on the issue of whether Sandoz’s
allegation that brimonidine is not useful for neuroprotection is justified. I
accept Dr. Parkinson’s testimony that (i) he and other ophthalmologists do in
fact prescribe brimonidine for neural protection for the treatment of NAION,
Leber hereditary optic neuropathy and glaucoma, and (ii) the Krupin study “demonstrates
that the topical administration of brimonidine to patients has a neuroprotective
effect by a mechanism unrelated to the effect of brimonidine on IOP.”
[208] Based on Dr.
Parkinson’s evidence and the Krupin study, I am satisfied that Allergan has met
its burden of demonstrating, on a balance of probabilities, that this allegation
made by Sandoz is not justified.
[209] Contrary to
Sandoz’s position, Allergan is not required to unequivocally demonstrate that
topically applied brimonidine has no neuroprotective effect. It is sufficient
for Allergan to demonstrate, on a balance of probabilities, that there is at
least a “mere scintilla” of utility (Eli Lilly, above, at para 76). In
my view, Allergan has more than met its burden in this regard.
(b) Was
the subject matter of the ‘626 Patent soundly predicted?
[210] In its
written submissions in this proceeding, Sandoz asserted that the animal testing
disclosed in the ‘626 Patent did not provide a sufficient basis for the alleged
inventors of that patent to soundly predict that the topical application of the
test compounds, let alone brimonidine, would have any neuroprotective effect in
humans. Sandoz added that the ‘626 Patent fails to disclose any articulable and
sound line of reasoning for such a prediction.
[211] In support of
its assertions, Sandoz noted that the two examples discussed in the ‘626 Patent
involved an in vitro test using cultures from nerves of a portion of rat
brains, and an in vivo test in which live rats were subjected to
dissection of the optic nerve that was then injured. Sandoz further noted that
the test compounds did not include brimonidine and were injected
intraperitoneally (into the abdomen). Sandoz also repeated that there was no
topical administration specifically mentioned anywhere in the ‘626 Patent, and
no examples provided involving the administration of any compounds to humans or
testing using human cells.
[212] Allergan
began its reply to the foregoing by noting that Sandoz did not allege in its
NOA that the inventors named in the ‘626 Patent did not have any basis to
predict that topically administered brimonidine would be neuroprotective in
humans. Allergan took the position that this allegation by Sandoz should
therefore not be considered in this proceeding.
[213] I agree.
Sandoz’s allegations with respect to a lack of sound prediction of the subject
matter of the ‘626 Patent were contained in the following three paragraphs of
its NOA:
135. In addition to only testing one
known compound, the patentee only tested two different types of methods that
create the alleged "injury" to the optical nerve cells: glutamate
toxicity, and "a nerve crush model of mechanical injury" (page 9,
line 1). However the patentee claims that Formula I compounds protect from any
"noxious action" (claims 1, 2 and 20, 21 and claims dependent
therefrom). Further, the patentee fails to disclose that any of the particular
claimed "noxious actions" (at claims 3-6; 15-19; 22-26) create
optical nerve damage that is in any way similar to the damage created by
putting a toxicity, or mechanical nerve crush.
136. For example, it was understood
that glutamate may result in one mode of cell injury and glaucoma (Quigley,
1995). The patentee has failed to demonstrate that all noxious actions will
create a similar mode of cell injury.
137. The
claims are therefore invalid as covering subject matter whose utility could not
be soundly predicted as of the priority date, and also the Canadian filing date
of the 626 patent (in the event the court determines the filing date to be the
relevant date, which Sandoz alleges is not the correct date).
[214] In my view,
it is readily apparent from the foregoing quoted text that Sandoz did not make
any allegation with respect to whether the disclosure in the ‘626 Patent
provided a basis to soundly predict that topically administered brimonidine
would be neuroprotective in humans. Accordingly, Sandoz is precluded from
raising this argument in the current proceeding.
[215] In the event
that I am found to have erred in reaching this conclusion, I will proceed below
to address Sandoz’s position on its merits.
[216] The doctrine
of sound prediction has three components, namely:
i.
there
must be a factual basis for the prediction;
ii. at the filing
date of the patent application, the inventor must have had an articulable
iii. and sound line of reasoning
from which the desired result can be inferred from the
factual basis; and
iv. there must be
proper disclosure.
(See: Apotex Inc v Wellcome Foundation Ltd,
[2002] 4 S.C.R. 153, at para 70 [Wellcome].)
[217] In Sanofi,
the Supreme Court confirmed that a sound prediction does not require certainty
and that there is a “public-interest in early disclosure of new and useful
inventions even before their utility has been fully verified by tests” (Sanofi,
above, at para 105). However, more than “a lucky guess or mere speculation” is
required (Wellcome, at para 69). In short, “a sound prediction requires
a prima facie reasonable inference of utility” (Eli Lilly, above,
at para 85).
[218] Dr. Jampel's
opinion that the disclosure in the ‘626 Patent did not provide the POSITA with
the basis to soundly predict that topically administered brimonidine would have
a neuroprotective effect in humans was based on three considerations. First,
the test compounds used in the in vivo study disclosed in Example 2 of
the patent were injected into the abdomen of the rats, rather than topically
administered into the rats’ eyes. Second, there is no discussion of topical
administration of any compound in the patent. Third, prior to June 1996, there
had been no demonstration of brimonidine or any other agent providing
neuroprotection in humans, and the animal testing reported in the ‘626 Patent
“was not sufficient to show the topical application of the test compounds, let
alone brimonidine, had any neuroprotective effects.”
[219] For the
reasons previously discussed, I accept Dr. Parkinson’s opinion that the topical
administration of brimonidine was contemplated by, and is within the scope of,
the ‘626 Patent. I also accept Dr. Parkinson’s evidence that a drug which
enters the eye reaches the retinal or optic nerve cells in one of two ways,
namely, (i) through the systemic blood circulation system, which brings a
topically administered drug to the eye in the same way as a drug administered
via injection, and (ii) diffusion inside the eye. Both Dr. Jampel and Dr. Mitra
agreed with this evidence. Dr. Jampel further agreed that the POSITA would have
been aware of this systemic affect of brimonidine in 1995. Taken together, the
foregoing negates the first two of the considerations relied upon by Dr. Jampel
in reaching his opinion.
[220] Therefore,
the key question that remains is whether the ‘626 Patent disclosed the factual
basis on which a POSITA could soundly predict in June 1996 that the topical
administration of brimonidine would have a neuroprotective effect in humans,
once the invention was reduced to practice (Merck & Co Inc v Apotex
Inc., 2010 FC 1265, at para 521 [Merck (2010 FC 1265)]).
[221] In Wellcome,
the factual basis for the sound prediction of a new use compound rested upon
the results of an in vitro test of AZT against the HIV in a human cell
line along with the inventor’s data on AZT, including animal tests. The line of
reasoning was found to be the inventor’s knowledge of the mechanism for
reproduction of a retrovirus (Wellcome, above, at para 72; Eli Lilly,
above, at para 85).
[222] Likewise, in
the case at bar, the factual basis for the sound prediction was provided by the
two examples with corresponding data that were disclosed in the ‘626 Patent. Notwithstanding
the fact that the experiments did not involve human cells, Dr. Parkinson relied
on the affirmative findings of a neuroprotective activity in rats to conclude
that “[t]he POSITA would understand that the data disclosed made it highly
likely that brimonidine would have some level of efficacy as a neuroprotective
agent in humans.” I found this evidence to be more persuasive and credible than
Dr. Jampel’s opinion on this point.
[223] In my view,
this line of reasoning, which was also disclosed in the ‘626 Patent, is prima
facie reasonable and entirely sound, particularly given that the test
compounds made their way to the rats’ eyes through the bloodstream, a fact that
was not contested. In short, it was known that, when brimonidine is topically
administered, some of it enters the systemic bloodstream. The experiments
disclosed in the patent demonstrated that, when introduced into the systemic
bloodstream, the compounds of Formula 1, which include brimonidine, reached the
rats’ eyes and provided a neuroprotective effect on the rats’ optic nerves.
Finally, Dr. Parkinson provided persuasive expert evidence that a POSITA would
understand from the results of those experiments that it was highly likely that
brimonidine would have some level of efficacy as a neuroprotective agent in
humans. In addition, Dr. Parkinson’s evidence that physicians often use animal
data as a basis upon which to treat their patients was not contradicted.
[224] My conclusion
in this regard is reinforced by (i) the fact that Dr. Jampel conceded in
cross-examination that the experiments disclosed in the ‘626 Patent
demonstrated that brimonidine did in fact have a neuroprotective effect in
rats, and (ii) one of the studies disclosed in the ‘626 Patent was an in
vivo study involving the optic nerves of a mammal. In this latter regard,
Sandoz did not dispute Allergan’s contentions that (i) in vivo animal
studies can often provide a much more sound basis upon which to predict an
effect in humans, than in vitro studies involving human cells, and (ii) in
vivo animal studies have been found to provide a sufficient basis upon
which to soundly predict a particular effect on humans (see, for example, Pfizer
Canada Inc v Canada (Minister of Health), 2007 FCA 209, at para 153,
another case that involved in vivo rat studies). Indeed, in vitro
animal studies have also been found to be sufficient in this regard (see, e.g.,
Merck (2010 FC 1265), above, at paras 506-511).
[225] I am also
satisfied that the disclosure in the ‘626 Patent is sufficiently fulsome and
clear. I note that the parties did not make any specific representations on
this third requirement of the doctrine of sound prediction.
[226] Based on the
foregoing, I have no hesitation in concluding that Allergan has satisfied its
burden of demonstrating, on a balance of probabilities, that Sandoz’s
allegation that the ‘626 Patent did not soundly predict that the topical
administration of brimonidine would have a neuroprotective effect in humans is
not justified.
V. Conclusion
and Disposition
[227] For the
reasons set forth above, I have concluded that Allergan has demonstrated, on a
balance of probabilities, that Sandoz’s allegations with respect to the
invalidity of the ‘764 Patent and the invalidity of the ‘626 Patent are not
justified.
[228] With respect
to infringement of the ‘626 Patent, I have concluded that Allergan has failed
to demonstrate that Sandoz’s PM for the Generic Product is likely to induce
infringement of the ‘626 Patent. However, in the event that I am found to have
erred in reaching this conclusion, I have concluded that Allergan has met its
burden of demonstrating, on a balance of probabilities, that Sandoz’s other
allegations of non-infringement are not justified.
JUDGMENT
THIS COURT’S ORDERS
AND AJUDGES that:
1. This
application is granted in part, with costs.
2. Pursuant
to subsection 6(2) of the Regulations, the Minister is prohibited from
issuing a Notice of Compliance to Sandoz in respect of the drug described in
Sandoz’s Product Monograph dated October 7, 2009 (Sandoz Brimonidine/Timolol)
until after the expiry of Canadian Letters Patent No. 2,440,764.
3. Allergan’s
application for a prohibition order, until the expiry of Canadian Letters
Patent No. 2,225,626, is dismissed.
“Paul S. Crampton”
.FEDERAL COURT
SOLICITORS OF RECORD
DOCKET: T-154-10
STYLE OF CAUSE: Allergan
Inc. et al v the Minister of Health et al
PLACE OF HEARING: Toronto, Ontario
DATE OF HEARING: October
17, 18, 19 and 20, 2011
REASONS FOR JUDGMENT
AND JUDGMENT: CRAMPTON J.
DATED: November
17, 2011
APPEARANCES:
Andrew J. Reddon
Steven G. Mason
Steven Tanner
|
FOR THE APPLICANTS
|
David Rieve
Angela Furlanetto
Ryan Evans
|
FOR THE RESPONDENT
SANDOZ CANADA INC.
|
SOLICITORS OF RECORD:
Andrew J. Reddon
Steven G. Mason
Steven Tanner
|
FOR THE APPLICANTS
|
Myles J. Kirvan
Deputy Attorney General of Canada
David Rieve
Angela Furlanetto
Ryan Evans
|
FOR THE RESPONDENT
THE MINISTER OF HEALTH
FOR THE RESPONDENT
SANDOZ CANADA INC.
|