[1]
The applicants H. Lundbeck A/S and Lundbeck
Canada Inc. (collectively Lundbeck) are seeking an order under
section 6 of the Patented Medicines (Notice of Compliance)
Regulations, SOR/1993-133 (Regulations) prohibiting the
Minister of Health (the Minister) from issuing a Notice of
compliance (NOC) to the respondent Apotex Inc. (Apotex) in
respect of 20 mg and 40 mg tablets of citalopram
hydrobromide (citalopram) until after the expiration of Canadian
Patent No. 2,049,368 ('368 Patent).
[2]
Before any new drug is marketed and sold in
Canada it must receive the approval of the Minister. It
must meet certain safety and other standards pursuant to the
Food and Drugs Act, R.S.C. 1985, c. F-27 and its
regulations. A NOC is only issued once those standards are
met (Food and Drug Regulations, C.R.C. c. 870, Division 8,
Part C (1978)). In conjunction with and as part of its new
drug submission, each manufacturer must submit a proposed product
monograph which sets out the proposed uses to which the product
may be put once approved by the Minister. The Minister will
not approve a product for a particular use unless the submitting
drug manufacturer has sought approval for that use. Once
approved, a final product monograph is issued by the Minister as
part of the NOC documents.
[3]
A drug manufacturer who holds a patent on a drug,
and who has been issued a NOC for the drug, can file a patent
list with the Minister in respect of that drug. This patent
list appears on a register maintained by the Minister (the
Register). There are no connections between the use
specified in the NOC and the use appearing on the patent
list. When a manufacturer applies for a NOC with respect to
a drug that is either compared or referenced to a patented drug
(which appears on the Register) it must support its application
with an allegation that the listed drug will not be
infringed. The Notice of allegation (NOA) must be served on
the patent holder. The latter then has 45 days to
challenge the NOA and apply for an order from the Federal Court
prohibiting the Minister from issuing the NOC (Regulations,
sections 3 to 5). By commencing a prohibition application
in response to a NOA, the applicant obtains a remedy which is
tantamount to a presumptive interlocutory injunction not
available to any other class of patentees (Apotex Inc. v.
Canada (Attorney General) (2000), 6 C.P.R. (4th)
165 at 178 (F.C.A.); Merck Frosst Canada Inc. v. Canada
(Minister of National Health and Welfare) (1998), 80 C.P.R.
(3d) 368 at para. 33 (S.C.C.); Merck Frosst Canada Inc. v.
Apotex Inc. (1977), 72 C.P.R. (3d) 170 at pp. 175-77
(F.C.A.); and Bayer AG v. Canada (Minister of National Health
and Welfare) (1993), 51 C.P.R. (3d) 329 at 337
(F.C.A.)).
[4]
Under paragraph 6(1) of the Regulations, the
burden of proof lies on the applicant. This burden is a
difficult one since the latter must disprove some or all of the
allegations made which, if left unchallenged, would allow the
Minister to issue an NOC. Therefore, the Court should start
from the proposition that the allegations of fact in the NOA are
true except to the extent that the contrary has been shown by the
applicant. The respondent is under no obligation to file
any evidence. Therefore, the applicant cannot expect to
make its case "out of the mouth of the respondent" (Merck
Frosst Canada Inc. v. Canada (Minister of National Health
and Welfare) (1994), 55 C.P.R. (3d) 302 at 320
(F.C.A.)). Moreover, the applicant is limited to the
grounds it has asserted in its Notice of application for
discharging its burden of establishing, on a balance of
probabilities, that the respondent's allegation of
non-infringement is not justified. (Merck Frosst Canada
Inc. v. Canada (Minister of National Health and Welfare),
supra, at 319 (F.C.A), aff'd (1994), 75 F.T.R. 97 (T.D.);
Hoffman-La Roche Ltd. v. Canada Minister of National Health
and Welfare (1996) 70 C.P.R. (3d) 206 (F.C.A.); SmithKline
Beecham Inc. v. Apotex Inc. (1999), 1 C.P.R. (4th)
99 at 111 (F.C.T.D.), aff'd. [2001] F.C.J. No. 3 (F.C.A.) (QL);
Abbott Laboratories, Ltd. v. Nu-Pharm Inc. (1998), 83
C.P.R. (3d) 441 at 445 (F.C.A.); and Pharmacia Inc. v. Canada
(Minister of National Health and Welfare) (1995), 60 C.P.R.
(3d) 328 at pp. 339-343 (F.C.T.D.), aff'd 64 C.P.R. (3d) 450
(F.C.A.)).
[5]
Furthermore, the proceedings contemplated by the
Regulations are not designed to address or consider speculative
suggestions about what might happen in the future. The
process envisions a summary proceeding whereby a patent owner may
deal with a specific assertion that the respondent will not
presently infringe its patent by making, using, and selling the
drug in question (Zeneca Pharma Inc. v. Canada (Minister of
National Health and Welfare) (1996), 69 C.P.R. (3d) 451 at
453 (F.C.A.); Pharmacia Inc. v. Canada (1994) 58 C.P.R.
(3d) 209 at 217 (F.C.A.); and Merck Frosst Canada Inc. v.
Canada (1994), 55 C.P.R. (3d) 302 at 320
(F.C.A.).
[6]
At issue in this case is H. Lundbeck A/S '368
Patent relating to citalopram.
[7]
H. Lundbeck A/S is a pharmaceutical company that
focusses solely on the treatment of central nervous system
problems. Lundbeck Canada Inc. is the Canadian subsidiary
of H. Lundbeck A/S of Denmark. Apotex is a Canadian generic
pharmaceutical manufacturer seeking the issuance of a NOC from
the Minister for the manufacturing and selling of citalopram
tablets, for use in the treatment of depression, a prior art
use.
[8]
On August 16, 1991, H. Lundbeck A/S
filed an application for the '368 Patent entitled Treatment of
Cerebro-Vascular Disorders. The patent was granted on
October 23, 2001, and will expire on August 16, 2011.
It was listed on the Register on November 29, 2001.
The '368 Patent covers the use of citalopram for the manufacture
of a medicament for the treatment of cognitive disorders or
amnesia associated with dementia and cerebro-vascular disorders
(CVD). The '368 Patent also covers a pharmaceutical
composition for the treatment of dementia or CVD comprising
citalopram (the claimed uses).
[9]
Claims 1 and 8 are relevant for this proceeding
and read as follows:
1. Use of [citalopram] or a
pharmaceutically-acceptable acid addition salt thereof, for
the manufacture of a medicament for the treatment of cognitive
disorders or amnesia associated with dementia and of
cerebrovascular disorders.
8. A pharmaceutical composition or
medicament for the treatment of dementia and cerebrovascular
disorders comprising an amount of [citalopram] or a
pharmaceutically-acceptable acid addition salt thereof,
which is effective for such purpose, and a
pharmaceutically-acceptable diluent or carrier.
[10]
On December 17, 2001, Lundbeck received a NOA
from Apotex whereby the latter claims no infringement to the '368
Patent. As for the legal and factual basis for the said
allegation, Apotex asserts that its product is not intended for
any of the claimed uses. More particularly, Apotex will not
seek approval for its product for any such uses that would be
included in the citalopram product monograph. Apotex
further asserts that the only use that will be included in
Apotex' product monograph will be use for the treatment of
depression, a use well known and documented in the prior art (the
unclaimed use).
[11]
On January 28, 2002, alleging that claims 1 and 8
will be infringed, Lundbeck applied for an order in accordance
with paragraph 6(1) of the Regulations prohibiting the Minister
from issuing a NOC to Apotex in respect of 20 mg and 40 mg
tablets of citalopram until after the expiration of the '368
Patent. Lundbeck has subsequently filed three affidavits,
namely, the affidavits of Jeff MacLean, President and General
Manager of Lundbeck Canada Inc., Dr. Kiran Rabheru, a
geriatric psychiatrist, and Dr. Serge Gauthier, a
neurologist. By their training, attested to by their
resumes, and considering that their qualifications as experts
were not challenged, Dr. Serge Gauthier and Dr. Kiran
Rabheru qualify as expert witnesses.
[12]
The facts are relatively simple. The '368
Patent contains a specific description of the drug, and a list of
21 claims. The novelty element in '368 Patent is the use of
citalopram to treat dementia and CVD (the claimed uses).
Citalopram is already known as an anti-depressant, as the patent
itself states. In this case, it is undisputed that Apotex
intends to manufacture and sell a drug containing
citalopram.
[13]
Citalopram is part of a class of pharmaceutical
drugs called "selective serotonin reuptake inhibitors" (SSRI), a
type of drug which has shown itself very useful in the treatment
of depression and depressive illness. SSRI acts on the
serotonic system, generally linked to mood, feelings of
well-being, anxiety, and such. At the present time,
Lundbeck is the only manufacturer of citalopram in Canada allowed
to sell the product, which is marketed under the registered brand
name Celexa®. Lundeck obtained a NOC for its product in
tablets of 10 mg, 20 mg and 40 mg in February 1999.
The NOC issued by the Department of Health specifies that
Celexa® is to be used for the symptomatic relief of
depressive illness. However, the NOC does not cover the
uses of Celexa® claimed in the '368 Patent (i.e., treatment
of senile dementia, CVD or any other disorder named in the patent
claims).
[14]
According to the specifications of the '368
Patent, senile dementia may be "senile dementia of any genesis
such as neurodegenerative, traumatic, cerebrovascular, anoxic,
etc., i.e. dementia of Alzheimer's type, multi-infarct dementia,
or vascular dementia, etc.", while CVD are "brain damages caused
by cerebral infraction, cerebral hemorrhage, cerebral
arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis,
cerebral embolism, or the like, e.g. ischemia, and the
psychological and neurological sequel of such
damages".
[15]
In their affidavits, both Dr. Rabheru and
Dr. Gauthier state that there are patients affected by both
depressive illness and cognitive impairment due to dementia or
CVD. According to Dr. Rabheru:
The relationship between depression and
cognitive impairment is complex (1,2). A major depressive
episode may precede the clinical manifestations of an
irreversible dementia (3). Conversely depressive syndrome
is common during the early stages of an established dementia
(4). In Alzheimer's patients having dementia, major
depression may occur in 15% of patients and less severe syndromes
in 30%-40% of the demented population (5). Depression has
been found to occur in approximately 25 % of patients with
cerebrovascular disease (6) and 30-60% of stroke patients
experience depression within 24 months of having a stroke
(7). Thus, there is a clear overlap of patients being
afflicted with both depressive illness and cognitive impairment
due to dementia and/or cerebrovascular disorders.
(My emphasis)
[16]
Dr. Gauthier agrees:
There is a wide range of prevalence figures in
the published literature, but there is consensus that depression
is more common in demented patients than the general population
(Table 1) below.
[17]
He also concludes:
There are sufficient data and biological
plausibility to support a broader action of citalopram as an
antidementia drug, above and beyond its original use as
antidepressant.
(My emphasis)
[18]
In view of the above evidence, Lundbeck argues
that Apotex will directly infringe claims 1 and 8 of '368
Patent. In this regard, Lundbeck submits that whether or
not Apotex intends to manufacture and sell its tablets for the
patented uses is irrelevant. Accordingly, Lundbeck submits that
infringement does not depend upon what Apotex intends to do but
upon what it actually does. Since citalopram treats both
depression and dementia or CVD, and since there is an overlap of
patients affected with both depression and dementia or CVD, there
will be direct infringement if a NOC were issued to Apotex.
(AB Hassle v. Canada (Minister of National Health and
Welfare) (2000), 9 C.P.R. (4th) 79 (F.C.T.D.) at
87; AB Hassle v. RhoxalPharma Inc., [2002] F.C.J. No. 1083
(T.D.) (QL); Zeneca Pharma Inc. v. Apotex Inc. (1995), 61
C.P.R. (3d) 190 (F.C.T.D.), rev'd on other grounds (1996), 69
C.P.R. (3d) 451 (F.C.A.); Computalog Ltd. v. Comtech Logging
Ltd. (1992), 44 C.P.R. (3d) 77 at 88 (F.C.A.)).
[19]
Apotex reiterates that it is not seeking approval
for any use specific in the patent nor will it be included in
their product monograph. The only use that will be included
in their product monograph will be the treatment of depression,
which was a prior art use. Adopting the position that
Lundbeck's evidence does not support a conclusion of direct
infringement, Apotex has chosen not to produce any evidence nor
to cross-examine the affiants of Lundbeck. Since the
allegations of fact in the NOA are to be considered true, except
to the extent that the contrary has been shown by the applicants,
Apotex invites the Court to dismiss the prohibition application
on the basis that Lundbeck has not established, on a balance of
probabilities, that issuing the NOC would result in an
infringement of the '368 Patent.
[20]
I have come to the conclusion that the present
application must fail for the following reasons.
[21]
First, I note that claim 1 of the '368 Patent
claims the manufacture of a drug product containing citalopram
for the claimed uses. Accordingly, if Apotex does not
manufacture citalopram tablets for the claimed uses, but rather,
manufacturers citalopram tablets solely for the unclaimed use,
there can be no direct infringement of claim 1.
Claim 8 is for the use of citalopram for the treatment of
dementia or CVD, where citalopram is "effective" for such
uses. Therefore, for Apotex's tablets to infringe claim 8,
it must be established that both the "purpose" of the tablet is
to be used for the treatment of dementia or CVD, and that the
tablet is "effective" for such uses. Neither of the
foregoing has been alleged, much less proven by Lundbeck in this
proceeding. I conclude that there can be no direct infringement
of claims 1 and 8 either by Apotex or by independent third
parties, namely, patients.
[22]
Second, there is no conclusive evidence to
sustain Lundbeck's allegation of direct infringement:
•
The statements made by Drs. Rabheru and Gauthier in their
respective affidavits provide a rather academic perspective
regarding the occurrence of dementia in depressed patients and
the beneficial effects of citalopram, based on their review of
some scientific literature concerning a wide variety of
disorders, including depression, anxiety, psychotic symptoms,
cognitive impairment, cerebrovascular dementia, behavioural and
psychological symptoms of dementia (BPSD) and dementia of the
Alzheimer's type.
•
Both experts admit that the relationship between depression and
cognitive disorder is "complex" and "poorly understood", and also
admit that there is a "wide range" of figures regarding the
prevalence of both ailments in patients in the published
literature. In this regard, the figures advanced to support
the "approximate incidence" of dementia and/or CVD among
depressed patient populations in the affidavits do not state
whether the depression and the dementia and/or CVD occurred
simultaneously in patients or whether these were two ailments
suffered by the patients over a prolonged period of time (for
example, depression merely "preceded" or was merely a "prodrome"
to the dementia or, perhaps, was completely unrelated to the
dementia).
•
Neither experts challenge the fact that citalopram will only be
legally approved and indicated for the treatment of depression
(the unclaimed use). Indeed, neither experts make any
mention as to whether they, or any other physicians, would
prescribe citalopram to patients suffering from both depression
and dementia or CVD.
•
Finally, Lundbeck has not produced surveys or other similar
evidence to demonstrate the prescription habits of
physicians, the frequency, if any, of physicians in failing
to diagnose dementia or CVD in depressed patients, and the
dispensation practices of pharmacists. This prove to be a
fatal flaw in the Lundbeck's evidence.
[23]
Third, the case law does not support Lundbeck's
assertion of direct infringement. The decisions relied upon
by Lundbeck are distinguishable on the basis that citalopram has
already been used to treat depressive illness (the unclaimed
use). Moreover, the overlap of patients affected with both
depression and dementia or CVD does not suffice per se to
establish direct infringement.
[24]
In this respect, the present application is
virtually the same as the one brought forward by Lundbeck against
Genpharm Inc., which was dismissed by this Court on October 3,
2003 (H. Lundbeck A/S v. Canada (Minister of Health) 2003
FC 1145). In H. Lundbeck A/S, supra,
Lundbeck produced the same evidence and made the same fundamental
arguments as in the present application. Blais J. found
Lundbeck's evidence inconclusive. Further, Blais J.
dismissed Lundbeck's assertion of infringement on the basis that
it was unfounded in law. In the present case, Lundbeck has
not convinced me that this decision (which is presently appealed)
is manifestly wrong nor that the Court failed to consider binding
authorities which would have produced a different result
(Glaxo Group Ltd. v. Canada (Minister of National Health and
Welfare) (1995), 64 C.P.R. (3d) 65 at pp. 67-68 (F.C.T.D.);
Apotex Inc. v. Merck & Co., [2002] F.C.J. No. 236 at
para.12 (T.D.) (QL)).
[25]
This Court and the Federal Court of Appeal
decisions in AB Hassle v. Canada (Minister of National
Health and Welfare) (2001), 213 F.T.R. 161 (T.D.), (2002), 22
C.P.R. (4th) 1 (F.C.A.) are relevant for this proceeding.
Curiously, the applicant has chosen to rely on another
decision, AB Hassle v. RhoxalPharma Inc. 2002 FCT
780 (Gibson J.), which dealt with the same issue but came to a
different conclusion.
[26]
In AB Hassle v. Canada (Minister of National
Health and Welfare), supra, the applicants had alleged
both direct and induced infringement. The patent at
issue claimed a new use of a known compound, omeprazole.
The claims of the patent were respectively directed to the use of
omeprazole for the treatment of campylobacter infections, the
manufacture of a medicament for such purpose, and a
pharmaceutical preparation for the same use wherein the active
ingredient was omeprazole. The generic manufacturer alleged
that no claim for the medicine or the use of the medicine would
be infringed, since its product would not be made, used or sold
for the treatment of campylobacter infections. At trial,
O'Keefe J. refused to issue the prohibition order because he was
not satisfied that infringement, direct or indirect, had been
established. He specifically held that, absent surveys of
physicians' practices or other similar evidence, there was no
evidence that physicians would prescribe Apotex' drug product for
any of the unapproved patented use. Justice O'Keefe's
decision was affirmed by the Federal Court of Appeal:
(2002), 22 C.P.R. (4th) 1
(F.C.A.).
[27]
That being said, I fully endorse the comments
made by Blais J. in H. Lundbeck A/S, supra, with
respect to the contrary decision rendered by Gibson in
AB Hassle v. RhoxalPharma Inc., supra,which
was rendered a few months before the Federal Court of Appeal
decision in AB Hassle v. Canada (Minister of National Health
and Welfare), supra.
[28]
The present case is clearly distinguishable from
the facts in Genpharm Inc. v. Procter & Gamble Inc.,
[2002] 20 C.P.R. (4th) 1 (F.C.A.); (2003) 26 C.P.R.
(4th) 180 (T.D.). In any event, as stated by the Federal
Court of Appeal in AB Hassle v. Canada (Minister
of
National Health and Welfare),
supra, at paragraph 56, Genpharm is not authority
for the proposition advanced today by Lundbeck that "mere sale by
a generic [manufacturer], without more, of a medicine subject to
a use patent is sufficient to constitute infringement for the
purpose of subpara. 5(1)(b)(iv) [of the Regulations]."
[29]
In Genpharm Inc., supra,
Proctor and Gamble (P & G) owned a patent for a new
way of using an existing drug (a polyphosphonate, specifically,
etidronate or etidronate disodium) in intermittent cycles in the
treatment of osteoporosis. The use of plyphosphanates to
inhibit bone loss was well known, but was not considered very
useful in a chronic condition, such as osteoporosis because it
also tendered inhibit bone formation. Genpharm proposed to
sell its product both in 200 and 400 mg tablets, although
P & G didronel, the equivalent in the market of
Pajet's disease and hypercalcenia of malignancy, was only
available in a 200 mg size. Contrary to the present
proceeding, P & G had adduced abundant evidence in respect of
Genpharm's intent, the product monograph, and the marketplace,
including possible interchangeability with the referenced brand
name drug product. Furthermore, in the present case, this
Court is not aware in what dosages citalopram tablets would be
prescribed for the claimed uses and the unclaimed use
(depression).
[30]
I further note that in Genpharm Inc.,
supra, the intermittent use of 400 mg tablets was
approved, patented and protected. A NOC had been issued for
that specific use. Issuing a NOC to Genpharm for similar
tablets was likely to give rise to infringement. Hence, the
Federal Court of Appeal had no difficulty to conclude that the
evidence "overwhelmingly demonstrated that the actions and
intentions of Genpharm would inevitably lead to an infringement"
(AB Hassle v. Canada (Minister of National Health and
Welfare), supra, at para. 18 (F.C.A.)). This is
not the case here. In fact, Lundbeck has not even
challenged Apotex' intentions nor its activities in respect of
the approval and marketing of its drug. At the hearing,
counsel for Lundbeck has suggested that the contraindications in
Apotex' product monograph should have mentioned that its product
was contraindicated in patients with Alzheimer's disease or
CVD. Unfortunately, I cannot pronounce myself on the merit
of this new argument who comes before this Court too late.
It should not be entertained any further as this Court received
no evidence with respect to any existing practice to mention
patent restrictions as contraindications in a product
monograph.
[31]
Finally, Lundbeck's assertion that '368 Patent
will be directly infringed is inconsistent with the purposes of
the Regulations and also raises serious policy issues. If
Lundbeck's proposed interpretation of the Regulations were
correct, Lundbeck would be able to artificially extend its
monopoly over the use and selling of the product simply because
there is always the possibility that someone somewhere will use
the drug for the prohibited, patented purpose. In doing so,
generic manufacturers would effectively be barred from entering
the market. Surely, this is not what is intended by the
Regulations. Absent evidence of future infringement, and
based solely on a mere theoretical future possibility of
infringement, a generic manufacturer should not be kept off the
market (AB Hassle v. Canada (Minister of National Health and
Welfare), supra, at para. 57 (F.C.A.); Zeneca
Pharma Inc. v. Canada (Minister of National Health and
Welfare), supra, at pp. 453-54 (F.C.A.); SmithKline
Beecham Inc. v. Apotex Inc., supra, at para. 40
(F.C.T.D.); and by analogy: Warner-Lambert Co. v. Apotex
Corp., Apotex Inc., and Torpharm Inc., 2003 U.S. App. Lexis
594 (U.S. Ct. App. Fed. Cir.)). Therefore, properly
construed, there can be no direct infringement to claims 1 and 8
to the aforesaid patent. With respect to indirect or
"induced" infringement, Lundbeck has not raised this ground and
is now barred from raising it at this late stage. In any
event, Lundbeck has failed here to allege and prove the requisite
elements of the test for induced infringement (AB Hassle v.
Canada (Minister of National Health and Welfare),
supra, at para. 68 (T.D.)).
[32]
In conclusion, I reiterate that the '368 Patent
makes no claim as to depression. Since that use was well
established, it could not have been patented. Apotex has
currently alleged that it will sell its citalopram tablets to
pharmacists and wholesalers, not to patients, in accordance, and
for, their approved use, namely, for the treatment of
depression. There has been no suggestions that Apotex's NOA
was inadequate or that it failed to address relevant patent
claims. The allegations of fact in the NOA are true except
to the extent that the contrary has been shown. In the case
at bar, Lundbeck's allegations of infringement are purely
speculative and are not supported by the evidence.
Manifestly, Lundbeck has not proved, on a balance of
probabilities that, if a NOC were issued to Apotex and it were to
manufacture, market, or sell the aforesaid tablets, claims 1 and
8 of the '368 Patent would be infringed.
ORDER
THIS COURT ORDERS that the
application requesting an Order in accordance with paragraph 6(1)
of the Regulations, prohibiting the Minister from issuing
a NOC to Apotex, be dismissed with costs in favour of
Apotex. There will be no order as to costs, in favour of or
against, the Minister.
__________________________________
Judge
FEDERAL COURT
NAMES OF COUNSEL
AND SOLICITORS OF RECORD
DOCKET:
T-135-02
STYLE OF CAUSE: H. LUNDBECK
A/S and LUNDBECK CANADA INC. v. THE MINISTER OF HEALTH and APOTEX
INC.
PLACE OF
HEARING:
MONTREAL
DATE OF
HEARING:
OCTOBER 21, 2003
REASONS FOR ORDER
AND ORDER: THE
HONOURABLE MR. JUSTICE MARTINEAU
DATED:
NOVEMBER 12, 2003
APPEARANCES:
Ms. Marie
Lafleur
FOR APPLICANTS
Mr. Martin Sheehan
Mr. Harry Radomski
FOR RESPONDENT
Mr. Andrew Brodkin
Apotex Inc.
SOLICITORS OF RECORD:
FASKEN MARTINEAU DuMOULIN
LLP
FOR APPLICANTS
Montreal, Quebec
GOODMANS LLP
FOR RESPONDENT
Toronto,
Ontario
Apotex Inc.
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