Date: 20070219
Docket: T-899-06
Citation: 2007
FC 188
Toronto,
Ontario, February 19, 2007
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
PFIZER CANADA INC. and PFIZER
INC.
Applicants
and
THE MINISTER OF HEALTH and
PHARMASCIENCE INC.
Respondents
REASONS FOR ORDER AND ORDER
[1]
This is a
motion brought under the provisions of section 6(5)(a) of the Patented
Medicines (Notice of Compliance) Regulations SOR/93-133 as amended,
SOR/2006-242 (NOC Regulations) requesting that this Court strike out in whole or
in part these proceedings as they relate to Canadian Patent 2,355,493 (493
patent). For the Reasons that follow I find that the motion is allowed with
costs.
[2]
This is a
motion brought under the provisions of section 6(5)(a) of the NOC Regulations
in its form as amended October 5, 2006. They state:
“6(5) In a proceeding in
respect of an application under subsection (1) the Court may, on a motion of a
second person, dismiss the application in whole or in part
(a) in respect of those
patents which are not eligible for inclusion on the register.”
[3]
These
provisions differ from section 6(5)(a) as it read prior to November 2006, in
that the application may now be dismissed “in whole or in part” and
subsection (a) previously read:
“(a) if the Court is satisfied
that the patents at issue are not eligible for inclusion on the register or…”
[4]
Counsel
for the Applicants Pfizer et al. has advised this Court that for purposes of
these proceedings (not just this motion) taken against Cobalt and
Pharmascience, they intend to assert only claim 22 of the 493 patent. Thus the
issues for consideration on this motion are:
1.
What is
the standard to be applied by the Court in assessing matters before it on a
motion under section 6(5)(a) of the NOC Regulations; and
2.
Is that
which is claimed in claim 22 of the 493 patent eligible for inclusion on the
register?
1. Standard
[5]
There has
been no reported judicial consideration as to the standard to be applied to a
motion brought under section 6(5)(a) of the NOC Regulations as they stand post October
5, 2006. That section as it previously stood was the subject of some
consideration by this Court and the Federal Court of Appeal.
[6]
The
Federal Court of Appeal in Apotex Inc. v. Canada (Minister of National Health and
Welfare)
(2000), 3 C.P.R (4th) 1, per Rothstein JA (as he then was) provided
guidance as to the general purpose of section 6(5)(a). The purpose of that provision
is to provide to the generics an opportunity to dismiss the application because
it is based on an ineligible patent included in the Register. At that time the
Court of Appeal commented that this solution was not perfect as the application
would only be dismissed if all patents were ineligible. That problem has been
solved by the October 5, 2006, amendments which provides for dismissal in whole
or in part. Rothstein, JA said at paragraphs 22 to 24:
22 Our second reason for
not interfering with the discretion exercised by the Minister in this case
relates to the scheme of the Regulations themselves. The Regulations expressly
provide a process by which generic manufacturers may obtain relief in the event
they are prejudiced by reason of ineligible patents being included on the
Register. Subsection 6(1) and paragraph 6(5)(a) provide in relevant part:
…
23 It is apparent that in
enacting paragraph 6(5)(a) of the Regulations, the Governor in Council was
aware of, and allowed for, the possibility that ineligible patents may find
their way onto the Register and may not be readily capable of being deleted
under subsection 3(1). Paragraph 6(5)(a) provides generic drug manufacturers
with the opportunity, if and when prohibition proceedings are commenced by a
patent holder in respect of a Notice of Allegation served by the generic, to
apply to the Court to dismiss the prohibition application because it is based
on an ineligible patent included on the Register.
24 This form of relief may
not be a perfect solution for the generic manufacturers because, as appellants'
counsel pointed out, the prohibition application will only be dismissed if all
the patents at issue are not eligible for inclusion on the Register and because
the proceeding does not provide for a court order requiring the Minister to
purge the Register of ineligible patents. However, the remedy provided by
paragraph 6(5)(a) does directly address the problem of a generic manufacturer
having to compare its product with the drug of a patent holder whose drug is
based on an ineligible patent. It provides a judicial forum in which the
eligibility of the specific patent or patents at issue can be decided by the
Court after hearing from the patent holder and the generic competitor.
[7]
The
Federal Court of Appeal did not address the standard to be applied by the Court
in considering a section 6(5)(a) motion.
[8]
Section 6(5)(a)
was considered by Gauthier,
J. of this Court
in Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health) (2003), 20 C.P.R. (4th)
180. She said at paragraphs 9 to 15 of her Reasons:
9 Before addressing the
main issues raised by Genpharm's motion, it is also important to note that
there has been no decision made pursuant to paragraph 6(5)(a) of the NOC
Regulations since the provision was added in 1998 and the parties disagree on
the standard or test to be applied in assessing the merits of this motion.
10 Paragraph 6(5) of the
NOC Regulations reads as follows:
…
11 In Bayer Inc. v. Apotex
Inc. (1999), 85 C.P.R. (3d) 334, Justice Joyal on a motion to dismiss under
paragraph 6(5)(b) of the NOC Regulations held that such motion should be
granted only where the Notice of Application is clearly improper and bereft of
any possibility of success. He agreed with the arguments presented to him that
paragraph 6(5)(b) simply gives the Court explicit jurisdiction to consider motions
to dismiss where earlier the Court had to rely on its own rules to do so. Thus,
the restrictive standard enunciated in Hunt v. Carey Canada Inc., [1990] 2
S.C.R. 959 at 980, should apply.
12 Procter argues that the
reasoning adopted in Bayer applies when dealing with a motion under paragraph
6(5)(a) while Genpharm submits that the purpose of this provision is to get rid
of groundless notices of application and there is thus no reason to adopt such
a restrictive approach.
13 The parties said little
more to support their respective position.
14 The administrative
scheme set out in sections 5 and 6 of the NOC Regulations is intended to apply
only where a notice of compliance is filed in respect of a drug that can be
compared with another drug for which a patent was properly included in a patent
list on the Register. Thus, a motion to strike a notice of application filed
under subsection 6(1) based on the fact that the only patent currently on the
Register should not be there, is or is akin to a motion to strike out the
proceeding on the basis that there is no reasonable cause of action.
15 It is settled law that
if this interpretation is correct, the restrictive standard set out in Hunt,
supra, should apply. Genpharm would thus have to prove that it is plain and
obvious that the '376 Patent was not eligible for inclusion in the Register.
[9]
Justice
Russell of this Court in Glaxo Smith Kline Inc. v. Apotex Inc. (2003),
29 C.P.R. (4th) 350 reviewed the decisions of Rothstein, JA and
Gauthier, J. above. He concluded that Gauthier, J. did not have the benefit of a full
argument on the point, and in particular, did not have Rothstein, JA’s reasons
before her. Russell, J. concluded that the issue as to which standard applies
under section 6(5)(a) remained to be determined. He said at paragraphs 18 to
21 of his Reasons:
18 It is clear from these
passages that Gauthier J. did not have the benefit of full argument on this
issue and was not asked to consider the general rationale for subsection 6(5)(a)
enunciated by Rothstein J.A. in Apotex, supra. This being the case, Gauthier
J.'s decision cannot be considered as strong authority on this point and, in
any event, Gauthier J. went on to decide that the relevant standard to be
applied under subsection 6(5)(a) was not determinative in Procter, supra,
because the Court "would have reached the same conclusion even if it had
not applied [the restrictive standard]."
19 The judgment of
Rothstein J.A. in Apotex, supra, does not specifically state what standard
should be applied in applications under subsection 6(5)(a), but, rather than
characterizing such an application as being analogous to a motion to strike on
the basis that there is no reasonable cause of action, it concludes that such
an application "provides a judicial forum in which the eligibility of the
specific patent or patents at issue can be decided by the Court after hearing
from the patent holder and the generic competitor."
20 If the court is not
being asked to decide that there are no reasonable grounds for GSK's section
6(1) application, but is merely examining eligibility after hearing from the
parties, there is no justification, as far as Apotex is concerned, for applying
the restrictive Hunt, supra, "plain and obvious" test under subsection
6(5)(a).
21 In my opinion, the
issue of which standard applies under 6(5)(a) still remains to be determined.
In the case before me, the matter is not determinative because, even if I apply
the less restrictive standard that is urged upon me by Apotex, I cannot, for
reasons that follow, allow this application.
[10]
Prothonotary
Morneau, in a decision made very shortly after that of Russell, J. and
apparently without having had that decision placed before him, or the earlier
decisions of Gauthier, J. or Rothstein, JA., said at paragraphs 12 and 13 of H.
Lundbeck A/S v. Canada (Minister of Health), 2003 FC 1333:
12 Pharmascience's motion
to dismiss asks the Court to consider the dismissal under both paragraphs of
subsection 6(5) of the Regulations.
13 In regard to the burden
of proof that Pharmascience must meet on this motion, it is essentially similar
to the one that a defendant must meet when it seeks to have a statement of
claim struck out under Rule 221 of the Federal Court Rules, 1998.
[11]
In Sanofi-Aventis
Inc. v. Novopharm Ltd. 2006 FC 1547, I held that with respect to section
6(5)(b) but not section 6(5)(a) that the standards used by the Court in
considering motions to strike under Rule 221 should be applied and that an
application should only be struck out where it was “plain and obvious” that it
could not succeed, citing Hunt v. Carey Inc., [1990] 2 S.C.R. 959 I said
at paragraph 11:
11 Taking section 6(5)(b)
on an equal footing with old Rule 419 or present Rule 221 we must start with
the well entrenched proposition as stated by the Supreme Court in Hunt v. Carey
Canada Inc., [1990] 2 S.C.R. 959 that a party should not be driven from the
judgment seat at an early stage before trial unless it is "plain and
obvious" that the matter cannot succeed. In dealing with an application
not an action, the Federal Court of Appeal in Norton v. Via Rail Canada (2005),
255 D.L.R. (4th) 311, at paragraph 15, states that striking out an application
before hearing is an extraordinary remedy, granted only in narrowly defined
circumstances. Finally, another classic decision of this Court should be cited,
Creaghan Estate v. The Queen, [1972] F.C.J. No. 60, 1972 FC 732 at 736:
(3) Finally, in my view, a
statement of claim should not be ordered to be struck out on the ground that it
is vexatious, frivolous or an abuse of the process of the Court, for the sole
reason that in the opinion of the presiding judge, plaintiff's action should be
dismissed. In my opinion, a presiding judge should not make such an order
unless it be obvious that the plaintiff's action is so clearly futile that it
has not the slightest chance of succeeding, whoever the judge may be before
whom the case could be tried. It is only in such a situation that the plaintiff
should be deprived of the opportunity of having "his day in Court".
and at paragraph 22:
22 A motion to dismiss
should not be used as a vehicle to resolve important, controversial points of
law. This is particularly so in an area which the law is currently evolving (Daniels
v. Canada, [2002] 4 F.C. 550). For this
reason I will not dismiss the proceeding in respect of the '089 and '948 patent
on this ground.
[12]
The “plain
and obvious” test was considered at length by the Supreme Court of Canada in Hunt
v. Carey Inc., [1990] 2 S.C.R. 959 where Rule 19(24)(a) of the British
Columbia Rules of Court were at issue. That Rule said:
“19(24) At any stage of a
proceeding the Court may order to be struck out or amended the whole or any
part of an endorsement, pleading, petition or other document on the ground that
(a) it discloses no reasonable
claim or defence as the case may be…”
[13]
The
Supreme Court, per Wilson, J. concluded at page 980 of her
reasons:
Thus, the test in Canada governing the application of
provisions like Rule 19(24)(a) of the British Columbia Rules of Court is the same as
the one that governs an application under R.S.C. O. 18, r. 19: assuming that
the facts as stated in the statement of claim can be proved, is it “plain and
obvious” that the plaintiff’s statement of claim discloses no reasonable cause
of action? As in England, if there is a chance that
the plaintiff might succeed, then the plaintiff should not be “driven from the
judgment seat”. Neither the length and complexity of the issues, the novelty
of the cause of action, nor the potential for the defendant to present a strong
defence should prevent the plaintiff from proceeding with his or her case.
Only if the action is certain to fail because it contains a radical defect
ranking with the others listed in Rule 19(24) of the British Columbia Rules of
Court should the relevant portions of a plaintiff’s statement of claim be
struck out under Rule 1((24)(a).
[14]
The
application of the “plain and obvious” test by the Supreme Court in Hunt v.
Carey Inc., supra, indicates that novel points of law which do not amount
to an abuse of process, should not be struck out. A party should be allowed to
make complete submission as to what the evidence at trial establishes. At page
988 Wilson, J. for the Court says:
The difficulty I have,
however, is that in this appeal we are asked to consider whether the
allegations of conspiracy should be struck from the plaintiff’s statement of
claim, now whether the plaintiff will be successful in convincing a court that
the tort of conspiracy should extend to cover the facts of this case. In other
words, the question before us is simply whether it is “plain and obvious” that
the statement of claim contains a radical defect.
It is plain and obvious that
allowing this action to proceed amounts to an abuse of process? I do not think
so. While there has clearly been judicial reluctance to extend the scope of
the tort beyond the commercial context, I do not think this court has ever
suggested that the tort could not have application in other contexts.
and at pages 989-990:
The issues that will arise at
the trial of the plaintiff’s action in conspiracy will unquestionably be
difficult. The plaintiff may have to make complex submissions about whether
the evidence establishes that the defendants conspired either with a view to
causing him harm or in circumstances where they should have known that their
actions would cause him harm. He may well have to make novel arguments
concerning whether it is enough that the defendants knew or ought to have known
that a class of which the plaintiff was a member would suffer harm. The trial
judge might conclude, as some of the defendants have submitted, that the
plaintiff should have sued the defendants as joint tortfeasors rather than
alleging the tort of conspiracy. But this Court’s statements in Inuit
Tapirisat of Canada and Operation Dismantle Inc., as well as decisions such as
Dyson and Drummond-Jackson, make clear that none of these considerations may be
taken into account on an application brought under Rule 19(24) of the British
Columbia Rules of Court.
[15]
The
balance that a Court must consider in this matter concerning section 6(5)(a) of
the NOC Regulations is whether, on the one hand, an application should continue
where at least one of the patents should not have been on the register in the
first place. It would be a waste of judicial resources and those of the
parties to do so. On the other hand, a party should not be deprived of its
opportunity to make full argument based on all the evidence that would
ultimately be before the Court. This latter point is tempered however in cases
such as this where the application is to proceed in a summary fashion based on
affidavit evidence and written transcripts of cross-examination alone and, at
the end of the day, a decision has no binding effect should the parties proceed
to an ordinary infringement and validity action.
[16]
Taking
these matters into consideration I find that a section 6(5)(a) motion should be
considered on the basis that if a determination can be made based on law and
the application of uncontroverted relevant evidence or admissions or plain and
obvious findings on the evidence, then the Court should proceed to make a
determination. Section 6(5)(a) must have a purpose that is not trivial. However,
if the Court finds itself determining the matter on disputed relevant evidence
or having to weight the merits of competing expert opinion, the matter should
be left to the hearing at trial. It is difficult to sum this up as simply
“plain and obvious”, it goes beyond that, but where the law can be applied to
admissions and relevant evidence that is quite reasonably found to be
undisputed or “plain and obvious” then the Court has a duty to make a
determination.
2. Is the ‘493 Patent Claim 22, properly
included on the Register?
a) The Issue
[17]
The
question is whether the ‘493 patent, and in particular claim 22, was properly
listed having regard to the notice of compliance granted to the Applicant
Pfizer Canada Inc. for NORVASC.
[18]
By reason
of the chemistry involved, Pfizer states the issue as: is a patent claiming a
single medicine (one enantiomer of a racemate) eligible to be listed on the
patent register against a drug containing that medicine plus an additional
medicine (the racemate, that is, both enantiomers).
[19]
The Court
must consider first what the “medicine” is having regard to the NOC Regulations
as they existed as of the time of listing, that is, pre-October 5, 2006. The
medicine is described in Pfizer’s notice of compliance simply as “amlodipine
besylate”.
[20]
Section
4(1) of the NOC Regulations provides that:
“4(1) A person who files, or
who has filed a submission for, or has been issued, a notice of compliance in
respect of a drug that contains a medicine may submit to the Minister a patent
list certified in accordance with subsection (7) in respect of the drug.”
A “medicine” is defined in section 2 of the NOC Regulations
as:
“a substance intended or
capable of being used for the diagnosis, treatment, mitigation or prevention of
a disease, disorder or abnormal physical state or symptoms thereof;”
[21]
A “drug”
is not defined in the NOC Regulations, however, the Federal Court of Appeal in Eli
Lilly Canada Inc. v. Canada (Minister of Health), [2003] 3 FC 140 at
paragraph 18 has stated that it has the same meaning as that found in the Food
and Drug Regulations, namely that a “drug” includes any substance or
mixture of substances manufactured, used or represented for use in the
diagnosis, treatment, mitigation or prevention of disease, disorder, abnormal physical
state, or the symptoms thereof, in human beings or animals.
[22]
In Eli
Lilly, supra, the Federal Court of Appeal reasoned that once any drug which
contained the medicine in question had been issued a notice of compliance, any
patent which claimed that medicine, even if the medicine of the notice of
compliance needed to be combined with another chemical to make it useful and as
claimed in the patent was not combined in that way, could be placed on the
patent list contemplated by section 4(1) of the NOC Regulations. Sharlow, JA.,
for the Court said at paragraphs 20 to 29:
20 The Minister's task is
facilitated by the form of the patent list. A separate patent list is submitted
for each drug product. The form requires the following information about the
drug: the name of the medicine in the drug, the brand name, the drug
identification number set out on the notice of compliance, the intended use
(human or veterinary), the route of administration, the pharmaceutical dosage
form, and the dosage. There follows a section in which the patents sought to be
included on the patent register are listed by patent number, date of grant and
expiration date. Each patent is marked by a code indicating the status of the
applicant as owner, exclusive licensee, or person with the consent of the
owner. The remainder of the form identifies the person submitting the patent
list and gives an address for service. The form also includes the required
certification.
21 Subsection 3(3) is
intended to ensure that the Minister does not give effect to a patent list
submitted in relation to a particular drug product until a notice of compliance
has been issued for that product. In this case it is common ground that the
requirements of subsection 3(3) are met.
22 Subsection 4(1) tells
the Minister who is entitled to file a patent list. That entitlement is given
to a person who files or has filed a new drug submission to obtain a notice of
compliance in respect of a "drug that contains a medicine", or a
person who has been issued a notice of compliance in respect of a "drug
that contains a medicine".
23 In the context of this
case, it is common ground that Tazidime is a drug containing ceftazidime, and
that Tazidime is a drug in respect of which Eli Lilly has been issued a notice
of compliance. There was some dispute in the court below as to whether
ceftazidime is a medicine.
24 The evidence is that
ceftazidime is an antibiotic. Amorphous lactose has no medicinal qualities but
prevents ceftazidime from degrading to toxicity. A formulation of ceftazidime
and amorphous lactose that is the subject of one of the claims of the 969
patent would be considered to be a "medicine" as that term is defined
in section 2 of the PMNOC Regulations: Hoffmann-La Roche Ltd. v. Canada (Minister
of National Health and Welfare) (1995), 62 C.P.R. (3d) 58 (F.C.T.D.), affirmed
(1996), 67 C.P.R. (3d) 25 (F.C.A.). However, it seems to me that ceftazidime
alone also meets the definition of "medicine".
25 The Judge reasoned
that, because ceftazidime by itself is toxic, it is not intended to be used for
the treatment of a disease or disorder, and is not capable of being so used. I
must respectfully disagree with that conclusion. An antibiotic does not cease
to be an antibiotic merely because it cannot function safely in the human body
until it is combined with a substance that prevents it from degrading to
toxicity. It would follow that for the purposes of the PMNOC Regulations,
ceftazidime is a medicine whether or not it is formulated with amorphous
lactose.
26 It would also follow,
paraphrasing the words of subsection 4(1), that because Eli Lilly has been
issued a notice of compliance in respect of a drug, Tazidime, that contains a
medicine, ceftazidime, Eli Lilly is permitted to submit a patent list in
respect of the drug Tazidime. However, subsection 4(1) does not specify what
patents Eli Lilly is entitled to include on the patent list. That question is
determined on the basis of paragraphs 4(2)(b) and 4(7)(b).
27 Pursuant to paragraph 4(2)(b),
the patent list submitted in respect of Tazidime may include any patent that
contains "a claim for the medicine itself". The word
"medicine" in paragraph 4(2)(b) must have the same meaning in that
provision as it does in subsection 4(1). If that is so, then in the case of a
patent list submitted for Tazidime, any patent that contains a claim for
ceftazidime itself, or that contains a claim for a formulation in which
ceftazidime is the active medicinal ingredient, is within the scope of
paragraph 4(2)(b).
28 I need not analyze the
requirements of paragraph 4(7)(b) in any detail. I understand that counsel for
the Minister has not taken the position that the 969 patent is not
"relevant to the dosage form, strength and route of administration" of
Tazidime.
29 Based on the foregoing
ordinary and grammatical reading of the PMNOC Regulations, the 969 patent
should be eligible for inclusion on the patent lists for Tazidime. That is the
interpretation that should be adopted unless the words of the PMNOC Regulations
can reasonably bear a different meaning that would accord better with the
purpose of the PMNOC Regulations.
[23]
This
reasoning may be tempered by the reasoning of the Supreme Court of Canada in
its recent decision in AstraZeneca Canada Inc. v. Canada (Minister of
Health), 2006 SCC 49. However, in view of my conclusions herein, I do not
need to consider that issue.
b) The Notice of Compliance
[24]
The notice
of compliance is that granted to Pfizer Canada Inc. dated 1997-08-01, which is
a supplemental notice respecting an earlier notice, for a prescription
pharmaceutical branded as NORVASC provided in tablet form for oral
administration of 5 mg; 10 mg and 25 mg. per tablet. The therapeutic class is
described as “antihypertensive – antianginal agent”. Only one medicinal
ingredient is named, it is:
“amlodipine besylate”
[25]
Pfizer
Canada Inc. makes available a product monograph respecting NORVASC first
prepared June 23, 1992 and revised June 8, 2005. In that monograph the
following pharmaceutical information is provided:
[26]
The
undisputed evidence is that amlodipine besylate is what is known as a racemate
or racemic composition, that is, it can be described in two dimensions by a
molecular depiction as shown in the product monograph but in three dimensions
it consists of equal amounts of two such molecular structures. In three
dimensions these two structures are twisted one way or the other. They are
mirror images of each other. Sometimes a description is given that one is the
right hand and the other is the left hand. Chemists call these structures
enantiomers and describe their orientation by means of symbols such as (+) or
(-) and R or S or a combination of those symbols. In this case it is
undisputed that amlodipine besylate is, and at all material times was known to
be, a racemate which comprised R(+) and S(-) enantiomers in equal amounts.
[27]
The
activity of enantiomers generally speaking from a pharmacological point of
view, is undisputed. In this regard, I quote from the affidavit of one of Pfizer’s
witnesses, Wasley, at paragraphs 42 to 44:
42. As noted above, enantiomers
arise where a molecule contains one or more asymmetric carbon atoms.
Enantiomers have identical physical and chemical properties except that they
rotate the plane of polarized light in opposite directions (otherwise known as
“optical rotation”) and their pharmacological properties are often different.
By “pharmacological properties”, I mean the activity of a compound in a
biological system, whether in vitro or in vivo.
43. Enantiomers can frequently,
although not invariably, display markedly different biochemical and
pharmacological effects. For example, administration of the enantiomers of a
potent dopamine D-2 receptor agonist was found to give rise to mutual
antagonism in which the two enantiomers each partially or completely inhibited
the effects of the other. This supported the use of the separate enantiomers
instead of the racemate.
44. In very few cases, the
pharmacological differences between enantiomers are not “active versus
inactive” or “active versus undesirably active”, but rather are cases of one
enantiomer having desirable activity and the other enantiomer having a
different desirable activity. Such is the case with amlodipine besylate.
[28]
The notice
of compliance for NORVASC lists “amlopidine besylate” as a single medicine, it
does not state that it is a racemate or that there are R(+) or S(-) enantiomers
of that compound. There is nothing on the record to show that any medicine has
been described in any notice of compliance granted to anyone in terms of its
component enantiomers. The record does indicate that notices of compliance
have been granted where medicines contain two different compositions are listed
in which case each composition is stated separately for example a drug called
ADVAIR contains two medicinal ingredients salmeterol xinafoate and fluticasone
propionate.
c) The 493 Patent
[29]
At this
point the ‘493 patent and claim 22 of that patent must be considered. It is
undisputed that as of the earliest date set out in the patent, the priority
date of August 23, 2000, NORVASC was a known drug containing as a medicine
amlodipine besylate, a known racemate.
[30]
The
Supreme Court of Canada has, in Whirlpool Corp v. Camco Inc., [2000] 2
S.C.R. 1067, provided substantial guidance as to how a patent is to be
considered in circumstances such as these. The construction of a patent,
including its claims, is a task to be undertaken by the Court prior to
consideration of issues such as infringement and validity (Whirlpool paragraphs
42 and 43). A purposive construction is to be given to the claims giving
effect to their meaning as understood in view of the whole of the disclosure
and the claims (Whirlpool paragraph 49(g)).
[31]
A
“dictionary” approach is to be avoided, a claim is not to be interpreted
through the eyes of a grammarian or etymologist, (Whirlpool paragraphs
51 to 53).
[32]
The
Supreme Court made it clear that construction is for the Court and not for
experts called by the parties. It stated in paragraph 57 of Whirlpool that
the role of the expert was not to interpret the patent claims but to put the
trial judge in a position of being able to do so in a knowledgeable way.
[33]
It is
apparent that in any seriously contested patent matter the parties will marshal
experts on one side and the other, whose views as to construction of the claims
will differ, favouring one party or the other. The Court will seek assistance
from experts when needed to explain terms not readily apparent and to provide
background, where needed, as to the concepts to be considered in the patent.
In the final analysis however construction is a matter for the court alone,
taking into consideration the whole of the description and claims and avoiding
a strict “dictionary” approach to a claim.
[34]
On this basis
the ‘493 patent, including in particular claim 22, is construed.
[35]
The title
of the patent is telling, it says, “Therapeutic Compositions Comprising Excess
Enantiomer”, thus the reader is told to expect a composition that is
therapeutic and contains an excess of one enantiomer over another.
[36]
Page 1
begins with a general description of the invention saying that the invention is
concerned with pharmaceutical composition containing a “mixture of amlodipine
enantiomers”.
The present invention is
concerned with pharmaceutical compositions comprising a mixture of amlodipine
enantiomers, which compositions have both anti-hypertensive and additional
cardiovascular properties derived respectively from their calcium
channel-blocking activity and their ability to release vascular nitric oxide
(NO).
[37]
The next
paragraph on page 1 sets out what is undisputed between the parties.
Amlodipine is a known medicine, a racemate, specifically as a besylate salt:
Amlodipine is a well-known
calcium channel-blocking agent which is used in the treatment of hypertension
and angina. Amlodipine is a dihydropyridine with an asymmetric centre at the
4-position; presently, amlodipine is only approved for administration in the
form of the racemate, specifically that of the besylate salt.
[38]
The next
two paragraphs at page 1 state that the enantiomers of the racemate have been
isolated and identified as R(+) and S(-) configurations and that specific
medicinal properties reside in each. The S(-) has the known channel blocking
actively of the racemate, the R(+) inhibits certain vascular smooth muscle
migration.
The individual enantiomers of
amlodipine have been isolated (J Med Chem 29 1696 (1986), Arrowsmith et
al) and identified as R(+) and S(-) (J Med Chem 35 3341-3344 (1992),
Goldmann et al). The calcium channel-blocking activity of the racemate has
been found to reside largely, but not exclusively, in the S(-) enantiomer (J
Cardiovasc Pharmacol 12 (Supp 6) S144, J W Rigby et al).
European Patent No. 0754043
describes the surprising ability of the R(+) enantiomer of amlodipine to
inhibit PDGF-induced vascular smooth muscle cell migration using an in vitro
system which effect may prove to be useful in the treatment of conditions such
as atherosclerosis, restenosis after angioplasty and endometriosis.
[39]
Then, at
the bottom of page 1, is the disclosure of the invention. The R(+) enantiomer
has another property, it releases NO (nitric oxide) having therapeutic effects:
It has now been found that the
R(+) enantiomer of amlodipine has another unexpected property, specifically the
ability to release NO, a potent vasodilator and inhibitor of platelet
aggregation and the active species in nitroglycerin (Kidney International 49
S2-S5 (1996), Ignarro), from endothelial and vascular smooth muscle cells (hereinafter
referred to as “vascular NO”).
[40]
The next
paragraph at the top of page 2 is extremely important. It advises that the
racemate should not be used as it places an “artificial limit” on the amount of
R(+) enantiomer that can be used for therapeutic effect:
When amlodipine is
administered as the racemate, the NO-induced cardiovascular effects of the R(+)
enantiomer are largely ‘masked’ by the potent anti-hypertensive effects of the
S(-) enantiomer. Furthermore, the amount of racemate which may safely be
administered is limited by the hypotensive activity of the S(-) enantiomer
which, in excess of about 0.5 mg/kg, can give rise to adverse effects such as a
marked and sustained fall in blood pressure and reduced coronary blood flow.
The R(+) enantiomer, on the other hand, is expected to provide beneficial
cardiovascular effects at concentrations far exceeding those at which the S(-)
enantiomer begins to produce unwanted effects. Thus using the racemate of
amlodipine places an artificial limit on the amount of R(+) enantiomer which
may be administered and deprives the patient of the full cardiovascular
benefits of said enantiomer.
[41]
The next
paragraph at page 2 articulates the problem that the patent seeks to address,
getting the right balance between the amount of S(-) enantiomer and the R(+)
enantiomer so as to achieve appropriate therapeutic benefits from each:
The problem which the present
invention seeks to address is to provide amlodipine compositions comprising
sufficient S(-) enantiomer to achieve the desired anti-hypertensive and
anti-anginal effects while also comprising sufficient R(+) enantiomer to
maximise the beneficial NO-induced cardiovascular effects of the latter. That
is, to improve blood flow to vital organs such as heart, kidney and brain by
vasodilation and inhibition of platelet aggregation without affecting normal
haemodynamics.
[42]
Other
benefits are then canvassed before the patent turns to a brief discussion as to
certain studies that revealed properties of the S(-) and R(+) enantiomer. The
two concluding paragraphs at page 3 discuss results from these studies as to
the release of NO by the R(+) enantiomer and concludes that if the racemate is
administered so as to get optimum S(-) therapeutic effect, there is a failure
to provide sufficient R(+) enantiomer for optimum NO release.
As indicated, maximum NO
release as measured by nitrite production was observed at a free concentration
of R(+) enantiomer of 109M or 0.4 ng/ml; this figure corresponds to a plasma
protein-bound concentration of about 30 ng/ml, that is, some 5x the optimum
plasma concentration for the S(-) enantiomer (Amer J Cardiol 73 A10-A17
(1994), D N Abernethy et al).
It follows that amlodipine
racemate administered for optimum anti-hypertensive effect of the S(-) enantiomer
fails to provide sufficient R(+) enantiomer for optimum NO release.
[43]
Applicants’
counsel seized on the word “optimum” to launch an argument that, by
implication, a sub-optimum release using the racemate is still contemplated.
This cannot be so in view of the clear statements in the first paragraph at
page 2 previously discussed that the benefits of the R(+) enantiomer are
“largely masked” in the racemate, that the amount of racemate that would have
to be administered would give rise to adverse effects and thus an artificial
limit is imposed on the amount to be administered which would deprive a patient
of the full benefits. In other words, don’t use the racemate alone if you want
the NO effects of the R(+) enantiomer.
[44]
This
position is further supported at page 4 and over to page 5 of the patent where,
after disclosure of some testing, the reader in told that the ratio of S(-) to
R(+) is important since the presence of S(-) inhibits R(+); the R(+) must
always exceed the S(-).
It follows that the dose of
amlodipine racemate administered for optimum anti-hypertensive effect of the
S(-) enantiomer limits the amount of R(+) enantiomer available for additional
protection of the heart from hypoxic damage.
According to the present
invention, therefore, there are provided compositions of amlodipine wherein the
amount of S(-) enantiomer present is in the range 1.25mg to 5mg and the ratio
of R(+) enantiomer: S(-) enantiomer exceeds the 1:1 ratio found in the
racemate. In order to achieve the desired combination of anti-hypertensive and
NO-induced cardiovascular effects, the compositions of the invention typically
contain a ratio of R(+) enantiomers S(-) enantiomer in the range 2:1 to 8:1,
ideally about 5:1.
[45]
Then, at
the first full paragraph of page 5 there is a statement critical to the
understanding of claim 22, page 5 says that the invention also contemplates
compositions comprising R(+) alone:
It is also within the scope of
the present invention that said compositions may exclusively comprise the R(+)
enantiomer when only those cardiovascular effects associated with elevated
levels of vascular NO are required, for example, in the treatment of
endothelial dysfunction arising from ischaemia and reperfusion of the heart.
[46]
Then the
patent speaks about combining the R(+) enantiomer with other things, not S(-),
not the racemate, but other drugs such as an ACG inhibitor or a PDE5 inhibitor.
It may also be useful to
combine the R(+) enantiomer with a cardiovascular drug of alternative
mechanism, for example, an ACE inhibitor, such as ramaprilat or quinapril, to
provide an additive or synergistic effect.
…
A similar synergy in NO effect
might be expected for the R(+) enantiomer of amlodipine in combination with
PDE5 inhibitor which combination is likely to potentiate the responses to
released NO. A particularly preferred PDE5 inhibitor for use in such a
combination might be sildenatil.
[47]
The patent
then discusses how to prepare the R(+) and S(-) enantiomers and at page 6 gives
three ways of preparing enriched mixtures namely (1) combining appropriate
amounts of R(+) and S(-); (2) adding R(+) to the racemate; or (3) preparing
mixed crystals each containing the required ratio of R(+) and S(-).
The enriched enantiomer
mixtures of the present invention may be prepared by (i) combining appropriate
amounts of the two enantiomers, (ii) adding an appropriate amount of ‘excess’
R(+) enantiomer to amlodipine racemate, or (iii) preparing ‘mixed’ crystals
each containing the required ratio of R(+) and S(-) enantiomers. When preparing
enriched mixtures in accordance with these methods, it is within the scope of
the invention to combine two free bases, a free base and a salt, or two salts.
Furthermore, when combining two salts, the salt of one enantiomer may be
combined with the enantiomer or racemate of the same or a different salt.
[48]
Nowhere in
the patent is it stated or suggested that the racemate alone will provide
therapeutic amounts of NO. In fact, as discussed previously, the paragraph at
the top of page 2 warns against such use.
[49]
Critical
to an understanding of the issue in this case is how enantiomers are derived
from racemates. The patent at pages 5 and 6 describe this process. The
racemate is, in effect, chemically broken apart into what are called
diastereoisomers. These diastereoisomers are separated and then regenerated to
create the enantiomers. It says:
The R(+) and S(-) enantiomers
used in preparing the compositions of the invention may be prepared by chiral
synthesis from a suitable optically pure precursor or obtained from amlodiine
racemate by any conventional technique, for example, by chromatographic
resolution using a ‘chiral’ column or by the preparation of diastereoisomers,
separation thereof and regeneration of the desired enantiomer.
Specifically, diastereoisomers
may be obtained by reaction of the racemate which a suitably optically active
acid or base. The diasteroisomers are then separated, for example, by
chromatography or fractional crystallisation, and the desired enantiomer
regenerated by treatment with an appropriate base or acid. The other
enantiomer may be obtained from the racemate in a similar manner or worked up
from the liquors of the first separation.
[50]
A detailed
description of the process is given in Examples 1 and 2 at pages 10 to 12.
[51]
The rest
of the patent describes other matters such as how the enantiomers may be formed
into tablets or other forms of administration and how they may be administered.
[52]
There are
32 claims in the patent. No claim is directed to the racemate alone. Claims 1
through 21 and 24 to 28 are directly or indirectly directed to a composition of
R(+) and
S(-) enantiomers with R(+) being present in excess of 1:1
and up to 10:1. Claim 5 and dependent claims are directed to achieving this
ratio by mixing R(+) and S(-) crystals. Claim 8 and in particular claim 9 are
directed to achieving this ratio by mixing R(+) crystals with a mixture of R(+)
and S(-) crystals including mixing R(+) with the racemate. Claim 9 is the only
claim using the word racemate or racemic and it is in a context where extra
R(+) is added. Claims 29 and 31 and their dependant claims are directed to a
mixture of R(+) enantiomers and another medicine such as an ACE or PDE5
inhibitor. Thus the claims recognize when a mixture occurs, R(+) can be mixed
with a racemate, or such things as ACE or PDE5 inhibitors.
[53]
No claim
says that the R(+) as found in a racemate is itself sufficient. Even its
broadest claim, claim 1, demands a ratio greater than 1:1 of R(+) to S(-)
(keeping in mind that the racemate is 1:1).
[54]
To return
to the construction of claim 22 which says:
The R(+) enantiomer of
amlodipine or a pharmaceutically acceptable salt thereof for use in the
treatment of a condition for which a vascular NO-release agent is indicated.
and having in mind that principles expressed by the Supreme
Court in Whirlpool, surpra, it is plain and obvious that claim 22 does
not refer to the racemate. Considering claim 22 in light of the description
and the rest of the claims, as is required by Whirlpool, it is plain and
obvious that what is claimed in claim 22 is a composition that comprises
essentially only the R(+) enantiomer and that it is therapeutically effective
in treating a condition in which NO-release is indicated. The patent expressly
teaches away from the use of the racemate for treatment of a condition in which
NO-release is indicated.
d) Does the 493 Patent Claim the
“Medicine” of the NOC
[55]
From the
foregoing analysis it can be seen that whereas the uncontradicted evidence
shows that the notice of compliance for NORVASC is directed to the racemate, claim
22 is directed to one of the enantiomers contained in the racemate, the R(+)
enantiomer.
[56]
Pfizer
characterizes the racemate as being composed of two medicines, the R(+)
enantiomers and the S(-) enantiomer. It says that the law states that where a
notice of compliance relates to two medicines a patent relating to one of those
medicines can be listed under the provisions of section 4(1) of the NOC
Regulations.
[57]
In support
of this proposition, Pfizer relies on the decision of the Federal Court of
Appeal in Eli Lilly, supra, and in particular paragraphs 23 to 27 which
I repeat:
23 In the context of this
case, it is common ground that Tazidime is a drug containing ceftazidime, and
that Tazidime is a drug in respect of which Eli Lilly has been issued a notice
of compliance. There was some dispute in the court below as to whether
ceftazidime is a medicine.
24 The evidence is that
ceftazidime is an antibiotic. Amorphous lactose has no medicinal qualities but
prevents ceftazidime from degrading to toxicity. A [page155] formulation of
ceftazidime and amorphous lactose that is the subject of one of the claims of
the '969 patent would be considered to be a "medicine" as that term
is defined in section 2 of the PM(NOC) Regulations: Hoffmann-La Roche Ltd. v.
Canada (Minister of National Health and Welfare) (1995), 62 C.P.R. (3d) 58
(F.C.T.D.); affirmed (1996), 67 C.P.R. (3d) 25 (F.C.A.). However, it seems to
me that ceftazidime alone also meets the definition of "medicine".
25 The Judge reasoned
that, because ceftazidime by itself is toxic, it is not intended to be used for
the treatment of a disease or disorder, and is not capable of being so used. I
must respectfully disagree with that conclusion. An antibiotic does not cease
to be an antibiotic merely because it cannot function safely in the human body
until it is combined with a substance that prevents it from degrading to
toxicity. It would follow that for the purposes of the PM(NOC) Regulations, ceftazidime
is a medicine whether or not it is formulated with amorphous lactose.
26 It would also follow,
paraphrasing the words of subsection 4(1), that because Eli Lilly has been
issued a notice of compliance in respect of a drug, Tazidime, that contains a
medicine, ceftazidime, Eli Lilly is permitted to submit a patent list in
respect of the drug Tazidime. However, subsection 4(1) does not specify what
patents Eli Lilly is entitled to include on the patent list. That question is
determined on the basis of paragraphs 4(2)(b) and 4(7)(b).
27 Pursuant to paragraph
4(2)(b), the patent list submitted in respect of Tazidime may include any
patent that contains "a claim for the medicine itself". The word
"medicine" in paragraph 4(2)(b) must have the same meaning in that
provision as it does in subsection 4(1). If that is so, then in the case of a
patent list submitted for Tazidime, any patent that contains a claim for
ceftazidime itself, or that contains a claim for a formulation in which
ceftazidime is the active medicinal ingredient, is within the scope of
paragraph 4(2)(b).
[58]
In that
case the drug for which a notice of compliance had been granted was Tazidime.
That drug included an active ingredient ceftazidime which required another
substance, amorphous lactose, to render it sufficiently less toxic so that it
could be administered safely. The question which the Court of Appeal answered
in the affirmative, was whether a patent directed to the active ingredient
alone, ceftazidime, could be listed. As Sharlow, JA. For the Court said in
paragraph 25:
“An antibiotic does not cease
to be an antibiotic merely because it cannot function safely in the human body
until it is combined with a substance that prevents it from degrading to
toxicity. It would follow that for purposes of the PMNOC Regulations,
ceftozidime is a medicine whether or not it is formulated with amorphous
lactose.
[59]
It is
wrong to conclude that the Federal Court has said that where the notice of
compliance covers a combination, a patent directed to one of its components may
be listed. In Eli Lilly, supra, there was always only one medicine,
ceftazidime, the other compound was not a medicine but rather an ingredient
that rendered the medicine less toxic. The medicine always was only ceftazidime.
[60]
Here the
notice of compliance is for the racemate, amlopidine besylate. It is not
simply a mixture of two enantiomers. To achieve those enantiomers the racemate
must be chemically broken apart, the resulting pieces are isolated then
reconstituted as enantiomers. It is a substantial chemical reworking of the
molecules.
[61]
The notice
of compliance itself speaks only of a single medical ingredient, amlodipine
besylate, it does not speak of something made of two components. It is simply
wrong to consider amlodipine besylate as a medicine comprising two medicines.
[62]
Even if
amlodipine besylate were to be considered to be two medicines it would not
satisfy the Eli Lilly circumstances since in Eli Lilly there was
only one medicine which in the notice of compliance form had been rendered less
toxic not by another medicine but a compound having no medical effect of its
own; it simply made the medicine less toxic.
[63]
Therefore,
it is clear that the “medicine” of the notice of compliance the racemate
amlodipine besylate is not the R(+) enantiomer of claim 22 of the 493 patent.
In Conclusion
[64]
The
analysis as to “medicine” has been conducted based on the patent itself, its
description and claims, and uncontradicted evidence. There is no serious controversy
as to the law. While the analysis has been lengthy for clarity purposes the
result is plain and obvious, the 493 patent should not be listed under the
provisions of section 4(1) of the NOC Regulations as against the notice of
compliance in question.
[65]
As a
result the motion will be allowed, striking out these proceedings as they
relate to the 493 patent with costs to the moving party.
ORDER
FOR THE REASONS PROVIDED
HEREIN:
THIS COURT ORDERS that:
1.
The motion
is allowed;
2.
These
proceedings as they relate to Canadian Patent No. 2,355,493 are struck out; and
3.
The moving
party, Pharmascience Inc., is entitled to its costs.
“Roger
T. Hughes”
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