Date: 20060217
Docket: T-1350-04
Citation: 2006
FC 220
Ottawa, Ontario, February 17, 2006
PRESENT: The Honourable Mr. Justice von Finckenstein
BETWEEN:
PFIZER
CANADA INC. and PFIZER LIMITED
Applicants
and
THE MINISTER OF HEALTH and
RATIOPHARM INC.
Respondents
REASONS FOR ORDER AND ORDER
[1]
This is an
application by the Applicant, Pfizer Canada Inc. (“Pfizer”), pursuant to the Patented
Medicines (Notice of Compliance) Regulations, SOR/93-133 (the “NOC
Regulations”) for an Order prohibiting the Minister of Health (the “Minister”)
from issuing a Notice of Compliance (“NOC”) to the Respondent, Ratiopharm Inc.
(“Ratiopharm”), until after the expiration of Canadian Patent 1,321,393 (the
“393 Patent”).
[2]
This
application involves the drug entitled amlodipine. It is a cardiac drug that
acts as a calcium channel blocker. This enhances the blood flow to the heart
and reduces blood pressure. Pfizer markets and sells amlodipine besylate under
the brand NORVASC.
[3]
Pfizer
listed two patents on the Patent Register against NORVASC: the 393 Patent and
Canadian Patent No. 1,253,865 (the “865 Patent”). The 865 Patent expires on May
8, 2006 and therefore is not the subject of these proceedings. Ratiopharm
seeks the issuance of a NOC to allow it to produce a generic version of the 5
mg and 10 mg amlodipine besylate tablets after the 865 Patent expires on May 8,
2006.
[4]
Pfizer
commenced this application by a Notice of Application dated July 19, 2004 in
response to the Notice of Allegation (“NOA”) from Ratiopharm dated May 31, 2004
regarding the 393 Patent. Given section 7(1)(e) of the Regulations, judgment
must be issued within 24 months of this date.
NATURE OF PROCEEDINGS
[5]
The nature
of these proceedings was summarized by Justice Layden-Stevenson in Fournier
Pharma Inc. v. Canada (Minister of Health) (2004), 38 C.P.R. (4th) 297,
2004 FC 1718 as follows:
6 As
noted, this proceeding is brought under the Regulations. The history and scheme
of the Regulations have been delineated in various decisions of the Federal
Court of Appeal and need not be repeated here. See: Merck Frosst Canada Inc.
v. Canada (Minister of
National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.);...
Basically, issues of non-infringement and validity between the patent holder
(first person) and the person seeking a NOC from the Minister (second person)
originate with a NOA, served on the first person by the second person, setting
out the second person's allegations, including the legal and factual basis in
support. The first person may disagree and apply to the court for an order
prohibiting the Minister from issuing a NOC to the second person until after
expiration of the patent. (...)
8
Section 6 proceedings are not to be likened to actions for determining validity
or infringement. They are proceedings in judicial review, to be held
expeditiously, whose aim is to determine whether the Minister is free to issue
the requested NOC. Their scope is confined to administrative purposes: Apotex
Inc. v. Canada (Minister of National Health and Welfare) (1997), 76
C.P.R. (3d) 1 (F.C.A.). The determination must turn on whether there are
allegations by the second person sufficiently substantiated to support a
conclusion for administrative purposes (the issuance of a NOC) that an
applicant's patent would not be infringed if the second person's product is put
on the market: Pharmacia Inc. v. Canada (Minister of National Health
and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.).
9 By
merely commencing the proceeding, the applicant obtains what is tantamount to
an interlocutory injunction without having satisfied any of the criteria a
court would require before enjoining issuance of a NOC: Merck Frosst Canada
Inc. v. Canada (Minister of National Health and Welfare) (1998), 80
C.P.R. (3d) 368 (S.C.C.);...). The Regulations allow a court to determine
summarily, on the basis of the evidence adduced, whether the allegations are
justified. Section 6 proceedings are not adjudicative and cannot be treated as
res judicata. The patentee is in no way deprived of all the recourses normally
available to enable it to enforce its rights. If a full trial of validity or
infringement issues is required, this can be obtained in the usual way by
commencing an action: Pfizer Canada Inc. v. Apotex Inc. (2001),
11 C.P.R. (4th) 245 (F.C.A.);...
[6]
In its
NOA, Ratiopharm alleges that the 393 Patent is invalid by reason of:
a) anticipation;
b) obviousness; and
c) being an improper selection patent.
Pfizer, not unexpectedly, disputes these
allegations and alleges that the NOA was insufficient.
[7]
In order
to decide whether to grant an order prohibiting the Minister from issuing
Pfizer a NOC until after the expiration of the underlying 393 Patent, this
Court must conclude that Ratiopharm's allegations are not justified, i.e.
the Court must form the view that the 393 Patent is valid, as non-infringement was
not raised as an issue in these proceedings.
[8]
I propose
to consider the issues in the following sequence:
a) sufficiency of NOA;
b) anticipation;
c) validity of selection patent; and
d) obviousness.
PRELIMINARY ISSUE: BURDEN OF PROOF
[9]
Before
dealing with the substance of the allegations, I need to say a few words about
the burden of proof. This issue has been extensively canvassed by this court
and the court of appeal. Yet, Pfizer in its application stated:
1. An
issued patent is valid, in the absence of any evidence to the contrary.
Patent Act, R.S.C., 1985,
c. P-4, s. 45 (the “Act”)
2. It is “well settled” that the
presumption of validity governs the allocation of the burden of proof in a
section 6 application under the PM(NOC) Regulations:
a) the first person (in this case,
Pfizer) has the burden of establishing that the second person’s (in this case,
Ratiopharm’s) allegations of invalidity are not justified;
b) because of the presumption of
validity, the first person can meet that burden merely by proving the
existence of the patent; and
c)
once the patent has been proved, the burden
shifts to the second person to prove that the patent is invalid, on a balance
of probabilities.
(A.R. Vol. 8 p. 1940)
[10]
The issue
of the interaction of s. 46 of the Act and the NOC Regulations has been dealt
with on numerous occasions by this court (see Pfizer Canada Inc. v. Apotex
Inc. (2002), 22 C.P.R. (4th) 466, 2002 FCT 1138 at para 82 and 83 per
Dawson J; Abbott Laboratories v. Canada (Minister of Health)
(2004), 36 C.P.R. (4th) 437 at paras 103-106 per Gibson J; aff’d (2005), 339
N.R. 277, 2005 FCA 250; GlaxoSmithKline Inc. v. Genpharm Inc.
(2003), 30 C.P.R. (4th) 360, 2003 FC 1248 at para 45 per Heneghan J; Janssen-Ortho
Inc. v. Novopharm Ltd. (2004), 35 C.P.R. (4th) 353, 2004 FC 1631 at
paras 13-21 per Mosley J.; Sanofi-Synthelabo Canada Inc. v. Apotex
Inc. (2005), 39 C.P.R. (4th) 202, 2005 FC 390 at 209 per Shore J.). All
these cases stand for the proposition that the applicant must demonstrate, on a
balance of probabilities, that the respondent's allegations of non-infringement
or invalidity of the patent are not justified. The applicant has the overall
legal burden of proof. Nevertheless, the respondent, as the entity which has
made the allegations in the NOA, has the obligation to put these allegations
"in play", i.e. to ensure there is sufficient evidence of these
allegations by which to present issues for examination by the court (Eli
Lilly & Co. v. Nu-Pharm Inc. (1996), 69 C.P.R. (3d) 1, [1996]
F.C.J. No. 904 (F.C.A.) (QL)).
[11]
It is thus
the duty of the court to consider each of the allegations of validity, and in
view of the evidence submitted by the respondent, determine whether the
evidence submitted was sufficient to rebut the statutory presumption of
validity. If the evidence was sufficient, the court then considers the
evidence as a whole to determine whether the applicant had satisfied its burden
of disproving the respondent’s allegation of invalidity.
[12]
The law is
quite settled on this point and the interpretation given by the Applicant,
based on a single paragraph of a Federal Court of Appeal decision, taken out of
context, does not convince me to accept a departure from accepted
jurisprudence.
EXPERTS
[13]
Each side
marshalled a number of well qualified experts. Pfizer’s experts included Dr.
Gerald Brenner and Dr. Stephen Byrn.
[14]
Dr.
Brenner is a Pharmaceutical Chemist who holds a Ph.D. in organic chemistry from
the University of Wisconsin. He worked at Merck for 33 years and
his last position was the Senior Director of Pharmaceutical Research and
Development, and the Department Head for Pharmaceutical Research. Since
retirement, he has worked as a consultant.
[15]
Dr. Byrn
holds a Ph.D. as a Physical Chemist and has worked at Purdue University in Indiana for over 30 years. He has authored
numerous textbooks and book chapters on the solid state chemistry of drugs, and
published over 100 scientific papers in the area of physical chemistry.
[16]
Ratiopharm’s
experts included Dr. Robert Miller, Dr. Eli Shefter, and Dr. Stephen
Houldsworth.
[17]
Dr. Miller
holds a Ph.D. in Pharmaceutics from Temple University in Philadelphia. He was employed by Merck for two years
and responsible for pharmaceutical product formulation. He then worked for
Novopharm performing pharmaceutical product formulation, manufacturing process
design, and manufacturing technical support. From 1994 to 2002, he taught at
the University of
British Columbia.
[18]
Dr.
Shefter holds a Ph.D. in Pharmaceutics and has published over 100 papers on a
variety of pharmaceutical topics. He has conducted research on crystal
structure and the pharmaceutical activity of dihydropyridines. He is now a
self-employed consultant for pharmaceutical and biotechnology companies, an
adjunct professor at the University of California, and the Chief Scientific Director for a
company providing product development services.
[19]
Dr.
Houldsworth holds a Ph.D. in Organic Chemistry from the University of Nottingham,
England and is the Operations Team Leader at Dalton Chemical Laboratories Inc.
He is responsible for the day-to-day operation of the company and serves as
project manager for many contracts.
[20]
This case
does not turn on expert evidence. On all the key points, the experts are in
agreement. Their evidence only differs on what a person skilled in the art
would have anticipated or considered obvious. Ultimately, these are questions
for the court to decide. Therefore, although the expert evidence is useful, it
is not determinative. Accordingly, I will treat the expert evidence in the
same way as Justice Campbell in A B Hassle v. Apotex (2003), 27
C.P.R. (4th) 465, 2003 FCT 771:
16 Each of
the expert witnesses to the present case has sworn that the evidence they have
provided is true. On this basis, an evaluator of the evidence must start from
the proposition that the witnesses are credible unless good cause is shown, and
can be articulated, to the contrary (for an example of this general principle
see: Maldonado v. Canada (Minister of Employment
and Immigration), [1980] 2 F.C. 302 (C.A.). That is, while they
might hold differing views on a given topic, it must be assumed that they are
not just saying things to bestow a benefit on the party who is relying on their
evidence. In my opinion, it is unfair to the witnesses and, accordingly, to
each of the parties, to make negative credibility findings in the guise of
findings of weight without seeing and hearing each witness testify.
17 I have
absolutely no reason to question the credibility of each of the experts in the
present case.
PATENT CONSTRUCTION
[21]
Any case
involving patents starts with construction of the patent. In Biovail
Pharmaceuticals Inc. v. Canada (Minister of National Health
and Welfare)
(2005), 37 C.P.R. (4th) 487, 2005 FC 9, Justice Harrington succinctly
summarized the jurisprudence on the rules for patent construction at paragraph
15 which I intend to follow:
It is a
pre-requisite to considerations of both patent validity and infringement that
the language of what is claimed in the patent be properly considered. The Court
can do no better than to take the same approach in an NOC proceeding, keeping
in mind the restricted purpose of the proceeding. The Supreme Court has done
much to codify and clarify patent claim construction in two recent cases handed
down the same day: Free World Trust v. Électro-Santé Inc., [2000]
2 S.C.R. 1024 and Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R.
1067. The reasons in both were given by Mr. Justice Binnie. I take the
following principles as having particular relevance to this case:
1. A patent
is construed as a bargain between the inventor and the public. In consideration
of disclosing the invention, the inventor is given a temporary monopoly to
exploit it.
2. It is a
statutory requirement that the patent contain a specification and end with a
claim or claims "defining distinctly and in explicit terms the
subject-matter of the invention for which an exclusive privilege or property is
claimed". The specification must be sufficiently full, clear, concise and
exact "as to enable any person skilled in the art or science to which it
pertains, or to which it is most closely connected, to make, construct,
compound or use it". (Patent Act, R.S.C. 1985, c. P-4, as amended,
s. 27)
3. The patent
is notionally addressed to a person skilled in the art or science of the
subject-matter and is to be read as such a person would have read it when it
first became public. (More will be said about this skilled reader.)
4. The claims
are to be read in an informed and purposive way to permit fairness and
predictability and to define the limits of the monopoly "[I]ngenuity of
the patent lies not in the identification of the desired result but in teaching
one particular means to achieve it. The claims cannot be stretched to allow the
patentee to monopolize anything that achieves the desired result" (Free
World Trust, paras. 31, 32).
5. The claim
portion of the patent specification takes precedence over the disclosure
portion in the sense that the disclosure is read to understand what was meant
by a word in the claims "but not to enlarge or contract the scope of the
claim as written and thus understood" (Whirlpool, para. 52).
6. It is only
such novel features that the inventor claims to be essential that constitute
the "pith and marrow" of the claim. "The key to purposive
construction is therefore the identification by the Court with the assistance
of the skilled reader, of the particular words or phrases in the claims that
describe what the inventor considered to be the "essential" elements
of his invention" (Whirlpool, para. 45).
7. Some elements
of the claimed invention are essential and others are not, based either on
common knowledge when the patent was published or according to the intent of
the inventor, expressed or inferred from the claims. This lies at the heart of
Biovail's position that Novopharm's allegation that it will not infringe the
'320 patent is not justified. Put another way, was it obvious at the time the
patent was published that the substitution of a variant would make a
difference?
8. To
overclaim is to lose everything. If the inventor underclaims, the court will
not broaden the monopoly in the interests of the "spirit" thereof.
This often, as in this case, results in layers of claims, each limitation
serving as a potential safety net so that if the broadest claims fall, the
monopoly may be saved in part by the more modest claims.
9. Yet a
patent is not an ordinary writing. It meets the definition of a
"regulation" in the Interpretation Act, and must be read to assure
the attainment of its objects. "Claims construction is a matter of law for
the judge, and he was quite entitled to adopt a construction of the claims that
differed from that put forward by the parties." (Whirlpool, para. 61.)
[22]
The only
claim in issue is claim 11 of the 393 Patent which reads as follows:
“The besylate salt of
amlodipine”
Thus, the only thing that is claimed is the
besylate salt of amlodipine. No claim is made regarding the selection that led
to the besylate salt of amlodipine, its properties, its use, or its state.
[23]
The
disclosure of the 393 Patent points out that besylate was selected because of
its unusual combination of desirable properties when preparing pharmaceutical
formulations in terms of solubility, stability, non-hygroscopicity and
processability (stickiness). The examples then teach two methods on how to
prepare a besylate salt of amlodipine, and how to formulate tablets, capsules
and sterile aqueous solutions.
[24]
The
disclosure further reveals that besylate was tested against eight other
pharmaceutically acceptable salts of amlodipine in respect of solubility,
stability, non-hygroscopicity and processability (stickiness) and then ranked
them as follows:
Solubility and pH
(combined)
1. acetate
2. besylate
3. salicylate
Stability
1. besylate
2. mesylate
3. tosylate
Non-hygroscopicity
1. maleate (tied)
1. besylate (tied)
3. tosylate
Processability
1. mesylate
2. besylate
3. tosylate
On the basis of these tests, the disclosure
teaches that the besylate is an outstandingly suitable candidate for the
pharmaceutical preparations of amlodipine given its overall ranking in all four
categories.
SUFFICIENCY OF NOA
[25]
Pfizer
alleged in the oral argument before me that the NOA is insufficient as it:
1. Makes no reference to the testing
regarding stability that Ratiopharm commissioned from Dalton Chemical
Laboratories Inc. regarding the stability of maleates (the “Dalton Testing”);
2. It fails to make
reference to s. 34(1) of the Act, yet Rationpharm’s pleadings point to the failure
to comply with s. 34(1); and
3. It does not contain
the allegation to support paragraph 95 of Ratiopharm’s pleadings that “the
limited number of salts tested in the 393 patent were purely selected to make
besylate appear advantageous”.
[26]
The Dalton
Testing was conducted on Ratiopharm’s behalf in December 2003 to test the
stability of the besylate and maleate salts of amlodipine. It involved the
following:
In December
2003 Dalton Chemical was retained by ratiopharm Limited of Mississauga, Ontario
(“ratiopharm”) to conduct thermal stability studies on the raw active
pharmaceutical ingredient (“API”) amlodipine besylate and amlodipine maleate
and 10 mg tablet formulations of that API (the “ratiopharm Retainer”).
Specifically, Dalton Chemical was contracted to conduct degradation tests (the
“Degradation Tests”) on the API and tablet formulations at two temperatures (50̊ C and 75̊C) at ambient
humidity. The API and the tablets were to be analyzed using high performance
liquid chromatography (“HPLC”) at time zero and after one week’s, two weeks’
and three weeks’ storage under the two temperature conditions. The purpose of
the Degradation Tests of the API was to measure the number and amount
(percentage of the active ingredient) of breakdown products at specified time
points. The purpose of the Degradation Tests of the tablet formulations was to
measure the number and amount (percentage of the claim on the label of the
active ingredient) of breakdown products.
(Dr. Houldsworth’s
affidavit A.R. Vol. 6 tab 12 p. 1557)
[27]
It is well
established that the NOA and the detailed statement of legal and factual basis
for the allegation must provide all the facts the generic producer intends to
rely upon in subsequent prohibition proceedings. The maker of the NOA cannot
rely on facts that exceed those laid out in its detailed statement (see Procter
& Gamble Pharmaceuticals Canada, Inc. v. Canada (Minister of Health), [2003] 1 F.C. 402, 2002 FCA
290 at para 21 to 26).
[28]
In its
NOA, Ratiopharm contended that besylate offers no advantage over maleate in
terms of stability over the follow terms:
With respect
to stability, there is no disclosure of the number and amount of each impurity
and no disclosure of the degree of difference in stability between the salts
tested from which it could be concluded that a substantial advantage is secured
by the besylate salt. As at the date of the ‘393 Patent., the standard test
for impurity quantification employed by high performance liquid chromatography
(HPLC). No HPLC test results are reported in the ‘393 Patent. The thin layer
chromatography (TLC) test results reported in the ‘393 Patent results are
qualitative in nature. In fact, the besylate salt offers no substantial or
practically significant improvement in stability over any of the other salts
tested, and in particular, offers no substantial or practically significant improvement
in stability over the maleate salt of amlodipine identified in the prior art as
being particularly preferred.
(A.R Vol. 1 p. 29)
[29]
There is
no reference to the Dalton Testing or its result in the NOA. Yet, the Dalton
Testing was done in December 2003 and the NOA is dated May 2004. The Dalton
Testing results represent new facts that should have been alleged in the NOA so
that Pfizer could have produced its own countertest should it have so chosen.
Not having been apprised of the Dalton Testing in the NOA (except by the
oblique indirect reference above cited), Ratiopharm cannot now rely on such
tests to impugn the findings of stability of besylate. Applying and following
Mayne Pharma (Canada) Inc v. Aventis Pharma Inc. (2005), 38
C.P.R. (4th) 1, 2005 FCA 50 at para 21 and Aventis Pharma Inc. v. Apotex
Inc. (2005), 43 C.P.R. (4th) 161, 2005 FC 1283 para 305, I shall disregard
the Dalton Testing evidence.
[30]
Peripherally,
I might add that the Dalton Testing results would not have greatly advanced
Ratiopharm’s case as by the admission of its own witnesses:
a) the
results at 50 degree are anomalous and cannot be scientifically explained;
(Dr. Miller affidavit A.R. Vol. 6 Tab 10 p.
1500)
b) the tester used the wrong version of the
protocol and no explanation for this is provided; and
(Dr.
Houldsworth’s cross-examination A.R. Vol. 7 Tab 18 p.1907)
(Dr.
Shefter’s cross examination A.R. Vol. 7 Tab 17 p. 1860)
c) the test results from only
one machine are reported, yet two machines were used. No evidence is provided
as to the results from the second machine or why they have not been furnished.
(Dr.
Houldsworth’s cross examination A.R. Vol. 7 Tab 18 p. 1907)
[31]
With
respect to s. 34(1) of the Patent Act, R.S.C. 1985, c. P-4, which is
also known as the pre-1989 Patent Act (the “Old Act”), I fail to see the merit
of Pfizer’s allegation. Section 34(1) provides
34(1) An
applicant shall in the specification of his invention
(a) correctly and fully describe the invention and its operation or use as
contemplated by the inventor.
[32]
Section 34
requires that the specification disclose the invention. Whether a
specification adequately discloses the invention is to be considered from the
perspective of a workman of ordinary skill in the art. Two things must be
described in the disclosure of a specification: 1) the invention and 2) the
operation or use of the invention. For a selection patent, it is necessary to
disclose in the specification the special advantages that the special members
of the class possess (see Sanofi-Synthelabo, supra at para 56).
[33]
Ratiopharm
alleges that the disclosure in the 393 Patent fails to show whether the
besylate salt has any special stability property of any material significance
over the other acid addition salts tested. It does not identify any special
property that is surprising or unexpected over the other acid addition salts
that would support the conclusion in the 393 Patent that it is any more
“outstandingly suitable for the preparation of formulations of amlodipine” than
any other of the salts evaluated. The fact that it did not cite s. 34(1) is of
no import. The NOA makes it clear that Ratiopharm challenges the 393 Patent on
the basis, inter alia, of not being a valid selection patent, which is
an indirect way of saying that it does not comply with s. 34(1).
[34]
As to the
third point in paragraph 25, this is implicit in a challenge that the 393
Patent is an improper selection patent. Thus, there is no need to set this out
specifically in the NOA. Either it is a valid selection patent or not; the
motives for the selection are not at issue.
ANTICIPATION
[35]
Pfizer
alleges that the 393 Patent was anticipated by the European counterpart of the
865 Patent which is the European Patent Application 0089167 (the “EPA”). It is
not disputed that the EPA predates the 393 Patent by more than two years.
Subsection 27(1) of the Old Act reads:
27 (1)
Subject to this section, any inventor or legal representative of an inventor of
an invention that was
(a)
not known or used by any other person before he invented it,
(b)
not described in any patent or in any publication printed in Canada
or in any other country more than two years before presentation of the petition
hereunder mentioned, and
(c)
not in public use or on sale in Canada more than two years prior to
his application in Canada, may, on presentation to the Commissioner of a
petition setting out the facts, in this Act termed the filing of the application,
and on compliance with all other requirements of this Act, obtain a patent
granting to him an exclusive property in the invention.
[36]
The law in
respect of anticipation and selection patents was recently summarized by my
colleague Justice
Shore in Sanofi-Synthelabo,
supra where he stated in paragraph 55 and 56:
55
Anticipation means that the exact invention had already been made and publicly
disclosed. The test for anticipation was described in Beloit, [1986]
F.C.J. No. 87, and adopted by the Supreme Court of Canada in Free World [at
para 26]:
One must, in
effect, be able to look at a prior, single publication and find in it all the
information which, for practical purposes, is needed to produce the claimed
invention without the exercise of any inventive skill. The prior publication
must contain so clear a direction that a skilled person reading and following
it would in every case and without possibility of error be led to the claimed
invention. (Emphasis added.)
The choice of
the phrase "in every case and without possibility of error" is an
important choice of words. The mere possibility that one could be within the
claim is not, in and of itself, sufficient for anticipation.
...
As was
decided by this Court in Pfizer Canada Inc. v. Apotex Inc. [See
Note 27 below], a claim to a specific chemical compound cannot be anticipated
by a prior art reference which only teaches a broad class or genus of compounds
into which the compound falls because the prior art reference does not give
directions which inevitably result in the specific compound.
56 With
respect to the identification of specific beneficial properties in a particular
compound selected from a more general class of compounds, Fox in Canadian Law
and Practice (4th edition) at pages 89-90 states the following:
Invention may
be exercised by selecting one out of a number of substances for a particular
purpose even though others of that class have been used before for the same
purpose, provided there is a special advantage to be derived from the use of
the selected substance and its selection constitutes a definite advance upon
existing knowledge. While one who merely picks out a number of items from an
already disclosed group or series has not invented anything, yet it may be
otherwise if his researches have led him to the discovery that certain items in
the group or series possess qualities or characteristics peculiar to themselves
and hitherto unknown. (Citations omitted and emphasis added.)
In Re E.I. Du
Pont Nemours & Co. Application [See Note 28 below], the House of
Lords, in regard to newly identified beneficial properties, held:
The law
regarding selection patents has been developed to deal with this problem... The
present position was compendiously stated by Lord Diplock:
... The
inventive step in a selection patent lies in the discovery that one or more
members of a previously known class of products possess some special advantage
for a particular purpose, which could not be predicted before the discovery was
made... The quid pro quo for the monopoly granted to the inventor is the public
disclosure by him in his specification of the special advantages that the
selected members of the class possess. (Beecham Group v. Bristol
Laboratories International S.A. [1978] R.P.C. 521 at 579). (Emphasis
added.)
[37]
Thus, the
question becomes was a person skilled in the arts given such a clear direction
by the EPA that in every case, and without possibility of error, he would make
the salt claimed in the 393 Patent, i.e. the besylate salt of
amlodipine?
[38]
Before
applying these principles to the 393 Patent, the court notes that there is no
dispute as to the following facts:
a) the EPA and the 865 Patent claim
the discovery of certain 1,4 dyhydropyridines (which include amlodipine) and
their pharmaceutically acceptable salts;
b) the EPA and the 865 patent disclose the use of said 1,4
dyhydropyridines (which include amlodipine) and their pharmaceutically
acceptable salts as an anti-ischaemic or anti-hypertensive agent together with
a pharmaceutically acceptable carrier;
c) pharmaceutically acceptable salts (given that amlodipine
is a base) refers to the 80 anions identified in the seminal article of
Stephen Berge of January 1977 (“Berge”) in the Journal of Pharmaceutical
Sciences entitled “Pharmaceutical Salts” which lists approximately 80 salts
including besylate.
[39]
Salt
selection is a difficult and time consuming process. Dr. Brenner describes it
as follows:
Many drugs
are pharmaceutically active in their un-ionized (free) form; they do not need
to form salts in order to exhibit their desired physiological effects.
However, salt forms can change the properties of the parent molecule, including
physical and chemical properties that can have a positive influence in the
development of a commercial dosage form. For free acids or bases that do not
have optimal properties for formulation, salt selection can be used to change
or improve them. Many different properties of a drug can be altered or
optimized by the salt selection process.
...
Some drugs in
their free acid or base forms will exist at room temperature as oils (for
example, once of the salts in example 18 of the European Application) or as
solids with low melting points. Oils are not easy to purify and are not easy
to work with. Other drugs in their free forms will exist at room temperature
as “amorphous” solids. These are easier to handle than oils, but they are not
easy to purify. Purification— e.g., by crystallization – is important
in pharmaceutical development for at least a couple of reasons: the drug is
freed from potentially toxic impurities; and for drugs that are less than
optimally stable, the purer the drug typically the more stable it tends to be.
Many salts
exist as crystalline solids at room temperature. For pharmaceuticals, this is
the optimal form not only because crystals are easier to handle than oils, but
also because crystallization is the major purification process applied to
drugs.
The higher
melting point of many salts is also desirable in commercial pharmaceutical
formulation. In the tablet-making process, for example, a drug is subjected to
pressures that are high enough to generate heat and cause melting. The higher
the melting point of the drug, the more robust it will be for tablet
manufacturing purposes. I note from the disclosure of the European Application
that the free base of amlodipine would not be acceptable for preparing a tablet
formulation because the melting point is too low (79-80̊C). One would want to
select an amlodipine salt with a higher melting point. Based on the discloser
of the ‘393 Patent, amlodipine besylate would be an example of such a salt.
The disclosure indicates that the besylate salt has a melting point of 201̊C.
As my
examples illustrate, salt selection is a very important part of the
pharmaceutical development process because it offers the opportunity to tailor
the properties of the drug to a particular purpose. For the commercial
formulation of tablets, for example, salt selection can be used to optimize the
combination of properties important to this process, including stability,
non-hygroscopicity, solubility, melting point, handling and others.
Despite the
importance of salt selection, there has never been a way to determine how a
given acid will behave in combination with a given molecule, what properties
any resulting salt will have, or which particular salt of a drug will be the
best for a given purpose. The characteristics of salts are unpredictable and
have always been so. Salt selection has thus been described – accurately in my
opinion – as ‘a difficult empirical task”: see the well known review article
entitled “Pharmaceutical Slats” by S.M. Berge et al. in J. Pharm. Sci.
(1977), 66:1-19, ...
(Dr. Brenner’s affidavit A.R.
Vol. 4 Tab 4 p 1063)
This
evidence was not challenged on cross examination.
[40]
Similarly,
while there are 80 pharmaceutically acceptable salts on the Berge table, this
does not simply mean 80 tests; rather, it means millions of tests. As Dr. Byrn
noted in his affidavit, which also was not challenged:
The skilled
person would have no indication from the existence of besylate salts of other
compounds about the prospects of amlodipine besylate having a desirable
combination of properties for pharmaceutical formulation.
The
proposition, if indeed this is Ratiopharm’s proposition, that it is obvious to
make every possible pharmaceutically acceptable salt of a given compound and
test them all to find out which is the best one, is in my opinion
unreasonable. In addition to the numerous syntheses of the salts themselves
and the extensive testing for physicochemical properties, once has to deal with
the crystal properties of the salts. To do this, once would need to perform
extensive crystallization experiments under varying conditions – that is, with
different solvents, at different temperatures, with different concentrations
and at different evaporation rates – to identify a stable, crystalline form.
Millions of experiments would be required. As a practical matter, this number
of experiments would not be done, not least because the huge amount of raw
material that would be needed.
(Dr.
Bryn’s affidavit A.R. Vol. 4 Tab 5 p. 1100)
[41]
The EPA
teaches that 1,4 dyhydropyridines (which includes amlodipine) and their
pharmaceutically acceptable salts can be made, and uses the example of maleate
to show how they are made. It also teaches that this process can be replicated
with any of the 80 pharmaceutically acceptable salts referred to in Berge.
However, it does not teach a skilled person:
i) why to select benzene sulphonic acid (besylate) as
one of the initial choices to form an acid-addition salt for amlodipine;
ii) whether benzene sulphonic acid would form a salt
of amlodipine in the solid state; or
iii) the particular properties of amlodipine besylate or
their advantage for pharmaceutical formulations.
[42]
In light
of the foregoing, it seems apparent that a person skilled in the arts would not
in every case, and without possibility of error, on the basis of the EPA make
the besylate salt. Accordingly, I do not find that the EPA anticipated the 393
Patent.
VALIDITY OF SELECTION PATENT
[43]
Ratiopharm
contends that the 393 Patent is invalid for obviousness double patenting and is
an improper selection patent. It contends that:
(a) the selection of amlodipine besylate over the prior
disclosed class of pharmaceutically acceptable acid addition salts of
amlodipine does not meet the criteria of a valid selection patent; and
(b) that the disclosure of the 393 Patent is insufficient to
support the selection of amlodipine besylate over the other acid addition salts
based on a combination of solubility, hygroscopicity, processability
and stability characteristics.
[44]
In Whirlpool
Corp. v. Camco Inc., [2000] 2 S.C.R. 1067, 2000 SCC 67, Justice
Binnie stated at para 66 and 67:
There is,
however, a second branch of the prohibition which is sometimes called
"obviousness" double patenting. This is a more flexible and less
literal test that prohibits the issuance of a second patent with claims that
are not "patentably distinct" from those of the earlier patent....
In
Consolboard, supra, Dickson J. referred to Farbwerke Hoechst as "the main
authority on double patenting" (p. 536) which stood for the proposition
that a second patent could not be justified unless the claims exhibited
"novelty or ingenuity" over the first patent …
[45]
The
experts for both parties agree that the 865 Patent is a genus patent that
includes amlodipine bysylate. Amlodipine is expressed in claim 12 of the 865
Patent in organic chemistry nomenclature (see Dr. Shefter’s affidavit A.R. Vol.
6, Tab 11, p. 1519 at para 12; Dr. Byrn cross-Examination A.R. Vol. 5, Tab 9,
p. 1421, q. 130 to 132).
[46]
Unless the
patent can be characterized as a selection patent, the concept of obviousness
double patenting as enunciated by Justice Binnie in Whirlpool, supra
prohibits the issuance of a second patent with claims that are not patentably
distinct from a prior patent.
[47]
Selection
patents have their origin in I.G Farbenindustrie A.G.’s Patents (1930),
47 R.P.C. 289 at p. 322 where Maughan observed:
Three general
propositions may, however, I think, be asserted as true:- First, a selection
patent to be valid must be based on some substantial advantage to be secured by
the use of the selected members. (The phrase will be understood to include the
case of a substantial disadvantage to be thereby avoided.) Secondly, the whole
of the selected members must possess the advantage question. Thirdly, the
selection must be in respect of a quality of a special character which can
fairly be said to be peculiar to the selected group.
[48]
The
rationale for such policy can be found in Lord Glaisdale’s observation in E.I.
Du Pont de Nemours & Co. (Witsiepse’s) Application, [1982] FSR 303 (H.L.)
at p. 313:
The type of
invention which the law of selection patents was designed to foster appears
from the speech of my noble and learned friend, Lord Diplock, in Beecham
Group Ltd. v. Bristol Laboratories International S.A. [1978] R.P.C.
521, 579:
“The
inventive step in a selection patent lies in the discovery that one or more
members of a previously known class of products possess some special advantage
for a particular purpose, which could not be predicted before the discovery was
made (In re I.G. Farbenindustrie A.G.’s Patents (1930) 47 R.P.C. 283 per
Maugham J. at pp. 322/3.) The quid prop quo for the monopoly granted to
the inventor is the public disclosure by him in his specification of the
special advantages that the selected members of the class possess.”
[49]
An
excellent summary of the state of the law is found in the British text by T.A.
Blanco White, Patents for Inventors and the Protection of Industrial
Designs, 5th ed. (London: Stevens & Sons, 1983) at p 62,
para 14-110 where it states:
The current
view is, that disclosure of a class, even a very small class, whether the
disclosure is in general terms or by enumeration of the members, is not
disclosure of the individual members so as to make them no longer new. In
particular, mere recital of the systematic name of a chemical compound is not a
publication of it: a compound is not an old compound until it has actually been
made. Furthermore, an invention involving knowledge of the properties of a
compound has not been made, and so cannot be published, until the compound has
been not only made but tested for the properties concerned. It follows from
this approach that in any ordinary selection case the question is not one of
novelty but one of obviousness, utility and sufficiency of description, these
in the ordinary way.
[50]
A careful
examination of the 393 Patent reveals that no rationale is given why the nine
salts are only tested for solubility, stability, non-hygroscopicity and
processability. This is astonishing given that Pfizer’s own memorandum states
at paragraph 24:
One problem
with amlodipine maleate was its tendency to degrade. The structure of the
maleate part of amlodipine maleate allowed it to participate in a chemical
process known as a Michael addition reaction (MAR). The MAR converted
amlodipine maleate into a different molecule (MAR Product). The MAR Product
was biologically active and, in uncontrolled concentrations, could have posed a
risk to patient safety. As a result, Pfizer took the unusual step of
abandoning amlodipine maleate in mid-clinical testing, and undertook research
to discover an alternative and more advantageous salt.
[A.R. Vol.8 para 24]
[51]
No
rationale is given for the selection of the threshold factors. If we look at
the thresholds for each characteristic we see the following:
a) the threshold for
solubility is at greater than 1 mg ml-1 at pH 1-7.5 (close to that
of the pH of blood at 7.5). Why 1 mg ml-1 is not explained. Yet
table 1 on page 3 of the 393 Patent shows besylate with a solubility of 4.6
while mesylate is at 25, and acetate and hydrochloride are both at 50. The pH
at saturation of acetate and besylate is the same. In addition, the expert
evidence makes it quite clear that the pH factor could easily be adjusted by
addition of pH. Dr. Miller stated in his affidavit:
“The Ordinary
Formulator could have adjusted the pH of each of the salts by the selection of
an appropriate alkaline or acidic excipient in the solid state to improve
dissolution.
(Dr. Miller’s affidavit A.R. Vol. 6, Tab 10, p. 1499, para 47)
The threshold for solubility is thus
totally unexplained.
b) the threshold for stability
is not stated. To test for stability, each salt was blended in a powder vehicle
(in the case of tablets, the vehicle was comprised of microcrystalline
cellulose in 50:50 combination with anhydrous dibasic calcium phosphate),
sealed in vials, and stored at 50° C and 75° C for up to three weeks. The
salt, and any breakdown products, were then compared and ranked according to
the number and amount of breakdown products that were produced. Besylate turned
out to be the most stable. However, neither the magnitude of the number and
quantity of the breakdown products, nor the magnitude of the difference between
one salt and another was disclosed. Thus, it is impossible to tell the degree
to which besylate was more stable than mesylate for instance, and whether this
difference was significant. As D.r Shefter stated:
All that can
be gleaned from the disclosure in the ‘393 Patent with respect to stability is
that the sulfonate salts (besylate, mesylate and tosylate) are more stable than
the other salts evaluated (which are not sulfonate salts), and that the
besylate salt is the most stable of the sulfonate salts. As a result, the
disclosure fails to show whether the besylate salt has any special stability
property of any material significance over the other salts evaluated. The ‘393
Patent identified that amlodipine maleate, the preferred salt form of
amlodipine disclosed in the European Application raised concerns with respect
to stability as it tended to break down in solution after a few weeks. If the
stability of the pharmaceutically acceptable acid addition salts of amlodipine
would therefore have been of concern to the inventors named in the ‘393
Patent, I would have expected the inventors to quantify the stability
properties of the salts evaluated in the ‘393 Patent and for the ‘393 Patent to
specify the degree to which the besylate salts possessed the most stable
properties of the salts evaluated.
(Dr.
Shefter affidavit, A.R. Vol. 6, Tab 11, p. 1535, para 41)
c) the
threshold for non-hygroscopicity was that the salt had to remain unanhydrous
when exposed to 75% relative humidity at 37° C for 24 hours and when exposed to
95% relative humidity at 30° C for three days. No rationale is provided why
these parameters were chosen, or why all three parameters were changed for the
second experiment. Furthermore, as Dr. Miller states in his affidavit:
In my opinion
the test at 95% humidity is an extreme test because it is exposing the salt to
essentially a wet condition. A standard test for hygroscopicity would be to
expose the salt to 75% humidity. In my opinion, the results of the test at 95%
relative humidity cannot be used to predict that the tosylate salt would not be
anhydrous in tablet form. In my opinion, there is no practical pharmaceutical
difference to the hygroscopicity among the maleate, tosylate and besyalte salts
of amlodipine. Furthermore, the patent does not disclose the degree to which
the other salts of amlodipine picked up water in the test at 75% relative
humidity. It is possible that the other salts only picked up a very small
quantity of water in which case there would be no practical pharmaceutical
difference between those other salts and the maleate, tosylate and besylate
salts.
(Dr. Miller affidavit A.R. Vol. 6 Tab 10, p. 1501, para 57)
d) the
threshold for processability is set out as meeting the degree of stickiness to
a tablet
punch that maleate exhibits.
No rationale is provided why the maleate was considered to
represent the ideal degree on
non-stickiness, nor why the relative minute difference are so significant, nor
why they could not be fixed by addition of a lubricant. As Dr. Shefter
observed:
The test for
stickiness disclosed in the ‘393 Patent has little meaning for a number of
reasons. First, the amount of amlodipine in the tablet material that stuck to
the tablet punch is very small for each of the salts evaluated. In my opinion,
the differences between these amounts would be insignificant from a practical
perspective. As of the publication of the European Application in 1983, the
Skilled Formulator would have recognized the need to include a lubricant such
as magnesium stearate in a commercial tablet formulation and would have
adjusted the tablet formulation to achieve good compressability and lubricity
and thereby eliminate virtually all stickiness.
In fact, the
‘393 Patent acknowledges that good compressability of a tablet can be achieved
using suitable diluting excipients (‘393 Patent, p. 5). Furthermore, the 5 mg
and 10 mg formulations of amlodipine besylate that Pfizer makes available
include the excipient magnesium stearate (Lombardi Affidavit, Exhibit B-49).
If the superiority of the processablity properties of the amlodipine besylate
was surprising and significant, Pfizer would not have had to include a
lubricant such as magnesium stearate in its commercial formulation of
amlodipine besylate.
(Dr. Shefter
affidavit A.R. Vol. 6, Tab 11, pp. 1539-1540, paras 52-53)
[52]
As can be
seen from the forgoing analysis, all four factors had a totally unexplained
minimum threshold. No evidence was presented to show that any of the four
characteristics were not known beforehand. Similarly, no evidence was provided
to justify the minimum threshold in terms of regulatory requirements, industry
standards, ease of production, or minimization of costs. The 393 Patent only
verified the extent of the characteristic and compared it to nine other salts.
Meeting or surpassing these minimum thresholds (which Ratiopharm claims were
arbitrarily set) is described in the 393 Patent in the following manner:
It has now
unexpectedly found that the benzene suphonate salt (hereinafter referred to as
the besylate salt) has a number of advantages over the known salts of
amolodipine and, additionally has unexpectedly been found to have a unique
combination of good formulation properties which make it particularly suitable
for the preparations of pharmaceutical formulations of amlodipine
[53]
However,
in my view it is nothing of the sort. Any combination of the four
characteristics in the nine salts can qualify as unique, and as being
particularly suitable for pharmaceutical preparations of amlodipine, so long as
no rationale is given for choosing the minimum threshold. Any alteration of
these thresholds could result in another salt having “a unique combination of
good formulation properties which make it particularly suitable for the
preparations of pharmaceutical formulations of amlodipine”. In effect, these
thresholds can be manipulated to get the outcome one desires.
[54]
The
purpose of selection patents is to reward the inventor for discovering hitherto
unknown characteristics peculiar to the members of the selection. The purpose
is not to permit the creation of valid selection patents simply by allowing an
‘inventor’ to test the degree of known characteristics, setting unexplained
minimum thresholds without any justification, and then claiming any product
that meets the combination of these characteristics is unique.
[55]
What
Pfizer did in this case, in essence, amounts to no more than verifying that
besylate has the following degree of:
a) solubility: 4.6 mg ml-1, pH 6.6;
b) stability: it is most stable amongst Hydrochloride,
Acetate, Maleate, Salicylate, Succinate, Tosylate, Mesylate and Besylate;
c) Non-hygroscopicity: it remains non-hygroscopic when
exposed to 90° C for three days; and
d) Processability:
1.17 Fg Amlodipine cm -2, i.e. 58% relative to maleate.
It is trite law that verifying existing properties or their degree
is not inventing (see H.G. Fox, The Canadian law and Practice Relating to
Letters Patent for Inventions (4th ed) (Toronto: The Carswell
Company Limited, 1969), p. 90). In this case, there is no “substantial
advantage to be secured by the use of the selected members” nor is there a
“quality of a special character which can fairly be said to be peculiar to the
selected group” as required by the threefold test of I G Farbenindustrie, supra.
[56]
As far as
the ‘unique combination’ of these characteristics is concerned, in a case such
as the present one where there is no rationale for either the selection of the
characteristics or the thresholds chosen, I have to agree with the logic of
Ratiopharm’s submission which states:
Pfizer
contends that the unique combination of the formulation properties of
amlodipine besylate cannot be predicted and therefore possess an unexpected
advantage. If this contention is correct it would lead to the absurd result
that the selection of any [salt] of an AI and the verification of its
properties could be patentable. Any selected salt could be tested for any of a
number of properties which could conceivably support a claim to “unique
properties” that could not be predicted. Pfizer’s contention must therefore be
rejected.
(R.R.
amended factum para 87)
[57]
Accordingly,
the 393 Patent is not a valid selection patent, and Pfizer has failed to
disprove Ratiopharm’s allegation that the 393 Patent is invalid for obviousness
double patenting.
[58]
In light
of the foregoing finding, there is no need to address Ratiopharm’s allegation
of obviousness.
ORDER
THIS COURT ORDERS that that this application be dismissed with costs to the Respondents.
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