Date: 20070628
Docket: T-985-05
Citation: 2007 FC 688
Ottawa, Ontario, June 28, 2007
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
ASTRAZENECA AB,
AB HASSLE and
ASTRAZENECA CANADA INC.
Applicant(s)
and
APOTEX INC. and
THE MINISTER OF HEALTH
Respondent(s)
REASONS FOR JUDGMENT AND JUDGMENT
[1]
This
is an application by Astrazeneca AB, AB Hassle
and Astrazeneca Canada Inc. seeking an order of prohibition under the provisions
of the Patented Medicines (Notice of Compliance) Regulations, S.O.R./93-133
to prevent the Respondent, the Minister of Health (Minister), from issuing a
Notice of Compliance (NOC) to the Respondent, Apotex Inc. (Apotex), for the
production of omeprazole for use in a combination therapy to treat Helicobacter
pylori (Hp) infections. As can be seen from the following citations, this
proceeding is one of a long line of Canadian cases which have considered
omeprazole patents: see, for example, AB Hassle v. Apotex Inc. (2006),
47 C.P.R. (4th) 329, 2006 FCA 51 aff’g (2005), 38 C.P.R. (4th)
216 (F.C.); AstraZeneca AB v. Apotex Inc. (2006), 46 C.P.R. (4th)
418, 2006 FC 7; AstraZeneca Canada Inc. Apotex Inc. (2005), 40 C.P.R. (4th)
449, 2005 FCA 216 aff’g (2004), 34 C.P.R. (4th) 450, 2004 FC
647; AstraZeneca Canada Inc. v. Canada (Minister of Health) (2005), 40
C.P.R. (4th) 353, 2005 FCA 189 rev’g (2004), 36 C.P.R. (4th)
519, 2004 FC 1277 rev’d (2006), 52 C.P.R. (4th) 145, 2006 SCC 49; AstraZeneca
AB v. Apotex (2005), 335 N.R. 1, 2005 FCA 183 aff’g (2004), 33 C.P.R. (4th)
125, 2004 FC 44; AstraZeneca Canada Inc. v. Canada (Minister of Health) (2005),
38 C.P.R. (4th) 212, 2005 FCA 58 aff’g (2004), 36 C.P.R. (4th)
141, 2004 FC 1278 leave to appeal to S.C.C. refused [2005] S.C.C.A. No. 255; AB
Hassle v. Apotex Inc. (2003), 29 C.P.R. (4th) 23, 312 N.R. 288 (F.C.A.)
aff’g (2002), 223 F.T.R. 43, 21 C.P.R. (4th) 173 (F.C.), leave to appeal to
S.C.C. refused March 25, 2004, S.C.C. Bulletin, 2004, page 471; AB Hassle v.
Canada (Minister of Health and Welfare) (2002), 22 C.P.R. (4th)
1, 2002 FCA 421 aff’g (2001), 16 C.P.R. (4th) 21, 2001 FCT 1264
leave to appeal to S.C.C. refused [2002] S.C.C.A. No. 531.
[2]
The
Applicants (collectively referred to hereafter as Astrazeneca) are the owners
of Canadian Patents 2,025,668 (’668) and 2,133,762 (’762). This proceeding was
commenced by Astrazeneca in response to a Notice of Allegation (NOA) from
Apotex dated February 8, 2005. Apotex’s NOA alleged both non-infringement and
invalidity with the respect to the ’668 and ’762 patents. Its position is
summarized in the following passages from its Memorandum of Fact and Law:
5. Apotex has already obtained an
NOC to market and sell its Apo-omeprazole capsules for non-Hp
indications, namely, to treat ulcers by simply suppressing gastric acid and
therefore heal the ulcer, rather than killing the bacteria that cause the
ulcer. Apotex now seeks approval to sell its omeprazole capsules as part of
the triple therapy regimen currently approved by Health Canada for the eradication of Hp.
This triple therapy regimen consists of a combination of the acid suppressant
omeprazole and two antibiotics, namely, clarithromycin and either amoxicillin
or metronidazole. Omeprazole alone is approved by Health Canada to treat an ulcer (by healing
the ulcer), but is not approved as a single therapy to eradicate the bacteria.
6. Apotex filed a Notice of Allegation
(“NOA”) dated February 8, 2005, in which Apotex alleged that, with respect
to the ’668 Patent, its Apo-omeprazole capsules will not infringe any of its
claims, since its capsules will not be marketed or include an indication for
the eradication of Hp by the use of omeprazole alone as a single drug
therapy (rather than as a multiple drug therapy). The NOA further alleged
invalidity of the ’668 Patent on the basis of anticipation, inutility, no sound
basis to predict and ambiguity. With respect to the ’762 Patent, Apotex
alleged that its Apo-omeprazole capsules will not infringe certain claims
thereof since Apotex’s triple therapy regimen includes the use of omeprazole as
an acid suppressant, clarithromycin as an acid degradable antibacterial, and an
antibacterial compound that is other than an acid degradable antibacterial
compound, namely, amoxicillin or metronidazole. Further, the Apotex NOA
alleged invalidity of the ’762 Patent on the bases of anticipation, ambiguity,
obviousness, inutility, lack of sound prediction and on the basis of subsection
53(1) of the Patent Act. In response, Astra initiated the within
proceeding.
Issues
[3]
The
parties have raised numerous issues of construction and validity but in view of
my findings that the ’668 Patent is invalid on the ground of anticipation and
that the ’762 Patent is
invalid on the grounds of anticipation and
obviousness it is unnecessary to deal with several additional allegations of
invalidity raised by Apotex. The issues which I have resolved are the
following:
1.
Is
Apotex precluded from challenging the subject patents on the ground of abuse of
process?
2.
What
are the appropriate burdens of proof resting upon the parties and have they
been met?
3.
Should
the ’668 Patent be construed as proposing the use of omeprazole as a single or
multiple drug therapy?
4.
Was
the ’668 Patent anticipated by prior art teachings and to what extent are those
teachings citable?
5.
How
should the term “bioavailability” be construed in the ’762 Patent?
6.
Was
the ’762 Patent anticipated by prior art teachings and to what extent are those
teachings citable?
7.
Is
the ’762 Patent invalid for obviousness?
8.
Is
the ’762 Patent eligible for inclusion on the Patent Register?
9.
Costs?
Analysis
Abuse of Process
[4]
As
a preliminary matter, Astrazeneca contends that its application for an order of
prohibition should be allowed because Apotex’s prior judicial conduct
constitutes an abuse of process which precludes any right to challenge the
subject patents. It is, accordingly, necessary to deal with this issue before
dealing with the substantive issues of non-infringement and invalidity.
[5]
Astrazeneca’s
argument is based on the prior history of litigation between these parties regarding
the same patents that are the subject of this application. Astrazeneca argues
that Apotex should not be permitted to litigate new issues of non-infringement
and invalidity in this proceeding which it could have raised in those earlier
proceedings. It says that the substantive issues raised by this application
are necessarily bound up in the prior allegation of non-infringement and, by
implication, the failure by Apotex in the earlier proceedings to mount a
comprehensive challenge to the subject patents constitutes an acceptance of
their validity.
[6]
While
there are certainly situations where subsequent litigation or re-litigation in
this type of proceeding may be an abuse of process, that principle does not
arise in the circumstances of this case. Indeed, there is nothing about the
conduct of Apotex in the advancement of its legal interests either in this
proceeding or in the earlier proceedings which can be fairly impugned.
[7]
In
the two earlier proceedings, Apotex alleged only that it would not infringe
either of Astrazeneca’s patents because Apotex would not market or sell its
omeprazole product to treat Hp infections or as part of a combination treatment
regimen: see AB Hassle v. Canada (Minister of National Welfare) (2001),
16 C.P.R. (4th) 21 (F.C.T.D.) aff’d (2002), 22 C. P. R. (4th)
1 (F.C.A.) (AB Hassle #1) and AstraZeneca AB v. Apotex Inc.
(2003), 33 C.P.R. (4th) 97 (F.C.) (AstraZeneca AB). At that earlier
point, Apotex was content to enter the market in a limited way solely for the provision
of omeprazole as an anti-acid therapy – that being an old and permitted use for
the medicine. Apotex did not attempt to challenge the validity of either
patent or to mount an argument of non-infringement based on contested points of
patent construction. Instead, it simply advised Astrazeneca that what it
intended to do would not infringe either of its patents. Astrazeneca then
opposed the issuance of a NOC to Apotex based on an argument that infringement
by third parties would necessarily occur if Apotex entered the omeprazole
market even in a limited and ostensibly permissible way. In an appeal from the
decision in AB Hassle #1 Justice Edgar Sexton upheld the finding of
non-infringement of the ’668 Patent. He also noted the limited scope of that
patent and Apotex’s narrow claim to the use of omeprazole in the following
passages at paras. 6 and 7:
[6] Omeprazole was a known or
existing compound. The patent held by Hassle only relates to the new use of
omeprazole. Therefore, the '668 patent only reserves exclusive rights to
omeprazole that are somehow related to the treatment of Campylobacter
infections; it does not contain any claims for the compound omeprazole itself.
[7] The Appellants received
Apotex' Notice of Allegation ("NOA") in a letter dated October 4,
1999. The NOA stated in part:
With respect to patent 2025668, we allege
that no claim for the medicine itself and no claim for the use of the medicine
would be infringed by the making, constructing, using or selling by us of
capsules for oral administration containing omeprazole in strengths 10 mg, 20
mg, and 40 mg.
The legal and factual basis for the
aforesaid allegation is as follows:
The claims of this patent relate to the
use and treatment of Campylobacter infections. Our product will not be made,
used or sold for the treatment of Campylobacter infections and, more
particularly, we are not seeking approval for such use and no such use will be
included in our product monograph.
The Court went on to hold that, absent
inducement, the likelihood of third party downstream patent infringement (by
patients, physicians and pharmacists) was not a legal basis for claiming
infringement by Apotex of a new use patent. Such a claim, the Court held,
would allow the patent holder to control not only the new uses for an old,
unprotected compound but also the compound itself (see para. 57).
[8]
The
same result was obtained in AstraZeneca AB, above, where the subject of
the proceeding was the ’762 Patent and where AstraZeneca similarly challenged Apotex’s
allegation of non-infringement. In finding for Apotex, Justice John O’Keefe
defined the issue before him as follows:
[74] AstraZeneca can only succeed on
the facts of this case, if the references to concomitant use, increases in
bioavailability and the other impugned product monograph references (pp. 16 and
17) establish that Apotex is seeking approval to make use of Apo-Omeprazole
concomitantly with antibiotic substances to increase bioavailability, that is
to use Apo-Omeprazole with an antibiotic such as clarithromycin to achieve
better treatment.
[9]
Justice
O’Keefe then concluded by finding that the use sought to be approved by Apotex
was limited to the old approved use for reducing gastric acid secretion and, in
the result, AstraZeneca had failed to establish infringement of the ’762
Patent.
[10]
When
considered in the context of the above judicial history, Astrazeneca’s complaint
about abuse of process is incongruous. Its arguments that Apotex was “lying in
the weeds” and had, by serving a new NOA, “conveniently” retracted its earlier
position of non-infringement are also unmeritorious.
[11]
There
is nothing inherently objectionable about a generic manufacturer attempting to
move into the market with a product that is no longer protected by a patent.
Apotex was entitled to limit the scope of its allegations to an issue of
non-infringement so long as it was prepared to accept the commercial trade-off
of gaining only a partial entry to the marketplace for omeprazole. The other
obvious disadvantage to Apotex by adopting a two-stage approach for the use of
omeprazole is that it subjected itself to the burden of two separate statutory
stays for the issuance of a NOC.
[12]
The
complaint by Astrazeneca that Apotex’s incremental challenge to its patents is
somewhat wasteful of judicial resources ignores the fact that Astrazeneca was
the unsuccessful instigator of the previous litigation. Astrazeneca had the
option of allowing a NOC to be issued to Apotex for its limited use claim. By
not getting out of the way, Astrazeneca obtained the benefit of a 2-year, and
arguably unjustified, stay of the issuance of a NOC to Apotex. That may well
have been an acceptable litigation strategy but Astrazeneca cannot then use its
own unmeritorious challenge as the foundation for an abuse of process argument
alleging juridical inefficiency.
[13]
This
is not a situation where Apotex was attempting to split its case around an
issue of patent validity or to avoid some earlier unfavourable judicial
disposition by bringing new allegations forward. There are situations where a
party is expected to put its best and strongest case forward in the first
instance and where subsequent litigation will not be permitted. A good example
of this can be found in AB Hassle et al. v. Apotex Inc. et al. (2005),
38 C.P.R. (4th) 216, [2005] 4 F.C.R. 229, 271 F.T.R. 30, 137 A.C.W.S. (3d)
613, 2005 FC 234, aff’d (2006), 47 C.P.R. (4th) 329 (AB Hassle #2)
- a decision heavily relied upon here by Astrazeneca. The circumstances there,
however, were markedly distinct from the facts of this case. There, Apotex was
attempting to re-litigate a point which had been determined in an earlier
proceeding. Justice Carolyn Layden-Stevenson described the nature of the
problem before her as follows:
[80] It seems to me that Apotex's
submission begs the question. It did, in the previous proceeding, allege
non-infringement. Thus, it put the issue of "infringement" into play.
It does not advance any explanation for its failure to put its best foot
forward in the previous proceeding. To accept its submission, in my view, is
tantamount to allowing it to split its case. It enables Apotex to test the
waters on the construction of the patent and then, if unsuccessful (as it was),
to [page244] recast its case and get a second bite at the cherry. While I would
not go so far as to say (using the words of Mr. Justice Evans in P & G,
supra) that Apotex has hidden in the weeds, holding back a defence for use in
subsequent litigation, it certainly put all its eggs in one basket. This omission
is not of a procedural or technical nature; it is substantive. Apotex has not
persuaded me that the conditions for issue estoppel have not been met regarding
the issue of "infringement".
Justice Layden-Stevenson went on to say
that by limiting its allegations in the first proceeding, Apotex was implicitly
accepting the validity of the patent and was, therefore, estopped from
subsequently asserting invalidity.
[14]
On
appeal, Justice Karen Sharlow upheld the abuse of process finding but did so
with a caveat that it was justified “in the particular circumstances of this
case”. The Court went on to observe that there will be situations where a
generic manufacturer will be allowed to submit more than one NOA in relation to
a certain patent in respect to the same generic product (see para. 24) and some
examples were noted (see para. 25).
[15]
In
the recent decision in Pharmascience v. Abbott, 2007 FCA 140, aff’g
[2006] F.C.J. No. 492, 2006 FC 341, the Federal Court of Appeal closely
examined many of the previous authorities which had considered issue estoppel
and abuse of process in the context of multiple NOA proceedings. There the
Court upheld the decision of Justice O’Keefe where he had applied issue
estoppel to bar the generic manufacturer from advancing a second NOA which
brought forward new allegations of patent invalidity. On appeal, Justice Sexton
held that multiple NOA’s from the generic manufacturer concerning the same
product and alleging invalidity of a particular patent will generally not be
permitted even where different grounds are advanced for establishing invalidity
(see para. 41). However, the Court also recognized that there is a valid
distinction to be made between cases which raise validity issues and those
which allege only non-infringement. For example, in the context of a
non-infringement NOA, the generic is entitled to raise new allegations based on
new formulations of its proposed product. The Court summed up the distinction
in the following passage at para. 47:
…As has already been explained, the
situation of NOAs directed to non-infringement is distinguishable from the
situation of NOAs directed to invalidity. Because infringement is a factual
circumstance that varies depending on the formulation of the drug made by the
generic and the process used by the generic for making the drug, among other
things, multiple non-infringement NOAs may be permitted. Multiple NOAs
alleging invalidity, on the other hand, will rarely be acceptable.
[Emphasis added]
[16]
A
case which is more closely comparable to this one is Aventis v. Apotex
(2005), 44 C.P.R. (4th) 108, 2005 FC 1504. There, too, Apotex had
initially alleged in a NOA that it would not infringe the subject patent. The
only argument of invalidity made in the first proceeding was raised on a conditional
basis in response to an anticipated counter-argument on a point of claim construction.
That invalidity issue was not pursued by either party. When Apotex served a
second NOA raising issues of invalidity due to anticipation, obviousness and
double patenting, it was met with an abuse of process argument based on the
conclusion reached in AB Hassle #2, above. While Justice Danièle
Tremblay-Lamer observed that multiple challenges to a patent may not enhance
the efficiency of the judicial system, she found that the regulatory scheme
contemplates a sequential approach provided that the underlying legal and
factual bases were separate and distinct (see para. 41). She also declined to
accept that a generic challenger would be deemed to have accepted the validity
of a patent by not putting validity in issue in the context of an earlier
proceeding which raised only the issue of non-infringement (see para. 39). She
rejected the abuse of process argument, in part, for the following reasons:
[47] Thus, Apotex was entitled to
serve the second NOA because the second allegation is separate and distinct
from the first one. While the first dealt with non-infringement, the second
alleges that the patents are invalid based on anticipation, obviousness and
double-patenting. The issue of invalidity of the '457 patent is therefore
properly before this Court and does not give rise to the doctrine of abuse of
process.
While some of Justice Tremblay-Lamer’s
comments in Aventis, above, have been called into question by the
Federal Court of Appeal decision in Pharmascience v. Abbott, above, her
recognition of a distinction between proceedings which are limited to issues of
non-infringement and those which raise issues of validity was accepted by the
Federal Court of Appeal in the following passage at para. 48:
[48] In addition, Pharmascience
points to Aventis Pharma Inc. v. Apotex Inc., 2005 FC 1504, in which
Tremblay-Lamer J. refused to find a second NOA alleging invalidity of a patent
to be an abuse of process on that basis that a previous NOA alleging
non-infringement had proceeded to a decision. That case is of no assistance
here, however, where both NOAs alleged invalidity.
[17]
I
accept Justice Tremblay-Lamer’s conclusion that a generic challenger should not
be deemed to accept the validity of a patent by not putting that issue in play
in the first instance, particularly where infringement is the only issue raised.
In appropriate cases the abuse of process or issue estoppel doctrines are
sufficient to deal with the problem without resorting to an evidentiary
presumption of this sort.
[18]
Here,
Apotex had a legitimate basis for limiting its initial allegations to a single
issue of non-infringement. Presumably its commercial interest at that time was
limited to a partial entry to the market and the subsequent litigation with
Astrazeneca was joined on that basis. Such an approach did not prejudice
Astrazeneca’s competing commercial interests because it continued to enjoy a
monopoly for the uses of omeprazole which were arguably protected by its new
use patents. It has since had the benefit of a second statutory stay to
prevent the issuance of a NOC to Apotex as a consequence of this proceeding.
It has also offered no evidence of actual prejudice to its legal or commercial
interests and, in the absence of established harm, its abuse of process
argument must fail: see Merck & Co. v. Apotex Inc. (2003), 25
C.P.R. (4th) 289, 2003 FCA 234 at para. 79.
Burden of Proof
[19]
The
parties spent considerable time debating the finer points of the burden of
proof in this proceeding and each of them was able to marshal considerable
authority in support of its position. Suffice it to say that the ultimate
burden in this proceeding clearly rests upon Astrazeneca to disprove Apotex’s
allegation of invalidity on a balance of probabilities and it has failed to
meet that burden. Although there continues to be some controversy around the
intermediate burden resting on the second party challenger (see Abbott
Laboratories et al. v. The Minister of Health and Apotex Inc., 2007 FCA 153
at paras. 9 and 10 and Pfizer Canada Inc. et al. v. The Minister of Health
and Apotex Inc., 2007 FCA 209, at paras. 109 and 110), I am satisfied that
Apotex led sufficient evidence to rebut the presumption of validity on a
balance of probabilities and that Astrazeneca, in turn, has failed to meet its
burden of showing that the Apotex allegations of invalidity are unjustified.
The ’668 Patent Claims
[20]
The
’668 Patent is titled “Use of Omeprazole as an Antimicrobial Agent”. It
claimed to be a new use patent based on the inventors’ discovery that
omeprazole had antimicrobial activity and could, therefore, be used effectively
in the treatment of Hp. Omeprazole had been previously used in the treatment
of ulcers caused by Hp but only because of its known anti-acid or antisecretory
effects and it was understood that it was not a cure.
[21]
The
’668 Patent contains the following three claims:
(a)
Use
of omeprazole or a pharmaceutically acceptable salt thereof for the manufacture
of a medicament for the treatment of Campylobacter [ie. Hp] infections.
(b)
Use
of omeprazole or a pharmaceutically acceptable salt thereof for the treatment
of Campylobacter infections.
(c)
A
pharmaceutical preparation for use in the treatment of Campylobacter infections
wherein the active ingredient is omeprazole or a pharmaceutically acceptable
salt thereof.
Construction of the ’668
Patent
[22]
It
is agreed by the parties that the ’668 Patent must be construed as of its
publication date on August 19, 1990. There is also no obvious disagreement
about the general principles of patent construction, including the point that a
patent must be construed before any issues of invalidity are addressed. With
respect to all of the construction issues arising in this proceeding, I have
applied the principles expressed by the Supreme Court of Canada in Whirlpool
Corp. v. Camco Inc., [2000] 2 S.C.R. 1067, 2000 SCC 67, and in Free
World Trust v. Électro Santé Inc., [2000] S.C.J. No. 67, 2000 SCC 66, which
are fairly summarized by Justice Layden-Stevenson in Wyeth-Ayerst Canada
Inc. v. Faulding (Canada) Inc. [2002] F.C.J. No. 1263, 2002 FCT 969 at paras.
30-34:
30 Claims construction is
antecedent to consideration of both validity and infringement issues. Claims
construction is a matter of law. Whether the [respondent's] activities fall
within the scope of the monopoly is a question of fact. It is the claims that
define the monopoly: Whirlpool Corp. v. Camco Inc. (2000), 9 C.P.R.
(4th) 129 (S.C.C.).
31 The Patent Act requires the letters
patent granting a patent monopoly to include a specification which sets out a
correct and full disclosure of the invention. The disclosure is followed by a
claim or claims stating distinctly and in explicit terms the things or
combinations that the applicant regards as new and in which he claims an
exclusive property or privilege. It is the invention thus claimed to which the
patentee receives the exclusive right, privilege and liberty of exploitation: Free
World Trust v. Électro Santé Inc. (2000), 9 C.P.R. (4th) 168 (S.C.C.).
32 The disclosure is the quid
provided by an inventor in exchange for the quo of a monopoly on the
exploitation of the invention. It is important to know what is prohibited and
where it is safe to go while the patent is still in existence. The public
notice function is performed by the claims that conclude the specification. An
inventor is not obliged to claim a monopoly on everything new, ingenious and
useful disclosed in the specification. The usual rule is that what is not claimed
is considered disclaimed: Whirlpool Corp., supra.
33 There is a high economic cost
attached to uncertainty and it is the proper policy of patent law to keep it to
a minimum. Predictability is achieved by tying the patentee to its claims;
fairness is achieved by interpreting those claims in an informed and purposive
way. A purely literal application of the text of the claims would allow a
person skilled in the art to make minor and inconsequential variations and
appropriate the substance of the invention with a copycat while staying just
outside of the monopoly. A broader interpretation risks conferring on the
patentee the benefit of inventions that he had not in fact made but which could
be deemed with hindsight to be equivalent to what in fact was invented. This
would be unfair to the public and unfair to competitors: Free World Trust,
supra.
34 In Free World Trust,
supra, Binnie J. identified the principles to be applied to resolve the tension
between "literal infringement" and "substantive infringement"
to achieve a fair and predictable result. The principles are:
(a) The Patent Act
promotes adherence to the language of the claims.
(b) Adherence to the
language of the claims in turn promotes both fairness and predictability.
(c) The claims language
must, however, be read in an informed and purposive way.
(d) The language of the
claims thus construed defines the monopoly. There is no recourse to such vague
notions as the "spirit of the invention" to expand it further.
(e) The claims language
will, on a purposive construction, show that some elements of the claimed
invention are essential while other are non essential.
(f) There is no
infringement if an essential element is different or omitted. There may still
be infringement, however, if non essential elements are substituted or omitted.
[23]
One
of the construction issues raised by the parties is whether the ’668 Patent
should be read as relating to the use of omeprazole as a form of monotherapy to
treat Hp or as a combination therapy to be used in conjunction with antibiotics.
[24]
Apotex
alleged in its NOA that the ’668 Patent should be construed as though it
claimed only the use of omeprazole as a single drug therapy for the treatment
of Hp infections. It then asserted that its proposed use of omeprazole would
be in combination with antimicrobial medicines and, as such, there would be no
infringement of any of the claims of the ’668 Patent. If Apotex is correct on
this issue, the resolution of its invalidity arguments becomes unnecessary.
[25]
It
is clear enough that the Patent claims referenced above say nothing explicit
about the use of omeprazole either as a single drug therapy or as a constituent
part of a combination therapy program involving other medicines. Apotex says
that, in the absence of any reference to the use of omeprazole in combination
with other medicines, it should be assumed that what was intended by the
inventors was the use of omeprazole alone to treat Hp infections. It says that
this construction is supported by the language of the claims including the
reference in claim 3 to “a pharmaceutical preparation for the use in the
treatment of [Hp] infections wherein the active ingredient is
[omeprazole]”. If the claims were intended to cover the use of omeprazole in
combination with other “active” medicaments, presumably the claims would have
said so and, in the absence of clarity, the claims should be narrowly
construed.
[26]
Apotex
also relies upon the language of the patent disclosure which it says clarifies
what the inventors intended. It points to references which seem to indicate
that the inventors were claiming the use of omeprazole alone to treat Hp
infections. Those references include assertions that omeprazole is
particularly efficacious in the treatment of Hp infections and was
“surprisingly” found to have “excellent antimicrobial activity”. The only
reference to other medications is a statement that commonly used antibiotics
have been found to have “insufficient effect” in treating Hp infections.
Apotex says that these statements are testimonials to the utility of omeprazole
to treat Hp infections as a new gold standard or “wonder drug” for monotherapy use.
[27]
Apotex
also relies upon several references in the disclosure to pharmaceutical
preparations and dosages which contain no reference to the use of other active
medicines in association with omeprazole, but only to inert substances.
[28]
On
this issue, Astrazeneca relied upon the evidence of Dr. Richard Hunt, a
professor of medicine at McMaster University in Hamilton, Ontario. He has taught
gastroenterology at McMaster since 1982. Dr. Hunt expressed the view that
because the ’668 Patent contains no limitations on the use of omeprazole either
alone or in combination with other medicines, it should be read without any limitation.
In other words, all that the patent was claiming was that omeprazole had a
beneficial antibacterial effect. According to Dr. Hunt, a person skilled in
the art would know that omeprazole would need to be administered as part of a
combination therapy because single drug therapy had been shown to be
ineffective in most cases for eradicating Hp infections. Notwithstanding the
promises contained in the patent disclosure of the supposed excellent
antibacterial properties of omeprazole, it would still be seen as an adjunct to
effective treatment and not, on its own, as a cure.
[29]
Apotex
relied upon the evidence given by Dr. David Graham, a professor of medicine and
molecular virology and microbiology at Baylor College of Medicine in Houston,
Texas.
Dr. Graham
appears to agree with Dr. Hunt that omeprazole would not have been viewed in
1990 as being efficacious as a stand-alone treatment for Hp. In his affidavit
at para. 30, he stated:
30. Additionally, as at August 10,
1990, the skilled reader would be aware that one would not obtain
“substantially the same result” when comparing omeprazole therapy to the
multiple drug therapy. As stated above, omeprazole therapy was disclosed in
the Unge Abstract as producing only transient reduction with no eradication,
and my aforesaid 1989 publication entitled In Vivo Susceptibility of
Campylobacter pylori (Exhibit F) disclosed H. pylori infection as
being not susceptible to omeprazole. In contrast, the prior art taught that
multiple drug therapy consisting of omeprazole and amoxicillin would result in
eradication of the infection in some patients. As discussed further below,
eradication of the infection was (and still is) viewed as being the only
relevant outcome when treating H. pylori infection. As such, the
skilled person would have understood that the use of a multiple drug therapy
would have had a material change in the way the claimed invention worked.
The above passage seems to indicate that
although omeprazole might suppress the Hp bacteria, it was unlikely to
eradicate the infection. Nevertheless, Dr. Graham stated elsewhere in his
affidavit that the “skilled reader would understand the patent to be teaching
that omeprazole was sufficient on its own to eradicate Hp”. That statement not
only seems to exceed the scope of Apotex’s NOA which accepted that the term
“treatment” in the ’668 Patent could include a reduction in the level of
infection, but it also contradicts what was known about omeprazole at the time.
[30]
The
idea that treatment with omeprazole was known to be unlikely to eradicate Hp
teaches away from a construction of the patent that limits its scope to single
use therapy. In my view, the skilled person construing a pharmaceutical patent
must bring to bear the accepted wisdom in the scientific art supported by the
application of commercial commonsense. This point is made by the English Court
of Appeal in Ranbaxy v. Warner, [2006] EWCA Civ 876 at paras. 19-21, in
the following passages:
[19] I do not accept this.
Overshadowing everything is the fact that the skilled reader would know that
the R,R-enantiomer was the form which had all or by far the preponderance of
the pharmaceutical activity. He would expect the patentee to know that too. And
he would know that the patent claim was drafted by someone who knew what its
function was - to 'demarcate the invention' (per Lord Hoffmann in Kirin at p 185). There simply is no rational
basis for supposing that the patentee would want to exclude the pure enantiomer
which he would have known was the substance which really mattered.
[20] Mr Waugh's suggestions as to
why the patentee would want to limit the monopoly to the racemate simply do not
stand up - they are merely reasons why he would want to cover the racemate too.
True it is that 'a patent may, for one reason or another, claim less than it
teaches or enables' (per Lord Hoffmann at p 186) but that is not a reason for
interpreting the claim in the context of the patent in a way that no rational
patentee would have intended.
[21] Lord Diplock said in the
Antaios case [1985] AC 191, 201:
'I take this opportunity of re-stating
that if detailed and semantic analysis of words in a commercial contract is going
to lead to a conclusion that flouts business commonsense, it must be made to
yield to business commonsense'
Lord Hoffmann made it clear in Kirin at
31 that this applies equally to the construction of patent claims. It applies
here.
[31]
In
this case, the better view was expressed by Dr. Hunt where he testified that
the expectation of a skilled practitioner would be that effective Hp treatment
would require the use of omeprazole in combination with other drugs and not on
its own. This point was given both in his testimony and in his affidavit where
he stated:
23. The term “antimicrobial” would
have been understood by a skilled person to refer to inhibitory activity
against the bacterium, either bacteriostatic (inhibiting growth) or
bacteriocidal (killing). “Antimicrobial agent” would thus have been understood
to include an agent capable of inhibiting or retarding the growth or
multiplication of the bacterium. Therefore, I agree with Apotex’ understanding
that the term “treatment” as used in the ‘668 patent claims includes reduction
of infections.
24. I do not agree with Apotex,
however that the claims are limited to either single drug or multiple drug
therapy. As discussed above, the invention is predicated on the finding that
omeprazole is useful as an antibacterial agent. Provided omeprazole is so
used, alone or as part of multiple drug therapy directed to treating H. pylori
infection, the skilled person would understand that use to be use of
omeprazole in an antibacterial treatment of H. pylori. Further, the
skilled person, as of August 10, 1990, having reviewed the entirety of the
patent would also understand that the patent does not preclude the use of
omeprazole in combination with another active ingredient, such as an
antibiotic, to treat H. pylori. To the contrary, in this infection, it
was understood from early experience that multiple drug therapy was necessary
to achieve a higher eradication rate. For example, bismuth, metronidazole and
tetracycline, three antibacterial agents, were used as a combination therapy
for treating H. pylori.
[32]
There
is no doubt that the problem of construing the ’668 Patent presented by this
case could have been avoided by one or two simple clarifying phrases.
Nevertheless, it is open to being construed and I accept the position advanced
by Astrazeneca, that is, that the patent is not limited to the use of
omeprazole as a single drug therapy. It contemplates a use for omeprazole as
an antibacterial agent in the treatment of Hp infections whether used in
combination with other medicines or not. It is the intended use of the
medicine as an antibacterial agent that is advanced by the patent and not
whether it will be used alone or in combination. The fact that the patent
disclosure statements indicated that omeprazole was found to be highly
efficacious in the treatment of Hp does not lead logically to a conclusion that
the invention was intended to be limited to monotherapy use. I accept, as
well, that the patent does not promise eradication and should not construed as
though it does.
[33]
On
this point, I also find support in the decision by Justice Konrad von Finckenstein
in Abbott Laboratories Ltd. v. Canada (Minister of
Health),
[2006] F.C.J. No. 1766, 2006 FC 1411, where a markedly similar issue of patent
construction was raised and resolved as follows:
25 As to point b) I see nothing in
either claim that imports a limitation that Lansoprazole has to be used alone.
We know from Whirlpool, supra as quoted in Biovail, supra
that:
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, paragraph 52 [61]).
26 Thus, even if there was a
limitation implicit or explicit in the disclosure, it could not be imported
into the claims. Drugs often are not administered in a pure state but mixed
with an excipient or other drugs and the use of such drugs would be highly
restricted if the mention of a use of a drug would be read as implying it has
to be used alone. Unless the use claimed specifically employs such words as
"alone" or "not in conjunction with other compounds" it
would be improper to read such a limitation into the claim….
To the extent that Apotex’s allegation of
inutility was premised on its construction that the patent promised eradication
of Hp as a result of the stand-alone use of omeprazole, that argument, too,
must fail.
The ’668 Patent - Anticipation
[34]
On
the issue of anticipation, I would adopt the test described by Justice Roger
Hughes in Janssen-Ortho Inc. v. Novopharm Ltd., [2006] F.C.J. No. 1535, 2006
FC 1234, where he applied the Supreme Court of Canada decision in Free World
Trust, above, as follows:
105 The Supreme Court of Canada in Free World Trust v.
Électro Santé Inc., [2000] 2 S.C.R. 1024, 2000 SCC 66 outlined the test for
anticipation is in Canada. The Court said at paragraph
26:
... The legal question is
whether the Solov'eva article contains sufficient information to enable a
person of ordinary skill and knowledge in the field to understand, without
access to the two patents, "the nature of the invention and carry it into
practical use without the aid of inventive genius but purely by mechanical
skill" ... In other words, was the information given by Solov'eva for
[the] purpose of practical utility, equal to that given in the patents in
suit"?: ... as was memorably put in General Tire & Rubber Co. v.
Firestone Tyre & Rubber Co., [1972] R.P.C. 457 (C.A.) at p. 486:
A signpost, however clear,
upon the road to the patentee's invention will not suffice. The prior inventor
must be clearly shown to have planted his flag at the precise destination
before the patentee.
The test for anticipation is difficult to
meet:
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. [Beloit
Canada Ltd. v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.), per Hugessen J.A.,
at p. 297].
106 The House of Lords in Synthon
v. SmithKline Beecham PLC's Patent, [2005] UKHL 59 para. 19 (Lexis), [2006]
1 All. E.R. 685, [2006] RPC 10 has put the matter succinctly: there are two
requirements for anticipation, enablement and disclosure.
107 The Defendant argues that the
phrases "purely by mechanical skill" and "produce the claimed
invention without the exercise of any inventive skill" mean that if an
ordinary person skilled in the art could bring to bear on the publication the
understanding of the day and routine techniques of the day, from which the
invention as claimed would result, there is anticipation. This is not the
correct interpretation of the test for anticipation as set out by the Supreme
Court of Canada.
108 The Supreme Court test requires
that the "flag" be planted at the point of the claimed invention and
that the direction as to how to arrive at that point must be so clear such that
an ordinary person skilled in the art would in every case, without possibility
of error, be led to that point. No such flag is planted and no such direction
is given in either the '840 patent or the Daiichi publication. There is no
anticipation of what is claimed in claim 4 of the Patent.
[35]
Apotex
alleged in its NOA that each of the claims of the ’668 Patent is invalid on the
basis of anticipation. To support that allegation, it relied upon an abstract
titled “Does Omeprazole, 40 mg o.m., Improve Antimicrobial Therapy
Directed Towards Gastric Campylobacter pylori in Patients with
Antral Gastritis?” (the Unge Abstract) published in November 1988 and the
Application for Canadian Patent 1,330,759 (the ’759 Application) filed in Canada on October
12, 1988.
[36]
With
respect to the Unge Abstract, Apotex asserted that it anticipated both the use
of omeprazole alone and in combination with other antibacterial medicines to
treat Hp. It further alleged that the ‘759 Application anticipated the use of
omeprazole as a combination therapy to treat Hp. Astrazeneca disputes that the
Unge Abstract or the ‘759 Application anticipated the claims of the ’668 Patent.
With respect to the Unge Abstract, it says that the person skilled in the art
would not have understood that omeprazole was being used by Unge as an
antimicrobial agent to treat Hp. Such a person would have understood that Unge
was investigating omeprazole only for its anti-acid properties.
[37]
Astrazeneca
also discounts the value of the Unge study by describing it as a small pilot
study with insignificant or inconclusive results.
[38]
Astrazeneca
argues, in addition, that the Unge Abstract disclosed nothing about the
usefulness of omeprazole as an antimicrobial agent and, thus, gave insufficient
information to enable the skilled person to understand the invention.
[39]
With
respect to the ‘759 Application, Astrazeneca argues that Apotex’s NOA is
insufficient to put it on notice that it intended to rely upon the Application
document for the ’759 Patent as anticipatory rather than the ’759 Patent
itself. It argues that this distinction is important because the ’759 Patent
was published in 1994, well after the relevant anticipation date in 1989 and
is, therefore, not citable art. With respect to the substance of the ‘759
Application, Astrazeneca says that it did not anticipate the claims of the ’668
Patent because it disclosed only the use of omeprazole as an acid suppressant
for ulcer treatment and did not disclose any antimicrobial properties. The use
of omeprazole in combination with other drugs to treat Hp will not, therefore,
be an inevitable consequence of following the teaching of the ’759
Application.
The Unge Abstract
[40]
The
Unge Abstract is quite brief and I have set it out below:
Does Omeprazole, 40 mg o.m., Improve
Antimicrobial Therapy Directed Towards Gastric Campylobacter pylori in Patients
with Antral Gastritis?
Gastric infections with Campylobacter
pylori are difficult to eliminate with antibiotic therapy. This small
double-blind pilot study was undertaken in order to investigate the effect of
amoxicillin and pronounced inhibition of gastric acid secretion, against C.
pylori and/or Campylobacter-like organisms (CLOs). A total of 24
patients were included in the study, all of whom were culture positive for C.
pylori and/or CLO positive by histology within 2 weeks of start of
treatment. The patients were randomly assigned to 14 days of treatment in one
of three therapy groups: Group 1, omeprazole, 40 mg o.m., plus amoxicillin,
750 mg b.d. (9 patients); Group 2, omeprazole, 40 mg o.m. (8 patients); Group
3, amoxicillin, 750 mg b.d. (7 patients). Gastroscopy, with biopsy for culture
and histology was performed pre-entry, after 2 weeks’ treatment and 4 weeks
after stopping therapy.
Immediately after treatment 7 (7/8), 1
(1/8) and 5 (5/7) patients were negative by culture and/or histology in
treatment groups 1, 2 and 3 respectively. Four weeks after stopping treatment,
5 out of 8 patients in the group receiving omeprazole and amoxicillin in
combination were still negative by culture and/or histology. Whereas, in the
amoxicillin and the omeprazole groups, 1 (1/7) and zero (0/8) respectively, of
the patients, were negative. Except for one patient (Group 1), withdrawn on
Day 5 because of severe diarrhoea, only minor adverse events occurred. Thus,
antibiotic treatment might be improved by effective inhibition of gastric acid
secretion. Further and extended study appears to be justified.
[41]
Dr.
Hunt was of the opinion that Unge was using omeprazole in his experiment as a
control substance and not to assess its value as an antimicrobial agent. It
was on this point that he sought to distinguish Unge. His evidence on this was
as follows:
The objective of the study is to look at
the effect of the two together [omeprazole and amoxicillin]. The other two
arms are there as controls, not given with any expectation in the case of
omeprazole that it would have any effect.
[42]
Whether
Unge was expecting the outcome that he obtained is not, to my thinking, the
issue. What is important is what Unge found and he clearly found that omeprazole
had antibacterial properties when it was used on its own in patients with Hp.
Unge’s results established that omeprazole, when used on its own, had
significant suppressant effects on Hp which, according to Dr. Hunt’s affidavit,
would fulfill his definition of an antimicrobial agent used in the treatment of
Hp. At para. 23 of his affidavit, Dr. Hunt described the patent claims as
follows:
23. The term “antimicrobial” would
have been understood by a skilled person to refer to inhibitory activity
against the bacterium, either bacteriostatic (inhibiting growth) or
bacteriocidal (killing). “Antimicrobial agent” would thus have been understood
to include an agent capable of inhibiting or retarding the growth or
multiplication of the bacterium. Therefore, I agree with Apotex’ understanding
that the term “treatment” as used in the ’668 patent claims includes reduction
of infections.
[43]
It
is noteworthy that Dr. Hunt’s affidavit focuses on Unge’s longer term results
of using omeprazole (after four weeks) and ignores the clear evidence of the
short term suppression of Hp from omeprazole therapy. Those early results
contradict Dr. Hunt’s conclusion that a skilled person would read Unge as
addressing only omeprazole’s anti-acid properties.
[44]
On
this point, I prefer the evidence of Dr. Graham which is summarized in the
following passage from his affidavit:
66.
As
previously stated, a skilled person reading and following the directions of the
Unge Abstract would be repeating Unge’s work and, therefore, his treatment
regimen. The skilled person is therefore directed to administer the combination
of amoxicillin, 750 mg (bd) and omeprazole, 40 mg (om), for 14 days to patients
infected with H. pylori. At the end of the 14 days of treatment the
skilled person is directed to examine the patient for evidence of H. pylori
infection. A follow-up examination is then conducted 4 weeks later.
67.
By
following these directions the skilled person would inevitably be doing what
the ’668 Patent generally claims – the use of omeprazole (including as part of
a multiple drug therapy) to treat H. pylori infections.
68.
Therefore,
assuming the multiple drug treatment interpretation of the claims, the Unge
Abstract would be an anticipating disclosure of each of the claims.
69.
Although
Dr. Hunt suggests that the ’668 Patent is distinguishable from the Unge
Abstract on the basis that the in vitro MIC test result provided the
inventors with a theory as to the mechanism by which omeprazole could act
against H. pylori infections, for the practical purpose of carrying out
the claimed invention such a theory adds nothing to the directions or results
contained in the Unge Abstract which, when followed, will inevitably result in
what the inventors have claimed as their invention.
70.
In my
opinion the Abstract teaches the skilled person that omeprazole has a direct or
indirect antimicrobial effect against H. pylori since Unge observed a
transient reduction against H. pylori infection.
71.
Although
the Unge Abstract does not measure the MIC value of omeprazole against H.
pylori 8005, as was done by the inventors, said in vitro information is
of no practical consequence to the in vivo use of omeprazole against H.
pylori infections, but merely serves to verify Unge’s observation of
transient reduction with omeprazole treatment. The in vivo effect of
omeprazole against H. pylori infections when used in accordance with the
directions of the ’668 Patent was already disclosed by Unge. A subsequent
measurement of its in vitro activity against H. pylori 8005 has
no significance to the manner in which the claimed invention is practiced.
72.
Additionally,
Dr. Hunt’s, at paragraph 71 of his affidavit, acknowledges that the underlying
theories as to how or why omeprazole works against an H. pylori
infection are of no practical consequence when following a prior teaching that
described the use of omeprazole to treat an H. pylori infection. Dr.
Hunt states that subsequent to the filing of the ’668 Patent the belief as to
why or how omeprazole exerts its effects against H. pylori in vivo has
been debated, with opinions varying from omeprazole having an antibacterial
effect in vivo to having an effect by changing the gastric milieu. The
etiologic theories may change over time, however, the practical application of
the prior art teachings do not.
73.
Therefore,
under either interpretation of the claims, the Unge Abstract anticipates each
of the claims of the ’668 Patent.
I am, accordingly, satisfied that Unge
anticipated the ’668 Patent claim that omeprazole had antibacterial
properties.
[45]
Support
for this conclusion can also be found in the decision of the United States
District Court in Astra Aktiebolag et a. v. Andrx Pharmaceuticals Inc. et
al., 222 F. Supp. 2d 423 (S.D.N.Y. 2002) aff’d 84 Fed. App’x. 76 (Fed. Cir.
2003) (in Re Omeprazole litigation) (hereafter referred to as Astra
Aktiebolag) which was rendered in 2002 following a 52-day patent
infringement trial in New York. One of the
infringement questions in that case was whether Astra Aktiebolag’s U.S.
Patent ’342, which also claimed for the use of omeprazole as an antimicrobial
agent in treating Hp, was anticipated by the Unge study. The Court concluded
that it was. The decision dealt with the argument relied upon in this case by
Astrazeneca that Unge was looking at the antisecretory effects of omeprazole
and not at its potential value as an antimicrobial agent. That argument was
soundly rejected in the following passage:
… Although Dr. Czinn repeatedly insisted
that Dr. Unge was only interested in “what omeprazole as an acid secretory
agent does” (see, e.g., Czinn Tr. 6065:14-18, 6066:25-6067:5), he offered no
explanation as to why, if that was what Dr. Unge was interested in, Dr. Unge
never tested how well the omeprazole suppressed acid secretion but rather
tested only for the effect of omeprazole on the Group 2 patients’ H. pylori infections.
[46]
In
this case Astrazeneca has not advanced the unmeritorious argument raised in Astra
Aktiebolag that omeprazole was being used by Unge as a placebo. Clearly
omeprazole is not an inert substance and would never be reasonably seen as a
placebo for experimental purposes. Astrazeneca says, though, that Unge was
using omeprazole as a control to be compared to the efficacy of the combination
therapy. That may be so, but it does not take anything away from the fact that
Unge was using omeprazole on its own for treating Hp infections and found that
it had a suppressant effect. The findings of the ’668 Patent add nothing of
significance to what Unge had already established about the potential value of
omeprazole as an antimicrobial agent particularly when used in combination
therapies.
[47]
In
Astra Aktiebolag, above, the Court concluded its decision on the issue
of anticipation in the following passage:
… In the treatment described in the Unge
Abstract, it is undisputed that all medication is being prescribed to treat the
H. Pylori infection itself. Whether Unge may have speculated that omeprazole
would treat the H. pylori infection or facilitate that treatment through its
affect on the bioavailability of the antibiotic through the mechanism of its acid
suppressant effect is irrelevant – Unge was treating H. pylori infections, and
the disclosure of Group 2 treatment in the Unge Abstract demonstrates an actual
antimicrobial effect by omeprazole itself. For the foregoing reasons, the
court finds that Defendants have proven through clear and convincing evidence
that claim 1 of the ’342 patent is invalid as anticipated.
[48]
Even
though I am not bound to follow Astra Aktiebolag, above, I find its
reasoning on the issue of anticipation to be persuasive and strongly supportive
of my own view.
The ’759 Application
[49]
On
the preliminary issue of the sufficiency of Apotex’s NOA, Astrazeneca contends
that it described the ’759 Patent and not the ’759 Patent application as the
anticipatory reference and, since the ’759 Patent was not published until 1994,
it is not citable art. Astrazeneca’s argument has no merit. The NOA makes it
very clear that what Apotex was asserting was the earlier application for the ’759
Patent:
The ’759 Patent was filed in Canada on October 12, 1988 as
Application No. 580,114. This filing date is before the claim date for the
’668 Patent (February 9, 1989). The ’759 Patent lists Exomed Australia
Pty. Ltd, Ostapat Pty. Limited, Gastro Services Pty. Limited, and Capability
Services Pty. Limited as applicants of the ’759 Patent.
[Emphasis added]
The above disclosure could not have left
Astrazeneca with any doubt about the document being referred to and the NOA
provided it with “sufficient understanding of the case it had to meet” on this
issue: see Aventis Pharma Inc. v. Apotex Inc. et al. (2006), 46 C.P.R.
(4th) 401 (F.C.A.), at para. 14.
[50]
Astrazeneca
goes on to argue that the ‘759 Application was not anticipatory because it did
not describe the use of antisecretory agents like omeprazole in a combination
therapy for any purpose other than its buffering effects. Since the ‘759
Application did not ascribe any antimicrobial value to omeprazole, it did not
anticipate.
[51]
The
problem with Astrazeneca’s position on this issue is that the ‘759 Application
proposed omeprazole for use as an effective adjunct to the treatment of Hp with
antibiotics. It was therefore recognized in the prior art as a medicament for
the synergistic treatment of Hp and its supposed antimicrobial effects were
inherent in that prior use. If Astrazeneca’s position was correct, Apotex
would be prevented from using omeprazole as part of a combination therapy to
treat Hp for its obvious and previously known value as an acid suppressant in
accordance with the teaching of the ’759 Application because to do so would
inevitably infringe the ’668 Patent.
[52]
On
this issue, I agree completely with Apotex’s Memorandum of Law where it was
stated:
Where the mechanism of action is
inherent, it is irrelevant whether that mechanism of action was precisely
disclosed in the prior art.
The same point is convincingly addressed in
Dr. Graham’s affidavit where he stated:
81. For the practical purpose of
carrying out the directions of the ’759 Patent with respect to the use of
omeprazole as part of a multiple drug therapy in the treatment of H. pylori
infections, the hypothetical unimaginative skilled reader does not need to know
how or why that therapy works in order to carry it out when he is told said
treatment is useful for that purpose. Knowing that omeprazole has
antimicrobial activity against H. pylori in vitro is of no practical
consequence when following the directions of either the ’759 Patent or the ’668
Patent for the purpose of using omeprazole as part of a multiple drug regimen for
the treatment of H. pylori infection. It will neither change the
purpose to which the treatment is directed, the manner in which the treatment
works or the manner in which the treatment is administered. As such, following
the directions of the ’759 Patent would “inevitable result in something within
the claims;” “give clear and unmistakable directions;” and “give information
which for the purpose of practical utility is equal to that given by the
subject patent.”
[53]
What
the ‘759 Application teaches is precisely the form of therapy that Apotex now
proposes to utilize and that proposed use cannot be blocked simply because
Astrazeneca has identified some previously unknown property of one of the
therapeutic constituents. In short, no new use for omeprazole is proposed by
the ’668 Patent beyond the use that was previously recognized. If omeprazole
was, in fact, an excellent antimicrobial agent presumably it would be used
alone for that effect, but even Dr. Hunt conceded that no rational clinician
would ever use it that way. Its true value was and remains as an acid
suppressant which enhances the effects of the co-administered antibiotics.
Presumably Astrazeneca intends to continue to use omeprazole in the same old
way to achieve the well-known therapeutic effects for treating Hp, but it
cannot extend its monopoly by now asserting its dubious value as an
antimicrobial agent. To my thinking, the ’668 Patent is a classic case of
evergreening and it is invalid.
The ’762 Patent Claims
[54]
The
’762 Patent is titled “Synergistic Combination of a Substance with Gastric Acid
Secretion Inhibiting Effect and an Acid Degradable Antibiotic”. The Patent
Abstract described the invention as follows:
The invention consists of a combination
of a substance that increases the intragastric pH and an acid degradable
antibacterial compound. By this combined product regimen it will be
possible to obtain maximal local antibacterial effect of acid degradable
antibiotics as well as enhanced bioavailability of the active antibiotic, thus
resulting in higher amounts of the active compound in the gastric mucosa due to
secretion of weak bases. Both pharmacological effects contribute to drastically
increased antimicrobial capacity of acid degradable antibiotics to be used
against local infections in the gastrointestinal tract causing gastritis and/or
peptic ulcer. The invention also selects to the use of said combination and a process
for the preparation thereof.
[Emphasis added]
[55]
In
discussing the relevant prior art, the Patent acknowledged the following:
Proton inhibitors e.g. omeprazole and its
pharmaceutically acceptable salts, which are used in accordance with the
invention, are known compounds, e.g. from EP 5129 and EP 124495 and can be
produced by known processes. From US 5093342 it is also know that omeprazole
can be used in the treatment of Helicobacter infections. Further it has
earlier been proposed in WO 92/04898 to use a specific antibiotic, amoxycillin,
which is stable in gastric acid, in combination with pantoprazole in the treatment
of duodenal ulcers. No specific test data are included in said document. It
has also been described earlier by the Applicant to use amoxycillin in
combination with omeprazole in the treatment of duodenal ulcers.
From e.g. Science, March 22, 1946, p.
359-361 it is known that if acid degradable penicillins are administered orally
they will be destroyed by the acid content in the stomach.
Further it is described in Eur. J. Clin.
Microbiol. Infect. Dis, August 1988, p. 566-569 that some acid degradable
antibiotics are active in vitro against Helicobacter pylori.
[56]
The
“unexpected” finding of the inventors was supposedly that the combined use of
acid-suppressant compounds like omeprazole with an acid degradable antibiotic
led to an increase in the bioavailability of the antibiotic.
[57]
It
is accepted by the parties that only Claims 68 to 77 of the ’762 Patent are in
issue on this application. Those claims speak to the issue of the increased
bioavailability of acid-degradable antibiotics when used in combination with
either a histamine-H2 receptor blocking compound or a proton pump
inhibitor (both acid inhibitors). Those claims assert:
68. Use of a histamine-H2
receptor blocking compound or of a proton pump inhibitor for increasing the bioavailability
of an acid degradable antibacterial compound.
69. Use according to claim 68 of
omeprazole or a pharmaceutically acceptable salt thereof.
70. Use according to claim 68 of
lansoprazole or a pharmaceutically acceptable salt thereof.
71. Use according to claim 68, 69
or 70 for increasing the bioavailability of a weak base antibiotic.
72. Use according to claim 68, 69
or 70 for increasing the bioavailability of a microlide.
73. Use according to claim 68, 69
or 70 for increasing the bioavailability of a penicillin.
74. Use according to claim 68, 69
or 70 for increasing the bioavailability of benzyl penicillin.
.
75. Use according to claim 68, 69
or 70 for increasing the bioavailability of erythromycin.
76. Use according to claim 68, 69
or 70 for increasing the bioavailability of clarithromycin.
77. Use of omeprazole for
increasing the bioavailability of erythromycin.
[58]
Apotex
says that its proposed treatment regime will combine omeprazole (a proton pump
inhibitor), clarithromycin (an acid degradable antibiotic) and either amoxycillin
or metronidazole (neither being an acid-degradable antibiotic). In the result,
it says that only claims 68, 69, 71, 72 and 76 would arguable be infringed by
its proposed drug product.
[59]
Apotex’s
NOA challenged the validity of the ’762 Patent on the grounds of anticipation,
obviousness, ambiguity, misrepresentation, misleading and failure to disclose.
Needless to say, Astrazeneca takes issue with all of Apotex’s assertions of
invalidity.
[60]
On
the issue of anticipation, Apotex relies upon two prior art publications, the
first being an abstract authored by Petrino and others entitled “Omeprazole and
Clarithromycin, Treatment of Helicobacter Pylori Associated Duadenal Ulcer”
(Petrino) and the second being a letter by Logan and others published on July
25, 1992 in the Lancet entitled “Clarithromycin and Omeprazole for Helicobacter
Pylori” (Logan).
Is Logan Prior
Citable Art?
[61]
Because
the publication date of the Logan letter falls between two potentially relevant
priority filing dates for the ’762 Patent, it is necessary, as a preliminary
matter, to determine which of those filing dates is operative before
determining whether Logan is prior citable art. Apotex says that the operative
filing date was June 8, 1993 so that Logan is citable.
Astrazeneca says that the operative filing date was April 24, 1992 and,
therefore, Logan is not
citable. Logan is
potentially important because it disclosed the results of a clinical trial
involving the combination of omeprazole and clarithromycin for the treatment of
Hp.
[62]
On
this issue, Apotex relies upon section 28.1 of the Patent Act, R.S.C.
1985, c. P-4, which creates a presumption that the claim date for a patent is
the Canadian filing date unless the subject matter defined by the claim was
previously disclosed. In G. D. Searle & Co. v. Novopharm Limited,
[2007] F.C.J. No. 120, 2007 FC 81, Justice Hughes held that the priority
application must disclose “the same invention as claimed in the ultimate
patent”.
Astrazeneca contends that the “subject matter” of its patent was reasonably
inferable from the first priority application made in Sweden on April 24,
1992 so that the same invention was disclosed.
[63]
The
specific issue is whether the first Swedish priority application disclosed the
use of omeprazole and clarithromycin as a combination therapy. If it did not,
then Logan is clearly
citable art.
[64]
The
first Swedish priority application makes no specific mention of
clarithromycin. Instead it refers to the “antibiotic used in the combination
is one with a very narrow spectrum such as benzylpenicillin or an antimicrobial
weak base such as erythromycin base”. It is noteworthy that the second Swedish
priority application quite explicitly referred to clarithromycin in both the
outline of the invention and in Claim 7.
[65]
It
is necessary, then, to determine whether the language of the first Swedish
priority application was sufficient to support an inference that it included
clarithromycin. In my view, it was not.
[66]
The
teaching of the subject patent is the use of an acid suppressant with an acid degradable
antibiotic. Erythromycin, which is expressly referred to in the first Swedish
priority application, is more acid unstable than clarithromycin. I accept the
argument by Apotex that, in referring to erythromycin as the exemplar
antibiotic, it does not obviously follow that a more acid stable antibiotic
like clarithromycin was intended to be included within the patent claim. The
fact that the inventors expressly included clarithromycin in the second Swedish
priority application also adds support to this construction; otherwise this
reference in the second application adds only redundancy.
[67]
Although
Apotex adduced some expert evidence on this construction issue, I am not disposed
to give it any weight because it was based on a grammatical analysis. That is
a task that the Court is well able to carry out without relying on expert
opinion. I do, however, think it significant that counsel for Apotex was
prevented from questioning Astrazeneca’s expert witness, Dr. Piquette-Miller,
on the construction issues that had a scientific aspect. I can identify no
valid reason in the transcript for that refusal to answer and I do draw an
adverse inference that Dr. Piquette-Miller’s answers on this issue would
have been unfavourable to Astrazeneca.
[68]
For
the above reasons, I accept Apotex’s argument that the operative filing date is
that pertaining to the second Swedish priority application and, therefore, Logan is citable
art.
What Is the Meaning of “Bioavailability”?
[69]
Having
determined that Logan is citable art, it is necessary to determine
whether that article and the Petrino abstract anticipated the ’762 Patent. However,
before embarking on that exercise, it is necessary to resolve a construction
issue with respect to the term “bioavailability” as it is used in the Patent.
Astrazeneca argues that the term was used by the inventors in the narrow sense
of referring only to increases in the blood concentration of the referenced
antibiotic. Apotex says that it includes an increase in the concentration of
the antibiotic anywhere in the body (particularly at the site of action within the
stomach mucosa). This question is arguably important because some of the prior
art publications with respect to the issues of anticipation and obviousness
refer, at least implicitly, to bioavailability effects. Thus the equivalency of
those prior art references to the language of the Patent must be assessed.
[70]
Astrazeneca’s
expert, Dr. Piquette-Miller, offered a definition of bioavailability in her
affidavit.
[71]
Dr.
Piquette-Miller is an Associate Professor of Pharmacokinetics at the University of Toronto with a
research field in pharmacokinetics and molecular pharmacology. In 1994, she
was awarded a doctoral degree in pharmaceutical science (pharmacokinetics).
Pharmacokinetics involves the study of the absorption, distribution, metabolism
and excretion of chemical compounds in the human body. Dr. Piquette-Miller is
not a physician and, as of the time she testified, she had not worked with
omeprazole.
[72]
Dr.
Piquette-Miller was asked by Astrazeneca to review claims 68 to 77 of the ’762
Patent and to answer the following three questions:
(a)
whether
claims 68 to 77 would have been understood by the skilled person to claim use
of a gastric acid inhibitor, such as omeprazole, for increasing blood levels
(bioavailability) of an acid degradable antibacterial compound;
(b)
whether
the documents relied on by Apotex would not be understood by the skilled person
to teach the use of a gastric acid inhibitor, such as omeprazole, for
increasing the bioavailability of an acid degradable antibacterial compound;
and
(c)
whether
the skilled person would not have been led directly and without difficulty to
use a gastric acid inhibitor, such as omeprazole, for increasing the
bioavailability of an acid degradable antibacterial compound.
[73]
Dr.
Piquette-Miller defined the concept of bioavailability as the rate and extent
to which a drug enters the blood circulation so that an increase in bioavailability
is generally described as an increase in the amount of the drug in a patient’s
blood measured over time. She said, however, that bioavailability does not
include an increase in the local effect of the drug. She also opined that the
bioavailability of a compound after oral administration can be difficult to
predict because it can be influenced by a number of variables. For instance,
the combination of compounds intended to achieve and enhance local effects or
pharmaceutical synergies may lead to actual decreases in bioavailability from
the interaction of the compounds. Thus, an increase in bioavailability cannot
always be assumed from the increased efficacy of such a combination. Dr.
Piquette-Miller offered the following conclusion about the scope of the subject
patent claims at paras. 29-30 of her affidavit:
29. In my opinion, as of November
11, 1993, the skilled person would have understood claims 68 to 77 to claim the
use of a gastric acid inhibitor, such as omeprazole for increasing the blood
levels of the antibiotic specified therein. The claims are specific to
increasing bioavailability such that the claims would not be understood to
be directed to other effects described above, namely, increased local effect
(as descried in (i)) or increased efficacy of the antibiotic (as described
in (iii) and distinct from what could be attributed to increased
bioavailability.
30. Indeed, in my opinion, a
skilled person would have understood that the ’762 patent disclosed a novel
finding that use of a gastric acid inhibitor to increase gastric pH increases
the amount of antibiotic that is available for absorption into systemic
circulation. The bioavailability of the antibiotic is thus increased with
consequent advantages related to optimization of therapy. The patent therefore
claims such use (claims 68 to 77) and an optimized combination for use to treat
gastritis and peptic-ulcer including those caused by H. pylori
infections.
[Emphasis added]
[74]
Dr.
Mayersohn gave evidence on behalf of Apotex. He was of the opinion that
bioavailability is a term which deals with the rate and extent to which a drug
becomes available at the site of action. He observed that not all drugs reach
the site of action through the blood system albeit that blood concentrations
are often used as a surrogate for measuring bioavailability. He also stated
that a skilled person would know that orally administered antibiotics have both
local and systemic effects. At para. 26 of his affidavit he drew support for
this broader interpretation from the following language of the ’762 Patent:
By reducing the acidity in the stomach it
is possible to markedly increase the bioavailability of acid degradable
antibiotics thus leaving more of a given dose of the compound available for
local antibacterial effect as well as for absorption.
[75]
Dr.
Graham’s affidavit offered an opinion of bioavailability that was similar to
Dr. Mayersohn. His affidavit evidence on this issue was as follows:
142. The term “bioavailability” as it
appears in claims 68-77 of the ’762 Patent would be understood by the skilled
person to mean the degree to which a drug (in this case the antibiotic) becomes
available at the site of physiological activity (in this case the stomach wall
where H. pylori resides) after administration. In the context of the
claims of the ’762 Patent, where the antibiotic exerts its effects topically or
locally as well as systemically, the term bioavailability is not limited to the
degree to which a drug (in this case the antibiotic) is absorbed into blood.
143. The patent describes three means
by which the availability of the antibiotic increases at the active site: (i)
a local effect resulting from a decrease in the degradation of the antibiotic
occurring in the stomach; (ii) via increased absorption into the blood
as a result of the decreased degradation, and therefore by implication there is
an increased delivery of the antibiotic back to the stomach wall; and (iii) in
the case of weak base antibiotics, the transportation of said antibiotics to
the gastric mucosa becomes enhanced, therefore allowing for its accumulation at
that site. See page 4b, line 12:
By reducing the acidity in the
stomach it is possible to markedly increase the bioavailability of acid
degradable antibiotics thus leaving more of a given dose of the compound
available for local antibacterial effect as well as for absorption.
And page 7, line 8:
… The high plasma concentrations of
antibiotics after reduction of gastric acid secretion is evidence for a great
reduction of the degradation in the stomach of the antibiotics used. This
results in an increased amount of the active antibiotic in the gastric lumen,
thus resulting in increased local antimicrobial effect. It also leads to a
larger amount of antibiotic available for absorption, thus resulting in
increased plasma and tissue levels of antibiotic (increased bioavailability)…
And page 21, third paragraph:
By reducing the gastric acid secretion or
acid neutralization in the stomach the pH increases. Due to the less acidic
milieu the orally administered acid degradable antibiotic will be less
catabolised and thus locally exerting its antimicrobial effect. Another
advantage is that increased amounts of the antibiotic will pass into the small
intestine where it will be absorbed in biologically active form.
And at page 4b, line 18:
… Due to known physico-chemical
properties in general of weak bases like for instance omeprazole, the selection
of weak bases e.g. erythromycin favours an increased accumulation of the
antibiotic in the stomach wall and gastric crypts where the microbs [sic] e.g.
Helicobacter pylori resides.
And at page 21, last paragraph:
Those antibiotics which are
weak bases e.g. macrolides will be excreted via the stomach wall due to its
physico-chemical properties in congruence with other known weak bases i.e.
nicotine aminopurine and omeprazole (Larsson et al., Scand. J. Gastroenterol.,
1983, 85-900-7). Thus, the antibiotic weak base will be biologically
concentrated in the stomach wall, where the bacetias (e.g. helicobacter pylori)
reside.
144. Therefore, in my opinion, claims
68-77 of the ’762 Patent, which claim the use of an acid reducing agent for
increasing the bioavailability of acid degradable antibiotics, would be
understood to mean the use of an acid reducing agent for increasing the
availability of said antibiotics at the site of physiological activity (in this
case the stomach wall where H. pylori resides) after administration.
The claims would include any means by which the availability of the antibiotic
was increased at this site.
[76]
Although
both Dr. Mayersohn and Dr. Piquette-Miller were cross-examined extensively on
references in the medical literature to definitions for bioavailability which
differed from their own use of that term, the impression that was left is that
its meaning is highly dependant upon the context in which it is used. Simply
put, it does not have a universally applied meaning in the medical or
scientific community.
[77]
On
this issue, I would adopt the opinions of Drs. Mayersohn and Graham. The
patent disclosure does not purport to limit the scope of the claim to increased
bioavailability to systemic or bloodstream concentration of the antibiotic. In
fact, it seems to indicate that the term was intended to include increases in
the concentration of the antibiotic at the site of action (ie. the stomach
wall). This is evident from the passages quoted by Dr. Mayersohn and Dr.
Graham in their respective affidavits as noted above. It is very clear that
the Patent did not equate increased bioavailability only with increases in
plasma concentration. Within the Patent disclosure the inventors expressly
refer to higher plasma concentrations of the antibiotic. This suggests that
they were using the term bioavailability in a different and broader sense.
[78]
Given
Dr. Piquette-Miller’s acknowledgement that bioavailability has more than one
accepted meaning in the art and, in the absence of specificity in the patent
claims, I agree with Apotex that the term ought to be construed in its broadest
sense – that is, to include an increased concentration of the antibiotic at the
site of action as well as in the patient’s bloodstream. If the inventors had a
more restrictive meaning of the term in mind than is often applied to it in the
medical community, they should, and presumably would, have said so.
[79]
I
also do not accept Dr. Piquette-Miller’s assertion that bioavailability should
be defined by how drug concentrations are typically measured. The fact that
concentrations of a drug are most often measured by blood assay is nothing more
than an acknowledgment that measurement at the site of action is a profoundly
more difficult exercise. It does not logically lead to a conclusion that an
increase in antibiotic concentration may not be occurring elsewhere in the
body. Indeed, Dr. Piquette-Miller conceded that “we have to measure something”
to determine bioavailability and that testing blood is a “surrogate” for
assessing the bioavailability of a drug. Such acknowledgements do not lend support
to her narrow construction of the term bioavailability.
The ’762 Patent -
Anticipation
[80]
I
now turn to the prior art publications relied upon by Apotex. The Logan publication had
previously described an experiment involving 25 patients with Hp who were each
administered a combination of omeprazole and clarithromycin. The experiment
resulted in an 80% eradication rate for the Hp. The authors then postulated
that the therapy was effective for the following reasons:
Omeprazole, a proton pump inhibitor, has
been proposed as a suitable adjunct to H pylori treatment because it
directly suppresses H pylori and may increase the antibacterial
effectiveness of an antibiotic (eg. amoxycillin) by lowering the gastric pH
towards its pK or by increasing the gastric mucosal concentration.
[Emphasis added]
The article concluded with the following
recommendation:
These results suggest that new
dual-treatment regimens containing neither bismuth nor metronidazole may be
effective in eradicating H pylori. Further studies are needed to
optimise the doses and duration of clarithromycin with an appropriate antisecretagogue.
[81]
The
Petrino abstract did not speak to the issue of increased bioavailability but it
did recognize that the use of omeprazole and clarithromycin could be an
effective and well-tolerated therapy and it clearly anticipated the use of that
combination to treat Hp.
[82]
Astrazeneca
argues that Logan and Petrino both failed to anticipate that omeprazole
increased the bioavailability of clarithromycin which was the central aspect of
the invention claimed by the ’762 Patent. Apotex says that Logan did
anticipate the enhanced bioavailability of clarithromycin in the phrase
“increasing the gastric mucosal concentration” of the antibiotic. In the
alternative, it says that anticipation is established as soon as Logan and
Petrino identified a synergistic effect from the use of these two drugs in
combination, whatever the effective mechanisms may have been. Those effects
are inherent and inevitable from the use of the combination and, therefore,
anyone following prior art teachings in attempting to treat Hp would
necessarily infringe the ’762 Patent.
[83]
There
seems to be no disagreement among the expert witnesses that Logan and Petrino
anticipated the synergistic value of combining omeprazole and clarithromycin or
that the claimed bioavailability effects of that combination were inherent and inevitable.
These points are convincingly covered in Dr. Graham’s and Dr. Mayersohn’s affidavits
and were not seriously challenged by Astrazeneca’s expert, Dr. Piquette-Miller.
Dr. Piquette-Miller essentially accepted these points in the following passages
from her testimony when she was being questioned about prior art teachings:
Q. …The patent says
that any combinations coming within it, and you have told me this is one such
combination, will have an increased bioavailability in the antibiotic, correct?
A. Yes.
Q. This is such a
combination; therefore, this combination has an increased bioavailability in
the antibiotic by definition, yes?
A. It is what I would
expect. I would anticipate that there had been an increased bioavailability.
Q. Not just you would
expect.
A. The patent --
Q. Unless the patent is
invalid, it must have had an increase, because that is the premise of the
patent, correct?
A. That is correct.
…
Q. Okay. Then they go
on to say in the super-additive sense, and I take it in your paragraph 53 you
understood that expression, “super-additive sense” - - maybe it is not your
understanding.
Would you understand
the super-additive sense to mean synergistic sense, two plus two equals five
sense?
A. Yes, I would.
Q. What they are
expressing in this paragraph, boiling it all down, is that in the treatment of
Helicobacter pylori, you can get a synergy when you combine the proton pump
inhibitor with an antibiotic?
A. Yes.
[84]
The
only difference between Dr. Piquette-Miller’s evidence and that offered by the
Apotex witnesses was her view that Petrino and Logan failed to discuss the
bioavailability effects of the omeprazole/clarithromycin combination and that
her definition of bioavailability was much narrower than that of the other
witnesses. On the latter point, she interpreted bioavailability to be limited
to increases in the antibiotic concentrations in a patient’s blood which
allowed her to distinguish the reference in Logan to increases
in the gastric mucosal concentration of clarithromycin.
[85]
The
issue of enhanced bioavailability is also important to Astrazeneca because that
is the only arguable aspect of the ’762 Patent which takes it outside of what
was already well known in the art about the synergistic value of combining
omeprazole with acid degradable antibiotics.
[86]
In
my view, Logan not only
anticipated the use of omeprazole and clarithromycin as an effective and
synergistic combination (as did Petrino) but it also anticipated that this
combination worked because of omeprazole’s value in enhancing the
bioavailability of clarithromycin. Here, I accept Dr. Mayersohn’s view as
expressed at para. 66, 75 and 76 of his affidavit:
66. In my opinion, the above
passage in Logan et al., therefore, discloses that omeprazole would
increase the concentration of a weak base antibiotic, such as clarithromycin,
at the gastric mucosa (i.e., increase the bioavailability of clarithromycin).
…
75. Logan et al. provides
the skilled reader with all the information which, for practical purposes, is
needed to produce the claimed invention without the exercise of any inventive
skill.
76. Logan et al. anticipates
claim 76 of the ’762 Patent. As discussed in paragraph 66 above, this document
provides an exact prior description of the use of omeprazole to increase the
bioavailability of clarithromycin by increasing the concentration of
clarithromycin in the gastric mucosa.
[87]
Furthermore,
I accept Apotex’s argument that Logan and Petrino anticipated the treatment
value of using omeprazole and clarithromycin in combination and it does not
matter whether they were able to identify the precise mechanisms of action of
that combination. Anyone following their teachings would inevitably create the
bioavailability effect and thereby run afoul of the principle that “what would
infringe if later, anticipates if earlier”. This principle is well explained
by Justice Karen Sharlow in Abbott Laboratories Limited v. The Minister of
Health, 2006 FCA 187, where she described the anticipation issue in the
following passage:
[24] The relevant question, in
relation to the claim of the 274 patent for Form 0, is this: Is Form 0 formed
in the process of making Form I or Form II? That is a question of fact, to
which the undisputed answer is yes. A skilled practitioner who makes Form I or
II following the teaching of the prior art inevitably would make Form 0, even
if no steps are taken to stabilize it. The Form 0 might not be recognized, but
that does not matter: see Smithkline Beecham PLC's (Paroxetine
Methanesulfonate) Patent, [2005] UKHL 59, per Lord Hoffman, at paragraph
22:
[...] the matter relied upon as prior art
must disclose subject-matter which, if performed, would necessarily result in
an infringement of the patent. That may be because the prior art discloses the
same invention. In that case there will be no question that performance of the
earlier invention would infringe and usually it will be apparent to someone who
is aware of both the prior art and the patent that it will do so. But patent
infringement does not require that one should be aware that one is infringing:
"whether or not a person is working [an] ... invention is an objective
fact independent of what he knows or thinks about what he is doing": Merrell
Dow Pharmaceuticals Inc v N.H. Norton & Co. Ltd. [1996] R.P.C. 76, 90.
It follows that, whether or not it would be apparent to anyone at the time,
whenever subject-matter described in the prior disclosure is capable of being
performed and is such that, if performed, it must result in the patent being
infringed, the disclosure condition is satisfied. The flag has been planted,
even though the author or maker of the prior art was not aware that he was
doing so.
[25] Because a person who makes Form
I or Form II following the teaching of the prior art inevitably would make Form
0, that person would infringe the 274 patent as surely as Ratiopharm would
infringe it by making the Form II for its product, as it proposes to do, by a
method that results in the creation of Form 0. The situation is aptly described
by the learned authors of Hughes and Woodley on Patents (2nd edition),
at page 134 (paraphrasing Rinfret J. in Lightning Fastener Co. v. Colonial
Fastener Co., [1933] S.C.R. 377 at page 381):
[...] what would infringe if later,
anticipates if earlier.
The same thought is expressed as follows
by Jacob L.J. in Technic France S.A.'s Patent, [2004] R.P.C. 919 at paragraph
77:
And yet another way of looking at the
problem is to ask whether what is disclosed [in the prior art] falls within the
claim - if it had been later would it infringe?
[26] In my view, the only reasonable
conclusion on the evidence in this case is that the Ratiopharm's allegation of
invalidity due to anticipation is justified.
[88]
It
follows from all of the above the ’762 Patent is invalid on the ground of
anticipation.
The ’762 Patent - Obviousness
[89]
In
the recent decision in Janssen-Ortho Inc. v. Novopharm Ltd., [2007]
F.C.J. No. 809, 2007 FCA 217, Federal Court of Appeal restated the test for
obviousness in the following passage:
23 The accepted legal test for
obviousness is stated as follows in the leading case of Beloit Canada Ltd.
et al. v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.) at page 294, per
Hugessen J.A.:
The classical touchstone for
obviousness is the technician skilled in the art but having no scintilla of
inventiveness or imagination; a paragon of deduction and dexterity, wholly
devoid of intuition; a triumph of the left hemisphere over the right. The
question to be asked is whether this mythical creature (the man in the Clapham
omnibus of patent law) would, in the light of the state of the art and of
common general knowledge as at the claimed date of invention, have come
directly and without difficulty to the solution taught by the patent. It is a
very difficult test to satisfy.
24 The inquiry mandated by the Beloit test is factual and
functional, and must be guided by expert evidence about the relevant skills of
the hypothetical person of ordinary skill in the art, and the state of the art
at the relevant time. The expert evidence must be carefully assessed as to its
credibility and reliability. The classic warning from Beloit about hindsight must always
be borne in mind (at page 295, per Hugessen J.A.):
Every invention is obvious after it has
been made, and to no one more so than an expert in the field. Where the expert
has been hired for the purpose of testifying, his infallible hindsight is even
more suspect. It is so easy, once the teaching of a patent is known, to say,
"I could have done that"; before the assertion can be given any
weight, one must have a satisfactory answer to the question, "Why didn't
you?"
25 There is no single factual
question or a set of questions that will determine every case, or any
particular case. Justice Hughes, at paragraph 113 of his reasons, proposes a
list of factors to be considered when the validity of patent is challenged on
the basis of obviousness. The list is apparently derived from a survey of
numerous cases from Canada, the United States and the United
Kingdom. In my
view, despite the continual debate as to whether the legal test for obviousness
is the same in all of those countries, the list of factors proposed by Justice
Hughes is helpful to guide the required factual inquiry, and as a framework for
the factual analysis that must be undertaken. What follows is an edited version
of his list:
Principal factors
1.
The
invention
What is in issue is the patent claim as
construed by the Court.
2.
The
hypothetical skilled person referred to in the Beloit quotation
It is necessary to identify
the skills possessed by the hypothetical person of ordinary skill in the art.
3.
The body
of knowledge of the person of ordinary skill in the art
The common knowledge of the hypothetical
person of ordinary skill in the art includes what the person may reasonably be
expected to know and to be able to find out. The hypothetical skilled person is
assumed to be reasonably diligent in keeping up with advances in the field to
which the patent relates (Whirlpool at paragraph 74). The presumed
knowledge of the hypothetical skilled person undergoes continuous evolution and
growth. Not all knowledge is found in print form. On the other hand, not all
knowledge that has been written down becomes part of the knowledge that a
person of ordinary skill in the art is expected to know or find.
4.
The
climate in the relevant field at the time the alleged invention was made
The general state of the art includes not
only knowledge and information but also attitudes, trends, prejudices and
expectations.
5. The motivation in
existence at the time the
alleged invention to solve a recognized
problem
"Motivation" in this context
may mean the reason why the claimed inventor made the claimed invention, or it
may mean the reason why one might reasonably expect the hypothetical person of
ordinary skill in the art to combine elements of the prior art to come up with
the claimed invention. If within the relevant field there is a specific problem
that everyone in the field is trying to solve (a general motivation), it may be
more likely that the solution, once found, required inventive ingenuity. On the
other hand, if there is a problem that only the claimed inventor is trying to
solve (a unique or personal motivation), and no one else has a reason to
address that problem, it may be more likely that the solution required
inventive ingenuity. However, if commonplace thought and techniques can come up
with a solution, there may be a reduced possibility that the solution required
inventive ingenuity.
6. The time and effort involved
in the invention
The length of time and expense involved
in the invention may be indicators of inventive ingenuity, but they are not
determinative because an invention may be the result of a lucky hit, or the
uninventive application of routine techniques, however time consuming and
expensive they may be. If the decisions made in arriving at the solution are
few and commonplace, that may indicate that no inventive ingenuity was required
to arrive at the solution. If the points for decision were many and choices
abundant, there may be inventiveness in making the proper decisions and
choices.
Secondary factors
These factors may be relevant but
generally bear less weight because they relate to facts arising after the date
of the alleged invention.
7.
Commercial
success
Was the subject of the invention quickly
and anxiously received by relevant consumers? This may reflect a fact that many
persons were motivated to fill the commercial market, which may suggest
inventive ingenuity. However, it may also reflect things other than inventive
ingenuity such as marketing skills, market power and features other than the
invention.
8.
Meritorious
awards
Awards directed to the alleged invention
may be recognition that the appropriate community of persons skilled in the art
believed that activity to be something of merit. That may or may not say
anything about inventive ingenuity.
…
27 I emphasize that this list is a
useful tool, but no more. It is not a list of legal rules to be slavishly
followed; nor is it an exhaustive list of the relevant factors. The task of the
trial judge in each case is to determine, on the basis of the evidence, sound
judgment and reason, the weight (if any) to be given to the listed factors and
any additional factors that may be presented.
28 I would also repeat the caution of
Justice Hughes that catchphrases derived from this list or from the
jurisprudence are not to be treated as though they are rules of law. I agree
with the following comment of Justice Hughes from paragraph 113 of his reasons:
In this regard phrases such as
"worth a try" and "directly and without difficulty" and
"routine testing" have been used by the courts. It is not useful to
use such phrases as they tend to work their way into expressions of law or
statements of expert witnesses. Sachs L.J. deprecated the coining of such
phrases in General Tire & Rubber Company v. Firestone Tyre & Rubber Company
Limited, [1972] R.P.C. 195 at pages 211-12.
In reaching my conclusion that the ’762
Patent is invalid for obviousness, I have applied the above principles.
[90]
Apotex’s
case for obviousness is compelling. Dr. Mayersohn’s affidavit contains a thorough
survey of prior art publications which established without a doubt that the
treatment efficacy of acid degradable antibiotics for treating Hp was known to
be enhanced by combining them with acid suppressants.
[91]
Contrary
to Dr. Piquette-Miller’s views, some of the prior art publications also
postulate that the reason for the enhanced efficacy of the combination therapy
was the increased bioavailability of the antibiotic. For example, Westblom and
others in a 1991 publication entitled “Enhancement of Antibiotic Concentrations
in Gastric Mucosal by H2 – Receptor Antagonist – Implications for
Treatment of Hp Infections” described an experiment “to test the hypothesis
that local pH changes at the mucosal level would influence the transport of
antibiotics into the stomach when the therapy was combined with an acid
suppressant”. The authors went on to opine that omeprazole would likely affect
the concentration of antibiotics in the stomach.
[92]
Presumably
the focus of much of the identified experimentation around this question had
more to do with whether and to what extent these combination therapies worked
and less to do with identifying the exact mechanisms for why they worked. But
in any event, according to Dr. McClelland the issue of “why” was also well understood
at least in the general sense of increased bioavailability:
57. The Apotex documents show that
histamine-H2-blockers and proton pump inhibitors increase the pH of
gastric juice. This was especially true of the proton pump inhibitors such as
omeprazole where the increase was quite significant – several pH units. Since
pH is a log scale, this corresponds to several orders of magnitude decrease in
acidity.
58. Seeing this, the skilled
Medicinal Chemist would immediately recognize that the combination of an acid
degradable drug and a substance with an inhibiting effect on gastric acid
secretion would lead to less degradation of the acid degradable drug in gastric
juice. Because of the greater stability (and less degradation), the skilled
Medicinal Chemistry would know that there is increased bioavailability. In
order words, it would be obvious to the skilled Medicinal Chemist that the
combination of an acid degradable drug and a substance that raised the pH of
gastric juice would lead to increased bioavailability of the former.
[93]
Dr.
Graham also disagreed with Dr. Piquette-Miller on the issue of obviousness and
noted that the ’762 Patent itself recognized the problem of acid degradable
antibiotics being introduced to the acidic environment of the stomach:
213. Therefore, I disagree with Dr.
Piquette-Miller’s opinion that the skilled person was not aware that the
co-administration of an acid suppressant such as omeprazole and an acid
degradable antibiotic would result in an increase of the bioavailability of
said antibiotic.
214. Dr. Piquette-Miller analysis has
overlooked the problem the inventors were attempting to solve – how to prevent
the degradation of acid degradable antibiotics caused by gastric acid in order
to allow for their use against H. pylori infection; see page 1 line 19:
Helicobacter pylori is affected by
certain antibiotic compounds e.g. macrolides and penicillins as has been shown
in vitro and in vivo. However, these products are degraded into
nonantibacterial metabolites in the presence of gastric acid, which drastically
reduces their antibacterial efficacy.
And at page 2, line 19:
From e.g. Science, March 22, 1946, p.
359-361 it is known that if acid degradable penicillins are administered orally
they will be destroyed by the acid content in the stomach.
And at page 4C, first paragraph:
The new combination is especially
directed to the treatment of gastropathies e.g. induced by Helicobacter pylori
infections. Helicobacter pylori is a gram-negative spirilliform bacterium which
colonises in the gastric mucosa. Treatment with commonly used acid degradable
antibiotics alone has given insufficient effect.
215. This problem had already been
recognized in the prior art. And so was its solution.
[94]
Dr.
Mayersohn also agreed with Drs. Graham and McClelland. His extensive review of
the prior art literature disclosed a number of instances where the increased
bioavailability of an acid degradable antibiotic was recognized as a mechanism
of action for these combination therapies. He then offered the following
summary of his findings:
118. In conclusion, I have reached
the opinion that the purported invention of claims 68 to 77 of the ’762 Patent
was anticipated and made obvious by the prior art literature discussed in this
affidavit. It is on this basis that I find incredulous the following statement
made by the inventors of the ’762 Patent:
(pages 2, line 27 to page 3, line 5)
It has now unexpectedly been found that
a combination of a substance with inhibiting effect on gastric acid secretion,
thus a substance which increases the intragastric pH (e.g. proton pump
inhibitors, histamine-H2-blockers, and one or more antibacterial
compounds which is acid degradable give high plasma concentration of the
antibiotic following oral administration.
This observation is not novel, new or
unexpected. It is completely consistent with what one of ordinary skill in the
art knew or was capable of predicting, based upon basic principles of chemistry
and the prior art.
119. Therefore, one of ordinary skill
in the art would have been able to reach the purported invention directly and
with no difficulty. Furthermore, the inventors of the ’762 Patent have
conducted no inventive experiments; but rather routine, typical and commonplace
testing, which anyone of ordinary skill could simply have conducted; there is
no inventive ingenuity in obtaining plasma samples and assaying for the
presence of antibiotic. The authors of the ’762 Patent have conducted simple,
straightforward experiments, which at best provided a validation for what was
known in the prior art by one of ordinary skill.
[95]
Dr.
Piquette-Miller’s position on obviousness was, of course, different from the
evidence of Apotex’s three experts. She again focussed on the issue of
bioavailability. She opined that the prior art publications were insufficient
to establish that a skilled person would have been led directly and without
difficulty to the use of omeprazole for increasing the bioavailability of an
acid degradable antibiotic like clarithromycin. Although Dr. Piquette-Miller
conceded in her testimony that an increase in the bioavailability of these
combination was inherent in the prior treatment models, her affidavit dismissed
the significance of the prior art teachings in the following passages:
76. Quite simply, the documents do
not, in any way, mention, propose, discuss or establish bioavailability. A
skilled person would not know and there was no suggestion that, in view of the
documents, that a gastric acid inhibitor could be used for increasing the
bioavailability of an acid degradable antibacterial compound.
77. I therefore disagree with
Apotex’ statement that the use of a substance that inhibits gastric acid
secretion and thus increases intragastric pH, to increase the bioavailability
of an acid degradable antibacterial compound was known.
[96]
There
is also a rather telling and lengthy exchange between Dr. Piquette-Miller and
counsel for Apotex which shows her to be somewhat less than an objective
analyst of the patent claims and of the prior art disclosures. When she was
asked the rather obvious question about whether a prior art publication
disclosed that the stability of amoxycillin was shown to be improved in the
presence of omeprazole, she disputed the point by suggesting that the
publication did not refer specifically to omeprazole. However, the publication
made it very clear that the stability of amoxycillin had been shown to be
improved in a more neutral pH environment. She also conceded that omeprazole
reduces the acidic levels in the stomach leading to increased pH levels.
Nevertheless, she refused to admit the obvious and rather weakly contended that
the publication lacked the necessary parameters to support counsel’s
suggestion. This was only one of a number of similar exchanges.
[97]
On
the issue of obviousness, Dr. Piquette-Miller’s definition of bioavailability
continued to be limited to increases in blood plasma concentrations of the
antibiotic. This allowed her to distinguish the prior art publications which
spoke of increased antibiotic concentrations in the stomach mucosa. For the
reasons previously given, I do not accept Dr. Piquette-Miller’s definition of
bioavailability as that term is used in the Patent. I, therefore, reject her
evidence insofar as it rests upon her definition of that term. I also reject
her interpretation of the Jones publication which identified an increase in the
blood serum concentration of benzylpenicillin in one of five patients tested
and wherein the authors described this as a “side effect” of the combination
therapy. Dr. Piquette-Miller was of the view that a skilled reader would
not interpret this article as having equated a side effect with an increase in
bioavailability. She also discounted the value of the study because it was limited
in scope and preliminary. She took issue with the significance of several of
the other prior art studies on similar grounds of insufficient methodology or
analysis. In a number of exchanges with counsel, Dr. Piquette-Miller
discounted the significance of prior art studies by arguing that the
postulations of the authors were unproven in the scientific sense. At one
point she described a publication as “meaningless” because it did not contain
“a meaningful statistical analysis”. She made essentially the same point in
the following subsequent exchange with counsel:
Q. Let me put it to you
this way. The idea, the idea, of combining omeprazole and an antibacterial
like amoxicillin to increase gastric mucosal concentration, that idea was
floated by this paper, by this abstract or this letter. That much you have to
agree with me on. Someone reading this woundn’t be able to claim, I came up
with that idea after reading this, because the idea is already set out in the
letter, isn’t that so?
A. They have also
proposed a number of different things.
Q. Try to answer my
question, please. Someone who has read this abstract or letter could not in
good conscience say, I have come up with a new idea that no one else has
thought of before. I am going to give omeprazole with amoxicillin, and I am
going to have, as a result, increased gastric mucosal concentration.
They couldn’t say
they that, because Logan has already said it, correct?
A. It is stated in this
abstract.
Q. So someone reading
this couldn’t in good conscience say, I have come up with a brand new idea that
no one else has thought of before, correct, because Logan thought of it, and
perhaps Westblom before Logan, correct?
A. You are saying it
would increase the antibacterial effectiveness?
Q. I am not saying what
the effect is. I am just talking about some person coming along, after they
have read this and after they read Logan, you would have to agree with me they
couldn’t in good conscience say, I have a brainstorm, I have a brand new idea that
no one else has ever thought of or written about; namely, I am going to put
omeprazole together with an antibiotic like amoxicillin and I am going to get
increased gastric mucosal concentration. That is my brand new idea.
It can’t be brand
new, because someone else has written about it already, correct?
A. Scientists always
write so much. They propose so many different things, and so if I said that
every single issue in science would have already been solved because someone
has already mentioned it in one of their papers or discussions and proposed it
as a potential mechanism, this has been one thing that they have proposed, and
it has not been proven. It has been proposed.
Only later did she acknowledge that the
prior art publications in question had at least proposed the idea that the Patent
had later claimed to have tested and proven. This point was somewhat
reluctantly conceded in the following response:
A. The idea I guess
would have been out there. It is not tested. There are a lot of ideas, a lot
of different types of combinations that were proposed for a lot of different
types of reasons, and they have stated that it was proposed.
[98]
I
do not accept that, for the purposes of establishing obviousness, the prior art
should be approached or interpreted with the rigour required to prove a
scientific hypothesis. This is particularly true of a patent which identifies
a supposed new property of a known drug therapy. The fact that many of these
studies were looking at issues of efficacy and did not look closely at
mechanisms of action may be a reflection of the absence of any scientific
interest in pursuing something that had no apparent utility or because it was so
obvious that the issue did not need verification. The issue as I see it is
whether a person skilled in the art would come directly and without difficulty
to the solution that the combination of an acid suppressant like omeprazole
with an acid degradable antibiotic like clarithromycin would increase
bioavailability of the antibiotic for the treatment of Hp.
[99]
I
do not accept Dr. Piquette-Miller’s rationalizations for distinguishing the
prior art publications relied upon by Apotex. They were not the sort of
“unsuccessful or inconclusive” experimental references that were of concern to
the Court in Procter and Gamble Co. v. Bristol-Myers Canada Ltd.(1978),
39 C.P.R. (2d) 145 (F.C.T.D.). I prefer the evidence from Drs. Mayersohn,
Graham and McClelland on this issue.
[100] Furthermore,
if the only thing that the ’762 Patent teaches is a partial mechanism of action
for a previously known and utilized combination drug therapy, it has described
nothing inventive. It does not describe a new use for the known therapy. It
is simply a description of an experiment looking at the properties of well-known
and previously used medications. On this point, I accept Dr. Mayersohn’s
description of the supposed discovery as stated in para. 119 of his affidavit:
Therefore, one of ordinary skill in the
art would have been able to reach the purported invention directly with no
difficulty. Furthermore, the inventors of the ’762 Patent have conducted no
inventive experiments, but rather routine, typical and commonplace testing,
which anyone of ordinary skill could simply have conducted; there is no
inventive ingenuity in obtaining plasma samples and assaying for the presence
of antibiotic. The authors of the ’762 Patent have conducted simple,
straightforward experiments, which at best provided a validation for what was
known in the prior art by one of ordinary skill.
[101] Dr. Graham
similarly dealt with the issue of inventiveness in the following passage from
his affidavit:
225. The antibiotic serum level
testing conducted by the inventors of the ’762 Patent did not involve inventive
ingenuity – particularly with respect to the combination of omeprazole and
clarithromycin since this combination was already known. The inventors’ work
over Petrino et al. or Logan et al. merely involved measuring the blood levels
of the same combination of drugs to quantify a pharmacological property of said
combination.
[102] Dr. Piquette-Miller
attempted to isolate the inventive new use in terms of the bioavailability
teachings of the Patent and her affidavit described the supposedly inventive
aspect of the Patent in those terms. Astrazeneca’s Memorandum also attempted
to link the discovered bioavailability effect with the issue of treatment in
the following way:
35. The advantage of the
combination of a compound that increases intragastric pH, such as omeprazole,
and an acid degradable antibiotic, is that the bioavailability of the
antibiotic will increase resulting in sufficient plasma levels for therapeutic
effects. It appears that the inventors believed that by increasing oral
bioavailability, higher plasma levels can be achieved, resulting in greater
amounts of drug being distributed or excreted to the site of action (such
as the stomach wall).
[Emphasis added]
The problem with the above analysis is that
the discovered increase in plasma levels in the antibiotic was an inherent
property of the prior therapy and it did not constitute a new use or a new form
of treatment. The increase in plasma levels of the antibiotic had already been
achieved by the use of omeprazole in combination therapies. The supposed
greater distribution of the antibiotic at the site of action was what it was,
and the Patent taught nothing about how higher plasma levels or better
distribution of the antibiotic could be achieved.
[103] The
difficulty with Dr. Piquette-Miller’s analysis is that she can only fairly
assert that the supposed new use disclosed by the Patent is the discovery of a
mechanism of action and not a new therapy. To my mind, a new use is not
satisfied by identifying an inherent effect of a known therapy – in this case by
identifying a bioavailability effect. Dr. Piquette-Miller incorrectly
conflates those concepts. Although the fact that omeprazole was shown to
increase bioavailability of an antibiotic is interesting, it is not inventive
and it is not a claim for the use of a medicine for the diagnosis, treatment,
mitigation or prevention of a disease, disorder or abnormal physical state as
contemplated by section 7(2) of the NOC Regulations. Dr. Piquette-Miller’s
affidavit seems to have acknowledged this inherent problem in her position when
she conceded that the subject patent claims did not claim any use for the
treatment of Hp. Her affidavit stated:
These claims, as discussed, do not claim
use for the treatment of H. pylori infections. These claims claim use of H2
blocking compound or a proton pump inhibitor, of which omeprazole is an
example, to increase bioavailability of an acid degradable antibacterial
compound.
[104] Dr. Mayersohn
picked up on this point and stated the following in his affidavit:
40. I agree with Dr.
Piquette-Miller in that these claims do not claim the use of the combinations
for the treatment of Hp. The claims do not claim the use of the combination
for any diagnosis, treatment, mitigation or prevention of a disease, disorder
or abnormal physical state, or the symptoms of thereof.
[105] After
reviewing the evidence of the expert witness on the issue of obviousness, I
accept the opinions of Drs. Graham, Mayersohn and McClelland and reject that of
Dr. Piquette-Miller. It follows that the ’762 Patent is also invalid on the
ground of obviousness.
[106] Quite apart
from the issues of invalidity discussed above, the fact that the Patent claims
relied upon by Astrazeneca do not contain any therapeutic aspects also
establishes that the ’762 Patent is ineligible for inclusion on the Patent
Register: see Abbott Laboratories v. Canada (Minister of
Health), [2006]
F.C.J. No. 1957, 2006 FC 1558, aff’d. [2007] F.C.J. No. 686, 2007 FCA 187.
Conclusion
[107] In
conclusion, the Court finds that Astrazeneca has not demonstrated that Apotex’s
allegations of invalidity are not justified and, for that reason, this
application is dismissed.
[108] I will award
costs to Apotex but will invite submissions from the parties as to quantum.
Those submissions shall not exceed five pages in length and are to be made
within fourteen days of the date of judgment.
JUDGMENT
THIS COURT ADJUDGES that this application is dismissed with costs payable to the
Respondent; the parties shall make submissions with respect to costs within
fourteen days of the date of this judgment.
“ R. L. Barnes ”