Ottawa, Ontario, November 4, 2005
PRESENT: MADAM JUSTICE TREMBLAY-LAMER
BETWEEN:
AVENTIS PHARMA DEUTSCHLAND GmbH
and
THE MINISTER OF HEALTH
REASONS FOR ORDER AND ORDER
INTRODUCTION
[1] This is an application by Aventis Pharma Inc. and Aventis Pharma Deutschland GmbH (collectively "Aventis") pursuant to the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the "Regulations") for (i) a declaration that a letter dated November 10, 2003 from Apotex Inc. ("Apotex") is not a Notice of Allegation ("NOA") as contemplated by the Regulations and (ii), in the alternative, an Order prohibiting the Minister of Health (the "Minister") from issuing a Notice of Compliance ("NOC") to Apotex in respect of ramipril oral capsules 1.25, 2.5, 5 and 10 mg until after the expiration of Canadian Patent 1,246,457 (the "'457" patent).
BACKGROUND
a) Previous Proceeding with Respect to the '457 Patent
[2] This is not the first time that Apotex has delivered an NOA in respect of the '457 patent. Approximately three months prior to the delivery of the putative NOA that gave rise to the present proceeding, Apotex served an NOA in August 2003, which became the subject of Court File T-1851-03 and was argued in April 2005 before Simpson J. That decision was released on October 11, 2005.
[3] Whereas the previous proceeding was based on Apotex's allegation that it would not infringe the claims of the '457 patent because its capsules would be made, used and sold solely for the treatment of hypertension, which use is not within the scope of the patent's claims, the within proceeding is based on Apotex's allegation that the claims in issue of the '457 (use to treat cardiac insufficiency) patent are invalid due to anticipation, obviousness and double patenting.
b) Overview of the scientific background
[4] Two conditions are relevant to this proceeding: heart failure and hypertension.
[5] Heart failure (and congestive heart failure), also known as cardiac insufficiency, is the inability of the heart to adequately pump enough oxygenated blood to meet the demands of the body. Heart failure is not a single disease, but rather a syndrome with a variety of origins and manifestations. It can occur in patients with normal blood pressure as well as those exhibiting high blood pressure, i.e. hypertension.
[6] One of the body's systems, the renin-angiotensin ("RAS") system, is known to be important for the treatment of both heart failure and hypertension because the RAS system plays a role in controlling the volume of fluid in the body, maintaining the volume and pressure of blood, and also maintaining arterial blood pressure.
[7] In simple terms, the kidneys are stimulated to produce renin, an enzyme which converts the peptide angiotensinogen (a substance found in the body) into the decapeptide (ten peptide units) angiotensin I ("Ang I"). Another particular enzyme known as angiotensin converting enzyme ("ACE") is responsible for converting Ang I into angiotensin II ("Ang II") (an octapeptide) by cleaving two peptide units. Ang II causes blood vessels to constrict or shrink, thereby raising blood pressure. ACE inhibitors inhibit or prevent the conversion of Ang I to Ang II.
EXPERT EVIDENCE
[8] Aventis filed expert evidence from the following witnesses:
[9] Dr. Gilles Dagenais, a cardiologist at the Québec Heart and Lung Institute Laval Hospital, previously professor and chairman, Department of Medicine, University of Montreal. Dr. Dagenais was co-chair of the HOPE and HOPE II Steering Committees, studies which considered the effects of ramipril in the prevention of heart attacks, stroke and cardiovascular death, heart failure and vascular revascularization.
[10] Dr. Morris Karmazyn, a professor at the University of Western Ontario and Career Investigator, Heart and Stroke Foundation of Ontario. He is also the Director of the Heart and Stroke Foundation of Ontario Program in heart failure.
[11] Dr. Reinhard Becker, a physician-pharmacologist employed by Aventis who introduced the Becker declaration described infra.
[12] Apotex filed expert evidence from the following witnesses:
[13] Dr. Robert McClelland, a professor in the Department of Chemistry at the University of Toronto. He is considered an international expert on Physical Organic Chemistry and Biological Chemistry and has received numerous prestigious awards for his accomplishments in this area. His affidavit served as a primer for the chemical nomenclature and structures in this case.
[14] Dr. Haralambos Gavras, a professor of medicine at Boston University School of Medicine, Boston, M.A. He is also Chief of the Hypertension and Atherosclerosis Section at Boston Medical Center, Director of the Specialized Center of Research in Molecular Genetics of Hypertension, and the immediate-past President of the American Society of Hypertension. He has been involved in a wide range of research related to hypertension, angiotensin, blood pressure maintenance and congestive cardiac failure and has received numerous awards throughout his career for his success. In particular, in February 2004, Dr. Gavras was awarded the Franz Volhard Award from the International Society of Hypertension for his research on the renin-angiotensin system, which award is the highest honour bestowed by the society. He is clearly an expert in the treatment of cardiovascular conditions, including both hypertension and chronic heart failure, the use of ACE inhibitors and the pharmacology of ACE inhibitors.
[15] Dr. John Parker, a professor emeritus of Medicine at Queen's University in Kingston, Ontario and a cardiologist at Kingston General Hospital in Kingston, Ontario (a former Chief Resident in medicine at the Kingston General Hospital). In addition, he was a research fellow in the cardiopulmonary laboratory of the Department of Medicine at Columbia University, New York, New York and a McLaughlin traveling fellow at Broussais Hospital, Paris, France and at the National Heart Hospital, London, England. In 1995, Dr. Parker was awarded the Research Achievement Award from the Canadian Cardiovascular Society for his research in cardiovascular disease. He is thus qualified as an expert in all aspects of the management of cardiac insufficiency (cardiac failure or congestive heart failure).
[16] Both Aventis and Apotex have tried to cast doubt on the credibility of one another's experts. However, I am satisfied that they are all experts in their respective fields and have assigned weight to their evidence according to the appropriate context and not with regard to their possible relationship with the party for whom they are testifying. In my view, if an expert's opinion is properly limited to his area of expertise, it is not appropriate to discount his evidence as self-serving or bias solely on the basis that the expert is an employee of one of the parties. While they may have different views on certain issues, I have found their evidence to be helpful and I see no reason to question their overall credibility.
CONSTRUCTION OF THE PATENT
[17] Construction of patent claims is a matter of law (see: Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067. As articulated by Binnie J. in Whirlpool, claims are to be construed in an informed and "purposive" way, read by a person skilled in the art at the date when the patent first became public. This involves an identification by the Court of what the inventor considered to be the "essential" elements of the invention (Whirlpool, ibid., at para. 45).
[18] The patent is not addressed to an ordinary member of the public, but to a worker skilled in the art described by Dr. Harold Fox as:
a hypothetical person possessing the ordinary skill and knowledge of the particular art to which the invention relates, and a mind willing to understand a specification that is addressed to him.
(H.G. Fox, The Canadian Law and Practice Relating to Letters Patent for Inventions, 4th Ed. (Toronto: Carswell Co. Ltd., 1969), cited in Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024 at para. 44.)
[19] A patent filed under the pre-1989 Patent Act, R.S.C. 1985, c. P-4 (the "old Patent Act") must be construed as of the date of issue: Free World Trust, ibid., at para. 54. The '457 patent was issued on December 13, 1988.
[20] The '457 patent is entitled "Method of Treating Cardiac Insufficiency". The invention relates to compositions for treating cardiac insufficiency by peroral or parenteral use of angiotensin-converting enzyme inhibitors of a general formula ("formula I").
[21] The '457 patent comprises 13 claims. The claims include within their scope pharmaceutical compositions containing ACE inhibitors selected from a class of compounds defined by formula I for treating cardiac insufficiency.
[22] Ramipril is one such ACE inhibitor, amongst others belonging to the class of compounds defined by formula I, covered by claims 1 through 3 of the '457 patent. These ACE inhibitors are also covered by claims 4 through 10 of the patent, with claim 8 specifically claiming pharmaceutical compositions containing ramipril for the treatment of cardiac insufficiency. Claims 11 through 13 relate to the corresponding metabolites of the ACE inhibitors described within claims 4 through 10 (e.g. ramiprilat).
[23] The issue around construction focuses on claim 8 of the '457 patent, which reads:
The composition as claimed in claim 1 containing (S,S,S,S,S)-N-(1-carbethoxy-3-phenyl-propyl)-alanyl-2-azabicyclo[3.3.0]octane-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
[24] While Aventis submits that the invention contained with the '457 patent is the use of ramipril for the treatment of heart failure, it is clear that the patent is not limited to the use of ramipril to treat heart failure. Rather, the patent claims a class of ACE inhibitor compounds useful in the treatment of heart failure, ramipril being one of a number of preferred compounds of the class.
[25] In my view, a person skilled in the art as of the date of issue would read the '457 patent as relating to a new use for known compounds, namely, the use of a class of ACE inhibitor compounds, including ramipril, for the treatment of heart failure.
ISSUES
(a) Abuse of process
(b) Sufficiency of the NOA
(c) Burden and Standard of Proof
(d) Invalidity of the '457 patent
i) Anticipation
ii) Obviousness
iii) Double patenting
ANALYSIS
(a) Abuse of process
[26] Aventis submits that the allegation made by Apotex relates to the same product and the same patent at issue in a proceeding before Simpson J., therefore the present proceeding constitutes an abuse of process.[1]
[27] The doctrine of abuse of process has been recently considered by the Supreme Court of Canada (see Danyluk v. Ainsworth Technologies Inc., [2001] 2 S.C.R. 460; Toronto (City) v. Canadian Union of Public Employees (C.U.P.E.), Local 79, [2003] 3 S.C.R. 77), as well as by this Court in the context of a proceeding under the Regulations (see AB Hassle et al v. Apotex Inc. et al (2005), 38 C.P.R. (4th) 216 (F.C.)).
[28] The doctrine provides the Court with an inherent and residual discretion to prevent the misuse of its procedure. The doctrine is flexible and is "unencumbered by the specific requirements of res judicata": C.U.P.E., supra, at para. 42. Whereas issue estoppel focuses "on the motive or status of the parties, the doctrine of abuse of process concentrates on the integrity of the adjudicate process": C.U.P.E., supra, at para. 51. As explained by Layden-Stevenson J. in AB Hassle, supra, at para. 94:
While critics have argued that when the doctrine of abuse of process is used as proxy for issue estoppel it obscures the true question, while adding nothing but a vague sense of discretion, that is not so. In all of its applications, the primary focus of the doctrine of abuse of process is the integrity of the adjudicative function of courts. The focus is less on the interests of the parties and more on the integrity of judicial decision making as a branch of the administration of justice. When the focus is properly on the integrity of the adjudicative process, the motive of the party who seeks to relitigate cannot be a decisive factor. [emphasis added]
[29] Abuse of process has a strong public policy dimension. Arbour J. in C.U.P.E., supra, stated that the policy grounds for both issue estoppel and abuse of process are essentially the same. At pages 103-104, she quoted from D. J. Lange, The Doctrine of Res Judicata in Canada (2000) at pp. 347-48:
The two policy grounds, namely, that there be an end to litigation and that no one should be twice vexed by the same cause, have been cited as policies in the application of abuse of process by relitigation. Other policy grounds have also been cited, namely, to preserve the courts' and the litigants' resources, to uphold the integrity of the legal system in order to avoid inconsistent results, and to protect the principle of finality so crucial to the proper administration of justice.
[30] In arguing that the current proceeding constitutes an abuse of process, counsel for Aventis relies on Layden-Stevenson J.'s decision in AB Hassle, supra. I find it helpful to review the facts of that case in detail.
[31] In that case, Apotex informed AstraZeneca Canada, by way of a notice of allegation, that it had filed a new drug submission with the Minister of Health for magnesium omeprazole tablets for oral administration in strengths of 10 mg and 20 mg. The patents referred to were owned by AB Hassle and AstraZeneca (collectively, "AstraZeneca"). By application, AstraZeneca sought, inter alia, an order prohibiting the Minister from issuing a notice of compliance until the expiration of the Canadian patent. Only claim 1 of the '693 patent was in issue.
[32] This was not Apotex's first NOA in respect of the '693 patent. Apotex first alleged non-infringement in April 1993. AstraZeneca's application in respect of that allegation was dismissed in May 1996. On December 18, 1997, an Apotex NOA alleged non-infringement of the same Canadian patents in the proceeding before Layden-Stevenson J. By an order dated May 18, 1999, the NOA was deemed to be withdrawn and the application was deemed to be discontinued. Finally, on August 1, 2000, an Apotex NOA with respect to the same Canadian patents as those in the proceeding alleged non-infringement. Kelen J. declared that the NOA did not constitute an NOA under the Regulations and granted an order prohibiting the Minister from issuing a NOC. Apotex appealed. In dismissing the appeal, Rothstein J.A. construed claim 1 of the '693 patent.
[33] On September 26, 2002, Apotex forwarded the NOA at issue in the proceedings before Layden-Stevenson J. to AstraZeneca and alleged both non-infringement and invalidity with respect to the '693 patent.
[34] AstraZeneca submitted that Apotex was precluded from bringing the allegation because it gave rise to issue estoppel. AstraZeneca alleged that the allegation of non-infringement in its NOA in that proceeding turned on the construction of claim 1 as did Apotex's allegation of non-infringement in the previous proceeding. The Federal Court of Appeal had determined the construction issue and Apotex could not relitigate it.
[35] On the issue of whether non-infringement was previously decided on Layden-Stevenson J. concluded that in the previous proceeding, Apotex had alleged non-infringement and could not allege it in the second case.
[36] Insofar as validity was concerned, she accepted AstraZeneca's argument that by alleging only non-infringement in the previous proceeding, Apotex necessarily accepted the validity of the '693 patent because if the patent was not valid, Apotex's formulation could not infringe the patent. She found that Apotex may have been "hiding in the weeds" and splitting its case in two parts. On this, she found issue estoppel to apply.
[37] Ultimately, she decided not to exercise her discretion in Apotex's favour not to apply the doctrine of issue estoppel.
[38] She also held that, if she were wrong in her determination that issue estoppel applied, then Apotex's NOA constituted an abuse of process for substantially the same reasons as the issue estoppel section of her reasons.
[39] With respect, I cannot accept that by alleging only non-infringement in the previous proceeding, Apotex necessarily accepted the validity of the '457 patent because if the patent was not valid, Apotex could not infringe.
[40] The regulatory scheme under the Regulations provides that allegations may be brought on a number of grounds. Subparagraph 5(1)(b)(iv) contemplates allegations that the patent will not be infringed by the second person. Subparagraph 5(1)(b)(iii) contemplates allegations that the patent is not valid.
[41] It is well-established law that multiple allegations are permissible provided that the legal and factual bases underlying each allegation are separate and distinct (see for example: Apotex Inc. v. Canada (Minister of National Health and Welfare) (1997), 76 C.P.R. (3d) 1 (F.C.A.), leave to appeal ref'd, [1998] 1 S.C.R. viii; Bayer AG v. Canada (Minister of National Health and Welfare) (1997), 77 C.P.R. (3d) 129 (F.C.T.D.) at paras. 12-15; Bayer AG et al v. Apotex Inc. et al (1998), 84 C.P.R. (3d) 23 (F.C.T.D.) at paras. 27-28, aff'd., (2001) 14 C.P.R. (4th) 263 (F.C.A.); Bayer Inc. et al v. Canada (Minister of National Health and Welfare) et al (1998), 82 C.P.R. (3d) 359 at paras. 9-14 (F.C.T.D.); AstraZeneca AB v. Apotex Inc. (2005), 335 N.R. 1 (F.C.A.) at para. 21.).
[42] Aventis argues that the second allegation - that of invalidity - could have and should have been raised in the previous proceeding and cites Procter and Gamble Pharmaceuticals Canada, Inc. v. Canada(Minister of Health) (2003), 33 C.P.R. (4th) 193 (F.C.A.). I do not find this argument to be persuasive. That case dealt with the question of whether a patent was eligible for inclusion on the patent register whereas in the present matter, the Court must determine patent validity pursuant to a regulatory scheme where multiple allegations, and consequently multiple proceedings, are provided for as long as the legal and factual bases underlying each are separate and distinct. Moreover, that case was decided on the doctrine of issue estoppel whereas this matter is only concerned with abuse of process.
[43] While the authorities are clear that the second person is not required to make separate and distinct allegations in the same notice, I believe the interest of the adjudicative function of the Court would be better served to proceed as such. If the second person knows of multiple grounds under which they intend to bring an NOA, it would be, in my opinion, more efficient to bring those grounds in a single NOA. While the Regulations do not require this, the Federal Court Rules, 1998, SOR/98-106, indicate that proceedings should be conducted in a just and expeditious manner. To do otherwise undermines the efficiency of the judicial system and the administration of justice.
[44] However, as I have stated above, the decisions of the Federal Court of Appeal have repeatedly held that the distinctive nature of the proceedings contemplated by the Regulations do not preclude a second person from advancing a subsequent allegation that is factually and legally distinct from any prior allegations.
[45] Is then the legal and factual basis underlying the present NOA separate and distinct from the legal and factual basis underlying the NOA in Court File T-1851-03?
[46] The allegation of invalidity in the former proceeding (Court file T-1851-03) was raised only on the conditional basis that if Aventis asserted the use of ramipril to treat hypertension was within the '457 patent, such construction could not be correct as it would invalidate the patent as claiming an old use. Aventis did not adopt that position, thus the conditional allegation of invalidity was not pursued any further. The former proceeding was therefore solely with regard to the issue of infringement of the '457 patent. This allegation is premised on separate and distinct factual and legal issues that have never been determined in a prior proceeding, namely that the '457 patent is invalid based on anticipation, obviousness and double patenting. The Regulations contemplate separate proceedings for multiple allegations.
[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.
(b) Sufficiency of the NOA
[48] The test for determining the sufficiency of an NOA has recently been formulated as follows: "whether [the second person] provided [the first person] with a sufficient understanding of the case it had to meet": Pfizer Canada Inc. v. Novopharm Ltd., [2005] F.C.J. 1318 (C.A.)(QL) at para. 16. Stated differently, "a detailed statement of the bases of an allegation must be sufficiently complete to enable a patentee to make an informed decision as to whether to respond to the allegation by instituting proceedings for an order of prohibition": AstraZeneca AB v. Apotex Inc. (2005), 335 N.R. 1 (F.C.A.) at para. 12, citing AB Hassle v. Canada(Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A ) at para. 21.
[49] Whether an NOA may be deficient due to a lack of particularity of the art is perhaps an open question. However, the fundamental inquiry - whether the first person is informed of the case it has to meet and is not left guessing at the bases for the second person's allegations - remains unchanged.
[50] In the present case, as in AstraZeneca AB, supra, there is no evidence to suggest that Aventis was unable to respond to Apotex's NOA because it lacked particulars. Therefore, in my view, Aventis had a sufficient understanding of the case it had to meet. The NOA is not deficient.
(c) Burden and standard of proof
[51] The burden of proof as to validity in proceedings under the Regulations has been discussed at length. It is well-established that the legal burden or persuasive burden rests with the applicant to refute the allegations set forth by the second person in its NOA. Aventis must establish on a balance of probabilities, that Apotex's allegations are not justified. However, while Aventis bears the overall legal burden of establishing its entitlement to the order sought, Apotex has an evidentiary burden to put the allegations set out in its NOA "in play": see Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) at pages 319-20, and the recent commentaries thereon in SmithKline Beecham Pharma Inc. v. Apotex Inc., [2001] 4 F.C. 518 (T.D.), aff'd. [2003] 1 F.C. 118 (F.C.A.) and in Janssen-Ortho Inc. v. Novopharm Ltd. (2004), 264 F.T.R. 202.
[52] In discharging its burden, Aventis is entitled to the rebuttable presumption that a patent is valid: see section 45 of the old Patent Act, subsection 43(2) of the new Patent Act, R.S.C. 1985, c. P-4. In Proctor & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health), [2005] 2 F.C.R. 269, Rothstein J.A., relying on the decision in Bayer Inc. v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285 as the governing authority with regard to burden and standard of proof, stated at paragraphs 15 and 16:
[15] [...] in Bayer v. Canada(Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285 (F.C.A.) which, on this point, is the governing authority. In Bayer, Sharlow J.A. dealt with the burdens of proof on the patentee and the generic in proceedings under the Regulations. She explained that the patentee, being the applicant for the order of prohibition, bears the burden of establishing its entitlement to the order sought. Subsection 43(2) of the Patent Act, R.S., c. P-4, s. 1, as amended, provides that "After the patent is issued, it shall, in the absence of any evidence to the contrary, be valid and avail the patentee..." Sharlow J.A. observed that because of that presumption of validity, the generic, as the party responding to the application for a prohibition order, has the burden of proof to displace the presumption.
[16] As to the standard of proof, at paragraph 9, she wrote:
The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves, on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant
Therefore, the standard of proof applicable to proving invalidity has been found to be proof on a balance of probabilities. [...]
[53] Aventis accepts that it bears the ultimate legal burden to convince the Court that it is entitled to the order sought. However, it relies on the Supreme Court of Canada's decision in Apotex Inc. v. Wellcome Foundation Ltd., [2002] 4 S.C.R. 153 in support of its argument that, in a proceeding under the Regulations, I should apply a higher threshold and find that the burden of showing invalidity lies on the person challenging the patent. The Supreme Court, in that case, found that the appropriate standard of review with regard to a finding of invalidity in a patent infringement action was reasonableness simpliciter, i.e. that the Commissioner's decision must withstand a somewhat probing examination. Aventis argues that this standard applies equally to NOC proceedings.
[54] In Pfizer Canada Inc. v. Canada(Minister of Health), [2005] F.C.J. No. 1607 (F.C.)(QL), Heneghan J. rejected a similar argument at paragraph 57:
¶ 57 In my opinion, the Applicants' reliance on Apotex v. Wellcome, supra, in relation to the question of the burden of proof is not well-founded. That decision came from an action involving issues of patent impeachment and infringement. The present proceeding is a summary proceeding pursuant to the NOC Regulations and the Federal Court Rules, 1998, supra governing application for judicial review. Again, a finding of invalidity or infringement, for the purposes of this kind of proceeding is not determinative of that issue in any subsequent action; see Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.) at page 216 where the Court said as follows:
...these proceedings are not actions for determining validity or infringement: rather they are proceedings to determine whether the Minister may issue a notice of compliance. That decision must turn on whether there are allegations by the generic company sufficiently substantiated to support a conclusion for administrative purposes (the issue of a notice of compliance) that the applicant's patent would not be infringed if the generic's product is put on the market....
[55] I agree with this reasoning. Thus, in my opinion, it would be inappropriate to apply a standard used for actions involving patent infringement to proceedings under the Regulations.
[56] In conclusion, while the legal burden rests with Aventis, Apotex must prove, on a balance of probabilities, by the evidence supporting its allegations in the NOA, that the '457 patent is invalid. Having determined the burden and standard of proof, I now turn to consider the issue of invalidity of the '457 patent.
(d) Invalidity of the '457 Patent
(i) Anticipation
[57] In alleging that the claim is invalid based on anticipation, Apotex submits that the invention embodied by the '457 patent was anticipated by four pieces of prior art: European Patent Application No. 50 800 A1 (the "'800 application"); the Journal of Cardiovascular Pharmacology (1983) 5: 643-654; European Patent Application No. 49 658 A1 (the "'658 application"); and a presentation to the American Society for Pharmacology and Experimental Therapeutics ("ASPET presentation").
[58] With respect to the '800 application, Apotex highlights the phrase that compounds covered by the invention are "useful in the treatment of cardiovascular
disorders and particularly mammalian hypertension". Apotex submits that a person skilled in the relevant art at the relevant time would have known that the term "cardiovascular disorders" included heart failure. While the '800 application does not specifically disclose ramipril per se, ramipril is included within the class of compounds claimed in the '800 application. As such, the '800 application taught that the use of the compounds of its invention, including ramipril, would be useful in the treatment of heart failure.
[59] The other anticipating documents, Apotex submits, each teach and disclose compounds that fall within the scope of the claims of the '457 patent and indicate that ACE inhibitor compounds are useful for the treatment of cardiac insufficiency. Claim 8 of the '457 patent, which specifically claims ramipril, is also anticipated in Apotex's view in that inventive ingenuity is not required to recognize that the ACE inhibitor compound ramipril can be functionally substituted for any of the other members of the class of compounds of formula I.
[60] Regarding the lack of clinical data, Apotex submits that by demanding human clinical trials, Aventis is attempting to elevate the standard to a regulatory approval standard. That is not the standard of patentability or anticipation, however, as borne out by the fact that the '457 patent itself does not include a reference to clinical testing in humans.
[61] Aventis submits that Apotex's approach to anticipation is plainly wrong in law. Apotex relies upon a class effect theory, and attempts to ascribe to ramipril the effects seen with other ACE inhibitors as disclosed in the prior art even though ramipril is neither disclosed nor claimed in that prior art (apart from the "'800 application"). In effect, Apotex argues that another compound was known for that use, ramipril is a member of that class and therefore anticipation is established. This approach, if sanctioned, would allow Apotex to broaden anticipation into an obviousness analysis.
[62] Insofar as the '800 application is concerned, Aventis submits that, according to its experts, the phrase "cardiovascular disorders" would not be understood by the person skilled in the art as meaning cardiac insufficiency. Moreover, Apotex's reliance on this statement conveniently ignores the particular reference to hypertension and the fact that cardiovascular disorders encompass a broad range of conditions. In short, ramipril is not specifically disclosed or claimed in the '800 application, nor is the use of heart failure disclosed or supported by data.
[63] Finally, Aventis contends thatthe '658 application and the Journal of Cardiovascular Pharmacology referenced by Apotex also lack testing data, and the ASPET presentation pertained to a hemodynamic study (a preclinical heart failure model in a dog) as opposed to a clinical trial with humans.
[64] Having set out the positions of the parties, I will now review the principles underlying the law of anticipation before turning to consider the application of those principles to the facts in the case at bar.
[65] Anticipation is a statutory doctrine which provides that that which is claimed lacks novelty. Subsections 27(1) and 61(1) of the old Patent Act, supra, are relevant to the issue of anticipation. They provide as follows:
| 27. (1) Subject to this section, any inventor or legal representative of an inventor of an invention that was
(a) not known or used by any other person before he invented it,
(b) not described in any patent or in any publication printed in Canada or in any other country more than two years before presentation of the petition hereunder mentioned, and
(c) not in public use or on sale in Canada for more than two years prior to his application in Canada,
may, on presentation to the Commissioner of a petition setting out the facts, in this Act termed the filing of the application, and on compliance with all other requirements of this Act, obtain a patent granting to him an exclusive property in the invention.
61. (1) No patent or claim in a patent shall be declared invalid or void on the ground that, before the invention therein defined was made by the inventor by whom the patent was applied for, it had already been known or used by some other person, unless it is established that
(a) that other person had, before the date of the application for the patent, disclosed or used the invention in such manner that it had become available to the public;
(b) that other person had, before the issue of the patent, made an application for patent in Canada on which conflict proceedings should have been directed; or
(c) that other person had at any time made an application in Canada which, by virtue of section 28, had the same force and effect as if it had been filed in Canada before the issue of the patent and on which conflict proceedings should properly have been directed had it been so filed.
|
27. (1) Sous réserve des autres dispositions du présent article, l'auteur de toute invention ou le représentant légal de l'auteur d'une invention peut, sur présentation au commissaire d'une pétition exposant les faits, appelée dans la présente loi le "dépôt de la demande", et en se conformant à toutes les autres prescriptions de la présente loi, obtenir un brevet qui lui accorde l'exclusive propriété d'une invention qui n'était pas :
a) connue ou utilisée par une autre personne avant que lui-même l'ait faite;
b) décrite dans un brevet ou dans une publication imprimée au Canada ou dans tout autre pays plus de deux ans avant la présentation de la pétition ci-après mentionnée;
c) en usage public ou en vente au Canada plus de deux ans avant le dépôt de sa demande au Canada.
61. (1) Aucun brevet ou aucune revendication dans un brevet ne peut être déclaré invalide ou nul pour la raison que l'invention qui y est décrite était déjà connue ou exploitée par une autre personne avant d'être faite par l'inventeur qui en a demandé le brevet, à moins qu'il ne soit établi que, selon le cas :
a) cette autre personne avait, avant la date de la demande du brevet, divulgué ou exploité l'invention de telle manière qu'elle était devenue accessible au public;
b) cette autre personne avait, avant la délivrance du brevet, fait une demande pour obtenir au Canada un brevet qui aurait du donner lieu à des procédures en cas de conflit;
c) cette autre personne avait à quelque époque fait au Canada une demande ayant, en vertu de l'article 28, la même force et le même effet que si elle avait été enregistrée au Canada avant la délivrance du brevet et pour laquelle des procédures en cas de conflit auraient dû être régulièrement prises si elle avait été ainsi enregistrée.
|
[66] The test for anticipation is difficult to meet. As Binnie J., reiterated in Free World Trust v. Électro Santé Inc., supra at para. 26, quoting from General Tire & Rubber Co. v. Firestone Tyre & Rubber Co., [1972] R.P.C. 457 (Eng. 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.
[67] The prior disclosure must clearly and unmistakably lead the skilled person to the patent-in-suit, as Hugessen J.A. remarked in Beloit Canada Ltd. et al v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.) at paragraph 30:
[...] 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 without possibility of error be led to the claimed invention. [...]
This test was cited with approval by the Supreme Court in Free World Trust, supra.
[68] It is not enough to select portions from more than one document to form a mosaic of information. Anticipation is not directed to the state of the art and common general knowledge at the time (see Beloit, supra). Additionally, when more than one result is possible, it cannot be said that the skilled person would arrive at the invention "in every case" or that the result is "inevitable" (see Reeves Brothers Inc. v. Toronto Quilting & Embroidery Ltd. (1978), 43 C.P.R. (2d) 145 (F.C.T.D.)).
[69] In the present matter, does any one of the documents of prior art contain so clear a direction that a skilled person would in every case and without possibility of error be led to the claimed invention?
[70] As stated above, Apotex relies on four documents to show anticipation: the '800 application; the Journal of Cardiovascular Pharmacology; the '658 application; and the ASPET presentation.
[71] In my opinion, Apotex has failed to show that any one of the four documents that it refers to satisfies the test for anticipation.
[72] Apotex argues that another compound of a class was known to treat heart failure, ramipril is a member of the class, and therefore anticipation is established. This argument, while it may be applicable to the test for obviousness, is irrelevant to the anticipation inquiry. I agree with Aventis that Apotex cannot rely on the Journal of Cardiovascular Pharmacology; the '658 application; and the ASPET presentation, which involved different compounds, albeit of the same class as ramipril (i.e. ACE inhibitors), to show anticipation. To do so would effectively nullify the distinction between anticipation, which asks whether a skilled person would be able to perform the invention based upon a single prior publication, and obviousness, which asks whether a skilled person would have known how to arrive at the invention based upon the state of the art and of common general knowledge at the relevant time (see Beloit, supra).
[73] To allow an anticipation argument based on these three documents would require the skilled person reading them, and following each in isolation, to assume that ramipril could have been substituted for the compounds used therein. This assumption may constitute the common general knowledge at the relevant time (i.e. the obviousness inquiry) but none of these three documents, on its own, would lead the skilled person, inevitably and in every instance, to perform the invention. Where more than one result is possible, anticipation has not been established.
[74] I found that Apotex's experts based their opinions on whether one could predict that ramipril would be useful in treating heart failure given the general state of the prior art, an obviousness inquiry, as opposed to whether such use was specifically disclosed in a single reference. In this regard, I assign weight to Dr. Parker's admission that he looked to multiple documents to form his opinion on anticipation. Dr. Parker, when cross-examined on anticipation, answered:
I am looking at the rather healthy file of data prior to 1984 about such drugs as captopril and enalapril, and some of ramipril, showed that this class of drugs was effective in improving symptoms, and also we reviewed a patent, Canadian patent '500, I think it is, 1980, and the European patent, which identified in those documents the role of ACE inhibitors in cardiac insufficiency, heart failure.
It would seem to me, as a non-lawyer, that there was anticipation; from the data there in the literature, plus these two previously existing patents, that there was anticipation in terms of benefit of ramipril and the other drugs in that class that I mentioned in the '457 patent. There was anticipation.
[75] Additionally, the Journal of Cardiovascular Pharmacology publication was published in July/August 1983 and does not meet the definition of paragraph 27(1)(b) of the old Patent Act, which requires that an anticipating document must be printed more than two years before the filing date of the Canadian application.
[76] Further, the '800 application provides that compounds of the invention can be administered to provide "compositions useful in the treatment of cardiovascular disorders and particularly mammalian hypertension". While ramipril falls within the scope of the class of compounds disclosed by the '800 application, the use to treat heart failure is not specifically disclosed. Instead, Apotex relies on the term "cardiovascular disorders" as encompassing heart failure.
[77] To perform the invention disclosed in the '457 patent on the basis of this document would have been contingent on the skilled person's understanding that the term "cardiovascular disorders" would undoubtedly mean heart failure. This amounts to, essentially, the person skilled in the art reading-in a medical condition that the prior publication does not mention explicitly. The question then becomes: would the skilled reader, following the '800 application, in every case, and without the possibility of error, be led to the claimed invention? In my view, this question must be answered in the negative.
[78] Counsel for Apotex submitted that the term "cardiovascular disorders" could be interpreted as meaning heart failure by looking to the other three documents. I cannot accept that one may use external documents to interpret the terms in a purported anticipating document. This amounts to a "mosaic-ing" of the prior art, which is impermissible in the anticipation inquiry. In order for an invention to be anticipated, its essential features must be disclosed in a single piece of prior art (see Beloit, supra).
[79] One of the essential features of the '457 patent is that the compounds listed be used to treat heart failure. For the reasons that follow, I am not satisfied that the skilled reader would draw the conclusion that "cardiovascular disorders" means heart failure.
[80] During the hearing, counsel for Apotex drew the Court's attention to this Court's decision in SmithKline, supra. In that case, Gibson J. determined an allegation of invalidity to be justified based on anticipation. He found that the "conventional methods" of formulation of paroxetine tablets disclosed in the first patent [the '060 patent] would be understood by persons skilled in the art to include wet granulation, dry granulation and direct compression. Gibson J. stated at page 546:
Having determined that a wet formulation of paroxetine tablets gives rise to a "pink hue problem", a problem of significant enough magnitude to cause a skilled person to seek out at least a partial solution to the problem, I am satisfied that a logical first step for a person skilled in the art would be to turn to the alternative formulation methods disclosed by the '060 patent and to determine whether each or any of those alternative formulation methods would solve, or at least partially solve, the problem. Such an enquiry would, I am satisfied, involve no inventive step or skill. It would simply involve application of the invention taught by the '060 patent.
[81] Gibson J. concluded that a person skilled in the art, on the basis of the '060 patent, and the existing common knowledge at the relevant time, would, in every case and without possibility of error, have arrived at the formulation claimed in the second patent. This decision was affirmed on appeal: [2003] 1 F.C. 118, leave to the Supreme Court of Canada dismissed without reasons on March 20, 2003: [2002] S.C.C.A. No. 324 (QL).
[82] Apotex submitted that "cardiovascular disorders" is a term of art, which would be understood by the skilled reader to mean heart failure. However, unlike SmithKline, supra, I am not satisfied that the logical step for a person skilled in the art would be to apply the invention taught by the '800 application to arrive at the use of ramipril in the treatment of heart failure. In SmithKline, supra, the three alternative formulation methods were disclosed in the first patent whereas in the present matter, the '800 application does not disclose the use of ramipril for the treatment of heart failure, but rather for the treatment of "cardiovascular disorders". The generic nature of this term undermines the suggestion that this application is a flag planted "at the precise destination before the patentee". While heart failure is a "cardiovascular disorder", it cannot be said that the skilled reader would inevitably be led to this invention based on the '800 application. I draw support for this conclusion based on Apotex's own experts, Dr. Parker and Dr. Gavras, who admitted that "cardiovascular disorders" includes a number of medical conditions. Apotex's experts also admitted that they would not rely on the '800 application for the proposition that the compounds claimed therein are useful in the treatment of heart failure.
[83] Although both parties brought forth submissions regarding the sufficiency and the possible requirement of clinical testing and data in support of their respective anticipation arguments, I find that this is better discussed under obviousness, where these submissions were more comprehensively presented.
[84] Thus, in my view, Apotex's allegation of invalidity, insofar as it is predicated upon anticipation, is not justified.
(ii) Obviousness
[85] Apotex submits that by the priority date of the '457 patent, the idea and effectiveness of ACE inhibitors for the treatment of heart failure were known by skilled persons. As conceded by Drs. Karmazyn and Dagenais, vasodilators were well accepted in the treatment and management of heart failure and ACE inhibitors were known to be vasodilators. The prior art shows that the mechanism of vasodilation by an ACE inhibitor, be it captopril, enalapril or ramipril, was known to be the same even if not fully understood.
[86] More particularly, Apotex argues that by April 1984, a skilled person would have been aware that ramipril is a potent orally active converting enzyme inhibitor, and a vasodilator, which was demonstrated to significantly improve the pumping action of the heart in a mammal.
[87] Apotex further submits that there can be no assertion that ramipril is in any way superior in its efficacy as compared to any other known ACE inhibitor for the treatment of heart failure. The literature demonstrates that ACE inhibitors share common properties and were known to be useful not only in the treatment of hypertension but also in the treatment of heart failure. Aventis is incorrect in suggesting that the prior art was merely investigational in nature. The idea of using ACE inhibitors to treat heart failure was well established as of the priority date. Moreover, the Aventis (former Hoechst) researchers, including one of the inventors of the '457 patent and Dr. Becker, were themselves disclosing prior to 1984 that ramipril would inhibit cardiac ACE, had long-lasting action, and, like other ACE inhibitor compounds, would be useful for cardiovascular disorders in addition to hypertension.
[88] Aventis submits that Apotex's argument that the use of ramipril to treat heart failure was obvious given the prior art cited cannot succeed on the evidence. First, both Drs. Gavras and Parker conceded that testing is required to determine a drug's effectiveness regardless of the state of the art. Aventis submits that this requirement of testing is, moreover, particularly evident given the fact that drugs within a class do vary as to their effectiveness and that ACE inhibitors were known to vary in several pharmacological parameters.
[89] Second, Aventis contends that, based on this evidence, the theory of class effect for ACE inhibitors simply cannot be supported. The need for testing to demonstrate the benefit of ramipril in heart failure precludes a finding of obviousness, since ramipril was not tested by April 1984. Though a skilled person may have thought that the use of ramipril to treat heart failure was worth a try, absent testing, it was by no means obvious.
[90] Aventis submits that by April 1984, only one compound (captopril) had been the subject of double-blind clinical testing for the treatment of heart failure and only two other compounds (enalapril and teprotide) had ever been tested for heart failure. The only document cited in the NOA that discusses the use of ramipril is Apotex Document 71 authored by, amongst others, the inventors of the '457 patent. Importantly though, this document does not disclose the use of ramipril in the treatment of heart failure and neither Dr. Parker nor Dr. Gavras had seen it before their involvement in this litigation. Therefore, it is unlikely that this document would have been located by a reasonably diligent search as of April 1984, and as such, little or no weight should be accorded to it.
[91] Finally, Aventis maintains that the Becker declaration clearly shows that ramipril had several unexpected advantages in the treatment of heart failure (i.e. effect on ventricular fibrillation) which were neither taught nor suggested in the prior art. Aventis submits there is no obligation in law to disclose all advantages of an invention in a patent or even understand all of the advantages of an invention.
[92] Having set out the positions of the parties, and before considering the evidence, I will review the law regarding the principles applicable to the obviousness inquiry.
[93] "The doctrine of obviousness involves a determination of whether or not the alleged invention required the exercise of inventive ingenuity": Windsurfing International Inc. et al v. Trilantic Corporation (now Bic Sports Inc.) (1985), 8 C.P.R. (3d) 241. A mere "scintilla of invention" is sufficient to support the validity of a patent: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350.
[94] The most frequently cited test for obviousness was provided by Hugessen J.A. (as he then was) in Beloit, supra at paragraph 18:
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. 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. [emphasis added]
[95] More recently, in Sanofi-Synthelabo Canada Inc. v. Apotex Inc. (2005), 39 C.P.R. (4th) 202 at paragraph 78, Shore J. described the test in these terms:
A patent is only obvious if the solution to the problem is very plain. Suggestions or signposts in the prior art are not sufficient to render a patent invalid for obviousness. The person skilled in the art must be able to say that he or she would know that the invention would work and would have the benefits associated with the invention in light of the publicly available information. The person skilled in the art must know that the solution or the benefits would be present without testing (excluding, of course, simple verification of already known information). The test for obviousness is not whether it was "worth a try". [...]
[96] As stated by Wetston J. in Apotex Inc. and Novopharm Ltd. v. Wellcome Foundation Ltd. (1998), 79 C.P.R. (3d) 193 (F.C.T.D.), varied but not on the issue of obviousness, [2001] 1 F.C. 495 (C.A.), aff'd [2002] 4 S.C.R. 153, at paragraph 243:
There is no inventiveness in following an obvious and well-charted route using known techniques and processes involving known compositions unless the inventor encounters difficulties that could not have been reasonably expected by a person versed in the art or overcome by the application of ordinary skill. [...]
[97] With regard to the Court's examination of the prior art, unlike the anticipation inquiry, which requires an exact prior description in a single source, with obviousness, the Court can take into account a mosaic of prior art to determine whether the person skilled in the art would have been led to the invention: AB Hassle v. Apotex Inc., (2003), 27 C.P.R. (4th) 465. In the present matter, this involves looking at all the patents and other prior publications that the skilled person would discover in a "reasonable and diligent search" to determine whether the mosaic of prior art leads to the invention: Illinois Tool Works Inc. v. Cobra Fixations Cie. (2002), 221 F.T.R. 161, aff'd on this point, varied only with respect to costs: (2003), 312 N.R. 184 (F.C.A.).
[98] With respect to the question of obviousness in particular, the parties rely heavily on expert opinion evidence and their assessment of the numerous prior art references put into issue by the Apotex NOA. Expert opinion is doubtless useful, however, I must be vigilant not to engage in a hindsight analysis, particularly in view of the tendency of experts to employ such an analysis. Before considering an expert's statement that he "could have done that", a court must also consider the question, "why didn't you?": AB Hassle v. Genpharm (2003) 243 F.T.R. 6 at paragraph 51 citing Beloit, supra. As Hugessen J. wrote in Beloit, supra.
While the evidence of experts is properly admissible even on an ultimate-issue question such as obviousness, it must be treated with extreme care. This is especially the case where the testimony is given as a matter of hindsight.
[99] Thus, while expert evidence is helpful, the ultimate determination remains with the Court.
[100] Having summarized the principles of obviousness, I will now turn to the application of those principles to the facts in the matter before me. This involves determining whether the skilled technician, in light of the state of the art and common general knowledge at the claimed date of the invention, would have come directly and without difficulty to the invention claimed in the patent.
[101] Applied to the present matter: as of April 1984, would the skilled technician have come directly and without difficulty to the solution of using ACE inhibitors, including ramipril, for the treatment of heart failure?
[102] For the reasons that follow, I will answer in the affirmative. In my opinion, it is clear from the prior art that, as of the claimed date, a skilled person would have known that vasodilators were useful in the treatment of heart failure, that ACE inhibitors acted as vasodilators and that the prior patents and prior publications showed that ACE inhibitors as a class were useful in the treatment of heart failure.
[103] There was extensive literature at the time which referred to the use of ACE inhibitors for the treatment of heart failure. In its NOA, Apotex lists 94 pieces of prior art. Dr. Parker's affidavit contains an extensive review of a number of these documents, which, in my view, makes it clear that the knowledge of the person skilled in the art would "have come directly and without difficulty to the solution taught by the patent", namely, that ACE inhibitors were useful in the treatment of heart failure. By 1984, many of the ACE inhibitor compounds that fall within the scope of the claims of the '457 patent were reported in the literature as being useful for the treatment of heart failure.
[104] Apotex Document 51 (1983) discloses that the ACE inhibitor compound known as SCH 31846 (described as being a member of the same class of compounds as enalapril) was expected to be clinically effective in the treatment of congestive heart failure.
[105] Apotex Document 33 (1982) discloses the results from preclinical trials on quinapril and SCH 31846. Both ACE inhibitor compounds showed good efficacy in experimental hypertension and provided hemodynamic benefit in acute heart failure models. The skilled reader is therefore taught that these compounds were beneficial in an acute heart failure model in a dog (a mammal), which serves as a predictor for their usefulness in humans.
[106] The '658 Application (1982) (Apotex Document 34) contains as its subject-matter a purported new group of ACE inhibitor compounds, of which quinapril, SCH 31846, trandlapril and "saturated quinapril" are members, which were reported as being useful for both hypertension and cardiac insufficiency.
[107] The '800 Application (1982) (Apotex Document 36) disclosed that the group of ACE inhibitor compounds specified therein, of which ramipril, SCH 31846 and trandolapril are members, would be useful for the treatment of cardiac insufficiency.
[108] Apotex also provides 29 exemplary extracts of prior art in its NOA. I find it helpful to review a number of these exemplary extracts.
[109] Apotex Document 1 (1977) entitled "Angiotension II Inhibition, Treatment of Congestive Cardiac Failure in a High-Renin Hypertension", describes ACE inhibition as constituting a rational treatment for cases of heart failure at page 882:
For these reasons, we suggest that in selected cases of congestive cardiac failure accompanied by myocardial ischemia and known to have elevated plasma renin activity, inhibition of angiotensin may be a treatment of choice.
[110] Apotex Document 3 (1978) entitled "Angiotension II Blockade in Congestive Heart Failure" states at page 175:
Our results suggest that specific inhibition of angiotensin may provide a new therapeutic approach in some patients with congestive heart failure particularly when they are treated with diuretics.
[111] Apotex Document 7 (1980) has as its title: "Sustained Effectiveness of Converting-Enzyme Inhibition in Patients with Severe Congestive Heart Failure". The opening paragraph states as follows:
Vasodilator therapy in patients with severe congestive heart failure has achieved wide acceptance, but an optimal agent has not been defined.
[112] While a number of these documents reference captopril specifically, the majority make references to ACE inhibitors as a class of compounds. For example, Document 8 entitled, "Treatment of Chronic Congestive Heart Failure with Captopril, an Oral Inhibitor of Angiotensin-Converting Enzyme", the authors state at page 120:
We have shown that oral treatment with captopril, an inhibitor of angiotensin-converting enzyme, in patients with congestive heart failure, induces substantial increases in cardiac output and reductions in right atrial, pulmonary-artery and pulmonary-wedge pressures.
[113] Document 12 (1981) entitled, "Effect of captopril on renal function in patients with congestive heart failure" states the following at page 522:
The renin angiotensin system has been postulated to play an important role in sustaining the high peripheral vascular resistance that is characteristic of severe congestive heart failure. This hypothesis has been supported by demonstration of haemodynamic and clinical improvement when angiotensin converting enzyme inhibitors are used as vasodilator treatment for patients with congestive heart failure.
[114] One other example of such a document is Apotex Document 15, entitled "Acute Regional Circulatory and Renal Hemodynamic Effects of Converting-enzyme Inhibition in Patients with Congestive Heart Failure". The opening paragraph states as follows:
Angiotensin converting-enzyme inhibitors lower systemic vascular resistance and enhance myocardial function in patients with congestive heart failure, focusing attention upon the rennin-angiotensin system as a cause of excessive vascular impedance.
[115] In Apotex Document 25 (1982) entitled "Angiotensin-Converting Enzyme Inhibition in Congestive Heart Failure: The Concept", the authors state the following in summary:
These data suggest that angiotensin II contributes to the systemic vasoconstriction of heart failure and that chronic inhibition of the renin-angiotensin system may have a salutary effect on left ventricular performance in patients with heart failure.
[116] Apotex Document 54 (1983) entitled "Enalapril: A New Angiotensin-Converting Enzyme Inhibitor in Chronic Heart Failure: Acute and Chronic Hemodynamic Evaluations" states in introduction:
Attenuation or inhibition of the vasoconstricting effects of angiotensin is associated with improved cardiac performance of patients with chronic heart failure. Both the competitive antagonism of angiotensin II and its decreased production from converting enzyme inhibition can produce this beneficial response.
[117] Apotex Document 71 (March 1984) reports on a series of experiments carried out to characterize the effects of Hoe-948 (ramipril), using the same dosage described in the '457 patent. The second paragraph states:
We conclude that Hoe-498 is a potent orally active converting enzyme inhibitor. Its effects of local inhibition of CE may have physiological importance for the regulations of coronary flow and force of myocardial contraction.
[118] The evidence of prior art is overwhelming that a person skilled in the art would be led to the use of ACE inhibitors for the treatment of heart failure.
[119] Aventis submits that the obviousness allegation cannot succeed because there was never a known "class effect" of ACE inhibitors in the treatment of heart failure. I do not accept Aventis' argument that the promise of other ACE inhibitors in the treatment of heart failure would not enable a skilled person to predict that ramipril would be similarly promising in the treatment of heart failure. In fact, I find the contrary to be true. I am satisfied that the literature is clear and demonstrates that ACE inhibitors shared common properties and were known to be useful in the treatment of both hypertension and heart failure. The literature also shows that while studies were conducted using one or more specific ACE inhibitors, the conclusions reached were drawn with regard to ACE inhibitor compounds as a class.
[120] I accept Dr. Parker's affidavit evidence in which he disagrees with Drs. Dagenais and Karmazyn's view that ACE inhibitors were not viewed as having a "class effect." Under the section entitled "ACE Class Effect and Cardiac ACE", Dr. Parker states that "ramipril was viewed as a member of the ACE inhibitor class of compounds and like captopril and enalapril was expected to be useful in the treatment of not only hypertension but also cardiovascular diseases (disorders) that the other members of this class were known to treat, such as cardiac insufficiency" (Parker Affidavit. Paras. 84-85, Applicant's Record, Vol. VI, Tab 10). I also accept Dr. Gavras' affidavit evidence which states the same. Ramipril, like captopril and enalapril, was viewed as a member of the ACE inhibitor class of compounds. In light of the state of the art and the common general knowledge as at the claimed date of invention, the skilled technician would be led to believe that it was obvious to use ramipril, as part of the ACE inhibitor class of compounds, for heart failure.
[121] I assign significant weight to Dr. Dagenais' admission on cross-examination that, by April 1984, based on the fact that ramipril, like captopril and enalapril, was an ACE inhibitor, "it had the potential to", and would be expected to, be useful in the treatment of heart failure. Dr. Dagenais also conceded on cross-examination that he was not aware of any ACE inhibitor compound that was not effective or useful in heart failure.
[122] On cross-examination, Dr. Dagenais stated as follows:
Q. [The '800 application] is a publication that came out 1982. It says it was published on May 5, 1982.
A. Yes.
Q. At that time it was known that ACE inhibitors were effective to treat hypertension?
A. Yes.
Q. It was also known that captopril and enalapril were effective to treat heart failure?
A. Yes.
...
Q. Without suggesting that each ACE inhibitor is the very same as the next ACE inhibitor - and I was not meaning to suggest that. The properties of being an ACE inhibitor, whatever the definition of "ACE inhibitor" is, once a chemical is an ACE inhibitor, do you agree that the carries with it a property to a lesser or greater extent in terms of the treatment of diseases?
A. Yes.
Q. The expectation is that, if something is an ACE inhibitor, it is going to lower blood pressure.
A. It is going to lower blood pressure if your patient is hypertensive.
Q. Of course, if the patient is hypertensive. That was known in 1984?
A. Yes.
Q. Similarly, if ACE inhibitors are known to be effective in the treatment of heart failure, it would be expected that that property would be common to all ACE inhibitors.
A. You can assume that. If I put myself as a skilled person, I don't know if there is a new molecule that is coming out that, although it has the same effect on the ACE inhibition, it will behave exactly the same.
Q. I am not saying exactly.
A. In general, it is possible that it will be the same.
Q. It is not only possible; it would be expected.
A. It would be expected; to use your word.
Q. We would expect that, and that was so in 1984?
A. It was so in 1984 but, when you don't know how the compound acts, you may question that. But you may expect it.
Q. When you say you may question that, you would want to verify that expectation?
A. Yes.
Q. I take it that you are not aware of any ACE inhibitor as of the summer of 1984 that was not effective or useful in heart failure?
A. No, I was not.
Q. The expectation that we spoke about a moment ago in 1984, the expectations that we have discussed were not just your personal opinion but those were the expectations that you would say a person skilled in the art had at the time.
A. Yes.
(Dagenais Cross-Examination. Q.406-418, Applicant's Record, Vol. IX, Tab 22)
[123] Aventis submits that the prior art was merely investigational in nature and that further clinical tests were required. I cannot accept either of these submissions. First, the experts all agree that the use of vasodilators, which included ACE inhibitor compounds, for the treatment of heart failure was well accepted by 1984. Second, Aventis' assertion is an attempt to elevate the standard for patentability and inventiveness to the standard for regulatory submission. The case law is clear that clinical studies required for approval from the Minister of Health are not required to show obviousness. In Apotex Inc. v. Wellcome Foundation Inc., supra, Wetston J., at trial stated at paragraph 104:
...the basis of my assessment is not, as is the case for the Minister of Health, whether the drug, as formulated, has been tested sufficiently so that it can be administered safely and effectively to humans. Rather, I must determine if an inventor can claim an invention which has utility, thus giving society proper consideration for the patent. However, A & N argues that the standard of utility to which a pharmaceutical invention must be held is safety and effectiveness...
He then quotes from the Food and Drug Regulations and concludes at paragraph 105:
In my opinion, these requirements are excessive in order for pharmaceuticals to be patentable and create too high a standard for a patent.
[124] At the Supreme Court of Canada, [2002] 4 S.C.R. 153 Binnie J. lent support for this argument at paragraph 3 where he stated:
[...] For [the Commissioner of Patents] to have required Glaxo/Wellcome to demonstrate AZT's efficacy through the clinical tests required by the Minister of Health for approval of a new drug for medical prescription would have been unfair to Glaxo/Wellcome. [...]
[125] Later, at paragraph 77, he reinforced that the prerequisites of proof for a manufacturer who wishes to market a new drug, required by the Minister of Health when dealing with a new drug submission (i.e. prior human clinical trials), are directed to a different purpose than patent law. "The former deals with safety and effectiveness. The latter looks at utility, but in the context of inventiveness."
[126] A similar argument regarding experimentation or testing as a requirement was advanced in Janssen-Ortho Inc., supra where Mosley J. concluded at paragraph 54 that:
[...] the test for obviousness does not exclude routine testing to determine characteristics of known compounds, not undertaken for the purpose of searching for something novel, but rather for the purpose of verifying the actual attributes of already known compounds, where the results indicate no new uses or surprising results or properties that are clearly superior to the already known parent compound.
[127] In Sanofi-Synthelabo, supra, Apotex sought to market a generic version of PLAVIX. Sanofi-Synethelabo held a patent for PLAVIX relating to the invention of a dextro-rotatory isomer of a racemate. A previous patent disclosed that compounds could exist as racemates or isomers. However, the previous patent did not contain any teaching on how to separate the racemates into their optical isomers.
[128] Shore J. found that the previous patent did not teach the separation of the racemates into their optical isomers. The expert evidence indicated that the result of separating the racemates was unknown and therefore not obvious. The prior art only taught to the point just before separation. The necessary additional step after following the teachings of the prior art was to separate the racemate into its isomers in order to obtain the dextro-rotatory isomer of the racemate. There was evidence of five different separation techniques. There was no evidence before the Court that the person skilled in the art would have known which one would work. Shore J. found that the only evidence before the Court was that the person skilled in the art would eventually have found the right technique. Through this evidence, he found that what the experts were saying, from a legal perspective, was that separating the racemate was "worth a try" and not obvious.
[129] This case illustrates, in my view, the distinction between whether the invention taught in the patent was obvious or merely "worth a try". The prior art in Apotex's NOA clearly indicates that it was known that ACE inhibitors would be useful for the treatment of heart failure. There was no necessary additional step required. It is evident that, to the person skilled in the art, the use of ACE inhibitors for the treatment of heart failure was more than merely "worthy a try"; it was obvious.
[130] Aventis' final submission relates to the surprising utility of ramipril in reducing the duration of ventricular fibrillations. This is irrelevant to the present matter as the use of ramipril to treat ventricular fibrillation was not a use claimed in the '457 patent and in fact, is not even mentioned in the patent. Aventis' relies on the following passage from Consolboard Inc. v. MacMillan Bloedel (Sask) Ltd., [1981] 1 S.C.R. 504 at 526:
Although (i) s. 36(1) requires the inventor to indicate and distinctly claim the part, improvement or combination which he claims as his invention and (ii) to be patentable an invention must be something new and useful (s. 2) and not known or used by any other person before the applicant invented it (s. 28(1)(a)), I do not read the concluding words of s. 36(1) as obligating the inventor in his disclosure or claims to describe in what respect the invention is new or in what way it is useful. He must say what it is he claims to have invented. He is not obliged to extol the effect or advantage of his discovery, if he describes his invention so as to produce it.
As Thorson P. stated in R. v. American Optical Company et al. at p. 85:
Nor is it any objection to the sufficiency of the disclosures that the advantages of the invention as enumerated by Professor Price were not set out in the specification ... If an inventor has adequately defined his invention he is entitled to its benefit even if he does not fully appreciate or realize the advantages that flow from it or cannot give the scientific reasons for them. It is sufficient if the specification correctly and fully describes the invention and its operation or use as contemplated by the inventor, so that the public, meaning thereby persons skilled in the art, may be able, with only the specification, to use the invention as successfully as the inventor could himself.
[131] This passage stands for the principle that sufficient disclosure in a patent does not require the inventor to include all the advantages or benefits that flow from the invention. In my view, this is not relevant to the question of obviousness, which does not question the sufficiency of disclosure given unlisted benefits, but rather whether the prior art would indicate to the skilled person that the invention was obvious.
[132] In conclusion, the prior art indicated that, as of April 1984, the skilled person would have been led directly and without difficulty to the conclusion that ramipril, as part of the ACE inhibitor class of compounds, was useful in the treatment of heart failure.
[133] The '457 patent is thus invalid for obviousness.
(iii) Double patenting
[134] In addition to the '457 patent, Aventis owns Canadian Patent No. 1,187,087 (the "'087 patent"), which specifically claims ramipril and discloses the use of the compound as an ACE inhibitor and for the treatment of hypertension.
[135] Apotex alleges that claim 8 of the '457 patent is invalid on the basis of double patenting. The '087 patent claims as claim 6 the compound ramipril per se, and it also describes ramipril as being a powerful and long-lasting ACE inhibitor useful in the treatment of hypertension. Apotex submits that there is no separate invention in using an ACE inhibitor compound known to treat hypertension for the treatment of cardiac insufficiency and particularly, congestive heart failure as at the relevant time, being April 1984.
[136] Alternatively, Apotex alleges that the invention set out in claim 8 was an obvious and non-inventive variation that did not warrant patent protection over the invention in the '087 patent.
[137] Aventis emphasizes the '087 patent contains no claims for the treatment of cardiac insufficiency, which is a distinct clinical indication from hypertension.
[138] The Supreme Court of Canada explained the issue of double patenting in Whirlpool Corp., supra. The prohibition against double patenting is premised on the idea that the inventor is only entitled to one patent for each invention. If a subsequent patent issues with identical or obvious claims, there is an improper extension of the monopoly. There are two branches of double patenting. The first is "same invention" double patenting, the test for which asks whether the claims are "identical or conterminous" The second branch, often called "obviousness" double patenting, is a more flexible and less literal test, which asks whether the claims of the second patent are "patentably distinct" from the claims of the earlier patent
[139] As both Drs. Dagenais and Karmazyn stated in their affidavits, hypertension and heart failure are distinct clinical indications. Patients with heart failure may or may not be hypertensive. Both experts agreed that the treatment of heart failure is neither the same nor obvious in light of the '087 disclosure. In my view then, the claims of the '457 patent cannot be said to be "identical or coterminous" with the claims of the '087 patent.
[140] With regard to obviousness double patenting, I should first note that a finding of invalidity based on obviousness does not lead automatically to a finding of invalidity based on obviousness double patenting. The grounds for alleging each may be different, as is the case here. Apotex alleges that it would have been obvious to a skilled person to use an ACE inhibitor compound known to treat hypertension for the treatment of cardiac insufficiency, but led no evidence to substantiate such a claim. Although I found previously that the invention in the '457 patent was obvious in light of the prior art, I did not make this finding given the skilled technician's knowledge that ACE inhibitors could already be used to treat hypertension. As stated, hypertension and cardiac insufficiency are distinct clinical disorders and I do not find that, in light of the '087 patent, it was obviousness double patenting. As I have previously constructed, this patent was a new use for a known compound, the subject matter of which one may properly obtain a patent over.
[141] In the result, this application is dismissed with costs.
ORDER
THIS COURT HEREBY ORDERS THAT:
The application for judicial review is dismissed with costs.
"Danièle Tremblay-Lamer"
JUDGE
FEDERAL COURT
NAME OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-2459-03
STYLE OF CAUSE: AVENTIS PHARMA INC ET AL v. APOTEX INC ET AL
PLACE OF HEARING: Toronto, Ontario
DATE OF HEARING: September 20-22, 2005
REASONS FOR ORDER: TREMBLAY - LAMER J.
APPEARANCES:
Mr. Gunars A. Gaikis
Ms. Kavita Ramamoorthy FOR APPLICANTS
Mr. H. B. Radomski
Mr. Andrew R. Brodkin
Mr. Rick Tuzi FOR RESPONDENTS
SOLICITORS OF RECORD:
SMART & BIGGAR LLP
438 University Avenue
Suite 1500, Box 111
Toronto, Ontario
GOODMANS LLP
250 Yonge Street
Suite 2400
Toronto, Ontario
(APOTEX)
John H. Sims, Q.C.
Department of Justice
Ontario Regional Office
The Exchange Tower
130 King St. W.
Suite 3400, Box 36
Toronto, Ontario
M5X 1K6 FOR RESPONDENT
(MINISTER OF HEALTH)
[1] At the time of the hearing of this matter, Simpson J.'s decision in T-1851-03 was still under reserve. An order was issued on October 6, 2005 followed by reasons released on October 11, 2005.