Glaxosmithkline Inc. v. Canada (Minister of Health)

Glaxosmithkline Inc. v. Canada (Minister of Health)
Court (s) Database
Federal Court Decisions
Date
2004-01-26
Neutral citation
2004 FC 116
File numbers
T-1871-01
Decision Content
Date: 20040126
Docket: T-1871-01
Citation: 2004 FC 116
Ottawa, Ontario, this 26th day of January, 2004
Present: THE HONOURABLE MR. JUSTICE SIMON NOËL
BETWEEN:
GLAXOSMITHKLINE INC.
-and-
SMITHKLINE BEECHAM CORPORATION
Applicants
and
THE MINISTER OF HEALTH
-and-
PHARMASCIENCE INC.
Respondents
AMENDED REASONS FOR ORDER AND ORDER
[1] This is an application by GlaxoSmithKline Inc. and SmithKline Beecham Corporation (referred to collectively as "GlaxoSmithKline") for an Order prohibiting the Minister of Health ("Minister") from granting to Pharmascience Inc. ("Pharmascience") a Notice of Compliance ("NOC") in respect of the medicine carvedilol, including 3.125 mg, 6.25 mg, 12.5 mg, 25 mg tablets, until after the expiration of Canadian Patents Nos. 2,212,548 ("the '548 Patent") and 1,259, 071 ("the '071 Patent").
[2] However, at the hearing, GlaxoSmithKline dropped its application for a prohibition Order with regard to the '71 Patent. The issue as to whether Pharmascience's allegation of non-infringement of this Patent is justified will therefore not be dealt with in this decision.
FACTUAL BACKGROUND
[3] The '548 Patent - Canadian Letters Patent No. 2, 212, 548 entitled "Use of Carbazol Compounds for the Treatment of Congestive Heart Failure", contains a series of claims for the use of the medicine carvedilol for the treatment of congestive heart failure and for the reduction in mortality resulting from congestive heart failure. The invention in this Patent is the use of the compound, not the formulation or the way the formulation was done. The '548 Patent was applied for in Canada on February 7, 1996, claiming a priority date of February 8, 1995 based on the corresponding German patent application. This Patent will expire on February 7, 2016.
[4] SmithKline Beecham Corporation is the owner of the '548 Patent, and GlaxoSmithKline Inc. is a licensee thereunder. The '548 Patent is listed on the Patent Register maintained by the Minister of Health pursuant to sections 3 and 4 of the Patented Medicines (Notice of Compliance) Regulations, SOR 93/133, as amended (" NOC Regulations") for the medicine carvedilol.
[5] This proceeding arises as a result of a submission by Pharmascience to the Minister for a NOC and to obtain approval to sell carvedilol tablets. In accordance with s. 5 of the NOC Regulations, Pharmascience had to address the patents by serving a Notice of Allegation ("NOA") on GlaxoSmithKline. The purpose of the NOA was to establish that Pharmascience's plan for its version of the drug would not infringe the relevant patents. GlaxoSmithKline was not persuaded by the NOA and is thus seeking the prohibition order contemplated by this application, as permitted by the NOC Regulations.
[6] Pharmascience's Notice of allegation - In its NOA, dated August 30, 2001, Pharmascience alleged that its carvedilol tablets will not infringe the claims of the '71 Patent and that both the '71 and the '548 Patents are invalid. Its allegations with respect to the '548 Patent are limited to grounds of invalidity. Pharmascience has not alleged that it will not infringe the claims of the '548 Patent; rather, it alleges that the claims of the '548 Patent are invalid given that they are either (i) anticipated; and/or (ii) obvious having regard to the prior art and the common general knowledge; and (iii) they cover improper subject matter. Further, Pharmascience made an allegation that the claims for decreasing mortality are not an "invention" as that term is defined in the Patent Act: it does not cover the results of a process, or the benefits of a process.
CARVEDILOL and CONGESTIVE HEART FAILURE
[7] The medicine in question, carvedilol, is a multi-action adrenoreceptor blocking agent that provides non-selective beta-adrenergic blocking activity. It combines in one molecule both beta-blocking and vasodilating activity. Beta-blockers were originally developed for the treatment of heart rhythm problems and angina pectoris in the late 1960's. They were first suggested as a treatment for hypertension in the mid-1970's. This came about from clinical observations of patients treated for angina, in whom it was noted that blood pressure was lowered with chronic administration. Following Phase III clinical trials, carvedilol received its first approval for use in hypertension in Germany in 1991 and subsequently received approval worldwide for the treatment of Congestive Heart Failure ("CHF").
[8] CHF is a clinical description of the inability of the heart to deliver sufficient oxygen to meet the body's needs. Under normal conditions, the heart acts as an effective pump delivering oxygenated blood to the body via the arteries, and collecting de-oxygenated blood via the veins. A person with damage to the heart that reduces its pumping ability is unable to deliver sufficient oxygenated blood to carry out the body's functions and is said to suffer CHF. Heart failure is both symptomatic as well as a progressive disease syndrome. Thus, the goals of therapy for heart failure are to slow the disease progression, thereby reducing the risk of morbidity and mortality, and to improve the quality of life and clinical status through the alleviation of symptoms.
PROCEDURAL BACKGROUND
[9] By Notice of Motion dated November 12, 2001, GlaxoSmithKline brought a motion seeking, inter alia, an Order compelling Pharmascience to produce portions of its Abbreviated New Drug Submission ("ANDS") filed with the Minister for its carvedilol tablets, as well as an Order limiting the number of documents that Pharmascience may rely upon to support its allegations of invalidity with respect to both the '71 and '548 Patents.
[10] By Order dated December 13, 2001, Prothonotary Lafrenière dismissed GlaxoSmithKline's motion to compel production of portions of the Pharmascience's ANDS, but granted an Order limiting the scope of Pharmascience's allegations of invalidity as follows:
1. The Respondent, Pharmascience Inc., shall only rely upon the reference by David T. Kelly in the journal Cardiology dated 1993 listed as item number 24 in Appendix "A" to Notice of Allegation in support of its allegation of invalidity by anticipation of Canadian Letters Patent No. 2, 212, 548 as set out on page 3 of the NOA under the heading "Anticipation".
2. The Respondent, Pharmascience Inc. shall serve on all parties a detailed description of the portions of the 60 references contained in Appendix "A" to the Notice of Allegation that are not specifically referred to in paragraphs 1 to 13 on pages 3 to 5 of the Notice of Allegation upon which Pharmascience is relying to support its allegations of invalidity by reason of obviousness of Canadian Letters Patent No. 2,212, 548 by Monday, December 17, 2001.
3. The Applicants are not precluded from contesting the sufficiency of the Notice of Allegation before the Judge hearing the within Application by reason of the delivery, by Pharmascience, of the further descriptions provided for in paragraph 2 above, or by reason of the delivery by the Applicants of affidavit evidence in response to such descriptions.
[11] Accordingly, Pharmascience served a description of the 60 references contained in Appendix "A" to the NOA. Although GlaxoSmithKline mostly directed the Court's attention to two main articles (Hampton, J.R., Choosing The Right Beta-Blocker: A Guide to Selection, Drugs 48(4): 549-568, 1994 (the "Hampton article") and Doughty, R.N. et al., Beta-Blockers in Heart Failure: Promising or Proved?, JACC 23(3): 814-21, March 1, 1994 (the "Doughty article"), GlaxoSmithKline had the full opportunity to have its experts review and give their opinion on all the references given.
LEGAL CONTEXT
[12] As mentioned above, Pharmascience' NOC application and NOA were submitted to the Minister and to GlaxoSmithKline pursuant to subparagraphs 5(1) (b) (iii) and (iv), and subsection 5(3) of the NOC Regulations, which read:
5. (1) Where a person files or has filed a submission for a notice of compliance in respect of a drug and compares that drug with, or makes reference to, another drug for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics and that other drug has been marketed in Canada pursuant to a notice of compliance issued to a first person and in respect of which a patent list has been submitted, the person shall, in the submission, with respect to each patent on the register in respect of the other drug,
...
(b) allege that
...
(iii) the patent is not valid, or
(iv) 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 that person of the drug for which the submission for the notice of compliance is filed.
...
5. (3) Where a person makes an allegation pursuant to paragraph (1)(b) or (1.1)(b) or subsection (2), the person shall
(a) provide a detailed statement of the legal and factual basis for the allegation;
(b) if the allegation is made under any of subparagraphs (1)(b)(i) to (iii) or (1.1)(b)(i) to (iii), serve a notice of the allegation on the first person;
(c) if the allegation is made under subparagraph (1)(b)(iv) or (1.1)(b)(iv),
(i) serve on the first person a notice of the allegation relating to the submission filed under subsection (1) or (1.1) at the time that the person files the submission or at any time thereafter, and
(ii) include in the notice of allegation a description of the dosage form, strength and route of administration of the drug in respect of which the submission has been filed; and
(d) serve proof of service of the information referred to in paragraph (b) or (c) on the Minister.
5. (1) Lorsqu'une personne dépose ou a déposé une demande d'avis de conformité pour une drogue et la compare, ou fait référence, à une autre drogue pour en démontrer la bioéquivalence d'après les caractéristiques pharmaceutiques et, le cas échéant, les caractéristiques en matière de biodisponibilité, cette autre drogue ayant été commercialisée au Canada aux termes d'un avis de conformité délivré à la première personne et à l'égard de laquelle une liste de brevets a été soumise, elle doit inclure dans la demande, à l'égard de chaque brevet inscrit au registre qui se rapporte à cette autre drogue :
...
b) soit une allégation portant que, selon le cas :
...
(iii) le brevet n'est pas valide,
(iv) aucune revendication pour le médicament en soi ni aucune revendication pour l'utilisation du médicament ne seraient contrefaites advenant l'utilisation, la fabrication, la construction ou la vente par elle de la drogue faisant l'objet de la demande d'avis de conformité.
...
5. (3) Lorsqu'une personne fait une allégation visée aux alinéas (1)b) ou (1.1)b) ou au paragraphe (2), elle doit :
a) fournir un énoncé détaillé du droit et des faits sur lesquels elle se fonde;
b) si l'allégation est faite aux termes de l'un des sous-alinéas (1)b)(i) à (iii) ou (1.1)b)(i) à (iii), signifier un avis de l'allégation à la première personne;
c) si l'allégation est faite aux termes des sous-alinéas (1)b)(iv) ou (1.1)b)(iv) :
(i) signifier à la première personne un avis de l'allégation relative à la demande déposée selon les paragraphes (1) ou (1.1), au moment où elle dépose la demande ou par la suite,
(ii) insérer dans l'avis d'allégation une description de la forme posologique, de la concentration et de la voie d'administration de la drogue visée par la demande;
d) signifier au ministre une preuve de la signification effectuée conformément aux alinéas b) ou c).
[13] A first person, or the innovator, who does not think that the allegations made by the generic manufacturer (the second person) are justified, can, within 45 days, apply for an order prohibiting the Minister from issuing the NOC to the second person, pursuant to section 6 of the NOC Regulations.
[14] As soon as that application is filed, and proof of its filing is served on the Minister, a statutory prohibition is imposed pursuant to section 7 of the NOC Regulations, and the Minister cannot issue the NOC in question for a period of 24 months.
[15] It has been established by the jurisprudence that the applicant, in this case, GlaxoSmithKline, bears the legal burden to demonstrate, on a balance of probabilities, that the allegations in the NOA are not justified. An allegation, in proceedings for an order of prohibition, is presumed to be true, except to the extent that the contrary has been shown: Merck Frosst Canada Inc. v. Canada (Minister of Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.), Hoffmann-La Roche Ltd. v. Canada (Minister of Health and Welfare) (1996), 70 C.P.R. (3d) 206 (F.C.A.)SmithKline Beecham Pharma Inc. v. Apotex Inc. (1999), 1 C.P.R. (4th) 99 (F.C.T.D.), aff'd (2001), 10 C.P.R. (4th) 338 (F.C.A.), Wyeth-Ayerst Canada Inc. v. Faulding (Canada) Inc. (2002), 21 C.P.R. (4th) 375 (F.C.T.D.) Thus, GlaxoSmithKline has the burden to establish that Pharmascience's allegations are not justified.
[16] GlaxoSmithKline claims that, to establish that the allegations are not justified, it is entitled to rely upon the statutory presumption of validity found in section 43 of the Patent Act, R.S.C. 1985, c. P-4, which reads:
43.(1)...
(2) After the patent is issued, it shall, in the absence of any evidence to the contrary, be valid and avail the patentee and the legal representatives of the patentee for the term mentioned in section 44 or 45, whichever is applicable.
43. (1)...
(2) Une fois délivré, le brevet est, sauf preuve contraire, valide et acquis au breveté ou à ses représentants légaux pour la période mentionnée aux articles 44 ou 45.
[17] In Bayer Inc. v. Canada (Minister of National Health and Welfare), [2000] F.C.J. No. 464, 6 C.P.R. (4th) 285 (C.A.), the Court discussed at paragraph 9, the relevance of the statutory presumption of the validity of a patent:
... 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: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.) at 359.
[18] Furthermore, it should be noted that these proceedings are not actions for determining infringement, as held by the Federal Court of Appeal in David Bull Laboratories (Canada) Inc. v. Pharmacia Inc. et al. (1994), 58 C.P.R. (3d) 209 at 216:
However this court made clear in Merck Frosst v. Canada, supra [(1994), 55 C.P.R. (3d) 302, (F.C.A.)], that 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. It is useful to reiterate what the court said in the Merck case.
The proceedings are not an action and their object is solely to prohibit the issuance of a notice of compliance under the Food and Drug Regulations. Manifestly, they do not constitute "an action for infringement of a patent".
[19] It is within the context of the foregoing that this Court must determine whether the allegations of invalidity of the '548 Patent are justified. If the Court determines the NOA is not justified, then an order for prohibition should be issued. On the other hand, if I determine that the NOA is justified, then the application will be dismissed.
ISSUES
[20] The main issue left with the Court after the hearing was whether Pharmascience's allegations of invalidity of the '548 Patent for reasons of anticipation and/or obviousness in light of prior art are justified.
ANALYSIS
[21] Are the Pharmascience allegations of invalidity of the '548 Patent for reasons of anticipation and/or obviousness in light of prior art justified? If GlaxoSmithKline is to be successful on its application, it must convince the Court on both reasons. However if it fails on one allegation, the application must be dismissed.
[22] As previously stated in paragraph 8, Pharmascience, in its NOA, did not allege that it would not infringe the claims of the '548 Patent; rather, it alleges that the '548 Patent contains nothing new or inventive and is therefore invalid given that the claims are either (i) anticipated, and/or (ii) obvious having regard to the prior art and the common general knowledge; and (iii) they cover improper subject matter. Further, Pharmascience made the allegation that the claims for decreasing mortality are not an "invention" as that term is defined in the Patent Act, as it does not cover the results of a process or the benefits of a process.
[23] The first question which I believe must be resolved before determining whether the allegations are justified, is whether the subject-matter of the claims of the '548 Patent is an "invention" within the meaning of section 2 of the Patent Act. Then, I will determine whether the allegations of invalidity based on anticipation and/or obviousness are justified.
[24] Is the '548 Patent an invention? - In its NOA, Pharmascience alleged the following:
"The claims for decreasing mortality are not an "invention" as that term is defined in the Patent Act. According to the Patent Act, an invention includes "any new and useful art, process, machine, manufacture or composition of matter..." It does not cover the results of a process, or the benefits of a process."
[25] GlaxoSmithKline submits that this allegation is without merit, since the idea of applying an old compound to a new, non-obvious use is inventive. Whereas GlaxoSmithKline argues that the application of this new knowledge to effect a desired result which has an undisputed commercial value is an "invention" within the meaning of the Patent Act, Pharmascience submits that the ingenuity of the Patent lies not in the identification of a desirable result (namely the reduction of mortality) but in teaching one particular means to achieve it.
[26] The complete definition of "invention" in section 2 reads as follow:
"invention" means any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture or composition of matter.
« invention » Toute réalisation, tout procédé, toute machine, fabrication ou composition de matières, ainsi que tout perfectionnement de l'un d'eux, présentant le caractère de la nouveauté et de l'utilité.
[27] Section 2 of the NOC Regulations specifies that a "claim for the use of the medicine" means:
a claim for the use of the medicine for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or the symptoms thereof.
« revendication pour l'utilisation du médicament » Revendication pour l'utilisation du médicament aux fins du diagnostic, du traitement, de l'atténuation ou de la prévention d'une maladie, d'un désordre, d'un état physique anormal, ou de leurs symptômes.
[28] As a tool to guide the Court in the interpretation of "use claim", I turn to the Manual of Patent Office Practice of the Canadian Intellectual Property Office, section 11.10.02, entitled "Method of Use and Use Claims":
...
When a compound has been patented previously or is in the public domain, claims directed to the obvious use of this compound should be objected to for lacking patentable subject matter. Claims directed to a new and unobvious use of the same compound are allowable. Likewise, claims directed to a method of using the compound for a new unobvious purpose are allowable. Furthermore, when an invention is directed to a novel and unobvious use of a known compound, claims to this known compound with the further recitation of a novel use are allowable (re application for patent of Wayne State University 22 C.P.R. (3d) 407). [my emphasis]
[29] Moreover, the idea of applying an old compound to a new, non-obvious use is inventive. In Shell Oil Co. v. Commissioner of Patents (1982), 67 C.P.R. (2d) 1, Mme Justice Wilson of the Supreme Court of Canada held :
What then is the "invention" under s. 2? I believe it is the application of this new knowledge to effect a desired result which has an undisputed commercial value and that it falls within the words "any new and useful art". I think the word "art" in the context of the definition must be given its general connotation of "learning" or "knowledge" as commonly used in expressions such as "the state of the art" or "the prior art". The appellant's discovery in this case has added to the cumulative wisdom on the subject of these compounds by a recognition of their hitherto unrecognized properties and it has established the method whereby these properties may be realized through practical application. In my view, this constitutes a "new and useful art" and the compositions are the practical embodiment of the new knowledge.
[30] In light of the above, I have no problem in saying that the '548 Patent is indeed an invention since it is directed to a novel or nonobvious (although that is still contended) use of a known compound. The spark of ingenuity in this Patent lies with the association made of the use of Carvedilol for the treatment of CHF with the benefit of reducing mortality.
[31] Now, whether the '548 Patent is valid or not on the basis that the invention was anticipated and/or obvious, requires a somewhat different analysis. First, I will consider the factual process on how the '548 Patent came to be, then I will set out the experts presented by the parties. Onwards I will study the law, the prior art and the experts' comments on the prior art for both invalidity grounds, obviousness and anticipation.
[32] The development of the drug - Heart failure development normally begins with a Phase I clinical trial. This is designed to assess the feasibility of administration and initial clinical safety of a new compound in normal, healthy control subjects. If promising, the drug may then advance to Phase II investigation. This is the initial "proof of principle" stage in which surrogate endpoints are evaluated in order to provide support for moving into large-scale randomized controlled morbidity and mortality trials (Phase III). In Phase II studies of heart failure, the most commonly evaluated endpoints are hemodynamics, heart function, quality of life, and exercise ability or capacity. Phase III trials represent the pivotal investigative experience with a new compound. According to GlaxoSmithKline's expert, Dr. William T. Abraham, the preliminary results in Phase II studies are not definitive and do not provide sufficient information to allow a cardiologist to adopt a new drug or treatment in his or her practice.
[33] As related by GlaxoSmithKline's experts, prior to February 1995 (the priority date of the '548 Patent), there were only three large scale clinical trials involving beta-blockers, the class of drugs to which carvedilol belongs; the Xamoterol Trial, 1990, the MDC Trial, 1993, and the CIBIS I Trial, 1994. In these trials, the beta-blocker under investigation showed promise in earlier and smaller trials, however, when tested in a large-scale trial, they either shortened patient's lives or showed no mortality benefit. It is for this reason that drugs development in CHF is one of the most closely scrutinized areas in terms of approach taken by physicians and regulatory bodies in reviewing that drugs lead to improve outcomes in CHF. In the case of carvedilol, the Phase II trials showed regression in left ventricular hypertrophy and in central hemodynamics. These are considered beneficial effects in CHF. The Phase II trials encouraged researchers to continue using carvedilol in clinical trials, and to go on and do the bigger trials.
[34] GlaxoSmithKline designed the U.S. Carvedilol Trials Program (the "U.S. Carvedilol Trial), which is the equivalent to a Phase II, to test the potential of carvedilol to improve symptoms in patients suffering from CHF. Although the U.S. Carvedilol Study was designed to determine the effect of carvedilol on certain surrogate endpoints such as exercise tolerance, given the other studies, GlaxoSmithKline was concerned about the possibility of carvedilol causing an increase in the mortality of patients. As such, they decided to utilize an independent Data Safety Monitoring Board ("DSMB") to monitor the effect of carvedilol on mortality to determine if patient safety was being compromised during the course of the trial.
[35] Despite the concerns regarding the possibility of carvedilol increasing mortality, the U.S. Carvedilol Trial demonstrated a result of a 65% decrease in the risk of mortality. As a consequence of these encouraging results, the DSMB recommended that the study be halted prematurely in February 1995. This recommendation was endorsed. Due to the results of the U.S. Carvedilol Trial, GlaxoSmithKline filed an application in Canada for the '548 Patent, with a priority date of February 1995, for the use of carvedilol in the treatment of CHF and the use of carvedilol for the reduction of mortality in patients with CHF.
[36] The U.S. Carvedilol Trial study was published on May 23, 1996, in the New England Journal of Medicine. In his affidavit at paragraph 79, Dr. Abraham commented the following regarding the US. Carvedilol Trial:
In 1995, the U.S. Carvedilol Heart Failure Trials Program was terminated prematurely. This trials program consisted of 4 individual clinical trials of carvedilol in patients with heart failure. One study evaluated carvedilol in mild heart failure, 2 studies evaluated carvedilol in patients with moderate heart failure, and 1 study evaluated patients with advanced heart failure. The primary endpoints of the individual studies included measures of quality of life and functional capacity and in 1 instance a composite measure of disease progression. Two of these individual studies were positive and 2 were negative. While the primary data was conflicting, an analysis of mortality in the entire cohort of 1,094 patients studied across all 4 protocols demonstrated a reduction in all-cause mortality. These observations were subsequently published in the New England Journal of Medicine in 1996. This study was far from definitive. In fact, it was highly criticized by the academic and practicing communities. For example, there were numerous letters to the editors of the New England Journal of Medicines citing the inherent weaknesses of the analysis. First, the assessment of mortality was performed on pooled data across 4 separate studies, 2 of which did not meet their primary endpoints for efficacy. In many ways, this analysis amounted to a post ad hoc analysis, which is inherently weak. There was also a run-in phase to these trials which was felt to have selected for a group of patients who tolerated the drug and this might benefit in a better than average way. In addition, the number of deaths in this population was relatively small. The overall combined analysis was considered underpowered to prospectively address the effects of carvedilol on mortality. Further evidence of the weakness of this data may be found in the initial presentation of carvedilol to the Cardiorenal Drugs Advisory Panel at the U.S. Food and Drug Administration. The outcome of this initial presentation was a vote for non-approval of the drug for the treatment of heart failure. It took fully another year before the database was considered sufficient to allow approval of the drug. At that time, the drug was not given an indication for reduction of mortality. There was broad acknowledgment within the regulatory, academic, and practicing communities that the questions of the effects of beta-blockade on mortality in heart failure remained unanswered. In fact, this question was not answered until much later and well after 1995 with the completion of the CIBIS II, MERIT-HF, and COPERNICUS studies.
[37] In order to address the concerns described above, GlaxoSmithKline sponsored the Copernicus Study designed to test the endpoint of mortality, including the effectiveness of treating patients presenting with more severe forms of CHF using carvedilol. The Copernicus Study was the first definitive mortality trial of carvedilol in heart failure, published on May 31, 2001, in the New England Journal of Medicine.
[38] The Expert evidence - In order to rebut the presumption of the veracity of Pharmascience's NOA, GlaxoSmithKline called upon the following experts. I will briefly expose their curriculum vitae for credibility concerns:
Dr. William T. Abraham holds a number of positions at the University of Kentucky College of Medicine and is currently the Gill Professor of Preventive Cardiology, Chief - Division of Cardiovascular Medicine, Medical Director - Heart Failure Management Program and Medical Director - Cardiac Transplantation Program. Although very knowledgeable in his field, Dr. Abraham only began practicing cardiology in December 1993 and was certified as a cardiologist in 1995.
Dr. Nadia S. Giannetti is currently an Assistant Professor in the Department of Medicine at McGill University and Medical Director at Heart Failure and Heart Transplant Centre at the McGill University Health Centre. However, as alleged by Pharmascience, Dr. Giannetti was not a certified cardiologist until 1998.
Dr. Mary Ann Lukas holds a sub-specialty certification in cardiology and is currently Director of Cardiovascular Therapeutic Area for GlaxoSmithKline. Pharmascience argues that as a co-inventor of the '548 Patent, Dr. Lukas has a personal interest in the subject-matter of the Patent and the issues before this Court and therefore lacks the necessary independence to be treated as an expert.
Dr. John Parker is a Professor of Medicine and Pharmacology at the University of Toronto, Director at the Cardiac Catheterization Laboratories of the University Health Network Hospitals, Clinical Service Chief of Cardiology at Mount Sinai Hospital and Director at the Harrowston Heart Failure Clinic of Mount Sinai Hospital.
[39] Pharmascience presented the following experts:
Dr. Bertram Pitt is a recognized authority in the field of cardiology and is currently a Professor of Internal Medicine at the University of Michigan School of Medicine, a Fellow of the American College of Cardiology, and an active member of the American Heart Association. He had been practicing as a cardiologist for an extensive period in 1995 when the prior art articles were published and can comment on what the schools of thoughts were prior to 1995.
Dr. Robert Rangno is a specialist in internal medicine and Associate Professor in the Department of Medicine and Pharmacology at the University of British Columbia. Although he is not a cardiologist and does not possess a sub-specialization in cardiology, he has a diploma in clinical pharmacology.
Dr. Lawrence Zisman is currently an Associate Professor of Medicine and Director, Heart Failure / Transplant Cardiology at the Heart Institute, Albany Medical Centre.
Is the '548 Patent invalid as being obvious?
[40] Since it was suggested in the Court of Appeal decision, Beloit Canada Ltd. v. Valmet OY (1986), 8 C.P.R. (3d) 289 ("Beloit"), that it is generally preferable to deal first with the issue of obviousness, I will address this issue first.
[41] As often stated in the related case law, the most commonly cited articulation of the test for obviousness is that of Mr. Justice Hugessen in Beloit, supra, which is in the following terms:
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.
[42] Further down in that same decision, the Court of Appeal provided the following caution upon considering evidence of obviousness:
While the evidence of experts is, in my view, properly admissible even on an "ultimate issue" question such as obviousness, it seems to me that it must be treated with extreme care.
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?"
[43] Keeping these comments in mind, I will begin my analysis from the premise that the patent is directed to the unimaginative skilled cardiologist, someone knowledgeable in the treatment of CHF, a practicing physician, or even a general practitioner. Further, because the priority date of the '548 Patent is February 8, 1995, and by virtue of sections 28.1 and 28.3 of the Patent Act, no publication published after that date will be relevant in determining the question of obviousness.
[44] The question of obviousness of a patent comes down to the issue of inventiveness. As stated by Mr. Justice Wetston in Apotex Inc. v. Wellcome Foundation Ltd. (1998), 79 C.P.R. (3d) 193 at page 269, "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." He further held:
The general question to be resolved is whether or not the alleged invention required the exercise of inventive ingenuity: Windsurfing International Inc. v. Trilantic Corp. (1985), 8 C.P.R. 241 (F.C.A.). That is, was the invention "plain as day" or "crystal clear" to a technician skilled in the art at the date of the invention: Bayer v. Apotex Inc., supra, at 79. Something is said to be obvious when it would occur directly to the ordinary person skilled in the relevant art searching for something novel without serious thought, research or experiment: G.F. Takach, Patents: A Canadian compendium of law and practice (Edmonton: Juriliber, 1993).
[45] The notion of obviousness ultimately means lack of inventiveness. In 1988, Mr. Justice Rouleau, in Cabot Corp. et al. v. 318602 Ontario Ltd. et al. (1988), 20 C.P.R. (3d) 132, commented on the fact that inventiveness is an essential element of patentability:
Although not specifically so stated in the Act, inventiveness is an essential element of patentability. As stated by H.G. Fox in his book Canadian Law and Practice Relating to Letters Patent for Inventions, at pp. 70 and 71:
In order that a thing shall be "obvious" it must be something that would directly occur to someone who was searching for something novel, a new manufacture, or whatever it might be, without the necessity of his having to do any experimenting or serious thought, or research, whether the research be in the laboratory or amongst literature. So, the means by which an object is attained may be quite simple and common, but yet there may be invention, if the patentee has discovered a variant that will render more useful that which has been previously described. Where there is a problem awaiting solution, a disclosure solving that problem is likely to be accepted as one involving invention, particularly if there have been unsuccessful attempts to solve that problem. There may be an inventive step in recognizing that a problem exists at all: but given a problem which is known to exist which it is the object of the invention to solve, the question always is: "Is the solution claimed by the patentee one which would have occurred to everyone of ordinary intelligence and acquaintance with the subject-matter of the patent who gave his mind to the problem?
[46] Accordingly, the next step I must take is to evaluate the prior art relating to the use of carvedilol and, based on it, determine whether the solution claimed by GlaxoSmithKline is one which would have occurred to everyone of ordinary intelligence and acquaintance with carvedilol who applied his mind to the problem.
[47] Evidence of prior art - I will approach this section chronologically. The knowledge about carvedilol originates from the knowledge that it is part of the class of drugs known as beta-blockers. The first breakthrough occurred in the late 1970's. Indeed, on June 30, 1979, Dr. Swedberg, Dr. Waagstein et al., published in The Lancet the results of their trial using beta-blockers in CHF in an article entitled "Prolongation of survival in congestive heart cardiomyopathy by beta-receptor blockade". They suggested that beta-blockers prolongs survival in patients with congestive cardiomyopathy:
Summary - 24 patients with congestive cardiomyopathy (group I) were compared with a group of 13 controls with similar clinical findings and myocardial function who were selected retrospectively (group II). All patients received digitalis and diuretics, but group I patients received ß-blockers as well. The survival-rate in group I patients (83%, 66%, and 52% after one, two, and three years respectively) differed significantly from that in group II subjects (46%, 19%, and 10% , respectively). This finding is supported by the demonstration that ß-blockade improved myocardial function in group I subjects. It is therefore suggested that ß-blockade prolongs survival in patients with congestive cardiomyopathy. [my emphasis]
[48] In that study, the doses of ß-blockers were raised gradually over one to four weeks until the maximum dosage for each was reached. Similarly, I note that the dosage in the '548 Patent also increases gradually.
[49] In 1983, the same doctors, in an article entitled "Beta-Blockers in Dilated Cardiomyopathies: They Work", published in the European Heart Journal, (1983) 4 (Supplement A), 173-178, an additional follow-up of data earlier published. In the article's conclusion the authors stated that:
[t]he question whether chronic beta-blockade improves survival in dilated cardiomyopathy can only be answered after performing a controlled randomized study over at least two years.
[50] Dr. Abraham was cross-examined regarding these two articles, particularly on the issue that these studies published by Dr. Swedberg and Waagstein were quite innovative for their time, and he confirmed that the idea of associating beta-blockers with prolonging survival was theirs:
...
Q So you're doing basically the same thing that the Swedberg study was doing.
A We are doing absolutely the same thing. And do we believe that this treatment approach to heart failure works or should be advocated? The answer is absolutely not. Do we want to put something in the literature that's provocative and stimulates peoples's thinking and stimulates others as well as ourselves to do more research in this area? The answer is absolutely yes.
Q And so that's what the Swedberg was doing too.
A. I believe so.
Q And in fact it worked because people picked up on his idea and followed up and did subsequent phase II and phase III trial with beta block