Docket: T-1871-01
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.
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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). |
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[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. |
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« 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. |
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[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. |
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« 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. |
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[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 blockers in congestive heart failure; correct?
A Yes.
... [my emphasis]
[See A.R. Vol. 1, p. 260]
[51] My understanding of Dr. Abraham's answers is that he acknowledges the fact that the idea of beta-blockers prolonging survival in CHF was first expressed following Dr. Swedberg's study. He also recognizes the influence of the 1979 article:
...
Q And I take it that based on your comments, this article [the Swedberg paper published in 1979], because it was so soundly rejected, has never seen the light of day again. Nobody refers to this article anymore; is that correct?
A Oh, no. Of course people refer to this article. (...) The Lancet, [...] likes to publish provocative things...
[See A.R. Vol.1, p. 257]
[52] From my reading of these articles, as well as Dr. Abraham's comments, it seems to me that the nucleus of the idea of having beta-blockers increase survival rates was first conceived by Dr. Swedberg, Dr. Waagstein, and the others involved in the 1979 study.
[53] It was not until 1990 before the field was informed of another study using beta-blockers in the treatment of CHF which directly involved carvedilol. Indeed, Dr. Das Gupta, published in the November 1, 1990 issue of The American Journal of Cardiology, an article entitled "Value of Carvedilol in Congestive Heart Failure Secondary to Coronary Artery Disease". The Das Gupta study was an uncontrolled open study to evaluate the efficacy and safety of carvedilol. This was the concept that became the basis for subsequent studies with carvedilol. As Dr. Pitt explains in his affidavit, this article indicates that carvedilol may be better tolerated because of the vasodilating properties, and these properties could serve to counteract the negative inotropism of beta adrenergic blockade. In this study, 17 patients with chronic CHF were treated with carvedilol starting with 12.5 mg twice a day for 8 weeks. Upward dose titration was carried out after 2 and 4 weeks, working up to 25 and 50 mg twice a day if required. Twelve patients completed the study, 11 of which showed a definite improvement, both symptomatically and clinically. Dr. Pitt states that the results of this study suggested symptomatic benefits such as an improvement in the left ventricular function, that would lead to the development of the use of carvedilol in the treatment of CHF. Furthermore, he added that these findings were also suggestive that one of the benefits of treating CHF patients with carvedilol could be reducing mortality.
[54] With regard to this study, GlaxoSmithKline's expert, Dr. Abraham, in cross-examination [See A.R. Vol., 1, pages 252-253], admitted that the people who are named in the '548 Patent are not the first people to have administered carvedilol to a patient suffering from CHF and that the Das Gupta group had given carvedilol to patients long before 1995.
[55] The record contains many reports, studies, reviews, etc. on the effect of carvedilol in the treatment of CHF. Inter alia, in 1993, there are the Krum and the Olsen abstract reports. The Krum abstract reports a double blind (when both the patients and the investigator are kept in the dark about the administered treatment), placebo controlled study, where 32 patients received therapy for 14 weeks while they were also taking digoxin, diuretics and ACE inhibitors. That trial showed an improvement in cardiac function and an increase in exercise tolerance. It also showed both the hemodynamic and clinical benefits from taking carvedilol.
[56] The Olsen abstract is about a study of 54 patients with CHF, who were given an initial dose of 6.25 mg twice daily, titrated over one month to a maximum dose of 25 mg twice daily. The patients tolerated the drug and showed an improvement in symptoms and in cardiac function.
[57] One of the co-inventors of the '548 Patent, Dr. Lukas, also an expert for GlaxoSmithKline, was cross-examined on the above two abstracts. Interestingly, in an article on the U.S. Carvedilol Trial, entitled "The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure", published in The New England Journal of Medicine, May 23, 1996, and written by Milton Parker, M.D. for the U.S. Carvedilol Heart Failure Study Group in which Dr. Lukas was a committee member, she analysed the Krum and Olsen studies and found that their results published in 1993 had show that carvedilol could reduce mortality:
...
103 Q. It [the U.S. Carvedilol Trial abstract] says, "However, since it was anticipated on the basis of earlier studies that carvedilol could reduce mortality, all statistical analyses were two-sided."
...
A. Oh, yes. (...) It was anticipated that it could, yes, but - - I'm sorry, but by the letter of what it says there, the analyses were two sided because it was also anticipated that it might not.
...
107 Q. But I take it, though - - what does it mean here, sorry, when it says "on the basis of earlier studies"? What earlier studies are you talking about there?
A. On the basis of earlier studies that carvedilol could reduce mortality?
108 Q. Mm-hmm.
A. I believe what it being referred to there is the pilot trials that were done with carvedilol, and specifically that would be Krum and Olsen, which were very small, had a numerical decrease in the number of patients who died on carvedilol in comparison to placebo. But I must stress that was numerical only. We're talking about 100 patients. That's a flip of the coin whether it would have been one way or the other.
... [My emphasis]
[See A.R. Vol. 4, pages 1423-1425]
[58] Further in the cross-examination, Dr. Lukas was again confronted with the Krum and Olsen studies of 1993. Throughout the questions, the expert was asked to compare the two abstracts with the U.S. Carvedilol Trial. Although there is a flagrant distinction in the number of patients involved in each study and a small difference in the length of the testing period, Dr. Lukas came to admit that the dosage of carvedilol given to patients in each study was basically the same; that is to say, the carvedilol trials were titrated up over a certain period (two to ten weeks) from 6.25 mg to 50 mg. [See A.R. Vol. 4, pages, 1473-1474]
[59] In the 1994 Doughty review article, supra, also very important, the authors note that there were initial studies (Swedberg/Waagstein, 1979) which suggested that survival was prolonged with beta-blockers. It states that long-term therapy has been well tolerated by patients and can result in significant hemodynamic improvement. This article indicates that while the MDC trial did not show a statistically significant effect on total mortality, fewer metoprol treated patients were placed on the transplant list. It also states that the mortality data from the numerous trials with beta-blockers after myocardial infarction are relevant and reassuring. In their conclusion, the authors submit that "further studies are required to determine whether beta-blockade can further reduce mortality in heart failure and thereby provide a useful addition to existing therapy".
[60] GlaxoSmithKline claims that what transpires from the above review article and from the Hampton review article, is uncertainty. The Hampton article, supra, provides a comprehensive summary of the state of the art with respect to the use of beta-blockers. In order to demonstrate that the question as to whether beta-blockers could help reduce mortality was still unanswered and uncertain in 1994, GlaxoSmithKline cross-examined Dr. Pitt on some excerpts of the Hampton article. Basically, GlaxoSmithKline tried to show that larger trials were necessary needed to ascertain the fact that beta-blockers could diminish fatalities in CHF:
...
262. Q. Right. And you see in that sentence that - - I'll quote, the second sentence:
"It could be argued, therefore, that an increase in mortality seen in this study would be particular to xamoterol and unlikely to be seen with any other beta blocker. In the absence of further trials with other beta blocking drugs, however, this is not necessarily a safe assumption to make."
Do you agree with that?
A. Let me think about that for a second. I think at that time that was a reasonable statement.
263. Q. Yes. And this is 1994?
A. Yes. They didn't have the mortality trials available to them. That's a reasonable statement.
...
279. Q. Right. And the last sentence then you see that in that paragraph, and I'll quote it:
"Until the results of such trials are available, clinicians will be best advised to limit themselves to the older drugs with their long track records."
Do you see that?
A. I do.
280. Q. And do you agree with that?
A. I do.
...
[See A.R. Vol. 5, pages 2265-2269]
[61] I take it from this excerpt of Dr. Pitt's cross-examination's transcript, as well as from the other evidence in general, that cardiologists and others in the field were led directly to understand the need to run a large scale clinical trial with carvedilol, in order to determine its benefits towards lower mortality rates. Pharmascience submits that literature prior to February 1995 made it clear that large scale trials were the next step to be carried out. I agree with this proposition, and I have all the more reasons to since it is supported by additional documentary evidence. There are two other articles which I believe are worth referring to: one is from David T. Kelly, Carvedilol in Heart Failure, published in the journal Cardiology in 1993 (82, suppl.3, pp.45-49), also used as the single prior art publication in the anticipation argument, and the other is from Dr. Hjalmarson and Dr. Waagstein, entitled "The Role of ß-Blockers in the Treatment of Cardiomyopathy and Ischaemic Heart Failure" (Drugs 47 (Suppl. 4):31-40, 1994).
[62] The Kelly article discloses that the dosing of beta-blockers was first developed by Waagstein and that the dosing is to be done by starting with a small dose and then increasing at intervals up to the therapeutic dose:
Patients will be given a test dose of 6.25 mg of carvedilol and then if satisfactory will be titrated to a maximal dose over a period of 2-3 weeks. The first dose of carvedilol is 3.125 mg. Patients will initially take 3.125 mg twice daily for 7 days, in the second week 6.25 mg, then 12,5 mg and the following week 25 mg twice daily, which will be the maximum dose used.[See A.R. Vol. 2, p. 846]
[63] I realize that in general the same dosage is used in the '548 Patent. Accordingly, it appears that the dosing regimen needed in the treatment of CHF with carvedilol was generally known prior to the registration of the said Patent. Cross-examined on the above, Dr. Abraham answered the following:
...
Q Right. Now in February of '95 I take it it was known that carvedilol had to be given starting in small doses and then up-titrated the dose.
A That's the way it was given in the clinical trials.
Q Yes. So things like Olsen and Krum, they started at 3.125 twice a day and then worked up to 6. 25 to 25 milligrams twice a day; is that correct?
A Correct.
Q And so before 1995 carvedilol had been used in patients suffering from CHF in these small phase II clinical trials?
A Correct.
...
[See A.R. Vol. 1, p. 247]
[64] Finally, the last article I wish to mention is the one written in 1994 by Hjalmarson and Waagstein. This paper tells us what the situation was at that time regarding the effects of beta-blockers on mortality:
It was first suggested by Swedberg and coworkers that long term ß-receptor blockade in patients with dilated cardiomyopathy might prolong survival. (...) ß-blockers therapy improved myocardial function and exercise capacity, and 3-year survival in this group was significantly superior to that in the controlled group. (...) A more recent long term follow-up study of another group of patients with idiopathic dilated cardiomyopathy showed similar results, with long term survival of about 50% (Waagstein et al. 1983).
The results of these 2 above-mentioned studies, which suggested improved survival on long term ß-blocker therapy in patients with idiopathic dilated cardiomyopathy, need to be confirmed in a large scale placebo-controlled trial. (...) We have to await the results of 3 large scale studies that are presently in progress in the US and Europe and that are investigating the effects of bucindolol, carvedilol and metoprolol on survival. [My emphasis]
Therefore, in 1994 it was general knowledge to associate carvedilol with prolonging survival. The only element that was missing was conclusive results as to its effect.
[65] It is true, as GlaxoSmithKline argues, that those skilled in the art did not consider the Phase II trials to provide sufficient teaching to use carvedilol because of previous experiences with drugs for use in heart failure, and specifically the collective experience of drugs with promising Phase II results that ultimately provided no benefit or actually increase the mortality rate when tested in larger Phase III studies. However, it is also true that those skilled in the art were aware that there had been positive results showing that some beta-blockers possibly had a beneficial function in reducing mortality in CHF.
[66] Although conceded by Pharmascience's experts that the small Phase II Trials conducted by Krum and Olsen, as well as the other relevant researches and review articles did not teach cardiologists to use carvedilol to treat patients with CHF, but rather suggested that a large scale Phase III trial with carvedilol was warranted, the obviousness of the eventual utilisation of carvedilol for mortality is not cancelled out. The evidence shows that all that what needed were confirmation results; the association between the use of carvedilol and the prolongation of survival in the treatment of patients with CHF happened in 1979 for Beta-Blockers as a class and in the late eighties for carvedilol. I find that the final Phase III results are merely there to eliminate the uncertainty reigning amongst the community of cardiologists and others. That element of creativity which is essential to an invention surely cannot be found in test results. Those results only confirm whether the invention can be used or not. The spark was in the association of the use of carvedilol for the purpose of prolonging survival for CHF. This is the invention and it was in the public domain prior to February 1995.As previously stated by the jurisprudence, "there is no inventiveness in following an obvious and well-charted route using known techniques and processes involving known compositions." If, as suggested by Dr. Abraham in his cross-examination [See A.R. Vol. 1, p. 229], there are a number of cardiology groups who ran clinical trials in CHF: the Waagstein-Swedberg group in Sweden, U.S. doctors Bristow, Packer, Colucci; Dr. Kelly in Australia; and Dr. Parker (GlaxoSmithKline's expert in this case) in Canada, then technically, these same groups could have run a large scale clinical trial such as the one done by GlaxoSmithKline. In such case, the element of inventiveness is very much diminished, or even non-existent.
[67] Relatively to the issue of obviousness, I am satisfied that the prior art, individually or taken together, would have led an unimaginative skilled technician (cardiologist) to the invention,specifically, to consider the use of carvedilol as a treatment for CHF, particularly to prolong survival, without undue experimentation, the whole thing subject to the results of the Phase III trials that were expected in 1994. The'548 Patent was rendered obvious by the prior art in existence at the date of the invention.
[68] To come to this conclusion, I have reviewed carefully the totality of the evidence adduced by affidavit and the transcripts of the expert witnesses' cross-examinations. GlaxoSmithKline has failed to discharge its burden, on a balance of probabilities, that the allegation of obviousness is not justified.
Is the '548 Patent invalid as being anticipated?
[69] With regard to anticipation, Pharmascience, in its NOA, alleged that
...the use of carvedilol in the treatment of CHF was known. (...) The use of carvedilol 3.125 mg twice daily for 7 days, in the second week 6.25 mg and then 12.5 mg and the following week 25 mg twice daily was known. (...) It was known to use carvedilol in the form of a pharmaceutical formulation comprising carvedilol or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for the treatment of CHF.
[70] The test for anticipation, set out in Beloit, supra, and affirmed by the Supreme Court of Canada in Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024, is the following:
It will be recalled that anticipation, or lack of novelty, asserts that the invention has been made known to the public prior to the relevant time. The inquiry is directed to the very invention in suit and not, as in the case of obviousness, to the state of the art and to common general knowledge. Also, as appears from the passage of the statute quoted above, anticipation must be found in a specific patent or other published document; it is not enough to pick bits and pieces from a variety of prior publications and to meld them together so as to come up with the claimed invention. One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention. Where, as here, the invention consists of a combination of several known elements, any publication which does not teach the combination of all the elements claimed cannot possibly be anticipatory.[my emphasis]
[71] Prothonotary Lafrenière, in its Order of December 13, 2001, ordered that Pharmascience "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 [the "Kelly article"] in support of its allegation of invalidity by anticipation of Canadian Letters Patent No. 2, 212, 548... [my emphasis]".
[72] Therefore, in support of this allegation of invalidity for reason of anticipation, Pharmascience could rely solely on the Kelly article, its experts, and the cross-examination of GlaxoSmithKline's experts.
[73] Pharmascience alleges that the Kelly article would provide all the information needed for practical purposes to produce the claimed invention without the exercise of any inventive skill. It argues that the "recipe" is there. The article sets out the design of a multicentre trial, it discloses that patients will be taking ACE inhibitors, as well as the dosing regimen for treating patients. Most importantly, the Kelly article provides directions that a large scale trial is needed.
[74] However, from my reading of the Kelly article and from my understanding of the expert evidence, I don't believe that "the information as to the alleged invention given by the prior publication [is], for the purposes of practical utility, [...] equal to that given by the subsequent patent", as stated by the Supreme Court of Canada in The King v. Uhlemann Optical Co. (1949), 11 C.P.R. 26, which further held that:
Whatever is essential to the invention or necessary or material for its practical working and real utility must be found substantially in the prior publication. It is not enough to prove that an apparatus described in it could have been used to produce a particular result. There must be clear directions so to use it. Nor is it sufficient to show that it contained suggestions which, taken with other suggestions, might be shown to foreshadow the invention or important steps in it. There must be more than the nucleus of an idea which, in the light of subsequent experience, could be looked on as being the beginning of a new development. The whole invention must be shown to have been published with all the directions necessary to instruct the public how to put it into practice. It must be so presented [page158] to the public that no subsequent person could claim it as his own. [My emphasis]
[75] The Kelly article misses an important element of the invention; the author does not mention, nor does he speculate on the medical purpose and effect of carvedilol on morbidity and mortality. The publication expresses the need for a large-scale, randomized, placebo-controlled study to determine whether carvedilol might be useful for treatment of CHF. Thus, not all the information needed to produce the claimed invention is explained. Having determined that there is an invention when the association of the beneficial use with carvedilol is made, the positive outcome (reduction of morbidity and mortality) resulting from the use of carvedilol is a crucial element of the invention. It cannot simply be implicit that the improvement in the treatment of carvedilol, that might result from the suggested trials, is going to be a reduction of mortality. It appears to me that the concept of "whole invention" must include in this case that the use of the drug is for the purpose of reducing mortality. As such, the Kelly article falls short of specifying the desired result that is needed to claim the invention of the use of carvedilol.
[76] I therefore conclude that GlaxoSmithKline discharged itself of its burden, on a balance of probabilities, and that the allegation of invalidity on the ground of anticipation is not justified.
[77] To arrive at the conclusions on the allegations of obviousness and anticipation, I have relied on my understanding and analysis of the contents of the monograms and the review articles from 1979 to February 1995. I have carefully reviewed the affidavits and transcripts of the cross-examinations. They were useful and permitted a good understanding of the medical issues. I was also reminded of the words of Mr. Justice Hugessen in Beloit, supra, when he wrote that the evidence of experts "... must be treated with extreme care." As argued by counsel for GlaxoSmithKline, Dr. W.T. Abraham and Dr. B. Pitt were generally in agreement with the facts of the medical issues. What had to be decided were the legal issues and this is what I have done.
CONCLUSION
[78] Because of my conclusion on the allegation of obviousness, the Application for an Order of prohibition is dismissed.
COSTS
[79] Pharmascience is entitled to its costs from GlaxoSmithKline in accordance with column III to the table to Tariff B of the Federal Court Rules, 1998. There will be no order as to costs for or against the Minister of Health.
ORDER
THIS COURT ORDERS THAT:
1. The Application is dismissed.
2. The Applicants shall pay the costs of this proceeding to Pharmascience in accordance with column III to the table to Tariff B of the Federal Court Rules, 1998.
"Simon Noël"
Judge
FEDERAL COURT
NAMES OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-1871-01
STYLE OF CAUSE:
GLAXOSMITHKLINE INC.
and
SMITHKLINE BEECHAM CORPORATION
Applicants
and
THE MINISTER OF HEALTH
and
PHARMASCIENCE INC.
Respondents
PLACE OF HEARING: Montreal, Quebec
DATE OF HEARING: June 10, 2003
AMENDED REASONS FOR ORDER: THE HONOURABLE MR. JUSTICE SIMON NOËL
APPEARANCES:
Mr. Patrick E. Kierans FOR THE APPLICANTS
Mr. Darren Noseworthy
Ms. Carol Hitchman FOR THE RESPONDENT
Ms. Paula Bremner PHARMASCIENCE INC.
SOLICITORS OF RECORD:
Ogilvy Renault FOR THE APPLICANTS
Toronto (Ontario)
Hitchman & Sprigings FOR THE RESPONDENT
Toronto (Ontario) PHARMASCIENCE INC.