Date: 20021105
Docket: T-2096-00
Neutral citation: 2002 FCT 1138
Ottawa, Ontario, Tuesday the 5th day of November 2002
PRESENT: The Honourable Madam Justice Dawson
BETWEEN:
PFIZER CANADA INC. and PFIZER INC.
Applicants
- and -
APOTEX INC. and THE MINISTER OF HEALTH
Respondents
[1] The applicants seek an order pursuant to section 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 ("Regulations") prohibiting the respondent Minister of Health ("Minister") from issuing a Notice of Compliance ("NOC") to the respondent Apotex Inc. ("Apotex") in connection with its version of the drug sertraline until after the expiration of Canadian Letters Patent No. 2,029,065 (" '065 Patent ").
1. BACKGROUND
[2] Pfizer Inc. is the owner of the '065 Patent and is joined as a party to this proceeding in accordance with subsection 6(4) of the Regulations. Pfizer Canada Inc. markets and sells sertraline in Canada under the trademark Zoloft. Together Pfizer Inc. and Pfizer Canada Inc. are referred to as "Pfizer" in these reasons.
[3] Apotex is a Canadian manufacturer of generic products.
[4] The Minister of Health neither filed materials on the application nor appeared at the hearing.
[5] Sertraline is not a new drug. On August 31, 1982, Canadian Letters Patent No. 1,130,815 (" '815 Patent ") were issued to Pfizer in relation to the use of sertraline for the treatment of depression. The '065 Patent discloses and claims new uses for sertraline for disorders which are distinct from depression. The patent states:
Sertraline may be used to prevent or alleviate anxiety and the symptoms associated with anxiety-related disorders in patients treated with the drug. It is therefore useful in the treatment and management of anxiety-related disorders such as panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, posttraumatic stress disorder, obsessive-compulsive disorder and avoidant personality disorder.
[6] The '815 Patent has expired. Upon its expiration Apotex received a NOC for Apo-Sertraline for the treatment of depression only.
(i) The '065 Patent
[7] The '065 Patent contains 13 claims which may be divided into three sets of claims.
[8] Claims 1 and 2 comprise the first set of claims. Claim 1 is a genus claim covering the use of sertraline to prepare a medicament to treat or prevent anxiety-related disorders. Claim 2 specifically sets out those disorders.
[9] Claims 3 to 10 are the second set of claims and they claim the use of sertraline to treat or prevent individual anxiety-related disorders. For example, claim 3 deals with the use of sertraline where the anxiety-related disorder is panic disorder ("PD"), claim 4 is with respect to generalized anxiety disorders and claim 10 is with respect to obsessive-compulsive disorder ("OCD").
[10] Claims 11, 12 and 13 comprise the third set of claims. Claims 11 and 12 relate to compositions of sertraline in amounts effective to treat anxiety-related disorders. Claim 13 is directed to a commercial package of sertraline sold with instructions on how the drug should be used for treating anxiety-related disorders.
[11] Sertraline is marketed, prescribed and sold in Canada for three indications: depression, PD, and OCD. Sertraline was first approved for depression by its first NOC issued on January 30, 1992. Sertraline was then approved for sale for PD in 1996 and for OCD in 1998.
(ii) The Notice of Allegation
[12] Apotex served its Notice of Allegation ("NOA") so that it might obtain a NOC which would enable it to sell Apo-Sertraline with additional uses in connection with OCD and PD. Apotex alleges that the '065 Patent is invalid on the basis that it does not contain inventive subject matter and does not comply with the Patent Act, R.S.C. 1985, c. P-4. Specifically, the legal and factual basis for the claim of invalidity is described as follows in the Notice of Allegation:
(a) Obviousness
1(a). The '065 Patent claims a priority filing date of November 2, 1989 from United States Patent Application No. 431,000. As of that date each of the claims of the '065 Patent are said to be invalid as being obvious on the basis that as of that priority date it was known that:
(a) sertraline was:
(i) a useful antidepressant drug;
(ii) a serotonin reuptake inhibitor; and
(iii) selective for serotonin inhibition over norepinephrine;
(b) serotonin played a role in anxiety-related disorders; and
(c) anxiety-related disorders:
(i) were treated with the use of antidepressants; and
(ii) were treated with the use of serotonin reuptake inhibitors; particularly those which were selective for serotonin inhibition over norepinephrine.
Therefore, it would have been obvious to a person skilled in the art to use the compound sertraline for the treatment of anxiety-related disorders.
1(b). As further support for the allegation of obviousness it is said that prior art in the form of an article entitled "The Clinical Utility of Pharmacological Agents that Act at Serotonin Receptors", Journal of Neuropsychiatry, (Summer 1989), Vol. 1, No. 3, 253-262 ("Peroutka article") disclosed that Phase II clinical trials were being conducted on the use of sertraline in the treatment of OCD.
1(c). A further ground of obviousness was asserted with respect to OCD in that it is said that the use of sertraline for the treatment of this disorder would have been obvious to persons skilled in the art given the state of the art as described in the notice of allegation and in light of the disclosures in the Peroutka article.
Apotex cited 96 literature articles as evidencing the state of the art and its assertion with respect to obviousness.
(b) Anticipation
2. Claims 1, 4, 10, 11, 12 and 13 of the ' 065 Patent are said to be invalid on the basis of anticipation. Those claims contain claims to the use of sertraline to prepare a medicament to treat or prevent OCD. The use of sertraline to prepare a medicament to treat or prevent OCD is said to have been disclosed before the priority date of the '065 Patent in the Peroutka article, and in addition claims 11, 12 and 13 of the '065 Patent are said to be anticipated by the disclosure of the '815 Patent.
(c) Insufficient Specification and Double Patenting
3. Claims 1 through 13 of the '065 Patent are said to be invalid on the basis that the specification of the patent does not comply with requirements of section 34 of the Patent Act and further on the basis of double patenting. Specifically it is alleged that the specification in the '065 Patent fails to:
(i) correctly and fully describe the invention and its operation or use;
(ii) set out clearly the method of using the compound sertraline to treat anxiety-related disorders in such full, clear concise and exact terms as to enable any person skilled in the art to use sertraline for the purpose of treating anxiety-related disorders; and
(iii) claim distinctly and in explicit terms the things that the patentee regards as new and in which he claims an exclusive property or privilege.
(d) Insufficient Specification and Ambiguity
4. Claims 11 through 13 of the '065 Patent are said to be invalid as being ambiguous and in contravention of subsection 34(2) of the Patent Act.
2. THE ISSUES
[13] The issue to be decided on this application is whether Apotex' allegation with respect to the validity of the '065 Patent is justified. The burden is on Pfizer to disprove the allegations in the NOA. This, in turn requires consideration of the following:
i) Is the '065 Patent invalid because it was obvious?
ii) Is the '065 Patent invalid because it was anticipated?
iii) Does the '065 Patent fail to provide sufficient specification or does it constitute double patenting?
iv) Is the '065 Patent invalid because of ambiguity?
3. THE EVIDENCE
[14] In addition to the evidence of its Vice-President, Government and Public Affairs, as to the approvals granted to Pfizer to sell sertraline and as to the service of two NOAs upon it, Pfizer relied upon the evidence of three expert witnesses: Doctors Lapierre, Greist and Rasmussen. Apotex relied upon the evidence of three expert witnesses: Doctors Deakin, Peroutka and Richter. Apotex also relied upon the affidavit of a senior secretary working for co-counsel for Apotex which attached copies of the 96 prior art references specified in the NOA.
[15] Each deponent was cross-examined on his or her affidavit.
[16] The evidence of each expert witness is summarized below.
(i) Pfizer's Experts
(a) Dr. Yvon Lapierre.
[17] Dr. Lapierre is a psychiatrist and professor of Psychiatry. He described his areas of expertise to be in psychiatry, psychopharmacology, consulting especially on diagnosis and psychopharmacological treatment of psychiatric disorders. He swore as follows (throughout the review of the evidence the parenthetic comments are my own).
[18] Each anxiety-related disorder is distinct and each requires its own therapy to be adequately treated. Anxiety disorders are distinct from depression. Some patients suffer from more than one of these disorders at the same time. In light of the overlap between disorders, if a person diagnosed with depression and OCD, or depression and PD, was treated with antidepressants, the practitioner could observe improvement in the OCD or PD symptoms. These observations led to the identification of antidepressants as a possible effective treatment for OCD.
Treatment of OCD
[19] In the late 1980s, different classes of antidepressants, tricyclics, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors ("SSRIs"), were attempted as treatment for OCD, generally without much success.
[20] The most successful drug for first-line treatment of OCD was clomipramine, a tricyclic. While it is a potent serotonin reuptake inhibitor, its primary metabolite is a potent inhibitor of norepinephrine uptake. Clomipramine has been found to be more effective in the treatment of OCD than more potent serotonin reuptake inhibitors. This suggests that its dual action or its inhibition of norepinephrine uptake plays a role in its efficacy.
Treatment of PD
[21] For panic disorder, benzodiazepenes, tricyclics and monoamine oxidase inhibitors were used in the 1980s. The latter two classes of drugs were used in conjunction with or without concomitant benzodiaxepine medication.
SSRIs in the treatment of OCD and PD
[22] In 1989, research identified some SSRIs (fluoxetine and fluvoxamine) as useful for treating OCD, but also mentioned another SSRI (zimelidine) as being ineffective. The use of sertraline for either of these conditions was not mentioned. At the time researchers felt it was unlikely that complex disorders such as OCD and PD would be caused by dysfunction of a single neurotransmitter. Attributing OCD or PD to dysfunction of a single neurotransmitter was considered simplistic in 1989 and still is today.
[23] It was only in the mid to late 1990s that SSRIs became more commonly recognized in the treatment of OCD and PD.
[24] Even today, what causes OCD is not fully understood, and understanding of its treatment, including the use of antiepileptic drugs, continues to evolve. It would be difficult to say that any hypothesis, such as the role of serotonin, is obvious, given the growing support for new explanations of OCD.
[25] Without conducting experiments with sertraline it was not known that sertraline would be effective for treatment of OCD and PD. The most that could be said was that it was worth a try to do a trial with sertraline.
[26] The Peroutka article does not anticipate the '065 Patent because it says nothing about whether sertraline is effective for the treatment of OCD.
(b) Dr. John Greist
[27] Dr. Greist is a psychiatrist and professor of psychiatry. His evidence was as follows.
[28] In 1989 the only published use of sertraline was for the treatment of depression.
Treatment of OCD and PD
[29] In the 1980s clomipramine, which is an SSRI as well as a norepinephrine reuptake inhibitor ("NRI"), was one of the drugs that worked for OCD. By the mid 1980s, some thought that noradrenergic neurotransmission was more likely to be involved in anxiety disorders, and that serotonergic neurotransmission was more likely to be involved in depression.
[30] The leading text on the subject edited by Jenike, et al. published in 1986 contained no emphasis on SSRIs in treating OCD. The focus of treatment of OCD was with behavioural treatments, or clomipramine or lithium. Antidepressants were noted to have been used extensively to treat OCD, but not all medications were found to work.
[31] In 1990, the second edition of the Jenike text on OCD said that a number of carefully controlled trials had demonstrated that some antidepressants are effective in treating OCD while others were ineffective. With respect to sertraline, the authors reported that preliminary data indicates that sertraline is not an effective treatment for OCD. The text also said that pure serotonergic agents may be less effective than drugs with concomitant effects on other systems.
[32] In Dr. Greist's view, because sertraline was known to be one of the most selective SSRIs, it would have been expected to be not as effective for OCD treatment as were less selective drugs.
OCD
[33] In a 1985 article, Insel concluded that the first double-blind trial of the SSRI zimelidine, versus the tricyclic clomipramine, versus placebo, showed that zimelidine was no better than the placebo in the treatment of OCD. The authors wrote they "found no evidence that a selective serotonin uptake inhibitor is more effective than a selective noradenergic uptake inhibitor for decreasing obsessional symptoms." This data led some researchers to hypothesize that SSRIs failed to work in OCD because of their lack of effects on other neurotransmitter systems such as norepinephrine.
[34] In 1989, research into the efficacy of SSRIs was an active area of study. However, there was debate as to whether OCD was more closely related to an anxiety disorder, a mood disorder or neither.
[35] The tricyclic clomipramine, which has effects on both serotonergic and noradrenergic reuptake, was the only drug that had been shown to work for OCD in randomized, double-blind placebo-controlled trials.
[36] In the late 1980s, studies found that fluoxetine (Prozac) and fluvoxamine, two SSRIs, demonstrated some efficaciousness with respect to OCD. However, in light of a lack of effectiveness shown with another SSRI, zimelidine, one could not say that every SSRI would be effective for the treatment of OCD.
[37] Dr. Greist and others were therefore brought together to conduct Phase II testing of sertraline, the purpose of which was to determine whether Phase III testing ought to be done to determine if sertraline was efficacious in the treatment of OCD. In 1990, the initial publication from one site of the trial reported that sertraline failed to improve OCD. (However, a correction was published in October of 1990 which revealed errors from incorrect computer entry of the randomization code. The result of the correction was that a stronger usefulness of sertraline was exhibited).
[38] In 1995, Dr. Greist published an article showing that SSRIs were significantly less effective than clomipramine for OCD. (His article did acknowledge that sertraline had been shown to be of substantial benefit for the treatment of OCD.)
PD
[39] In 1989, benzodiazepenes were still the drug of choice for anxiety-related disorders. As with OCD, there were several competing theories to explain PD.
Anticipation
[40] With respect to the Peroutka article, sertraline is not mentioned under the headings OCD or PD. As for its mention of Phase II clinical trials of sertraline, Phase II clinical trials are not studies to determine effectiveness for a particular treatment, but are preliminary guides to possible efficacy and a prelude to Phase III trials where safety and efficacy are investigated. Further, there is no reference to the results of this Phase II clinical trial. It only states that tests are being done.
Obviousness
[41] At the relevant time, it was not substantiated that because antidepressants were effective in OCD, then SSRIs would also be effective. Competing theories implicating different neurotransmitters were being researched. The consensus in November 1989 was that it would be unreasonable to assume that a complex disorder such as OCD could be explained by examining only one neurotransmitter and a more likely explanation would come from the complex interaction of neurotransmitters.
(c) Dr. Steven Rasmussen
[42] Dr. Rasmussen is a psychiatrist and associate professor of psychiatry who specializes in treatment of anxiety-related disorders including OCD. His evidence is summarized as follows.
[43] He conducted a literature search relating to sertraline. The earliest document which stated that sertraline was effective for OCD is dated 1990, and the earliest document which stated sertraline was effective for PD is dated 1998.
[44] None of the results of the Phase II clinical trials referenced in the Peroutka article had been made public by the relevant date. He participated in those trials. The Peroutka article conveys no information about the efficacy of sertraline for OCD other than the fact that it is being tested. Sertraline is not mentioned in those portions of the article entitled "Obsessive-Compulsive Disorder" and "Panic Disorder".
Phase II Clinical Trials
[45] The term "Phase II clinical trials" was understood both in 1989 and now to refer to early controlled clinical studies that are conducted on a small number of humans (50 to 300). The trials are aimed at obtaining a preliminary determination of the efficacy of a drug and are generally the first studies conducted on humans afflicted with the disease or condition the drug is intended to treat. It is generally accepted in medical and regulatory communities that nothing decisive can be said about a drug's efficacy prior to the conclusion of Phase II testing. Until Phase II clinical trials are completed, sufficient information regarding efficacy can not be obtained to support a decision by a drug company to conduct Phase III clinical trials.
[46] Phase I clinical trials involve the same number or fewer patients, who are not afflicted with the condition, and are aimed at establishing the metabolic and pharmacokinetic profile of the drug in humans.
[47] Phase III clinical trials involve several hundred to one thousand patients and are designed to measure the safety and efficacy of the drug so that if confirmed, the safety and efficacy can be extrapolated to the general population.
Obviousness
[48] The theory that SSRIs played a role in OCD and PD was uncertain, unproven and a matter of active debate in 1989. Without experimentation one would not know if sertraline was in fact effective.
OCD
[49] In 1985, the tricyclic antidepressant clomipramine was the only drug to be shown to work in OCD in randomized, double blind placebo controlled tests. This led to a hypothesis that there was a deficit in serotonergic neurotransmission in OCD. In 1985, the first double blind trial of an SSRI in OCD was published, showing that the SSRI zimelidine was no better than a placebo and that clomipramine was better in the treatment of OCD.
[50] In 1988, an article noted that further tests would need to be done to determine whether the ability to enhance serotonergic activity is necessary for a drug to have anti-obsessional activity. Thus, the hypothesis that serotonin affected OCD symptoms was only one of several competing theories. The most respected research textbook in 1987 did not mention the use of SSRIs or sertraline in the treatment of anxiety states.
[51] A 1988 study by Zak and others concluded that the association between OCD and serotonin was "weak and sparse despite much speculation on the serotonin hypothesis." (However, in its conclusion the article stated:
[...] numerous studies from widespread centers have suggested that serotonin reuptake inhibitors are more effective than other psychotropic medications in the treatment of OCD, although the response rate does not appear to be as marked as that found in patients with major depressive illness and panic disorder who are treated with agents appropriate for those disorders. However, in view of the absence of alternative treatments and the chronically disabling nature of this illness, there is little doubt that the most promising line of investigation to be pursued is with serotonin reuptake inhibitors that seem to be more selective for OCD.) [underlining added] See: "Potential role of Serotonin Reuptake Inhibitors in the Treatment of Obsessive Compulsive Disorders" J. Clin. Psychiatry 1988: 495: 23-30.
[52] A 1989 study supported the hypothesis that an association between serotonin and OCD was not a complete explanation for the disorder. A 1989 review article suggests that the basis for OCD is complex, that serotonin has been implicated in OCD, but a variety of factors complicate this hypothesis.
[53] Due to sertraline's selectivity, there was considerable doubt among some consultants meeting for the design of the Phase III trial that sertraline would prove effective.
[54] An article published in 1995 showed that SSRIs were significantly less effective than clomipramine in treating OCD (although the article noted that sertraline is of a substantial benefit for the treatment of OCD).
PD
[55] With respect to PD, at the time there were three competing theories regarding neurotransmission dysfunction in PD. The first theory implicated deficits in serotonergic neurotransmission. The second theory implicated deficits in noradrenergic transmission, while the third theory pointed a finger at gamma amino butyric acid.
[56] The noradrenergic theory was supported by two studies by Charney et al. A study by Sheehan et al. in 1988 found there was insufficient evidence that SSRIs exerted their anti-panic effect via the seratonergic system. A 1988 study by den Boer and Westenberg suggested that both the noradergenic and serotonergic systems "exert their influence through a final common pathway" and "that in some patients there is an imbalance between the two systems".
Obviousness
[57] It was not common knowledge in the medical community, as demonstrated by the reports, that in 1989 each and every SSRI would work for the treatment of OCD and PD.
(ii) Apotex' Experts
(a) Dr. William Deakin
[58] Dr. Deakin is a psychiatrist and professor of psychiatry. His evidence was as follows.
Obviousness
[59] Prior to the priority date (November 2, 1989) it was well-known that depression and anxiety co-exist, that many antidepressant drugs were shown in double-blind controlled trials to be effective in such mixed disorders, and that antidepressants were better than benzodiazepine.
[60] Prior to 1989, at least six studies had shown that tricyclic antidepressants were effective in mixed anxiety-depression states and more effective than benzodiaxepine medication for anxiety. _ Antidepressant drugs were known to be preferable in the treatment of patients with prominent anxiety symptoms.
[61] Prior to the priority date, it had become a well-established principle that drugs with prominent actions on serotonin reuptake were effective in the treatment of PD. A practitioner skilled in the art might well have used sertraline to treat a patient with panic attacks, as two other SSRIs, fluoxetine and fluvoxamine perceived to be selective inhibitors of serotonin reuptake, had been proven useful in studies published in 1987 and 1987-1988 respectively.
[62] OCD has the longest history of being associated with serotonin dysfunction, and in a 1984 review a researcher concluded that OCD was sensitive to antidepressants with actions on the serotonin system. By 1988, one study concluded that rational treatment for OCD would either be clomipramine or fluvoxamine (both were viewed as potent inhibitors of serotonin reuptake. However, the metabolite of the former was a noradrenaline reuptake inhibitor. One of the articles referred by the witness stated that "drugs that selectively inhibit the reuptake of serotonin are logical candidates for use with OCD patients." [underlining added]).
[63] Before 1989, two trials showed that the SSRIs fluoxetine and fluvoxamine were effective in OCD, and by November 2, 1989, the concept was firmly abroad that antidepressants with actions on 5HT would be effective in the treatment of OCD. Sertraline could reasonably have been used to treat OCD on those who were not tolerating other 5HT-active drugs.
[64] There was therefore nothing inventive in the idea of using sertraline to treat an anxiety-related disorder such as OCD or PD.
Anticipation
[65] The fact that fluoxetine and fluvoxamine had been demonstrated to be efficacious in the treatment of OCD would itself have taught the use of sertraline in the treatment of OCD. The Peroutka article further taught that sertraline, referred to as being in Phase II clinical trials for OCD, would be expected to have anti-OCD activity.
Response to Pfizer Experts
[66] To the extent that Pfizer's experts assert that the SSRI zimelidine was shown to be ineffective in the treatment of anxiety, only one study (Insel) found zimelidine to be less effective than imipramine in OCD. Insel's study of zimelidine versus clomipramine was not placebo-controlled and only five subjects completed the zimelidine arm of the study. The experience with zimelidine had far less salience than the accumulating experience with fluoxetine and fluvoxamine in OCD. Another study found zimelidine to be superior to a noradrenaline uptake inhibitor.
[67] Each of Pfizer's experts fails to distinguish between evidence that serotonin is involved in the causation of OCD, and evidence that drugs which affect serotonin are useful in the treatment of the disorder.
[68] It was clear before 1989 that drugs with a single action on 5HT reuptake were effective in the treatment of PD and that other members of the class would also, with a high probability, be effective. By 1989, it was clear that drugs with the ability to enhance synaptic 5HT concentrations, as well as two of the SSRIs, were probably effective in treating OCD.
[69] With respect to clomipramine, prior to 1989 the weight of the trials was that the noradrenergic agents were ineffective in OCD. There was no protagonist of the theory that actions on noradrenaline were an important therapeutic possibility.
(b) Dr. Stephen J. Peroutka
[70] Dr. Peroutka is a neuropharmacologist and chief medical officer at Collabra Pharma. He is the author of the Peroutka article and swore as follows.
Anticipation
[71] The reference in the 1989 Peroutka article to sertraline undergoing Phase II clinical trials would have been understood to mean that some patients were being administered sertraline for the purpose of determining whether it was effective in treating OCD. Therefore, the article teaches that patients were being administered sertraline for the purpose of treating the condition of OCD. (Nonetheless, on cross-examination Dr. Peroutka admitted that a Phase II clinical trial is a regulatory required study to look for the "first signs of efficacy and safety". Many drugs in development, he said, never get past Phase II trials.)
[72] The Peroutka article gives an exact prior description of the teachings and claims contained in the '065 Patent relating to OCD. His conclusion in this regard is unchanged even if the '065 Patent is interpreted as teaching the efficacy of sertraline for OCD. (In cross-examination he agreed that in 1989 his thinking was that the possibility selective serotonin uptake blockers might be more efficacious in the treatment of OCD was an area of active interest and research. There was room for progress to be made. Dr. Peroutka also admitted that, while the Peroutka article referred to sertraline as being in Phase III clinical trials for treatment of depression and obesity, he did not know if it proved to be effective for that latter condition.)
Obviousness
[73] Given that SSRIs had been shown to be clinically effective in the treatment of OCD and PD by mid-1989, and the fact that sertraline is an SSRI, a person skilled in the art would have predicted or expected that sertraline would be clinically effective in the treatment of OCD and PD. The means of proving the efficacy of sertraline for these conditions would be to conduct clinical trials. The notional skilled person would have conducted such trials. The patent is therefore obvious.
[74] Five cited pieces of prior art support his opinion that a notional person skilled in the art would have known to conduct clinical trials or would have provided direction to that person that clinical trials should be conducted.
(c) Dr. Peggy Richter
[75] Dr. Richter is a psychiatrist and assistant professor of psychiatry. Her evidence was as follows.
Anticipation
[76] Any clinician skilled in the art, having read the Peroutka article, would have known that sertraline worked for OCD. The Peroutka article teaches that sertraline is being administered to patients for the indication or treatment of OCD. With the exception of the dose range which is provided in the '065 Patent, the Peroutka article gives an exact prior description of the patent. However, the dose range for OCD taught by the '065 Patent overlaps with the dose range recommended when sertraline is used in treating depression. Thus, any skilled clinician would automatically have tried sertraline for OCD within the depression dose range, and would likely have observed efficacy.
[77] At the relevant time, SSRIs were regarded by her and others as first-line medications for the treatment of OCD, and were routinely used as soon as they became available on the market.
Obviousness
[78] Sertraline had previously been described as an antidepressant SSRI in the '815 Patent issued on August 31, 1982. It was also known that depression and anxiety disorders commonly existed comorbidly, and both types of conditions benefited from treatment with antidepressants.
[79] Most antidepressants used at the time were tricyclics and monoamine oxidase inhibitors, both of which were known to impact on noradrenergic and serotonergic neurotransmission. In the mid to late 1980s, SSRIs were being investigated in anxiety disorders. Sertraline, being an SSRI, would have been viewed by persons skilled in the art as being potentially useful in the treatment of OCD. With respect to PD, the prior art suggested that sertraline as an SSRI was potentially useful in its treatment.
[80] As of November 2, 1989, it would therefore have been obvious to any competent clinical psychiatrist to use sertraline for the treatment of OCD or PD. (In cross-examination she admitted that not all antidepressants were effective in the treatment of OCD and PD.)
4. ANALYSIS
(i) Preliminary Issues
(a) The Nature of Proceedings under the Regulations and the Burden of Proof
[81] The Regulations ensure that generic manufacturers who apply for a NOC for their version of a patented drug do not obtain a NOC until the relevant patent expires, or until the Court considers the generic's allegation that the patent is expired, invalid or would not be infringed.
[82] In SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001), 14 C.P.R. (4th) 76 (T.D.), Mr. Justice Gibson considered the evidentiary burden in proceedings under the Regulations where an allegation of invalidity is made. At paragraphs 14 and 15 he wrote:
14 Against the foregoing, I conclude that while an "evidential burden" lies on Apotex to put each of the issues raised in its Notice of Allegation "in play", if it is successful in doing so, the "persuasive burden" or "legal burden" then lies with SmithKline. Assuming Apotex to be successful in putting the issue of validity of the '637 Patent "in play", SmithKline is entitled to rely on the presumption of validity of the patent created by subsection 43(2) of the Act.
15 The "persuasive burden" or "legal burden" that lies with SmithKline in the circumstances described in the preceding paragraph is, however, impacted by the nature of the proceeding here before the Court. In Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare), [(1994), 55 C.P.R. (3d) 302 (F.C.A.)] Mr. Justice Hugessen, for the Court, wrote at pages 319-20:
As I understand the scheme of the regulations, it is the party moving under s. 6, in this case Merck, which, as the initiator of the proceedings, has the carriage of the litigation and bears the initial burden of proof. That burden, as it seems to me, is a difficult one since it must be to disprove some or all of the allegations in the notice of allegation which, if left unchallenged, would allow the Minister to issue a notice of compliance
. . . . .
In this connection, it may be noted that, while s. 7(2)(b) [of the Regulations] seems to envisage the court making a declaration of invalidity or non-infringement, it is clear to me that such declaration could not be given in the course of the s. 6 proceedings themselves. Those proceedings, after all, are instituted by the patentee and seek a prohibition against the Minister; since they take the form of a summary application for judicial review, it is impossible to conceive of them giving rise to a counterclaim by the respondent seeking such a declaration. Patent invalidity, like patent infringement, cannot be litigated in this kind of proceeding.
Thus, the burden on SmithKline is only to disprove the allegations in the notice of allegation, not to justify declarations of validity and infringement or conversely to negative claims for declarations of invalidity and non-infringement.
[83] Mr. Justice Gibson's decision was affirmed on appeal, 2002 FCA 216, and so I take the above statements to accurately reflect the evidentiary obligations of the parties.
(b) Must Apotex Allege and Lead Evidence that Each Claim of the '065 Patent is Invalid?
[84] Pfizer asserts that for Apotex to succeed in this proceeding, the Court must be satisfied that Apotex' allegation of patent invalidity is justified with respect to each of the 13 claims of the '065 Patent. Pfizer says that Apotex has provided no evidence, for example, that claim 8 of the patent, which claims the use of sertraline to treat post-traumatic stress disorder, is invalid as being obvious. Pfizer also says that Apotex in its NOA does not even attempt to demonstrate that all of the '065 Patent's claims are invalid. Therefore Pfizer argues that because Apotex has not put the issue of the validity of the non-PD and non-OCD claims "in play", Pfizer may rely upon the presumption of validity of the patent created by subsection 43(2) of the Act. Pfizer says that it has therefore disproved the allegation that the patent is invalid so that the application for prohibition should be allowed on this ground alone.
[85] In support of this argument Pfizer relies upon:
i) the language of the NOA which claims that the entire patent is invalid and that each claim of the patent is invalid as being obvious;
ii) jurisprudence such as AB Hassle v. Canada (Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.), to the effect that the detailed statement provided by the generic manufacturer pursuant to paragraph 5(3)(a) of the Regulations must be exhaustive and any deficiency cannot be remedied; and
iii) subsection 6(2) of the Regulations which says that the Court shall make an order of prohibition if it finds that none of the allegations is justified.
[86] In reply, Apotex argues that this interpretation makes a mockery of the Regulations. Apotex points out that on the basis of this argument Pfizer would keep Apotex out of the market for the authorized uses of PD and OCD on the ground that Apotex has not adduced some evidence putting in issue the validity of the patent as it relates to non-authorized uses of sertraline.
[87] Counsel for the parties were unable to cite any authority which has considered this issue.
[88] For the reasons which follow, I have concluded that Apotex is not obliged to put in issue the validity of claims contained in the '065 Patent that are irrelevant to the authorized use of sertraline to treat PD and OCD.
[89] The obligation of the generic manufacturer who seeks a NOC and who compares its drug to another to establish bioequivalence is set out in subsection 5(1) of the Regulations which provides:
| 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, (a) state that the person accepts that the notice of compliance will not issue until the patent expires; or (b) allege that (i) the statement made by the first person pursuant to paragraph 4(2)(c) is false, (ii) the patent has expired, (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. [underlining added]
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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 : a) soit une déclaration portant qu'elle accepte que l'avis de conformité ne sera pas délivré avant l'expiration du brevet; b) soit une allégation portant que, selon le cas : (i) la déclaration faite par la première personne aux termes de l'alinéa 4(2)c) est fausse, (ii) le brevet est expiré, (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. [Le souligné est de moi.] |
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[90] The generic's obligation under the Regulations is therefore triggered by the filing of a submission for a NOC in circumstances where a comparison is made between the generic's drug and another drug which has been marketed in Canada pursuant to a NOC.
[91] The evidence of Pfizer's Vice-President, Government and Public Affairs establishes that NOCs have issued to Pfizer with respect to sertraline for the treatment of depression, PD and OCD. Apotex has already received a NOC for the sale of its version of the drug sertraline for the treatment of depression. Sertraline has not been approved for use in Canada for the treatment of any disorders referred to in the '065 Patent other than PD and OCD.
[92] Therefore, ignoring depression, the only comparison which Apotex can make under subsection 5(1) of the Regulations is to Pfizer's sertraline being marketed in Canada for PD and OCD.
[93] Use of Apotex's version of sertraline in connection with PD or OCD will not infringe the other use claims contained in the '065 Patent, for example the claim for the use of sertraline to treat agoraphobia. The only claims in the '065 Patent which are relevant to the use of sertraline for PD and OCD are those two use claims and the broader related claims contained in the patent.
[94] Proceeding on the basis that legislation is to be interpreted having regard to the purpose of the legislation and the intention of Parliament (see, for example, Rizzo & Rizzo Shoes Ltd. (Re), [1998] 1 S.C.R. 27) the purpose of the Regulations is to prevent infringement. Given that intention, no purpose, in my view, would be served by requiring a generic manufacturer in proceedings under the Regulations to invalidate patent claims that are irrelevant to the proposed use by the generic and irrelevant to the comparison which triggers application of section 5 of the Regulations.
[95] Put the other way, under a purposive interpretation of the Regulations, if an innovator is unable to disprove an allegation that a use claim is invalid, the purpose of the Regulations is served by the issuance of a NOC in connection with that use. Here, the relevant allegation in substance relates to the use of sertraline for PD and OCD, together with the broader related claims, and does not relate to uses of sertraline not authorized in Canada.
[96] The purpose of the Regulations does not, in my view, require that allegations be made that irrelevant use claims are invalid, at least where the irrelevant use claims relate solely to non-approved uses of a drug.
[97] It would follow that if sertraline is in the future approved for other uses claimed in the '065 Patent, and if Apotex then wishes to apply for a NOC in connection with those uses, Apotex would be required to serve a new NOA making allegations relevant to those new approved uses as required by paragraph 5(1)(b) of the Regulations.
[98] This interpretation is consistent with jurisprudence which has contemplated the service of successive NOAs, see for example Apotex Inc. v. Canada (Minister of National Health and Welfare) (1997), 76 C.P.R. (3d) 1 (F.C.A.).
[99] The final argument to be considered with respect to this issue is Apotex' language in the NOA to the effect that the patent as a whole is alleged to be invalid. Pfizer relies upon that language and argues that Apotex has not adduced evidence to support that full extent of its allegation. I accept the submission advanced by counsel for Apotex that this is the form of the allegation which the Regulations require be made. It is clear, however, from the expert evidence filed on Pfizer's behalf with its repeated emphasis on PD and OCD that Pfizer at all times knew the grounds and basis for Apotex's allegation that the patent would not be infringed.
(c) Construction of the '065 Patent
[100] I accept the submission of counsel for Pfizer that the essence of the invention claimed in the '065 Patent is the recognition that different anxiety-related disorders may be treated with sertraline. The inventive step claimed is the discovery that the use of sertraline will aid in the treatment of anxiety-related disorders.
(d) Is the '065 Patent invalid as being obvious?
[101] I turn first to the allegation of invalidity on the ground of obviousness in light of the comment of the Court of Appeal in Beloit Canada Ltd. v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.) that it is generally preferable to deal first with the issue of obviousness.
[102] The most commonly cited articulation of the test for obviousness is that of Mr. Justice Hugessen in Beloit 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 be solution taught by the patent. It is a very difficult test to satisfy.
[103] Put another way, the general question is whether the alleged invention required the exercise of inventive ingenuity: Windsurfing International Inc. et al. v. Trilantic (1985), 8 C.P.R. (3d) 241 (F.C.A.) at page 256.
[104] As noted in Beloit, the test for obviousness is difficult to satisfy. This is because a "scintilla of inventiveness" will do: Diversified Products Corp. v. Tye-Sil Corp. (1991), 125 N.R. 218 (F.C.A.) page 368. Every invention is obvious after it has been made so that the evidence of experts given with the benefit of hindsight must be treated with extreme care: See: Beloit, supra, page 289.
[105] Notwithstanding, as Mr. Justice Wetston noted in Apotex Inc. v. Wellcome Foundation Ltd. (1998) 79 C.P.R. (3d) 193; affirmed (2000) 10 C.P.R. (4th) 65 (F.C.A.) at paragraph 243 "[t]here 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".
[106] In the case before him, Justice Wetston was satisfied that the prior art "would not have led an unimaginative skilled technician to the invention without undue experimentation" (at paragraph 264). This expression of the test was found to be without error by the Court of Appeal (at paragraph 63).
[107] What then is the extent of experimentation or manipulation the unimaginative skilled technician, the paragon of deduction, is entitled to conduct?
[108] Pfizer relies upon authority such as Bayer Aktiengesellschaft v. Apotex Inc. (1995), 60 C.P.R. (3d) 58 (Ont. Ct. (Gen. Div.)) appeal dismissed, cross-appeal allowed on a different issue (1998), 82 C.P.R. (3d) 526 (Ont. C.A.)) leave to appeal to the Supreme Court of Canada denied [1998] S.C.C.A. No. 563, to argue that making inquiries or testing is outside the ken of the notional technician, and that it is not enough for there to be clues which made the invention "worth a try".
[109] In Bayer, Mr. Justice Lederman wrote at pages 80 and 81:
There appears, however, to be a significant difference in the abilities of the English hypothetical skilled technician and the Canadian one. Indeed, making inquiries or testing, seems to be something outside the ken of the notional Canadian skilled technician. In Cabot Corp. v. 318602 Ontario Ltd. (1988), 20 C.P.R. (3d) 132 at p. 146, 19 C.I.P.R. 204, 9 A.C.W.S. (3d) 317 (F.C.T.D.), Rouleau J. quoted H.G. Fox in Canadian Law and Practice Relating to Letters Patent for Inventions at pp. 70-1, as stating in part:
"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."
(My emphasis.) Thus, although one would normally imagine that this mythical person's laboratory is filled with mythical test tubes and Petri dishes and that his or her daily life is spent in experimentation, for the purposes of this legal exercise, no research of any kind can be contemplated. So, although it may have been logical to an actual skilled person at the time, based on the state of the art, to conduct certain testing, that is not open to the mythical skilled technician. The mythical researcher cannot have an inquiring or thinking mind which ultimately would lead him or her to the answer but rather he or she is expected to instantly and spontaneously exclaim, without more, "I already know the answer and it is obvious". Nor is it appropriate to say that there were significant telltales which pointed the way for the mythical expert or that there were sufficient clues which made the invention "worth a try". In Farbwerke Hoechst Aktiengesellschaft Vormals Meister Lucius & Bruning v. Halocarbon (Ontario) Ltd. (1974), 15 C.P.R. (2d) 105 at p. 114, [1974] 2 F.C. 266 (T.D.), Collier J. in rejecting the "worth a try" test stated:
Using the magnifying spectacles of hind-sight (a half borrowed phrase), it is easy to say that any experiment, if time and expense are unlimited... is or was worth a try.
[110] However, notwithstanding that no research is to be conducted by the skilled technician, he or she is, as noted by Mr. Justice Hugessen in Beloit, a paragon of deduction and dexterity. He or she is also reasonably diligent in keeping up with advances in the field: Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 at paragraph 74.
[111] Turning to the application of those principles to the facts before me, I begin from the premise that the patent is directed to the skilled psychiatrist or someone knowledgeable in the treatment of anxiety-related disorders. The parties are agreed that because the '065 Patent claims a priority filing date of November 2, 1989, that is the relevant date on which to assess obviousness. As of that date was inventiveness required for a skilled psychiatrist to treat PD or OCD with sertraline? Or would the skilled psychiatrist plod directly and without difficulty to the use of sertraline to treat PD and OCD?
[112] In assessing the conflicting opinions of the experts on the issue of obviousness, the Court has often remarked upon the difficulty of weighing evidence in the absence of viva voce evidence.
[113] However, having considered the totality of the evidence adduced by affidavit and the transcripts of the cross-examinations, and bearing in mind that the test for obviousness is difficult to satisfy, and that the solution to the problem must be plain as day or crystal clear without the need for experimenting or serious thought, I am satisfied that Pfizer has failed to meet its burden to establish on a balance of probabilities that the allegation of obviousness is not justified.
[114] I conclude on the evidence that a skilled psychiatrist keeping up with developments in his field would be taught by the literature that SSRIs, of which sertraline is one, were logical candidates for further investigation for both OCD and PD, that sertraline was in trials with respect to OCD, that sertraline was probably one of the SSRIs that would be a cornerstone of OCD treatment and that preliminary results suggested that drugs, including sertraline, should have anti-panic activity. I see no inventive step or undue experimentation required in that circumstance for the notional skilled psychiatrist to prescribe sertraline for OCD or PD.
[115] The inventive step, that is the discovery that the use of sertraline will aid in the treatment of PD and OCD, was clearly advocated and recommended as of November 2, 1989. I so conclude for the following reasons.
[116] First, I have been mindful of the admonition that the opinions of experts given in hindsight must be treated with extreme care. Therefore, I have reviewed with attention what was written in the literature prior to November 2, 1989. Of particular significance, in my view, are the following 4 articles, the first three dealing with OCD, the fourth with PD.
(a) Evidence with respect to OCD
1. Dr. T. Perse in an article published in February 1988 wrote:
The only antidepressants that have been shown to be effective treatments in methodologically sound, double-blind trials are clomipramine and fluvoxamine. However, their nonavailability for general use in this country necessitates the choice of other medications. Current research suggests that clomipramine's success in the treatment of OCD may be related to its effect on the serotonin neurotransmitter system. Therefore, drugs that selectively inhibit the reuptake of serotonin are logical candidates for use with OCD patients. [underlining added]
2. In an article "Pharmacology of Sertraline: A Review" published in the August 1988 Journal of Clinical Psychiatry, the authors concluded:
Sertraline represents a new class of psychotherapeutic agents that provides a means for specific enhancement of serotonergic tone in the central nervous system. Biochemical, electrophysiological, and behavioral studies have demonstrated potent and selective inhibition of serotonin reuptake by sertraline, leading to enhanced serotonergic neurotransmission.
[...]
Increased serotonergic function appears to be a common feature of various antidepressant treatments, including monoamine reuptake inhibitors, MAOIs, and electroconvulsive shock. This mechanistic observation fits well with hypotheses linking serotonergic hypofunction to depression and suicidal behavior. It is not surprising, therefore, that in preclinical assays, sertraline produces results that are thought to be predictive of antidepressant activity. Indeed, the anticipated antidepressant efficacy of sertraline has now been established in preliminary clinical trials.
In addition to affecting mood, serotonin is considered to be a major factor in the regulation of various biological drives and their associated behaviors. This suggests that sertraline and other selective serotonin reuptake inhibitors have potential for broader application in psychiatry because their efficacy may be not limited to affective illness. For example, both appetitive disorders and obsessive compulsive behavior may be responsive to serotonergic manipulation. Although the development of selective serotonin reuptake inhibitors is a pharmacological milestone, understanding the full potential of these new drugs as psychotherapeutic agents awaits the outcome of more extensive clinical testing. [footnote omitted, underlining added]
3. Dr. Rasmussen, one of Pfizer's experts, in "Serotonergic Agents in Obsessive-Compulsive Disorder: Fluvoxamine as an Antiobsessional Agent" with others wrote in a 1989 article which Apotex cited as prior art in its NOA:
There are now a number of double-blind studies demonstrating that the potent serotonin reuptake inhibitor clomipramine is more effective than placebo in obsessive-compulsive disorder (OCD) (Insel & Zohar 1987). Fewer studies have directly compared clomipramine to other antidepressants; however, most of these studies suggest that less potent blockers of serotonin are not efficacious in treating obsessive-compulsive symptoms.
[...]
Two small studies of fluoxetine in OCD are promising (Fontaine & Chouinard 1985; Turner et al. 1985), but there are presently no published double-blind trials. Citalopram was reported beneficial in a single case of OCD (White et al. 1986). Placebo-controlled studies of sertraline are underway, but no outcome data are currently available. Of the selective and potent serotonin reuptake inhibitors, fluvoxamine (investigational in the United States) has been most thoroughly studied as a treatment for OCD.
[...]
The studies reviewed here suggest that the potent and selective serotonin reuptake inhibitor fluvoxamine is an effective treatment for OCD. [underlining added]
(b) Evidence with respect to PD
1. In an article published in August of 1988 in the Journal of Clinical Psychiatry, Dr. Sheehan and others wrote:
More recently, three new serotonin reuptake inhibitors - fluvoxamine, sertraline, and fluoxetine (Prozac) - have been studied in detail for the treatment of depression. These drugs have not yet been studied systematically in the treatment of panic disorder, but preliminary results warrant such investigation because the available data suggest that any drug that significantly inhibits serotonin reuptake or that significantly increases serotonin in the synaptic cleft should have antipanic activity.
Although the data are preliminary, the balance of evidence suggests that serotonin reuptake inhibitors are effective in panic disorder. However, there is insufficient evidence to either support or refute the hypothesis that these drugs exert their antipanic effects via the serotonergic system. [underlining added]
[117] Those articles teach, prior to the effective date, that current research suggested that SSRIs were logical candidates for use with OCD patients, that sertraline was in clinical trials as a treatment for OCD, that the balance of the evidence suggested SSRIs are effective in PD and preliminary results warrant investigating sertraline for PD. On the basis of this literature no inventive ingenuity, or undue experimentation was required in order to prescribe sertraline for the treatment of PD or OCD. To paraphrase Mr. Justice Wetston in Apotex Inc. v. Wellcome Foundation Ltd, supra, there was no inventiveness in following an obvious and well-charted route using known techniques and known compositions unless unexpected difficulties were encountered.
[118] Second, my conclusion with respect to obviousness is supported by the opinions of Doctors Deakin, Peroutka and Richter, which I do not find to have been significantly impugned on cross-examination and which I therefore find to be reliable and trustworthy.
[119] Dr. Deakin was of the view that a skilled practitioner might well have used sertraline to treat a patient with panic attacks and that sertraline could reasonably have been used to treat OCD in those who were not tolerating other 5HT drugs.
[120] Dr. Peroutka expressed the opinion that by mid-1989 a person skilled in the art would have predicted or expected that sertraline would be clinically effective in the treatment of OCD and PD.
[121] Dr. Richter was of the view that it would have been obvious to any competent clinical psychiatrist to use sertraline for the treatment of OCD or PD.
[122] Third, I find the opinions of Pfizer's experts Dr. Greist and Dr. Lapierre to have been significantly limited in cross-examination in the following respects.
[123] In cross-examination Dr. Greist admitted that in October 1989 it was his view that "[t]he cornerstones of OCD treatment are serotonin reuptake blocking medications (clomipramine and fluvoxamine proven; fluoxetine and sertraline probable) and behaviour therapy (exposure in vivo and imagination plus response prevention)." [underlining added]
[124] Dr. Greist so wrote in an abstract published in Psychiatry Today. In an interlocutory order, Prothonotary Aronovitch ruled it could not, in view of the decision of the Federal Court of Appeal in AB Hassle, supra, be relied upon as prior art. However, the learned Prothonotary also confirmed in her order that the rights of the parties on cross-examination were preserved. Prothonotary Aronovitch's order was confirmed on appeal by Mr. Justice Blanchard, 2002 FCT 152.
[125] Pursuant to authority such as Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.), at page 320, any document may be put to a witness to contradict a statement or to impeach their credibility. Dr. Greist's view in October of 1989 as to whether sertraline would be effective for the treatment of OCD was a proper area for cross-examination of Dr. Greist. Because Dr. Greist confirmed the accuracy of the content of his abstract on cross-examination, I find it proper and persuasive to have regard to that admission secured on his cross-examination.
[126] Dr. Lapierre confirmed in cross-examination that he attended the VIII World Congress of Psychiatry in Greece in October 1989, that he presented a paper at the Congress, and that a book of abstracts was given out to registrants. Abstract number 565 was entitled "Sertraline is Effective in Obsessive Compulsive Disorder". The abstract referred to the results of the first use of sertraline in OCD, and in it Pfizer scientists announced that sertraline is effective in treating OCD.
[127] This abstract was not disclosed by Apotex as prior art and could not therefore be relied upon to establish prior art and to argue invalidity. However, in view of Dr. Lapierre's evidence that in 1989 there was no mention in the literature of the use of sertraline for OCD or PD, I am satisfied that Dr. Lapierre could on cross-examination properly be asked to identify the document as one distributed at the Congress which he attended.
[128] Even without regard to abstract number 565 of the World Congress in Greece, I would conclude that the patent is invalid on the ground of obviousness.
[129] Fourth, in preferring the evidence of Apotex' experts over the opinions of Doctors Lapierre, Griest and Rasmussen, I have also considered that much of Pfizer's expert evidence centered on uncertainty as to the etiology or pathogenesis of OCD and PD (or in other words uncertainty as to the cause of OCD and PD).
[130] This is reflected in the summary of the Pfizer experts' evidence above. In brief, Dr. Lapierre opined that even today what causes OCD is not fully understood so it would be difficult to say that any hypothesis as the role of serotonin is obvious. Dr. Greist noted that in November 1989 it was unreasonable to assume a complex disorder such as OCD could be explained by examining only one neurotransmitter. Dr. Rasmussen testified that the theory that SSRIs played a role in OCD and PD was uncertain.
[131] After reviewing many of the scientific articles in evidence, I am satisfied that the articles tend to draw a distinction between pathogenesis and treatment. Notwithstanding the uncertainty as to pathogenesis, the articles I have referred to reported as to the effectiveness of sertraline for treatment.
[132] Dr. Deakin expressed this distinction in cross-examination in the following terms:
It is essential to separate the two kinds of theories - how the drugs work and how the diseases come about. They are totally separate. It is kind of nice if the drug reverses an abnormality that is demonstrably present in the disorder because it is working on a primary mechanism, but it often doesn't happen like that. So they are separate exercises, establishing how the drugs work and what is wrong in the disorder.
[133] In reaching my conclusion as to obviousness I also considered the existence of prior art which taught away from the efficacy of SSRIs and sertraline because such teachings would render the use of sertraline to treat PD or OCD less obvious.
[134] Pfizer's experts relied particularly on the fact that the SSRI zimelidine had been shown to be ineffective in the treatment of anxiety, and that the initial publication from one site of the sertraline trial reported that sertraline failed to improve OCD. This was said to show the effectiveness of sertraline to be uncertain.
[135] However, the evidence of Apotex's expert Dr. Deakin was not contradicted that:
Each of the doctors asserts that the SSRI zimelidine was shown to be ineffective in the treatment of anxiety. In particular Dr. Greist at paragraph 28 and Dr. Rasmussen at paragraph 52 of his affidavit make reference to a study by Insel as demonstrating that zimelidine was ineffective in treating OCD. However, only one study found zimelidine to be less effective than imipramine in the treatment of OCD. Another found it to be superior to a noradrenaline uptake inhibitor. In addition, Insel's study of zimelidine vs. clomipramine and DMI in 1985 was not placebo-controlled and only five subjects completed the zimelidine arm. The Insel study does not demonstrate that zimelidine was not superior to DMI and that neither were effective. It should also be kept in mind that the zimelidine was not on the market long enough for it to have any impact on the perception of SSRIs and their spectrum of action. The experience with zimelidine had far less salience than the accumulating experience with fluoxetine and fluvoxamine in OCD.
[136] With respect to the negative sertraline test result reported by Jenike, and relied upon by Pfizer's experts, the result initially reported was subsequently corrected. The correction revealed that errors had been made in the computer entry of the randomization code. When corrected, the results exhibited stronger usefulness of sertraline.
[137] Dr. Deakin's evidence quoted above and the correction of the initial sertraline test result diminish significantly Pfizer's arguments based on contrary teachings in the prior art.
[138] Finally, I have considered the assertion of Pfizer's experts that Apotex' selection of prior art was selected with hindsight and was not representative of the state of the art. Pfizer points to evidence from its experts, and relies upon authority such as Xerox of Canada Ltd. v. IBM Canada Ltd. (1977), 33 C.P.R. (2d) 24 (F.C.T.D.) at pages 60-62 to argue that Apotex should have led evidence establishing how items said to be prior art were found, and establishing that the references were not selected with hindsight. In the absence of such evidence, it is argued by Pfizer that the Court should give less weight to Apotex' experts opinions which were formed on prior art of unknown provenance.
[139] This argument is potentially significant in view of the fact that Apotex provided no evidence as to how the prior art it relies upon was selected. The prior art references were simply appended to the affidavit of a secretary who had no scientific background, who did not do the literature search and who did not know how the search was done.
[140] In order to assess this argument, it is significant in my view that the evidence provided by Pfizer's experts as to hindsight in the selection of prior art was generalized, not specific. Accordingly that evidence is difficult to assess. In the absence of specific reference to significant omissions in the selected literature, what I find most telling is that in oral argument counsel for Pfizer referred to the prior art as containing five key documents which were: Exhibits H, L, M, N, and O to the affidavit of Dr. Rasmussen.
[141] All but one of those documents were contained in Apotex' list of prior art. The only one not contained in the list of prior art is Exhibit H, which is a 1983 article by Insel and others entitled "Obsessive-Compulsive Disorder - A Double-Blind Trial of Clomipramine and Clorgyline". However, Apotex' reference number 66 was a later article by Zohar and Insel entitled "Obsessive-Compulsive Disorder: Psychobiological Approaches to Diagnosis, Treatment and Pathophysiology" which at page 671 of the article, referenced the 1983 paper.
[142] In light of the failure of Pfizer's experts to point to specific significant omissions in the prior art relied upon by Apotex, and Pfizer's counsel's reliance on the five articles discussed above, I have not been persuaded that Apotex' evidence of prior art is flawed. I have therefore not discounted the opinions of Apotex's experts on this basis.
[143] It follows that, for these reasons, I have found Pfizer has not established that Apotex' allegations with respect to claims 3 and 10 are unjustified.
[144] Claims 1 and 2 of the '065 Patent include claims to all anxiety-related disorders, including PD and OCD. On the basis of my findings, claims 1 and 2 therefore claim something which was not properly patentable. To that extent, Pfizer has not established that Apotex' allegation with respect to claims 1 and 2 being obvious is not justified.
[145] Similarly, the claimed new invention was the use of sertraline for the treatment of conditions other than depression. There was nothing inventive in the creation of the composition of the drug, the dosage range or the commercial package. I accept the submission of counsel for Apotex that these are obvious aspects dependent upon the claimed use invention. Therefore, Pfizer has failed to establish that the allegations of invalidity with respect to claims 11, 12 and 13 as they relate to OCD and PD are not justified. See: Merck & Co. v. Apotex Inc. (1995), 60 C.P.R. (3d) 356 at page 376 and following.
(e) Is the '065 Patent invalid as it was anticipated?
[146] In the event that my conclusion on the issue of obviousness is in error, I next consider the issue of anticipation.
[147] In Beloit, supra, Mr. Justice Hugessen described the test for anticipation in the following terms:
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; is it 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.
[148] This test was affirmed by the Supreme Court of Canada in Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1025 at paragraph 26. Mr. Justice Binnie, writing for the Court, noted in the same paragraph that the legal test for anticipation is whether the specific piece of prior art contains sufficient information to enable a person of ordinary skill and knowledge in the field to understand, without access to the patent, "the nature of the invention and carry it into practical use without the aid of inventive genius but purely by mechanical skill." He further observed that the test is difficult to meet.
[149] Turning to the application of those principles to the present case, Apotex cites two references in support of its allegation of anticipation. One is the '815 Patent which is said to anticipate claims 11, 12 and 13 of the '065 Patent. The other is the Peroutka article which is said to anticipate claims 1, 4, 10, 11, 12 and 13 of the '065 Patent, although the NOA only suggests that the reference anticipates claims relating to the use of sertraline for OCD.
i) The '815 Patent
[150] Apotex argues that the '815 Patent disclosed sertraline and compositions which contained sertraline.
[151] However, the evidence of Pfizer's expert Dr. Lapierre that anxiety disorders are distinct from depression was unchallenged. The '815 Patent disclosed the administration of sertraline for the treatment of depression. Claims 11, 12 and 13 of the '615 Patent all relate to the use of sertraline to treat anxiety-related disorders or their symptoms.
[152] I am not satisfied that a skilled psychiatrist looking at the '815 Patent without the exercise of inventive skill would be led without the possibility of error to the teaching of claims 11, 12 and 13 as they relate to use for the treatment of anxiety. I am therefore not satisfied that the allegation of anticipation by the '815 Patent is justified.
ii) The Peroutka article
[153] The Peroutka article reported in the summer of 1989 that sertraline was undergoing Phase II clinical trials for the use of sertraline in the treatment of OCD.
[154] Apotex relies upon the following evidence to argue that claims 1, 10, 11, 12 and 13 of the patent are anticipated by the Peroutka article:
1. Dr. Richter's evidence that:
As such, the Peroutka article teaches that sertraline is being administered to patients for the indication or treatment of OCD. With the exception of the dose range which is provided on page 3 of the '065 Patent, the Peroutka article gives an exact prior description. However, the dose range for OCD which is given by the '065 Patent is extremely broad and overlaps with the dose range which is recommended when sertraline is used in treating depression; ie 50-200mg. Thus, any clinician skilled in the art would have automatically tried sertraline for OCD within the depression dose range, and would have likely observed efficacy.
2. Dr. Peroutka's evidence that:
The phrase PHASE II CLINICAL TRIALS has a generally accepted meaning. During Phase II trials a drug is tested for some indication of its clinical efficacy. In the context of this reference, it would have been understood that some patients were being administered sertraline for the purpose of determining whether or not it was effective in treating OCD. Therefore this reference teaches that patients were being administered sertraline for the purpose of treating the condition of OCD.
3. Apotex's expert, Dr. Lapierre's advice on cross-examination that someone reading that a Phase II clinical trial for sertraline was being conducted for the indication of OCD would understand that sertraline was being administered to persons suffering from OCD to see if it succeeds in treating the ailment.
4. The evidence of Apotex's expert Dr. Rasmussen on cross-examination that a Phase II clinical trial is performed on persons suffering from the condition that the researcher is trying to treat and that all of the people in the clinical trial are being treated for the ailment, some with the placebo and some with the medicine.
[155] Pfizer submits that while the Peroutka article comes "tantalisingly close" to anticipating the patent, it does not, because the mere mention of the existence of a Phase II trial does not provide information that sertraline works for OCD. Until the results of the trial are published there is no disclosure of efficacy. Pfizer notes that often the result of Phase II trials is negative. Pfizer further points to the fact that the portion of the Peroutka article which discusses OCD mentions some specific drugs being effective, but does not mention sertraline.
[156] In my view, however, it is not necessary for the Peroutka article to say that sertraline is effective for the treatment of OCD in order for the article to anticipate the '065 Patent. To require that level of advice is to ignore the requirement at law that the prior publication must simply contain sufficient information to enable a person of ordinary skill and knowledge in the field to understand the nature of the invention and carry it into practical use without the aid of inventive genius, but purely by mechanical skill.
[157] Thus, in SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001) 14 C.P.R. (4th) 76 (F.C.T.D.), affirmed 2002 FCA 216, Mr. Justice Gibson considered whether a patent for a novel formulation of a drug to avoid a pink discolouration was anticipated by a prior patent for the drug. In finding the later patent to be anticipated, Mr. Justice Gibson wrote at paragraph 40:
Having determined that a wet formulation of paroxetine tablets gives rise to a "pink hue problem", a problem of significant enough magnitude to cause a skilled person to seek out at least a partial solution to the problem, I am satisfied that a logical first step for a person skilled in the art would be to turn to the alternative formulation methods disclosed by the '060 Patent and to determine whether each or any of those alternative formulation methods would solve, or at least partially solve, the problem. Such an enquiry would, I am satisfied, involve no inventive step or skill. It would simply involve application of the invention taught by the '060 Patent.
[158] Similarly, in the present case I conclude that the skilled clinician who read the Peroutka article would have learned that persons suffering from OCD were being administered sertraline to see if it succeeded in treating the condition. No inventive step would be required for that clinician to then administer sertraline to a patient suffering from OCD.
[159] To the extent that the Peroutka article does not disclose the dosage range which is information provided in the patent, I am persuaded by the logic of Dr. Richter's evidence that because the dosage range for OCD overlaps with the recommended dosage for the treatment of depression, a skilled clinician would have tried sertraline for OCD within that range and would likely have observed efficacy. That would not have involved inventive skill or an inventive step.
[160] I therefore conclude that Pfizer has failed on the evidence to discharge its burden to establish that the allegation of invalidity of claims 1, 10, 11, 12 and 13 on the ground of anticipation by the Peroutka article is not justified.
(f) Insufficient Specification, Double Patenting, Ambiguity
[161] Brief arguments were made by Apotex with respect to further grounds of invalidity arising from the fact that depression and anxiety-related conditions are frequently comorbid. This was said to give rise to "obviousness" double patenting and ambiguity. In view of the conclusions which I have reached on obviousness and anticipation, it is not necessary for me to consider those submissions.
5. CONCLUSION
[162] Based on the foregoing, the application for an order of prohibition is dismissed.
6. COSTS
[163] The respondent Apotex is entitled to its costs from the applicants. Those costs, if not agreed, should be assessed 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 either for or against the respondent Minister.
ORDER
[164] IT IS HEREBY ORDERED THAT:
1. The application is dismissed.
2. The applicants shall pay the costs of this proceeding to Apotex Inc. If not agreed, the costs shall be assessed in accordance with column III to the table to Tariff B of the Federal Court Rules, 1998.
"Eleanor R. Dawson"
Judge
FEDERAL COURT OF CANADA
TRIAL DIVISION
NAMES OF SOLICITORS AND SOLICITORS ON THE RECORD
COURT FILE NO.: T-2096-00
STYLE OF CAUSE: Pfizer Canada Inc. and Pfizer Inc. v.
Apotex Inc. and the Minister of Health
PLACE OF HEARING: Vancouver, British Columbia
DATE OF HEARING: August 22, 2002
REASONS FOR ORDER AND ORDER BY THE HONOURABLE MADAM JUSTICE DAWSON
DATED: November 5, 2002
APPEARANCES:
Mr. Anthony Creber FOR APPLICANTS
Ms. Jennifer Wilkie
Mr. H.B. Radomski FOR RESPONDENTS
Mr. Rick Tuzi
SOLICITORS OF RECORD:
Gowling Lafleur Henderson LLP FOR APPLICANTS
Suite 2600, 160 Elgin Street
Ottawa, Ontario, K1P 1C3
Goodmans LLP FOR RESPONDENTS
250 Yonge Steet, Suite 2400
Toronto, Ontario, M5B 2M6