Eli Lilly Canada Inc. v. Novopharm Limited

Eli Lilly Canada Inc. v. Novopharm Limited
Court (s) Database
Federal Court Decisions
Date
2011-11-10
Neutral citation
2011 FC 1288
File numbers
T-1048-07
Decision Content
Date: 20111110
Docket: T-1048-07
Citation: 2011 FC 1288
Ottawa, Ontario, November 10, 2011
PRESENT: The Honourable Mr. Justice O'Reilly
BETWEEN:
ELI LILLY CANADA INC.,
ELI LILLY AND COMPANY,
ELI LILLY AND COMPANY LIMITED AND ELI LILLY SA
Plaintiffs
(Defendants by Counterclaim)
and
NOVOPHARM LIMITED
Defendant
(Plaintiff by Counterclaim)
REASONS FOR JUDGMENT AND JUDGMENT
I. Overview
[1] The plaintiffs [collectively “Lilly”] sued Novopharm for infringement of a patent for a medicine called olanzapine, whose brand name is Zyprexa. Psychiatrists prescribe olanzapine primarily for the treatment of schizophrenia. Novopharm markets a generic version of olanzapine, called novo-olanzapine. Olanzapine is the subject of a Canadian patent (No 2,041,113) [the ‘113 patent]. Lilly applied for the ‘113 patent in 1991 and was granted it in 1998.
[2] Olanzapine was also included within an earlier Lilly patent (No 1,075,687) [the ‘687 patent]. The ‘687 patent was a so-called “genus patent”. It covered 15 trillion compounds all with a similar chemical structure – three-ring molecules called “thienobenzodiazepines”. The ‘113 patent, therefore, is a so-called “selection patent” which identifies an already-patented compound for separate patent protection based on its alleged advantage over the other members of its chemical family.
[3] In an earlier judgment, Eli Lilly Canada Inc v Novopharm Limited, 2009 FC 1018 [Trial Judgment], I dismissed Lilly’s action for infringement primarily on the basis that Lilly was not entitled to a second patent for olanzapine. I found that Novopharm had proved on the balance of probabilities that, at the 1991 filing date for the ‘113 patent, Lilly did not have enough information about olanzapine either to have shown or soundly predicted that it would have the utility described in the patent. In addition, I found that the patent did not set out a sufficient description of the alleged invention. Because I concluded that olanzapine did not amount to a separate and distinct invention from the ‘687 patent, I also found that the ‘113 patent had been anticipated by the ‘687 patent and that olanzapine had been double-patented. However, I found that olanzapine was not an obvious choice for the inventors of the ‘113 patent to take into development. But this alone, I concluded, did not mean that olanzapine met the definition of an invention in s 2 of the Patent Act because it did not represent an invention over and above the compounds of the ‘687 patent.
[4] Lilly appealed my decision and the Federal Court of Appeal allowed the appeal: Eli Lilly Canada Inc v Novopharm Ltd, 2010 FCA 197 [FCA Judgment]. Justice Layden-Stevenson, writing for the Court, found that I had erred in my approach to selection patents. She also concluded that the ‘113 patent was not invalid for anticipation, double patenting or obviousness. However, she referred the issues of utility and sufficiency back to me. A fuller discussion of my original judgment and Justice Layden-Stevenson’s decision is set out below in order to make clear the task now assigned to me. I will also briefly consider below two other Federal Court decisions involving Lilly, olanzapine, and the ‘113 patent that arose out of proceedings under the Patented Medicines (Notice of Compliance) Regulations, SOR/98-166, as amended SOR 93-113 [PMNOC Regulations].
[5] The parties agreed that the issues of utility and sufficiency could be determined on the basis of the evidentiary record generated by the first trial. In fact, as will be seen below, there are actually few disputes between the parties about the evidence. The main controversies relate to the inferences and conclusions that can be drawn from that evidence. Accordingly, many of the findings of fact I made during the first trial are repeated here.
[6] For ease of reference, I have set out relevant statutory provisions in Annex “A”, and a summary of expert witnesses’ backgrounds and qualifications in Annex “B”.
[7] As mentioned, the issues before me are whether Novopharm has established that the ‘113 patent is invalid on one or both of these grounds:
1. Lack of Utility
2. Insufficient Disclosure
[8] I find that Novopharm has met its burden in relation to the issue of utility, but not on the issue of sufficiency. Therefore, I conclude that the ‘113 patent is invalid and must dismiss Lilly’s action for infringement.
II. Factual Background
[9] Schizophrenia is a chronic form of psychosis affecting about 1 percent of the population. Generally speaking, symptoms fall into two categories. The first, called “positive” symptoms, includes hallucinations and delusions. The second, called “negative” symptoms, includes withdrawal, lack of motivation and impaired mental functioning.
[10] There is no known cure for schizophrenia. However, over the course of the past 50 or 60 years, scientists have found some drugs that mitigate some of the worst symptoms. Patients typically remain on drug treatment for many years. The drug chlorpromazine was a breakthrough in the early 1950s. But chlorpromazine had a serious side-effect liability. In particular, it induced an array of uncomfortable motor effects called “extra-pyramidal symptoms”, or EPS. EPS include restlessness, stiffness, twitching and facial contortions. Chlorpromazine and analogous drugs that share this liability to cause EPS are referred to as “typical” or “first-generation” antipsychotics.
[11] A better drug, clozapine, came onto the market in the late 1960s. Clozapine’s main advantage was that it did not induce EPS. However, after years on the market, it was found to cause a rare but serious blood disorder, called agranulocytosis, in which the body abruptly stops making white blood cells. Clozapine was taken off the market in the 1970s, but returned in the late 1980s. Patients taking clozapine must take frequent blood tests to ensure their white blood cell count is normal. Clozapine and other drugs with a low EPS liability are referred to as “atypical” or “second-generation” antipsychotics.
[12] Once clozapine was off the market, many scientists, including those at Lilly, looked for a safe, clozapine-like compound - one that would treat both the positive and negative symptoms of schizophrenia, have little liability to produce EPS, and not affect production of white blood cells.
[13] Various tests can be used to determine a compound’s potential as an antipsychotic. The same tests have been used for decades. Compounds are tested in mice to see if they reduce locomotor activity and induce hypothermia (good signs for an antipsychotic). A compound’s capacity to block a conditioned avoidance response [CAR] in rats is of interest because it, too, indicates antipsychotic activity. Essentially, a CAR test measures a compound’s ability to interfere with rats’ learned behaviour (e.g., avoiding electric shock). On the other hand, a compound’s liability to induce catalepsy [CAT] in rodents is an important indicator of its liability to produce EPS in humans. A compound will be a potential atypical or second-generation antipsychotic if it shows good CAR-CAT separation (i.e., its CAR score is high and its CAT score is low).
[14] As described above, in the 1970s, scientists were looking for a safe clozapine-like compound. Lilly was exploring compounds that were chemically similar to clozapine as part of that quest.
[15] Having heard about clozapine and its potential as an antipsychotic, Dr. Jiban Chakrabarti, a Lilly chemist, attended a conference in Prague in the early 1970s. He met the scientists who had made and developed clozapine. Dr. David Tupper, another Lilly chemist, recalls that, when Dr. Chakrabarti returned, he was very excited about what he had heard there. He believed that he could make compounds that would be clozapine-like in terms of their antipsychotic effect but would avoid the problems associated with clozapine. Dr. Chakrabarti suggested replacing one of clozapine’s phenyl rings with a thiophene ring.
[16] Dr. Tupper, after visiting the library and determining that no such compounds had previously been made, worked out ways to synthesize them. The end result was the family of compounds covered by the ‘687 patent.
[17] The ‘687 patent was filed in 1975 and issued to Lilly in 1980. Its inventors were Dr. Chakrabarti and Dr. Tupper, both of whom worked at Erl Wood, Lilly’s research facility in Sussex, United Kingdom. The ‘687 patent described a “novel class of compounds” called “thienobenzodiazepines” with a three-ring chemical structure, similar to clozapine’s. The patent asserted that this family of compounds had displayed useful central nervous system activity in animal tests, and had potent neuroleptic, sedative, relaxant and anti-emetic properties. They showed good CAR-CAT separation. These properties, the patent stated, rendered the compounds useful in the treatment of mild anxiety states, and certain kinds of psychotic conditions such as schizophrenia. Further, the compounds had a high therapeutic index (meaning that there was a wide margin between the effective dose and a gross toxic effect) and were effective across a broad dosage range (from 0.1 mg/kg/day to 10 mg/kg/day).
[18] The focus of the ‘687 patent was clearly on the nature of the compounds themselves – their constituents, their structure, the processes by which they could be made, and the possibilities for formulating the active ingredients. Still, the patent specifically asserted that the utility of the compounds of the invention lay in their potential use in the treatment of central nervous system disorders, including schizophrenia. Dr. Ian Pullar testified that Lilly was hopeful that the class of compounds described in the ‘687 patent would be effective in treating both the positive and negative symptoms of schizophrenia, and have low EPS liability. One of the vast number of compounds covered by the ‘687 patent (15 trillion) was olanzapine. In fact, it fell within a group of the “most preferred compounds” of the invention, although it was not specifically named.
[19] Over the years following the filing of the ‘687 patent, Lilly scientists worked at bringing some of the compounds of the invention to market. A few dozen were synthesized and tested in vitro. Dr. Chakrabarti published a paper in 1980 that gave data on 45 of the ‘687 compounds, including their CAR and CAT values. From that study, flumezapine and ethyl flumezapine, which had been specifically identified in the ‘687 patent, looked promising. A few others also looked favourable, but Dr. Chakrabarti noted that the “profile of activity needs further development of this class of compounds” (D-39, at p 883).
[20] Lilly began tests on ethyl flumezapine, but discontinued this work in 1978 after dog studies showed the compound caused a reduction in white blood cells, just as clozapine had been known to do, which was the major side effect sought to be avoided. At that point, Lilly turned its attention to flumezapine. Dog studies on flumezapine did not show any problem with white blood cells, although other problems were detected – weight loss, anemia and elevated prolactin. Still, in due course, in 1981, Lilly was granted permission by the U.S. Food and Drug Administration [FDA] to administer flumezapine to healthy volunteers, and then to begin clinical trials with patients experiencing schizophrenia.
[21] Lilly halted its clinical trials on flumezapine in April 1982 after receiving reports of elevated liver enzymes and a muscle enzyme called creatine phosphokinase [CPK] in some patients. Lilly passed on those reports to officials at the FDA who asked Lilly to discontinue treating patients with flumezapine.
[22] Lilly decided not to resume the clinical trials on flumezapine, even though there were signs that it was an effective antipsychotic. Investigators “were very impressed with the efficacy of the drug, as well as the significant absence of extrapyramidal side effects . . .” (D-84, at p 8). Lilly could have changed the clinical trial protocols, for example, by reducing the maximum dose, or by monitoring patients more closely for liver enzymes and CPK. Dr. Paul Leber, an FDA official who was involved in the discussions about flumezapine at the time, testified that the FDA did not halt Lilly’s development of flumezapine:
It was simply an assertion that, in the current state, they should not do further clinical testing until they submitted new reports to us and we reviewed them. Then we would explain to them what they could or could not do.
(Transcript, Vol 6, p 150, lines 15-20)
[23] However, continuing with flumezapine would have required considerable time and effort. Lilly would have had to persuade the FDA to allow it to continue clinical trials. While the project team felt that studies of flumezapine should be continued, Lilly management concluded that further investment in flumezapine was unwarranted. Lilly discontinued, but did not completely abandon, its request to have flumezapine approved. Still, in effect, as of 1982, flumezapine was for Lilly a tainted product.
[24] Dr. Pullar, who was the chairman of the flumezapine project team, described this as a “black time” at Erl Wood. Yet, the team felt there was enough promise within the ‘687 compounds that they went looking for another candidate. There was pressure coming from Lilly management to show that the substantial corporate investment in developing an antipsychotic would pay off. Erl Wood, established in 1967, had only produced one drug in its then 15-year existence that had actually made it to market.
[25] Within a few weeks of the discontinuation of flumezapine, Dr. Tupper and his colleague, Mr. Terrence Hotten, synthesized seven more of the ‘687 compounds, one of which was olanzapine. Dr. Tupper felt that, given that flumezapine had gone quite far in its development, the focus should be on methyl compounds like olanzapine, not ethyl. Ethyl flumezapine had been an abject failure. At first, Dr. Pullar did not think that olanzapine would be a good choice for development because it did not show particularly dramatic potency in animal tests. But the rest of the team favoured olanzapine based on its overall performance on an array of animal and in vitro tests. Dr. Pullar now feels glad he was outvoted and, naturally, is proud of his association with a drug that treats many patients effectively. As he said, the team “carried out very good research in order to put [olanzapine] on the market”. Dr. Tupper expressed similar sentiments and cited numerous prizes the Lilly scientists had received for their work.
[26] So, by 1983, Lilly was satisfied, based on animal and in vitro tests, that olanzapine showed potential as an antipsychotic. Studies continued and Lilly’s hopes were confirmed by further preliminary results. Beginning in 1986, Lilly gave olanzapine to healthy volunteers and, in 1989, started clinical trials in patients. By 1990, bringing olanzapine to market became a top priority for Lilly. It recognized a market opportunity, given that clozapine was about to be reintroduced, and new drugs, such as risperidone, were about to come on stream. A patent for olanzapine was filed in the United Kingdom in 1990 and in Canada in April 1991. Lilly was granted its Canadian patent, the ‘113, in 1998.
[27] By the time it filed the ‘113 patent, Lilly had received the results of its healthy volunteer studies, as well as some preliminary data from clinical trials. It had also concluded a six-month study in dogs. The patent mentions some of these studies and provides some general information about what they disclosed.
III. The ‘113 Patent
[28] The ‘113 patent is entitled “Thienobenzodiazepine Derivatives and Their Use as Pharmaceuticals”. The introduction describes the side-effect issues encountered with antipsychotic drugs, particularly EPS, and the “need for better products that control or eliminate the symptoms in a safer and more effective way”.
[29] The patent explains that schizophrenia patients are prone to drug-induced EPS, including drug-induced Parkinsonism, acute dystonic reactions, akathisia, tardive dyskinesia and tardive dystonia. Most antipsychotics produce these symptoms at therapeutic doses, which frequently results in poor compliance rates in patients who must take them. Long-term use can lead to irreversible EPS.
[30] The patent cites the example of haloperidol which was known to cause EPS and tardive dyskinesia. Clozapine is also mentioned, with reference to its liability to cause agranulocytosis.
[31] The patent refers to the British Patent (No 1533235), the equivalent of the ‘687 patent, and the experience with flumezapine – termination of the clinical trial due to concerns about CPK and liver enzymes. In addition, two patients on flumezapine appeared to experience EPS.
[32] Then the inventors of the ‘113 patent announce that “[w]e have now discovered a compound which possesses surprising and unexpected properties by comparison with flumezapine and other related compounds”. The patent sets out a drawing of olanzapine and its chemical nomenclature and goes on to say that the “compound of the invention has given surprising and excellent results . . . in experimental screens for testing activity on the central nervous system and in clinical trials, which results indicate its usefulness for the relatively safe and effective treatment of a wide range of disorders of the central nervous system”.
[33] The test results for olanzapine are then described, beginning with in vitro tests showing that it operates as an antagonist of dopamine at the D-1 and D-2 receptors, has antimuscarinic and anticholinergic properties, and has antagonist activity at noradrenergic receptors. These properties, the patent states, indicate that olanzapine is “a potential neuroleptic with relaxant, anxiolytic or anti-emetic properties” and that it is “useful in treating psychotic conditions such as schizophrenia, schizophreniform diseases and acute mania”.
[34] Later in the patent, the results of rodent tests are set out. These are described as “standard behavioural tests predictive of antipsychotic activity”. Olanzapine antagonized apomorphine-induced climbing behaviour and hypothermia in mice. CAR and CAT data are provided, noting that the separation “indicates that the compound is less likely to induce extrapyramidal side effects in the clinic”.
[35] Regarding testing in humans, the patent states that olanzapine has shown a “high level of activity in the clinical evaluation of psychiatric patients suffering from schizophrenia . . . at surprisingly low dosage levels”. A summary of the results of an open label study follows. The patent states that six of eight patients who completed at least two weeks of treatment showed between 66% and 87% improvement at four weeks at dosages of between 5 and 30 mg. The patent mentions that other trials are ongoing and that preliminary results suggest high efficacy at low doses.
[36] The ‘113 patent sets out a number of advantageous qualities of olanzapine. These can be grouped into two main categories. First, the patent identifies certain advantages of olanzapine over the other compounds from the ‘687 patent. Second, the ‘113 patent states that olanzapine is superior to other known antipsychotic drugs used in the treatment of schizophrenia and related conditions.
(a) Olanzapine’s advantages over the other ‘687 compounds
[37] As mentioned, the ‘113 patent says that olanzapine displays “surprising and unexpected properties” as compared to flumezapine and other related compounds; i.e. compounds of the ‘687 patent. There are four specific comparisons in the patent.
[38] The first two comparisons relate specifically to flumezapine. The patent summarizes Lilly’s experience with flumezapine, and the concerns about elevated liver enzymes and CPK. In contrast, the ‘113 patent states that patients treated with therapeutic doses of olanzapine experienced “a low incidence of only mild and transient elevation of liver enzymes”, and CPK levels were lower than with flumezapine.
[39] There is a third comparison with flumezapine regarding EPS. Early in the patent, the inventors explain that many antipsychotic drugs cause EPS. The patent also states that “[i]n clinical trials with flumezapine two of the patients showed the emergence of extra pyramidal side effects . . .” Immediately thereafter, the assertion appears that “[w]e have now discovered a compound which possesses surprising and unexpected properties by comparison with flumezapine and other related compounds”. Then, further on in the patent, the inventors state that olanzapine “is less likely to induce extrapyramidal side effects in the clinic”.
[40] The ‘113 patent also mentions a dog study in which olanzapine was compared with ethyl olanzapine, another of the ‘687 compounds. The patent reports the outcome of the study as indicating “that four out of eight dogs showed a significant rise in cholesterol levels, whereas the compound of the invention did not show any rise in cholesterol levels” at a dosage of 8 mg/kg.
[41] Therefore, the ‘113 patent explicitly compares olanzapine favourably to two other compounds of the ‘687 patent in respect of the following parameters:
• lower incidence of liver enzyme elevations compared to flumezapine;
• lower CPK levels than flumezapine;
• lower EPS than flumezapine; and
• no increase in cholesterol compared to ethyl olanzapine.
(b) Olanzapine’s advantages over other antipsychotic drugs
[42] The patent declares that olanzapine shows “surprising and excellent results” in experimental screens and clinical trials. In particular, olanzapine shows a “high level of activity in the clinical evaluation of psychiatric patients suffering schizophrenia” at doses lower than were expected based on animal models. The patent refers to the open-label study and preliminary results from three other ongoing clinical trials.
[43] The patent states that olanzapine caused a “low incidence of only mild and transient elevation of liver enzymes in patients treated with therapeutic doses”. Further, olanzapine “causes lower elevation of prolactin levels than other currently used neuroleptic drugs”.
[44] The patent also states that no alteration of white blood cell count was observed during clinical studies of olanzapine.
[45] These statements are followed by the following broad assertion about olanzapine:
Overall, therefore, in clinical situations, the compound of the invention shows marked superiority and a better side effects profile than prior known antipsychotic agents, and has a highly advantageous activity level.
[46] The introductory words of the sentence (“overall, therefore”) appear to preface a summary of the collective advantages of olanzapine in respect both of efficacy and the particular side effects discussed in the preceding passages. I will come back to this statement below when discussing the “promise” of the ‘113 patent.
[47] For the moment, however, I would simply point out that this statement, despite its apparent breadth, does not appear to assert the superiority of olanzapine in respect of all possible side effects. However, a fair interpretation of the patent is that it asserts the superiority of olanzapine in respect of the side effects specifically identified in it, including the ones that presented the greatest concern to schizophrenia patients – EPS and agranulocytosis. No antipsychotic would be considered to be markedly superior or have a better side effects profile than other antipsychotics if its EPS or agranulocytosis liability was disadvantageous.
[48] Therefore, the advantages of olanzapine over other antipsychotic drugs addressed in the ‘113 patent include:
• a high level of efficacy at low doses;
• lower elevation of prolactin;
• lower EPS liability; and
• no alteration of white blood cell count.
[49] There is also an implied comparison with respect to liver enzymes, given the linkage made between flumezapine and chlorpromazine in that area. The patent says that “in respect of its tendency to raise liver enzyme levels, flumezapine is similar to chlorpromazine, an antipsychotic which has long been in use but whose safety has been called into question”. However, it is unnecessary to discuss this characteristic separately as it is covered by the comparison with flumezapine.
IV. Other Federal Court Proceedings involving the ‘113 Patent
[50] The ‘113 patent was litigated in two previous applications before the Federal Court under the PMNOC Regulations. In the first, before Justice Johanne Gauthier, Lilly sought and obtained an order prohibiting the Minister of Health from issuing a Notice of Compliance [NOC] that would have allowed Apotex Inc. to make and sell a generic version of olanzapine (Eli Lilly Canada Inc v Apotex Inc, 2007 FC 455) [Lilly (1)].
[51] Justice Gauthier construed the ‘113 patent and found that it disclosed a number of advantages of olanzapine which, taken together, amounted to an assertion that olanzapine was “an antipsychotic that, in clinical situations, had overall a better profile than prior known antipsychotic agents (including the compounds encompassed in the ‘687 Patent)” (para 334).
[52] Apotex had alleged that the ‘113 patent was invalid on grounds of anticipation, obviousness, double patenting, and violation of s 53 of the Patent Act, RSC 1985, c P-4. Justice Gauthier found that Apotex’s allegations were not justified. However, she also found that the additional question of whether the ‘113 met the criteria for a valid selection patent was not properly before her as it had not been specifically alleged by Apotex. The Federal Court of Appeal confirmed that finding: Eli Lilly Canada Inc v Apotex Inc, 2008 FCA 44.
[53] In a separate proceeding under the PMNOC Regulations, involving, essentially, the same parties as are before me, Justice Roger Hughes concluded that the advantages described in the ‘113 patent amounted to a promise and had to be adequately described in the patent specification.
[54] He found that they were not adequately described, and that Novopharm’s allegation that the ‘113 patent’s disclosure was insufficient was justified. He refused to issue an order prohibiting the Minister from granting Novopharm a NOC to enter the olanzapine market (Eli Lilly Canada Inc v Novopharm Limited, 2007 FC 596) [Lilly (2)]. Soon thereafter, Novopharm obtained its NOC. Lilly launched an appeal, but the Federal Court of Appeal found the proceeding to be moot, given that Novopharm had already obtained its NOC (Eli Lilly Canada Inc v Novopharm Limited, 2007 FCA 359). By then, Lilly had commenced this action for infringement of the ‘113 patent.
[55] Justice Hughes addressed a key issue that was not before Justice Gauthier – whether the ‘113 is a valid selection patent – in particular, whether the ‘113 patent’s disclosure was sufficient. He found that the ‘113 patent failed to describe what the “surprising and unexpected properties” of olanzapine were in comparison with the other compounds of the ‘687 patent. On appeal, Lilly argued that Justice Hughes erred by requiring patents to set out comparative data. However, the Court did not agree that Justice Hughes had stipulated that comparative data were required in selection patents.
[56] The essence of Justice Hughes’ decision is set out in the following paragraph (para 162):
I find that the ‘113 patent fails to provide sufficient disclosure in its specification as to the invention, if any, in selecting olanzapine from a previously disclosed group of compounds. The prior art British Patent teaches the whole class of compounds [is] to be useful in treating central nervous system disorders. The invention in selecting olanzapine is the so called “surprising and unexpected” properties of olanzapine in “comparison with flumezapine and other related compounds”. No such comparison is made anywhere in the ‘113 patent. No data was given. We are left only with rhetoric such as “high level of efficiency” and “mild and transient” and “lower” side effects. The puzzling and scant mention of a dog study refers only to ethyl olanzapine and tells nothing of flumezapine or other compounds.
[57] Justice Hughes concluded that the ‘113 did not adequately distinguish between olanzapine’s qualities and the characteristics of the previously patented family of compounds, of which olanzapine was a member. Therefore, the ‘113 was not a valid selection patent.
V. The Federal Court of Appeal’s Approach to Selection Patents
1. The Trial Judgment
(a) The Nature of the Action
[58] Lilly alleged in its Statement of Claim that Novopharm’s generic version of olanzapine would infringe the ‘113 patent.
[59] Novopharm responded by alleging that the ‘113 patent was invalid on numerous grounds, including anticipation, obviousness, and double-patenting. In addition, Novopharm alleged that the ‘113 patent was an invalid selection patent, given that olanzapine fell within the claims of the ‘687 patent and failed to meet the criteria set out in long-standing case law, that selected compounds must be “previously undiscovered, constituting a special advantage, particular to themselves, not attributable to them by virtue of their belonging to the class of the [genus patent], and defined in clear terms in the specification” (Third Amended Statement of Defence and Counterclaim, para 14).
[60] In the same vein, Novopharm maintained that the ‘113 patent failed to satisfy the requirements for a valid selection patent because the “inventors of the ‘113 Patent had not made and tested a sufficient number of the compounds from the ‘687 Patent in order to support or soundly predict any of the asserted advantages in the ‘113 Patent and in particular the assertion that ‘overall, therefore, in clinical situations, the compound of the invention shows marked superiority, and a better side effect profile than prior known antipsychotic agents, and has a highly advantageous activity level’” (para 14.2). Further, according to Novopharm, Lilly did not have sufficient information to soundly predict that olanzapine would have the characteristics described in the ‘113 patent, or possess an articulable and sound line of reasoning to support that prediction, or provide proper disclosure in the patent (para 25).
[61] In its Reply and Defence to Counterclaim, Lilly disputed Novopharm’s assertion that the ‘113 was not a valid selection patent. Lilly contended that the ‘113 was a valid selection patent given that olanzapine has a number of substantial and peculiar advantages that are described in the patent. In addition, olanzapine has a better side effect profile than prior-known antipsychotic agents, has a high activity level at low doses, and a number of advantages over the compounds of the ‘687 patent. Lilly maintained that the ‘113 patent was a valid selection patent because olanzapine has special advantages that could not have been predicted before it was made and tested. In particular, olanzapine avoided problems associated with the compounds of the ‘687 patent, namely, elevation of liver enzymes, muscle enzymes, prolactin, and cholesterol, and did not cause blood disorders or EPS.
[62] Lilly also asserted that olanzapine had been proven, as of the filing date, to be an effective antipsychotic based on the clinical trials conducted to that point. Accordingly, the issue of sound prediction had no application. However, Lilly also contended that it had a factual basis for all of the characteristics of olanzapine promised in the ‘113 patent, had an articulable and sound line of reasoning supporting the prediction of those characteristics, and had provided proper disclosure in the ‘113 patent.
[63] As can be seen from the pleadings, the question of the ‘113’s validity as a selection patent was at the forefront of this action. The bulk of the evidence and the legal arguments surrounded that issue.
(b) The Reasons
(i) Utility
[64] In my original judgment, I started from the premise that a valid patent must disclose an invention. Section 2 of the Patent Act defines an invention as a “new and useful . . . composition of matter, or any new and useful improvement in any . . . composition of matter”. This is true of selection patents, just as it is with any other kind of patent. However, I noted that a selection patent must disclose an invention over and above what was contained in the prior patent – the “genus patent” – covering the selected compound. In other words, there must be something distinctly useful about the selected compound as compared to the class of compounds defined by the genus patent.
[65] I relied on Justice Marshall Rothstein’s statement that selection patents must define their utility. Justice Rothstein set out the relevant principles in Sanofi-Synthelabo Canada Inc v Apotex Inc, 2008 SCC 61, [2008] 3 SCR 265 [Sanofi-Synthelabo], relying on the well-known precedent of Re I.G. Farbenindustrie AG’s Patents (1930), 47 RPC 289 (Ch D) [Farbenindustrie]:
1. There must be a substantial advantage to be secured or disadvantage to be avoided by the use of the selected members.
2. The whole of the selected members (subject to “a few exceptions here and there”) [must] possess the advantage in question.
3. The selection must be in respect of a quality of a special character peculiar to the selected group. If further research revealed a small number of unselected compounds possessing the same advantage, that would not invalidate the selection patent. However, if research showed that a larger number of unselected compounds possessed the same advantage, the quality of the compound claimed in the selection patent would not be of a special character (para 10).
[66] I interpreted these principles as setting out a requirement that olanzapine have a substantial and peculiar advantage over the other compounds of the ‘687 patent. In addition, the patent must clearly describe the selected compound’s substantial and special advantage. Justice Rothstein said that “the specification of the selection patent [must] define in clear terms the nature of the characteristic which the patentee alleges to be possessed by the selection for which he claims a monopoly” (para 114).
[67] I then reviewed the ‘113 patent to determine what advantages were being asserted for olanzapine. I found there to be a general assertion in the ‘113 patent that olanzapine is superior to the class of compounds covered by the ‘687 patent. The patent states that olanzapine displays “surprising and unexpected properties” as compared to flumezapine and other related compounds. As described above, the patent specifies four examples of superiority in respect of two ‘687 comparator compounds (flumezapine and ethyl olanzapine). The patent says that olanzapine is better and different from those two compounds in the following respects:
(i) Olanzapine has lower elevations of liver enzymes than flumezapine;
(ii) Olanzapine has lower elevations of CPK than flumezapine;
(iii) Olanzapine has less EPS liability than flumezapine; and
(iv) Olanzapine does not elevate cholesterol, but ethyl olanzapine does.
[68] I did not find it necessary to refer to expert testimony to construe this aspect of the patent, given that the asserted advantages were clearly stated in the patent.
[69] I went on to consider the other advantages of olanzapine that are asserted in the patent. In this respect, I considered how a skilled reader familiar with the history of the development of anti-psychotics would read the patent. I found that “reading the ‘113 patent as a whole, the skilled reader, aware of the ‘687 patent, would interpret the alleged superiority of olanzapine over other antipsychotic drugs on the market as being another major advantage of olanzapine over the other ‘687 compounds” (Trial Judgment, para 53).
[70] While the ‘113 patent refers only to two of the ‘687 compounds and their disadvantages, it is clear that neither of them had been used for the treatment of schizophrenia or any other condition. By contrast, according to the ‘113 patent, not only could olanzapine be used for that purpose, it was, “overall”, markedly superior to, and had a better side effects profile than, other drugs on the market. That assertion related both to olanzapine’s efficacy and the particular advantages of olanzapine in respect of the side effects that were discussed in the patent. I found that a fair reading of that statement was that the patent “asserts the superiority of olanzapine in respect of the side effects specifically identified in it, including the ones that presented the greatest concern to schizophrenia patients – EPS and agranulocytosis” (Trial Judgment, para 47).
[71] As mentioned, the specific advantages of olanzapine over other antipsychotic agents as stated in the patent were:
(i) olanzapine has a high level of efficacy at low doses;
(ii) olanzapine has a lower elevation of prolactin;
(iii) olanzapine has lower EPS liability; and
(iv) olanzapine does not alter white blood cell counts.
[72] I considered whether one or more of these asserted advantages of olanzapine was known to exist, or could have been soundly predicted, at the time the ‘113 patent was filed in 1991. I reviewed the information known about the drugs with which olanzapine was compared and the main thrust of the expert evidence before me, then applied the test for sound prediction set out by Justice Binnie in Apotex Inc v Wellcome Foundation Ltd, [2002] 4 SCR 153 [AZT].
[73] I then determined whether at least one of those advantages could be considered a substantial advantage over the ‘687 compounds and somewhat peculiar to olanzapine. I also considered whether the disclosure of that substantial and special advantage in the ‘113 patent was adequate.
[74] I found that the evidence before me showed no advantage for olanzapine over other compounds of the ‘687 patent. Nor was there a sufficient factual basis to support a prediction that olanzapine would have the asserted advantages over those compounds. The tests that had been carried out by the relevant date simply could not support a prediction of any of those advantages. Further, I could find no articulable line of reasoning that would support a sound prediction of the advantages. Finally, the patent did not disclose any factual basis or line of reasoning that would permit a person skilled in the art to appreciate what the alleged invention - a superior compound to the ‘687 class – actually was.
[75] In addition, I found that the evidence before me showed no advantage, and no factual basis for a sound prediction of an advantage, for olanzapine in comparison with other antipsychotic agents. Again, the tests that had been carried out simply did not support a prediction of such an advantage. There was no evidence of a sound line of reasoning leading to a conclusion that olanzapine would display superiority over other drugs. Nor was there any disclosure in the patent of facts or reasoning that would support olanzapine’s alleged superiority.
[76] In turn, I considered whether, even if they had existed, the asserted advantages of olanzapine could be considered “substantial and peculiar”. I found the alleged advantages of olanzapine over flumezapine and ethyl olanzapine were not substantial. To the extent they existed at all, their magnitude was insignificant. Further, there was no evidence that olanzapine was superior to any other compounds in the ‘687 class in respect of the particular characteristics described in the ‘113 patent. The comparisons did not relate to the class as a whole and there was no evidence that any advantage was peculiar to olanzapine.
[77] On the other hand, I found that olanzapine’s alleged superiority over other antipsychotic drugs on the market would certainly have amounted to a substantia