Eli Lilly Canada Inc. v. Novopharm Limited, 2011 FC 1288 (2011)

Parts:Eli Lilly Canada Inc. v. Novopharm Limited
Reporting Judge:The Honourable Mr. Justice O'Reilly
Docket Number:T-1048-07
 
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Federal Court - Eli Lilly Canada Inc. v. Novopharm Limited

Source: http://decisions.fct-cf.gc.ca/en/2011/2011fc1288/2011fc1288.html

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...

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