Novopharm Limited v. Eli Lilly and Company, 2010 FC 915 (2010)

Parts:Novopharm Limited v. Eli Lilly and Company
Reporting Judge:The Honourable Mr. Justice Barnes
Docket Number:T-811-08
 
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Federal Court - Novopharm Limited v. Eli Lilly and Company

Source: http://decisions.fct-cf.gc.ca/en/2010/2010fc915/2010fc915.html

Federal Court

Cour fédérale

Date: 20100914

Docket: T-811-08

Citation: 2010 FC 915

Ottawa, Ontario , September 14, 2010

PRESENT: The Honourable Mr. Justice Barnes

BETWEEN:

NOVOPHARM LIMITED

Plaintiff and

ELI LILLY AND COMPANY

Defendant

REASONS FOR JUDGMENT AND JUDGMENT

[1] In this action Novopharm Ltd. (now known as Teva Canada Limited but hereafter referred to as Novopharm) seeks a declaration under ss. 60(1) of the Patent Act , R.S.C. 1985,c. P-4 (Patent Act) that Eli Lilly and Company's (hereafter referred to as Lilly) Canadian Patent No. 2,209,735 (the 735 Patent) is invalid and void.

[2] The ’735 Patent was filed in Canada on January 4, 1996 claiming priority to United States Patent application no. 08/371,341 filed on January 11, 1995 (the ’590 Patent). The ’735 Patent names Dr. John Heiligenstein and Dr. Gary Tollefson as the inventors and it claims the use of tomoxetine (renamed and referred to hereafter as "atomoxetine") to treat attention deficit hyperactivity disorder (ADHD) in adults, adolescents and children.

[3] In its Statement of Claim Novopharm asserts that as an interested party [1] it is entitled to bring this proceeding under ss. 60(1) of the Patent Act . It alleges that each of the 16 claims of the ’735 Patent are invalid on the grounds of obviousness, incomplete disclosure concerning the selection of atomoxetine from an earlier genus patent, anticipation, and inutility. Lilly's Statement of Defence asserts the validity of the ’735 Patent. Lilly pleads that none of the prior art publications relied upon by Novopharm either anticipated the invention or made it obvious to a person skilled in the art. Lilly also maintains that the ’735 Patent is not a selection patent, but rather, claims a new and inventive use for atomoxetine. Finally, Lilly pleads that it "had established that atomoxetine was effective in the treatment of ADHD" as of the Canadian filing date "by virtue of studies that had been conducted". Although Lilly denies that any issue of sound prediction of utility arises it pleads, in the alternative, that "there was a factual basis for the alleged predictions" and "there was an articulable and sound line of reasoning from which the desired result could be inferred".

I. Background

The Trial and the Evidence Generally

[4] The trial of this action proceeded at Toronto , Ontario between May 11, 2010 and June 9, 2010. Testimony was received from six witnesses including three experts on behalf of Novopharm (Dr. Stanley Kutcher, Dr. Adil Virani and Dr. Mark Riddle) and one expert on behalf of Lilly (Dr. James McGough). In addition, fact evidence was given by one witness from Novopharm and one witness from Lilly. Discovery evidence taken from one of the ’735 Patent inventors, Dr. John Heiligenstein, was accepted by the Court on consent of the parties.

[5] Unfortunately and for reasons that were not made clear to me, Lilly was not able to secure the voluntary attendance of any witness with direct knowledge of the Massachusetts General Hospital clinical study (the MGH Study) that constituted Lilly's evidence of utility. This was surprising because Lilly was the sponsor of the MGH Study clinical trial and had provided the necessary resources for its completion. An attempt by Novopharm to obtain this evidence by commission was, notwithstanding the Lilly's concurrence, resisted by the Massachusetts General Hospital and the evidence in that form was not presented. I was, therefore, left in the unsatisfactory position of assessing the merits of the MGH Study in the absence of evidence from any of the several witnesses who were best placed to defend it and to discuss the significance of its data. What was offered in substitution was the evidence from witnesses who had no direct involvement in the MGH Study and who were required to assess its strengths and limitations from the incomplete information contained in the Study report. Nevertheless, I draw no inference from the absence of the best evidence on this issue. My conclusions about the value of the MGH Study are necessarily based on the strength of the evidence before me.

[6] The expert evidence tendered by Novopharm consisted of the reports and testimony of Dr. Virani, Dr. Riddle and Dr. Kutcher. The primary focus of Dr. Virani's evidence concerned the significance of the MGH Study in proof of atomoxetine's efficacy as an ADHD drug. The evidence of Dr. Riddle and Dr. Kutcher primarily addressed the prior art as it related to the issues of anticipation and obviousness. Dr. McGough addressed all of these issues on behalf of Lilly.

[7] All of the expert witnesses were well qualified to speak to the issues for which they were called. There was little, if any, disagreement among them as to the definition of the person of skill in the art [2] or about what was generally known about ADHD and its treatment. They were also in general agreement about how psychotropic drugs were, at the relevant time, understood to affect the transmission of signals between brain neurons (see, for example, the evidence of Dr. McGough at paragraphs 17 to 35 of Exhibit 1 to his report and the evidence of Dr. Riddle at paragraphs 28 to 36 of his report).

[8] In the end the disagreement among the experts concerning the prior art rested on a fundamental difference about how likely it would have been to a person of skill in the art that atomoxetine ought to work to treat ADHD. Dr. Riddle and Dr. Kutcher opined that the efficacy of atomoxetine would have been self-evident because its profile closely matched those of several other successful ADHD drugs. Dr. McGough candidly acknowledged that atomoxetine would have been an interesting compound for study as an ADHD drug but that no prediction of its usefulness could have fairly been drawn from the available prior art. This disagreement seemed to me to be based on honestly held differences about the predictive value of the prior art concerning the likelihood that atomoxetine ought to work.

[9] The disagreement between Dr. Virani and Dr. McGough concerning the value of the MGH Study was no less fundamental. Dr. Virani described the MGH Study as a pilot with so many methodological limitations that its data were only preliminary and, at best, interesting. According to Dr. Virani, a far more exacting clinical trial would have been needed to establish atomoxetine's effectiveness as an ADHD drug. Dr. McGough's contrary view was essentially that the MGH Study data were proof of atomoxetine's efficacy because they showed, in a statistically significant way, that atomoxetine had worked to treat several of the patients studied for at least the duration of the trial. This permitted Dr. McGough to discount the significance of the methodological issues that were identified by the MGH Study team, by Dr. Heiligenstein and by Dr. Virani. This, too, seemed to me to be a principled disagreement arising from different views about what depth or quality of research is required to prove the utility of a medicinal compound.

Attention Deficit Hyperactivity Disorder

[10] ADHD is a common neurobehavioral disorder that occurs in children, adolescents and adults. It is characterized by age inappropriate hyperactivity, inattention and impulsivity and it often causes functional impairments in school, at work and in social settings. According to the Diagnostic and Statistical Manual of Mental Disorders there are three subtypes of ADHD:

(a) primarily inattentive;

(b) primarily hyperactive/impulsive; and

(c) a combination of the other two types.

[11] The cause or causes of ADHD are unknown and it has no cure. Nevertheless, the symptoms of ADHD can, in many cases, be successfully ameliorated.

[12] Since the 1950s ADHD has most often been treated with stimulant therapy, and this remains the first line treatment choice. The stimulants, though, did not work for every patient. For some patients with co-morbidities or with substance abuse issues, the stimulants were not appropriate. For other ADHD sufferers the stimulants simply did not work. This led to a search for alternative therapies and by at least the 1970s non-stimulant medications began to be used off-label as second-line treatment choices. Since that time, the most commonly utilized non-stimulant medications have been the tricyclic antidepressants or TCAs (e.g. imipramine, desipramine and nortriptyline), alpha-2 adrenergic agonists (e.g. clonidine and guanfacine) and bupropion. These drugs, though, came with their own set of limitations including less than desirable side-effect profiles. Accordingly, the search for alternative drug therapies continued and it was out of that effort that atomoxetine emerged.

The Development of Atomoxetine

[13] Dr. Martin Hynes gave evidence on behalf of Lilly concerning the development of atomoxetine. He testified that the compound first came to his attention in 1979 as a result of antidepression research Lilly was conducting on the racemate nisoxetine. During the next decade Lilly sponsored a number of studies looking at atomoxetine as an antidepressant.

[14] In the early 1980s, Lilly scientists reported the discovery that atomoxetine was a potent isomer of nisoxetine with a "remarkable specificity in inhibiting the uptake sites of [norepinephrine]". This characteristic was postulated to offer an advantage over the TCAs in the treatment of depression.

[15] Further published research by Lilly from 1983 and 1984 appeared to confirm atomoxetine's potential to treat depression on the basis of its selective inhibition of the reuptake of norepinephrine in animals and in humans.

[16] In a May 1984 paper authored by Chouinard and others [3] atomoxetine was reported to be an efficacious antidepressant medication in eight of 10 patients treated in an open study. Atomoxetine was also...

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