Novopharm Limited v. Eli Lilly and Company

Novopharm Limited v. Eli Lilly and Company
Court (s) Database
Federal Court Decisions
Date
2010-09-14
Neutral citation
2010 FC 915
File numbers
T-811-08
Decision Content
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 reported to have no sedative effects. The observed mood elevating effect and the reported side effects of insomnia, agitation, palpitations and abdominal spasm were speculated to be the result of atomoxetine's noradrenergic action.
[17] As of January 1988, Lilly had supported no less than seven clinical studies of atomoxetine in humans which examined the drug’s potential to treat depression. Two of those studies were open and uncontrolled and five were double-blind and controlled. One of the controlled studies [HFAB] was a multicenter, randomized, double-blind, parallel study which compared atomoxetine to placebo in 243 patients with major depression disorder. The results of this study showed that atomoxetine was statistically superior to placebo. Nevertheless, the other controlled clinical trials for atomoxetine either lacked sufficient enrollment to permit analysis or showed no significant benefit. All of Lilly's research into atomoxetine as an antidepressant was terminated in 1991 because of the inability to establish its efficacy for that indication.
[18] At a meeting of the American Academy of Child and Adolescent Psychiatry in late 1994, Dr. Heiligenstein had a discussion with Dr. Thomas Spencer of the Massachusetts General Hospital (MGH) about the development of a new ADHD medication. Dr. Spencer was, at that time, a leader in this area of research and was interested in securing Lilly's support for his work. Dr. Heiligenstein suggested that Dr. Spencer might want to look at atomoxetine which was then on Lilly's "shelf" and they agreed that atomoxetine might be a good candidate for further research. Both took the idea back to their respective employers and quickly obtained the necessary approvals to develop a research protocol. By the end of 1994 an agreement between Lilly and MGH was in place to jointly sponsor a clinical trial of atomoxetine as a treatment for ADHD. Dr. Heiligenstein's evidence described the subsequent steps as follows:
A What happened is that the -- I was on the agenda to present, so I would have -- I was planning to present for the last meeting of 1994 before the holiday break. And due to other business, they took me off the agenda, and so it -- it required an approval independent of the typical process of the presentation. And I went to my boss, Dr. Tollefson, and said we’ve been bumped, we need to get this study launched because of the expiry date of the material, and if we wait until after the new year, the study will never get done, so he went to the committee, probably twisted a few arms and was successful in getting approval without my making a presentation.
Q Okay. And obviously you weren’t at that meeting, so you don’t know exactly what he had to say to get that?
A I don’t.
Q So you say the last meeting of 1994. I take it that was before the Christmas break, so sometime in December, early December?
A It would have been probably the week or two before Christmas holiday.
Q Okay. And do you recall how -- was the approval immediate, so that he came back from that meeting --
A Came back to me immediately and said it’s a go. So we did the -- we -- I called the Mass General group to let them know that we had approval, that we would be shipping drug and placebo, that the budget had been approved, that their protocol -- internally within the neuroscience group, we had enough information that we felt comfortable with it.
Q Okay.
A So they could then move forward with the study.
Q And were they the prime authors of the protocol?
A Were they the prime authors? It was a collaborative effort, but I would say that, you know, because of the exempt process, they had to have a larger role, but in terms of our involvement, we had considerable involvement because of the -- some review of the protocol, you know, inquiry into the instruments, assessments, the laboratory, you know, we -- I don’t recall specifically, but we may have had some unique interest in the laboratory studies, approval of a budget; provision of data, as I said earlier, from the safety profile of the drug would have been necessary. There had to be correspondence with our regulatory group for them to secure approval to file for an independent from ND, so there was -- there was mutual activity around the whole notion.
Q Okay. So in terms of the -- the number of subjects that were going to be looked at in the context of the study, you would have had some involvement in developing that part of the protocol?
A The number of subjects to be enrolled in the study, there would have been some discussion, but one could not -- I think, as I recall the original -- it’s very fuzzy -- was hoping to get maybe 30 patients, I can’t remember, but we knew that that was, you know -- in the limited time frame, because the drug material expired April the 1st, 1995, that to -- to screen and approve patients would be a stretch, you know, a number of subjects for the study, so we weren’t sure that we’d get to 30. In fact, we did not.
[19] Dr. Heiligenstein characterized the MGH Study as a "pilot" designed to test the hypothesis that atomoxetine "might be useful in treating ADHD".
[20] The MGH Study protocol called for the enrollment of 40 well characterized ADHD patients but ultimately 22 adult patients were selected. The MGH Study was designed as a double-blind, placebo-controlled, cross-over evaluation. This involved the blinded exposure of one half of the patients to placebo and one half to atomoxetine for three weeks. After a one week washout period the patient groups were switched. The assessment measures included standardized patient interviews and other neuropsychological tests designed to measure sustained attention. Testing was administered before exposure and after each arm of the study. The data obtained indicated a positive and statistically significant response rate for atomoxetine over placebo that met the predetermined standard set by the evaluators. The conclusions contained in the initial draft report were expressed by the MGH researchers in the following way:
Treatment with tomoxetine was well tolerated. All but one patient completed the study, the avenge dose attained was very close to the targeted dose, and no serious adverse effects were observed. While common adverse effects included appetite suppression, insomnia. constipation and dry mouth, the only symptom that occurred statistically more often on tomoxetine was appetite suppression. This relatively benign adverse effect profile is even more remarkable considering that, because only tablets of 40 mg were available, the study had a limited ability for slow adjustments of dose.
Tomoxetine differs from existing antidepressants in being selectively noradrenergic. It has little affinity for other neurotransmitter systems and minor effects on cardiac conduction, repolarization or function. Our findings confirm the expected high tolerability, low side effect profile and cardiac neutral status of tomoxetine in this sample of ADHD adults at a clinically effective dosage. Since noradrenergic activity appears to be shared by other compounds that have shown efficacy In ADHD (11), the efficacy of tomoxetine shown in this study provides further support for a noradrenergic hypothesis of the disorder.
The results of this study should be viewed in light of methodological limitations. These include the use of a crossover design, a relatively short exposure to medication, and dosing restrictions. Since a previous study of a noradrenergic antidepressant (10) found that the full extent of anti-ADHD action was not apparent until at least 6 weeks, it is possible that our results underestimate the effectiveness of long term tomoxetine treatment. Furthermore, medication carry-over effects can produce unwanted confounds in a crossover study. While order effects did not reach statistical significance in the current study, a parallel design would be optimal. Nevertheless, reduction in ADHD symptoms was robust enough to be detectable in a parallel groups comparison. Lastly, while 80 mg. of tomoxetine was well tolerated, it is unclear whether this is the optimal dose for anti-ADHD efficacy. Open dose-response trials to determine the optimal anti-ADHD dose of tomoxetine may provide guidance for subsequent controlled trials.
Despite these limitations, this study has shown that tomoxetine significantly improved ADHD symptoms and was well tolerated. Although preliminary, these promising initial results provide support for further studies of tomoxetine in the treatment of ADHD using a wide range of doses over an extended period of treatment.
[21] As a result of the findings of the MGH Study, Lilly established a working group chaired by Dr. Hynes to further examine three ADHD drug candidates, one of which was atomoxetine. Eventually atomoxetine was chosen by Lilly for development, and regulatory approval was obtained in the United States on November 26, 2002 and in Canada on December 24, 2004. Atomoxetine has since been marketed by Lilly under the trade name STRATTERA.
II. Issues
[22] What is the standard of proof required?
[23] Was Lilly’s claim that atomoxetine could be used to treat ADHD obvious to person of skill in the art?
[24] Was the ’735 Patent anticipated by either the ’009 Patent or the ’430 Patent?
[25] Was the ’735 Patent anticipated by prior disclosure by the inventor, John Heiligenstein?
[26] Is the ’735 Patent a selection patent requiring elevated disclosure of its alleged inventive promise?
[27] As of the Canadian filing date of the ’735 Patent, did Lily have evidence that demonstrated the utility of atomoxetine to treat ADHD in humans and, if not, did the ’735 Patent meet the requirements of disclosure for a sound prediction of such utility?
III. Analysis
Standard of Review and Burden of Proof
[28] The parties agree that Novopharm bears the burden of proof on a balance of probabilities of establishing the invalidity of the ’735 Patent. Lilly contends, though, that the decision of the Supreme Court of Canada in Apotex Inc. v. Wellcome Foundation Ltd., 2002 SCC 77, 21 C.P.R. (4th) 499 (hereafter referred to as AZT) superimposes the administrative standard of review of reasonableness for issues of mixed fact and law where the validity of a patent is in issue. In other words, Lilly says that to the extent that the decision of the Commissioner to approve the ’735 Patent was based on evidence, the decision is entitled to a degree of deference.
[29] It is not entirely clear to me what was meant by Justice Ian Binnie in the discussion in AZT, above, about the administrative standard of review and, like Justice Johanne Gauthier in Eli Lilly & Co. v. Apotex Inc., 2009 FC 991, 80 C.P.R. (4th) 1, I think its application ought to be limited to statutory appeals brought under s. 41 of the Patent Act, R.S.C. 1985, c. P-4. Justice Binnie himself noted at para. 41 that the degree of expected deference due to the Commissioner was “limited” and had to be applied with a recognition that, notwithstanding the Commissioner’s expertise, the judicial record included considerable evidence that was not available to the Commissioner. As was noted by Justice Gauthier in Eli Lilly & Co. v. Apotex Inc., above, it is difficult to reconcile the concept of reasonableness with a process of subsequent trial review that is based on a judicial record that does not correspond to the initial administrative record, where the administrative record is not before the Court, and where no reasons are provided by the Commissioner in support of the decision to approve a patent.
[30] It seems to me that, to the extent that any deference is owed to the Commissioner in cases like this one, it is completely subsumed by the presumption of validity created by ss. 43(2) of the Patent Act, R.S.C. 1985, c. P-4 and is essentially extinguished where any evidence to the contrary is placed before the Court.
[31] I will, therefore, proceed on the basis that Novopharm bears the onus of establishing on a balance of probabilities the grounds of invalidity it asserts.
’735 Patent
[32] There is no dispute about the inventive promise of the ’735 Patent. The 16 patent claims involve the use of atomoxetine for treating ADHD in three of its manifestations among all age groups (children, adolescents and adults). The patent does not claim the compound atomoxetine but only its use to treat ADHD. The patent does not assert nor would it have been expected by a person of skill that atomoxetine would work for every person.
[33] The patent specification sets out a non-controversial history of ADHD and the then-current treatments of choice for the disorder. The oldest and largely successful medications are said to be a class of stimulants which includes methylphenidate. Other effective drugs, it states, are antidepressant tricyclics including imipramine, desipramine, nortriptyline, amitriptyline and clomipramine. Nevertheless, the side-effects and usage limitations of the available treatments created a “need for a safe and convenient treatment for ADHD” which, in turn, led to “the present invention” (’735 Patent at p. 2, lines 3-4, 7).
[34] The patent acknowledges that atomoxetine “is a well-known drug” with a recognized mechanism of activity as a norepinephrine reuptake inhibitor (’735 Patent at p. 2, line 15). The specification also states the following:
Tomoxetine is quite active in that function, and moreover is substantially free of other central nervous system activities at the concentrations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.
Tomoxetine is a notably safe drug, and its use in ADHD, in both adults and children, is a superior treatment for that disorder because of its improved safety. Further, tomoxetine is effective at relatively low doses, as discussed below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of patients, particularly children and disorganized adults, are completely avoided (’735 Patent at p. 2, lines 21-35).
[35] The specification also contains preferred dosage ranges for children and adults but ultimately defers this question to the judgment of the treating physician[4]. The specification concludes with the statement that “there is no significant difference in the symptoms or the details of the manner of treatment among patients of different ages” (’735 Patent at p. 7, lines 21-23).
[36] As with the ’590 Priority Patent, the ’735 Patent offers no information about the nature or sources of the evidence relied upon by the inventors to support the promise of atomoxetine’s utility to treat ADHD by demonstration or by sound prediction.
Obviousness: Legal Principles
[37] In Sanofi-Synthelabo Canada Inc. v. Apotex Inc. , 2008 SCC 61, 69 C.P.R. (4th) 251 the Supreme Court of Canada considered the issue of obviousness in the context of a challenge to the validity of a pharmaceutical selection patent. The decision is particularly instructive in a case where the line of inquiry pursued by an inventor would be thought by others to be at least promising or with a semblance of a chance of success. Although the Court accepted that "obvious to try" was one of several factors that should be considered, it also said that this consideration needed to be applied with caution and with particular regard to the need to encourage pharmaceutical research and development. The obvious-to-try test was said to be satisfied only where it was self evident that what is being tried ought to work.
[38] At paragraph 67 the Court adopted the following four step framework for an obviousness inquiry:
(a) identify the notional person skilled in the art and the relevant common general knowledge of that person;
(b) identify the inventive concept of the claim or claims in issue and, if necessary, construe them;
(c) identify the differences, if any, between the “state of the art” and the inventive concept of the patent; and
(d) viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention.
[39] It is only at the fourth step of the above analysis that "obvious to try" will arise. I would add to this that what may be obvious to examine may not be obviously useful if more than simple verification is required in proof. The obvious to try analysis will, in each case, turn on several further considerations including the number of available options or solutions to the problem, the nature and extent of effort required to achieve the invention (routine trials versus prolonged or arduous experimentation), the extent to which others had tried and failed to find a solution, and the degree of motivation to find a solution. Ultimately if the evidence only establishes the possibility that a promising compound or approach might work, obviousness is not made out: see Apotex Inc. v. Pfizer Canada Inc., 2009 FCA 8, 72 C.P.R. (4th) 141 at para. 45.
Obviousness: The Evidence
[40] As previously noted, the parties were in essential agreement in their characterization of a person skilled in the art and with respect to the inventive concept of the '735 Patent. What was contested was whether the prior art established that the identification of atomoxetine to treat ADHD was obvious or uninventive. The point of particular evidentiary controversy was whether, in 1995, it was obvious that atomoxetine ought to work to treat ADHD based on the established efficacy of several medications with arguably similar selectivity profiles. This disagreement largely centred around the fourth step of the Sanofi obviousness inquiry.
[41] It was acknowledged by all of the witnesses that the causes of ADHD have always been unknown and I accept Lilly’s point that understanding the etiology of a disease or disorder can be an important element in the search for an effective treatment. That is particularly true where the looked-for treatments would be curative. It is important to recognize, though, that the drugs that have been found helpful to treat ADHD do not alter the underlying pathophysiology of the disorder. Instead, they provide temporal relief from its symptoms. Although there is much that is not known about the etiology of ADHD, that lack of knowledge has not prevented the development of drugs useful in reducing its symptomology.
[42] The identification of atomoxetine as one such agent was not unduly hindered by the underlying uncertainty about the precise causes of ADHD just as had been the case with the stimulants and the TCAs. Here I accept the evidence of Dr. Kutcher that the search for psychotropic medication has typically been carried out in steps. First, a helpful agent and its properties are identified. The focus then moves to discovering or developing agents that would be even more selective for the desirable characteristics or less prone to causing unwanted side-effects. That was the process followed in the development of the TCAs where imipramine led to desipramine, amitriptyline led to nortriptyline, and clonidine led to guanfacine: see para. 78 of Dr. Kutcher’s report and pp. 405-408 of his direct examination.
[43] Dr. McGough also recognized this approach in his cross-examination:
Q. That was like the development from imipramine to desipramine and amitriptyline to nortriptyline?
A. So the body, when it takes amitriptyline, turns it into nortriptyline, and when it takes imipramine turns it into desipramine. So out of that understanding that perhaps that was what was having the positive effect, they developed a more specific molecule (p. 2314).
[44] It seems to me that the more problematic etiological issue concerns the level of knowledge in 1995 about why the successful ADHD drugs worked. Without a sound understanding of the mechanism of action involved in achieving treatment, it is a profoundly more difficult task to predict whether a promising drug candidate ought to work.
[45] The question for the Court is whether the step taken by the named inventors identifying atomoxetine as a useful drug for treating ADHD was inventive or, conversely, more or less self evident. On the evidence before me I have no doubt that a person skilled in the art would be interested in looking at atomoxetine as a potential ADHD drug because of its known profile as a selective norepinephrine reuptake inhibitor (NRI) and because it had been used uneventfully in earlier depression research. The more difficult question is whether such a person would have concluded that atomoxetine ought to be useful to that end.
[46] Dr. John Heiligenstein is one of the inventors named in the ’735 Patent. Dr. Heiligenstein’s evidence from discovery was tendered at trial by agreement of the parties. That evidence indicated that the idea of using atomoxetine to treat ADHD came to Dr. Heiligenstein during his job interview with Lilly in 1985 or 1986. It is clear from that evidence that it was atomoxetine’s profile as a selective NRI that attracted his immediate interest. That evidence was as follows:
Q So as I understand it, you can correct me if I’m wrong, but you – you came up with the idea to look at tomoxetine in connection with ADHD; is that fair?
A Yes.
Q And where were you at that point in time in terms of the positions that we ran through?
A My first expression of interest in the study of tomoxetine for ADHD occurred during my interview, my first interview at Lilly with Dr. Leigh, L-E-I-G-H, Thompson, who was at that time the executive director of medical. That was the first occurrence.
Q So that was the first time you had mentioned it in the context of those positions with Lilly, but I take it you didn’t just come upon that idea when you were sitting there in the interview.
A I did.
Q Oh, you did?
A Yes.
Q And that was just through the discussion in the course of the interview?
A Yes.
Q Was that a – was that a – was it a job interview or was it a welcome to Lilly sort of interview?
A It was a job interview.
Q So this would be in around 1986, then?
A It would have been in ’85, ’86. I can’t recall when that interview occurred.
Q Okay. Prior to actually getting the job at Lilly, though?
A Yes.
Q Do you recall, I’m just curious, what – if you recall, what about that discussion caused you to put the two together? I know it’s a long time ago.
A The two being tomoxetine for ADHD?
Q Correct.
A Yes, I do recall.
Q Okay.
A Dr. Thompson was reviewing the molecules in development that I would be involved with if I were to join Lilly, and as he described the primary mechanisms of action and I noted the noradrenergic, primary noradrenergic uptake activity of tomoxetine, I said oh, that would be an interesting molecule to try in ADHD. (pp. 26-28)
[47] Dr. Riddle also testified about a conversation he had in 1991 or 1992 with Dr. Heiligenstein concerning the use of atomoxetine to treat ADHD. Dr. Heiligenstein had no recollection of this discussion and I have no basis to doubt that a discussion of this sort took place. Dr. Riddle’s evidence was as follows:
And John Heiligenstein sort of served as, chaperon’s not the right thing, but John was kind of my guide to take care of me while [sic] was there during the day. Because I had met for a couple of hours with he and Leigh Thompson and a few other folks. But the rest of the time I was there, he was with me, showed me around a bit, we had lunch together.
And we were chitchatting and talking about various things. We are both child psychiatrists, both interested in child psychiatric disorders and drug development. And I said, ‘John, besides what’s going on here with Prozac, the other thing that’s going on for me is that we were really getting really excited about desipramine and then in the summer of 1990 there is this reportedly sudden unexplained deaths, and we look into it and there are more reports’. And we all got concerned about ‘do we want to continue to do that’.
And I actually had come back from vacation that summer planning to write a grant to, you know, study more desipramine. And I said ‘you don’t have anything, we don’t have anything to replace it, you know, do you have any ideas’. And he says ‘well, you know, we have this norepinephrine reuptake inhibitor, tomoxetine, that has failed at trials for depression and, as you probably know, it’s sort of on the shelf’. And I was like, ‘geez, you know, you ought to try that for ADHD’. And that was pretty much the end of that conversation. John didn’t get excited about that and didn’t want to continue it, but that was pretty much that (pp. 1420-1421).
[48] Both Dr. Riddle and Dr. Heiligenstein undoubtedly had higher degrees of inventive ingenuity at the time of these discussions and would thus not fit the more restrictive definition of persons skilled in the art. Nevertheless, it is clear from this evidence that in considering atomoxetine as an ADHD drug, Dr. Riddle and Dr. Heiligenstein were not applying any more insight to the problem than would be expected from such a person. Indeed, the fact that the idea came so readily to both of them in the context of informal discussions indicates that they each thought that atomoxetine was at least a promising candidate for the treatment of ADHD. It was also clear to both of them that it was the relative selectivity of atomoxetine as an NRI that made it particularly interesting.
[49] Notwithstanding Lilly’s contention to the contrary, the overwhelming weight of the evidence established that a promising line of investigation for non-stimulant medications to treat ADHD involved compounds like atomoxetine that interacted with the norepinephrine pathway. Atomoxetine was a particularly obvious candidate because it was available and had been the subject of prior assessment in human trials as a potential antidepressant. Those studies had indicated its clinical safety. This was undoubtedly what prompted Dr. Riddle and Dr. Heiligenstein to readily identify atomoxetine as a good candidate for ADHD research when the compound was initially brought to their attention. I accept Dr. Riddle’s characterization at para. 128 of his report that “there were only a limited number of options available” of which atomoxetine was clearly one. During direct examination Dr. Kutcher also testified that there were only a finite number of known drugs the skilled person could have thought would work for ADHD and that “atomoxetine was one of those drugs” (p. 428). Dr. McGough essentially conceded that atomoxetine was a promising candidate for further study when he said under cross-examination that it “would be a very worthwhile agent to try and hope that it worked, but there would be no presumption that it would work” (p. 2410). These views are consistent with the weight of the prior art which implicated the noradrenergic pathway in ADHD and in the treatment of its symptoms. What is telling about these sources is, however, the highly qualified language that is used to express the postulate that drugs used to treat ADHD in some way impact the noradrenergic system. Several examples of this from the prior art evidence before me are as follows:
• “However, ample evidence has been amassed that some drugs effective for ADD alter noradrenergic turnover”: Alan J. Zametkin & Judith L. Rapoport, “Neurobiology of Attention Deficit Disorder with Hyperactivity: Where Have We Come in 50 Years?” (1987) 26(5) J. Am. Acad. Child Adolesc. Psychiatry 676 at 678;
• “Moreover, the significant reduction in urinary MHPG after desipramine, which is moderately efficacious in ADDH, also implicates the noradrenergic system”: Alan J. Zametkin & Judith L. Rapoport, “Neurobiology of Attention Deficit Disorder with Hyperactivity: Where Have We Come in 50 Years?” (1987) 26(5) J. Am. Acad. Child Adolesc. Psychiatry 676 at 678;
• “A role for the noradrenergic system in ADHD is further suggested by the efficacy of clonidine in reducing disruptive behaviours in some children with ADHD”: Steven R. Pliszka, James T. McCracken & James W. Maas, “Catecholamines in Attention-Deficit Hyperactivity Disorder: Current Prespectives” (1996) 35(3) J. Am. Acad. Child Adolesc. Psychiatry 264 at 268;
• “Since DMI has a powerful and selective inhibitory effect on the neuronal uptake of noreprinephrine and alters its metabolism and effects on adrenergic receptors in the mammalian brain, these findings may suggest that the somewhat delayed anti-ADDH effects of DMI, like its anti-depressant effects may be related to the drug’s actions on this central neurotransmitter system by actions partly shared with those of the stimulants”: Joseph Biederman et al., “A Double-Blind Placebo Controlled Study of Desipramine in the Treatment of ADD: I” (1989) 28(5) J. Am. Acad. Child Adolesc. Psychiatry 777 at 783;
• “Today competitive inhibition is not described as a mechanism of action of amphetamine upon noradrenergic systems, but there is certainly evidence that some drugs effective for ADDH decrease noradrenergic turnover”: see Zametkin and Rapoport “The Pathophysiology of Attention Deficit Disorder with Hyperactivity – A Review” Alan J. Zametkin & Judith L. Rapoport, “The Pathophysiology of Attention Deficit Disorder with Hyperactivity” (1986)(9) Adv. Clinical Child Psychology 177 at 187;
• “The antidepressants are slower-acting medications that have been shown to produce behavioural effects similar to those of the stimulants with ADHD children. This is presumably due to their agonistic effects on the noradrenergic system as obtained with the CNS stimulants”: Russell A. Barkley, Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (New York: The Guilford Press, 1990) at 607;
• “Although several lines of evidence support a role for the noradrenergic systems in both the pathophysiology of ADDH and mediation of drug response, major questions remain”: Alan J. Zametkin & Judith L. Rapoport, “The Pathophysiology of Attention Deficit Di