STRATTERA – DIVERGENT RESULTS IN CANADA AND THE UNITED STATES April 4, 2012 Patrick S. Smith

2 DIVERGENT RESULTS As will be discussed in STRATTERA, for all practical purposes the findings of fact and relevant statutory sections are the same in Canada and the United States The patents at issue claim the use of atomoxetine hydrochloride for use in the treatment of ADHD The United States application was filed before the results of a clinical trial was received by the patentee – the U.S. Patent was found to be valid The positive clinical trial results were received before the Canadian application was filed – yet the Canadian Patent was found to be invalid

3 RESULTS OF VALIDITY CHALLENGES U.S. Trial Decision -Patent invalid for something the Trial Judge refers to as “lack of enablement/utility” Eli Lilly and Co. v. Actavis Elizabeth LLC et al., 731 F. Supp. 2d 348 (D.N.J. 2010) U.S. Court of Appeal for the Federal Circuit -Trial decision overturned -Disclosure sufficient -Invention has utility Eli Lilly and Co. v. Actavis Elizabeth LLC et al., Appeal No (Fed. Cir. July 29, 2011) Canadian Trial Decision -Not enough testing to demonstrate long term clinical effectiveness -Patent invalid for want of disclosure of sound prediction Novopharm v. Eli Lilly and Co., 2010 FC 915, 87 C.P.R. (4 th ) 301 Canadian Appeal Decision -Upholds trial decision Eli Lilly and Co. v. Teva Canada Ltd. (formerly known as Novopharm Ltd.), 2011 FCA 220, 94 C.P.R. (4 th ) 95

4 BACKGROUND ON ADHD ADHD is a complex, chronic and inheritable neurobiological disorder that is characterized by a developmentally inappropriate level of inattention, hyperactivity and impulsiveness. The prevalence of ADHD is about three to five percent in school-age children. Up to 60% of patients with childhood ADHD carry symptoms into adulthood. Academic achievement is often impaired, leading to conflict with family and school authorities. Familial relationships are often strained because parents believe that the afflicted child’s troublesome behaviour is willful. Symptoms of hyperactivity in adults include holding multiple jobs, difficulty in participating in sedentary activities, and avoiding jobs and hobbies that provide limited opportunity for constant motion. U.S. Trial Decision – p. 5

5 KNOWN TREATMENTS FOR ADHD No cure but symptoms can be ameliorated Stimulants -controlled substances (diversion/substance abuse potential) -not effective for all patients -in early 1990’s, no sustained release version -stigma including principal office visits Tricyclic Antidepressants -not as effective as stimulants -in early 1990’s, desipramine implicated in sudden death of some children U.S. Trial Decision, pp. 6, 16, 25 Canadian Trial Decision, pp. 6, Lilly’s Strattera atomoxetine hydrochloride was the first non-stimulant ADHD drug approved by the FDA and Health Canada

6 THE STRATTERA ATOMOXETINE HYDROCHLORIDE STORY Atomoxetine first synthesized by Lilly scientists around 1980 Throughout the 1980’s, Lilly conducted clinical studies on the use of atomoxetine in the treatment of depression The totality of these clinical trials lead to the abandonment of atomoxetine for use in depression These Lilly studies (mostly unpublished) did show that atomoxetine was well tolerated by patients U.S. Trial Decision, p. 51 Canadian Trial Decision, pp. 7-8

7 ATOMOXETINE AND ADHD Two Lilly scientists conceived that atomoxetine may be effective in the treatment of ADHD One of the Lilly scientists, Dr. Heiligenstein (a child psychiatrist) approached leading ADHD researchers (Spencer and Biederman) at the Massachusetts General Hospital (teaching hospital associated with Harvard) and asked that MGH run an ADHD study with atomoxetine Lilly funded the study, provided atomoxetine and placebo and allowed MGH access to Lilly’s confidential FDA filings for the purpose of running the study US Appeal Decision, pp. 5-6 Canadian Trial Decision, p. 8

8 CHRONOLOGY OF THE MGH STUDY AND LILLY’S PATENT APPLICATIONS December 1, 1994, MGH submits Investigational New Drug (IND) application to the FDA January 3, 1995, FDA approval for study (MGH IRB approval also obtained about this time) January 11, 1995, Lilly files US patent application that results in U.S. Patent No. 5,658,590 (the ‘590 Patent) May 1995, positive results from MGH Study were reported to Lilly October 1995, positive results reported by MGH researchers at the world’s largest meeting of ADHD practitioners (American Association of Child and Adolescent Psychiatry (AACAP) January 4, 1996, Canadian patent application filed that results in Canadian Patent No. 2,209,735 (the ‘735 Patent) U.S. Trial Decision, pp U.S. Appeal Decision, pp. 5-6

9 THE MGH STUDY 22 adult ADHD patients enrolled – 21 completed study Double-blind, placebo-controlled, cross-over evaluation 3 week treatment arms with a one week washout Assessment included standardized patient interviews and other neuropsychological tests Overall response rate for ADHD symptoms was clinically and statistically higher during atomoxetine treatment than during placebo (53% v. 10.5%; p.0.05) Canadian Trial Decision, pp U.S. Trial Decision, p. 53

10 OCTOBER 1995 – AACAP ABSTRACT Objective: The assessment of an experimental, highly noradrenergic antidepressant tomoxetine as an alternative treatment for adult attention- deficit/hyperactivity disorder (ADHD). Method: This was a double-blind, placebo-controlled, crossover study of tomoxetine in well-characterized adults with ADHD attending to issues of psychiatric comorbidity. Results: Treatment with tomoxetine at an average oral daily dose of 76 mg/day was well tolerated. The overall response rate for ADHD symptoms was clinically and statistically higher during tomoxetine treatment than during placebo (53% vs. 10.5%; p< 0.05). There was a highly significant drug by time interaction (z = 3.4, p = 0.001) in the reduction in ADHD symptoms that was robust enough to be detectable in a parallel groups comparison during the first four weeks of the protocol (z = 3.1, p =.002). Conclusions: This preliminary study has shown that tomoxetine significantly improved ADHD symptoms and was well tolerated.

11 THE DISCLOSURE IN STRATTERA PATENTS The disclosure and claims of the US ‘590 and CDN ‘735 Patents are virtually the same The patents disclose that atomoxetine is effective in all forms of ADHD in children, adolescents and adults Improved safety profile of atomoxetine is disclosed Recommended dosing is provided The truthfulness of the above is not disputed in either Canada or the U.S. invalidity proceedings Details or results of MGH Study are not provided in the patent disclosures

12 RESULTS OF VALIDITY CHALLENGES U.S. Trial Decision -Patent invalid for something the Trial Judge refers to as “lack of enablement/utility” Eli Lilly and Co. v. Actavis Elizabeth LLC et al., 731 F. Supp. 2d 348 (D.N.J. 2010) U.S. Court of Appeal for the Federal Circuit -Trial decision overturned -Disclosure sufficient -Invention has utility Eli Lilly and Co. v. Actavis Elizabeth LLC et al., Appeal No (Fed. Cir. July 29, 2011) Canadian Trial Decision -Not enough testing to demonstrate long term clinical utility -Patent invalid for want of disclosure of sound prediction Novopharm v. Eli Lilly and Co., 2010 FC 915, 87 C.P.R. (4 th ) 301 Canadian Appeal Decision -Upholds trial decision Eli Lilly and Co. v. Teva Canada Ltd. (formerly known as Novopharm Ltd.), 2011 FCA 220, 94 C.P.R. (4 th ) 95

13 SIMILAR STATUTORY PROVISIONS UTILITY United States “Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.” 35 U.S.C. §101 Canada “invention” means any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture or composition of matter;” c. P-4, R.S.C s. 2

14 SIMILAR STATUTORY PROVISIONS ENABLEMENT/DISCLOSURE United States The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 35 U.S.C. § 112

15 SIMILAR STATUTORY PROVISIONS ENABLEMENT/DISCLOSURE Canada The specification of an invention must (a) correctly and fully describe the invention and its operation or use as contemplated by the inventor; (b) set out clearly the various steps in a process, or the method of constructing, making, compounding or using a machine, manufacture or composition of matter, in such full, clear, concise and exact terms as to enable any person skilled in the art or science to which it pertains, or with which it is most closely connected, to make, construct, compound or use it; Patent Act, c. P-4, R.S.C. 1985, s. 27(3)

16 WHY DID THE RESULTS DIFFER 1. The information regarding utility that must be disclosed in a patent 2. Different dates for determining utility 3.How the Usefulness of an invention is determined - Promise of Patent / Utility Standards

17 1. What Information Regarding Utility Must be Disclosed in a Patent U.S. Trial Division (p. 60) Trial Judge referred to this part of decision as “lack of enablement/utility” Because the ‘590 Patent did not disclose test results showing that atomoxetine could be used to treat ADHD and because a person of ordinary skill would not have recognized the claimed method’s utility in light of the specification, the patent was not properly enabled contrary to 35 U.S.C. § 112

18 1. What Information Regarding Utility Must be Disclosed in a Patent U.S. Court of Appeals for the Federal Circuit The first paragraph of § 112 requires nothing more than objective enablement The ‘590 Patent describes and enables the utility of atomoxetine to treat ADHD In the case of atomoxetine, however, the norepinephrine relationship was known, safety for antidepressant activity had been established, the specification contained a full description of the utility, experimental verification had been obtained before the patent was granted, and the examiner had not requested additional information. There was no evidence that the disclosure is “on its face, contrary to generally accepted scientific principles.” U.S. Appeal Decision, p. 17

19 1. What Information Regarding Utility Must be Disclosed in a Patent Canadian Trial and Appeal Decisions If patent’s utility is based upon demonstrated utility, patent must provide sufficient disclosure to allow a person skilled in the art to make and use the invention (this requirement was set by the ‘735 Patent) However, because the invention of the ‘735 Patent was based upon a sound prediction (because long term clinical trials had not been conducted) the patent needed to disclose the factual basis and line of reasoning for the prediction which would include disclosing the results of the MGH Study. Canadian Trial Decision, pp Canadian Appeal Decision, pp

20 2. What is the Appropriate Date for Determining Utility Important issue because results of the MGH Study not received by Lilly until after U.S. patent application filed U.S. Trial Division, p. 55 Enablement or utility is determined as of the application filing date U.S. Court of Appeals for the Federal Circuit, p. 16 When priority is not at issue, generally the applicant may provide data obtained either before or after the patent application was filed. With reference to demonstration of utility, in Brana, 51 F.3d at 1567 n.19 the court noted that post-filing evidence “can be used to substantiate any doubts as to the asserted utility since this pertains to the accuracy of a statement already in the specification.” Here the utility of tomoxetine is accurately stated in the specification; there is no allegation of falsity in the disclosed utility, and the patent examiner did not require the presentation of additional data.

21 2. What is the Appropriate Date for Determining Utility Canada The Canadian filing date is the relevant date for determining utility but additional disclosure obligations may arise depending upon how utility is characterized (demonstrated/soundly predicted)

22 3. What Does it Mean for an Invention to be Useful In both Canada and the United States, if a claimed invention does not work at all, it is said to be inoperable and the claim will be invalidated for want of utility United States If a credible utility is disclosed and there is no finding of inoperability, a patent will not be invalidated for inutility

23 3. What Does it Mean for an Invention to be Useful Canada In addition to inoperability, a utility analysis will be measured by reference to the “promise of a patent” If there is no promise of utility disclosed, a scintilla of usefulness will suffice If, however, a Court discerns a promise of utility (when the specification is viewed through the perspective of a person skilled in the art) usefulness will be measured by reference to the promise

24 3. What Does it Mean for an Invention to be Useful If the patentee has demonstrated the utility of the promise, no non-statutory disclosure obligations arise If the patent’s utility is based upon sound prediction, the patent must also disclose the factual basis and sound line of reasoning for the prediction. For the ‘735 Patent (implied promise of long term usefulness), the results of the MGH Study were required to be disclosed Thus, the disclosure obligations of a patentee in Canada may only be known after the Court construes the promise of the patent

25 Policy Considerations Disclosure -The relatively objective statutory enablement or disclosure standards increase certainty in patent systems -Coupling disclosure obligations to characterization of how utility is shown needlessly introduces subjectivity and uncertainty into patent disputes -If a patent discloses a new, unobvious and useful invention and provides sufficient information to allow a person of skill to make and use an invention, there is sufficient consideration for the grant of a patent

26 Policy Considerations Relevant Utility Dates -Patent applicants should not be rewarded for pure guesses -If an applicant provides sufficient disclosure with a credible utility, a patent should only be invalidated if the invention is inoperable -This encourages early disclosure of useful inventions and gives effect to the presumption of validity

27 Policy Considerations Utility Standards -Anything that isn’t useless is useful -“Scintilla” or “Not Devoid of Utility” should be the threshold standard for utility -Increasing the utility standards by reference to a promise of the patent discourages applicants from discussing the attributes of their invention for fear of being held to a higher utility standard

montréal  ottawa  toronto  hamilton  waterloo region  calgary  vancouver  moscow  london Thank You PATRICK S. SMITH COMPARATIVE INTELLECTUAL PROPERTY LAW SYMPOSIUM APRIL 4, 2012