Eli Lilly & Co. v. Actavis Elizabeth LLC (731 F. Supp. 2d 348, 2010)

OPINION

DENNIS M. CAVANAUGH, District Judge.

This matter comes before the Court by Complaint of Eli Lilly & Co. (“Plaintiff’ or “Lilly”), against Defendants Actavis Elizabeth LLC, Apotex Inc., Aurobindo, Sun Pharmaceuticals, Teva Pharmaceuticals, Sandoz Inc. and Mylan Pharmaceuticals Inc. (“Defendants”). This case concerns the validity and alleged infringement of U.S. Patent No. 5,658,590 (“the '590 Patent”).

This Court conducted a non-jury trial in this matter on May 18-19, and from May 24-27, 2010. This Opinion constitutes the Court’s findings of fact and conclusions of law pursuant to Fed. R. Civ. P. 52(a). For the reasons stated herein, a finding in favor of Defendants will be entered.

BACKGROUND

I. The Parties

Plaintiff Eli Lilly and Company is an Indiana corporation having its principal place of business at Lilly Corporate Center, Indianapolis, Indiana 46285. Pretrial Order Stipulation of Facts, Doc. No. 561 (“SF”), ¶ 1. Defendant Sun is a corporation organized under the laws of India, having its principal place of business at Acme Plaza, Andheri Kurla Road, Andheri (East) Mumbai, 400 059, India. Id. ¶ 2. Defendant Sandoz is a corporation organized under the laws of Colorado and has its principal placé of business in Princeton, New Jersey. Id. ¶ 3. Defendant Mylan is a corporation organized under the laws of West Virginia having its principal place of business at 781 Chestnut Ridge Road, Morgantown, West Virginia 26504. Id. ¶4. Defendant Apotex is a corporation organized under the laws of Canada having its principal place of business at 150 Signet Drive, Toronto, Ontario, Canada M9L 1T9. Id. ¶ 5. Defendant Aurobindo is a corporation organized under the laws of India having its principal place of business at Plot # 2, Maitri Vihar, Ameerpet, Hyderabad — 500 038, Andhra Pradesh, India. Id. ¶ 6. Defendant Actavis Elizabeth LLC is a corporation organized under the laws of Delaware having its principal place of business at 200 Elmora Avenue, Elizabeth, New Jersey 07207. Id. ¶7. Defendant Teva Pharmaceuticals USA, Inc. is a corporation organized under the laws of Delaware having its principal place of business at 1090 Horsham Road, North Wales, Pennsylvania 19454. Id. ¶ 8. Defendant Glenmark Generics Inc., USA (formerly Glenmark Pharmaceuticals, Inc., USA) is a corporation organized under the laws of Delaware having its principal place of business at 750 Corporate Drive, Mahwah, New Jersey 07430. Id. ¶ 9. Defendant Synthon Laboratories, Inc. is a corporation organized under the laws of Virginia having its principal place of business at 7130 Heritage Village Plaza, Suite 201, Gaines-ville, Virginia 20155. Id. ¶ 10. Defendant Zydus Pharmaceuticals, USA, Inc. is a corporation organized under the laws of New Jersey having its principal place of business at 506 Carnegie Center, Princeton, New Jersey 08450. Id. ¶ 11

II. The '590 Patent

United States Patent No. 5,658,590 (“the '590 patent”) issued on August 19, 1997, and is entitled “Treatment of Attention-Deficit/Hyperactivity Disorder.” SF ¶ 7.

Plaintiff is the owner by assignment of the '590 patent. SF ¶ 12. The '590 patent issued from U.S. Application No. 08/371,-341, filed January 11, 1995, and will expire on November 26, 2016. Id. ¶ 13. The initial U.S. patent application was filed by Plaintiffs in-house patent attorney Joseph A. Jones. Id. ¶ 9. Plaintiffs pediatric exclusivity associated with the '590 patent expires on May 26, 2017. Id. Drs. John H. Heiligenstein and Gary D. Tollefson are the inventors named on the '590 patent. Id. ¶ 14.

The '590 patent contains one independent claim (claim 1) and 15 dependent claims (claims 2-16). Id. ¶ 15. Claim 1 reads as follows: A method of treating attention-deficit/hyperactivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine. Id. ¶ 16. Claims 2-16 depend either directly or indirectly on claim 1 and recite methods of treating the predominantly inattentive type of attention-deficit/hyperactivity disorder, the predominantly hyperactive-impulsive type of attention-deficit/hyperactive disorder, and the combined type of attention-deficit/hyperactivity disorder, in adults, adolescents and children. Id. ¶ 17.

Strattera® is the brand name for the commercial formulation of atomoxetine hydrochloride, developed, manufactured and sold by Plaintiff. Id. ¶ 13. Atomoxetine was formerly known as tomoxetine, and is referred to by that name in the '590 patent. Id. ¶ 14. The terms “atomoxetine” and “tomoxetine” are used interchangeably throughout this Opinion.

III. FDA Approval

The FDA approved New Drug Application No. 21-411 (“Plaintiffs NDA”) for Strattera® capsules in strengths Eq. 10 mg, 18 mg, 25 mg, 40 mg and 60 mg for use in the treatment of Attention Deficit/Hyperactivity Disorder in children, adolescents and adults, on or about November 26, 2002. SF ¶ 15. Strattera® capsules in strengths of Eq. 80 mg and 100 mg were approved on or about February 14, 2005, for the same indications. Id. Pursuant to 21 U.S.C. § 355(b)(1) and related regulations, the '590 patent is listed in the FDA’s “Approved Drug Products With Therapeutic Equivalence Evaluations” (the “Orange Book”) for Plaintiffs atomoxetine hydrochloride products.

Each of the ten Defendants named in this action filed an Abbreviated New Drug Application (“ANDA”) seeking FDA approval to market generic atomoxetine hydrochloride products in 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg dosage strengths for the treatment of ADHD. SF ¶¶ 17-31. Each Defendant’s ANDA contains a paragraph IV certification with respect to the '590 patent. The Defendants’ paragraph IV certifications allege that the '590 patent is invalid, unenforceable, and/or will not be infringed by the manufacture, use, sale, or importation of the drug products described in the Defendants’ AND As. Id.

IV. Attention Deficit Hyperactivity Disorder & Treatments

ADHD is a complex, chronic and inheritable neurobiological disorder that is characterized by a developmentally inappropriate level of inattention, hyperactivity and impulsiveness. See Plaintiffs Proposed Findings of Fact, Doc. No. 639, (“Pl-PFF”), ¶ 34. ADHD is the most common childhood neuropsychiatric disorder. Id. ¶ 35. The prevalence of ADHD is about three to five percent in school-age children. Id. Up to 60% of patients with childhood ADHD carry symptoms into adulthood. Id. ¶ 36. In children, ADHD affects many facets of a patient’s life including social, familial and scholastic. Id. ¶ 37. Academic achievement is often impaired, leading to conflict with family and school authorities. Id. Familial relationships are often strained because parents believe that the afflicted child’s troublesome behavior is willful. Id.

ADHD is more than a school disorder. Individuals with ADHD may obtain less schooling than their peers and have poorer vocational achievement. Id. ¶ 38. Impulsive behavior may lead to accidents and to engagement in potentially dangerous activities without consideration of possible consequences. Id. 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. Id. ¶ 39. Patients with ADHD frequently have coexisting disorders. Id. ¶ 40. In children with ADHD, the frequency of a tic disorder or Tourette’s syndrome is particularly high. Id. ADHD’s impact on society is enormous in terms of its financial cost, stress to families, adverse academic and vocational outcomes, and negative effects on self-esteem. Id. ¶ 41.

Treatments of ADHD have existed for many years. Id. ¶ 57. The first medications used to treat ADHD were the stimulants. Id. ¶ 58. Prior to 1995, the stimulants, including methylphenidate (e.g., Ritalin®), amphetamines (e.g., Dexedrine®), and pemoline (Cylert®), were the only pharmaceuticals approved by the FDA for the treatment of ADHD. Id. ¶ 59. Stimulants were approved for treating ADHD only in children and adolescents, not adults. Id. ¶ 60. Despite their widely validated beneficial effects in treating ADHD, stimulants were well known to have certain side effects and disadvantages. Id. ¶ 61. At least 10% of ADHD patients do not adequately respond to stimulant therapy or are unable to tolerate the side effects of stimulants. Id. In treating patients with ADHD who also suffer tic disorders, stimulants may be particularly problematic as they may trigger or exacerbate motor or vocal tics. Id. ¶ 62. Indeed, the labeling of the stimulants advises against their use in patients with tic disorders. Id. In addition, stimulants are categorized as Schedule II controlled substances because they have considerable abuse potential. Id. ¶ 63. The Controlled Substance Act mandates that only a licensed practitioner can prescribe stimulants and that the patient must return for further assessment for each refill. Id. These restrictions result in increased time and effort for physicians and patients using these medications. Id. Physicians may prescribe only a limited quantity of stimulants to a patient at one time. Id. Patients must visit the pharmacy in person to refill prescriptions and cannot do so by mail. Id. Adults with ADHD also have high rates of alcohol and substance abuse, which may limit use of stimulant medications. Id. ¶ 64. Another common and serious concern with the stimulants is diversion, i.e., sale or use of the stimulants as recreational drugs. Id. ¶ 65. Due to their short half-life and limited period of action, stimulants yield incomplete coverage for late afternoon and evening symptoms. Id. ¶ 66. Some patients suffer from a “rebound” phenomenon where hyperactivity and impulsivity are exacerbated in the late afternoon and evening. Id. Thus, they require multiple doses per day. Id. Treatment of ADHD with stimulants may also lead to development of tolerance to the therapeutic effects, inhibition of growth, worsening of coexisting disorders, loss of appetite and insomnia. Id. ¶ 67.

V. Procedural History

On August 9, 2007, Lilly sued Actavis in this District (Civ. No. 07-CV-3770) for alleged infringement of the '590 patent pursuant to 35 U.S.C. § 271(e)(2)(A). SF ¶ 32. On September 5, 2007, Lilly filed a First Amended Complaint naming as defendants Aetavis, Glenmark, Sun, Sandoz, Mylan, Teva, Apotex, Aurobindo, Synthon and Zydus, and alleging that each defendant infringes the '590 patent pursuant to 35 U.S.C. § 271(e)(2)(A). Id. ¶ 33. Defendants filed Answers and Counterclaims to Lilly’s First Amended Complaint, denying infringement and seeking declarations that the claims of the '590 patent are invalid, not infringed, and unenforceable due to inequitable conduct before the U.S. Patent and Trademark Office (“PTO”). Id. ¶¶ 34-38.

A. Stipulations as to Various Parties

This Court entered a Consent Judgment and Order on December 12, 2007, finally resolving this action between Lilly and Zydus. Pl-PFF, at ¶ 25. This Court entered a Consent Judgment and Order on July 2, 2008, finally resolving this action between Lilly and Glenmark. Id. This Court entered a Stipulation and Order of Dismissal on August 21, 2008, dismissing Lilly’s claims against Synthon, and Synthon’s defenses and counterclaims, without prejudice. Id. This Court entered a Stipulation on April 8, 2010, staying Lilly’s claims against Teva and Teva’s defenses. Id. This Court entered a Stipulation on April 19, 2010, staying Lilly’s claims against Actavis and Actavis’s defenses. Id.

B. Prior Summary Judgment Motions

On May 21, 2009, the Court granted Defendants’ motion for partial summary judgment of no direct infringement of the '590 patent. SF ¶ 39. On December 29, 2009, in Eli Lilly & Co. v. Actavis Elizabeth LLC, 676 F.Supp.2d 352 (D.N.J.2009), the Court granted Lilly’s motion for summary judgment as to induced infringement of the '590 patent, and denied Defendants’ corresponding cross-motions for summary judgment of no induced infringement of the '590 patent. Id. ¶ 40. In its Opinion, the Court granted in part and denied in part Lilly’s motion for summary judgment of no inequitable conduct, id. ¶ 41; granted Lilly’s motion for summary judgment of no invalidity based on anticipation, id. ¶ 42; denied Defendants’ motion for summary judgment of invalidity based upon lack of enablement/utility and based upon obviousness, holding that there were genuine issues for trial. Id. ¶ 43. On January 19, 2010, the Court granted Defendants’ motion for summary judgment of no contributory infringement. Id. ¶ 44.

On February 8, 2010, this Court denied Apotex’s motion to reconsider the Court’s December 31, 2009, grant of summary judgment of induced infringement. Id. ¶ 45. On February 23, 2010, in Eli Lilly & Co. v. Actavis Elizabeth LLC, 2010 WL 715411, 2010 U.S. Dist. LEXIS 16156 (D.N.J. Feb. 23, 2010), the Court denied Lilly’s motion to reconsider the “portion of [the Court’s] Opinion of December 31, 2009, wherein the Court denied Defendants’ motion for summary judgment of non-enablement.” Id. ¶ 46.

The remaining issues in this matter were tried before this Court without the benefit of a jury on May 18-19, and from May 24-27, 2010.

VI. Trial Experts

At trial, this Court heard testimony from a number of expert witness, provided by Defendants and Plaintiff.

A. Defendants’ Expert Witnesses

Primarily in support of their obviousness argument, Defendants introduced the testimony of Dr. Craig Berridge, their expert in neuroscience and neuropharmacology. Def-PFF, at 7, ¶ 1. Dr. Berridge received a Bachelor of Arts degree in psychology as well as biochemistry and cell biology from the University of California, San Diego, in 1982. Id. at 8, ¶ 2. He received a Ph.D in neuroscience from the University of Florida School of Medicine in 1988. Id. Dr. Berridge is a Professor of Psychology and Psychiatry at the University of Wisconsin in Madison, having held that position since 2002, and has been on the faculty of the Department of Psychology at the University of Wisconsin for nearly 15 years. Id. at 8, ¶ 2. Prior to joining the faculty at the University of Wisconsin, Dr. Berridge was employed in a number of capacities including as an Assistant Research Psychobiologist in the Department of Psychiatry at the University of California in San Diego, California, a Post-Graduate Researcher in the Department of Psychiatry at the University of California, San Diego, a PostDoctoral Fellow at the Department of Pharmacology of the Yale Medical School and a Post-Graduate Researcher at the Department of Psychiatry at the University of California in San Diego. Id. For the past 25 years, Dr. Berridge has focused on the field of behavioral neuroscience, with an emphasis on the behavioral actions of monoamine neurotransmitters, particularly norepinephrine. Id. at 7, ¶ 1. Dr. Berridge holds a broad specialty in behavioral neuroscience and an expertise in neurotransmitter systems including the class of neurotransmitters known as catecholamines, which include norepinephrine and dopamine. Id. Throughout his work, Dr. Berridge has worked with drugs extensively to manipulate neurotransmitter systems and different aspects of neurotransmitter function, including drugs that are commonly used to treat ADHD. Id. Dr. Berridge has extensive teaching experience as well as experience in the private sector. Id. at 8, ¶¶ 3-4.

Regarding their argument that the '590 patent was not enabled to its full scope, Defendants introduced the expert testimony of Dr. James R. Johnson, who has a Doctorate of Philosophy in Pharmaceutics, a Masters of Science in Pharmaceuticals, and a Bachelor of Science degree in Pharmacy, from the University of Minnesota. Id. at 69, ¶ 2. He spent twenty years, from 1976 through 1996, working for Schering-Plough. Id. at 69, ¶ 2. Prior to working at Schering-Plough, Dr. Johnson worked at Ayerst Laboratories from 1968 through 1976. Id. His work was devoted to the development of dosage forms. Id. Dr. Johnson is currently an Associate Professor at the University of Tennessee in the Department of Pharmaceutical Sciences in the College of Pharmacy, where he has taught since 1986. Id. at 70, ¶ 3. Dr. Johnson has formulated a multitude of dosage forms including, for example, depot injections, suspensions, tablets, chewable tablets, coated gums, aerosols, sustained release formulations and transdermal formulations. Id. at 70, ¶ 4. Dr. Johnson, was qualified by the Court as an expert in the field of pharmaceutical dosage form development and drug delivery system development. Id. at 70, ¶ 5.

In support of their position that the '590 patent was invalid as a result of inequitable conduct before the PTO, Defendants introduced the testimony of John T. Goolkasian, Esq. Mr. Goolkasian has twenty-five years of experience working at the PTO, including as a Protest and Inter Partes Examiner specifically investigating allegations of inequitable conduct, and, for approximately ten years, as a Judge on the Board of Patent Appeals and Interferences (“the Board”). Id. at 138, ¶ 1. Mr. Goolkasian has a degree in chemical engineering, although he conceded that he does not qualify as a person of ordinary skill in the art. Id. at 138, ¶ 2; Pl-PFF, ¶ 162.

In connection with their arguments regarding the secondary considerations of nonobviousness, Defendants introduced the testimony of Mr. Harry Boghigian and Dr. Jud Staller. Def-PFF, at 38, ¶ 8.

Mr. Boghigian has nearly forty years of experience in the pharmaceutical industry, including 30 years with Hoffmann-La Roche. Id. He has served as a sales representative; a division sales manager; a manager of market research, where he did the research that was involved in putting together strategic and tactical plans for commercializing drug products; a regional director; a product director responsible for specific therapeutic drug product areas; a group product director; and vice president of marketing. Id.

Jud A. Staller M.D. testified as Defendants’ expert in the area of psychiatry and the pharmacological treatment of disorders including ADHD. Id. at 41, ¶ 18. Dr. Staller is currently in private practice in child, adolescent and adult psychiatry with a Clinical Associate Professor appointment in the Division of Child and Adolescent Psychiatry at SUNY Upstate Medical University. Id. at 41, ¶ 18 n. 4.

B. Plaintiffs Expert Witness

Plaintiff relied upon the testimony of Dr. Steven Pliszka. Dr. Pliszka received a bachelor’s degree in psychology from the University of Texas at Austin in 1977. Pl-PFF, ¶ 138. He attended medical school at the University of Texas Health Science Center in San Antonio, graduating in 1981. Id. He completed his residency in psychiatry at that same institution, completing his child and psychiatry training in 1986. Id. Dr. Pliszka was actively involved in the ADHD field prior to and in 1995, reviewed the relevant pre-1995 publications prior to 1995, and had occasion to comment on them and incorporate them in his own work prior to 1995. Id. ¶ 137. Dr. Pliszka has an active clinical practice, has conducted clinical trials for ADHD treatments, and has conducted research on the neurobiology of ADHD and treatment of ADHD and comorbid disorders. Id. ¶ 139. Dr. Pliszka’s clinical practice includes treating in excess of 500 children with ADHD, developmental disabilities, and other psychiatric disorders. Id. ¶ 140. Dr. Pliszka also teaches psychopharmacology and neurobiology to medical students and psychiatry residents. Id. ¶ 141. Dr. Pliszka is the principal author of the Practice Parameters of the American Academy of Child and Adolescent Psychiatry (“AACAP”) for the diagnosis and treatment of ADHD. Id. ¶ 142. AACAP is considered the leading national organization of child and adolescent psychiatrists in the United States. Id. Dr. Pliszka has participated in numerous clinical trials of ADHD agents, including tomoxetine, in the treatment of ADHD. Id. ¶ 143. Dr. Pliszka has authored several publications and books related to ADHD and its treatment. Several of his relevant publications were published prior to 1995. Id. ¶ 144.

FINDINGS OF FACT AND CONCLUSIONS OF LAW

Having received voluminous documentary and testimonial evidence from the parties’ experts, as well as substantial briefing and oral argument on the various issues presented in this matter, the Court issues this Opinion which constitutes its findings of fact and conclusions of law pursuant to Fed. R. Crv. P. 52(a). The Court’s findings of fact and conclusions of law with respect to each of the various grounds for invalidity/unenforceability of the '590 patent are discussed below: (I) obviousness, (II) inequitable conduct, (III) lack of enablement to the full scope of the patent’s claims, and (IV) lack of enablement/utility.

I. Obviousness

Defendants assert that the '590 patent is invalid for obviousness. Defendants argue that the '590 patent merely “substitut[ed] one potent selective norepinephrine reuptake inhibitor (atomoxetine) for another (desipramine) known to be effective in treating ADHD.” Defendants’ Posh-Trial Brief, Doc. No. 645, (“DPTB”), at 7. Accordingly, Defendants assert, “it would have been obvious to a person of ordinary skill in the art ... to make that simple exchange with a reasonable expectation of success.” Id.

Plaintiff responds that Defendants’ argument must fail because: (i) a truly selective norepinephrine reuptake inhibitor was not thought to be desirable, and (ii) desipramine’s selectivity was associated with fatal side effects.

A. Applicable Law

Under 35 U.S.C. § 103(a), a party may not receive patent protection for an invention that is “obvious”; as § 103(a) states:

A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.

Upon issuance, however, a patent is presumed valid and “included within the presumption of validity is ... a presumption of nonobviousness.” Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d 707, 714 (Fed.Cir.1984). Accordingly, “[a] party seeking to invalidate a patent based on obviousness must demonstrate by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so.” Procter & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed.Cir.2009) (internal quotation omitted).

The Supreme Court has enumerated four factors to be considered by courts to assess whether an invention is obvious. Takeda v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1356-57 (Fed.Cir.2007) (citing Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)). The four factors are: (1) the scope and content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed subject matter and the prior art; and (4) secondary considerations, or “objective indicia of non-obviousness.” Id.; see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 405, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). The “objective indicia” of non-obviousness, the fourth Graham factor, instructs courts to consider the circumstances surrounding the invention process including, but not limited to: meeting a long-felt need, the inventors’ success despite the failure of others, commercial success, copying, praise and recognition for the invention, unexpected results, and significant effort and serendipity. See Ruiz v. A.B. Chance Co., 234 F.3d 654, 660-62 (Fed.Cir.2000); see also Procter & Gamble, 566 F.3d at 994 (Fed.Cir.2009); Ortho-McNeil, 520 F.3d 1358, 1364 (Fed.Cir.2008). A court must make findings of fact and conclusions of law as to each of the Graham factors.

B. The Scope and Content of the Pri- or Art

This Court will first define the scope and content of the prior art at the time of the patent’s filing. The '590 patent relates to the fields of pharmaceutical chemistry and psychiatric medicine. The relevant scope and content of the prior art is to be assessed as of the January 11, 1995 filing date of the '590 patent.

1. Drug Discovery — Generally

The parties agree that there are two ways that new drugs are discovered when individuals of skill in the art seek an effective treatment for a particular disorder. Def-FFCL, at 18, ¶ 30. A scientist could, for example, focus on the structural formula of a drug, and draw inferences from differences or similarities as to how changes in a given molecule might affect the function of that molecule. Id. Alternatively, a scientist could look at the properties of two structurally dissimilar compounds and draw inferences from their properties. Id. at 18, ¶ 31. For instance, a scientist might look at the properties of an existing drug and find others with similar therapeutic effects. Id.

It is the latter method of drug discovery that is of primary concern here, as that was the approach used by Dr. Berridge in his assessment of the prior art concerning ADHD treatment. Id. at 18-19, ¶¶ 31-32. Dr. Pliszka confirmed that looking at the properties of existing drugs to find others with similar therapeutic effects was one recognized approach to drug discovery. Id. at 19, ¶ 32. Using that approach, Dr. Berridge explained that in studying the treatment of ADHD one might look to a drug like desipramine (known to be effective in the treatment of ADHD) as a basis for looking for other drugs having the same therapeutic properties. Id.

2. Types of Drugs Used to Treat ADHD Dr. Berridge began his analysis with the four main classes of drugs that had been used, prior to January of 1995, in the treatment of ADHD. Id. at 19, ¶ 33. The first of those classes is the stimulant drugs — the most effective (and most commonly prescribed) drugs for the treatment of ADHD. Id. These compounds in general act pharmacologically by blocking norepinephrine reuptake, thereby increasing the amount of norepinephrine present in the synapse (i.e., the functional connection where one neuron transmits signals to another neuron) and increasing norepinephrine transmission. Id. They also block dopamine, another neurotransmitter like norepinephrine, thus serving to increase dopamine in the synapse. Id.

The second most significant group of drugs commonly used and studied for ADHD treatment is referred to as the tricyclic antidepressants or TCAs. Id. at 19, ¶ 34. They share, to some degree, the pharmacological action of the stimulants in that they also block the reuptake of monoamines, generally targeting both norepinephrine and serotonin reuptake. Id. These drugs therefore increase norepinephrine neurotransmission. Id.

The third class of drugs commonly used and studied for ADHD treatment' is referred to as the alpha-2 agonists. Id. at 20, ¶ 35. These drugs bind to and stimulate the alpha-2 receptor, producing the biochemical response that the receptor drives. Id. In that way, alpha-2 agonists mimic the action of norepinephrine. Id. It was known in January of 1995 that, by stimulating the alpha-2 receptors on the post-synaptic neuron, these drugs increase norepinephrine neurotransmission. Id.

The fourth class of drugs used and studied for ADHD treatment, monoamine oxidase inhibitors (“MAOIs”), increase the amount of serotonin and dopamine available for release into the synapse. Id. at 20, ¶ 36. MAOIs can be severely toxic at high dosages. Id. These drugs block the monoamine oxidase enzyme, thereby increasing the amount of norepinephrine, and have dangerous and potentially fatal interactions with other drugs and even certain common foods, such as dairy products and beverages. Pl-PFF, ¶ 70. As a result, physicians did not feel comfortable prescribing MAOIs for the treatment of ADHD outside of a research setting.

The focus of the parties’ arguments regarding the content of the prior art surrounded the teachings related to the stimulant drugs and the TCAs, as they were known to be the first and second most effective lines of drugs for treating ADHD, respectively. See Def-PFF, at 19, ¶ 33.

3. Norepinephrine (“NE”) Reuptake Inhibition

Norepinephrine is a neurotransmitter affected by drugs that treat ADHD. Id. at 13, ¶ 15. The role of norepinephrine in ADHD treatment is critical to this Court’s obviousness analysis, as Defendants essentially argue that the '590 patent is obvious because the inventors simply “substitut[ed] one potent selective norepinephrine reuptake inhibitor (atomoxetine) for another (desipramine) known to be effective in treating ADHD.” DPTB, at 7.

In forming his opinion, Dr. Berridge reviewed a number of articles including 1984 and 1985 articles by Dr. David Gastfriend, et al. (Gastfriend 1984 and Gastfriend 1985). The Gastfriend 1985 article proposed that:

DMI may be more effective than imipramine in ADD, because of its greater specificity in blocking norepinephrine re-uptake in the central nervous system. DMI may also be better tolerated than imipramine, because of its reduced anticholinergic and anti-alpha adrenergic effects.

Def-PFF, at 22, ¶ 43.

Dr. Berridge also relied on a 1986 article by Dr. Maureen Donnelly, et al., from the National Institutes of Health, National Institute of Mental Health (“Donnelly”). Id. at 20, ¶ 39. Donnelly describes a double-blind study in which desipramine was used to treat ADHD in children. Id. The authors determined that their study results “support a noradrenergic mechanism in the mediation of drug effects” on ADHD — i.e., a norepinephrine-related mechanism was involved in the study’s success. Id. at 21, ¶ 41. The Donnelly Publication also observed that desipramine is “a less potent inhibitor of al-adrenergic, muscarinic, and Hl-receptors” when compared to other TCAs — that is, its activity was more selective as to norepinephrine reuptake inhibition. Id. at 21, ¶ 40.

Although Donnelly stated that desipramine was more selective than other TCAs with respect to NE reuptake inhibition (e.g., imipramine), it also stated that desipramine “has been shown to affect other neurotransmitters centrally,” Pl-PFF, ¶ 196, and that “[t]he interactions among different areas of the brain and the involvement of neurons, neurotransmitters, and receptors that affect attention, impulse control, and other higher cognitive functions (often referred to as ‘executive functions’) are highly complex.” Id. ¶ 44. The Donnelly Publication explained that the “literature describing the neurochemistry of learning and memory is voluminous, complex, and often contradictory.” Id. ¶ 177. In particular, it noted that “both noradrenergic and dopaminergic mechanisms are involved in the mediation of stimulant-induced behavioral improvement in [ADHD].” Id. ¶ 68.

Next Dr. Berridge relied on a 1993 article by Dr. Thomas Spencer et al. titled “Desipramine treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette’s syndrome” (“Spencer”). Def-PFF, at 22-23, ¶ 44. In the article, Dr. Spencer notes that desipramine was useful in treating ADHD, and observed that it was a relatively selective NE reuptake inhibitor compared to other TCAs, and caused fewer side effects. Id. at 22-23, ¶ 44. Although Dr. Spencer describes desipramine’s usefulness in ADHD and its selectivity, he does not explicitly find that the drug’s selectivity was the cause of its effectiveness in treating ADHD. Id. at 22-23, ¶ 44.

Moreover, Dr. Spencer’s assertion as to the drug’s selectivity was made in comparison to other TCAs. Pl-PFF, ¶ 190. In fact, Dr. Spencer explained that because desipramine has actions on other neurotransmitter systems, when compared to drugs more broadly, it is “distinctly not selective” — an opinion shared by his colleague Dr. Biederman who opined that desipramine was a “dirtier drug” with effects on other neurotransmitters and was considered selective only when compared to other TCAs. Id.

Although the Gastfriend and Donnelly quotations discussed above certainly implicate NE inhibition in the treatment of ADHD (Gastfriend more directly than Donnelly), two aspects of these references illustrate why such a conclusion was uncertain. First, even within the Donnelly source there are various suggestions as to why the studied compounds were effective in treating ADHD. In fact, it appears to indicate that NE inhibition is one, among many, factors that contribute to the clinical efficacy of tomoxetine. The Court must bear these various possibilities in mind when determining the reference’s teachings.

Second, and related to the first point, the prior art as a whole did not suggest that NE inhibition was necessarily the paramount or exclusive contributor to efficacy in ADHD treatment. A comprehensive view of the prior art is essential in defining the prior art and comparing it with the invention in question (i.e., assessing the 1st and 3rd Graham Factors), as “the correct test of invention or nonobviousness focuses on the teachings of the prior art as a whole, not the disclosures of individual references taken singly.” 2-5 CHISUM ON PATENTS § 5.04, n. 14; see Takeda Chem. Indus. v. Alphapharm, Pty., Ltd., 492 F.3d 1350, 1363 (Fed.Cir.2007); Novartis Pharms. Corp. v. Teva Pharms. USA, Inc., 2007 WL 2669338, at *6, 2007 U.S. Dist. LEXIS 65792, at *16-17 (D.N.J. Sept. 6, 2007) (finding that even if one reference points to a particular lead compound, this suggestion is negated when other prior art references contain conflicting teachings); see also Custom Accessories, Inc. v. Jeffrey-Allan Indus., 807 F.2d 955, 962 (Fed.Cir.1986) (“The person of ordinary skill is a hypothetical person who is presumed to be aware of all the pertinent prior art”). The Court now turns to this second consideration: the teaching of the prior art as a whole.

As an initial matter, at the time the Gastfriend articles were written, the role of norepinephrine itself was unclear. For example, in 1984, a publication by Dr. Dennis H. Langer et al. titled “Pilot Trial of Mianserin Hydrochloride for Childhood Hyperactivity” (“Langer”) indicated that mianserin, a compound believed to block pre-synaptic alpha-2 adrenergic receptors (resulting in an increase in norepinephrine levels), was actually found to be ineffective in ADHD treatment. Pl-PFF, ¶ 77. That is, the reference suggested that an increase in NE may not be desirable. Conversely, clonidine, which was thought to stimulate pre-synaptic alpha-2 adrenergic receptors resulting in a decrease in norepinephrine levels, was found to be moderately effective in children with ADHD in a 1985 article titled “Clonidine Benefits Children with Attention Deficit Disorder and Hyperactivity: Report of a Double-Blind Placebo-Crossover Therapeutic Trial” (“HUNT”) by Dr. Robert D. Hunt et al. Id. It was not until later that NE reuptake inhibition was deemed critical to treating ADHD. See id. ¶ 179.

Although the stimulant and TCA classes of drugs are each norepinephrine reuptake inhibitors, in the period of time leading up to 1995, this Court finds that there was no consensus on the specific neurotransmitters or areas of the brain involved in the pathophysiology of ADHD. Id. ¶ 175. Critically, the scientific data did not imply prominent involvement of a single neurotransmitter. Id. ¶ 176.

This lack of consensus is reflected in a 1987 review by prominent researchers at the National Institute of Mental Health (“NIMH”), Dr. Alan Zametkin and Dr. Judith L Rapoport, titled “Neurobiology of Attention Deficit Disorder With Hyperactivity: Where Have We Come In 50 Years?” (“Zametkin and Rapoport”) Id. ¶ 179. Drs. Zametkin and Rapoport reviewed the prior 50 years of ADHD treatments and the varied pharmacologic characteristics of prior art ADHD compounds, and concluded that “[i]t is clear by now that the array of effective agents has put to rest any single transmitter hypothesis.” Id. An impact on norepinephrine alone was pronounced “necessary but not sufficient for clinical efficacy” in ADHD. Id. The authors suggested that the most promising areas for future research involved trials of a combination of dopaminergic and noradrenergic agents. Id.

In 1989, Drs. Mefford and Potter, also from NIMH, published another hypothesis regarding etiology of ADHD in “A Neuroanatomical and Biochemical Basis for Attention Deficit Disorder with Hyperactivity in Children: A Deficit in Tonic Adrenaline Mediated Inhibition of Locus Coeruleus Stimulation” (“Mefford and Potter”) Id. ¶ 180. They suggested that increasing epinephrine (adrenaline), particularly in brainstem neurons, would treat the condition. Id. They argued that the “ideal therapeutic agent” for ADHD would itself be taken up into norepinephrine terminals and storage vesicles, and would, unlike tomoxetine, possess potent inhibitory properties toward MAO type A. Id. Alternatively, the authors suggested that “a site selective alpha-2 agonist acting only at the brainstem level [also unlike tomoxetine] might be effective.” Id.

Also in 1989, a publication by Dr. Joseph Biederman et al, “A Double-Blind Placebo Controlled Study of Desipramine in the Treatment of ADD: I. Efficacy” (“Biederman”), confirmed the uncertainty regarding the effect of NE inhibition. See id. ¶ 196. The study found that “[t]he pharmacological mechanism of action of DMI [desipramine] in ADDH remains unknown.” Id.

In 1991, Dr. James McCracken of the UCLA Neuropsychiatric Institute reviewed ADHD and its treatments in “A Two-Part Model of Stimulant Action on Attention-Deficit Hyperactivity Disorder in Children” (“McCracken”). Id. ¶ 181. Dr. McCracken found that “[i]t is reasonable to surmise that the amine reuptake blockade [norepinephrine reuptake inhibition] shared by desipramine, imipramine, and clomipramine is likely related to the moderate therapeutic effect of the tricyclics” — i.e., this action was instrumental in treating ADHD. Def-PFF, at 31, ¶ 63. He determined, however, that while NE inhibition may be related to ADHD treatment, its role was not clear, as he also asserted that “as yet there is no consensus on the precise mechanism of action of ADHD’s most commonly prescribed treatment (the stimulants) or of the etiology of ADHD itself.” Pl-PFF, ¶ 178. In fact, Dr. McCracken suggested that a beneficial drug might stimulate the pre-synaptic dopamine receptors (decreasing the level of dopamine) and stimulate alpha-2 adrenergic receptors (decreasing the level of norepinephrine). Id. Tomoxetine does not fulfil these prerequisites.

In a 1992 article by Dr. Andrew Shenker, “The Mechanism of Action of Drugs Used to Treat Attention-Deficit Hyperactivity Disorder: Focus on Catecholamine Receptor Pharmacology” (“Shenker”), Dr. Shenker emphasized the uncertainty of NE inhibition as the single cause of the drug’s effectiveness. Although Dr. Shenker stated that desipramine was effective to some degree in treating ADHD, and that the drug inhibited NE reuptake, he also determined that the roles of dopamine and norepinephrine in ADHD treatment “remain unresolved.” Id. He further explained that “[i]t may very well be that increased synaptic availability of both DA and NE is required for optimal pharmacotherapy of ADHD.” Id. This proposition is supported on page 356 of his article, where Dr. Shenker considers that “[t]he clinical promise of nomifensine in ADHD could not be pursued because of its toxic effects, but several new drugs that are potent blockers of both DA and NE uptake systems have been described, including LU 19-005, diclofensine, mazindol and BTCP.” In fact, Dr. Shenker went so far as to write that “[a]ny discussion of the efficacy of imipramine and desipramine in ADHD must include the fact that, unlike amphetamine, they are fairly potent antagonists at alAR [adrenergic receptor] and certain other brain receptors.” Id. ¶ 196. Dr. Shenker noted that “[w]hether these properties contribute to or detract from [desipramine’s] clinical efficacy remains to be seen.” Id. In this regard, desipramine’s alpha-1 receptor activity was of particular interest, because this property was shared with the antipsychotic medications that had been found to be effective in ADHD. Id. In short, the article did not give an indication that NE reuptake inhibition selectivity was a sufficient property for a successful ADHD treatment.

Moreover, Dr. Shenker’s research findings in general are qualified, as he (and other researchers) have found that there are

treacherous waters [to] ... be crossed between basic research and clinical applications in ADHD. Our growing knowledge of the basic pharmacology of DA and NE systems involved in rodent behavior is encouraging, but it must be applied judiciously in studying the effects of stimulants and other drugs in humans. Drug effects in rodent models are extremely dependant on drug dose, strain of rat tested, test conditions, behavioral measurement, and age of the animal.

Id. ¶ 177. He explicitly states that “Mo-dents may have inherently limited value as animal models of ADHD.” Id.

To summarize, while the prior art demonstrated that norepinephrine reuptake inhibition was relevant to ADHD treatment, the literature does not appear to indicate that it was alone sufficient. Id. ¶ 184. The fact that desipramine (as a TCA) was a more selective NE inhibitor than other TCAs does not indicate that it (and all other selective NE inhibitors) were optimal ADHD treatments — that is particularly so because the TCAs, as a class, exhibited affinities for a large, diverse set of receptors, including alpha-1, alpha-2, cholinergic, dopaminergic, muscarinic, noradrenergic, serotonergic, and histaminergic receptors. Id. ¶ 188. As data introduced at trial indicates, desipramine is selective when compared to imipramine, but far less selective than tomoxetine with regard to selectivity. Id. ¶ 193.

In arriving at this conclusion, the Court found both Defendants’ and Plaintiffs expert to be credible and qualified. This Court’s independent consideration of the entirety of the prior art, however — after having the benefit of both experts’ synopses — aligns more closely with the view of Dr. Pliszka. In so concluding, the Court also finds it significant that Dr. Pliszka was directly involved in the relevant field of study during the key period (i.e., the time of patent filing in 1995, and the period leading up to filing). His testimony was particularly helpful to the Court in that Dr. Pliszka described the various trends in ADHD treatment that would have been known to an individual of skill in the art.

4. Decrease in the Use of Desipramine

Despite desipramine’s apparent success in treating ADHD, by the early 1990s, its use decreased as a result of a severe side effect. Id. ¶200. In particular, there were reports of sudden deaths in apparently healthy children taking desipramine. Id. These deaths led to speculation that desipramine was more toxic than TCAs (including imipramine). Id. ¶ 200-01. The desipramine product label was modified to reflect these new toxicity-related dangers. Id.

In a 1993 article by Mark A. Riddle, M.D., he explained one possible explanation for the dangers associated with desipramine:

It is possible desipramine differs from other tricyclics in ways that make it potentially more lethal. This possibility is supported by the findings of a recent study indicating that the chance of death after an overdose is greater for desipramine than for other tricyclic drugs (Kapur et al., 1992). Desipramine’s most distinctive feature among the class of tricyclic drugs is that it is the most specific inhibitor of uptake of norepinephrine. All the tricyclic drugs available in the United States block the uptake of both norepinephrine and serotonin into neurons. Desipramine is most selective for the norepinephrine site whereas clomipramine is most selective for the serotonin site; other tricyclics are intermediate in their selectivity. Thus, desipramine, by increasing noradrenergic neurotransmission, increases cardiac sympathetic tone. There is an evolving literature indicating that increased cardiac sympathetic tone predisposes vulnerable persons to ventricular tachyarrhythmias, syncope, and sudden death.

Id. ¶ 205. Plaintiff argues that the evidence shows that there was widespread concern over the use of desipramine, and that many clinicians stopped using it, or began using it only as a last resort. The extent of the actual drop-off in desipramine use is not clear. As Plaintiff acknowledges, there was debate within the medical community about the safety of desipramine. Id. ¶204. Nonetheless, Dr. Pliszka, and a number of other doctors who Plaintiff has relied upon in its case, continued using desipramine — and even recommended it under certain conditions. See Def-PFF, at 37, ¶¶ 72-74; Pl-PFF, ¶ 204. The doctors concluded that the risk was appropriate in light of the therapeutic advantages of desipramine. See Pl-PFF, ¶ 204. Moreover, when use of desipramine was continued, it was done subject to appropriate cautions, such as cardiac monitoring. Id. ¶ 76.

Although the precise impact that the reports of sudden death had on prescription of desipramine is not clear, the Court finds that it is reasonable to conclude that the dangers associated with desipramine (and the additional precautions required) must have had some impact. Doctors would have been less likely to use the drug given an alternative. As a result, the safety issues associated with desipramine would have — to some degree — discouraged a person of skill in the art from using the compound (or others like it) as long as there was another option available.

With respect to any conflict in the testimony of Doctors Berridge and Pliszka on this point, the Court largely credits that of Dr. Pliszka, as he was a practicing clinician in the field during the relevant time period. See Pl-PFF, ¶¶ 146-50, 209. Dr. Berridge lacks clinical experience, and conceded that he doesn’t “really know the full manifestation of cardiac effects, or cardiovascular effects,” and was not confronted with the desipramine situation in a clinical setting. See id. Although the Court does not find that this lack of clinical experience detracts from Dr. Berridge’s testimony as a whole (for example, with respect to certain testimony as to the prior art, and general explanations regarding neuroscience and pharmacology), with respect to the use of a particular drug in treating patients, Dr. Pliszka’s testimony is more reliable, and is given more weight by this Court.

C. The Level of Skill in the Art

The parties’ proposed definitions of the level of skill in the art are substantially similar. Essentially they agreed that a person of ordinary skill in pharmaceutical chemistry or psychiatric medicine as of January 1995 (i.e., the filing date) would have at least a M.D. or a Ph.D. in chemistry, pharmacology, or the biological sciences, and at least 3-5 years of experience in the development of drug products and therapies for psychological disorders. Pl-PFF, ¶ 168; Def-PFF, at 17, ¶¶ 28-29. The parties’ dispute centers around whether this hypothetical person of skill in the art must also have had two or more years of post-doctoral experience in research relating to the behavioral pharmacology of ADHD.

The critical difference between the parties’ definition is that Plaintiff asserts that the person of skill in the art must have “experience in the development and clinical use of drug products and therapies for psychological disorders.” Pl-PFF, ¶ 168 (emphasis added). Plaintiff argued that “[ejxperience in clinical use of drugs for psychological disorders is necessary because it (i) provides perspective on how patients respond to medications and the drive to develop agents in the field, and (ii) allows one to evaluate the biology of the disorder in the human, not just in an animal model.” Id. The Court agrees with Plaintiff.

D. The Differences between the Pri- or Art and the Claimed Method

For many of the reasons set forth above, this Court finds that the differences between the prior art and the invention covered by the '590 patent are significant. See generally Section I.B, supra.

With respect to the patent itself, the '590 patent describes atomoxetine as a “well-known drug” having activity as a norepinephrine reuptake inhibitor:

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.

see '590 Patent, at col. 1,11. 60, et seq. The specification of the '590 patent goes on to describe atomoxetine as a “notably safe drug” and states that it represents “a superior treatment” for ADHD by reason of its improved safety. Id. at col. 1, 11. 66, et seq. The patent claims a method of treating attention-deficit/hyperaetivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine

First, this Court finds that the prior art was not in accord as to the role of NE reuptake inhibition in ADHD treatment. Indeed, several of the various references above specifically indicate that NE inhibition may not be necessary to a successful ADHD treatment. For example, two of the references, from 1984 and 1985, suggest the NE reuptake inhibition was not necessary (e.g., Langer and Hunt). Similarly, the 1989 Mefford and Potter article suggested that a drug that did not share the properties of tomoxetine would be successful in the treatment of ADHD. A person of ordinary skill in the art would view these references as diverging drastically from the claimed subject matter of the '590 patent.

Second, even the later references which indicate that NE reuptake inhibition was relevant to a successful ADHD treatment do not definitively define the role of NE reuptake inhibition. For example, the Biederman, McCracken, and Zametkin and Rapoport articles suggest that the mechanism of action of ADHD was unknown. Even more significant is the fact that many of these same articles indicate that perhaps activity at two or more receptor sites was necessary and/or ideal for an optimal ADHD treatment (e.g., Donnelly, McCracken, Shenker and Zametkin and Rapoport).

Third, during the period preceding the filing of the '590 patent — specifically, in the years closest to the time of filing— there were negative reports concerning desipramine. This factor must weigh to some extent away from using atomoxetine as a potential ADHD treatment (even if not as much as Plaintiff urges), as desipramine was functionally a similar compound to atomoxetine.

% # * ❖ # ❖

In view of this Court’s findings with respect to the Graham Factors, this Court cannot does not find that the Defendants have established, by clear and convincing evidence, that the '590 patent was obvious.

As noted above in this Court’s discussion of the various references discussed by the parties, the prior art must be considered as a whole. See 2-5 CHISUM ON PATENTS § 5.04, n. 14; see Takeda Chem., 492 F.3d at 1363; Novartis Pharms, 2007 WL 2669338, at *6, 2007 U.S. Dist. LEXIS 65792, at *16-17; see also Custom Accessories, 807 F.2d at 962. Here, although excerpts from several of the references can be read to suggest that NE reuptake inhibition is a key component to an effective ADHD treatment, the majority of the prior art stresses that the mechanism of action of ADHD was unclear at the time the patent application was filed.

Even in references that support Defendants’ position, there are frequently qualifications as to the optimal type of drug necessary for an ADHD treatment. In some references there are even theories that would appear to be directly contrary to the theory espoused by the inventors and patent applicants here (i.e., that “truly” selective NE reuptake inhibitor would be effective in ADHD treatment). These other teachings within the cited references are critical — just as the prior art must be considered in its entirety, “[i]t is impermissible ... to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art.” In re Wesslau, 53 C.C.P.A. 746, 353 F.2d 238, 241 (C.C.P.A.1965).

Additionally, negative developments with desipramine (i.e., a drug that was functionally similar to tomoxetine) would further discourage tomoxetine’s use as a model for further research.

Considering the prior art at the time of filing, this Court finds that the subject matter claimed in the '590 patent was not obvious. Although segments of the prior art can be selected so as to create a path leading to the patent’s method of ADHD treatment, this is insufficient to demonstrate obviousness. Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1379 (Fed.Cir.2006) (“Mere identification in the prior art of each component of a composition does not show that the combination as a whole lacks the necessary attributes for patentability, i.e. is obvious.”); see also KSR, 550 U.S. at 421, 127 S.Ct. 1727 (cautioning against “the distortion caused by hindsight bias” and “arguments reliant upon ex post reasoning” in determining obviousness); Processing Corp. v. Am. Maize-Products Co., 840 F.2d 902, 907 (Fed.Cir.1988) (noting that in considering obviousness, “[c]are must be taken to avoid hindsight reconstruction by using the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit.”) (internal citations omitted). Having considered the prior art as a whole — and being mindful of the complexities of ADHD, the causes of which remain unknown to this day — the Court cannot find that a person of skill in the art would consider it obvious to use atomoxetine to treat ADHD.

For the reasons stated, the Court finds that the '590 patent is not invalid as obvious over the prior art.

E. Secondary Considerations of Non-obviousness

As Defendants have failed to demonstrate obviousness in accordance with the initial Graham factors, the Court need not consider the objective indicia of nonobviousness. See Takeda, 492 F.3d at 1363 (“In light of our conclusion that [the patent challenger] failed to prove that the claimed compounds would have been prima facie obvious, we need not consider any objective indicia of nonobviousness.”); Unigene Labs., Inc. v. Apotex, Inc., 2009 WL 2762706, at *15, 2009 U.S. Dist. LEXIS 78051, at *48-49 (S.D.N.Y. Aug. 31, 2009) (same).

II. Inequitable Conduct

Defendants assert that the '590 patent is unenforceable because the applicants’ patent prosecution counsel engaged in inequitable conduct before the PTO. Defendants’ claim of inequitable conduct is premised upon the applicants’ (i.e. Lilly) failure to disclose two documents during prosecution of the '590 patent. Specifically, Defendants allege that Plaintiff improperly failed to disclose a prior art reference concerning the compound tandamine, Saletu et al., “Tandamine — a New Norepinephrine Reuptake Inhibitor,” Int. Pharmacopsychiat., 12:137-52 (1977) (“the Tandamine Reference”), and an Opinion from the Board of Patent Appeals and Interferences (“BPAI”). Plaintiff responds that Defendants cannot establish the requisite materiality or intent with respect to each of the references to demonstrate inequitable conduct.

A. Facts

On January 11, 1995, the patent applicants filed the application for the '590 patent. Pl-PFF, ¶ 122. The application was submitted by Joseph A. Jones, an attorney at Lilly. Id.

The application for the '590 patent set out the background of the invention by describing the prior use of the stimulant methylphenidate (Ritalin®) to treat ADHD, and setting forth its disadvantages, such as requiring several doses per day, producing a rebound effect as each dose fades away, and causing sleeplessness and lack of appetite in some patients. Id. ¶ 124. The application also described the prior use of tricyclic antidepressants such as imipramine, desipramine, nortriptyline, amitriptyline, and clomipramine, to treat ADHD and stated that the TCAs “have a number of physiological mechanisms and, as a class, tend to produce a number of side effects and require careful supervision and dose titration.” Id. The application explained that the “need for a safe and convenient treatment for ADHD, applicable to both children and adults and without the disadvantages possessed by methylphenidate continues to be a concern of the psychiatric profession.” Id.

1. Facts Related to the Tandamine Reference

On April 19, 1995, Mr. Jones submitted an Information Disclosure Statement (“IDS”) enclosing 37 references, with an accompanying “List of References Cited by Applicant” related to its application to the PTO. Id. ¶ 126. These references contained information regarding imipramine, desipramine, nortriptyline, amitriptyline, clomipramine, bupropion, fluoxetine, chlorpromazine and clonidine. Id. The references also included published reports of Lilly’s trials with tomoxetine for depression, as well as a large number of publications referring generally to tomoxetine. Id. On August 2, 1995, and August 3, 1995, Examiner James M. Spear signed the IDS and initialed next to each of the references listed in the IDS, attesting that he had considered all of the references submitted. Id. ¶ 126. The examiner also conducted searches of the PTO files and a computer database for prior art. Id.

In a first office action, the '590 patent examiner rejected all claims under 35 U.S.C. § 103, relying on three references that Jones cited in the IDS — the Ryan reference, the Green reference, and the Wong reference. Def-PFF, at 143, ¶ 30. In rejecting the claims for obviousness, the examiner noted that atomoxetine was known in the prior art to inhibit norepinephrine (monoamine) uptake, citing the Wong reference. Id. at 143, ¶ 31. The examiner also stated that the Ryan reference suggests using selective inhibitors of monoamine uptake, such as tricyclic antidepressants, to treat ADHD. Id. at 143, ¶ 32. The examiner also referenced a “motivating factor” for using the newly developed antidepressant, atomoxetine, in treating ADHD, which was “a desire to more selectively inhibit monoamine uptake with potent inhibitors having longer durations of action and potentially fewer side effects.” Id. at 143, ¶ 33.

In October 1996, Robert Titus, another Lilly patent attorney, filed a brief appealing the examiner’s final rejection. Pl-PFF, ¶ 131. The brief explained that a rejection of the claims for obviousness was improper because:

An artisan skilled in the relevant art is well aware that the tricyclic antidepressants as a class, in addition to their mixed serotonin and norepinephrine re-uptake inhibition activity, bind directly to a wide variety of receptors. Wong discloses (pages 63-64, section entitled “Receptor affinity in vitro”), for example, that the tricyclic antidepressants desipramine and imipramine have high affinity at alpha-1, alpha-2, histamine-1, and muscarinic receptors. Furthermore, Cusack reports (Cusack, et al., Psychopharmacology, 114, 559-565 (1994); PTO-1449 entry CAA, page 564, Table 2) that many of the tricyclic antidepressants have affinity at the human histamine-1, muscarinic, alpha-1, alpha-2, 5-HTla, and 5-HT2 receptors. The tricyclic antidepressants exhibit high affinity for a broad, diverse set of receptors. The pharmacological benefit of this class could be mediated by any single neurotransmitter or by some combinat