UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`Alkermes Pharma Ireland, Ltd.
`and Alkermes, Inc.
`Petitioners,
`
`v.
`
`Otsuka Pharmaceutical Co., Ltd.
`Patent Owner
`
`Patent No. 9,125,939 B2
`Issued: September 8, 2015
`Filed: August 2, 2006
`Inventors: Tetsuro Kikuchi, Taro Iwamoto, Tsuyoshi Hirose
`
`Title: CARBOSTYRIL DERIVATIVES AND MOOD STABILIZERS FOR
`TREATING MOOD DISORDERS
`
`___________________
`
`Inter Partes Review No. IPR2017-00287
`
`DECLARATION OF ALLEN FRANCES, M.D. IN SUPPORT OF THE
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,125,939
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`Page
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`V.
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`ASSIGNMENT ................................................................................................ 4
`I.
`QUALIFICATIONS AND EXPERIENCE ..................................................... 5
`II.
`III. MATERIALS CONSIDERED ........................................................................ 7
`IV. HISTORICAL BACKGROUND: TREATMENT OF BIPOLAR
`DISORDERS WITH ANTIPSYCHOTICS .................................................... 7
`A. Antipsychotics .......................................................................................... 8
`B. Mood Stabilizers .................................................................................... 11
`C. Combination Therapy ............................................................................ 12
`SUMMARY OF PRIOR ART IN THE PERIOD IMMEDIATELY
`PRECEDING THE PATENT APPLICATION ............................................ 15
`VI. DIAGNOSTIC CLASSIFICATION OF RELEVANT DISORDERS ......... 25
`VII. CHALLENGED CLAIMS OF THE ’939 PATENT .................................... 28
`VIII. LEGAL STANDARD FOR OBVIOUSNESS (35 U.S.C. § 103) ................ 30
`IX. PERSON OF ORDINARY SKILL IN THE ART ........................................ 31
`X.
`CLAIM CONSTRUCTION .......................................................................... 32
`XI. OPINIONS ..................................................................................................... 34
`A. Claims 2, 6, 7, and 9 are Obvious Based on American Psychiatric
`Association Practice Guidelines 2002, in view of Keck or BMS/Otsuka
`Press Release .......................................................................................... 34
`B. Claims 2, 6, 7, 9 are Obvious Based on American Psychiatric
`Association Practice Guidelines 2002, Keck or the BMS/Otsuka Press
`Release, and Tohen ................................................................................ 40
`C. Claims 2, 6, 7, 9 are Obvious Based on Tohen in view of Keck or
`BMS/Otsuka Press Release .................................................................... 43
`D. Claims 2, 6, 7, 9 are Obvious Based on Citrome in view of the
`American Psychiatric Association Practice Guidelines 2002 ................ 44
`E. Claims 2, 6, 7, 9 are Obvious Based on Citrome in view of Tohen
`and/or Keck or BMS/Otsuka Press Release ........................................... 46
`F. Claims 2, 6, 7, 9 are Obvious Based on Expert Consensus 2000 in view
`of Keck or BMS/Otsuka Press Release ................................................. 48
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`G. Secondary Considerations Fail to Demonstrate the Non-Obviousness of
`Claims 2, 6, 7, and 9 .............................................................................. 50
`XII. COMPENSATION ........................................................................................ 51
`XIII. SUPPLEMENTATION ................................................................................. 52
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`I, Allen Frances, M.D., submit this declaration on behalf of Petitioners
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`Alkermes Pharma Ireland Ltd. and Alkermes, Inc. (collectively, “Alkermes”) to
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`address the obviousness of claims 2, 6, 7, and 9 of U.S. Patent No. 9,125,939 to
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`Kikuchi et al., titled “Carbostyril Derivatives and Mood Stabilizers for Treating
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`Mood Disorders” (“the ’939 Patent”, Ex. 1001), and to provide technical
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`background, scientific and clinical information that is relevant to that analysis.
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`I.
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`ASSIGNMENT
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`1.
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`I was asked to offer opinions on the level of ordinary skill in the field
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`to which the ’939 patent pertains, that is, the qualifications of an individual to
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`whom the alleged invention described in the ’939 patent would be directed to. I
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`understand that the application that resulted in the issuance of the ’939 patent was
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`filed on May 23, 2003. I understand that I have been asked to offer my opinions
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`from the point of view of a person of ordinary skill prior to that date, that is,
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`May 22, 2003 or earlier.
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`2.
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`I was also asked to opine on whether the inventions of claims 2, 6, 7,
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`and 9 of the ’939 patent would have been obvious to a person of ordinary skill as
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`of May 22, 2003, in view of the knowledge and experience of that person as well
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`as the prior art, that is, whether the above-referenced individual would have found
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`the alleged invention of the ’939 patent to be a routine advancement in the
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`scientific field, requiring nothing more than a knowledge of scientific references
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`that were available at the time, together with ordinary practice.
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`II. QUALIFICATIONS AND EXPERIENCE
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`3.
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`I am a board certified clinical psychiatrist with nearly 50 years of
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`experience treating patients for psychiatric and mood disorders. I received a B.A.
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`from Columbia College (1963) and an M.D. from Downstate Medical Center
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`(1967), and I completed my residency and fellowship in psychiatry and
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`psychoanalytic medicine at Columbia University hospitals and the New York State
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`Psychiatric Institute.
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`4.
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`I am currently Professor Emeritus and former Chair of the Department
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`of Psychiatry and Behavioral Sciences at Duke University, where I have been since
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`1991. Prior to that, I held professorial positions in psychiatry at the Columbia
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`University College of Physicians and Surgeons and at the Cornell University
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`Medical College.
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`5.
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`I was Chair of the DSM-IV Task Force and also held leadership
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`positions in the preparation of DSM-III and DSM-IIIR. DSM refers to Diagnostic
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`and Statistical Manual of Mental Disorders, a set of standards used by health
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`professionals in the United States for the classification and diagnosis of mental
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`disorders. My responsibilities as Chair of the DSM-IV Task Force included
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`establishing the methods used in its preparation; recruiting the approximately one
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`thousand diagnostic experts who comprised the DSM-IV Task Force, Work
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`Groups, and Advisors; chairing all Task Force meetings and conference calls;
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`participating in all Work Group meetings and conference calls; and editing the
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`final draft of DSM-IV texts, criteria sets, and introductory material.
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`6.
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`I have written several hundred papers and book chapters and more
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`than a dozen books on various aspects of psychiatric diagnosis and treatment. I
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`have also been the recipient of about a dozen research grants, including grants for
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`DSM-IV Field Trials; treatment strategies for schizophrenia and schizoaffective
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`disorders; and the treatment of chronic depression.
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`7.
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`I was the founding editor of two psychiatric journals (The Journal of
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`Personality Disorders and The Journal of Psychiatric Practice) and have been on
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`the editorial board or served as a reviewer of many other psychiatric journals and
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`book series.
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`8. My 50-year career in psychiatry provides me with a long view
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`perspective on the historical evolution of clinical practice in the field generally and
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`of Bipolar Disorder specifically. I was involved in the early testing of lithium for
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`safety, efficacy, and dosing several years before it was approved for use in Bipolar
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`Disorder in the United States and was among the early users of haloperidol and
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`other first generation antipsychotics in Bipolar Disorder and Schizophrenia.
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`9.
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`A copy of my curriculum vitae with a complete and accurate summary
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`of my academic and professional background and experience is available at Ex.
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`1003.
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`III. MATERIALS CONSIDERED
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`10. The materials upon which I rely and otherwise considered in
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`formulating my opinions are set forth in this declaration below, including the
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`specification (written description and claims) and the file history of the ’939
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`patent, and the materials cited in the various Appendices referenced herein. I also
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`rely on my education, professional training and expertise in psychiatry, which I
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`have developed in over 50 years of experience as a psychiatric clinician, teacher,
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`administrator, and researcher.
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`IV. HISTORICAL BACKGROUND: TREATMENT OF BIPOLAR
`DISORDERS WITH ANTIPSYCHOTICS
`11.
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`In this section, I will briefly sketch the history of diagnosis and
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`treatment of Bipolar Disorder over the past sixty-five years. The literature
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`demonstrates clearly that the combination of antipsychotic medication and mood
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`stabilizer medication had already been the well-established and widely accepted
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`standard of care in psychiatry for many decades before this patent application was
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`submitted. The combination of antipsychotic medication and mood stabilizer
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`medication would have been a perfectly obvious treatment to any clinician treating
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`a patient with Bipolar Disorder. As new antipsychotics have come on the market
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`over the years, each one has been used in the treatment of Bipolar Disorder in a
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`way equivalent to preceding antipsychotic drugs. A psychiatrist of ordinary skill
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`would have expected aripiprazole to have the same well-established pattern of
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`usefulness in combination with mood stabilizing drugs in the treatment of Bipolar
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`Disorder.
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`A. Antipsychotics
`12. Modern medication treatment of Bipolar Disorder began with the
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`discovery of chlorpromazine in France in the early 1950’s and its approval by the
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`FDA for use in the United States in 1954. Subsequently, a number of other first
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`generation antipsychotics (haloperidol, thioridazine, fluphenazine, perphenazine,
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`and trifluoperazine) were also approved and also widely used by practitioners. All
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`of these so-called “first generation antipsychotics” were helpful in the treatment of
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`Schizophrenia; Schizoaffective Disorder; the manic phase of Bipolar Disorder;
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`mixed mood states in Bipolar Disorder; agitation and psychosis in the depressive
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`phase of Bipolar Disorder; and agitation and psychosis in Major Depressive
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`Disorder. Until the approval of lithium in 1970, antipsychotics were the preferred
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`treatment for these conditions. Even after the introduction of lithium (and later,
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`other mood stabilizing drugs), antipsychotics remained essential in the treatment of
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`mania, psychosis, agitation, and mixed states – because these conditions often do
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`not respond sufficiently or nearly quickly enough to mood stabilizing medications
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`when prescribed alone.
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`13. Clozapine, discovered in the 1960’s and used for the first time in the
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`1970’s, was the first of the atypical antipsychotic medications. However, because
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`of its dangerous side effect profile, clozapine is used only infrequently, and only
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`for those patients whose schizophrenic symptoms have proven to be refractory and
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`unresponsive to other treatments.
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`14. A variety of other atypical or “second generation” antipsychotic
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`medications have been approved since the early 1990’s (including risperidone,
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`olanzapine, aripiprazole, quetiapine, ziprasidone, and lurasidone). For example,
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`risperidone was approved for sale in the U.S. in 1993. Olanzapine was approved
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`for clinical use in the U.S. in 1996. Aripiprazole was discovered in 1988,
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`published in 1990, studied throughout the 1990’s, and approved for clinical use in
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`November, 2002 for acute exacerbations of Schizophrenia and for prevention of
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`relapse.
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`15. Second generation antipsychotics have become more widely used than
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`the first generation because their side effect profile is more tolerable to many
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`patients. In summary, clinicians typically will chose among first and second
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`generation antipsychotic medications based on side effect profile rather than
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`differences in efficacy.
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`16. Antipsychotic treatment is usually essential when treating manic or
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`mixed episodes, because these patients are extremely impulsive, energetic, and
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`agitated, and likely to get into trouble. Such patients are also liable to make
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`terrible decisions; to inflict harm on themselves or others; to have serious
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`accidents; to create financial or sexual messes; to commit crimes; to travel
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`inappropriately; and to succumb to physical exhaustion, sometimes to the point of
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`death. Patients with mixed episodes often have symptoms that are especially
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`urgent and severe.
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`17. Antipsychotic treatment is also usually essential to control agitated
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`and/or delusional depression, which can lead to self-harm, harm to others, bad
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`decisions, accidents, severe weight loss, incapacitating insomnia, inability to
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`function, and lost jobs and relationships. And while mood stabilizers are
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`enormously helpful in the long-term management of Bipolar Disorder once the
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`patient is stabilized; they rarely work quickly or completely enough to deal with
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`the substantial risk inherent in acute episodes. Moreover, mood stabilizers are often
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`only partially effective for long-term maintenance treatment of Bipolar Disorder
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`and require the addition of adjunctive antipsychotic medication.
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`18.
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`In summary, antipsychotic medications were used for the treatment of
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`Bipolar Disorder for many years prior to the approval and availability of lithium,
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`the first mood stabilizer. Even after the introduction of mood stabilizers, they have
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`continued to be a mainstay of treatment for Bipolar Disorder. Clinicians in the last
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`five decades would expect that every new antipsychotic medication would be
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`useful in the treatment of Bipolar Disorder, but that these medications may differ
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`in side effect profile. Indeed, the use of antipsychotic medications in Bipolar
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`Disorder is one of the oldest and best-established indications in all of psychiatry, as
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`documented in textbooks, review articles, practice guidelines, surveys and
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`individual papers. This use of antipsychotic medications for the treatment of
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`Bipolar Disorder is one of the first things psychiatric residents would learn and
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`would be a fundamental and an enduring component of practice throughout the
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`career of a treating psychiatrist.
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`B. Mood Stabilizers
`19. Mood stabilizers have also been important in the treatment of Bipolar
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`Disorder. They include lithium, valproate or divalproex sodium, carbamazepine,
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`and lamotrigine.
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`20. Lithium was first proven effective for treatment of Bipolar Disorder in
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`the early 1950s, but was not approved by the FDA for use in the United States until
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`1970. Lithium is useful in treating the manic phase of Bipolar Disorder, but works
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`much more slowly than the antipsychotics and is often only partially effective.
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`Lithium is also helpful in reducing relapses, improving depression, and reducing
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`the risk of suicide and self-harm in patients with Bipolar Disorder. Lithium
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`remains one of the most effective treatments for Bipolar Disorder – perhaps even
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`underutilized compared to other mood stabilizers because of greater difficulty in
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`titrating its dose and greater risks of side effects and complications.
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`21. Other mood stabilizers include divalproex, shown in the late 1980’s to
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`be safe and effective in treating acute mania, comparing favorably with lithium and
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`superior to placebo; carbamazepine, used for the treatment of mania and mixed
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`episodes in Bipolar Disorder since the mid 1970’s; and lamotrigine, not helpful in
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`the treatment of acute mania or depression and approved only for the maintenance
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`phase of Bipolar Disorder.
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`22. None of the mood stabilizers work quickly enough or consistently
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`enough to control acute mania or mixed states in Bipolar Disorder or agitation in
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`psychosis complicating a major depressive episode. Since these conditions are
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`urgent, sometimes emergent, antipsychotic medications are almost always the first
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`line and an essential part of treatment.
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`C. Combination Therapy
`23. The combination of antipsychotics and mood stabilizers, often along
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`with an antidepressant, is, and for a long time has been, the standard treatment for
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`Bipolar Disorder. A series of appendices attached to this declaration document the
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`pervasiveness and consistency of recommendations suggesting the use of
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`combination therapy consisting of mood stabilizers and antipsychotics to treat
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`Bipolar Disorder; with copious evidence already present starting from the early
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`1970’s and continuing in uninterrupted fashion throughout the subsequent decades
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`preceding the patent application of 2003.1 In 2003, there was absolutely nothing
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`novel or inventive about combination therapy utilizing an antipsychotic medication
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`and a mood stabilizing medication, as this combination had been in use, and
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`universally recommended, for over 30 years. In fact, in May 2003, the
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`combination of antipsychotics with mood stabilizers such as lithium was viewed as
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`potentially more effective than either agent alone (see Ex. 1009, American
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`Psychiatric Association Practice Guidelines 2002).
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`24. Specifically, prior to May 2003, manic or mixed episodes were being
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`treated with lithium or valproate plus an antipsychotic, preferably an atypical
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`antipsychotic because of their more benign side effect profiles (Ex. 1009,
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`American Psychiatric Association Practice Guidelines 2002; Ex. 1026, Expert
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`1 Appendix A contains relevant excerpts from several editions of standard
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`psychiatry textbooks to document this point. Appendix B documents relevant
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`excerpts from practice guidelines. Appendix C provides relevant excerpts from
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`surveys. Appendix D provides relevant excerpts from research papers. The
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`materials in the appendices represent only a small sample of a much larger
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`universe of similar comments made in research papers, textbooks, surveys, and
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`guidelines.
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`Consensus 2000; Ex. 1027, American Family Physician 2000). Atypical
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`antipsychotics were also recommended for long term treatment of Bipolar Disorder
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`(Ex. 1026, Expert Consensus 2000). Antipsychotics are usually not necessary in
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`the hypomanic phase of Bipolar II Disorder, but are often necessary during Major
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`Depressive Episodes when these are accompanied by agitation or psychotic
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`features (Ex. 1009, American Psychiatric Association Practice Guidelines 2002).
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`And antipsychotics were considered essential to treat psychotic mania, as might be
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`encountered in Bipolar I Disorder (Ex. 1026, Expert Consensus 2000).
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`25. Moreover, well before May 2003, experts in the field of psychiatry
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`were already recommending the addition of an atypical antipsychotic to augment a
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`partial response to treatment with a mood stabilizing medication (Ex. 1026, Expert
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`Consensus 2000). The antipsychotic used in combination therapy treatment could
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`be replaced with another antipsychotic if the patient were not responding to the
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`initial antipsychotic (Ex. 1026, Expert Consensus 2000, “If a patient is not
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`responding to the combination of a mood stabilizer and an antipsychotic, it may be
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`appropriate to change the antipsychotic earlier than the mood stabilizer.”)
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`26. The popularity of the various different antipsychotic drugs and the
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`various different mood stabilizing drugs has changed over time as new products
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`have come to market, but the use of combination therapy for the treatment of
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`Bipolar Disorder in the form of a mood stabilizer and an antipsychotic is one of the
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`best-established aspects of all psychiatric practice.
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`V.
`SUMMARY OF PRIOR ART IN THE PERIOD IMMEDIATELY
`PRECEDING THE PATENT APPLICATION
`27. Below is a selection of references from the vast literature of
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`guidelines, surveys, and papers on the subject of the treatment of Bipolar Disorder
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`that immediately precede the filing of the patent application that issued as the ’939
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`patent. This selection is not meant to be exhaustive.2
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`28. American Psychiatric Association Practice Guidelines 2002 – Ex.
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`1009, American Psychiatric Association, Practice Guideline for the Treatment of
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`Patients With Bipolar Disorder (Revision), April 2002, provided guidance to
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`psychiatrists on the treatment of Bipolar Disorder, including treatment of manic or
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`mixed episodes. American Psychiatric Association Practice Guidelines 2002
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`advised that “the first-line pharmacological treatment for more severe manic or
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`mixed episodes is the initiation of either lithium plus an antipsychotic or valproate
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`plus an antipsychotic,” and that “the combination of an antipsychotic with either
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`lithium or valproate may be more effective than any of these agents alone.” Id. at
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`4, 9. American Psychiatric Association Practice Guidelines 2002 also advised that
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`2 The Appendices to this declaration provide additional references, but are still not
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`meant to be exhaustive.
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`monotherapy with lithium or an antipsychotic such as olanzapine may be sufficient
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`for less ill patients, but when such first line treatment fails, it is recommended to
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`add an antipsychotic or change from one antipsychotic to another. Id. at 9.
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`American Psychiatric Association Practice Guidelines 2002 also recommended
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`that atypical antipsychotics are preferred over typical antipsychotics because of
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`their more benign side effect profile. Id. at 4, 9, 10. American Psychiatric
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`Association Practice Guidelines 2002 is a printed publication that was available to
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`psychiatrists and the public as of April, 2002, and is thus prior art to the ’939
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`patent. American Psychiatric Association Practice Guidelines 2002, produced by
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`the American Psychiatric Association in the period immediately before the patent
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`was submitted, makes crystal clear that the combination of an atypical
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`antipsychotic and mood stabilizer was, at that time, the community standard of
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`care.
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`29. Expert Consensus 2000 - Ex. 1026, The Expert Consensus Guideline
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`Series Medication Treatment of Bipolar Disorder 2000, A Postgraduate Medicine
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`Special Report, April 2000, is another set of widely-used guidelines for the
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`treatment of Bipolar Disorder. Expert Consensus 2000 recommended
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`antipsychotics as first line in the treatment of mania or depression with psychosis,
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`and as potential adjuncts in non-psychotic episodes. Id. at 5. Atypical
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`antipsychotics, such as olanzapine and risperidone, were generally preferred over
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`conventional antipsychotics, especially for long-term therapy. Id. at 5, 10.
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`Moreover, if treatment with the combination of a mood stabilizer and an
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`antipsychotic was not providing the desired therapeutic result, Expert Consensus
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`2000 recommended substituting antipsychotics before substituting the mood
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`stabilizer. Id. at 19. Expert Consensus 2000 reported that the combination of a
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`mood stabilizer with an antipsychotic was either the treatment of choice or an
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`alternative treatment for euphoric mania. Id. at 7.
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`30. Moreover, Expert Consensus 2000 indicated that the combination of a
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`mood stabilizer with an antipsychotic was either the treatment of choice or an
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`alternative treatment for mania with psychosis, dysphoric mania or true mixed
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`mania, and euphoric mania:
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`Id. at 16. Expert Consensus 2000 is a printed publication that was available to the
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`public as of April, 2000, and is thus prior art to the ’939 patent. Expert Consensus
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`2000 is yet another compelling indication that the combination of atypical
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`antipsychotic and mood stabilizer was a standard of care in psychiatry.
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`31. American Family Physician 2000 – Ex. 1027, Griswold et al.,
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`Management of Bipolar Disorder, Am. Fam. Physician 62(6):1343-1353,
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`September 15 2000, provided guidance on the treatment of Bipolar Disorder to
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`physicians. American Family Physician 2000 gave recommendations for the use
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`of lithium to treat euphoric and mixed mania, and for the use of valproic acid to
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`treat euphoric mania, mixed manic episodes, mania with rapid cycling, and for
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`long-term maintenance therapy in patients who did not tolerate lithium. Id. at
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`Table 4. It also recommended that antipsychotics be used as adjunctive treatment
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`for mania with psychosis or psychotic depression. Id. American Family Physician
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`2000 is a printed publication that was available to the public as of September,
`
`2000, and is thus prior art to the ’939 patent. American Family Physician 2000
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`documents that a combination of antipsychotic medication and mood stabilizer was
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`also a standard of care for family and general practitioners.
`
`32. Lim – Ex. 1053, Lim et al., Medication Prescribing Patterns for
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`Patients with Bipolar I Disorder in Hospital Settings: Adherence to Published
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`Practice Guidelines, Bipolar Disorders 2001: 3 (2001) 165-173, examined the
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`medication prescribing patterns for Bipolar I Disorder in hospital settings and
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`compared them to recently published expert consensus guidelines for medication
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`treatment of Bipolar Disorder. Lim surveyed 1846 patients with Bipolar I disorder,
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`and reported that the combined therapy of a mood stabilizer and an antipsychotic
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`was by far the most common form of therapy for Bipolar I mania with psychotic
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`features. It was also a common form of therapy for Bipolar I mania without
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`psychotic features, and for Bipolar I depression, with or without psychotic features.
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`Id. at 168-69.
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`33. Frye 2000 – Ex. 1029, Frye et al., The Increasing Use of
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`Polypharmacotherapy for Refractory Mood Disorders: 22 Years of Study, J Clin
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`Psychiatry 61:1, January 2000, pp. 9-15, discussed the use of mood stabilizers in
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`conjunction with antipsychotics to treat mood disorders such as Bipolar Disorder.
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`In particular, Frye 2000 reported that as of 1996, patients with Bipolar Disorder
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`were commonly being treated with lithium supplemented by, among other things,
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`antipsychotics. Id. at 9. Frye 2000 reported that the most common type of
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`combined therapy, the use of adjunctive medication, was present in 28% to 75% of
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`diverse patient populations, and that recent reviews suggested this was common
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`practice. Id. at 10. Frye 2000 also reported that 70% of patients with an affective
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`relapse did better on combined therapy when compared to an existing regimen of
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`lithium monotherapy. Id. Frye 2000 is a printed publication that was available to
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`the public as of January, 2000, and is thus prior art to the ’939 patent. Frye 2000
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`demonstrates again that the combined use of antipsychotics and mood stabilizers
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`was already common practice amongst clinicians before the submission of the
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`patent application.
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`34. Keck – Ex. 1007, Keck et al., Aripiprazole Versus Placebo in Acute
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`Mania, Abstracts of the 2002 Annual Meeting of the American Psychiatric
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`Association, Abstract NR314, described a randomized placebo-controlled efficacy
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`study done on aripiprazole versus placebo in patients with acute bipolar mania.
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`The study evaluated the severity of manic episodes using the Young Mania Rating
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`Scale (Y-MRS), a multiple choice diagnostic questionnaire. Keck reported that
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`aripiprazole provided a higher response rate and statistically significant
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`improvement in the Y-MRS total score. Keck concluded that aripiprazole was
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`effective and well tolerated in the treatment of acute mania in patients with Bipolar
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`Disorder. The 2002 Annual Meeting of the American Psychiatric Association was
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`held May 18-23, 2002. See Cover. Abstracts from Annual Meetings of the
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`American Psychiatric Association were made available in print form to
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`psychiatrists and to the public on or before the first day of the conference and
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`would have been provided to the interested psychiatric public starting on May 18,
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`2002, if not earlier. Therefore, Keck is a printed publication that was available to
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`the public as of May 18, 2002, and is thus prior art to the ’939 patent.3 Keck
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`demonstrates that the value of aripiprazole to treat Bipolar Disorder was known
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`before the patent application was submitted.
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`35. BMS/Otsuka Press Release – Ex. 1028, Data Demonstrate
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`Aripiprazole Significantly Improved Symptoms of Acute Mania in Patients With
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`Bipolar Disorder; New Data Presented Today at American Psychiatric Association
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`Annual Meeting, PR Newswire, May 22, 2002, available at
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`http://www.prnewswire.com/news-releases/data-demonstrate-aripiprazole-
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`significantly-improved-symptoms-of-acute-mania-in-patients-with-bipolar-
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`3 I have attended more than 20 Annual Meetings of the American Psychiatric
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`Association and was vice-chair of its Program Committee for 6 years. Abstracts
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`from Annual Meetings of the American Psychiatric Association are routinely made
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`available in print form to psychiatrists and to the public on or before the first day
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`of the conference. The American Psychiatric Association is the main professional
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`organization of psychiatrists and trainee psychiatrists in the United States, and the
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`largest psychiatric organization in the world, with over 36,500 members practicing
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`in more than 100 countries. The Annual Meetings of the American Psychiatric
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`Association would have been well advertised to, and well attended by, psychiatrists
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`in the field.
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`disorder-77570072.html, is a press release from Bristol-Myers Squibb (“BMS”)
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`and Otsuka Pharmaceutical Co., Ltd. (“Otsuka”). The BMS/Otsuka Press Release,
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`citing Keck, disclosed that aripiprazole showed significant improvement in
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`symptoms of acute mania, had a rapid onset of action, significantly reducing
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`symptoms of acute mania by day four of treatment, and was well tolerated, with
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`discontinuations of therapy due to adverse events similar to placebo. Id. at 1.
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`Additionally, aripiprazole did not show clinically meaningful weight change when
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`compared with placebo. Id. The BMS/Otsuka Press Release noted that BMS and
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`Otsuka were currently conducting clinical trials with aripiprazole in psychotic
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`illnesses including Bipolar Disorder. Id. at 2. BMS/Otsuka Press Release is a
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`printed publication that was available to the public as of May 22, 2002, and is thus
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`prior art to the ’939 patent. BMS/Otsuka Press Release demonstrates that the value
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`of aripiprazole to treat Bipolar Disorder was known before the patent application
`
`was submitted.
`
`36. Tohen – Ex. 1006, Tohen et al., Efficacy of Olanzapine in
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`Combination With Valproate or Lithium in the Treatment of Mania in Patients
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`Partially Nonresponsive to Valproate or Lithium Monotherapy, Arch Gen
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`Psychiatry 59, January 2002, pp. 62-69, described a 6-week double blind,
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`randomized, placebo-controlled trial to determine the efficacy of the combination
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`of olanzapine with valproate or lithium when compared with valproate or lithium
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`monotherapy, in the treatment of Bipolar Disorder. Tohen reported that olanzapine
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`co-therapy improved patients’ Y-MRS total scores and clinical response rates
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`significantly when compared with monotherapy with a mood stabilizer. Id. at 62.
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`Tohen concluded that compared with the use of valproate or lithium alone, the
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`addition of olanzapine provided superior efficacy in the treatment of manic and
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`mixed bipolar episodes. Id. Tohen is a printed publication th