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
`
`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
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ........................................................................................... 1(cid:3)
`I.(cid:3)
`PRELIMINARY STATEMENT ..................................................................... 1(cid:3)
`II.(cid:3)
`III.(cid:3) MANDATORY NOTICES ............................................................................. 4(cid:3)
`A.(cid:3)
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ............................ 4(cid:3)
`B.(cid:3)
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ..................................... 4(cid:3)
`C.(cid:3)
`Lead and Back-up Counsel Under 37 C.F.R. § 42.8(b)(3) ................... 5(cid:3)
`D.(cid:3)
`Service Information Under 37 C.F.R. § 42.8(b)(4) ............................... 5(cid:3)
`IV.(cid:3) PAYMENT OF FEES ..................................................................................... 6(cid:3)
`V.(cid:3) GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a) ..................... 6(cid:3)
`VI.(cid:3) THE ’939 PATENT ......................................................................................... 6(cid:3)
`A.(cid:3)
`Challenged Claims of the ’939 Patent ................................................... 6(cid:3)
`B.(cid:3)
`Prosecution History of the ’939 Patent ................................................. 7(cid:3)
`C.(cid:3)
`Claim Construction ............................................................................... 9(cid:3)
`D.(cid:3)
`Level of Ordinary Skill in the Art ....................................................... 11(cid:3)
`VII.(cid:3) SCOPE AND CONTENT OF THE PRIOR ART ......................................... 12(cid:3)
`A.(cid:3)
`Bipolar Disorder .................................................................................. 12(cid:3)
`B.(cid:3)
`Treatment of Bipolar Disorder ............................................................ 12(cid:3)
`1.(cid:3)
`Antipsychotics ........................................................................... 13(cid:3)
`a.(cid:3)
`Keck (Ex. 1007) .............................................................. 14(cid:3)
`b.(cid:3)
`BMS/Otsuka Press Release (Ex. 1028) .......................... 15(cid:3)
`2.(cid:3) Mood Stabilizers ....................................................................... 16(cid:3)
`3.(cid:3)
`Combination Therapy ............................................................... 17(cid:3)
`a.(cid:3)
`APA Practice Guidelines 2002 (Ex. 1009) ..................... 18(cid:3)
`b.(cid:3)
`Expert Consensus (Ex. 1026) ......................................... 19(cid:3)
`c.(cid:3)
`Tohen (Ex. 1006) ............................................................ 21(cid:3)
`d.(cid:3)
`Citrome (Ex. 1008) ......................................................... 22(cid:3)
`VIII.(cid:3) GROUNDS FOR PETITION ........................................................................ 23(cid:3)
`A.(cid:3) DETAILED EXPLANATION UNDER 37 C.F.R. § 42.104(b) ......... 24(cid:3)
`
`i
`
`

`

`2.(cid:3)
`
`3.(cid:3)
`
`4.(cid:3)
`
`1.(cid:3)
`
`Ground 1: Claims 2, 6, 7, and 9 are Obvious Based on APA
`Practice Guidelines 2002 (Ex. 1009), in view of Keck (Ex.
`1007) or BMS/Otsuka Press Release (Ex. 1028) ...................... 24(cid:3)
`Ground 2: Claims 2, 6, 7, and 9 are Obvious Based on Tohen
`(Ex. 1006) in view of Keck (Ex. 1007) or BMS/Otsuka Press
`Release (Ex. 1028) .................................................................... 30(cid:3)
`Ground 3: Claims 2, 6, 7, and 9 are Obvious Based on Expert
`Consensus (Ex. 1026) in view of Keck (Ex. 1007) and/or
`BMS/Otsuka Press Release (Ex. 1028) ..................................... 32(cid:3)
`Ground 4: Claims 2, 6, 7, and 9 are Obvious Based on APA
`Practice Guidelines 2002 (Ex. 1009), Keck (Ex. 1007) or the
`BMS/Otsuka Press Release (Ex. 1028), and Tohen (Ex. 1006)
` ................................................................................................... 34(cid:3)
`Ground 5: Claims 2, 6, 7, and 9 are Obvious Based on Citrome
`(Ex. 1008) in view of APA Practice Guidelines 2002 (Ex. 1009)
` ................................................................................................... 37(cid:3)
`Ground 6: Claims 2, 6, 7, and 9 are Obvious Based on Citrome
`(Ex. 1008) in view of Tohen (Ex. 1006) and/or Keck (Ex. 1007)
`or BMS/Otsuka Press Release (Ex. 1028) ................................ 39(cid:3)
`No Secondary Considerations Support Non-Obviousness ....... 41(cid:3)
`a.(cid:3)
`The Hirose Data are Unreliable ...................................... 44(cid:3)
`b.(cid:3)
`Hirose’s Conclusion is Statistically Unsound ................ 46(cid:3)
`c.(cid:3)
`The Experimental Design Cannot Show Synergy .......... 47(cid:3)
`d.(cid:3)
`The Results are
`Insufficient
`to Establish Non-
`Obviousness .................................................................... 48(cid:3)
`IX.(cid:3) CONCLUSION .............................................................................................. 50(cid:3)
`
`5.(cid:3)
`
`6.(cid:3)
`
`7.(cid:3)
`
`ii
`
`

`

`LIST OF EXHIBITS
`Description
`
`Ex. 1005
`Ex. 1006
`
`Alkermes
`Ex. No.
`Ex. 1001 U.S. Patent 9,125,939
`Ex. 1002 Declaration of Allen Frances, M.D. in Support of the Petition for
`Inter Partes Review of U.S. Patent No. 9,125,939
`Ex. 1003 Allen Frances, M.D., Curriculum Vitae
`Ex. 1004 Declaration of Jessie Au, Pharm.D., Ph.D. in Support of the Petition
`for Inter Partes Review of U.S. Patent No. 9,125,939
`Jessie Au, Pharm.D., Ph.D., Curriculum Vitae
`Tohen et al., Efficacy of olanzapine in combination with valproate
`or lithium in the treatment of mania in patients partially
`nonresponsive to valproate or lithium monotherapy, ARCH. GEN.
`PSYCHIATRY, v. 59(1): 62-69 (2002)
`“Tohen”
`Ex. 1007 Keck PE Jr et al., Aripiprazole versus placebo in acute mania,
`Abstracts of the 2002 Annual Meeting of the American Psychiatric
`Association; Philadelphia, PA. USA (2002) (New Research Abstract
`314 (NR314)).
`“Keck”
`Ex. 1008 Citrome et al., Pharmacokinetics and safety of aripiprazole and
`concomitant mood stabilizers, Abstracts of the 2002 Annual
`Meeting of the American Psychiatric Association; Philadelphia, PA.
`USA (2002) (New Research Abstract 317 (NR317)).
`“Citrome”
`American Psychiatric Association, Practice guideline for the
`treatment of patients with bipolar disorder (Revision), AM. J.
`PSYCHIATRY, 159:4, April 2002 Supplement.
`“APA Practice Guidelines 2002”
`Ex. 1010 Kowatch R.A. et al., The use of mood stabilizers and atypical
`antipsychotics in children and adolescents with bipolar disorders,
`CNS SPECTRUMS, 8(4): 273-280 (2003).
`“Kowatch”
`Ex. 1011 Vieta, Eduard, et al., Olanzapine as long-term adjunctive therapy in
`treatment-resistant bipolar disorder, J. CLIN. PSYCHOPHARMACOL.,
`v.21(5): 469-473 (2001).
`“Vieta”
`Ex. 1012 Ketter, TA. et al., Rapid efficacy of olanzapine augmentation in
`nonpsychotic bipolar mixed states [letter], J. CLIN. PSYCHIATRY,
`
`Ex. 1009
`
`iii
`
`

`

`59:83-85. (1998)
`“Ketter”
`Ex. 1013 McElroy SL, et al., Olanzapine in treatment-resistant bipolar
`disorder, J. AFFECT DISORD. 49:119-122. (1998)
`“McElroy”
`Ex. 1014 Sachs, G.S. et al., Quetiapine versus placebo as adjunct to mood
`stabilizer for the treatment of acute mania, BIPOLAR DISORDER 4
`suppl. I. 133. (2002)
`“Sachs I”
`Ex. 1015 Yatham, Lakshmi N. et al., The role of novel antipsychotics in
`bipolar disorder, J. CLIN. PSYCHIATRY 63: 10-14 (2002)
`“Yatham”
`Petrie, J.L. et al., Aripiprazole, a new atypical antipsychotic: phase
`II clinical trial results. EUR. NEUROPSYCHOPHARM 7 (Suppl 2):S227
`(1997)
`“Petrie”
`Ex. 1017 Goodwin, G.M., Typical and atypical antipsychotics in the
`treatment of mania, EUR. NEUROPSYCHOPHARM 11 (Suppl 3): S132
`(2001)
`“Goodwin”
`Ex. 1018 Chang, Kiki D. and Ketter, Terence A., Mood stabilizer
`augmentation with olanzapine in acutely manic children, J. CHILD
`AND ADOLESCENT PSYCHOPHARMACOLOGY, v:10(1): 45-49 (2000)
`“Chang”
`Ex. 1019 Del Bello M.P. et al., A double-blind, randomized, placebo-
`controlled study of quetiapine as adjunctive treatment for adolescent
`mania, J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 41: 1216-1223.
`(2002)
`“Del Bello”
`Tohen M. et al., Efficacy of olanzapine in acute bipolar mania: a
`double-blind, placebo-controlled study, ARCH. GEN. PSYCHIATRY
`57(9): 841-849 (2000)
`“Tohen II”
`Ex. 1021 Haddad P. et al., Adjunctive use of olanzapine in the treatment of
`mania, INT. J. PSYCHIATRY IN CLIN PRACTICE, v3: 213-215 (1999)
`“Haddad”
`Excerpts from the Diagnostic and Statistical Manual of Mental
`Disorder-IV
`“DSM-IV”
`
`Ex. 1022
`
`Ex. 1016
`
`Ex. 1020
`
`iv
`
`

`

`Ex. 1023
`
`Ex. 1026
`
`Jordan, S. et al., The antipsychotic aripiprazole is a potent, partial
`agonist at the human 5-HT1A receptor, EUR. J. PHARMACOL.,
`441(3):137-40 (2002)
`“Jordan”
`Ex. 1024 Miller, D.S., et al., Comparative efficacy of typical and atypical
`antipsychotics as add-on therapy to mood stabilizers in the
`treatment of acute mania, J. CLIN. PSYCHIATRY, v62:975-980 (2001)
`“Miller”
`Ex. 1025 Carlson, G.A. et al., The stages of mania. A longitudinal analysis of
`the manic episode, ARCH. GEN. PSYCHIATRY, 28(2): 221-228 (1973)
`“Carlson”
`The Expert Consensus Guideline Series Medication Treatment of
`Bipolar Disorder 2000, A Postgraduate Medicine Special Report,
`April 2000
`“Expert Consensus”
`Ex. 1027 Griswold et al., Management of Bipolar Disorder, AM. FAM.
`PHYSICIAN 62(6):1343-1353 (2000)
`“American Family Physician”
`Ex. 1028 Data Demonstrate Aripiprazole Significantly Improved Symptoms of
`Acute Mania in Patients With Bipolar Disorder; New Data
`Presented Today at American Psychiatric Association Annual
`Meeting, PR Newswire, May 22, 2002,
`“BMS/Otsuka Press Release”
`Frye et al., The Increasing Use of Polypharmacotherapy for
`Refractory Mood Disorders: 22 Years of Study, J CLIN PSYCHIATRY
`61(1): 9-15 (2000)
`“Frye 2000”
`Zar, Measures of Dispersion and Variability, in Biostatistical
`Analysis, Prentice Hall (1974)
`“Zar”
`Shimokawa, High Performance Liquid Chromatographic Methods
`for the Determination of Aripiprazole with Ultraviolet Detection in
`Rat Plasma and Brain: Application to the Pharmacokinetic Study,
`JOURNAL OF CHROMATOGRAPHY 21, 8-14, 13 (2005)
`“Shimokawa”
`Ex. 1032 Chiu and Franklin, Analysis and Pharmacokinteics of Olanzapine
`(LY170053) and Two Metabolites in Rat Plasma Using Reversed-
`Phase HPLC with Electrochemical Detection, JOURNAL OF
`
`Ex. 1031
`
`Ex. 1029
`
`Ex. 1030
`
`v
`
`

`

`Ex. 1036
`
`PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 14, 609-615 (1996)
`“Chiu and Franklin”
`Ex. 1033 Mattiuz et al., Disposition and Metabolism of Olanzapine in Mice,
`Dogs, and Rhesus Monkeys, DRUG METABOLISM AND DISPOSITION,
`25: 573-583 (1997)
`“Mattiuz”
`Ex. 1034 Aravagiri et al., Pharmacokinetics and Tissue Distribution of
`Olanzapine in Rats, BIOPHARMACEUTICS & DRUG DISPOSITION, 20:
`369–377 (1999)
`“Aravagiri”
`Ex. 1035 Gunaratna et al., An automated blood sampler for simultaneous
`sampling of systemic blood and brain microdialysates for drug
`absorption, distribution, metabolism, and elimination studies,
`JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS 49:
`57-64 (2004)
`“Gunaratna”
`Furukawa, Modifications by Lithium of Behavioral Responses to
`Methamphetamine and Tetrabenazine, PSYCHOPHARMACOLOGIA, 42,
`243-248 (1975)
`“Furukawa”
`Ex. 1037 Okada, Inhibition by Antimanic Drugs of Hyperactivity Induced by
`Methampehtamine-Chlordiazepoxide Mixture in Mice,
`PHARMACOLOGY BIOCHEMISTRY & BEHAVIOR, 35, 897-901 (1990)
`“Okada”
`Takigawa, Intracranial Self-Stimulation and Locomotor Traces as
`Indicators for Evaluating and Developing Antipsychotic Drugs,
`JAPANESE J. PSYCH. AND NEUROLOGY, 48, 1, 127-132 (1994)
`“Takigawa”
`Ex. 1039 Ago, Lithium Attenuates Methamphetamine-Induced
`Hyperlocomotion and Behavioral Sensitization Via Modulation of
`Prefrontal Monoamine Release, NEUROPHARMACOLOGY 62, 1634-
`1639 (2012)
`“Ago”
`Zhao et al., Comparison of Methods for Evaluating Drug-Drug
`Interaction, FRONTIERS IN BIOSCIENCE E2, 241-249 (2010)
`“Zhao 2010”
`Fraser, The Antagonism Between the Actions of Active Substances,
`BRITISH MED. J., 457-459 (1872)
`“Fraser”
`
`Ex. 1038
`
`Ex. 1040
`
`Ex. 1041
`
`vi
`
`

`

`Ex. 1046
`
`Ex. 1042 Berenbaum, A Method for Testing for Synergy with Any Number of
`Agents, JOURNAL OF INFECTIOUS DISEASES,137, 2, 122-130, (1978)
`“Berenbaum”
`Ex. 1043 Chou and Talalay, Quantitative Analysis of Dose-Effect
`Relationships: the Combined Effects of Multiple Drugs or Enzyme
`Inhibitors, in ADVANCES IN ENZYME REGULATION, Vol. 22, (1983)
`“Chou and Talalay”
`Ex. 1044 Greco, Application of a New Approach for the Quantitation of Drug
`Synergism to the Combination of cis-Diamminedichloroplatium and
`1-b-D-Arabinofuranosylcytosine, CANCER RESEARCH 50, 5318-
`5327, (1990)
`“Greco 1990”
`Ex. 1045 Greco, The Search for Synergy: A Critical Review from a Response
`Surface Perspective, PHARMACOLOGICAL REVIEWS, 47, 2, 331-385
`(1995)
`“Greco 1995”
`Zhao et al., Evaluation of Combination Chemotherapy: Integration
`of Nonlinear Regression, Curve Shift, Isobologram, and
`Combination Index Analyses, CLINICAL CANCER RESEARCH, 10,
`7994-8004, (2004)
`“Zhao 2004”
`Johnston et al., Synergy Between 3’-Azido-3’-deoxythymidine and
`Paclitaxel in Human Pharynx FaDu Cells, PHARM. RESEARCH
`20(7):957-61 (2003)
`“Johnston”
`Intentionally Left Blank
`Ex. 1048
`Intentionally Left Blank
`Ex. 1049
`Ex. 1050 Namima, Lithium Inhibits the Reverse Tolerance and the c-Fos
`Expression Induced by Methamphetamine in Mice, BRAIN
`RESEARCH, 782, 83-90 (1998)
`“Namima”
`Ex. 1051 Da-Rosa, Effects of Lithium and Valproate on Oxidative Stress and
`Behavioral Changes Induced by Administration of m-AMPH,
`PSYCH. RESEARCH, 198, 521-526 (2012)
`“Da-Rosa”
`Feier, Lithium and Valproate Modulate Energy Metabolism in an
`Animal Model of Mania Induced by Methamphetamine,
`PHARMACOLOGY, BIOCHEMISTRY, AND BEHAVIOR, 103, 589-596
`(2013)
`
`Ex. 1047
`
`Ex. 1052
`
`vii
`
`

`

`Ex. 1053
`
`Ex. 1054
`
`Ex. 1056
`
`Ex. 1057
`
`Ex. 1058
`
`Ex. 1059
`
`Ex. 1061
`
`Ex. 1062
`
`Ex. 1063
`
`Ex. 1064
`
`“Feier”
`Lim et al., Medication Prescribing Patterns for Patients with Bipolar
`I Disorder in Hospital Settings: Adherence to Published Practice
`Guidelines, BIPOLAR DISORDERS 2001: 3 165-173 (2001)
`“Lim”
`Leucht, S. et al, Second-Generation Antipsychotic Agents in the
`Treatment of Acute Mania: A Systematic Review and Meta-
`analysis of Randomized Controlled Trials, ARCH. GEN. PSYCHIATRY
`64:4, 442-455 (2007)
`“Leucht”
`Ex. 1055 Center for Drug Evaluation and Research, Application No. 21-436,
`Approval Letter and Label
`Excerpts from Kolb, M.D., Modern Clinical Psychiatry, 8th Ed.
`(1973), Chap. 32, “Pharmacological Therapy,” pp. 620-638 at 632.
`Excerpts from Kaplan et al., Comprehensive Textbook of
`Psychiatry, 3rd Ed. (1980)
`Excerpts from Kaplan et al., Comprehensive Textbook of
`Psychiatry, 4th Ed. (1985)
`Excerpts from Kaplan et al., Comprehensive Textbook of
`Psychiatry, 5th Ed. (1989)
`Ex. 1060 Excerpts from Kaplan et al., Comprehensive Textbook of
`Psychiatry, 6th Ed. (1995)
`Excerpts from Sadock et al., M.D., Comprehensive Textbook of
`Psychiatry, 7th Ed. (2000)
`Excerpts from Talbott et al., The American Psychiatric Press
`Textbook of Psychiatry, 1st Ed. (1988)
`Excerpts from Hales et al., American Psychiatric Press Textbook of
`Psychiatry, 2nd Ed. (1994)
`Excerpts from Hales et al., The American Psychiatric Press
`Textbook of Psychiatry, 3rd Ed. (1999)
`Excerpts from Goodwin et al., Manic-Depressive Illness, (1990).
`Suppes et al., Texas Medication Algorithm Project: Development
`and Feasibility Testing of a Treatment Algorithm for Patients with
`Bipolar Disorder, J. CLIN. PSYCHIATRY 62:6 (June 2001)
`“Suppes I”
`Suppes et al., Report of the Texas Consensus Conference Panel on
`Medication Treatment of Bipolar Disorder 2000, J. CLIN.
`PSYCHIATRY 63:4 (Apr. 2002)
`“Suppes II”
`
`Ex. 1065
`Ex. 1066
`
`Ex. 1067
`
`viii
`
`

`

`Ex. 1068
`
`Joseph F. Goldberg, Treatment Guidelines: Current and Future
`Management of Bipolar Disorder, J. CLIN. PSYCHIATRY 2000;61
`(suppl 13)
`“Goldberg”
`Ex. 1069 Bauer et al., Clinical Practice Guidelines for Bipolar Disorder from
`the Department of Veteran Affairs, J. CLIN. PSYCHIATRY 60:1 (Jan.
`1999)
`“Bauer”
`Ex. 1070 W. Konig et al., Long-term Therapy of Affective Disorders:
`Monotherapy or Polypharmacy?, PHARMACOPSYCHIAT. 21 (1988)
`“Konig”
`Ex. 1071 Nichol, M.B. et al., Factors Predicting the Use of Multiple
`Psychotropic Medications, J. CLIN. PSYCH. 56 (1995)
`“Nichol 1995”
`Sachs, G.S. et al., Adjunctive Clonazepam for Maintenance
`Treatment of Bipolar Affective Disorder, J. CLIN.
`PSYCHOPHARMACOL. 10 (1990)
`“Sachs II”
`Excerpts from Lawrence C. Kolb, M.D., Modern Clinical
`Psychiatry, 9th Ed. (1977)
`Excerpts from Lawrence C. Kolb, M.D., Modern Clinical
`Psychiatry, 10th Ed. (1982)
`Sachs, G.S. et al., Combination of a Mood Stabilizer with
`Risperidone or Haloperidol for Treatment of Acute Mania: A
`Double-Blind, Placebo-Controlled Comparison of Efficacy and
`Safety, AM. J. PSYCHIATRY 159:7 (July 2002)
`“Sachs III”
`File History, U.S. Pat. No. 9,125,939
`
`Ex. 1072
`
`Ex. 1073
`
`Ex. 1074
`
`Ex. 1075
`
`Ex. 1076
`
`ix
`
`

`

`I.
`
`INTRODUCTION
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42 et seq., Alkermes
`
`Pharma Ireland Limited and Alkermes, Inc. (collectively, “Petitioners”) petition for
`
`Inter Partes Review (“IPR”) of claims 2, 6, 7, and 9 of U.S. Patent No. 9,125,939
`
`to Kikuchi et al., titled “Carbostyril Derivatives and Mood Stabilizers for Treating
`
`Mood Disorders” (“the ’939 patent,” Ex. 1001), which is assigned to Otsuka
`
`Pharmaceutical Company, Ltd. (“Patent Owner”).
`
`II.
`
`PRELIMINARY STATEMENT
`
`Claims 2, 6, 7, and 9 of the ’939 patent are drawn to methods of treating
`
`bipolar disorder using a combination of lithium and aripiprazole. As demonstrated
`
`herein, the prior art is replete with references teaching that bipolar disorder could
`
`be effectively treated with a combination of lithium and atypical antipsychotics,
`
`including aripiprazole, particularly in patients who were partially nonresponsive to
`
`lithium monotherapy. Accordingly, the claimed methods were obvious.
`
`In May 2003 (the earliest filing date for an application to which the ’939
`
`patent claims priority), lithium was one of most commonly used drugs for the
`
`treatment of bipolar disorder. It was also well known prior to May 2003 that
`
`patients with severe manic symptoms or patients who did not adequately respond
`
`to lithium benefitted from the addition of an antipsychotic in combination with
`
`lithium.
`
`1
`
`

`

`Aripiprazole was approved by the FDA in 2002, making it the latest FDA-
`
`approved drug belonging to the family of atypical antipsychotics as of May 2003.
`
`Studies with aripiprazole showed that it was effective in treating patients with
`
`bipolar disorder and had an improved side effect profile as compared to other
`
`antipsychotics such as olanzapine. In particular, aripiprazole did not cause weight
`
`gain in psychotic patients, which was a characteristic side effect of other atypical
`
`antipsychotics, such as olanzapine.
`
`A person ordinarily skilled in the art would have been motivated to use a
`
`combination of aripiprazole with a mood stabilizer, e.g., lithium, because it was
`
`well known in the art that combinations of antipsychotics, also known as
`
`neuroleptics, together with mood stabilizers are more effective than monotherapy.
`
`It was also well known that atypical antipsychotics, compared to typical
`
`antipsychotics and other neuroleptics, alone or in combination with mood
`
`stabilizers, have side effect profiles that are more tolerable to many patients.
`
`Based on this understanding, the person of ordinary skill in the art in May 2003
`
`would have readily selected aripiprazole in a combination with lithium to treat
`
`bipolar disorder, and would have reasonably expected that such a therapy would
`
`treat bipolar disorder in patients partially non-responsive to lithium or valproate
`
`monotherapy. Therefore, the evidence produced herein demonstrates that claims 2,
`
`6, 7, and 9 were obvious.
`
`2
`
`

`

`
`
`The obviousness of these claims is supported by the attached Declaration of
`
`Allen Frances, M.D. (Ex. 1002). Dr. Frances, a psychiatrist with more than 50
`
`years practicing in the field, provides his opinion that combining the newest
`
`atypical antipsychotic, aripiprazole, with lithium to treat bipolar patients who did
`
`not respond well to lithium monotherapy would have been standard practice in
`
`May 2003. Indeed, Dr. Frances discusses the breadth of knowledge regarding
`
`combination therapy for patients with bipolar disorder taught in the prior art. Dr.
`
`Frances further discusses, inter alia, clinical results in patients diagnosed with
`
`bipolar disorder with lithium alone, aripiprazole alone, and lithium in combination
`
`with atypical antipsychotics such as aripiprazole. Additionally, Dr. Frances
`
`discusses clinical results demonstrating that aripiprazole was not only known in
`
`May 2003 to be safe, effective, and well-tolerated in treating bipolar disorder
`
`patients, but that it could be safely administered in combination with lithium.
`
`Any alleged secondary considerations cannot overcome this overwhelming
`
`case of obviousness. Patent Owner, faced with a final rejection of prima facie
`
`obviousness during prosecution, argued that there was evidence of unexpected
`
`“synergy” and supported this assertion with a declaration from inventor Hirose.
`
`See e.g., Ex. 1076 at 1160-64. But, contrary to Patent Owner’s arguments, the
`
`evidence submitted fails to establish that the combination of aripiprazole and
`
`lithium produces an unexpected synergy. The data and conclusions drawn in the
`
`3
`
`

`

`Hirose Declaration were based on a mouse model for mania in bipolar disorder
`
`(not clinical data, and in spite of the fact that the closest prior art presented clinical
`
`data), and, when statistically analyzed, do not show synergy or even superiority
`
`when compared to the controls.
`
`In the attached Declaration of Jessie Au, Pharm. D., Ph.D. (Ex. 1004), Dr.
`
`Au, who has worked for more than 30 years developing statistically sound methods
`
`to analyze drug-drug interactivity and developing drug combinations that produce
`
`additive or synergistic antitumor activity, provides her opinions that the results
`
`presented in the Hirose Declaration do not show any unexpected results or synergy.
`
`Thus, Petitioners will demonstrate that the challenged claims 2, 6, 7, and 9
`
`of the ’939 patent are invalid as obvious.
`
`III. MANDATORY NOTICES
`
`A.
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`
`
`
`Alkermes Pharma Ireland Limited and Alkermes, Inc. are the real parties-in-
`
`interest for the Petitioners. Alkermes plc, the parent company of Alkermes Pharma
`
`Ireland Limited and Alkermes, Inc., is also identified as a real party-in-interest out
`
`of an abundance of caution.
`
`B.
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2)
`
`
`
`Petitioners are not aware of any reexamination or pending prosecution
`
`concerning the ’939 patent. Petitioners are not party to any prior or pending
`
`litigation regarding infringement or invalidity of the ’939 patent. Petitioners
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`4
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`

`

`identified the following prior litigation regarding infringement or invalidity of the
`
`’939 patent: Otsuka Pharmaceutical Co., LTD. v. Stason Industrial Corp., et al.,
`
`No. 1:16-cv-00557-JBS-KMW (D.N.J.). This case was voluntarily dismissed
`
`without prejudice by Otsuka Pharmaceutical Co., LTD.
`
`C.
`
`Lead and Back-up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`
`
`Pursuant to 37 C.F.R. §§ 42.8(b)(3) and 42.10(a), Petitioners provide the
`
`following designation of counsel.
`
`Lead Counsel
`
`Back-Up Counsel
`
`Theresa C. Kavanaugh
`(Reg. No. 50,356)
`GOODWIN PROCTER LLP
`100 Northern Avenue
`Boston, Massachusetts 02210
`(617) 570-1000 (Tel.)
`(617) 523-1231 (Fax)
`tkavanaugh@goodwinlaw.com
`
`Nicholas K. Mitrokostas
`(pro hac vice to be submitted)
`GOODWIN PROCTER LLP
`100 Northern Avenue
`Boston, Massachusetts 02210
`(617) 570-1000 (Tel.)
`(617) 523-1231 (Fax)
`nmitrokostas@goodwinlaw.com
`
`Carolyn S. Elmore
`(Reg. No. 37,567)
`Elmore Patent Law Group, P.C.
`484 Groton Road
`Westford, MA 01886
`(978) 251-3509 (phone)
`
`(978) 251-3973 (fax)
`celmore@elmorepatents.com
`
`D.
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`
`Please direct all correspondence to the lead counsel and back-up counsel at
`
`the contact information provided above. Petitioners consent to service by
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`5
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`

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`electronic mail at tkavanaugh@goodwinlaw.com, celmore@elmorepatents.com,
`
`and nmitrokostas@goodwinlaw.com.
`
`IV. PAYMENT OF FEES
`
`The Patent Trial and Appeal Board is hereby authorized to charge all fees
`
`due in connection with this matter to Attorney Deposit Account 506989.
`
`V.
`
`
`
`GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`
`Petitioners hereby certify that the ’939 patent is available for IPR and that
`
`Petitioners are not barred or estopped from requesting IPR on the grounds
`
`identified herein.
`
`VI. THE ’939 PATENT
`
`The ’939 patent issued on September 8, 2015, from Application No.
`
`10/556,600 (“the ’600 application”), which was filed on May 19, 2004. The ’600
`
`application claims priority to U.S. Provisional Application No. 60/473,378, filed
`
`on May 23, 2003. Therefore, any printed publication by others dated before May
`
`23, 2003 qualifies as prior art under 35 U.S.C. § 102(a), and any printed
`
`publication dated before May 23, 2002 qualifies as prior art under 35 U.S.C. §
`
`102(b).
`
`A.
`
`Challenged Claims of the ’939 Patent
`
`The ’939 patent has 10 claims, of which claims 1 and 2 are independent.
`
`This Petition challenges claim 2 and claims 6, 7, and 9, each of which is dependent
`
`on claim 2. Claim 2 is reproduced below:
`
`6
`
`

`

`2. A method of treating bipolar disorder in a patient partially
`nonresponsive to lithium or valproic acid, divalproex sodium or
`a salt thereof monotherapy comprising:
`administering separately a first amount of aripiprazole, and a
`second amount of lithium, wherein the amount of lithium is
`about 0.01 to 500 parts by weight and the amount of aripiprazole
`is about 1 part by weight,
`wherein the bipolar disorder is chosen from bipolar disorder I,
`polar disorder II, bipolar disorder with or without psychotic
`features, mania, acute mania, bipolar depression, and mixed
`episodes.
`
`Claim 6 further requires that the bipolar disorder is bipolar disorder II.
`
`Claim 7 further requires that the bipolar disorder is mania with bipolar disorder I.
`
`Claim 9 further requires that the bipolar disorder is mixed episode associated with
`
`bipolar disorder I.
`
`B.
`
`Prosecution History of the ’939 Patent
`
`
`
`During prosecution of the ’939 patent, claims substantially corresponding to
`
`claims 2, 6, 7, and 9 were repeatedly rejected as obvious over Kowatch et al. (CNS
`
`Spectrum, April 2003, Vol. 8, No. 4, pp. 273-280)(“Kowatch,” Ex. 1010). See
`
`e.g., Ex. 1076 at 944-46, 1030-31, 1085-87, 1128, 1180-81, 1227-29. According
`
`to the examiner, although Kowatch did not explicitly teach a composition
`
`comprising lithium and aripiprazole, or a method of treating bipolar disorder
`
`employing aripiprazole and lithium, it rendered the claims obvious. The examiner
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`7
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`

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`stated that it would have been obvious to a person of ordinary skill in the art at the
`
`time of invention to combine the atypical antipsychotic agent aripiprazole with
`
`lithium because Kowatch teaches that the combination of olanzapine, an atypical
`
`antipsychotic like aripiprazole, with lithium gives better overall response in the
`
`method of treating bipolar disorder. Id.
`
`Patent Owner initially argued that the claims were not obvious over
`
`Kowatch based solely on the prior art. Id. at 985-88, 1061-64, 1114-16.
`
`According to Patent Owner, Kowatch provided no specific teaching of a
`
`combination of lithium and aripiprazole or a specific example of such a
`
`combination, nor a teaching, motivation, or suggestion of a patient population
`
`which is partially nonresponsive to lithium or valproate monotherapy as recited in
`
`the present claims. See id. After several cycles of examiner rejections and
`
`responsive arguments by Patent Owner, Patent Owner submitted an inventor
`
`declaration (“the Hirose Declaration”; id. at 1160-64) to support the argument that
`
`the combination of lithium and aripiprazole resulted in unexpected, “significantly
`
`enhanced” results or synergy.
`
`The Hirose Declaration contained data from a mouse model comparing
`
`controls, aripiprazole alone, olanzapine alone, olanzapine in combination with
`
`lithium, and aripiprazole in combination with lithium. See id. at 1162. The Hirose
`
`Declaration further asserted that the animal data demonstrated that aripiprazole in
`
`8
`
`

`

`combination with lithium suppressed locomotion function in mice to a higher
`
`degree than any of the other tested substances, and purported to use the data to
`
`show a synergistic effect by the claimed combination therapy. Id. at 1163. In a
`
`series of Office Actions following the Patent Owner’s initial submission of the
`
`Hirose Declaration, the examiner raised several issues regarding the reliability of
`
`the data presented in the Hirose Declaration, and disagreed with the conclusion of
`
`synergy. Id. at 1184-85, 1229-30. Nonetheless, following successive office action
`
`and response cycles, and an interview with the examiner, the Patent Owner
`
`presented the same data in a different way (id. at 1264), and the examiner finally
`
`allowed the claims on the basis of that data. See Ex. 1004 at ¶¶ 47-63.
`
`C.
`
`Claim Construction
`
`
`
`Because the ’939 patent has not yet expired and will not expire during the
`
`pendency of this proceeding, the challenged claims should be given their “broadest
`
`reasonable construction in light of the specification of the patent in which it
`
`appears.” 42 C.F.R. §42.100(b). See also Cuozzo Speed Technologies, LLC v.
`
`Lee, 579 U. S. ____ (2016). Applying the broadest reasonable interpretation
`
`(“BRI”) to the claims of the ’939 patent, as Dr. Frances explains, one of ordinary
`
`skill in the art would understand the following claim terms to have the following
`
`meanings:
`
`9
`
`

`

`(cid:120) “bipolar disorder,” “wherein the bipolar disorder is chosen from bipolar
`
`disorder I, polar [sic] disorder II, bipolar disorder with or without psychotic
`
`features, mania, acute mania, bipolar depression, and mixed episodes”
`
`appearing in claims 2, 6, 7, and 9, generally refers to a “mood disorder
`
`characterized by the presence (or history) of manic episodes, mixed
`
`episodes, or hypomanic episodes, usually accompanied by the presence (or
`
`history) of major depressive episodes” and includes at least the following:
`
`Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder with or without
`
`psychotic features, mania, acute mania, Bipolar Disorder with Depressive
`
`Episodes, and Bipolar Disorder with Mixed Episodes. Ex. 1002 at ¶ 59.
`
`(cid:120) “a patient partially nonresponsive to lithium or valproic acid, or divalproex
`
`sodium or a salt thereof monotherapy,” appearing in claim 2, means “a
`
`patient that has shown an inadequate response to lithium, valproic acid, or
`
`divalproex sodium or salt thereof, as a monotherapy.” Ex. 1002 at ¶ 59.
`
`(cid:120) “administering,” appearing in claim 2, means “the oral, intravenous,
`
`intradermal, subcutaneous, intraperitoneal or intrarectal administration of a
`
`pharmaceutical preparation,” as stated in the specification. Ex. 1001, col.
`
`15, lines 15-27. In the case of separate administration of aripiprazole and a
`
`mood stabilizer, “each one of aripiprazole and a mood stabilizer are
`
`contained individually in a pharmaceutical preparation respectively, and
`
`10
`
`

`

`each one of these preparations may be administered at the same or different
`
`times.” Ex. 1001, col. 15, lines 28-37; Ex. 1002 at ¶ 59.
`
`(cid:120) “aripiprazole,” appearing in claim 2, means a compound having the
`
`following chemical name and structure:
`
`7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy}-3,4-dihydro-2(1H)-
`
`quinolino