UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`SLAYBACK PHARMA LLC,
`Petitioner,
`
`v.
`
`SUMITOMO DAINIPPON PHARMA CO., LTD.,
`Patent Owner.
`
`_________________
`
`Case IPR2020-01053
`U.S. Patent 9,815,827
`
`_________________
`
`
`
`PATENT OWNER’S RESPONSE
`
`
`
`

`

`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`TABLE OF CONTENTS
`
`
`INTRODUCTION ............................................................................................... 1 
`I. 
`II.  BACKGROUND ................................................................................................. 3 
`A.  Schizophrenia, Manic Depressive Psychoses, The Prior Standard of Care,
`and Antipsychotic-Induced Weight Gain ........................................................... 3 
`B.  Antipsychotic Drugs Exhibit Complex Pharmacologic Mechanisms ......... 6 
`1.  Olanzapine .............................................................................................. 6 
`2.  Quetiapine ............................................................................................... 8 
`3.  Risperidone ........................................................................................... 10 
`4.  Ziprasidone ........................................................................................... 11 
`C.  The Mechanisms Underlying Weight Gain Are Complex and Poorly
`Understood ....................................................................................................... 12 
`III.  THE ’827 PATENT AND ITS PROSECUTION HISTORY ........................... 14 
`A.  The Claimed Invention Solved Prior Problems Associated with
`Antipsychotics .................................................................................................. 14 
`B.  The ’827 Patent Prosecution History ......................................................... 17 
`IV. CLAIM CONSTRUCTION .............................................................................. 24 
`V.  PERSON OF ORDINARY SKILL ................................................................... 24 
`VI. ARGUMENT ..................................................................................................... 26 
`A.  The “Manic Depressive” Claims are Entitled to the August 22, 2002
`Provisional Application Filing Date (Grounds 1 and 2) .................................. 26 
`1.  The ’927 provisional application provides written description support
`for the manic depressive claims. ................................................................ 27 
`2.  Slayback’s priority argument is legally flawed .................................... 32 
`B.  Claims 1-75 are Patentable over Saji ’372 (Ground 3) ............................. 33 
`1.  Saji ’372 does not disclose or suggest the claimed dosing regimen. .... 37 
`2.  The claimed dosing regimen unexpectedly does not cause weight gain. .
`
` ............................................................................................................... 40 
`  Horisawa does not establish that lack of weight gain was
`expected. ............................................................................................... 41 
`
`i
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`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`i.  Patent Owner never admitted that “SM-13496” was known in
`the prior art to be lurasidone. ........................................................ 41 
`ii.  Receptor binding affinity does not predict weight gain. ........ 42 
`  Ziprasidone’s lack of weight gain does not establish that
`lurasidone’s lack of weight gain was expected. ................................... 45 
`  Lack of weight gain was not expected based on “diversity of
`humans.” ............................................................................................... 50 
`3.  Lack of weight gain is not inherent in the prior art. ............................. 52 
`4.  Objective evidence demonstrates that the claimed dosing regimen
`would not have been obvious. ................................................................... 53 
`  Commercial Success. .................................................................... 54 
`  Long Felt Need and Failure of Others. ......................................... 56 
`Industry Skepticism. ..................................................................... 58 
` 
`5.  The Prior Art Taught Away from Dosing Regimens in Which
`Lurasidone was the Sole Active Ingredient (Claims 40-75). .................... 59 
`CONCLUSION .......................................................................................... 62 
`
`
`
`VII. 
`
`
`
`ii
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`

`

`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`EXHIBIT LIST
`
`Exhibit Description
`
`Exhibit
`No.
`2001
`
`2002
`2003
`2004
`2005
`
`2006
`
`2007
`
`2008
`
`López-Muñoz et al., “History of the discovery and clinical introduction
`of chlorpromazine,” Annals of Clinical Psychiatry. 17:113–35 (2005).
`ZYPREXA® (olanzapine) Label (2000).
`ABILIFY® (aripiprazole) Label (2002).
`LATUDA® (lurasidone) Label (2018).
`Laursen, “Excess Early Mortality in Schizophrenia,” Annu. Rev. Clin.
`Psychol. 10:425-48 (2014).
`Olfson et al., “Premature Mortality Among Adults with Schizophrenia
`in the United States,” JAMA Psychiatry 72(12) 1172-81(2015).
`Complaint filed 2/13/2018 in Sumitomo Dainippon Pharma Co., Ltd.
`and Sunovion Pharmaceuticals Inc. v. Emcure Pharmaceuticals Ltd.,
`Case 2:18-cv-02065.
`Complaint filed 2/23/2018 in Sumitomo Dainippon Pharma Co., Ltd.
`and Sunovion Pharmaceuticals Inc. v. Aurobindo Pharm Ltd. et al.,
`Case 2:18-cv-02620.
`Complaint filed 8/31/2018 in Sumitomo Dainippon Pharma Co., Ltd.
`and Sunovion Pharmaceuticals Inc. v. Piramal Healthcare UK
`Limited, Case 2:18-cv-13478.
`Complaint filed 9/12/2018 in Sumitomo Dainippon Pharma Co., Ltd.
`and Sunovion Pharmaceuticals Inc. v. Macleods Pharmaceuticals Ltd.
`and Macleods Pharma USA Inc., Case 2:18-cv-13833.
`Complaint filed 10/09/2018 in Sumitomo Dainippon Pharma Co., Ltd.
`and Sunovion Pharmaceuticals Inc. v. Alkem Laboratories Ltd., Case
`2:18-cv-14787.
`Press Release: “Sumitomo Dainippon Pharma Announces Resolution
`of Disputes Under Consolidated Patent Infringement Lawsuit
`Regarding ANDAs for Latuda® in the U.S.,” November 27, 2018.
`2013 Meltzer, “Treatment of Schizophrenia and Spectrum Disorders:
`Pharmacotherapy, Psychosocial Treatments, and Neurotransmitter
`Interactions,” Biol. Psychiatry 46:1321-1327 (1999).
`
`2009
`
`2010
`
`2011
`
`2012
`
`iii
`
`

`

`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`Stip, “Novel antipsychotics: issues and controversies. Typicality of
`atypical antipsychotics,” J. Psychiatry Neurosci 25(2):137-53 (2000).
`Tarazi and Stahl, “Iloperidone, Asenapine and Lurasidone: A Primer
`on their Current Status,” Expert Opin. Pharmacother. 13(13): 1911-22
`(2012).
`Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition,
`1980 (Excerpt).
`Neel Burton, A Short History of Bipolar Disorder, Psychology Today,
`updated September 7, 2017.
`RESERVED
`Diagnostic and Statistical Manual of Mental Disorders, 4th Edition,
`2005, pp. 350-358.
`Newcomer, “Second-Generation (Atypical) Antipsychotics and
`Metabolic Effects: A Comprehensive Literature Review,” CNS
`DrugsTM Supplement, vol. 19, supplement 1, pp. 1-93 (2005).
`Allison et al., “Antipsychotic-Induced Weight Gain: A
`Comprehensive Research Synthesis,” Am J Psychiatry 156:1686-96
`(1999).
`Green et al., “Weight Gain from Novel Antipsychotic Drugs: Need for
`Action,” General Hospital Psychiatry 22:224-35 (2000).
`Risperdal® Label.
`Attachment 1 Ziprasidone (Ziprasidone HCI) NDA 20-825 Approval
`Letter and Labeling (2001).
`Geodon® Label (2017).
`Dawkins et al., “Antipsychotics: Past and Future, National Institute of
`Mental Health Division of Services and Intervention Research
`Workshop, July 14, 1998,” Schizophrenia Bulletin 25(2):395-405
`(1999).
`Stahl, S., 2013. Stahl’s Essential Psychopharmacology. 4th ed.
`Cambridge University Press, Chapter 5.
`Casey et al., “The Pharmacology of Weight Gain with Antipsychotics,”
`J Clin. Psychiatry 62[suppl 7]:4-10 (2001).
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`2024
`
`2025
`2026
`
`2027
`
`2028
`
`iv
`
`

`

`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`2029
`
`2030
`
`2036
`
`2037
`
`Reynolds, “Weight Gain, Antipsychotic Drug Treatment and
`Pharmacogenomics,” Pharmacogenomics 3(5):567-70 (2002).
`Loebel and Citrome, “Lurasidone: a novel antipsychotic agent for the
`treatment of schizophrenia and bipolar depression,” BJPsych Bulletin
`39:237-41 (2015).
`Notice of allowance mailed 8/13/15 (U.S. 9,174,975).
`2031
`2032 Wong et al., U.S. Patent No. 6,964,962.
`2033
`Pozuelo, U.S. Patent Pub. No. 2001/0047010.
`2034
`Seroquel XR (quetiapine fumarate) Extended-Release Tablets Label
`2009.
`2035 Wirshing et al., “Novel Antipsychotics: Comparison of Weight Gain
`Liabilities,” J Clin Psychiatry 60:358-63 (1999).
`Jones et al., “Weight Change and Antipsychotic Treatment in Patients
`with Schizophrenia,” J Clin Psychiatry 62[suppl 2]:41-44 (2001).
`Loebel et al., “Efficacy and safety of lurasidone 80 mg/day and 160
`mg/day in the treatment of schizophrenia: A randomized, doubleblind,
`placebo- and active-controlled trial,” Schizophrenia Research 145:101-
`109 (2013).
`Daniel et al., “Ziprasidone 80 mg/day and 160 mg/day in
`the Acute Exacerbation of Schizophrenia and
`Schizoaffective Disorder: A 6-Week Placebo-Controlled
`Trial,” Neuropsychopharmacology 20(5):491-505 (1999).
`Reynolds et al., “The 5-HT2C receptor and antipsychotic induced
`weight gain – mechanisms and genetics,” J. Psychopharmacology
`20(4) Supplement 15-18 (2006).
`Certified Translation of Horisawa et al., Japanese Journal of
`Neuropsychopharmacology 19(6) 1999.
`2041 Mentalhelp.net “Schizophrenia Symptoms, Patterns and Statistics and
`Patterns”, downloaded from the internet at
`https://www.mentalhelp.net/schizophrenia/statistics/ on September 10,
`2020.
`Ritchie et al. “Mental Health,” downloaded from the internet at
`https://ourworldindata.org/mental-health on September 10, 2020.
`
`2040
`
`2038
`
`2039
`
`2042
`
`v
`
`

`

`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`2049
`2050
`
`2051
`
`2052
`
`2053
`
`2054
`
`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`FDA Atypical Antipsychotic Drugs Information, downloaded from the
`internet at https://www.fda.gov/drugs/postmarket-drug-safety-
`information-patients-and-providers/atypical-antipsychotic-drugs-
`information on September 10, 2020.
`Franklin, “Lurasidone for the treatment of bipolar depression: an
`evidence-based review,” Neuropsychiatric Disease and Treatment,
`2015:11 2143–2152 (2015).
`Shayegan et al., “Atypical Antipsychotics: Matching Receptor Profile
`to Individual Patient’s Clinical Profile,” CNS Spectrums 9(10)(suppl
`11):6-14 (October, 2004).
`Kane et al. “Clozapine for the Treatment-Resistant Schizophrenia.”
`Arch Gen Psychiatry, Vol. 45, September 1988, pp. 789-796.
`Nashed et al., “Olanzapine-Induced Weight Gain in Patients with
`Bipolar I Disorder: A Meta-Analysis,” Prim. Care Companion CNS
`Disord. 13(6) (2011).
`Symbyax® Label.
`Seroquel® Label.
`Lieberman et al., “Effectiveness of Antipsychotic Drugs in Patients
`with Chronic Schizophrenia,” New Eng. J. Med. 353(12) 1209-1223
`(September 22, 2005).
`Thase, “Quetiapine monotherapy for bipolar depression,”
`Neuropsychiatric Disease and Treatment 4(1) 21-31, pp. 11-21 (2008).
`Hoyberg et al., “Risperidone versus perphenazine in the treatment of
`chronic schizophrenic patients with acute exacerbations,” Acta
`Psychiatr. Scand 88:395-402 (1993).
`Lombardo et al., “Two 6-Week, randomized, Double-Blind, Placebo-
`Controlled Studies of Ziprasidone in Outpatients with Bipolar I
`Depression,” J Clin Psychopharmacol. 32(4) pp. 470-478 (2012).
`Sachs et al., “Efficacy and Safety of Adjunctive Oral Ziprasidone for
`Acute Treatment of Depression in Patients With Bipolar I Disorder: A
`Randomized, Double-Blind, Placebo-Controlled Trial,” J Clin
`Psychiatry 72(10):1413-1422 (2011).
`
`vi
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`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`2055
`
`2056
`
`2057
`
`2058
`
`Pacher et al., “Cardiovascular Side Effects of New Antidepressants and
`Antipsychotics: New Drugs, Old Concerns?” Curr Pharm Des.
`10(20):2463-2475, 6 (2004).
`Stimmel at al., “Ziprasidone: An Atypical Antipsychotic Drug for the
`Treatment of Schizophrenia,” Clinical Therapeutics 24(1): 21-37
`(2002).
`Fala, “Latuda (Lurasidone HCL) Receives 2 New Indications for Use
`in Bipolar Depression as Monotherapy and as Adjunctive Therapy with
`Lithium or Valproate,” American Health & Drug Benefits, Vol. 7, pp.
`123-126 (2014).
`CONFIDENTIAL D1050231 Clinical Study Report, October 23,
`2009.
`CONFIDENTIAL D1050233 Clinical Study Report, May 3, 2011.
`2059
`CONFIDENTIAL D1050249 Clinical Study Report, October 5, 2009.
`2060
`2061 Meltzer et al., “Lurasidone in the Treatment of Schizophrenia: A
`Randomized, Double-Blind, Placebo- and Olanzapine-Controlled
`Study,” Am J Psychiatry 168:957-967 (2011).
`RESERVED
`RESERVED
`Correll et al., “Effects of Olanzapine Combined With Samidorphan on
`Weight Gain in Schizophrenia: A 24-Week Phase 3 Study”, Am. J.
`Psych., vol. 177, No. 12, 1168-78 (Dec. 2020).
`RESERVED
`Reiffen et al., “Generic Drug Industry Dynamics,” The Review of
`Economics and Statistics, Vol. 87, No. 1, pp. 37-49 (2005).
`DiMasi et al. “The price of innovation: new estimates of drug
`development costs,” Journal of Health Economics, Vol. 22, 151-185
`(2003).
`Samalin et al., “Clinical potential of lurasidone in the management of
`schizophrenia,” Therapeutics and Clinical Risk Management, Vol. 7,
`pp. 239–250 (2011).
`CONFIDENTIAL Lurasidone, Strategic Business Plan, October 1,
`2009.
`
`2062
`2063
`2064
`
`2065
`2066
`
`2067
`
`2068
`
`2069
`
`vii
`
`

`

`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`2070
`2071
`
`2072
`
`2073
`
`2074
`2075
`
`2076
`
`2077
`
`2078
`2079
`
`2080
`
`2081
`2082
`
`2083
`
`Latuda® Product Monograph.
`O’Day et al., “Long-term cost-effectiveness of atypical antipsychotics
`in the treatment of adults with schizophrenia in the U.S.,”
`ClinicoEconomics and Outcomes Research, Vol. 5, pp. 459–470
`(2013).
`Dainippon Sumitomo Pharma Co., Ltd., Supplementary Financial Data
`for Year Ended March 31, 2014.
`Jancin, Newer Atypical Antipsychotics Draw Praise, Internal Medicine
`News, March 22, 2011.
`CONFIDENTIAL Latuda Financial Information FY11-FY20 YTD.
`CONFIDENTIAL LATUDA Monthly Commercial Analytics
`Meeting, June 2016.
`CONFIDENTIAL LATUDA Situational Assessment – FY 2020, Aug
`2, 2020.
`Albright, “Three key antipsychotics lose patent protection,”
`downloaded from the internet at:
`https://www.behavioral.net/article/three-key-antipsychotics-lose-
`patent-protection on September 20, 2018.
`CONFIDENTIAL Latuda® (lurasidone HCl) 2013 Brand Plan.
`Pareek, “Factors Affecting Non-Compliance to Psychotropic Drugs of
`Patients with Psychosis as Perceived by their Family Members
`Attending the Psychiatric Outpatient Department at Selected Hospital,
`Mangalore”, Nursing and Midwifery Research Journal, Vol. 9, No. 2,
`April 2013 pp. 56-62.
`CONFIDENTIAL Latuda Physician ATU Tracker Findings, Q3’11
`Insights Report.
`RESERVED
`CONFIDENTIAL LATUDA – Bipolar Depression HCP ATU, FY16-
`Q4, March 20, 2017.
`CONFIDENTIAL The Bipolar Disorder Patient Journey, Sunovion
`Commercial Insights & Analytics, INSYNC, June 22, 2020.
`
`viii
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`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`2084
`
`2085
`
`2086
`
`Ng-Mak et al., “Patient Preferences for Important Attributes of Bipolar
`Depression Treatments: A Discrete Choice Experiment,” Patient
`Preference and Adherence, Vol. 12, pp. 35-44 (2018).
`Ng-Mak et al., “Efficacy and Metabolic Effects of Lurasidone Versus
`Brexpiprazole in Schizophrenia: A Network Meta-Analysis,” J. Comp.
`Eff.Res., 7(8), pp. 737-748 (2018).
`Rajagopalan et al., “Cost-Utility Analysis of Lurasidone Versus
`Aripiprazole in Adults with Schizophrenia,” Pharmacoeconomics,
`34:709-721 (2016).
`2087 Mattingly et al., “Switching to Lurasidone Following 12 Months of
`Treatment with Risperidone: Results of a 6-Month, Open-Label
`Study,” BMC PSYCHIATRY, 20:199 (2020).
`2088 Mak et al., Cost Savings Associated with Improved Adherence Among
`Patients with Schizophrenia Using Lurasidone, APA Annual Meeting
`Abstract Submission, 2016.
`CONFIDENTIAL Sunovion Senior Leadership Budget Presentation,
`Latuda Brand Strategy and Budget, December 10, 2010.
`CONFIDENTIAL Latuda® 2012 Budget Presentation Meeting,
`November 7, 2011.
`Comparison of Atypical Antipsychotics,” Pharmacists Letter (2015).
`Available at:
`http://pharmacistsletter.therapeuticresearch.com/pl/ArticlePDF.aspx?D
`etailID=310701.
`CONFIDENTIAL Covance Cardiac Safety Services, Phase III
`Repolarization Assessment Plan, Lurasidone, Feb. 13, 2007.
`CONFIDENTIAL Medifacts International, Review of the Preliminary
`Results from MK-3756 Protocol 023, February 7, 2007.
`CONFIDENTIAL Clinical Pharmacology and Biopharmaceutics
`Review Aid, Dainippon Sumitomo Pharma America, Inc., Lurasidone.
`CONFIDENTIAL Sunovion FDA Contact Report, Lurasidone HCl,
`October 25, 2010.
`Poyurovsky et al., “Attentuation of Olanzapine-Induced Weight Gain
`in Patients with Schizophrenia: A Double Blind, Placebo-Controlled
`Study,” Am J. Psychiatry, 160:297-302 (2003).
`
`2093
`
`2089
`
`2090
`
`2091
`
`2092
`
`2094
`
`2095
`
`2096
`
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`Case No.: IPR2020-01053
`
`Poyurovsky et al., “Attentuating Effect of Reboxetine on Appetite and
`Weight Gain in Olanzapine-Treated Schizophrenia Patients: A
`Double-Blind, Placebo-Controlled Study,” Psychopharmacology,
`192:441-448 (2007).
`Zhuo et al., “Topiramate and Metformin Are Effective Add-On
`Treatments in Controlling Anti-Psychotic Weight Gain: A Systematic
`Review and Network Meta-Analysis,” Frontiers in Pharmacology,
`9:1393 (2018).
`RESERVED
`
`2097
`
`2098
`
`2099-
`2130
`2131
`2132
`2133
`2134
`2135
`
`CONFIDENTIAL Declaration of Dr. Stephen Stahl.
`CONFIDENTIAL Declaration of Dr. Brian Reisetter.
`Declaration of Scott Stancell-Condron.
`Deposition Transcript (Dr. Thomas Kosten).
`Hummel et al., “Clozapine as Add-On Medication in the Maintenance
`Treatment of Bipolar and Schizoaffective Disorder,” Neuropsychology,
`45 (suppl. 1):37-42 (2002).
`2136 McElroy et al., “Pharmacologic Agents for the Treatment of Acute
`Bipolar Mania,” Biol. Psychiatry, 48:539-557 (2000).
`2137 Weiden, “Partial Compliance and Risk of Rehospitalization Among
`California Medicaid Patients with Schizophrenia, Psychiatric
`Services,” August 2004, Vol. 55, No. 8.
`CONFIDENTIAL Memorandum With Respect to Lurasidone
`Development Handover Status (2007).
`Tohen et al., Am J. Psychiatry, 156:702-709 (1999).
`2139
`2140 Möller, J. Clin. Psych., 64 (Suppl. 6):23-27 (2003).
`2141
`News Release: “FDA Approves Once-Daily Latuda® (lurasidone
`HCl) for Treatment of Patients with Schizophrenia,” October 28, 2010.
`News Release: “Sunovion Pharmaceuticals Inc. Announces FDA
`Approval of Latuda® (lurasidone HCl) as Monotherapy and
`Adjunctive Therapy in Adult Patients with Bipolar Depression,” June
`28, 2013.
`
`2138
`
`2142
`
`
`
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`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`
`I.
`
`INTRODUCTION
` Schizophrenia and bipolar disorder are chronic and severely disabling
`
`mental disorders.1 Medications for treating these conditions have been around
`
`since the 1950s, but suffer problems ranging from lack of efficacy to dangerous
`
`side effects.2 Patent Owner’s product, Latuda®, approved in 2010, offered a
`
`unique treatment option to psychiatrists and patients, not only because of its
`
`efficacy but also its unique safety profile.3 That unique profile enabled it to fill an
`
`unmet need in the market, propelling it to blockbuster status despite the majority of
`
`its competition being cheaper generic alternatives.4 That unique safety profile
`
`included drastically reducing the risk of weight gain, a side effect that had plagued
`
`this class of drugs for decades and was known to reduce patient life expectancy by
`
`
`1 Ex. 2131 (Stahl), ¶¶ 32-40; Exs. 2013-2015; 2017; 2019; 2041-2042; 2044; 1023.
`
`2 Ex. 2131 (Stahl), ¶¶ 43-64; Exs. 2001-2003; 2013-2015; 2022-2027; 2029; 2046-
`
`2049; 2015-2054; 1041-1042.
`
`3 Ex. 2131 (Stahl), ¶¶ 76, 161; Ex. 2004, 2-7.
`
` 4
`
`
`
` Ex. 2132 (Reisetter), ¶¶ 29-32, 49-51.
`
`1
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`Attorney Docket No.: 46094-0002IP1
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`an average of 20-30 years.5 For their innovation, the inventors were awarded U.S.
`
`9,815,827 (Ex. 1001, “the ’827 patent”).
`
`The ’827 patent covers a method for treating psychoses, including
`
`schizophrenia and bipolar disorder, by administering daily 20-120 mg lurasidone
`
`(the active ingredient in Latuda®), or a salt thereof, to a patient without a weight
`
`gain. Latuda® embodies the methods claimed in the ’827 patent.6
`
`Over a 16 month period, Patent Owner asserted the ’827 patent against
`
`almost two dozen different generic drug companies,7 every single case resulting in
`
`a favorable settlement.8 Slayback, not one of those original challengers, now
`
`alleges that claims 1-75 of the ’827 patent are unpatentable based on three grounds.
`
`The first two grounds rely on a flawed priority analysis. The third ground relies on
`
`a reference (Ex. 1009, “Saji ’372”) that the ’827 patent explicitly discusses and that
`
`the Examiner previously considered. Slayback’s superficial and incomplete
`
`analysis of obviousness ignores the complexity and unpredictability of atypical
`
`
`5 Ex. 2131 (Stahl), ¶¶ 73-75; Exs. 2022; 2037;
`
`generally Exs. 2005 and 2006.
`
`; 2061; see
`
`6 See Ex. 2131 (Stahl), ¶¶ 90-97; Exs. 1001; 2004.
`
` 7
`
` 8
`
` Exs. 2007-2011.
`
` Ex. 2012.
`
`2
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`Attorney Docket No.: 46094-0002IP1
`Case No.: IPR2020-01053
`anti-psychotics generally and the weight gain phenomenon specifically. As such,
`
`Slayback fails to demonstrate that claims 1-75 are unpatentable.
`
`II. BACKGROUND
`A.
`Schizophrenia, Manic Depressive Psychoses, The Prior Standard
`of Care, and Antipsychotic-Induced Weight Gain
`Schizophrenia is a chronic and severe mental disorder characterized by
`
`abnormal social behavior and failure to understand reality. Schizophrenia
`
`manifests in several ways: (1) positive symptoms (e.g., visual and auditory
`
`hallucinations); (2) negative symptoms (e.g., social isolation and withdrawal); (3)
`
`cognitive symptoms (e.g., loss of attention and working memory); and (4)
`
`neurodevelopmental and neurodegenerative problems.9
`
`Bipolar disorder, once known as manic depressive psychosis, is a chronic
`
`and often severely disabling mental disorder. It is characterized by the occurrence
`
`of at least one manic, hypomanic, or mixed-manic episode during the patient’s
`
`lifetime.10 A manic episode is described as a distinct period of abnormally and
`
`persistently elevated, expansive, or irritable mood and increased goal-directed
`
`activity or energy, lasting at least one week.11 Bipolar disorder and schizophrenia
`
`
`9 Ex. 2131 (Stahl), ¶¶ 32-35; Exs. 2013-2015.
`
`10 Ex. 2131 (Stahl), ¶¶ 36-37; Exs. 2017; 2019; 2044; 1023.
`
`11 Ex. 2131 (Stahl), ¶ 37; Ex. 1023.
`
`3
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`can have symptoms in common, including hallucinations and delusions.12 While
`
`treatable, patient compliance with antipsychotic drug regimens is critical and can
`
`be negatively impacted by undesirable side effects.13
`
`First generation, or “typical” antipsychotics, were a mainstay of
`
`schizophrenia treatment from the 1950s until the 1990s, but these drugs were
`
`linked to severe side effects, most commonly extrapyramidal symptoms (“EPS”).
`
`EPS are drug-induced movement disorders often presenting as Parkinson-like tics
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`and tremors. 14 In the 1990s, FDA began approving second generation drugs, or
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`“atypical,” antipsychotics (“AAPs”) for schizophrenia. The AAPs generally
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`carried a lower risk of EPS than previous drugs but many are associated with
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`substantial weight gain.15
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`The weight gain caused by AAPs is far more than a cosmetic problem. It is
`
`
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`12 Ex. 2131 (Stahl), ¶ 37; Ex. 2140.
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`13 Ex. 2131 (Stahl), ¶ 40; Exs. 2022; 2044; Ex. 2134, 35:14-38:12.
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`14 Ex. 2131 (Stahl), ¶¶ 41-42; Ex. 1001, 1:47-67; Ex. 2134, 35:14-38:12; Exs.
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`2014-2015; 2045-2046; 1042.
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`15 Ex. 2131 (Stahl), ¶¶ 41-44, 49-50, 55, 58; Ex. 2134, 37:16-38:12; Exs. 2013-
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`2015; 2020; 2027, 2029; 2046; 2051-2052.
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`one of the primary reasons for treatment non-compliance, which leads to relapse,
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`psychotic episodes, and higher hospitalization rates.16 Just as critical, weight gain
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`can lead to serious health problems. The life expectancy of patients with
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`schizophrenia and bipolar disorder is 20-30 years less than healthy people, in part
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`because these patients suffer from higher rates of major medical conditions,
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`including premature cardiovascular disease (“CVD”).17 Excess CVD risk in these
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`patients results from higher rates of obesity, lipid abnormalities, diabetes,
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`hypertension, and physical inactivity, often because of the weight gain and related
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`metabolic side effects of psychiatric medications.18
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`Most of the early AAPs caused substantial weight gain. For example,
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`olanzapine (Zyprexa®) is associated with significant short- and long-term weight
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`gain.19 Quetiapine (Seroquel®) and risperidone (Risperdal®) are two other AAPs
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`that carry substantial weight gain risk.20
`
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`16 Ex. 2131 (Stahl), ¶ 80; Exs. 2022; 1041.
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`17 Ex. 2006, Table 1.
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`18 Ex. 2022, 3.
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`19 Ex. 2131 (Stahl), ¶¶ 49-51; Exs. 2027; 2029; 2047; 1041-1042; Ex. 2134, 41:11-
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`42:3.
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`20 Ex. 2131 (Stahl), ¶¶ 55, 58; Ex. 2027; 2051-2052; 1042; Ex. 1042.
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`Although there are some AAPs that do not carry a risk of substantial weight
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`gain, those drugs suffer from other problems that limit their utility. For example,
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`ziprasidone (Geodon®) is associated with smaller increases in body weight than
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`many AAPs, but may lead to QT prolongation—a cardiac side effect that can end
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`in sudden death—prompting FDA to include warnings on the labeling.21
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`B. Antipsychotic Drugs Exhibit Complex Pharmacologic
`Mechanisms
`Antipsychotic drugs exhibit some of the most complex pharmacologic
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`mechanisms of any drug class in clinical psychopharmacology. Each AAP drug
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`has a unique and multifaceted pharmacological profile, along with variable
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`receptor binding profiles.22 Patent Owner’s expert, Dr. Stephen Stahl, illustrates
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`this point by comparing olanzapine, quetiapine, risperidone, and ziprasidone.23
`
`1. Olanzapine
`Olanzapine (Zyprexa®) is an atypical antipsychotic that FDA approved in
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`
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`1996 for the treatment of schizophrenia.24 In 2003, FDA approved olanzapine in
`
`
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`21 Ex. 2131 (Stahl), ¶¶ 64; Exs. 2024-2026; 2055-2056; Ex. 2134, 39:20-40:7.
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`22 Ex. 2131 (Stahl), ¶¶ 47-48, 53-54, 57, 62, 66, 77; Exs. 2004; 2027.
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`23 Ex. 2131 (Stahl), ¶¶ 46-64.
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`24 Id., ¶ 46; Ex. 1039.
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`combination with fluoxetine (Symbyax®) for the treatment of depressive episodes
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`associated with bipolar I depression.25 Olanzapine is not approved as a
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`monotherapy for the treatment of bipolar depression.
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`
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`The current understanding of olanzapine’s receptor binding profile is
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`reproduced below.26 The D2 receptor is identified in a red box with a dashed,
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`vertical line through it, and the 5HT2A receptor is a light purple box outlined in red.
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`Other receptors are identified below with different color schemes. Olanzapine’s
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`affinity for a given receptor is identified by one, two, or three plus (“+”) signs,
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`with “+++” representing high affinity and “+” representing low affinity.27
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`As shown in the above figure, olanzapine has a complex pharmacology, binding to
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`at least 21 receptors, several more potently than the D2 receptor.28
`
`
`
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`25 Ex. 2131, ¶ 46; Exs. 2047-2048.
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`26 Ex. 2131 (Stahl), ¶ 47; Ex. 2027.
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`27 Ex. 2131 (Stahl), ¶ 47; Ex. 2027. Binding properties vary greatly with technique
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`and from one lab to another.
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`28 Ex. 2131 (Stahl), ¶ 48; Ex. 2027.
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`Olanzapine has a high risk of causing metabolic side effects like weight gain
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`
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`compared to other antipsychotic drugs.29 Olanzapine is also associated with other
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`adverse effects. For example, as Dr. Stahl notes, olanzapine ranks among the
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`antipsychotics with the greatest known cardiometabolic risks, as it robustly
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`increases fasting triglyceride levels and increases insulin resistance by an as-yet
`
`unknown pharmacologic mechanism.30 As a result, olanzapine may be considered
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`a second-line treatment for patients with significant weight gain or who develop
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`significant cardiometabolic risks like dyslipidemia or diabetes.31
`
`2. Quetiapine
`Quetiapine (Seroquel®) was approved by FDA in 1997 for the treatment of
`
`
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`schizophrenia.32 It is currently approved to treat manic or mixed episodes
`
`associated with bipolar I disorder (both as monotherapy and adjunctive therapy
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`with lithium or divalproex), acute treatment of depressive episodes associated with
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`bipolar I disorder (approved in 2006), maintenance treatment of bipolar I disorder
`
`
`29 Ex. 2131 (Stahl), ¶¶ 49-50; Exs. 2029; 2047; 1041-1042.
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`30 Ex. 2131 (Stahl), ¶ 51; Ex. 2027.
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`31 Id.
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`32 Ex. 2131 (Stahl), ¶ 52; Ex. 2049.
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`with lithium or divalproex, and adjunctive treatment of major depressive
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`disorder.33
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`
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`The figure below illustrates the current understanding of quetiapine’s
`
`receptor binding profile.34 Quetiapine is an antagonist at both the serotonin 5HT2A
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`and dopamine D2 receptors, but notably does not have particularly potent binding
`
`at D2 receptors.
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`
`
`
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`As reflected in the figure above, quetiapine has a complex set of binding
`
`properties to various neurotransmitters, many of which have higher potency than
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`quetiapine’s affinity for the D2 receptor.35 Quetiapine has high affinity for the H1
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`histamine and α1 adrenergic receptors.36 Like olanzapine, quetiapine can cause
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`weight gain, particularly when given in moderate to high doses.37
`
`
`
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`33 Ex. 2131 (Stahl), ¶ 52; Exs. 2049; 2051.
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`34 Ex. 2131 (Stahl), ¶ 53; Ex. 2027.
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`35 Ex. 2131 (Stahl), ¶ 54; Ex. 2027.
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`36 Id.
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`37 Ex. 2131 (Stahl), ¶ 55; Exs. 2051; 1042.
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`3.
`Risperidone
`Risperidone (Risperdal®) is an atypical antipsychotic approved by FDA in
`
`
`
`1993 for the treatment of schizophrenia.38 Like many antipsychotic drugs,
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`risperidone is now also approved for the treatment of manic and mixed episodes of
`
`bipolar I disorder, alone or in combination with lithium or valproate.39
`
`
`
`The current understanding of the receptor binding profile of risperidone is
`
`reproduced below.40 As shown in the below figure, risperidone binds to a variety
`
`of receptors. The binding profile of risperidone differs from that of olanzapine and
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`quetiapine both in terms of types of receptors it binds to and its affinity for various
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`receptors. For example, risperidone has higher affinity for the D2 receptor as
`
`compared to olanzapine and quetiapine. In addition, risperidone has high affinity
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`for the D4 receptor, whereas quetiapine does not.41
`
`
`
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`38 Ex. 2131 (Stahl), ¶ 56; Ex. 2023.
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`39 Id.
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`40 Ex. 2131 (Stahl), ¶ 57; Ex. 2027.
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`41 Id.
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`
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`As Dr. Stahl explains, risperidone, like olanzapine and quetiapine, is associated
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`with a risk for weight gain.42 Risperidone is also associated with other adverse
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`events, including hyperlipidemia, or elevated cholesterol that contributes to the
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`development of atherosclerosis.43
`
`4.
`Ziprasidone
`Ziprasidone (Geodon®) is another atypical antipsychotic approved by FDA
`
`
`
`in 2001 for the treatment of schizophrenia.44 Ziprasidone has subsequently been
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`approved to manage both acute mania and mixed states associated with bipolar
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`disorde