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
`Patent 9,815,827
`
`DECLARATION OF DR. STEPHEN STAHL
`
`1
`
`Exhibit 2131
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`
`
`TABLE OF CONTENTS
`
`PAGES
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`
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`  QUALIFICATIONS AND PROFESSIONAL EXPERIENCE .................................................. 4 
`  FEES AND PRIOR EXPERT TESTIMONY............................................................................. 7 
`  INFORMATION CONSIDERED .............................................................................................. 8 
`  SUMMARY OF OPINIONS ...................................................................................................... 8 
`  PERSON OF ORDINARY SKILL IN THE ART ...................................................................... 8 
`  CLAIM CONSTRUCTION ...................................................................................................... 10 
`  LEGAL PRINCIPLES .............................................................................................................. 10 
` BACKGROUND ...................................................................................................................... 13 
`A.  Psychotic Disorders .............................................................................................................. 13 
`1. Schizophrenia ....................................................................................................................... 13 
`2. Bipolar Disorder................................................................................................................... 14 
`B.  Atypical Antipsychotics ........................................................................................................ 16 
`C.  The Mechanisms Underlying Weight Gain Are Complex and Poorly Understood. ............. 31 
`  U.S. PATENT NO. 9,815,827 .................................................................................................. 36 
`  OPINIONS REGARDING PRIORITY .................................................................................... 38 
`  OPINIONS REGARDING OBVIOUSNESS ........................................................................... 42 
`A.  Claims 1-75 of the ’827 Patent Are Not Obvious Over Saji ’372. ....................................... 44 
`B.  Lack of Weight Gain Was Surprising and Unexpected ........................................................ 50 
`1. Horisawa Does Not Establish That Lack of Weight Gain Was Expected. .......................... 50 
`2. Ziprasidone’s Lack of Weight Gain Does Not Establish That Lurasidone’s Lack of Weight
`Gain Was Expected. ............................................................................................................ 55 
`3. Lack of Weight Gain Was Not Expected Based on “Diversity of Humans.” ...................... 59 
`C. Long Felt Need and Failure of Others Supports Non-Obviousness. ....................................... 60 
`D. Industry Skepticism Supports Non-Obviousness. ................................................................... 63 
`E.  The Prior Art Taught Away from Dosing Regimens in Which Lurasidone was the Sole
`Active Ingredient. ................................................................................................................. 68 
`F.  Lack of Weight Gain Is Not Inherent in the Prior Art. ......................................................... 69 
`XII. CONCLUSION ........................................................................................................................ 70 
`
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`2
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`3
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`
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`My name is Dr. Stephen Stahl. I am being offered as an expert to
`
`testify on behalf of Patent Owner Sumitomo Dainippon Pharma Co., Ltd.
`
`(“Sumitomo”) regarding the patentability of U.S. Patent No. 9,815,827 (“the ’827
`
`patent”) in the above captioned case.
`
` QUALIFICATIONS AND PROFESSIONAL EXPERIENCE
`
`
`
`I have attached my curriculum vitae as Appendix A to this report. I
`
`have summarized my educational and professional background below.
`
`
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`I received my undergraduate and medical degrees from
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`Northwestern University, Evanston, Illinois in 1973 and 1974, respectively. I
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`received my Ph.D. in Neuropharmacology from the University of Chicago, Chicago,
`
`Illinois in 1976.
`
`
`
`I have trained in three specialties: internal medicine at the
`
`University of Chicago; neurology at the University of California, San Francisco; and
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`psychiatry at Stanford University. I am board certified in psychiatry and have been
`
`since 1981.
`
`
`
`I have held faculty positions at Stanford University (1981-1985),
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`the University of California, Los Angeles (1985-1988), the Institute of Psychiatry in
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`London (1985-1988), the Institute of Neurology and the National Hospital for
`
`Nervous Disease in London (1987-1988). Currently, I am a Professor of Psychiatry
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`at the University of California, San Diego and a Professor of Psychiatry and
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`
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`Neuroscience at the University of California, Riverside. I am also an Honorary
`
`Visiting Senior Fellow in the Department of Psychiatry at the University of
`
`Cambridge in the United Kingdom.
`
`
`
`I formerly served as the Assistant Director at the Stanford Mental
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`Health Clinical Research Center at Sanford University Medical Center (1981-1985),
`
`a Guest Research Physician at the Donner Laboratory, Positron Emission
`
`Tomography Unity at Lawrence Berkeley Laboratories, University of California,
`
`Berkeley (1985-1985), and the Medical Director at the Institute for
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`Psychopharmacology Research in San Diego and Carlsbad, California (1991-2001).
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`I am currently the Director of Psychopharmacology for services and academic
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`programs for the 5 facility, 6,500 patient California Department of State Hospital
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`System.
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`
`
`I was formerly the Director of Clinical Sciences, Associate Medical
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`Director and Principal Scientist at Alza Corporation in Palo Alto, California (1982-
`
`1984). I was also the Executive Director of Clinical Neuroscience and Director of
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`the Laboratory of Clinical Neuropharmacology at the Merck Neuroscience Research
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`Center in Harlow, Essex, United Kingdom (1985-1988). I currently serve as the
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`Chairman of both the Neuroscience Education Institute and The Arbor Scientia
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`Group located in Carlsbad, California.
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`Throughout my career, I have served or currently serve as a
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`consultant to various pharmaceutical companies including, for example, Sunovion,
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`Sumitomo Dainippon Pharma, Pfizer, Takeda, Allergan, Lundbeck, and Otsuka.
`
`
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`During the course of my career, I have authored over 550 articles
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`and chapters, and more than 2,000 scientific presentations and abstracts. I have
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`written 53 books and edited 15 others, including the best-selling and award winning
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`textbook, Stahl’s Essential Psychopharmacology, now in its fifth edition, and the
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`best-selling and award winning clinical manual, Essential Psychopharmacology
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`Prescriber’s Guide, now in its seventh edition.
`
`
`
`I have been awarded numerous honors and prizes over the years,
`
`some of which I summarize below. For example, in 2002, I was awarded the
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`International College of Neuropsychopharmacology (CINP) Lundbeck Foundation
`
`Award in Education for my contributions to postgraduate education in psychiatry and
`
`neurology. I was also awarded the A.E. Bennett Award of the Society of Biological
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`Psychiatry, the American Psychiatric Association (“APA”)/San Diego Psychiatric
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`Society Education Award, the University of California, San Diego’s department of
`
`psychiatry residency teaching award, and I have been cited as both one of
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`“America’s Top Psychiatrists” and one of the “Best Doctors in America.” In 2013 I
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`received the Distinguished Psychiatrist Lecturer and Award from the American
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`Psychiatric Association. I was also named the 2016 David A. Mrazek Memorial
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`Award Winner by the American Psychiatric Association and delivered the Mrazek
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`Lecture at the 2016 annual meeting of the APA. Recently my alma mater,
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`Northwestern University, named their annual award for the best medical student
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`going into psychiatry the Stephen Stahl Award. I was awarded an honorary doctorate
`
`of science degree by Üsküdar University in Istanbul in March 2018 for my
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`contributions in psychiatry.
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`
`
`FEES AND PRIOR EXPERT TESTIMONY
`
`
`
`I am being compensated for my time at my standard rate of $600
`
`for each hour of service that I provide in connection with this case. This
`
`compensation is not contingent upon my opinions or testimony, the outcome of this
`
`case, or any issues involved in or related to this case.
`
`
`
`In the past four years, I have testified as an expert witness in the
`
`following cases: Sumitomo Dainippon Pharm Co., Ltd. and Sunovion
`
`Pharmaceuticals Inc. v. Emcure Pharmaceuticals, Ltd. et al., 2:18-cv-02065 (lead)
`
`and 2:18-cv-02630 (D.N.J.); Brown v. Daiichi Sankyo, Inc., Forest Laboratories,
`
`LLC, et al., 1:15-cv-4775, 1:15-cv-4774, 1:15-cv-4772, 1:15-cv-4772, 1:15-cv-4770,
`
`1:15-cv-4768, 1:15-cv-4767, 1:15-cv-4765, 1:15-cv-4778 (D.N.J.) consolidated into
`
`In Re: Benicar (Olmesartan) Products Liability Litigation, 1:15-md-2606 (D.N.J.);
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`and Truskie v. Huang et al., GD-15-017525 (PA Court of Common Pleas -
`
`Allegheny).
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`INFORMATION CONSIDERED
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`
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`This declaration and the opinions set forth herein are based on the
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`references and other documents listed in attached Appendix B, and my personal
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`education, professional experience and general knowledge of the art as of the 1999 to
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`2002 timeframe and thereafter.
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` SUMMARY OF OPINIONS
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`
`
` Based on the information currently available to me, and as set forth
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`below, it is my opinion that (a) a person of ordinary skill, reading the ’927
`
`provisional application (Ex. 1005), filed on August 22, 2002, would recognize that as
`
`of the August 22, 2002 filing date, the inventors had possession of the subject matter
`
`of claims 8-18, 25-28, 30-31, 33-34, 46, 48-60, 62, 64, 66, 67, 69, 71, 73, and 75 of
`
`the ’827 patent (“the manic depressive claims”) and (b) claims 1-75 of the ’827
`
`patent would not have been obvious.
`
`
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`
`
`I have reviewed the description of a hypothetical person of ordinary
`
`skill in the art identified in Plaintiffs’ Responses to Defendants’ Invalidity
`
`Contentions dated June 22, 2018, submitted in Sumitomo Dainippon Pharm Co., Ltd.
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`and Sunovion Pharmaceuticals Inc. v. Emcure Pharmaceuticals, Ltd. et al., 2:18-cv-
`
`02065 (lead) and 2:18-cv-02630 (D.N.J.), which is set forth below:
`
`The person of ordinary skill in the art (“POSITA”) to whom the
`’827 Patent is directed is a person with a scientific degree (either
`8
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`
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`M.D., Ph.D., or Pharm. D.), who has at least 2-3 years of
`experience developing or investigating methods for treating
`patients with psychiatric disorders such as schizophrenia or bipolar
`disorder. The POSITA may also work in collaboration with other
`scientists and/or clinicians who have experience developing or
`characterizing antipsychotic drugs, running clinical trials related to
`such drugs, treating patients with such drugs, or researching the
`effects of such drugs. Collaborators of the POSITA could include,
`for example, pharmacologists and /or neuropharmacologists,
`psychiatrists, endocrinologists, statisticians and/or biostatisticians
`and analytical and/or medicinal chemists.
`
`
`
`Based on my review of the ’827 patent and knowledge of the field
`
`to which it pertains, and my investigation and study, I agree with this description of a
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`hypothetically skilled artisan.
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`
`
`I have also reviewed the description of a hypothetical person of
`
`ordinary skill in the art identified in Slayback’s IPR Petition (Petition at 23), which is
`
`reproduced below:
`
`A POSA had the education and experience of a medical doctor
`trained in psychiatry who spent several years using psychiatric
`medications to treat patients with schizophrenia and bipolar
`disorders and had several years experience developing or
`investigating psychiatric medications and was familiar with the
`literature on drugs for schizophrenia and bipolar disorders.
`
`
`
`The two definitions are similar. Based on my experience, I am at
`
`least a person of ordinary skill in the art under both definitions, and have been since
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`well before 2002.
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`In forming my opinions expressed in this report I have considered
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`both definitions of a person of ordinary skill in the art. My opinions would be the same
`
`under either definition.
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` CLAIM CONSTRUCTION
`
`
`
`I understand that Petitioner and Dr. Kosten have proposed
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`constructions for 4 claim terms: (1) “a patient” and “the patient;” (2) “treating a
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`patient with an antipsychotic;” (3) “manic depressive psychosis;” and (4) “a
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`pharmaceutical composition comprising … a sole active ingredient.” For purposes of
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`my opinions, I have applied the constructions proposed by Petitioner and Dr. Kosten.
`
`For all other terms, I have applied their ordinary meaning.
`
` LEGAL PRINCIPLES
`
`
`
`It is my understanding that the patentability of a patent claim is to
`
`be determined through the application of statutory and judicially created standards.
`
`My understanding of the relevant standards is discussed throughout this declaration.
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`
`
`I have been informed that Petitioner bears the burden of showing
`
`by a preponderance of the evidence that the challenged claims are unpatentable. I
`
`understand that “preponderance of the evidence” requires Petitioner to prove that
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`someone, upon examining the evidence, would conclude that it is more likely than
`
`not that the claim is unpatentable.
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`I have also been informed that analyzing whether a claim is
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`unpatentable is a two-step process. The first step is interpretation of the claim terms.
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`For the purposes of this step I have applied the constructions set forth above in
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`Section VI.
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`
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`I have been informed that a patent claim is obvious if the
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`differences between the claimed subject matter and what the prior art teaches are
`
`such that the subject matter of the claim as a whole would have been obvious to a
`
`person of ordinary skill in the art at the time that the invention was made. Thus, the
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`use of hindsight is not permitted.
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`
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`I have been informed that four factual inquiries guide the
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`determination of whether a claim is obvious in view of the prior art: (1) the scope
`
`and content of the prior art, (2) the differences between the prior art and each claim,
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`(3) the level of ordinary skill in the pertinent art at the time of the invention, and (4)
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`the objective indicia of non-obviousness.
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`
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`I understand that objective indicia of non-obviousness include: the
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`invention fulfilled a long-felt but unresolved need that existed prior to the invention;
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`skepticism before or after the invention; failure of others to solve the same problem
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`before or after the invention; the invention produced unexpected results; others
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`copied the invention after the invention became known; commercial success of the
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`invention; and praise for the invention.
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`I further understand that for objective indicia to show non-
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`obviousness, there must be a link or “nexus” between the patented invention and the
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`objective indicia. For example, there must be a nexus between the claimed invention
`
`and the unexpected results, i.e., the unexpected results must be due, at least in part, to
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`the novel aspects of the claimed invention.
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`
`
` I have further been informed that to render a claim obvious, the
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`Petitioner must show by a preponderance of evidence that a person of ordinary skill
`
`in the art would have been motivated to modify or combine prior art references to
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`achieve the claimed invention. I have been informed that determining whether a
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`person of ordinary skill in the art would have been motivated to modify or combine
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`prior art references is a flexible inquiry, and that the motivation need not be found in
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`any particular prior art reference.
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`
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`Moreover, to show a patent claim is obvious in light of prior art, the
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`person of ordinary skill in the art must have had a reasonable expectation of success
`
`that modifying and/or combining the prior art would have resulted in the claimed
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`invention.
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`
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`I understand that a patent may claim priority to an earlier-filed
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`patent application. I further understand that a requirement for a claim to be entitled
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`to the filing date of the earlier-filed patent application is that a person of ordinary
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`skill, reading the earlier-filed patent application, would understand that the inventors
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`were in possession of the claimed invention.
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` BACKGROUND
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`
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`I understand from Patent Owner’s counsel that with respect to the
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`’827 patent, my analysis should be conducted as of the time of the invention. Below
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`I discuss the state of the art as of this time period.
`
`A. Psychotic Disorders
`1. Schizophrenia
`Schizophrenia is a chronic and severe mental disorder characterized
`
`
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`by abnormal social behavior and failure to understand reality.1
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`
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`The complexity of schizophrenia is reflected in the fact that it is
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`characterized by not only psychotic features or positive symptoms (e.g., visual and
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`auditory hallucinations and delusions), but can also include negative symptoms (e.g.,
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`social isolation and withdrawal), cognitive symptoms (e.g., loss of executive
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`functions such as attention and working memory), and neurodevelopmental and
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`neurodegenerative aspects as well.2
`
`
`
`1 Ex. 2015 (Tarazi), 1.
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`2 Ex. 2013 (Meltzer), 4.
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`13
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`Schizophrenia typically manifests in late adolescence or early
`
`adulthood.3 People with schizophrenia often have additional mental health problems
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`such as anxiety, depression, or substance-abuse disorders.4
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`
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`While schizophrenia is commonly associated with the positive
`
`symptoms of schizophrenia (e.g., hallucinations and delusions), approximately 25%
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`of patients with schizophrenia will experience at least one depressive episode in their
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`lifetime, likely tied to an increase in suicide rates in the overall population of patients
`
`with schizophrenia.5
`
`2. Bipolar Disorder
`Bipolar disorder, previously known as manic depressive psychosis,
`
`
`
`is another chronic and often severely disabling mental disorder.6
`
`
`
`Bipolar disorder is characterized by the occurrence of at least one
`
`manic, hypomanic, or mixed-manic episode during the patient’s lifetime.7 A manic
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`episode is described as a distinct period of abnormally and persistently elevated,
`
`
`
`3 Ex. 2015 (Tarazi), 1.
`
` Id.
`
` Ex. 2014 (Stip), 2.
`
` Ex. 2017 (Burton), 1; Ex. 2044 (Franklin), 1 (2143).
`
` 4
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` 5
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` 6
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`7 Ex. 2019 (DSM-IV), 6-7, 10.
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`14
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`expansive, or irritable mood and increased goal-directed activity or energy, lasting at
`
`least one week.8 Bipolar disorder and schizophrenia can have symptoms in common,
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`including hallucinations and delusions.9
`
`
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`Most patients also, at other times, have one or more depressive
`
`episodes.10 Bipolar depression refers to the “lows,” or depressive phase, of bipolar
`
`disorder.
`
`
`
`Bipolar disorder is an episodic or cyclical illness, characterized in
`
`most patients by the intermittent, lifelong appearance of episodes of illness, either
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`mania or depression, in between which most patients experience an interval during
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`which they more or less return to their normal state of well-being.11
`
`
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`Treatment of bipolar disorder aims for remission of symptoms:
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`manic, depressive, or both. Pharmacotherapy options for bipolar disorder are
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`typically grouped by the targeted symptoms. Yet effective treatment is not easy to
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`achieve; the remission rate for bipolar mania is approximately 40% to 50%. Bipolar
`
`
`
`15
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`8 Ex. 1023 (DSM-IV), 91.
`
` 9
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` See Ex. 2140 (Möller), 4.
`
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`10 Ex. 2019 (DSM-IV), 7.
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`11 Id., 10.
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`depression remains a treatment challenge, with remission rates of only 25 to 60%
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`after recommended treatment.12
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`B. Atypical Antipsychotics
`
`Lurasidone (Latuda®), the drug that is the subject of the ’827
`
`patent, belongs to a class of drugs referred to as “atypical” or “second generation”
`
`antipsychotics. A common feature of antipsychotics in this class is that they target
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`both dopamine D2 and serotonin 5HT2A receptors in the brain.13 This is in contrast to
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`the “typical” or “first generation” antipsychotics that generally target only D2
`
`receptors.14 As a result, second generation antipsychotic drugs are associated with
`
`fewer extrapyramidal symptoms (“EPS”).15
`
`
`
`EPS, a common and prevalent side effect associated with first
`
`generation antipsychotics, involves various movement disorders characterized by
`
`repetitive, involuntary muscle movements, restlessness, or an inability to initiate
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`movement. EPS symptoms include dystonia (continuous spasms and muscle
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`contractions), akathisia (motor restlessness), Parkinsonism (characteristic symptoms
`
`
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`12 Ex. 2044 (Franklin), 2.
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`13 Ex. 2045 (Shayegan), 1.
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`14 Ex. 2046 (Kane), 1-2; Ex. 1042 (Wetterling), 5-6.
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`15 Ex. 1042 (Wetterling), 5; Ex. 2014 (Stip), 2; Ex. 2015 (Tarazi), 2.
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`16
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`such as rigidity), bradykinesia (slowness of movement), tremors, and tardive
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`dyskinesia (irregular, jerky movements).
`
`
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`Clozapine (Clozaril®) was considered to be the prototype of
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`atypical antipsychotics and viewed as a breakthrough drug because of its
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`effectiveness in treating schizophrenia with much lower levels of EPS than seen with
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`typical antipsychotics.16
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`
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`Around 2000, in addition to clozapine, a “new wave” of atypical
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`antipsychotic drugs were available to treat schizophrenia, including olanzapine
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`(Zyprexa®), quetiapine (Seroquel®), risperidone (Risperdal®), and ziprasidone
`
`(Geodon®).17
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`
`
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`
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`I discuss these drugs in greater detail below.
`
`1. Olanzapine
`
`
`
`Olanzapine (Zyprexa®) is an atypical antipsychotic that FDA
`
`approved in 1996 for the treatment of schizophrenia.18 In 2003, the FDA approved
`
`olanzapine in combination with fluoxetine (Symbyax®) for the treatment of
`
`
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`16 Ex. 2014 (Stip), 5; Ex 2015 (Tarazi), 2; Ex. 2013 (Meltzer), 2; Ex. 2046 (Kane), 2.
`
`17 Ex. 2014 (Stip), 5.
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`18 Ex. 2002 (Zyprexa® Label), 1.
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`
`17
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`depressive episodes associated with bipolar I depression.19 Olanzapine is not
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`approved as a monotherapy for the treatment of bipolar depression.
`
`
`
`The current understanding of olanzapine’s receptor binding profile
`
`is reproduced below.20 The D2 receptor is identified in a red box with a dashed,
`
`vertical line through it, and the 5HT2A receptor is a light purple box outlined in red.
`
`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, with
`
`“+++” representing high affinity and “+” representing low affinity.21
`
`
`
`As shown in the above figure, olanzapine has a complex
`
`pharmacology, binding to at least 21 receptors, several more potently than the D2
`
`receptor.
`
`
`
`
`
`19 Ex. 2047 (Nashed), 1; Ex. 2048 (Symbyax® Label), 1.
`
`20 Ex. 2027 (Stahl’s Essential), 59.
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`21 Binding properties vary greatly with technique and from one lab to another.
`
`
`18
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`Olanzapine has a high risk of causing metabolic side effects like
`
`weight gain compared to other antipsychotic drugs.22 Several studies reported a
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`significant increase in body weight in patients with schizophrenia treated with
`
`olanzapine.23 “Bodyweight gain was more frequent and higher in patients treated
`
`with olanzapine than those receiving haloperidol or risperidone (BMI within 8 weeks
`
`+1.3 vs 0.7 for olanzapine and risperidone, respectively).”24
`
`
`
`More recently available data show that bipolar patients in addition
`
`to schizophrenic patients treated with olanzapine experience a significant weight
`
`gain.25
`
`
`
`Olanzapine is also associated with other adverse effects. For
`
`example, olanzapine ranks among the antipsychotics with the greatest known
`
`cardiometabolic risks, as it robustly increases fasting triglyceride levels and increases
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`insulin resistance by an as-yet unknown pharmacologic mechanism.26 As a result,
`
`olanzapine may be considered a second-line treatment for patients with significant
`
`
`
`22 Ex. 2029 (Reynolds), 1.
`
`23 Ex. 1042 (Wetterling), 7; Ex. 1041 (Allison), 8.
`
`24 Ex. 1042 (Wetterling), 7.
`
`25 Ex. 2047 (Nashed), 1.
`
`26 Ex. 2027 (Stahl’s Essential), 58.
`
`19
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`weight gain or who develop significant cardiometabolic risks like dyslipidemia or
`
`diabetes.27
`
`
`
`2. Quetiapine
`
`
`
`Quetiapine (Seroquel®) was approved by FDA in 1997 for the
`
`treatment of schizophrenia.28 It is currently approved to treat manic or mixed
`
`episodes associated with bipolar I disorder (both as monotherapy and adjunctive
`
`therapy with lithium or divalproex), acute treatment of depressive episodes
`
`associated with bipolar I disorder (approved in 2006), maintenance treatment of
`
`bipolar I disorder with lithium or divalproex, and adjunctive treatment of major
`
`depressive disorder.29
`
`
`
`The figure below illustrates the current understanding of
`
`quetiapine’s receptor binding profile.30 Quetiapine is an antagonist at both the
`
`serotonin 5HT2A and dopamine D2 receptors, but notably does not have particularly
`
`potent binding at D2 receptors.
`
`
`
`27 Id.
`
`28 Ex. 2049 (Seroquel® Label), 1.
`
`29 Id.; Ex. 2051 (Thase), 2-3.
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`30 Ex. 2027 (Stahl’s Essential), 60.
`
`20
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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 quetiapine’s affinity for the D2 receptor.31 Quetiapine has high affinity for the
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`H1 histamine and α1 adrenergic receptors.
`
`
`
`Quetiapine follows the same characteristics of other atypical
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`antipsychotics in that it causes minimal EPS. Nevertheless, quetiapine can cause
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`weight gain, particularly when given in moderate to high doses. In one study, the
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`proportion of patients treated with quetiapine who experienced a ≥ 7% body weight
`
`gain was 11-25% of the patients, compared to 4-5% of patients receiving the placebo
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`drug.32 In another report of pooled quetiapine-treated patient weight change data, a
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`weight increase of ≥ 7% was observed in 7.1% of patients receiving 300 mg/day of
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`quetiapine and 10.0% of patients receiving 600 mg/day, compared to just 2.4% of
`
`patients receiving placebo.33
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`
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`31 Id., 61.
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`32 Ex. 1042 (Wetterling), 7.
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`33 Ex. 2051 (Thase), 8.
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`21
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`3. Risperidone
`
`
`
`Risperidone (Risperdal®) is an atypical antipsychotic approved by
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`FDA in 1993 for the treatment of schizophrenia.34 Like many antipsychotic drugs,
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`risperidone is now also approved for the treatment of manic and mixed episodes of
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`bipolar I disorder, alone or in combination with lithium or valproate.35
`
`
`
`The current understanding of the receptor binding profile of
`
`risperidone is reproduced below.36 As shown in the below figure, risperidone binds
`
`to a variety of receptors. The binding profile of risperidone differs from that of
`
`olanzapine and quetiapine both in terms of types of receptors it binds to and its
`
`affinity for various receptors. For example, risperidone has higher affinity for the D2
`
`receptor as compared to olanzapine and quetiapine. In addition, risperidone has high
`
`affinity for the D4 receptor, whereas quetiapine does not.
`
`
`
`
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`34 Ex. 2023 (Risperdal® Label), 1.
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`35 Id.
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`36 Ex. 2027 (Stahl’s Essential), 70.
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`22
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`Like olanzapine and quetiapine, risperidone is also associated with
`
`a risk for weight gain.37 For example, in one study, 39% of patients with chronic
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`schizophrenia gained bodyweight after 8 weeks of treatment with risperidone, which
`
`was about twice the number of patients who increased in bodyweight while receiving
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`perphenazine (a first generation antipsychotic drug).38 Body weight increase has also
`
`been shown to correlate with the dose of risperidone.39 Weight gain can particularly
`
`be a problem for children treated with risperidone.40
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`
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`Risperidone is also associated with other adverse events, including
`
`dyslipidemia, or elevated cholesterol that contributes to the development of
`
`atherosclerosis.41
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`
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`
`
`4. Ziprasidone
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`
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`Ziprasidone (Geodon®) is another atypical antipsychotic approved
`
`by FDA in 2001 for the treatment of schizophrenia.42 Ziprasidone has subsequently
`
`
`
`37 Id.
`
`38 Ex. 2052 (Hoyberg), 6.
`
`39 Ex. 1042 (Wetterling), 10.
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`40 Id.; Ex. 2027 (Stahl’s Essential), 70.
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`41 Ex. 2027 (Stahl’s Essential), 70.
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`42 Ex. 2025 (Geodon® Label 2017), 1; Ex. 2024 (Geodon® approval letter), 5.
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`23
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`
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`been approved to manage both acute mania and mixed states associated with bipolar
`
`disorder.43 It is not FDA approved for treating bipolar depression.
`
`
`
`Although ziprasidone has several properties that suggest it could
`
`have antidepressant actions, it has never been proven to have antidepressant actions
`
`in large clinical trials.44
`
`
`
`The current understanding of ziprasidone’s receptor binding profile
`
`is reproduced in the figure below.45 As can be seen from the figure, in addition to
`
`binding to dopamine D2 and serotonin 5HT2A receptors like all atypical
`
`antipsychotics, ziprasidone has affinity for a variety of other receptors, including a
`
`relatively high affinity for the 5HT2C receptor.46
`
`
`
`
`
`Ziprasidone is unusual as compared to other atypical antipsychotics
`
`because of the way it is dosed, specifically twice a day with food.47 Failure to dose
`
`
`
`43 Ex. 2025 (Geodon® Label 2017), 1.
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`44 Ex. 2027 (Stahl’s Essential), 73; Ex. 2053 (Lombardo), 1; Ex. 2054 (Sachs), 1.
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`45 Ex. 2027 (Stahl’s Essential), 73.
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`46 Ex. 2024 (Geodon® approval letter), 1; Ex. 2025 (Geodon® Label 2017), 16.
`
`47 Ex. 2024 (Geodon® approval letter), 20; Ex. 2025 (Geodon® Label 2017), 1; Ex.
`
`24
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`

`

`
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`the drug with about 500 calories may reduce oral absorption by half and result in
`
`inconsistent efficacy.48
`
`
`
`Ziprasidone is also associated with side effects, specifically QT
`
`prolongation.49 QT syndrome is a heart rhythm disorder that can cause serious
`
`irregular heart rhythms (arrhythmias). In prolonged QT syndrome, the heart muscle
`
`requires a longer than normal amount of time to recharge between beats. This
`
`electrical disturbance, which often can be seen on an electrocardiogram, is called a
`
`prolonged QT interval. Prolongation of the QT interval is associated with the ability
`
`to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic
`
`ventricular tachycardia, and sudden death.50
`
`
`
`
`
`
`
`2027 (Stahl’s Essential), 72.
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`48 Ex. 2025 (Geodon® Label 2017), 1, 14; Ex. 2024 (Geodon® approval letter), 20,
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`23; Ex. 2026 (Dawkins), 5.
`
`49 Ex. 2024 (Geodon® approval letter), 5-7; Ex. 2025 (Geodon® 2017), 1, 4-5; Ex.
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`2055 (Pacher), 1; Ex. 2056 (Stimmel), 12-14; Ex. 2026 (Dawkins), 5.
`
`50 Ex. 2024 (Geodon® approval letter), 5-7; Ex. 2025 (Geodon® Label 2017), 1, 4-5.
`
`25
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`5. Lurasidone
`
`
`
`Lurasidone (Latuda®) is an atypical antipsychotic developed by
`
`Patent Owner.51
`
`
`
`The Latuda® label states that Latuda® exhibits combined activity
`
`and high affinity for dopamine D2 (1 nM Ki) and serotonin 5HT2A (0.5 nM Ki)
`
`receptors.52 Latuda® displays high affinity for 5HT7 (0.5 nM Ki), as well as
`
`moderate affinity for 5HT1A (6.4 nM Ki) and adrenergic α2 (11 nM Ki) receptors.53
`
`Latuda® has low affinity for the 5HT2C receptor and little, if any, affinity for H1
`
`histamine and muscarinic M1 receptors.54 The current understanding of Latuda®’s
`
`receptor binding profile is reproduced below.55
`
`
`
`51 Ex. 2004 (Latuda® Label), 1, 18.
`
`52 Id., 13.
`
`53