Filed on behalf of: Corcept Therapeutics, Inc.
`
`Entered: May 20, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`———————————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————————
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`NEPTUNE GENERICS, LLC,
`Petitioner,
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`v.
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`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`
`———————————
`
`Case IPR2018-01494
`U.S. Patent No. 8,921,348
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`———————————
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`DECLARATION OF DR. NED H. KALIN, M.D. IN SUPPORT OF
`PATENT OWNER’S RESPONSE
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`Ex. 2016-0001
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`
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`Entered: May 20, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`———————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————————
`
`NEPTUNE GENERICS, LLC,
`Petitioner,
`
`v.
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`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`
`———————————
`
`Case IPR2018-01494
`U.S. Patent No. 8,921,348
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`———————————
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`DECLARATION OF DR. NED H. KALIN, M.D. IN SUPPORT OF
`PATENT OWNER’S RESPONSE
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`Ex. 2016-0001
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`IPR2018-01494 (USP 8,921,348)
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`TABLE OF CONTENTS
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`Dr. Kalin’s Declaration
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`Page
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`I.
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`II.
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`INTRODUCTION AND QUALIFICATIONS ............................................... 1
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`ASSIGNMENT ................................................................................................ 3
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`III.
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`PERSON OF ORDINARY SKILL IN THE ART .......................................... 4
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`IV. SUMMARY OF OPINIONS ........................................................................... 6
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`V.
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`TESTS FOR MEASURING PSYCHIATRIC DRUG EFFICACY ................ 7
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`A. Hamilton Depression Rating Scale ....................................................... 8
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`B.
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`C.
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`Brief Psychiatric Rating Scale............................................................... 9
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`Clinical Global Impression Rating Scales ........................................... 10
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`VI. THE CITED PRIOR ART REFERENCES DESCRIBE CLINICAL
`TESTS FOR ASSESSING SYMPTOMATOLOGY TO EVALUATE
`AND MONITOR EFFICACY AND DETERMINE WHETHER TO
`ADJUST MIFEPRISTONE TREATMENT ................................................. 12
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`VII. THE ’348 PATENT DESCRIBES AND CLAIMS A METHOD OF
`MEASURING MIFEPRISTONE SERUM LEVELS IN ORDER TO
`PREDICT EFFICACY AND GUIDE DOSING ........................................... 17
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`VIII. THE DIFFERENCE BETWEEN THE MECHANISM OF ACTION
`FOR MENTAL DISEASE AND CONTRACEPTION ................................ 21
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`
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`i
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`Ex. 2016-0002
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`I.
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`INTRODUCTION AND QUALIFICATIONS
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`
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`Dr. Kalin’s Declaration
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`1.
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`I have been retained by Corcept Therapeutics, Inc. (“Patent Owner” or
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`“Corcept”) to provide certain opinions related to U.S. Patent No. 8,921,348 (“the
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`’348 Patent”) in support of Patent Owner’s Response in IPR2018-01494.
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`2.
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`I am being compensated at my standard hourly rate of $500 per hour,
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`with reimbursement for reasonable expenses, for my work related to the IPR
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`proceeding cited above. My compensation is not dependent on, and in no way
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`affects, the substance of my statements in this Declaration.
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`3.
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`I am the Hedberg Professor and Chairman of the Department of
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`Psychiatry at the University of Wisconsin School of Medicine and Public Health. I
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`am the Editor-in-Chief of the American Journal of Psychiatry, a premier scientific
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`journal of the American Psychiatric Association. I am the Director of the
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`HealthEmotions Research Institute and the Lane Neuroimaging Laboratory, a
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`Professor in the Department of Psychology at the University of Wisconsin, and an
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`affiliate scientist at the Wisconsin Regional Primate Center and the Harlow
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`Primate Laboratory.
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`4.
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`I serve as the principal investigator for several ongoing NIH funded
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`research projects and have published over 200 peer-reviewed journal articles
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`related to the adaptive and maladaptive expression of emotion and anxiety. My
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`research focuses on uncovering basic mechanisms that relate stress to the
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`Ex. 2016-0003
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`development of psychopathology and understanding the mechanisms that cause
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`some children to be vulnerable for the development of anxiety and depression. In
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`addition to my research activities, I treat patients who suffer from anxiety and
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`depression who are refractory to standard treatment.
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`5.
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`I earned my medical degree from Jefferson Medical School in
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`Philadelphia, Pennsylvania. I did my residency in the Department of Psychiatry at
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`the University of Wisconsin and my fellowship in Neuropsychopharmacology at
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`the National Institute of Mental Health. I am board certified by the American
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`Board of Psychiatry and Neurology. I am a fellow of the American College of
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`Neuropsychopharmacology and the American College of Psychiatry.
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`6.
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`I have been recognized for numerous awards including the 1985 A.E.
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`Bennett Award for basic science research in biological psychiatry, the 2005
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`Edward A. Strecker Award, the 2007 American College of Psychiatrists Award for
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`research in mood disorders, the 2007 Gerald Klerman Senior Investigator Award,
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`and
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`the 2015 Anna-Monika Prize of
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`the European College of
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`Neuropsychopharmacology. In 2013, I was inducted as a Fellow in the American
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`Association for the Advancement of Science, and, in 2015, I was elected as a
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`member of the National Academy of Medicine.
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`7.
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`In 2017, I was inducted as a Distinguished Life Fellow of the
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`American Psychiatric Association and was appointed to the Editorial Board of the
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`2
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`Ex. 2016-0004
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`Journal of Psychiatric Research. I served as President of the International Society
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`of Psychoneuroendocrinology, as President of the Society of Biological Psychiatry,
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`and as a member of the National Advisory Mental Health Council. I was Co-
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`Editor for the international journal, Psychoneuroendocrinology. I lecture regularly
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`at national and international meetings.
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`8.
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`From time to time, I have worked on various projects for Corcept.
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`Over the past ten years, Corcept has paid me $5,750 for my efforts. Corcept has
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`also provided grant support to the University of Wisconsin. Those grants have
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`been used in part to fund my research team, but I also receive funding from other
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`sources, including, for example, from the National Institute of Mental Health.
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`9.
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`A copy of my curriculum vitae is attached as Ex. 2017.
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`II.
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`ASSIGNMENT
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`10.
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`In forming my opinions in this Declaration, I have reviewed the
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`materials cited in and listed in the Appendix to this Declaration. I have been asked
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`to explain the tools and tests that clinicians and psychiatrists use to evaluate and
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`monitor the efficacy of psychiatric drugs for treating various mental disorders such
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`as depression, stress disorders, delirium, and others. I have based this on my
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`academic pursuits, training, and experience as a practicing psychiatrist since 1979.
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`I have prescribed various drugs for the treatment of various psychiatric diseases,
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`Ex. 2016-0005
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`including depression, stress disorders, and delirium. I have treated hundreds of
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`patients over the years for various mental diseases.
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`11.
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`I have reviewed the six prior art references that I understand Petitioner
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`is relying upon in asserting that the Challenged Claims are invalid as obvious and I
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`have reviewed the ’348 Patent, including the claims. In particular, I have been
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`asked to analyze the methodology that each publication describes for evaluating
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`and monitoring efficacy. I have also been asked to analyze the method described
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`and claimed in the ’348 Patent for evaluating and monitoring the efficacy of using
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`mifepristone to treat chronic disorders, such as mental disorders. In addition, I
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`have been asked to compare the methodologies in the prior art references, as well
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`as those traditionally used in the field of psychiatry, to the method described and
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`claimed in the ’348 Patent.
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`12.
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`I have also been asked to explain the mechanism of action for
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`antidepressants—i.e., the mechanism by which therapeutic effect is achieved—as
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`compared to the mechanism of action for contraceptives.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`I understand that the relevant analysis of the prior art and the
`13.
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`invention in the ’348 Patent must be conducted from the perspective of a person of
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`ordinary skill in the art (“POSA”) at the time of the invention. I understand that
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`the earliest patent application leading to issuance of the ’348 Patent was filed on
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`Ex. 2016-0006
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`August 30, 2007. I understand that the Petitioner does not dispute that the relevant
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`date for the analysis is August 30, 2007. Neptune Petition at 5. My opinions in
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`this Declaration are based on the knowledge and perspective of a POSA as of this
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`date.
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`14.
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`I understand that Petitioner has defined the POSA as an individual
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`with “either a Pharm. D or a Ph.D. in organic chemistry, pharmacy, pharmacology,
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`or a related discipline; or a Bachelor’s or Master’s degree in organic chemistry or a
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`related field with at least four years of experience relating to the study of
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`pharmacokinetics or dosing of drugs, their detection and quantification, or their
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`metabolism.” Neptune Petition at 12. Petitioner has further stated that the “POSA
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`may have collaborated with others having expertise in, for example, methods of
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`treating diseases and administering medicines.” Neptune Petition at 12.
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`15.
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`I understand that Dr. Derendorf has opined that the POSA is an
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`individual with either a Pharm. D or Ph.D. in pharmacy, pharmacology, or a
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`related discipline; or a Bachelor’s or Master’s degree in pharmacy or a related field
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`with at least four years of experience relating to the study of pharmacokinetics and
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`pharmacodynamics, including the relationship between the two, as well as
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`experience with measuring, monitoring, and adjusting drug levels. Derendorf
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`Declaration at ¶ 26. Dr. Derendorf further states that the POSA would have
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`Ex. 2016-0007
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`collaborated with others, such as physicians, clinicians, or psychiatrists with
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`experience treating mental disease. Derendorf Declaration at ¶ 26.
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`16. Thus, I understand Petitioner and Dr. Derendorf agree that the POSA
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`would have collaborated with physicians with experience in the treatment of
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`psychiatric disease. Neptune Petition at 12; Derendorf Declaration at ¶ 28.
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`IV.
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`SUMMARY OF OPINIONS
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`17. Each of the Belanoff and Murphy prior art references relied upon by
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`Petitioner, which discuss the use of mifepristone to treat various psychiatric
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`disorders, describe formal psychiatric assessments and neuro-psychiatric tests to
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`evaluate and monitor efficacy. In my opinion, they describe psychiatric tests that
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`clinicians traditionally use and rely upon in determining the efficacy of a particular
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`psychiatric drug in treating the underlying symptoms of the given mental disease.
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`18.
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`In contrast, the method described and claimed in the ’348 Patent
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`describes evaluating and monitoring potential efficacy based on measuring drug
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`serum (mifepristone) levels in the blood. In my opinion, the method in the ’348
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`Patent is very different from the traditional methods described in these prior art
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`references.
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`In
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`the history of modern psychopharmacology,
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`traditional
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`antidepressant or antipsychotic treatments did not measure or assess drug blood
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`levels because no correlation with drug level and efficacy was evident.
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`Ex. 2016-0008
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`19.
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`In my opinion, the discovery in the ’348 Patent that drug level
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`correlates with efficacy was new and important as of the 2007 priority date of the
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`’348 Patent. It describes a more efficient clinical protocol for evaluating treatment
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`and predicting efficacy, as compared to the subjective and imprecise clinical
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`assessments traditionally used.
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`20. Psychiatric drugs are typically dosed daily for an extended period of
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`time. These types of drugs require longer exposure time with multiple doses,
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`including the ability to pass the blood-brain barrier. While I am not an
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`obstetrician/gynecologist, I understand that the mechanism of action is very
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`different for contraceptive drugs (modulating progesterone activity rather than
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`glucocorticoid activity). In addition, drugs to terminate pregnancy are generally
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`effective within a much shorter period than psychiatric drugs and do not require
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`distribution of the drug into the nervous system.
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`V.
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`TESTS FOR MEASURING PSYCHIATRIC DRUG EFFICACY
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`21. Traditional tests for monitoring the efficacy of psychiatric drugs have
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`focused on clinical questionnaires and rating scales aimed at qualitatively and
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`quantitatively assessing symptoms, both in terms of identifying the types of
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`symptoms a patient is experiencing and the severity with which the patient is
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`experiencing particular symptoms.
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`Ex. 2016-0009
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`22. Three such clinical tests that have been traditionally used include the
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`Hamilton Depression Rating Scale, the Brief Psychiatric Rating Scale, and the
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`Clinical Global Impression scales. These tests may be completed by patients in
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`consultation with their physicians periodically throughout the course of their
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`treatment. Clinicians also frequently use their subjective judgement based on an
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`interview. Clinicians use these tests, and their judgment, to compare symptoms
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`observed at the start of treatment and after a period of treatment with a certain
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`psychiatric drug. Based on the results, clinicians make decisions on whether to
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`adjust the dosage of the medication, add in an additional medication, or switch to a
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`different medication.
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`A. Hamilton Depression Rating Scale
`23. The Hamilton Depression Rating Scale (“HAM-D,” “HAMD-21,” or
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`“HDRS”) is a psychiatric test designed to rate the severity of depression in patients
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`and to measure the effectiveness of psychiatric drugs in treating symptoms of
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`depression. It is a questionnaire that identifies 21 different clinical symptoms of
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`depression including: depressed mood, feelings of guilt, suicide, insomnia, work
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`and interests, retardation, agitation, anxiety, somatic symptoms, sexual desire,
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`hypochondriasis, weight loss, insight, diurnal variation, depersonalization and
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`derealization, paranoid symptoms, and obsessional symptoms.
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`24. A patient, with their physician, completes the evaluation in order to
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`identify whether the patient is experiencing the various symptoms, as well as the
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`degree of severity at which he or she is experiencing them. The degree of severity
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`is measured through a numerical scale of 0 through 4: 0 represents that the
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`symptom is absent, while 4 indicates frequent and incapacitating symptoms. The
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`physician then calculates the score based on the patient’s answers to the questions.
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`25. Clinicians use the HAMD-21 test to determine whether a given
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`psychiatric drug is effective in treating the patients’ symptoms based on the
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`differences between the occurrence and severity of symptoms at the start of
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`treatment and periodically through treatment. Clinicians may use the results of the
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`HAMD-21 test to determine whether to adjust dose to improve efficacy and/or
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`minimize side effects or to switch a patient to a different psychiatric drug.
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`26. This test is relatively subjective rather than objective. Each clinician
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`applies their own heuristics when analyzing the patient that will necessarily vary
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`from clinician to clinician.
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`Brief Psychiatric Rating Scale
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`B.
`27. The Brief Psychiatric Rating Scale (“BPRS”) is a clinical psychiatric
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`test designed to assess symptoms associated with depression and other psychiatric
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`disorders, and it can be used to determine the effectiveness of antidepressants. The
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`BPRS was first published in 1962. It is one of the oldest and most widely used
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`scales to measure symptoms of depression and other psychiatric disorders.
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`28. The test contains 18 categories: somatic concern, anxiety, emotional
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`withdrawal, conceptual disorganization, guilt feelings, tension, mannerism and
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`posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory
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`behavior, motor retardation, uncooperativeness, unusual thought content, blunted
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`affect, excitement, and disorientation. Each of the 18 categories is attributed a
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`numerical score on a scale of 0 to 7. A score of 0 means “not assessed,” 1 means
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`“not present,” and 7 means “extremely severe.”
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`29. Clinicians may use the BPRS test to determine whether an
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`antipsychotic medication is effective in treating a patient’s symptoms based on
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`changes between the number and severity of symptoms between the start of
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`treatment and periodically through treatment. Clinicians may use the BPRS results
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`to make determinations on whether to adjust dosage of the current drug in an
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`attempt to improve efficacy and/or minimize side effects, or switch a given patient
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`to a different psychiatric drug.
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`30. This test is relatively subjective rather than objective. Each clinician
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`applies their own heuristics when analyzing the patient that will necessarily vary
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`from clinician to clinician.
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`C.
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`Clinical Global Impression Rating Scales
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`Ex. 2016-0012
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`31. Clinical Global Impression (“CGI”) is a group of rating scales
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`designed to measure symptom severity, treatment response, and the efficacy of
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`treatment in patients with mental disorders. The scale is relatively subjective and
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`requires the clinician to compare the results across patients with the same
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`diagnosis.
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`32. The Clinical Global Impression – Severity scale (CGI-S) is a 7-point
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`scale that requires the clinician to rate the severity of the patient’s illness at the
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`time of assessment, ranging from “normal, not at all ill” up to “among the most
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`extremely ill patients.” The Clinical Global Impression – Improvement scale
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`(CGI-I) is a 7-point scale designed to assess how much the patient’s illness has
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`improved or worsened relative to the start of treatment, ranging from “very much
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`improved” to “very much worse.” The Clinical Global Impression – Efficacy
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`Index is a 4 x 4 rating scale that assesses the therapeutic effect of treatment with
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`psychiatric medication and associated side effects. There are four rating
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`possibilities for therapeutic effect ranging from “marked – vast improvement” to
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`“unchanged or worse” and four rating possibilities for side effects ranging from
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`“none” to “outweigh therapeutic effect.”
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`33. Clinicians use the Clinical Global Impression – Efficacy Index to
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`determine whether a psychiatric drug is effective in treating the patient’s symptoms
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`(in the context of the side effect profile) based on the effects comparatively seen in
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`other patients. Clinicians use the CGI results to make determinations on whether
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`to adjust dosage of the current drug in an attempt to improve efficacy and/or
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`minimize side effects or to switch a patient to a different psychiatric drug.
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`34. This test is relatively subjective rather than objective. Each clinician
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`applies their own heuristics when analyzing the patient that will necessarily vary
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`from clinician to clinician.
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`VI. THE CITED PRIOR ART REFERENCES DESCRIBE CLINICAL
`TESTS FOR ASSESSING SYMPTOMATOLOGY TO EVALUATE
`AND MONITOR EFFICACY AND DETERMINE WHETHER TO
`ADJUST MIFEPRISTONE TREATMENT
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`35.
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`I understand that Petitioner relies on five prior art references which
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`describe using mifepristone to treat certain psychiatric disorders: Belanoff ’953
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`(Ex. 1010);1 Belanoff ’848 (Ex. 1024);2 Belanoff 2002 (Ex. 1007);3 Chu &
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`Belanoff (Ex. 1023);4 and Murphy (Ex. 1006).5 Each of the references describes
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`1 U.S. Patent No. 6,964,953.
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`2 U.S. Patent App. Pub. No. 2004/0029848A1.
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`3 “An Open Label Trial of C-1073 (Mifepristone) for Psychotic Major Depression”
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`published by Belanoff et al. in Biological Psychiatry.
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`4 “Successful Long-Term Treatment of Refractory Cushing’s Disease with High-
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`Dose Mifepristone (RU 486)” published by Chu, Belanoff et al. in The Journal of
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`Clinical Endocrinology & Metabolism.
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`Ex. 2016-0014
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`using the clinical, psychiatric assessment tests described above—HAMD-21,
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`BPRS, and CGI—to evaluate and monitor clinical efficacy.
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`36. The Belanoff ’953 (Ex. 1010) and Belanoff ’848 (Ex. 1024)
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`references are similar and describe using mifepristone to treat stress disorders and
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`delirium, respectively. Ex. 1010 at Abstract, Ex. 1024 at Abstract. The references
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`contain substantially similar sections entitled “Treating Stress Disorders with
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`Mifepristone” (Belanoff ’953) and “Treating Delirium With Mifepristone”
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`(Belanoff ’848), that describe a three-step process: (1) “Patient Selection”; (2)
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`“Dosage Regimen and Administration of Mifepristone”; and (3) “Assessing
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`Treatment of Stress Disorders” or “Assessing Treatment of Delirium,”
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`respectively. Ex. 1010 at 17:55-18:25 (Example 1); Ex. 1024 at [0092] – [0099]
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`(Example 1).
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`37. For step 3, Belanoff ’953 and Belanoff ’848 teach: “To delineate and
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`assess the effectiveness of mifepristone in ameliorating the symptoms of stress
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`disorders [or delirium], formal psychiatric assessment and a battery of neuro-
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`psychological tests and assessments are administered to all patients.” Ex. 1010 at
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`5 “Possible Use of Glucocorticoid Receptor Antagonists in the Treatment of Major
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`Depression: Preliminary Results Using RU 486” published by Murphy et al. in the
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`Journal of Psychiatry & Neuroscience.
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`Ex. 2016-0015
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`18:15-25; Ex. 1024 at [0099]. Belanoff ’953 and Belanoff ’848 state that “[t]he
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`patients’ performance on a standardized test instrument appropriate to the stress
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`disorder [or form of delirium] under study will be determined.” Ex. 1010 at 18:15-
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`25; Ex. 1024 at [0099]. Belanoff ’953 and Belanoff ’848 note that “[t]hese tests
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`and diagnostic assessments take place at baseline (patient’s entry into treatment)
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`and periodically throughout treatment.” Ex. 1010 at 18:15-25; Ex. 1024 at [0099].
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`38.
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` Both Belanoff ’848 and Belanoff ’953 instruct that a patient should
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`be treated with mifepristone for a certain period of time (one week in Belanoff
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`’848 and six months in Belanoff ’953) and then evaluated by the noted
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`psychological tests to determine whether an adjustment in dose is necessary. Ex.
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`1024 at [0096] (“The glucocorticoid receptor (GR) antagonist, mifepristone, is
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`used in this study. It is administered in dosages of 600-1200 mg daily for one
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`week. Patients are evaluated as described below. Dosages will be adjusted if
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`necessary and further evaluations will be performed periodically throughout
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`treatment.”); Ex. 1010 at 18:5-12 (“The glucocorticoid receptor (GR) antagonist,
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`mifepristone, is used in this study. It is administered in dosages of 200 mg daily.
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`Individuals will be given 200 mg of mifepristone daily for six months and
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`evaluated as describe below. Dosages will be adjusted if necessary and further
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`evaluations will be performed periodically throughout treatment.”).
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`Ex. 2016-0016
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`39. Belanoff 2002 (Ex. 1007) teaches the use of mifepristone to treat
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`psychotic major depression. Ex. 1007 at 386. Belanoff 2002 describes an open-
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`label study where thirty patients with psychotic major depression received either
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`50 mg, 600 mg, or 1200 mg of mifepristone. Belanoff 2002 teaches administration
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`of mifepristone for seven days before evaluating efficacy. Ex. 1007 at 386. To
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`evaluate efficacy, Belanoff 2002 teaches that “[f]ormal psychiatric assessments,
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`including the HAMD-21, BPRS, and CGI were carried out on day 0, day 3, and
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`day 7.” Ex. 1007 at 389. It further explains that “[t]he positive symptom subscale
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`of the BPRS was used because it focuses on symptoms characteristic of PMD. The
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`items of the BPRS included in this scale were items 4 (conceptual disorganization),
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`11 (suspiciousness), 12 (hallucinatory behavior), and 15 (unusual thought
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`content).” Ex. 1007 at 389. To determine whether treatment was effective,
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`Belanoff 2002 specifies that their “response criteria were a 30% reduction on the
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`BPRS, a 50% reduction on the BPRS positive symptom subscale, and a 50%
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`reduction on the HAMD-21.” Ex. 1007 at 389.
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`40. Chu & Belanoff (Ex. 1023) describes a study where one patient with
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`Cushing’s syndrome, including the symptom of psychotic depression, was treated
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`with mifepristone for 18 months. Ex. 1023 at 3568. It describes using the BPRS
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`test throughout the 18 months of treatment to evaluate whether the mifepristone
`
`treatment was effective.
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` Chu & Belanoff reports
`
`that “[t]he patient’s
`
`15
`
`Ex. 2016-0017
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`
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`IPR2018-01494 (USP 8,921,348)
`
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`neuropsychiatric status improved dramatically.” Ex. 1023 at 3571. Specifically,
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`Dr. Kalin’s Declaration
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`
`
`the patient’s “elevated BPRS score, indicating psychosis, entirely resolved; and his
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`mood normalized.” Ex. 1023 at 3571. In addition, the patient’s “cognition
`
`improved substantially, with dramatic correction in all aspects of the Stroop color-
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`word and paragraph recall tests.” Ex. 1023 at 3571. Chu & Belanoff also
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`discusses dose adjustment based on symptoms of hypercortisolism. Ex. 1023 at
`
`3570 (“During the initial 8 months of mifepristone treatment, the dose was
`
`gradually increased to a maximum of 2000 mg / d (~25 mg/kg·d) in response to
`
`continued signs of hypercortisolism (Fig. 2).”).
`
`41. Murphy (Ex. 1006) describes mifepristone treatment in four patients
`
`with major depression for up to eight weeks. Ex. 1006 at 209. It utilizes the
`
`HRSD test throughout the up to eight-week treatment period to evaluate efficacy.
`
`Specifically, Murphy describes that “[d]uring treatment, independent psychiatric
`
`assessments were carried out weekly, usually by two physicians, using the 21-item
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`HRSD.” Ex. 1006 at 210. Figure 1 details the HRSD ratings for each of the four
`
`patients. Ex. 1006 at 212, Figure 1. Murphy concludes that “[t]he mean scores on
`
`the Hamilton Rating Scale for Depression of three patients decreased . . .
`
`suggest[ing] that glucocorticoid antagonists may be effective in the treatment of
`
`major depression and merit further exploration.” Ex. 1006 at 209.
`
`16
`
`Ex. 2016-0018
`
`
`
`
`
`IPR2018-01494 (USP 8,921,348)
`
`
`VII. THE ’348 PATENT DESCRIBES AND CLAIMS A METHOD OF
`MEASURING MIFEPRISTONE SERUM LEVELS IN ORDER TO
`PREDICT EFFICACY AND GUIDE DOSING
`
`Dr. Kalin’s Declaration
`
`42. The ’348 Patent concerns the use of mifepristone as a therapy in a
`
`variety of chronic disorders, including mental disorders. The patent explains that
`
`some patients may not respond to mifepristone therapy because the drug does not
`
`reach therapeutic levels in their blood, even when they are given a dose that would
`
`be therapeutic in other patients. The ’348 Patent describes and claims a way for
`
`physicians to identify potentially poor responders to mifepristone treatment and
`
`adjust their dosing based on the drug serum levels in the blood.
`
`43. The ’348 Patent explains that “optimizing” mifepristone levels refers
`
`to the process of testing mifepristone blood levels and adjusting the dosage of
`
`mifepristone where needed in order to achieve mifepristone blood levels above
`
`1300 ng/mL. Ex. 1001 at 5:53-56.
`
`44. Claim 1 of the ’348 Patent is as follows.
`
`1. A method for optimizing levels of mifepristone in a patient
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`suffering from a disorder amenable to treatment by mifepristone, the
`
`method comprising:
`
`treating the patient with seven or more daily doses of
`
`mifepristone over a period of seven or more days;
`
`17
`
`Ex. 2016-0019
`
`
`
`IPR2018-01494 (USP 8,921,348)
`
`
`
`
`
`Dr. Kalin’s Declaration
`
`testing the serum levels of the patient to determine whether the
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`blood levels of mifepristone are greater than 1300 ng/mL;
`
`and
`
`adjusting the daily dose of the patient to achieve mifepristone
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`blood levels greater than 1300 ng/mL.
`
`45. Claims 2-7, which depend from claim 1, further specify the disorder
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`(claims 2-3), specify that the seven or more daily doses are administered orally
`
`(claim 4), describe 28 or more daily doses over a period of 28 or more days (claim
`
`5), specify a plasma sampling collection device suitable for detecting mifepristone
`
`serum levels (claim 6), and describe that the adjusting step comprises increasing
`
`the daily dose of the patient to achieve mifepristone blood levels greater than 1300
`
`ng/mL (claim 7).
`
`46. The ’348 Patent describes and claims a three-step method for
`
`optimizing blood levels of mifepristone in patients. Ex. 1001 (’348 Patent) at 1:40-
`
`49; 16:25-35. First, the patient is administered seven or more daily doses of
`
`mifepristone over a period of seven or more days. Ex. 1001 at 1:43-45, 16:29-30.
`
`Second, the serum levels of the patient are tested and compared to the threshold
`
`level of 1300 ng/mL to determine whether it has been exceeded. Ex. 1001 at 1:45-
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`47, 16:31-33. Third, the daily dose is adjusted to achieve mifepristone blood levels
`
`greater than 1300 ng/mL. Ex. 1001 at 1:47-49, 16:34-35.
`
`18
`
`Ex. 2016-0020
`
`
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`IPR2018-01494 (USP 8,921,348)
`
`
`
`
`
`Dr. Kalin’s Declaration
`
`47. The methodology is supported by data reporting clinical trial results
`
`from hundreds of patients, comparing those who responded well to treatment with
`
`those who did not. The patent data show that the percentage of patients having the
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`desired response to treatment (at least 50 percent drop from baseline after 7 days)
`
`was essentially identical to placebo when blood serum levels were below 1357
`
`ng/mL. By contrast, in patients where blood serum levels were above 1357 ng/mL,
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`the response rate was significantly higher than placebo (40% compared to 26%).
`
`48. This is important because the efficacy of the drug is directly linked to
`
`its plasma level; it was not known that the amount of drug administered will
`
`achieve these plasma levels. Derendorf Declaration at ¶¶ 62-74. Using the plasma
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`level greatly increases the likelihood of a positive response, which is not the case
`
`with most of the psychiatric drugs we use. This finding is surprising, and would
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`have been to one of skill in the art as of the priority date of the ’348 Patent, as most
`
`of the drugs we use have a wide dosing range related to efficacy, and their efficacy
`
`has not been found to be predicted by plasma drug levels.
`
`49. The optimization methodology described and claimed in the ’348
`
`Patent is very different from the clinical assessments described in the prior
`
`Belanoff and Murphy references and those traditionally used by psychiatrists for
`
`treating mental disease. Rather than utilizing questionnaires aimed at subjectively
`
`assessing the presence and severity of psychiatric symptoms, the ’348 Patent
`
`19
`
`Ex. 2016-0021
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`
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`IPR2018-01494 (USP 8,921,348)
`
`
`instead focuses on the objective assessment of drug blood levels. This approach
`
`Dr. Kalin’s Declaration
`
`
`
`would have been surprising to a POSA as of 2007 because most psychiatric drugs
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`generally failed to demonstrate a correlation between drug serum level and
`
`efficacy.
`
`50. For this reason, clinical treatment has been forced to focus on various
`
`subjective surveys to determine amelioration of symptoms. These clinical
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`assessments, while consistently used, are relatively subjective and imprecise.
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`Additionally, the clinical response, which is reflected by these tools, is frequently
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`delayed in relation to medication administration. Thus, getting plasma levels that
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`are earlier predictors of treatment can be very helpful in not only enhancing the
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`likelihood of recovery but also allowing for more rapid titration of medication to
`
`therapeutic levels. Unfortunately, however, data from interviews and rating scales
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`are tools that the field of clinical psychiatry has relied on for years because no
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`superior methodology has been discovered for evaluating and monitoring dosing to
`
`achieve a greater likelihood of efficacy.
`
`51. The method described and claimed in the ’348 Patent offers a
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