Inter Partes Review of USP 9,138,432
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`
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`In re Inter Partes Review of:
`)
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`U.S. Patent No. 9,138,432 B2
`)
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`Issued: Sept. 22, 2015
`)
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`Application No.: 14/150,575
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`Filing Date: Jan. 8, 2014
`)
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`For: Methods for the Administration of Iloperidone
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`FILED VIA PRPS
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`DECLARATION OF DAVID L. FOGELSON, M.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,138,432
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`
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 001
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
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`TABLE OF CONTENTS
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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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`Summary Of Opinions ..................................................................................... 5
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`III. Understanding Of The Governing Law ........................................................... 7
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`A.
`B.
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`Invalidity by Obviousness ..................................................................... 7
`Interpreting Claims Before the Patent Office ...................................... 10
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`IV. The Person Of Ordinary Skill In The Art Of The ’432 Patent ...................... 11
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`V.
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`Perspective Applied In This Declaration ....................................................... 12
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`VI. Overview Of The ’432 Patent ........................................................................ 13
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`A. Disclosure of the ’432 Patent .............................................................. 13
`B.
`Prosecution History ............................................................................. 16
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`VII. Claim Construction ........................................................................................ 21
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`A.
`B.
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`Legal Standard ..................................................................................... 21
`Construction of Claim Terms .............................................................. 22
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`VIII. The State Of The Art Prior To The ’432 Patent ............................................ 22
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`A.
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`B.
`C.
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`D.
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`E.
`F.
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`G.
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`The Prior Art Taught Adjusting Drug Dosages Based on
`CYP2D6 Drug Interactions ................................................................. 22
`The Prior Art Taught that Fluoxetine is a CYP2D6 Inhibitor ............ 27
`The Prior Art Taught Halving the Dose of CYP2D6 Substrates
`Co-administered with Fluoxetine ........................................................ 29
`The Prior Art Taught that Iloperidone is Used to Treat
`Schizophrenia ...................................................................................... 33
`The Prior Art Taught that Iloperidone is a CYP2D6 Substrate .......... 33
`The Prior Art Taught that Increased Exposure to Iloperidone is
`Associated with a Risk of QT Prolongation ........................................ 34
`The Prior Art Taught Iloperidone Doses of 12 mg/day and 24
`mg/day ................................................................................................. 36
`
`i
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 002
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
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`IX. Relied Upon References ................................................................................ 38
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`FDA Guidance 1999 (Exhibit 1005) ................................................... 38
`A.
`B. Mutlib (Exhibit 1006) .......................................................................... 39
`C.
`Brøsen (Exhibit 1007) ......................................................................... 40
`D.
`The Abilify Label (Exhibits 1008 and 1009) ...................................... 41
`E. Mealy (Exhibit 1010) .......................................................................... 44
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`X. Motivation To Combine The Prior Art References ....................................... 44
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`A. Motivation to Combine FDA Guidance 1999, Mutlib, Brøsen,
`and Mealy ............................................................................................ 44
`B. Motivation to Combine FDA Guidance 1999, Mutlib, the
`Abilify Label, and Mealy .................................................................... 49
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`XI. Grounds Of Invalidity .................................................................................... 51
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`A. Ground 1: Claim 1 is Invalid Under 35 U.S.C. § 103 on the
`Ground That it is Rendered Obvious by FDA Guidance 1999 in
`View of Mutlib, Brøsen, and Mealy .................................................... 51
`Ground 2: Claim 1 is Invalid under 35 U.S.C. § 103 on the
`Ground That it is Rendered Obvious by FDA Guidance 1999 in
`View of Mutlib, the Abilify Label, and Mealy ................................... 56
`
`B.
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`XII. Secondary Considerations Fail To Overcome The Strong Evidence Of
`Obviousness ................................................................................................... 59
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`XIII. Conclusion ..................................................................................................... 59
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`ii
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 003
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
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`I, Dr. David Fogelson, resident of Santa Monica, California, hereby declare
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`as follows:
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`I.
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`INTRODUCTION AND QUALIFICATIONS
`1.
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`I have been retained by Roxane Laboratories, Inc. (“Roxane”) to
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`provide my opinions concerning Claim 1 of U.S. Patent No. 9,138,432 (Ex. 1001,
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`“the ’432 Patent”) in support of Roxane’s Petition for Inter Partes Review of U.S.
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`Patent No. 9,138,432. I have not previously been employed or retained by Roxane
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`in any capacity.
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`2.
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`Claim 1 of the ’432 Patent relates to a method of administering
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`iloperidone to a patient, where the dose of iloperidone is reduced if the patient is
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`concurrently being treated with fluoxetine.
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`3.
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`I have extensive and ongoing expertise in treating psychotic disorders,
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`including prescribing iloperidone for the treatment of schizophrenia
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`4.
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`I am a Clinical Professor of Psychiatry at the David Geffen School of
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`Medicine at the University of California, Los Angeles (UCLA) School of Medicine
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`and the UCLA Department of Psychiatry and Biobehavioral Sciences. In the past,
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`I have served as Assistant Director of the UCLA Outpatient Psychiatry
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`Department, Assistant Director of the UCLA Mood Disorders Outpatient Clinic,
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`Director of the UCLA Outpatient Psychopharmacology Clinic, Director of the
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`UCLA Anxiety Disorder Clinic at UCLA, and Director of the Westwood Hospital
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`
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`1
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 004
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
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`Intensive Care Unit. I am a clinical supervisor for the psychiatry residents in the
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`UCLA Outpatient Psychiatry Department, in which capacity I teach residents,
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`interns, and medical students current community standard psychiatric practices,
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`including how to account for potential drug-drug interactions while treating
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`patients. I also regularly speak publicly at hospitals, universities, and clinics on
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`various topics in psychopharmacology and schizophrenia.
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`5.
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`I have treated patients as a licensed physician since 1977. I have been
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`board certified in psychiatry and neurology since 1984. I currently see about 60
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`patients weekly and I supervise the care of dozens of others. Within the past 20
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`years, I have treated thousands of patients for schizophrenia. I have prescribed all
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`major approved atypical antipsychotics, including iloperidone. I have also treated
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`tens of thousands of patients for depression, and I estimate that I have administered
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`fluoxetine over five thousand times. In my clinical practice, I have significant and
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`ongoing experience adjusting the dosages of drugs administered to patients based
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`on patients’ medical histories and concurrent medications.
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`6. My primary areas of research have focused on the genetics,
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`pathophysiology, and pharmacologic treatment of schizophrenia and related
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`disorders. I was the Medical Director for the UCLA Family Study of
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`Schizophrenia, a long-term clinical genetics study of schizophrenia. I previously
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`served as President of the Pacific Psychopharmacology Research Institute, where I
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`2
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 005
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`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
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`conducted numerous clinical trials, including trials for the antipsychotics
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`aripiprazole, ziprasidone, olanzapine, and sertindole and the antidepressants
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`fluoxetine, fluvoxamine, and tandospirone. In the aripiprazole trials, for example,
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`we tested the safety and efficacy of switching to aripiprazole from other
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`antipsychotics.
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`7.
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`I have been a member of numerous professional societies, including
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`the Schizophrenia International Research Society, the American Academy of
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`Clinical Psychiatrists, the West Coast College of Biological Psychiatry, the
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`American Medical Association, the American Psychiatric Association, and the
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`American Association for the Advancement of Science. I was previously President
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`of the Southern California Psychiatric Society, and I am a continuing Board
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`Member of the same.
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`8.
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`I have also served on many professional committees at UCLA and in
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`Southern California. For example, at UCLA I chaired the Clinical Care Utilization
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`Committee and the Adult Patient Care Evaluation Committee, and I was a member
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`of the Medical Records Committee and the Specialty Clinics Committee. Within
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`the Southern California Psychiatric Society, I chaired the Health Care Reform
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`Committee and the Hospital Psychiatric Committee, and I was a member of the
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`Scientific Program Committee. At Woodview Calabasas Hospital, I chaired the
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`Pharmacy Committee, and I was member of the Adult Psychiatric Committee.
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`
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`3
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 006
`
`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`
`9.
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`Over the past 30 years, I have authored or co-authored over 25 peer
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`reviewed publications, over 20 abstracts, and various letters and book chapters. I
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`am an associate editor of eFocus, the electronic continuing medical education
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`journal of the American Psychiatric Association, and I am a reviewer for a number
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`of other journals, including the American Journal of Psychiatry, the Journal of
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`Clinical Psychopharmacology, Brain and Behavior, the Journal of Neuropsychiatry
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`and Clinical Neurosciences, and Schizophrenia Research. I also currently chair the
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`Psychopharmacology Journal Club for the UCLA clinical faculty.
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`10. My awards and honors received include my designation as a
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`Distinguished Lifetime Fellow of the American Psychiatric Association. I have
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`been elected by my peers for inclusion in the Best Doctors in America® list every
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`year since 1996, and I was designated a Fellow in Psychopharmacology at McLean
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`Hospital, a division of Harvard Medical School.
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`11.
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`I completed my undergraduate degree in 1972 at the University of
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`California at Santa Cruz and in 1977 I received an M.D. from Harvard Medical
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`School.
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`12.
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`In summary, I have extensive experience related to pharmacological
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`drug interactions and treating schizophrenia and depression.
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`13. My curriculum vitae is attached as Exhibit 1004. My work in this
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`matter is being billed at my standard consulting rate of $600 per hour. I
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`
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`4
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 007
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
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`understand that the expert search service that initially contacted me regarding this
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`matter is billing an additional $180 per hour for my work. My compensation is not
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`in any way contingent upon the outcome of any petition for inter partes review. I
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`have no financial or personal interest in the outcome of this proceeding or any
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`related proceeding or litigation.
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`II.
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`SUMMARY OF OPINIONS
`14. Claim 1 of the ’432 Patent recites:
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`A method of decreasing a risk of QT prolongation in a patient being
`treated for schizophrenia with iloperidone, the method comprising:
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`administering to the patient a dose of iloperidone that is 24 mg/day if,
`and because, the patient is not being treated with fluoxetine; and
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`administering to the patient a dose of iloperidone that is 12 mg/day if,
`and because, the patient is being treated with fluoxetine.
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`15.
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`In my opinion Claim 1 of the ’432 Patent would have been obvious to
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`a person of ordinary skill in the art as of September 30, 2004, the earliest claimed
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`priority date for the ’432 Patent.
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`16. The prior art specifically instructed that when a CYP2D6 substrate
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`(such as iloperidone) is administered to a patient together with a CYP2D6 inhibitor
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`(such as fluoxetine), the dosage of the CYP2D6 substrate should be cut in half in
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`order to prevent adverse effects arising from elevated blood levels of the CYP2D6
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`substrate. The prior art also taught the specific dosages of iloperidone used to treat
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`
`
`5
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 008
`
`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`schizophrenia, and the prior art taught practitioners to determine any dosage
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`adjustment warranted to account for potential CYP2D6 drug interactions.
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`17. By September 30, 2004, a person of ordinary skill in the art knew that
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`iloperidone is a CYP2D6 substrate and that fluoxetine is a CYP2D6 inhibitor.
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`Accordingly, a person of ordinary skill therefore knew that, when co-administered,
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`fluoxetine would alter the pharmacokinetics of iloperidone elimination, such that
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`iloperidone should be dosed at one-half of its normal dose. A person of ordinary
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`skill would also have been motivated to test this interaction to determine the
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`optimum dosage of iloperidone when co-administering fluoxetine, and would have
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`been likely to arrive at the claimed dosage amounts.
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`18. The prior art (which I discuss in more detail in Sections VIII and IX
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`below) provided all of this information to those of ordinary skill in the art. Those
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`of ordinary skill in the art (who, as I understand from counsel for Roxane, are
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`presumed to be aware of this prior art, and as I discuss in more detail in Section IX
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`below) were highly motivated to combine this prior art by September 30, 2004,
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`which all relates to the safe administration of drugs commonly administered by
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`psychiatrists, consistent with the FDA’s guidelines. By combining the prior art, a
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`person of ordinary skill in the art by September 30, 2004, would achieve the
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`claimed method of administering one-half the dosage of iloperidone when co-
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`administering fluoxetine.
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`
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`6
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 009
`
`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
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`19. Therefore, it is my opinion that Claim 1 of the ’432 Patent would have
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`been obvious to a person of ordinary skill in the art by September 30, 2004.
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`III. UNDERSTANDING OF THE GOVERNING LAW
`A.
`Invalidity by Obviousness
`20.
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`I have been informed by counsel for Roxane that a patent claim is
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`invalid if it is obvious in view of the prior art. I am informed by counsel for
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`Roxane that obviousness is analyzed from the perspective of a hypothetical person
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`of ordinary skill in the art at the time of the alleged invention. I understand from
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`counsel for Roxane that a claim may be obvious over one prior art reference or a
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`combination of prior art references. I am also informed by counsel for Roxane that
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`a person of ordinary skill in the art is presumed to have been aware of all the
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`pertinent prior art at the time of the alleged invention.
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`21.
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`I understand from counsel for Roxane that 35 U.S.C. § 103 governs
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`the determination of obviousness. According to 35 U.S.C. § 103:
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`A patent may not be obtained though the invention is not identically
`disclosed or described as set forth in section 102, if the differences
`between the subject matter sought to be patented and the prior art are
`such that the subject matter as a whole would have been obvious at
`the time the invention was made to a person having ordinary skill in
`the art to which said subject matter pertains. Patentability shall not be
`negatived by the manner in which the invention was made.
`
`
`
`7
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 010
`
`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
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`22.
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`I am also informed by counsel for Roxane that the first three factors to
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`be considered in an obviousness inquiry are: (1) the scope and content of the prior
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`art; (2) the differences between the prior art and the claims; and (3) the level of
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`ordinary skill in the pertinent art. I have been informed by counsel for Roxane that
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`a patent claim may be considered obvious if, at the time of the invention,
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`combining known elements according to known methods would have yielded no
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`more than predictable results. I have also been informed by counsel for Roxane
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`that a patent claim may be considered obvious if there existed at the time of
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`invention a known problem for which there was an obvious solution.
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`23. Further, I understand from counsel for Roxane that when a patent
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`claims a genus, that claim is obvious if a single embodiment falling within the
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`scope of the claims is obvious. I also understand from counsel for Roxane that an
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`invention may be obvious to try based on a design need and a finite number of
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`predictable solutions. And I understand from counsel for Roxane that the
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`optimization of a variable in a known process, or the discovery of an optimum
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`value in a known range of values, is ordinarily obvious, particularly when such
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`optimization may be obtained by routine experimentation by a person of ordinary
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`skill in the art.
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`24.
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`I have been informed by counsel for Roxane that a claim may be
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`obvious if a person of ordinary skill in the art would have been motivated to
`
`
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`8
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 011
`
`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`combine elements of the prior art or knowledge within the prior art to achieve the
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`claimed invention and would have had a reasonable expectation of success in
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`doing so. I also understand that the reason to select and combine features, the
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`predictability of the results in doing so, and a reasonable expectation of success of
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`doing so may be found in the teachings of the prior art themselves, in the nature of
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`any need or problem in the field that was addressed by the patent, in the knowledge
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`of persons of ordinary skill in the art at the time, as well as in common sense or the
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`level of creativity exhibited by a person of ordinary skill in the art. There need not
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`be an express or explicit suggestion to combine references.
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`25.
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`I am also informed by counsel for Roxane that when there is some
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`recognized reason to solve a problem, and there are a finite number of identified,
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`predictable solutions, a person of ordinary skill in the art has good reason to pursue
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`the known options within his or her technical grasp. If such an approach leads to
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`the anticipated success, it is likely the product not of innovation but of ordinary
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`skill and common sense. In such a circumstance, when a patent simply arranges
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`old elements with each performing the same function it had been known to perform
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`and yields no more than one would expect from such an arrangement, the
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`combination is obvious.
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`26.
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`I am also informed by counsel for Roxane that certain factors,
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`sometimes known as “secondary considerations,” must be considered, if present, in
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`
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`9
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 012
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
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`an obviousness determination. These secondary considerations include: (i) long-
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`felt need, (ii) unexpected results, (iii) skepticism of the invention, (iv) teaching
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`away from the invention, (v) commercial success, (vi) praise by others for the
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`invention, and (vii) copying by other companies.
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`27.
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`I am also informed by counsel for Roxane that the earliest patent
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`application leading to the ’432 Patent was filed on September 30, 2004. I have
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`therefore analyzed obviousness as of that day or somewhat before, understanding
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`that as time passes, the knowledge of a person of ordinary skill in the art will
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`increase.
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`B.
`28.
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`Interpreting Claims Before the Patent Office
`I understand that Inter Partes Review is a proceeding before the
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`United States Patent & Trademark Office (“PTO”) for evaluating the validity of
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`issued patent claims. I understand that in an Inter Partes Review a claim term is
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`given the broadest reasonable interpretation that is consistent with the patent’s
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`specification. I understand that a patent’s “specification” includes all the figures,
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`discussion, and claims within the patent. I understand that the PTO will look to the
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`specification to see if there is a definition for a given claim term, and if not, will
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`apply the broadest reasonable interpretation from the perspective of a person of
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`ordinary skill in the art at the time in which the alleged invention was made.
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`
`
`10
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 013
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART OF THE ’432
`PATENT
`29. The purported invention of the ’432 Patent involves an understanding
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`of several common concepts of treating schizophrenia in a patient who is also
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`receiving a CYP2D6 inhibitor antidepressant.
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`30. The purported invention of the ’432 Patent involves the application of
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`well-known and conventional concepts of drug-drug interactions between CYP2D6
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`substrates and CYP2D6 inhibitors in the context of drugs administered by
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`psychiatrists.
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`31. Based on those factors, a “person of ordinary skill in the art” in
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`September 2004 would have had, at a minimum:
`
`i.
`
`ii.
`
`iii.
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`a graduate degree in medicine, pharmacy, pharmacology, or a related
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`field;
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`at least 2-3 years of practical experience in the field of psychiatry
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`and/or clinical pharmacology, including pharmacogenomics; and
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`familiarity with adjusting drug dosages based on a patient’s drug
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`metabolism or drug regimen.
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`32. This description is approximate, and a higher level of education or
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`skill might make up for less experience, and vice-versa.
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`
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`11
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 014
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`V.
`
`PERSPECTIVE APPLIED IN THIS DECLARATION
`33.
`
`I believe that I would qualify as a person of at least ordinary skill in
`
`the art in September 2004 and that I have a sufficient level of knowledge,
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`experience, and education to provide an expert opinion in the field of the ’432
`
`Patent.
`
`34.
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`I have conducted research on and treated patients for depression and
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`schizophrenia for over thirty-five years. I have substantial experience relating to
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`the co-administration of interacting drugs, including an extensive understanding of
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`how and when to adjust drug dosages based on a drug’s metabolic pathways of
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`elimination and/or individual patient need. In my roles as a professor, researcher,
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`and practicing clinician, I worked with, supervised, and advised individuals who
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`were persons of ordinary skill in the art as defined above, including researchers,
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`drug developers, and fellow practicing psychiatrists. Accordingly, I am well-
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`acquainted with the level of experience and understanding of a person of ordinary
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`skill in the art as defined above, and I can approach technical issues from the
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`perspective of such a person.
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`35. My opinions in this declaration are based on the perspective of a
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`person of ordinary skill in the art as of September 2004. This is true even if the
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`testimony is stated in the present tense. Each of the statements below reflects my
`
`
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`12
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 015
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`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`opinion based on my review of the prior art, the disclosures of the ’432 Patent, its
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`file history, and the challenged claim.
`
`VI. OVERVIEW OF THE ’432 PATENT
`A. Disclosure of the ’432 Patent
`36. The ’432 Patent is directed to the well-known practice of reducing the
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`dosage of a drug administered to a patient if the patient has decreased ability to
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`metabolize the drug. Ex. 1001, ’432 Patent at 2:21-27. It claims to invent the
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`discovery that, when a known drug (such as iloperidone), which is known to be
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`metabolized by the CYP2D6 enzyme, is known to produce a side effect (here,
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`prolongation of the electrocardiographic QT interval) a lower dose of the drug is
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`safer for a patient with reduced CYP2D6 enzyme activity. Id. at 2:21-27.
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`37. As I discuss in Section VIII.F below, the QT interval is a measure of
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`the duration of a cardiovascular electric potential, and its prolongation is a well-
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`known side effect associated with many drugs.
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`38. The ’432 Patent claims this practice in the context of treating a patient
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`with iloperidone, a CYP2D6-metabolized antipsychotic drug, while the patient is
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`concurrently receiving the antidepressant fluoxetine, a CYP2D6 enzyme inhibitor.
`
`Id. at 2:65-3:3, Claim 1. Claim 1 recites:
`
`A method of decreasing a risk of QT prolongation in a patient being
`treated for schizophrenia with iloperidone, the method comprising:
`
`
`
`13
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 016
`
`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`
`administering to the patient a dose of iloperidone that is 24 mg/day if,
`and because, the patient is not being treated with fluoxetine; and
`
`administering to the patient a dose of iloperidone that is 12 mg/day if,
`and because, the patient is being treated with fluoxetine.
`
`Id. at Claim 1.
`
`39. The ’432 Patent states
`
`that
`
`iloperidone was known
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`to
`
`treat
`
`schizophrenia. Id. at 1:45-53. The ’432 Patent also acknowledges that iloperidone
`
`methods of use and dosages were known in the art by September 2004. Id. at 1:42-
`
`44, 11:15-22.
`
`40. The ’432 Patent describes that variations in a patient’s ability to
`
`metabolize a drug can be dangerous to the patient where an “increased
`
`concentration of a non-metabolized drug or its metabolites is capable of producing
`
`unwanted physiological effects.” Id. at 1:29-34. It states as background that
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`“[a]mong the unwanted physiological effects associated with an increased
`
`concentration of
`
`iloperidone or
`
`its metabolites
`
`is prolongation of
`
`the
`
`electrocardiographic QT interval.” Id. at 1:56-58.
`
`41. The ’432 Patent also references a corrected QT interval, “QTc,” which
`
`is equivalent to the QT interval corrected by a mathematical formula, such as the
`
`Fridericia formula (QTcF). Id. at 2:40-48.
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`
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`14
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`Exhibit 1003
`Page 017
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`

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`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`
`42. As the ’432 Patent notes, CYP enzymes are also referred to as “P450”
`
`enzymes, and the CYP2D6 enzyme is also referred to as “P450 2D6” and
`
`“debrisoquine hydroxylase.” Id. at 1:35-37. Herein, I use “CYP2D6” to reference
`
`the CYP2D6 enzyme, and “CYP2D6 genotype” to reference the genotype that
`
`encodes the CYP2D6 enzyme.
`
`43. As the ’432 Patent also states, by September 2004, iloperidone was
`
`known to be metabolized by the CYP2D6 enzyme, as were many other drugs. Id.
`
`at 1:35-42. Iloperidone is therefore referred to as a CYP2D6 “substrate.” Id. at
`
`4:46-48. The ’432 Patent further describes that another CYP enzyme, CYP3A4,
`
`also contributes to iloperidone’s metabolism. Id. at 4:46-50.
`
`44. According to the ’432 Patent, by September 2004, mutations in the
`
`CYP2D6 genotype were associated with drug metabolism-related phenotypes,
`
`including ultra-rapid metabolizer (UM), extensive metabolizer (EM), intermediate
`
`metabolizer (IM), and poor metabolizer (PM) phenotypes. Id. at 1:58-63. The
`
`term “genotype” refers to an individual’s genetic make-up, whereas “phenotype”
`
`refers to their set of observable characteristics.
`
`45. As the ’432 Patent also acknowledges, “lower CYP2D6 activity in a
`
`CYP2D6 poor metabolizer may be due to factors other than genotype,” such as if a
`
`patient is being administered a CYP2D6 inhibitor. Id. at 10:4-8. One well-known
`
`CYP2D6 inhibitor is fluoxetine.
`
`
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`15
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 018
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`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`
`46. Accordingly, the ’432 Patent defines all “[p]atients who have lower
`
`than normal CYP2D6 activity” as “Poor Metabolizers.” Id. at 2:29-30. As
`
`the ’432 Patent recognizes, “[w]here a particular drug is capable of producing
`
`unwanted physiological effects in its metabolized or non-metabolized forms, it is
`
`desirable to determine whether a patient is a poor metabolizer of the drug prior to
`
`its administration.” Id. at 1:63-67.
`
`47. The ’432 Patent’s specification describes a study concerning
`
`concentrations of iloperidone and its metabolites in patients with various CYP2D6
`
`genotypes as well as concentrations before and after administration of a CYP2D6
`
`inhibitor, paroxetine. Id. at 4:24-41, 5:28-10:67. With regard to the known
`
`CYP2D6 inhibitor fluoxetine, the ’432 Patent only states that, “[a]ddition of the
`
`CYP2D6 inhibitor fluoxetine, along with iloperidone resulted in increases of the
`
`area under the curve (AUC) for iloperidone and P88 of 131% and 119%
`
`respectively.” Id. at 4:51-54.
`
`B.
`48.
`
`Prosecution History
`
`I have reviewed the prosecution history of the ’432 Patent.
`
`49. Based on my review of the prosecution history, Claim 1 appears to
`
`only have been allowed based on the specific 12 mg/day and 24 mg/day dosages
`
`that it recites. Ex. 1002, ’432 Patent Prosecution History Excerpts (“Prosecution
`
`History”) at 4/22/2015 Applicant Summary of Interview at Continuation Sheet
`
`
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`16
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`Exhibit 1003
`Page 019
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`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`(stamped page 319). The Examiner repeatedly rejected nearly identical claims that
`
`only differed from Claim 1 by reciting broader ranges of dosages (such as 12-24
`
`mg/day and 12 mg/day or less), recognizing that the prior art provided motivation
`
`to lower iloperidone’s dose in a patient also receiving a CYP2D6 inhibitor (like
`
`fluoxetine). Ex. 1002, Prosecution History at 6/2/2015 Notice of Allowance at
`
`Interview Summary, 4/28/2015 Applicant Amendment After Final at 3, and
`
`4/22/2015 Applicant Summary of Interview at Continuation Sheet (stamped pages
`
`361, 330, 319).
`
`50. Also, the Examiner maintained throughout prosecution that “to the
`
`extent that the use of a lower known dosage of iloperidone reduces the risk of QT
`
`prolongation, this is an inherent benefit of the use of such [] dosage (and the
`
`dosage is suggested by the teachings of the art).” Ex. 1002, Prosecution History at
`
`1/28/2015 Office Action at 15 (stamped page 292).
`
`51. For completeness, I present a more comprehensive summary of the
`
`prosecution history below.
`
`52. The ’432 Patent issued from U.S. Patent Application No. 14/150,575
`
`(the “’432 Patent Application”), which was filed on January 8, 2014 with claims
`
`directed to methods for administering reduced dosages of iloperidone to a patient
`
`receiving a CYP2D6 inhibitor. Ex. 1002, Prosecution History at 1/8/2014
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`Application at 25-26 (stamped pages 42-43). The ’432 Patent claims priority to
`
`
`
`17
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 020
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`

`
`Declaration of David Fogelson, M.D., in Support of
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432
`
`U.S. Provisional Paten