UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`LIMITED,
`Petitioner,
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`v.
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`UCB PHARMA GMBH,
`Patent Owner.
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`Case No. IPR2016-00510
`Patent No. 6,858,650 B1
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`DECLARATION OF WILLIAM R. ROUSH, PH.D.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0001
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`Table of Contents
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`I.
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`INTRODUCTION ............................................................................................... 1
`A. Background and Qualifications ..................................................................... 1
`B. Materials Considered ..................................................................................... 8
`II. SUMMARY OF OPINIONS ............................................................................ 11
`III. LEGAL STANDARDS .................................................................................. 12
`IV. THE ‘650 PATENT ........................................................................................ 14
`V. PERSON HAVING ORDINARY SKILL IN THE ART ................................. 16
`VI. THERE IS NO EVIDENCE THAT 5-HMT WOULD NOT BE ORALLY
`ABSORBED ............................................................................................................ 16
`VII. A PRODRUG APPROACH WOULD NOT HAVE BEEN CONSIDERED
`SUITABLE FOR 5-HMT ........................................................................................ 19
`IN DECIDING TO PURSUE A PRODRUG OF 5-HMT, A PERSON OF
`VIII.
`ORDINARY SKILL WOULD HAVE FACED MANY OPTIONS WITH NO
`EXPECTATION OF SUCCESS.............................................................................. 23
`A. A Person of Ordinary Skill Would Have Had To Select the Type of
`Prodrug ................................................................................................................. 23
`B. A Person of Ordinary Skill Would Have Needed to Select Where to Add
`the Prodrug Substituent ........................................................................................ 25
`C. Even Having Selected an Ester Group, a Person of Ordinary Skill Would
`Have Had Thousands of Compounds to Consider ............................................... 27
`IX. THE (R) ENANTIOMER OF FESOTERODINE WOULD NOT HAVE
`BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART .......... 30
`X. THE FUMARATE SALT OF FESOTERODINE WOULD NOT HAVE
`BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART .......... 31
`XI. CLEAVAGE RATES FOR FESOTERODINE AND OTHER ESTER
`PRODRUGS OF 5-HMT WERE UNPREDICTABLE .......................................... 33
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0002
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`I.
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`INTRODUCTION
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`1. I, William R. Roush, Ph.D., have been retained by White & Case LLP,
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`counsel for Patent Owner UCB Pharma GmbH (“UCB”), as an expert witness in
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`the above-captioned inter partes review of United States Patent No. 6,858,650 (the
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`“‘650 patent”). I understand that Mylan Pharmaceuticals Inc. and Mylan
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`Laboratories Limited (collectively with Mylan Pharmaceuticals Inc., “Petitioner”)
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`have petitioned for inter partes review of the ‘650 patent, and request that the
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`United States Patent and Trademark Office (“PTO”) cancel as unpatentable certain
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`claims of the ‘650 patent.
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`2. This declaration sets forth my analyses and opinions based on the
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`materials I have considered thus far, as well as the bases for my opinions.
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`A. Background and Qualifications
`3. I am a chemist with more than 35 years of professional experience in
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`organic chemistry and medicinal chemistry. I am Professor of Chemistry and
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`Executive Director of Medicinal Chemistry of the Scripps Research Institute in
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`Jupiter, Florida (“Scripps Florida”). I am also the Associate Dean of the Graduate
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`Program at Scripps Florida. A copy of my curriculum vitae is attached as Exhibit
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`2003.
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` My educational background and my professional experience are
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`summarized below.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0003
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`4. I obtained a Bachelor of Science degree in Chemistry from the University
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`of California, Los Angeles in 1974, graduating summa cum laude. I obtained my
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`Ph.D. in Chemistry from Harvard University in 1977.
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`5. After a year of post-doctoral work at Harvard (1977-78), I joined the
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`faculty at the Massachusetts Institute of Technology (MIT) as an Assistant
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`Professor of Chemistry. I taught chemistry courses and performed research at MIT
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`from 1978 to 1987. My research interests included the total synthesis of natural
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`products and the development of new synthetic methods.
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`6. In 1987, I moved to Indiana University, where I ultimately became
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`Distinguished Professor of Chemistry. At Indiana University, I initiated a research
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`program on the design and synthesis of inhibitors of cysteine proteases. These
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`inhibitors, designed to combat certain tropical parasitic diseases, are chemical
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`compounds which prevent (i.e., inhibit) an enzyme, specifically a cysteine
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`protease, from performing an essential chemical reaction in the parasite, resulting
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`in the death of the microorganism.
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`7. In 1997, I was appointed the Warner-Lambert/Parke-Davis Professor of
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`Chemistry at the University of Michigan. This is an endowed chair established by
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`a gift from Parke-Davis to the University of Michigan. I subsequently served as
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`the Chairman of the Department of Chemistry at the University of Michigan from
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`2002-2004. While at the University of Michigan, I served as Co-Director of the
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0004
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`Life Sciences Initiative Commission, which conceived the Life Sciences Institute
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`(LSI), and laid out the blueprint for its creation and development to stimulate
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`interdisciplinary research in the biomedical sciences. I also continued to develop
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`my research program focusing on the synthesis of biologically active natural
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`products, the development of new synthetic methodology, and the design and
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`development of inhibitors of cysteine proteases.
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`8. In 2004, I was recruited to join the Scripps Research Institute at its new
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`campus in Florida. I assumed my current positions – Executive Director of
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`Medicinal Chemistry, Professor of Chemistry, and Associate Dean of the Graduate
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`Program – in 2005. Scripps Florida is an expansion of the well-known Scripps
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`Research Institute, which is headquartered in La Jolla, California. The Scripps
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`Research Institute is one of the leading biomedical research institutes in the world
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`and is internationally recognized for its commitment to, and its basic research in,
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`the
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`fields of
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`immunology, biology, chemistry, neurosciences, virology,
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`autoimmune and cardiovascular diseases, and synthetic vaccine development.
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`Particularly significant is the Scripps Research Institute’s study of the basic
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`structure and design of biological molecules.
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`9. As Associate Dean of the Graduate Program at Scripps Florida, I am
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`developing and leading the graduate program on the Jupiter campus.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0005
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`10. I currently serve as Executive Director of Medicinal Chemistry in the
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`Drug Discovery Division of Scripps’ Translational Research Institute at Scripps
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`Florida. In this position, I direct the research of twelve to sixteen (12-16) staff
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`medicinal chemists who are charged with performing structure-activity relationship
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`(“SAR”) studies to optimize drug candidates for several drug discovery projects
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`internal to Scripps. Projects at Scripps Florida that have been performed under my
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`directorship, or are still active, include the development and optimization of
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`enzyme inhibitors for cancer targets, central nervous system diseases (e.g.,
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`Parkinson’s disease), and metabolic diseases, among others. In addition, I
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`personally direct an academic research program with twelve (12) graduate students
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`and postdoctoral associates that is funded primarily by the National Institutes of
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`Health (“NIH”). This program includes medicinal chemistry research projects
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`focusing on development of agonists and antagonists of nuclear receptors,
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`development of inhibitors of enzyme targets (including kinases, cysteine proteases,
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`metallomatrix proteinases, histone deacetylates, and cytochrome P51, among
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`others) and development of inhibitors of transporters responsible for active
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`transport of molecules into and out of cells.
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`11. An important aspect of my work is an understanding of the biochemistry
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`of biological drug targets. I frequently work with biologists and pharmacologists
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`on projects and I regularly review and assess the results of biological experiments
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0006
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`and use those results to make decisions about how to further improve the
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`compounds that are the subjects of these medicinal chemistry research projects.
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`12. From 2007 through 2014 I served as the Chairman of the Chemistry
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`Coordination Committee of the Scripps Molecular Screening Center, which was
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`one of four centers forming the Molecular Libraries Production Centers Network
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`(MLPCN), an NIH-funded program which screened potential drug targets and
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`performed SAR studies to optimize potential drug candidates.
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`13. I have served a five-year term on the National Institutes of Health (NIH)
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`Medicinal Chemistry Study Section, including two (2) years as Chair. The
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`Medicinal Chemistry Study Section reviewed research proposals in medicinal
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`chemistry submitted to the NIH, and ranked these applications in terms of their
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`scientific merit.
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`14. I have presented my research in more than two hundred (200) invited
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`lectures at universities and pharmaceutical companies. In addition, I have been
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`invited to deliver more than one hundred (100) named, keynote, or plenary lectures
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`at universities and national and international symposia and conferences. All of the
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`invited, named, keynote and plenary lectures that I have presented during my
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`career have been based on my research on compound synthesis and/or the
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`biological evaluation of specific compounds that I have synthesized.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0007
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`15. I have published extensively in the scientific literature and have
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`authored or co-authored over three hundred forty (340) papers relating to organic
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`synthesis and medicinal chemistry, including more than fifty (50) scientific articles
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`dealing specifically with the synthesis and biochemical and/or biological
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`evaluation of small molecule inhibitors of protein targets.
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`16. I have experience with the discovery and development of prodrugs due
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`to my work as a medicinal chemist. By consulting in the pharmaceutical industry,
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`I have gained first-hand exposure to the selection and optimization of prodrug
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`candidates. I have been involved in research in which prodrugs were used to
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`evaluate the activity of inhibitors in appropriate biological assays. I have also been
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`involved in the development of a commercial process for manufacture of a prodrug
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`(Clindamycin Phosphate) that was marketed by Genzyme Corporation beginning in
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`the late 1980s.
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`17. I am currently engaged in an NIH funded project to develop a novel
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`class of prodrugs, specifically antibody-drug conjugates, in which the antibody
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`targets specific cells, and the drug is cleaved by enzymes within the cell after the
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`conjugate is internalized.
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`18. I am an Associate Editor of the Journal of the American Chemical
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`Society. In addition, I am on the editorial board of Organic Letters and previously
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`served on the editorial advisory board of Chemical Biology and Drug Design. I am
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0008
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`also a member of the Boards of Directors of Organic Syntheses, Inc. and Organic
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`Reactions, Inc., which publish the Organic Syntheses and Organic Reactions
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`monographs.
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`19. I regularly consult with pharmaceutical and biotechnology companies.
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`These consultations focus, in general, on aspects of medicinal chemistry, synthetic
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`chemistry, and process chemistry for companies engaged in drug discovery and
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`development. I also participate, as a consultant, in strategic planning exercises.
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`The companies I currently consult with are Eli Lilly and Company and IFM
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`Therapeutics. In the past I have also consulted with Pfizer Inc., Genzyme
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`Corporation, Lycera Corporation, ArQule Inc., NeXstar Pharmaceuticals Inc. and
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`GMP-Immunotherapeutics, among others.
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`20. I have received a number of awards for my research, including the
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`Arthur C. Cope Scholar Award (1994) from the American Chemical Society, the
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`Paul G. Gassmann Distinguished Service Award from the American Chemical
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`Society Division of Organic Chemistry, and the Ernest Guenther Award in the
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`Chemistry of Natural Products from the American Chemical Society. In 2006, I
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`was elected a Fellow of the American Association for the Advancement of
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`Science, and in 2009, I was elected a Fellow of the American Chemical Society.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0009
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`B. Materials Considered
`21. The opinions that I express in this declaration are based on the
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`information and evidence currently available to me. The following table lists the
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`materials that I considered in forming my opinions set forth in this declaration. I
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`also relied on my general knowledge, experience, and my own scientific analysis.
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`Exhibit
`No.
`1001
`1002
`1003
`1004
`1005
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`1006
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`1007
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`1008
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`1009
`1010
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`Materials
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`United States Patent No. 6,858,650.
`The file history of United States Patent No. 6,858,650.
`Declaration of Dr. Steven Patterson, Ph.D.
`C.V. for Dr. Steven Patterson, Ph.D.
`“Novel 3,3-
`WO 94/11337 Filed 6 November 1992 –
`Diphenylpropylamines, Their Use and Preparation” (“Johansson”).
`BJU International (1999), 84, 923-947 – “The Pharmacological
`Treatment of Urinary Incontinence”; KE Andersson, R. Appell, L.D.
`Cardozo, C. Chapple, H.P. Drutz, A.E. Finkbeiner, F. Haab, and R.
`Vela Navarrete (“Andersson Review”).
`N. Brynne et al., Pharmacokinetics and Pharmacodynamics of
`Tolterodine in Man: A New Drug for the Treatment of Urinary Bladder
`Overactivity, 35 INT’L J. CLIN. PHARMACOLOGY & THERAPEUTICS 287
`(1997) (“Brynne 1997”).
`British Heart Journal (1995), 74, 53-56 – “Concentration dependent
`cardiotoxicity of terodine in patients treated for urinary incontinence”;
`S. Thomas, P. Higham, K Hartigan-Go, F. Kamali, P. Wood, R.
`Campbell, and G. Ford (“Thomas”).
`Detrol® Label.
`Drug Metabolism and Disposition (1998), 26 (4), 289-293 –
`“Tolterodine, A New Muscarinic Receptor Antagonist, Is Metabolized
`by Cytochromes P450 2D6 and 3A in Human Liver Microsomes”; H.
`Postlind, A. Danielson, A. Lindgren, and S. Andersson (“Postlind”).
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0010
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`1011
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`1012
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`1013
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`1014
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`1015
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`1016
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`1017
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`1018
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`1019
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`1020
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`1021
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`Niclas Brynne et al., Influence of CYP2D6 Polymorphism on the
`Pharmacokinetics and Pharmacodynamics of Tolterodine, 63 CLIN.
`PHARMACOLOGY & THERAPEUTICS 529 (1998) (“Brynne 1998”).
`Hans Bundgaard, DESIGN OF PRODRUGS (Hans Bundgaard ed. 1985)
`(“Bundgaard”).
`JOURNAL OF PHARMACEUTICAL SCIENCES (1977), 66 (1), 1-19 –
`“Pharmaceutical Salts”; S. Berge, L., Bighley, and D. Monkhouse
`(“Berge”).
`(1998), 26(6), 528-535 –
`Drug Metabolism and Disposition
`“Biotransformation of
`tolterodine, a new muscarinic receptor
`antagonist, in mice, rats, and dogs”; S. Andersson, A. Lindgren, and H.
`Postlind (“Andersson 1998”).
`Lisbeth Nilvebrant et al., Antimuscarinic Potency and Bladder
`Selectivity of PNU-200577, a Major Metabolite of Tolterodine, 81
`PHARMACOLOGY & TOXICOLOGY 169 (1997) (“Nilvebrant 1997”).
`P&T (2012), 37(6), 345-361 – “Management of Urinary Incontinence”;
`G. DeMaagd and T. Davenport (“DeMaagd”).
`UROLOGY (1997), 50, 90-96 – “Clinical efficacy and safety of
`tolterodine in the treatment of overactive balder: a pooled analysis”; R.
`Appell (“Appell”).
`Home Care Provider (1997), 2(3), 117-120 – “Is My Antihistamine
`Safe?”; L. Ashworth (“Ashworth”).
`Christopher A. Lipinski et al., Experimental and Computational
`Approaches to Estimate Solubility and Permeability in Drug Discovery
`and Development Settings, Advanced Drug Delivery Reviews 23
`(1997) 3-25 (“Lipinski”).
`WO 92/08459 Filed 11 November 1991 – “Topical Compositions for
`Transdermal Delivery of Prodrug Derivatives of Morphine”
`(“Bundgaard patent”).
`American Urological Association Education and Research (2014) –
`“Diagnosis and Treatment of Overactive Bladder (Non-Neorogenic) in
`Adults: AUA/SUFU Guideline”; E. Gormley, et al.
`(“AUA
`Guideline”).
`
`9
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0011
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`
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`1022
`
`1023
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`1024
`1025
`1026
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`1027
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`1028
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`1029
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`1030
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`1031
`
`2001
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`2003
`2004
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`2006
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`2007
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`Aug. 2, 2012 “Study Shows Toviaz is Effective in Reducing Urge
`Urinary Incontinence in Patients with Overactive Bladder After
`Suboptimal Response to Detrol LA” – www.pfizer.com (“Pfizer 2012
`Press Release”).
`April 1, 2012 “Overactive Bladder Market: Managing the Future” –
`www. pm360online.com (“PM360”).
`“Toviaz® Label” – Pfizer Labs
`“FDA Approval Letter” –NDA20-771
`Applications Covered by Section 505(b)(2) – October 1999 – FDA
`(CDER) (“FDA Guidance”).
`INTERNATIONAL JOURNAL OF PHARMACEUTICS (1986), 3, 201-217 –
`“Salt Section for Basic Drugs”; P. Gould (“Gould”).
`Discovery & Development of Selective M3 Antagonists for Clinical
`Use, 60 LIFE SCIENCE 1053 (1997) (“Alabaster”).
`1,2,3,4-Tetrahydro-2-Isoquinolinecarboxylate Derivatives: A Novel
`Class of Selective Muscarinic Antagonists, III, in 213th ACS National
`Meeting, San Francisco, Abst. 046 (Apr. 13-17, 1997) (“Takeuchi”).
`CLINICAL PHARMACOLOGY & THERAPEUTICS (1997) 61(1), 59-69 –
`“DuP 532, an angiotensin II receptor antagonist: First Administration
`and comparison with losartan”; M. Goldberg, M. Lo, D. Christ, R.
`Chiou, C. Furtek, O. Amit, A. Carides, J. Biollaz, V. Piguet, J.
`Nussberger, H. Brunner (“Goldberg”).
`J. PHARM. PHARMACOL. (1996), 48, 136-146 – “The Blood-brain
`Barrier: Principles for Targeting Peptides and Drugs to the Central
`Nervous System”; D. Begley (“Begley”).
`Memorandum Opinion, Pfizer Inc. et al. v. Sandoz, Inc. et al, 13-cv-
`01110 (D. Del.).
`C.V. of William R. Roush.
`Lisbeth Nilvebrant et al., Tolterodine – A New Bladder Selective
`Muscarinic Receptor Antagonist: Preclinical Pharmacological and
`Clinical Data, 60 LIFE SCIENCES 1129 (1997) (“Nilvebrant 1997 II”).
`Trial Transcript, July 13-16, 2015, Pfizer Inc. et al. v. Sandoz, Inc. et al,
`13-cv-01110 (D. Del.).
`The file history of United States Patent No. 7,384,980.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0012
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`2013
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`2014
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`2015
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`2016
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`2017
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`2018
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`II.
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`Jeffrey P. Krise et al., Novel Prodrug Approach for Tertiary Amines:
`Synthesis and Preliminary Evaluation of N-Phosphonooxymethyl
`Prodrugs, 42 J. MED. CHEM. 3094 (1999) (“Krise”).
`A.A. Sinkula et al., Rationale for Design of Biologically Reversible
`Drug Derivatives: Prodrugs, 64 J. PHARM. SCI. 181 (1975) (“Sinkula”).
`Hans Bundgaard, Novel Chemical Approaches in Prodrug Design, 16
`DRUGS OF THE FUTURE 443 (1991) (“Bundgaard (1991)”).
`Michael W. Jann et al., Clinical Pharmacokinetics of the Depot
`Antipsychotics, 10 CLINICAL PHARMACOKINETICS 315 (1985) (“Jann”).
`R. Beresford et al., Haloperidol Decanoate a Preliminary Review of Its
`Pharmacodynamic and Pharmacokinetic Properties and Therapeutic
`Use in Psychosis, 22 DRUGS 31 (1987) (“Beresford”).
`United States Patent No. 7,384,980.
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`SUMMARY OF OPINIONS
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`22. I have reviewed the Declaration of Steven E. Patterson, Ph.D. (the
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`“Patterson Decl.”), Petitioner’s Petition for inter partes review of the ‘650 patent,
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`and the specifications, claims, and file histories of the ‘650 patent, as well as U.S.
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`Patent Nos. 7,384,980 (the “‘980 patent”), 7,855,230 (the “‘230 patent”),
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`8,338,478 (the “‘478 patent”), and 7,985,772 (the “‘772 patent”) (collectively, the
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`“‘980 patent family”) and their associated file histories. I disagree with a number
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`of the opinions expressed in the Patterson Declaration and the positions taken in
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`the Petition regarding the obviousness of the challenged claims of the ‘650 patent.
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`The Petition alleges that the challenged claims would have been obvious because
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`the fumarate salt form of fesoterodine would have been obvious. I disagree. It is
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0013
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`my opinion that fesoterodine fumarate would not have been obvious to a person of
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`ordinary skill in the art.
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`III. LEGAL STANDARDS
`23. I am not an attorney, and therefore, my understanding of patent law and
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`the legal standards set forth in this report is based on explanations provided by
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`counsel.
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`24. I understand that even if an alleged claimed invention is not identically
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`disclosed or described in a single piece of prior art, the patent claim may still be
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`unpatentable if the differences between the claimed invention and the prior art
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`(alone or in combination) are such that the claimed invention as a whole would
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`have been obvious to a person having ordinary skill in the art at the time the
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`invention was made. I understand that the level of ordinary skill in the pertinent
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`art is evaluated as of the time of the invention, here the effective filing date of the
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`‘650 patent.
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`25. I also understand that, in addressing obviousness, the following factors
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`must be considered from the perspective of a hypothetical person of ordinary skill
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`in the relevant art: (1) the scope and content of the prior art; (2) the differences
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`between the claimed invention and the prior art; (3) the level of ordinary skill in
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`the art; and (4) any other indications (“objective indicia”) of non-obviousness, such
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0014
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`as commercial success, long-felt but unsolved needs, failure of others, industry
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`acclaim, and unexpected results.
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`26. I understand that if an experiment leads to unexpected results or a
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`compound exhibits unexpected properties, that result or compound likely would
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`not have been obvious to a person of ordinary skill in the pertinent art. In that
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`instance, such unexpected results or properties suggest that the compound would
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`not have been obvious.
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`27. I understand that prior art references may be combined to render a claim
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`obvious if a person of ordinary skill in the art would have been motivated to
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`combine those teachings to derive the claimed subject matter with a reasonable
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`expectation of success. I also understand that the use of hindsight to select or
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`combine prior art references is improper for purposes of an obviousness analysis.
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`28. I understand that in considering obviousness, it is relevant to consider
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`whether the art includes references that “teach away” from the claimed invention.
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`I have been informed that a reference teaches away from the claimed invention if a
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`person of ordinary skill, reading the reference, would be discouraged from
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`following the path of the claimed invention or would be led in a divergent
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`direction.
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`29. I also understand that for a chemical compound to be unpatentable as
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`obvious, generally there is identified a lead compound (or compounds) in the prior
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0015
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`art that would have reasonably been the subject of further development work by a
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`person of skill in the art seeking to discover a new and improved drug. I also
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`understand that for a chemical compound to be unpatentable as obvious there must
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`be some reason why a person of ordinary skill in the art would have made the
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`specific molecular modifications necessary to convert the lead compound(s) into
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`the claimed compound. I also understand that for a chemical compound to be
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`unpatentable as obvious a person of skill in the art would have a reasonable
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`expectation that the compound would be successful, in that it would work for its
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`intended purpose.
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`IV. THE ‘650 PATENT
`30. I understand that Petitioner has petitioned for review and cancellation of
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`the following claims of the ‘650 patent: claims 1-5 and 21-24.
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`31. I understand that the challenged claims cover the chemical compound
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`fesoterodine, which is the active ingredient in Toviaz®, salt forms of fesoterodine,
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`pharmaceutical compositions containing fesoterodine, or methods of treating
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`overactive bladder (“OAB”) with fesoterodine.
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`32. I understand that Petitioner alleges that the challenged claims are invalid
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`because fesoterodine and the use of fesoterodine to treat OAB would have been
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`obvious as of the priority date of the ‘650 patent. I understand that Petitioner
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`asserts two different combinations of prior art in support of its Petition:
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0016
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`•
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`•
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`Postlind (Ex. 1010) and Bundgaard (Ex. 1012) in view of the Detrol®
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`label (Ex. 1009) and Berge (Ex. 1013).
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`Brynne 1998 (Ex. 1011) and Bundgaard (Ex. 1012) in view of
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`Johansson (Ex. 1005).
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`See, e.g., ‘650 Petition at 3.
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`33. I understand that the priority date of the ‘650 patent is November 16,
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`1999. I note that Dr. Patterson assessed the prior art as of May 11, 1998 in his
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`Declaration. (Patterson Decl. at ¶ 24.) Except where expressly stated below, I
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`have conducted my analysis as of that date as well, and I note where my opinion
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`would change if the art were assessed as of November 16, 1999.
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`34. I provided expert testimony in the action, Pfizer Inc. et al., v. Sandoz
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`Inc., C.A. No. 13-1110-GMS (D. Del.), also related to the ‘650 patent. I was cited
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`by the Court for a number of facts relevant to the Court’s determination that the
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`asserted claims of the ‘650 patent were not obvious. See Exs. 2001, 2006. The
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`Court determined that I am an expert in the fields of medicinal chemistry and drug
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`design, including design of prodrugs and synthetic chemistry. In view of my work
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`as an expert in that case and my review of materials in connection with this
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`declaration, I am knowledgeable about the chemical and biological properties of
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`tolterodine and its metabolite 5-HMT. I am also knowledgeable about the
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`compound fesoterodine and the fumarate salt form of that compound.
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`15
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0017
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`
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`V.
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`PERSON HAVING ORDINARY SKILL IN THE ART
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`35. It is my view that a person having ordinary skill in the art to which the
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`‘650 patent pertains would have at least a Ph.D. or Sc.D. degree in Chemistry or
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`Pharmacology, or would be a highly skilled scientist lacking a Ph.D. or Sc.D., but
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`with several years of experience working with pharmaceutical compound synthesis
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`or pharmacology. Such a person would be familiar with the synthesis,
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`optimization, and testing of pharmaceutical compounds; with the desired and
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`favorable characteristics of pharmaceutical compounds; and with the tests and data
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`designed to discern those characteristics. Because the ‘650 patent relates to the
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`field of treatment of OAB with pharmaceuticals, the person of ordinary skill in the
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`art would review the prior art regarding the physiology of the bladder, the causes
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`and symptoms of OAB, and the pharmaceuticals used to treat OAB.
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`36. I have reviewed Dr. Patterson’s definition of a person of ordinary skill
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`in the art. (Patterson Decl. at ¶¶ 22-23.) I have applied my definition in forming
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`my opinions. However, my opinions would not change if I applied the definition
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`of a person of ordinary skill in the art given by Dr. Patterson.
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`VI. THERE IS NO EVIDENCE THAT 5-HMT WOULD NOT BE
`ORALLY ABSORBED
`
`37. Dr. Patterson assumes that a person of ordinary skill in the art would
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`have concluded that 5-HMT was not likely to be well absorbed when administered
`
`orally. (Patterson Decl. at ¶¶ 112-115.) Dr. Patterson’s assumption is based on 5-
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`16
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0018
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`
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`HMT’s lipophilicity relative to tolterodine. However, even if a person of ordinary
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`skill considered 5-HMT to be less lipophilic than tolterodine, a compound known
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`to be bioavailable and well-absorbed, it does not follow that 5-HMT had a
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`bioavailability or absorption problem because bioavailability and oral absorption
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`are not determined solely by lipophilicity. See, e.g., Bundgaard (Ex. 1012) at 183.
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`Other factors such as pKa, solubility, and active transport may affect a compound’s
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`oral absorption properties. Due to the variety of factors that influence oral
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`absorption, persons of ordinary skill in the art would not have assumed that 5-
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`HMT had an oral absorption problem without testing it.
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`38. Dr. Patterson cites no prior art stating or otherwise suggesting that 5-
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`HMT would not be well absorbed if administered orally. In fact, neither the
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`Petitioner nor Dr. Patterson point to any reference or any data that 5-HMT has ever
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`been orally administered to humans or that its bioavailability properties had been
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`determined. Based on my own review, I am not aware of any such information.
`
`39. Dr. Patterson cites a publication that provides guiding principles for
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`gauging whether a compound will have poor absorption, a 1997 publication by
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`Christopher Lipinski that describes the so-called “Rule of 5.” (Ex. 1019).
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`According to Lipinski, if a compound meets two of the following four factors, poor
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`absorption is a possibility: (1) the compound has more than 5 H-bond donors, (2)
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`its molecular weight is over 500, (3) its LogP is over 5 (or MlogP is over 4.15), or
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`17
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0019
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`
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`(4) it has more than 10 H-bond acceptors. Lipinski (Ex. 1019) at 9. All of these
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`properties are inherent to a compound and would have been readily discernible to a
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`person of ordinary skill in the art in the 1998-1999 period, including for 5-HMT. I
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`note as well that the Lipinski “rules” are not absolute and serve only as guidelines
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`of properties above which absorption is potentially problematic.
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`40. Figure 1 depicts the structure of 5-HMT.
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`
`
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`As can be seen in the table below, 5-HMT does not “violate” any of the four
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`Figure 1. 5-HMT.
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`factors addressed by Lipinski:
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`18
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0020
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`
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`Lipinski Factors that Disfavor
`Oral Absorption
`
`Properties of
`5-HMT
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`Is Absorption of 5-HMT
`Disfavored Based on
`Lipinski?
`
`More than 5 H-bond donors
`(expressed as the sum of OH’s and
`NH’s)
`
`2
`
`Molecular weight is over 500
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`341.487
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`LogP is over 5 (or MlogP is over
`4.15)
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`More than 10 H-bond acceptors
`(expressed as the sum of N’s and
`O’s)
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`3.7
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`3
`
`NO
`
`NO
`
`NO
`
`NO
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`
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`41. The conclusion a person of ordinary skill would have drawn from
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`Lipinski is that there would have been no reason to suspect that 5-HMT would
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`possess poor oral absorption. If a person of ordinary skill focused on 5-HMT’s
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`lipophilicity, he would not have seen any “red flag” regarding absorption.
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`VII. A PRODRUG APPROACH WOULD NOT HAVE BEEN
`CONSIDERED SUITABLE FOR 5-HMT
`
`42. In view of the teachings of the prior art, several approaches other than a
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`prodrug design would have been preferable to address the alleged problems
`
`confronting a person of ordinary skill with 5-HMT – lack of bioavailability. For
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`example, assuming she had determined that 5-HMT was not orally absorbed, a
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`person of ordinary skill in the art would have considered a formulation approach, a
`
`larger dose, or addressing solid-state issues through, for example, crystalline
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`19
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`Patent Owner, UCB Pharma GmbH – Exhibit 2002 - 0021
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`polymorphs, amorphous forms, or micronization. Each of these solutions was
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`well-known in the art in 1998 and would have been a more straight-forward design
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`choice.
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`43. For example, as of 1998, a person of ordinary skill would have known
`
`that micronizing particle size and increasing surface area could significantly
`
`impact a compound’s rate of dissolution in water, and that increasing the rate of
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`dissolution could mirror the effects of increased water solubility, which would
`
`improve bioavailability. In addition, formulation alternatives such as using water-
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`miscible co-solvents, surfactants, and solid-dispersion techniques were generally
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`accepted ways of improving aqueous solubility.
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`44. Further, Dr. Patterson does not addres