UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`
`LIMITED,
`
`Petitioner,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case Nos. IPR20l6-00510; IPR20I6—005l2; IPR2016—005l4; IPR20l6—005I6;
`IPR20I6-00517
`
`Patent Nos. 6,858,650; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF WILLIAM R. ROUSH, PH.D.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0001
`
`

`
`Table of Contents
`
`I.
`
`INTRODUCTION ............................................................................................. .. l
`
`A.
`
`Background and Qualifications ................................................................... ..1
`
`B. Materials Considered ................................................................................... ..8
`
`II. SUMMARY OF OPINIONS .......................................................................... .. 12
`
`III.
`
`LEGAL STANDARDS ................................................................................ ..l3
`
`IV.
`
`THE CHALLENGED CLAIMS .................................................................. ..15
`
`V. PERSON HAVING ORDINARY SKILL IN THE ART ............................... ..18
`
`VI.
`
`PRODRUG DEVELOPMENT IS EXTREMELY COMPLEX AND
`
`UNPREDICTABLE ............................................................................................... .. 19
`
`VII. 5-HMT WOULD NOT HAVE BEEN SELECTED AS A LEAD
`
`COMPOUND ......................................................................................................... ..25
`
`VIII.
`
`THERE IS NO EVIDENCE THAT 5-HMT WOULD NOT BE ORALLY
`
`ABSORBED .......................................................................................................... ..26
`
`IX. A PRODRUG APPROACH WOULD NOT HAVE BEEN CONSIDERED
`
`SUITABLE FOR 5—HMT ...................................................................................... ..32
`
`X.
`
`IN DECIDING TO PURSUE A PRODRUG OF 5-HMT, A PERSON OF
`
`ORDINARY SKILL WOULD HAVE FACED MANY OPTIONS WITH NO
`
`EXPECTATION OF SUCCESS ............................................................................ ..40
`
`A Person of Ordinary Skill Would Have Had To Select the Type of
`A.
`Prodrug ............................................................................................................... ..40
`
`A Person of Ordinary Skill Would Have Needed to Select Where to Add
`B.
`the Prodrug Substituent ...................................................................................... ..46
`
`Even Having Selected an Ester Group, a Person of Ordinary Skill Would
`C.
`Have Had Thousands of Compounds to Consider ............................................. ..5l
`
`THE (R) ENANTIOMER OF FESOTERODINE WOULD NOT HAVE
`XI.
`BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART ........ ..55
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0002
`
`

`
`1.
`
`INTRODUCTION
`
`1.
`
`I, William R. Roush, Ph.D., have been retained by White & Case LLP,
`
`counsel for Patent Owner UCB Pharma GmbH (“UCB”), as an expert witness in
`
`the above—captioned inter partes reviews of United States Patent Nos. 7,384,980
`
`(the “‘980 patent”), 7,855,230 (the “‘230 patent”), 8,338,478 (the “‘478 patent”),
`
`and 7,985,772 (the “‘772 patent”) (collectively,
`
`the “‘980 patent family”) and
`
`6,858,650 (the “‘650 patent”).
`
`I understand that Mylan Pharmaceuticals Inc. and
`
`Mylan Laboratories Limited (collectively with Mylan Pharmaceuticals Inc.,
`
`“Petitioner”) have petitioned for inter partes review of the ‘980 patent family and
`
`the ‘650 patent and request that the United States Patent and Trademark Office
`
`cancel as unpatentable certain claims of the ‘980 patent family and the ‘650 patent.
`
`2. This declaration sets forth my analyses and opinions based on the
`
`materials I have considered thus far, as well as the bases for my opinions.
`
`I
`
`understand that this declaration will be used in each of the above mentioned inter
`
`partes reviews, as the subject matter is overlapping.
`
`A.
`
`Background and Qualifications
`
`3.
`
`I am a chemist with more than 35 years of professional experience in
`
`organic chemistry and medicinal chemistry.
`
`I am currently Professor of Chemistry
`
`and Executive Director of Medical Chemistry in the Drug Discovery Division of
`
`Scripps Translational Research Institute in Jupiter, Florida (“Scripps Florida”). I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0003
`
`

`
`previously served as the Associate Dean of the Graduate Program at Scripps
`
`Florida. A copy of my curriculum vitae is attached as Exhibit 2003. My
`
`educational background and my professional experience are summarized below.
`
`4.
`
`I obtained a Bachelor of Science degree in Chemistry from the University
`
`of California, Los Angeles in 1974, graduating summa cum laude.
`
`I obtained my
`
`Ph.D. in Chemistry from Harvard University in 1977.
`
`5. After a year of post-doctoral work at Harvard (1977-78), I joined the
`
`faculty at
`
`the Massachusetts Institute of Technology (MIT) as an Assistant
`
`Professor of Chemistry.
`
`I taught chemistry courses and performed research at MIT
`
`from 1978 to 1987. My research interests included the total synthesis of natural
`
`products and the development of new synthetic methods.
`
`6. In 1987,
`
`1 moved to Indiana University, where I ultimately became
`
`Distinguished Professor of Chemistry. At Indiana University, I initiated a research
`
`program on the design and synthesis of inhibitors of cysteine proteases. These
`
`inhibitors, designed to combat certain tropical parasitic diseases, are chemical
`
`compounds which prevent
`
`(i.e.,
`
`inhibit) an enzyme,
`
`specifically a cysteine
`
`protease, from performing an essential chemical reaction in the parasite, resulting
`
`in the death of the microorganism.
`
`7. In 1997, I was appointed the Warner—Lambert/Parke—Davis Professor of
`
`Chemistry at the University of Michigan. This is an endowed chair established by
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0004
`
`

`
`a gift from Parke-Davis to the University of Michigan.
`
`I subsequently served as
`
`the Chairman of the Department of Chemistry at the University of Michigan from
`
`2002-2004. While at the University of Michigan, I served as Co—Director of the
`
`Life Sciences Initiative Commission, which conceived the Life Sciences Institute
`
`(LSI), and laid out the blueprint for its creation and development to stimulate
`
`interdisciplinary research in the biomedical sciences.
`
`I also continued to develop
`
`my research program focusing on the synthesis of biologically active natural
`
`products,
`
`the development of new synthetic methodology, and the design and
`
`development of inhibitors of cysteine proteases.
`
`8. In 2004, I was recruited to join the Scripps Research Institute at its new
`
`campus in Florida.
`
`I assumed my current positions — Professor of Chemistry and
`
`Executive Director of Medical Chemistry — in 2015.
`
`Scripps Florida is an
`
`expansion of the well-known Scripps Research Institute, which is headquartered in
`
`La Jolla, California.
`
`The Scripps Research Institute is one of the leading
`
`biomedical research institutes in the world and is internationally recognized for its
`
`commitment to, and its basic research in,
`
`the fields of immunology, biology,
`
`chemistry, neurosciences, virology, autoimmune and cardiovascular diseases, and
`
`synthetic vaccine development. Particularly significant is the Scripps Research
`
`Institute’s study of the basic structure and design of biological molecules.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0005
`
`

`
`9. As Associate Dean of the Graduate Program at Scripps Florida (2005-
`
`2016), I developed and led the graduate program on the Jupiter campus.
`
`10.
`
`I currently serve as Executive Director of Medicinal Chemistry in the
`
`Drug Discovery Division of Scripps’ Translational Research Institute at Scripps
`
`Florida.
`
`In this position, 1 direct the research of twelve to sixteen (12-16) staff
`
`medicinal chemists who are charged with performing structure—activity relationship
`
`(“SAR”) studies to optimize drug candidates for several drug discovery projects
`
`internal to Scripps. Projects at Scripps Florida that have been performed under my
`
`directorship, or are still active,
`
`include the development and optimization of
`
`enzyme inhibitors for cancer
`
`targets, central nervous system diseases (e.g.,
`
`Parkinson’s disease), and metabolic diseases, among others.
`
`In addition,
`
`I
`
`personally direct an academic research program with eleven (1 I) graduate students
`
`and postdoctoral associates that is funded primarily by the National Institutes of
`
`Health (“NIH”). This program includes medicinal chemistry research projects
`
`focusing on development of agonists and antagonists of nuclear
`
`receptors,
`
`development of inhibitors of enzyme targets (including kinases, cysteine proteases,
`
`metallomatrix proteinases, histone deacetylates, and cytochrome P51, among
`
`others) and development of inhibitors of transporters responsible for active
`
`transport of molecules into and out of cells.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0006
`
`

`
`l 1. An important aspect of my work is an understanding of the biochemistry
`
`of biological drug targets.
`
`I frequently work with biologists and pharmacologists
`
`on projects and I regularly review and assess the results of biological experiments
`
`and use those results to make decisions about how to further improve the
`
`compounds that are the subjects of these medicinal chemistry research projects.
`
`12. From 2007 through 2014 I served as the Chairman of the Chemistry
`
`Coordination Committee of the Scripps Molecular Screening Center, which was
`
`one of four centers forming the Molecular Libraries Production Centers Network
`
`(MLPCN), an NIH—funded program which screened potential drug targets and
`
`performed SAR studies to optimize potential drug candidates.
`
`13.
`
`I have served a five-year term on the National Institutes of Health (NIH)
`
`Medicinal Chemistry Study Section,
`
`including two (2) years as Chair.
`
`The
`
`Medicinal Chemistry Study Section reviewed research proposals in medicinal
`
`chemistry submitted to the NIH, and ranked these applications in terms of their
`
`scientific merit.
`
`14.
`
`I have presented my research in more than two hundred (200) invited
`
`lectures at universities and pharmaceutical companies.
`
`In addition, I have been
`
`invited to deliver more than one hundred (100) named, keynote, or plenary lectures
`
`at universities and national and international symposia and conferences. All of the
`
`invited, named, keynote and plenary lectures that I have presented during my
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0007
`
`

`
`career have been based on my research on compound synthesis and/or the
`
`biological evaluation of specific compounds that I have synthesized.
`
`15.
`
`I have published extensively in the scientific literature and have
`
`authored or co-authored over three hundred forty (340) papers relating to organic
`
`synthesis and medicinal chemistry, including more than fifty (50) scientific articles
`
`dealing specifically with the
`
`synthesis and biochemical and/or biological
`
`evaluation of small molecule inhibitors of protein targets.
`
`16.
`
`I have experience with the discovery and development of prodrugs due
`
`to my work as a medicinal chemist. By consulting in the pharmaceutical industry,
`
`I have gained first hand exposure to the selection and optimization of prodrug
`
`candidates.
`
`1 have been involved in research in which prodrugs were used to
`
`evaluate the activity of inhibitors in appropriate biological assays.
`
`I have also been
`
`involved in the development of a commercial process for manufacture of a prodrug
`
`(Clindamycin Phosphate) that was marketed by Genzyme Corporation beginning in
`
`the late 1980s.
`
`17.
`
`I am currently engaged in an NIH funded project to develop a novel
`
`class of prodrugs, specifically antibody-drug conjugates,
`
`in which the antibody
`
`targets specific cells, and the drug is cleaved by enzymes within the cell after the
`
`conj ugate is internalized.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0008
`
`

`
`18.
`
`I am on the editorial board of Organic Letters and previously served on
`
`the editorial advisory board of Chemical Biology and Drug Design.
`
`I am also a
`
`member of the Boards of Directors of Organic Syntheses,
`
`Inc. and Organic
`
`Reactions, Inc., which publish the Organic Syntheses and Organic Reactions
`
`monographs.
`
`In addition, I previously served as an Associate Editor of the Journal
`
`of the American Chemical Society.
`
`19.
`
`I regularly consult with pharmaceutical and biotechnology companies.
`
`These consultations focus, in general, on aspects of medicinal chemistry, synthetic
`
`chemistry, and process chemistry for companies engaged in drug discovery and
`
`development.
`
`I also participate, as a consultant, in strategic planning exercises.
`
`The companies I currently consult with are Eli Lilly and Company and IMF
`
`Therapeutics.
`
`In the past
`
`I have also consulted with Pfizer Inc., Genzyme
`
`Corporation, Lycera Corporation, ArQule Inc., NeXstar Pharmaceuticals Inc. and
`
`GMP—Immunotherapeutics, among others.
`
`20.
`
`I have received a number of awards for my research,
`
`including the
`
`Arthur C. Cope Scholar Award (1994) from the American Chemical Society, the
`
`Paul G. Gassmann Distinguished Service Award from the American Chemical
`
`Society Division of Organic Chemistry, and the Ernest Guenther Award in the
`
`Chemistry of Natural Products from the American Chemical Society.
`
`In 2006, I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0009
`
`

`
`was elected a Fellow of the American Association for the Advancement of
`
`Science, and in 2009, I was elected a Fellow of the American Chemical Society.
`
`B. Materials Considered
`
`21. The opinions that
`
`I express in this declaration are based on the
`
`information and evidence currently available to me. The following table lists the
`
`materials that I considered in forming my opinions set forth in this declaration.
`
`I
`
`also relied on my general knowledge, experience, and my own scientific analysis.
`
`Exhibit
`
`N0.
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1007
`
`Materials
`
`The United States Patent that is the subject of this proceeding (either
`U.S.P.N. 7,384,980; 7,855,230; 8,338,478; 7,985,772; or 6,858,650).
`
`The file history for Exhibit 1001.
`
`Declaration of Dr. Steven Patterson, Ph.D.
`
`C.V. for Dr. Steven Patterson, Ph.D.
`
`WO 94/11337
`
`Filed
`
`6 November
`
`1992
`
`—
`
`“Novel
`
`3,3-
`
`Diphenylpropylamines, Their Use and Preparation” (“Johansson”).
`
`(1999), 84, 923-947 — “The Pharmacological
`BJU International
`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”).
`
`and Pharmacodynamics of
`al., Pharmacokinetics
`N. Brynne et
`Tolterodine in Man: A New Drug for the Treatment of Urinary Bladder
`Overactivity, 35 1NT’L J. CLIN. PHARMACOLOGY & THERAPEUTICS 287
`(1997) (“Brynne 1997”).
`
`1008
`
`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”).
`W Detrol® Label.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0010
`
`

`
`1012
`
`1013
`
`(4), 289-293 —
`26
`Drug Metabolism and Disposition (1998),
`“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”).
`
`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”).
`
`—
`528-535
`26(6),
`(1998),
`Drug Metabolism and Disposition
`new muscarinic
`receptor
`a
`“Biotransformation of
`tolterodine,
`antagonist, in mice, rats, and dogs”; S. Andersson, A. Lindgren, and H.
`Postlind (“Andersson 1998”).
`
`et al., Antimuscarinic Potency and Bladder
`Lisbeth Nilvebrant
`Selectivity of PNU-200577, a Major Metabolite of Tolteroaline, 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 efiicacy and safety of
`tolterodine in the treatment of overactive balaler: 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”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0011
`
`

`
`American Urological Association Education and Research (2014) —
`“Diagnosis and Treatment of Overactive Bladder (Non—Neorogenic) in
`Adults: AUA/SUFU Guideline”;
`E. Gorrnley,
`et
`al.
`(“AUA
`Guideline”).
`
`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.pf1zer.com (“Pfizer 2012
`Press Release”).
`
`1023
`
`April 1, 2012 “Overactive Bladder Market: Managing the Future” —
`www. pm360online.Com (“PM360”).
`
`1024
`
`“Toviaz® Label” — Pfizer Labs
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1050
`
`2001
`
`“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”).
`
`CL.1N1CAL PHARMACOLOGY & THERAPEUTICS (1997) 61(1), 59-69 —
`“DaP 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”).
`
`(1996), 48, 136-146 4 “The Blood-brain
`J. PHARM. PHARMACOL.
`Barrier: Principles for Targeting Peptides and Drugs to the Central
`Nervous System”; D. Begley (“Begley”).
`
`File History for U.S. Patent No. 5,686,464.
`
`Memorandum Opinion, Pfizer Inc. et al. v. Sandoz, Inc. et al,
`01110 (D. Del.).
`
`l3—cv—
`
`2003
`
`CV. of William R. Roush.
`
`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0012
`
`

`
`2006
`
`2007
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`Lisbeth Nilvebrant et al., Tolterodine — A New Bladder Selective
`Muscarinic Receptor Antagonist: Preclinical Pharmacological and
`Clinical Data, 60 LIFE SCIENCES 1 129 (1997) (“Nilvebrant 1997 II”).
`
`Trial Transcript, July 13-16, 2015, Pfizer Inc. et al. v. Sandoz, Inc. et al,
`13—cv-0l 110 (D. Del.).
`
`The file history of United States Patent No. 7,384,980.
`
`Jeffi‘ey 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 (l99l)”).
`
`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 ofIts
`Pharmacodynamic and Pharmacokinetic Properties and Therapeutic
`Use in Psychosis, 22 DRUGS 31 (1987) (“Beresford”).
`
`United States Patent No. 7,384,980.
`
`United States Patent No. 6,858,650.
`
`Transcript of the Deposition of Steven Patterson, Ph.D., dated October
`4, 2016, Case 1PR20l6—00510, Case 1PR2016—00512, Case 1PR20l6-
`
`00514, Case 1PR20l6-00516, Case IPR20l6-00517 (“Patterson Tr.”).
`
`L.P. Balant et al., Prodrugsfor the Improvement of Drug Absorption
`via Different Routes of Administration,
`15 EUROPEAN J. DRUG
`METABOLISM & PHARMACOKINETICS 143 (1990) (“Balant”).
`
`Kevin Beaumont et a1., Design of Ester Prodrugs to Enhance Oral
`
`to the
`Absorption of Poorly Permeable Compounds: Challenges
`Discovery Scientist, 4 CURR. DRUG. METAB. 461 (2003) (“Beaumont”).
`
`Valentino J. Stella et a1., Prodrugs and Site-Specific Drug Delivery, 23
`J. MEDICINAL CHEMISTRY 1275 (1980) (“Stella”).
`
`a1., Lessons Learned from Marketed and
`et
`Peter Ettmayer
`Investigational Prodrugs, 47 J. MED. CHEM. 2393 (2004) (“Ettniayer”).
`
`11
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0013
`
`

`
`2051
`
`2052
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`
`2059
`
`Bruce D. Roth et a1., Relationship Between Tissue Selectivity and
`Lipophilicityfor Inhibitors ofHMG-CoA Reductase, 34 J. MED. CHEM.
`463 (1991) (“Roth”).
`
`J. Magyar et al., Effects of Norfluoxetine on the Action Potential and
`Transrnembrane Ion Currents in Canine Ventricular Cardiornyocytes,
`370 NAUNYN SCHMIEDEBERGS ARCH.
`PHARMACOL.
`203
`(2004)
`(“Magyar”).
`
`U.S. Patent No. 5,382,600 (the “‘600 patent”).
`
`Prescribing Information for Accupri1® retrieved on March 10, 2015.
`
`Milind M. Narurkar et 211., Synthesis, Physicochemical Properties, and
`Cytotoxicity of a Series of 5 ’—Ester Prodrugs of
`5—Iodo—2’-
`Deoxyuridine, 5 PHARM. RES. 734, 734 (1988) (“Narurkar”).
`
`Thomas Hartung, Food for Thought Look Back in Anger — What
`Clinical Studies Tell Us About Preclinical Work, 30 ALTEX 275 (2013)
`(“I-lartung”).
`
`Chart of FDA Approvals of New Drug Applications for New Molecular
`Entities and New Active Ingredients from January 1994 — December
`1998.
`
`Daniel S. Sitar, Clinical Pharmacokinetics of Bambuterol, 31 CLIN.
`
`PHARMACOKJNET. 246 (1996) (“Sitar”).
`
`J. Greg Slatter et a1., Bioactivation of the Anticancer Agent CPT- 11 to
`SN-38 by Human Hepatic Microsomal Carboxylesterases and the in
`vitro Assessment ofPotential Drug Interactions, 25 DRUG METABOLISM
`& DISPOSITION 1157 (1997) (“slatter”).
`
`2060
`
`Alan J. Wein, Pharmacologic Options for the Overactive Bladder, 51
`UROLOGY (SUPP. 2A) 43 (1998).
`
`II.
`
`SUMMARY OF OPINIONS
`
`22.
`
`I have reviewed the Declaration of Steven E. Patterson, Ph.D.
`
`(the
`
`“Patterson Dec1.”), Petitioner’s Petitions for inter partes review of U.S. Patent
`
`Nos.
`
`7,384,980,
`
`7,855,230,
`
`8,338,478,
`
`7,985,772,
`
`and
`
`6,858,650,
`
`the
`
`specifications, claims, and file histories of the ‘980 patent family, as well as the
`
`12
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0014
`
`

`
`‘650 patent and its associated file history.
`
`I disagree with a number of the opinions
`
`expressed in the Patterson Declaration and the positions taken in the Petitions
`
`regarding the obviousness of the challenged claims of the ‘980 patent family and
`
`the ‘650 patent. The Petition alleges that the challenged claims would have been
`
`obvious because fesoterodine and the fumarate salt form of fesoterodine would
`
`have been obvious.
`
`I disagree.
`
`It is my opinion that neither fesoterodine nor its
`
`fumarate salt form would have been obvious to a person of ordinary skill in the art.
`
`lll. LEGAL STANDARDS
`
`23.
`
`I am not an attorney, and therefore, my understanding of patent law and
`
`the legal standards set forth in this report is based on explanations provided by
`
`counsel.
`
`24.
`
`I understand that even if an alleged claimed invention is not identically
`
`disclosed or described in a single piece of prior art, the patent claim may still be
`
`unpatentable if the differences between the claimed invention and the prior art
`
`(alone or in combination) are such that the claimed invention as a whole would
`
`have been obvious to a person having ordinary skill
`
`in the art at the time the
`
`invention was made.
`
`I understand that the level of ordinary skill in the pertinent
`
`art is evaluated as of the time of the invention, here the effective filing date of the
`
`‘980 patent family or the ‘650 patent.
`
`13
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0015
`
`

`
`25.
`
`I also understand that, in addressing obviousness, the following factors
`
`must be considered from the perspective of a hypothetical person of ordinary skill
`
`in the relevant art: (1) the scope and content of the prior art; (2) the differences
`
`between the claimed invention and the prior art; (3) the level of ordinary skill in
`
`the art; and (4) any other indications (“objective indicia”) of non—obviousness, such
`
`as commercial success,
`
`long—felt but unsolved needs, failure of others, industry
`
`acclaim, and unexpected results.
`
`26.
`
`I understand that if an experiment
`
`leads to unexpected results or a
`
`compound exhibits unexpected properties, that result or compound likely would
`
`not have been obvious to a person of ordinary skill in the pertinent art. In that
`
`instance, such unexpected results or properties suggest that the compound would
`
`not have been obvious.
`
`27.
`
`I understand that prior art references may be combined to render a claim
`
`obvious if a person of ordinary skill
`
`in the art would have been motivated to
`
`combine those teachings to derive the claimed subject matter with a reasonable
`
`expectation of success.
`
`I also understand that the use of hindsight to select or
`
`combine prior art references is improper for purposes of an obviousness analysis.
`
`28.
`
`I understand that in considering obviousness, it is relevant to consider
`
`whether the art includes references that “teach away” from the claimed invention.
`
`1 have been informed that a reference teaches away from the claimed invention if a
`
`14
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0016
`
`

`
`person of ordinary skill, reading the reference, would be discouraged from
`
`following the path of the claimed invention or would be led in a divergent
`
`direction.
`
`29.
`
`I also understand that for a chemical compound to be unpatentable as
`
`obvious, generally there is identified a lead compound (or compounds) in the prior
`
`art that would have reasonably been the subject of further development work by a
`
`person of skill in the art seeking to discover a new and improved drug.
`
`I also
`
`understand that for a chemical compound to be unpatentable as obvious there must
`
`be some reason why a person of ordinary skill in the art would have made the
`
`specific molecular modifications necessary to convert the lead compound(s) into
`
`the claimed compound.
`
`I also understand that for a chemical compound to be
`
`unpatentable as obvious a person of skill
`
`in the art would have a reasonable
`
`expectation that the compound would be successful, in that it would work for its
`
`intended purpose.
`
`IV.
`
`THE CHALLENGED CLAIMS
`
`30.
`
`I understand that Petitioner has petitioned for review and cancellation of
`
`the following claims (collectively, the “challenged claims”):
`
`0 Claims 1-16 of the ‘98O patent;
`
`0 Claims 1-5 of the ‘230 patent;
`
`0 Claims 1-3, 5-8, and 10-12 ofthe ‘478 patent;
`
`15
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0017
`
`

`
`0 Claims 1, 3, 4, and 6-8 ofthe ‘772 patent; and
`
`0 Claims 1-5 and 21-24 of the ‘650 patent.
`
`31.
`
`I understand that the challenged claims cover the chemical compound
`
`fesoterodine furnarate, which is the active ingredient in Toviaz®, other salt forms
`
`of fesoterodine, pharmaceutical compositions containing fesoterodine, or methods
`
`of treating overactive bladder (“OAB”) with fesoterodine.
`
`32.
`
`I understand that Petitioner alleges that the challenged claims are invalid
`
`because fesoterodine fumarate and the use of fesoterodine fumarate to treat OAB
`
`would have been obvious as of the priority date of the ’980 patent family and/or
`
`the ‘650 patent.
`
`33.
`
`I understand that the priority date of the ‘980 patent family is May 12,
`
`1998.
`
`I understand that the priority date of the ‘650 patent is November 16, 1999.
`
`I note that Dr. Patterson assessed the prior art as of May 11, 1998 in his
`
`Declaration.
`
`(Patterson Decl. at $1 24.)
`
`I have conducted my analysis on the basis
`
`of May 12, 1998 for the ‘980 patent family and November 16, 1999 for the ‘650
`
`patent, but I note that my opinion would not change if I assessed the prior art for
`
`all patents as of May 11, 1998.
`
`34.
`
`I understand that between July 20-26, 2016,
`
`the PTAB instituted an
`
`inter parres review of the challenged claims on the following grounds:
`
`16
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0018
`
`

`
`I
`
`Obviousness over
`
`the combination of Postlind (Ex. 1010),
`
`the
`
`Bundgaard publications (Exs. 1012 and 1020), the Detrol® Label (Ex.
`
`1009), and Berge (Ex. 1013); and
`
`0
`
`Obviousness over the combination of Brynne 1998 (Ex. 1011), the
`
`Bundgaard publications (Exs. 1012 and 1020), and Johansson (Ex.
`
`1005).
`
`See Paper 12 (July 20, 2016) (“‘980 Decision”) at 29; Paper 12 (July 22, 2016)
`
`(‘“230 Decision”) at 29; Paper 12 (July 26, 2016) (“‘478 Decision”) at 30; Paper
`
`12 (July 20, 2016) (“‘772 Decision”) at 29; Paper 12 (July 20, 2016) (“‘650
`
`Decision”) at 29.
`
`35.
`
`I provided expert testimony in the action, Pfizer Inc. et al., v. Scmdoz
`
`Inc, CA. No. 13-1110-GMS (D. Del.), also related to the ’980 patent family and
`
`the ‘650 patent.
`
`I was cited by the Court for a number of facts relevant to the
`
`Court’s determination that the asserted claims of the ‘980 patent family and ‘650
`
`patent were not obvious. See e.g., Exs. 2001 at 15-18, 2006 at 590-637. The Court
`
`determined that
`
`I am an expert
`
`in the fields of medicinal chemistry and drug
`
`design, including design of prodrugs and synthetic chemistry.
`
`36.
`
`I have also provided expert
`
`testimony in the form of reports and
`
`deposition testimony in the pending action between the parties to this proceeding,
`
`17
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0019
`
`

`
`Pfizer Inc. v. Mylan Pharmaceuticals Inc, No. 1:15-CV—00079—GMS, also related
`
`to the ‘98O patent family and the ‘650 patent.
`
`37. In view of my work as an expert in the above cases and my review of
`
`materials in connection with this declaration,
`
`I am knowledgeable about
`
`the
`
`chemical and biological properties of tolterodine and its metabolite 5—HMT.
`
`I am
`
`also knowledgeable about the compound fesoterodine and the fumarate salt form of
`
`that compound.
`
`V.
`
`PERSON HAVING ORDINARY SKILL IN THE ART
`
`38.
`
`It is my view that a person having ordinary skill in the art to which the
`
`‘980 patent family and the ‘650 patent pertain would have at least a Ph.D. or Sc.D.
`
`degree in Chemistry or Pharmacology, or would be a highly skilled scientist
`
`lacking a Ph.D. or Sc.D., but with several years of experience working with
`
`pharmaceutical compound synthesis or pharmacology. Such a person would be
`
`familiar with the
`
`synthesis, optimization,
`
`and testing of pharmaceutical
`
`compounds; with the desired and favorable characteristics of pharmaceutical
`
`compounds; and with the tests and data designed to discern those characteristics.
`
`Because the ‘980 patent family and ‘650 patent relate to the field of treatment of
`
`OAB with pharmaceuticals, the person of ordinary skill in the art would review the
`
`prior art regarding the physiology of the bladder, the causes and symptoms of
`
`OAB, and the pharmaceuticals used to treat OAB.
`
`18
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2022 - 0020
`
`

`
`39.
`
`I have reviewed Dr. Patterson’s definition of a person of ordinary skill
`
`in the art.
`
`(Patterson Decl. at W 22-23.)
`
`I also understand that the PTAB has
`
`accepted Petitioner’s definition for purposes of institution. See, e. g., ‘650 Decision
`
`at 6.
`
`40.
`
`l have applied my definition in forming my opinions. However, my
`
`opinions do not change if I apply Petitioner’s definition of a person of ordinary
`
`skill in the art.
`
`Vl.
`
`PRODRUG DEVELOPMENT IS EXTREMELY COMPLEX AND
`
`UNPREDICTABLE
`
`41. As a general proposition, drug design is complex,
`
`time-consuming,
`
`resource—intensive, and highly unpredictable. Beginning with a desired mechanism
`
`of action and biological
`
`target, a medicinal chemist selects a lead compound,
`
`decides to make any number of modifications to the lead compound, determines
`
`how to synthesize each variant of the compound, and tests each resulting
`
`compound for the desired properties. A successful compound must have potent
`
`activity at the intended biological target and lesser activity at other unintended
`
`targets.
`
`A compound must also exhibit
`
`favorable “ADMET” properties
`
`(absorption, distribution, metabolism, elimination, and toxicity), and suitable
`
`physicochemical
`
`properties
`
`(eg,
`
`stability,
`
`solubility),
`
`to
`
`be worthy of
`
`consideration as a pharmaceutical. Any one of the numerous small modifications
`
`19
`
`Patent Owner, UCB Pha