UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`
`LIMITED,
`
`Petitioners,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case Nos. IPR20l6-00510; IPR20I6—O05l2; IPR2016-00514; IPR20l6—O05I6;
`IPR20I6-00517
`
`Patent Nos. 6,858,650 B1; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF HANS MAAG, Sc.D.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0001
`
`

`
`Table of Contents
`
`I.
`
`INTRODUCTION ............................................................................................................ ..
`
`A.
`
`Background and Qualifications ................................................................................ _.
`
`1
`
`1
`
`B. Materials Considered ............................................................................................... .. 5
`
`SUMMARY OF OPINIONS .......................................................................................... .. 10
`
`LEGAL STANDARDS .................................................................................................. .. 13
`
`THE CHALLENGED CLAIMS ..................................................................................... .. 15
`
`PERSON HAVING ORDINARY SKILL IN THE ART ............................................... .. 18
`
`OAB DRUGS AND DRUG DEVELOPMENT AS OF 1998 ........................................ .. 19
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`A. Antimuscarinic and Mixed Action Drugs .............................................................. .. 19
`
`B.
`
`C.
`
`Non—Antimuscarinic Drugs .................................................................................... .. 30
`
`New Drugs Under Investigation ............................................................................ .. 32
`
`A PERSON OF ORDINARY SKILL IN THE ART WOULD NOT HAVE FOCUSED
`VII.
`ON TOLTERODINE .................................................................................................................. .. 37
`
`VIII. CYPZD6 POLYMORPHISM WOULD NOT HAVE MOTIVATED A PERSON OF
`
`ORDINARY SKILL TO PIVOT FROM TOLTERODINE TO 5—HMT ................................... .. 42
`
`IX.
`
`PRODRUG DESIGN WAS AND REMAINS PARTICULARLY UNPREDICTABLE
`
`AS EVIDENCED BY THE INVENTORS’ WORK DEVELOPING FESOTERODINE ......... .. 48
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Prodrug Design ...................................................................................................... .. 48
`
`The Inventors’ Work and F esoterodine ................................................................. .. 50
`
`Fesoterodine Is Rapidly and Efficiently Converted to 5—HMT ............................. .. 53
`
`Fesoterodine’s Permeability Across Biological Membranes Was Unexpected ..... .. 55
`
`Fesoterodine’s Superior Properties Could Not Have Been Predicted ................... .. 57
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0002
`
`

`
`1.
`
`INTRODUCTION
`
`1.
`
`I, Hans Maag, Sc.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
`
`(“PTO”) 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 medicinal chemist with thirty-five (35) years of professional
`
`experience in organic and medicinal chemistry in the pharmaceutical industry.
`
`I
`
`am currently Principal of Chemistry & Drug Discovery Consulting, LLC. A copy
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0003
`
`

`
`of my curriculum vitae is attached hereto as Exhibit 2030. My educational
`
`background and my professional experience are summarized below.
`
`4.
`
`I obtained a Diploma degree (equivalent to a Bachelor of Science degree)
`
`in Chemistry in 1969, and a Sc.D. in Organic Chemistry in 1973, from the Federal
`
`Institute of Technology (ETH) in Zurich, Switzerland.
`
`I then conducted two (2)
`
`years of post-doctoral work at California Institute of Technology (Cal Tech) (1973-
`
`l975), where my research interests included studies on the synthesis of the
`
`steroidal antibiotic fusidic acid. Synthesis is the process by which a molecule is
`
`constructed from commercially available precursors. Synthesis of drug substances
`
`frequently involves the design of a target compound structure,
`
`followed by
`
`synthesis and testing of the compound. Based on the testing results obtained, the
`
`next target structure is designed, synthesized, and tested.
`
`5.
`
`I also have extensive industry experience in medicinal chemistry, which I
`
`obtained at Hoffmann-LaRoche Inc.
`
`(“Hoffman11—LaRoche"), Syntex Discovery
`
`Research (“Syntex”), Roche Bioscience and Roche Palo Alto LLC (collectively,
`
`“Roche”). From 1975 to 1985, I served as Senior Scientist, Assistant Research
`
`Group Chief, and Research Fellow at Hoffmann-LaRoche.
`
`Among other
`
`responsibilities, I was in charge of the synthesis of antibiotics, cardiovascular
`
`agents of the prostaglandin type, and compounds targeting central nervous system
`
`(“CNS”) diseases.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0004
`
`

`
`6.
`
`In 1985, I moved to Syntex, where I served as Research Section Leader
`
`of the Institute of Bio—Organic Chemistry and Principal Scientist of the Institute of
`
`Organic Chemistry.
`
`In 1995, Syntex was acquired by Roche.
`
`I remained at Roche
`
`until
`
`the facility closed in 2010. During that time,
`
`I served as the Principal
`
`Scientist and Program Leader, Senior Research Scientist, Acting Director of
`
`Medicinal Chemistry, Director of Medicinal Chemistry, and Vice President of the
`
`Neurobiology Unit, eventually being named Vice President and Deputy Head of
`
`Chemistry for Roche Palo Alto. There, I led numerous project teams, from early
`
`drug discovery and lead identification stages to preclinical development and
`
`Investigational New Drug Application (“IND”) stages.
`
`7. At Syntex and Roche, a focus of my work in medicinal chemistry was the
`
`design of drug compounds to treat viral infections, incontinence, pain, depression,
`
`cognitive deficits, as well as modulators of the immune system.
`
`In particular, I led
`
`a medicinal chemistry group for the preclinical development of a prodrug of the
`
`antiviral agent ganciclovir.
`
`In addition, from 1996 to 2003,
`
`I headed a lead
`
`optimization program directed at an incontinence target and a preclinical
`
`overactive bladder (“OAB”) drug development effort.
`
`In this role, I directed an
`
`OAB team that researched lead compounds for the development of novel anti-
`
`muscarinic compounds, two (2) of which made it to the clinical phase. As a part of
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0005
`
`

`
`this project,
`
`I familiarized myself with the scientific literature on OAB and
`
`attended conferences on OAB drug development.
`
`8. In 2010,
`
`I founded Chemistry & Drug Discovery Consulting, LLC,
`
`through which I have advised, and continue to advise, biotech and pharmaceutical
`
`companies in the United States and in Europe on all aspects of medicinal
`
`chemistry.
`
`I provide advice on wide—ranging aspects of medicinal chemistry and
`
`synthetic chemistry to companies engaged in preclinical drug discovery and
`
`development, with a particular focus on identifying successful lead compounds for
`
`drug development.
`
`9.
`
`I have taught organic chemistry at Stanford University, serving as a
`
`Consulting Professor of Chemistry from 1995 to 1997.
`
`In addition,
`
`I have
`
`authored or co—authored over twenty (20) original papers pertaining to medicinal
`
`and synthetic chemistry, including prodrug chemistry.
`
`1 also served as one (1) of
`
`the editors of the two (2)-volume book entitled PRODRUGS: CHALLENGES AND
`
`REWARDS (Valentino J. Stella et al. eds., 2007). More recently, I authored a paper
`
`on the role of prodrugs for oral drug delivery. Maag, H., Overcoming Poor
`
`Permeability — The Role 0fPr'0drugs for Oral Drug Delivery, DRUG DISCOVERY
`
`TODAY: TECHS., 9, 121-30 (2012).
`
`I am also an inventor or co—inventor on over
`
`twenty (20) patents,
`
`including patents covering prodrugs and drugs targeting
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0006
`
`

`
`muscarinic receptors.
`
`The patents and publications are fully listed in my
`
`curriculum vitae attached as Exhibit 2030.
`
`B. Materials Considered
`
`10. 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 education, training, and experience as a medicinal chemist and
`
`pharmaceutical scientist.
`
`Exhibit
`
`N0.
`
`1001
`
`1002
`
`1003
`
`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.
`
`W C.V. for Dr. Steven Patterson, Ph.D.
`1005
`W0
`94/11337
`Filed
`6 November
`
`1992
`
`—
`
`“Novel
`
`3,3-
`
`Diphenylpropylamines, Their Use and Preparation” (“Johansson”).
`
`1006
`
`1007
`
`(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”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0007
`
`

`
`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”).
`
`1009
`
`Detrol® Label.
`
`1010
`
`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”).
`
`Nielas 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
`“Biotransforrnation 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 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 — “1s 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”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0008
`
`

`
`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”).
`
`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.corn (“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
`
`“FDA Approval Letter” —NDA20-771.
`
`Applications Covered by Section 505(b)(2) — October 1999 — FDA
`(CDER) (“FDA Guidance”).
`
`INTERNATIONAL JOURNAL OF PIIARMACEUTICS (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 —
`“DMP 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 — “The Blood-brain
`J. PHARM. PHARMACOL.
`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.).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0009
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`

`
`Lisbeth Nilvebrant et al., Tolterodine — A New Bladder Selective
`Mascarinic 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.
`
`A. R. Wein et al., Pharmacologic Treatment of Voiding Dysfunction, in
`URODYNAMICS: PRINCIPLES, PRACTICE AND APPLICATION (A. R. Mundy
`et al. eds., 2d ed. 1994) (“Wein 1994”).
`
`United States Patent No. 7,384,980.
`
`Transcript of the Deposition of Steven Patterson, Ph.D., dated October
`4, 2016, Case IPR20l6-00510, Case IPR20l6-00512, Case IPR20l6-
`
`00514, Case lPR2016-00516, Case lPR20l6-00517 (“Patterson Tr.”).
`
`Transcript of the Deposition of Culley C. Carson III, M.D., dated
`August 25, 2016, C.A. No. 15~cv—0079 (D. De1.).
`
`Jiunn H. Lin & Anthony Y_H. Lu, Role of Pharmacokinetics and
`Metabolism
`in
`Drug
`Discovery
`and
`Development,
`49
`PHARMACOLOGICAL REVIEWS 407 (1997) (“Lin & Lu”).
`
`N. Brynne et al., Fluoxetine Inhibits the Metabolism of Tolterodine —
`Pharmacokinetic Implications and Proposed Clinical Relevance 48 BR.
`J. CLIN. PHARMACOL. 553-63 (“Brynne 1999”).
`
`C.V. of Hans Maag.
`
`Alan J. Wein, Pharmacologic Options for the Overactive Bladder, 51
`UROLOGY (SUPP. 2A) 43 (1998) (“Wein 1998”).
`
`2006
`
`2007
`
`2008
`
`2018
`
`2020
`
`2030
`
`2031
`
`2032
`
`Lisbeth Nilvebrant et al., Tolterodine — A New Bladder-Selective
`
`Antirnuscarinic Agent, 327 EUR.
`(hereinafter, “Nilvebrant 1997 III”).
`
`J.
`
`PHARMACOL.
`
`196
`
`(1997)
`
`J . Andrew Fantl et al., URINARY INCONTINENCE IN ADULTS: ACUTE AND
`
`CHRONIC MANAGEMENT,
`
`in CLINICAL PRACTICE GUIDELINE 1996
`
`UPDATE (U.S. Dep’t of Health & Human Servs., AHCPR Publication
`No. 96-0682, 1996) (“AHCPR”).
`
`H. Madersbacher et al., Trospium Chloride Versus Oxybutynins A
`Randomized, Double-Blind, Malticentre Trial
`in the Treatment of
`Detrusor Hyper-Reflexia, 75 BR. J. UROL. 452 (1995).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0010
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`

`
`2036
`
`2037
`
`2038
`
`G. Schladitz-Keil et al., Determination of the Bioavailability of the
`Quaternary Ammonium Compound Trospium Chloride in Man from
`Urinary Excretion Data, 36 ARZNEIMITTEL FORSCHUNG/DRUG RES. 984
`(1 98 6).
`
`Ditropan XL® Prescribing Information, Revised 07/2013.
`
`R.J. Baigre et al., Oxybutynin: Is It Safe?, 62 BRIT. J. UROL. 319 (1988).
`
`H. Madersbacher et al., A Urodynamically Controlled Multicenter
`Study in Patients with Urge Incontinence." Tolerability and Efficacy of
`Propiverine Hydrochloride
`in Comparison
`to Oxybutynin,
`in
`International Continence Society, 27th Annual Meeting, Yokohama,
`Abst. 187 (Sept. 1993).
`
`Hiroyuki Miyachi et al., Novel Imidazole Derivatives with Subtype-
`Selective Antimuscarinic Activity (1), 8 BIOORG. MED. CHEM. LETT.
`2163 (1998) (“Miyachi”).
`
`Lisbeth Nilvebrant, Clinical Experiences with Tolterodine, 68 LIFE. SCI.
`2549 (2001).
`
`Carolyn M. Smith & Rob M. Wallis, Characterization of [ H]-
`Darifenacin as a Novel Radioligand for the Study of ll/luscarinic M3
`Receptors, 17 J. RECEPT. SIGNAL TR. R. 177 (1997).
`
`Karl-Erik Andersson, The Overactive Bladder: Pharmacologic Basis of
`Drug Treatment, 50 UROLOGY (SUPP. 6A) 44 (1997) (“Andersson
`1997”).
`
`Taniguchi et al., Agents for the Treatment of Overactive Detrusor. IX.
`Synthesis and Pharmacological Properties of Metabolites of N—tert-
`Butyl—4,4—diphenyl-2-cyclopentenylamine (FK5 84) in Human Urine, 44
`CHEM. PHARM. BULL. 1188, (1996).
`
`Yasuo Sasaki et al., Effect of NS—2l, an Anticholinergic Drug with
`Calcium Antagonistic Activity, on Lower Urinary Tract Function in a
`Rat Model of Urinary Frequency, 4 INT. J. UROL. 401 (1997) (“Sasaki
`(1997)”).
`
`Hiroaki Kikukawa, Pharmacologic Actions of Temiverine (p-INN) and
`its Active Metabolite, RCC-36, on Isolated Human Urinary Bladder
`Muscle, 5 INT. J. UROL. 268 (1998).
`
`2046
`
`N. Mealy & J. Castafier, YM-905, 24 DRUGS FUTURE 871 (1999)
`(“Mealy & Castafier”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0011
`
`

`
`2068
`
`Karl—Erik Andersson, Current Concepts in the Treatment of Disorders
`of Micturition, Drugs 35:477-494 (1988) (“Andersson 1988”).
`
`“History of SPM 007” dated November 17, 2000.
`
`“Chemical Development Plan, Incontinence Project,” dated February
`20, 1998.
`
`“Timetable of the development of Fesoterodine.”
`
`2093
`
`2094
`
`2095
`
`II.
`
`SUMMARY OF OPINIONS
`
`11.
`
`I have reviewed the Declaration of Steven E. Patterson, Ph.D.
`
`(the
`
`“Patterson Decl.”), Petitioner’s Petition 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 ‘650 patent and
`
`its associated file history, and the PTAB’s Decisions on Institution.
`
`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 Petitions alleges that the challenged
`
`claims would have been obvious because the fumarate salt form of fesoterodine
`
`would have been obvious.
`
`I disagree.
`
`It is my opinion that fesoterodine fumarate
`
`would not have been obvious to a person of ordinary skill in the art.
`
`In particular,
`
`it is my opinion that it would not have been obvious to develop a prodrug of 5-
`
`hydroxymethyltolterodine (“5-HMT”), tolterodine’s active metabolite, for use as
`
`an improved OAB drug.
`
`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0012
`
`

`
`12.
`
`I disagree that a person of skill in the art likely would have selected 5-
`
`HMT as a lead compound over the many, other available options as of the relevant
`
`date; a skilled artisan would have been just as likely, if not more likely, to select
`
`one of the many other compounds known in the art as promising leads for a new
`
`OAB drug candidate.
`
`13. Additionally, there is nothing in the prior art that would have suggested
`
`to a person of skill in the art that a prodrug of 5-I-IMT would provide any favorable
`
`or improved properties over tolterodine or any other OAB drug.
`
`If anything,
`
`highly relevant prior art suggested that a 5—HMT prodrug would be inferior to
`
`tolterodine, at least as to side effects, and particularly at doses escalated above the
`
`then-approved dosages of tolterodine.
`
`The reasons that Dr. Patterson offers for
`
`why a person of skill in the art would have pursued a prodrug of 5-HMT are
`
`factually inaccurate, unsupported by the prior art, and,
`
`in my view, hindsight-
`
`driven in order to mirror the same design approach taken by the Inventors of the
`
`‘98O patent family and the ‘650 patent.
`
`14. The true state of the art was that there was considerable and diverse
`
`research being undertaken in furtherance of developing new and improved OAB
`
`drugs as of 1998, including in my group at Roche, yet I am not aware of any other
`
`scientist or research team that considered a prodrug of 5—HMT, of any other
`
`tolterodine analog, or of any other non-specific antimuscarinic, which both
`
`11
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0013
`
`

`
`tolterodine and 5-HMT are.
`
`Instead, the state of the art was focused on identifying
`
`agents
`
`that had new or
`
`improved mechanisms of action, or
`
`identifying
`
`antimuscarinic agents that exhibited improved “tissue selectivity” for the bladder
`
`over other organs, with the ultimate goal of providing a more effective drug. Dr.
`
`Patterson has not identified, and I am not aware of, any reason why a person of
`
`skill in the art would have suspected that a prodrug of 5—HMT would have met
`
`either of those goals.
`
`15.
`
`It
`
`is also my opinion that
`
`fesoterodine was a surprisingly and
`
`unexpectedly superior compound.
`
`In particular, fesoterodine was surprisingly and
`
`unexpectedly superior
`
`to novel
`
`structural analogs
`
`that were designed and
`
`synthesized by the Inventors.
`
`It was also surprisingly and unexpectedly superior
`
`relative to the prior art compounds tolterodine and the active metabolite of
`
`tolterodine, 5-HMT. These unexpected results of fesoterodine are demonstrated by
`
`numerous data, including the data reported in the ‘65O patent and the ‘980 patent
`
`families, and preclinical and clinical
`
`testing conducted in the development of
`
`fesoterodine by Schwarz Pharma AG (“Schwarz”) and Pfizer.
`
`l6. Notably, it is my opinion that fesoterodine achieved an ideal balance of
`
`properties in terms of metabolic conversion, permeability, bioavailability, off-
`
`target effects, stability, and safety. This optimal balance of properties is extremely
`
`difficult to achieve; that any compound would achieve this balance of properties
`
`12
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0014
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`
`could not have been predicted by a person skilled in the art at
`
`the time of
`
`fesoterodine’s
`
`invention.
`
`Nor could a skilled person have predicted that
`
`fesoterodine, in particular, would achieve this balance, especially as compared to
`
`the numerous other
`
`structurally similar prodrug compounds
`
`the Inventors
`
`synthesized and tested.
`
`lll. LEGAL STANDARDS
`
`17.
`
`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.
`
`18.
`
`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.
`
`19.
`
`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
`
`13
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0015
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`

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`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.
`
`20.
`
`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.
`
`21.
`
`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.
`
`22.
`
`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
`
`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.
`
`14
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0016
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`

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`23.
`
`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
`
`24.
`
`I understand that Petitioner has petitioned for review and cancellation of
`
`the following claims (collectively, the “challenged claims”):
`
`0 Claims 1-16 of the ‘980 patent;
`
`0 Claims 1-5 of the ‘230 patent;
`
`0 Claims 1-3, 5-8, and 10-12 ofthe ‘478 patent;
`
`I Claims 1, 3, 4, and 6-8 ofthe ‘772 patent; and
`
`0 Claims 1-5 and 21-24 of the ‘65O patent.
`
`15
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0017
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`25.
`
`I understand that the challenged claims cover the chemical compound
`
`fesoterodine, which is the active ingredient in Toviaz®, salt forms of fesoterodine,
`
`pharmaceutical compositions containing fesoterodine, or methods of treating
`
`overactive bladder (“OAB”) with fesoterodine.
`
`26.
`
`I understand that Petitioner alleges that the challenged claims are invalid
`
`because fesoterodine and the use of fesoterodine to treat OAB would have been
`
`obvious as of the priority date of the ‘980 patent family and/or the ‘650 patent.
`
`27.
`
`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 fl 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.
`
`28.
`
`I understand that between July 20-26, 2016,
`
`the PTAB instituted an
`
`inter partes review of the challenged claims on the following grounds:
`
`0
`
`Obviousness over the combination of Postlind (Exhibit 1010),
`
`the
`
`Bundgaard Publications (Exhibits 1012 and 1020), the Detrol® Label
`
`(Exhibit 1009), and Berge (Exhibit 1013); and
`
`16
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0018
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`

`
`0
`
`Obviousness over the combination of Brynne (Exhibit 1011),
`
`the
`
`Bundgaard Publications (Exhibits 1012 and 1020), and Johansson
`
`(Exhibit 1005).
`
`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.
`
`29.
`
`I provided expert testimony in the action, Pfizer Inc. et al., v. Sandoz
`
`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 the
`
`‘650 patent were not obvious. See Exs. 2001, 2006 at 13-15, 18. The Court
`
`determined that
`
`1 am an expert
`
`in the fields of medicinal chemistry and drug
`
`design, including OAB drug design and prodrug design. See Ex. 2006 at 523:11-
`
`17 (July 15, 2015).
`
`30.
`
`1 have also provided expert
`
`testimony in the form of reports and
`
`deposition testimony in the pending action between the parties to this proceeding,
`
`Pfizer Inc. and UCB Pharma GmbH 12. Mylan Pharmaceuticals Inc, No. 1:15-Cv-
`
`000079(GMS) (D. Del.), also related to the ‘980 patent family and the ‘650 patent.
`
`17
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0019
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`31. 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 as well
`
`as about the compound fesoterodine and the fumarate salt form of that compound.
`
`I am also knowledgeable about OAB drug design at and around the time of the
`
`priority date since I was working in this very field at the relevant time.
`
`V.
`
`PERSON HAVING ORDINARY SKILL IN THE ART
`
`32.
`
`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 patents 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
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`Patent Owner, UCB Pharma GmbH — Exhibit 2021 - 0020
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`33.
`
`I have reviewed Dr. Patterson’s definition of a person of ordinary skill
`
`in the art. See, e.g.,
`
`‘650 Pet. at 6 (citing 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.
`
`34.
`
`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.
`
`V1. OAB DRUGS AND DRUG DEVELOPMENT AS OF 1998
`
`A.
`
`Antimuscarinic and Mixed Action Drugs
`
`35. Antimuscarinic compounds block the action of acetylcholine, preventing
`
`abnormal detrusor contractions
`
`from occurring and hopefully relieving the
`
`patient’s symptoms.
`
`Because they block these contractions, antimuscarinic
`
`compounds have long been used to treat OAB. However, muscarinic receptors are
`
`present in a variety of tissues in addition to the bladder, such as the heart, brain,
`
`gut, and salivary glands. Administration of antimuscarinic compounds to patients
`
`can therefore have effects other than preventing bladder contractions;
`
`they can
`
`increase heart rate, produce central nervous system (“CNS”) side effects like
`
`dizziness or confusion, cause constipation, or prevent secretion of saliva, resulting
`
`in dry mouth. See, e.g., A. R. Wein et al., Pharmacologic Treatment of Voiding
`
`Dysfunction, in URODYNAMICSZ PRINCIPLES, PRACTICE AND APPLICATION, at 53 (A.
`
`19
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`Patent Owner, UCB Pharma GmbH