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. IPR2016-00510; IPR20l6—005l2; IPR20l6—00514; IPR2016—005l6;
`IPR20l6-00517
`
`Patent Nos. 6,858,650; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF SCOTT A. MACDIARMID, M.D., FRCPSC
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`
`LIMITED,
`
`Petitioners,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case Nos. IPR2016-00510; IPR20l6—005l2; IPR20l6—00514; IPR2016—005l6;
`IPR20l6-00517
`
`Patent Nos. 6,858,650; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF SCOTT A. MACDIARMID, M.D., FRCPSC
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0001
`
`
`
`Table of Contents
`
`I.
`
`INTRODUCTION ........................................................................................ .. 1
`
`A. Background and Qualifications ............................................................. .. 1
`
`B. Materials Considered ............................................................................ .. 3
`
`II.
`
`SUMMARY OF OPINIONS ...................................................................... .. 10
`
`III. LEGAL STANDARDS .............................................................................. .. 12
`
`IV. THE CHALLENGED CLAIMS ................................................................. .. 13
`
`V. PERSON HAVING ORDINARY SKILL IN THE ART ............................ .. 15
`
`VI. BACKGROUND ........................................................................................ .. 16
`
`A. Overview of Overactive Bladder (“OAB”) ......................................... .. 16
`
`B. Muscarinic Receptors ......................................................................... .. 18
`
`C. Treatment of OAB in 1998 ................................................................. .. 20
`
`VII. FESOTERODINE (TOVIAZ®) ................................................................. .. 27
`
`A. Fesoterodine is an Efficacious OAB Treatment .................................. .. 28
`
`B. Toviaz® Has a Favorable Safety and Tolerability Profile ................... .. 30
`
`C. Toviaz® Offered the First “True” Dose—Escalation Treatment Option for
`Patients ....................................................................................................... .. 33
`
`D. Toviaz® Offers Superior Efficacy ...................................................... .. 35
`
`VIII. FESOTERODINE SATISFIED A LONG—FELT CLINICAL NEED FOR AN
`
`IMPROVED OAB TREATMENT ..................................................................... .. 37
`
`IX. FESOTERODINE HAS SEVERAL UNEXPECTED BENEFICIAL
`
`PROPERTIES THAT COULD NOT HAVE BEEN PREDICTED .................... .. 41
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0002
`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I, Scott A. MacDiarmid, M.D., FRCPSC, 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 review 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 “‘65O 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
`
`petitions, as the subject matter is overlapping.
`
`A.
`
`Background and Qualifications
`
`3.
`
`I have practiced as a urologist since I was certified as a Fellow of the
`
`Royal College of Physicians and Surgeons of Canada (“FRCPSC”) in September
`
`1991. After relocating to the United States, I was certified by the American Board
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0003
`
`
`
`of Urology in February 1996 and have been practicing in the United States since
`
`that time.
`
`4. Presently, I am the Director of the Alliance Urology Specialists Bladder
`
`Control and Pelvic Pain Center in Greensboro, North Carolina and a Clinical
`
`Associate Professor in the Department of Urology at
`
`the University of North
`
`Carolina at Chapel Hill.
`
`I am a sub—specialist
`
`in Reconstructive Urology and
`
`urinary incontinence and have over 20 years of experience in treating male and
`
`female patients with voiding dysfunction and overactive bladder.
`
`I have been
`
`affiliated with the Moses Cone Health System in Greensboro, North Carolina since
`
`2006.
`
`I previously held university appointments at Wake Forest University School
`
`of Medicine,
`
`the University of Tennessee, and the University of Arkansas for
`
`Medical Sciences.
`
`1 was also previously an attending urologist at North Carolina
`
`Baptist Hospitals, Inc. in Winston-Salem, North Carolina.
`
`5.
`
`I received my B.S. and M.D. from Dalhousie University in Halifax, Nova
`
`Scotia in 1981 and 1985, respectively. For my clinical training, I was a rotating
`
`intern at Dalhousie University in 1985-1986 and a resident in urology at Dalhousie
`
`University in 1987-1991. Between 1991 and 1993, I completed fellowships in
`
`Reconstructive Urology and Urodynamics at Duke University Medical Center, in
`
`Reconstructive Urology and Urodynamics
`
`at
`
`the University of Otago in
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0004
`
`
`
`Christchurch, New Zealand, and in Neuro—Urology and Reconstructive Urology at
`
`the Lodgemoor Spinal Unit of the University of Sheffield in England.
`
`6.
`
`I am presently a reviewer for numerous peer—reviewed journals, including
`
`the Journal of Urology, Urology, World Journal of Urology,
`
`International
`
`Urogynecology Journal, Neurology and Urodynamics, and the International
`
`Journal of Clinical Practice.
`
`7.
`
`I have been a Visiting Professor or Guest Lecturer at numerous university
`
`or industry conferences.
`
`I have acted as a primary investigator or co—investigator
`
`on numerous clinical trials,
`
`including trials related to fesoterodine, tolterodine,
`
`oxybutynin, mirabegron, and solifenacin.
`
`I have served as a key opinion leader
`
`and/or served on advisory boards for numerous pharmaceutical companies in
`
`connection with their overactive bladder (“DAB”) treatments, including Ortho-
`
`McNeil, Pfizer, Astellas, Watson, Novartis, Schwarz, GlaxoSmithKline, Allergan,
`
`and Sanof1—Aventis.
`
`I have published numerous articles in peer—reviewed
`
`literature, many focusing on the management of patients with OAB.
`
`8. A copy of my curriculum vitae, which sets forth additional information
`
`regarding my education and experience, is attached as Exhibit 2060.
`
`B. Materials Considered
`
`9. The opinions that
`
`I express in this declaration are based on the
`
`information and evidence currently available to me. The following table lists the
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0005
`
`
`
`materials that I considered in forming my opinions set forth in this declaration.
`
`I
`
`also relied on my extensive knowledge of the OAB literature, experience, and my
`
`understandings based on my interactions with urologists and other physicians.
`
`Exhibit
`
`No.
`
`1001
`
`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.
`
`2-2
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`W0
`94/11337
`Filed
`6 November
`1992
`~
`“Novel
`Diphenylpropylamines, Their Use and Preparation” (“J ohansson”).
`
`3,3-
`
`(1999), 84, 923947 — “The Pharmacological
`BIU 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 Pharrnacodynamics of
`a1., Pharmacokinetics
`et
`N. Brynne
`Tolterodine in Man: A New Drug for the Treatment of Urinary Bladder
`Overactivity, 35 1NT’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”).
`
`W
`
`Detrol® Label.
`
`Drug Metabolism and Disposition (1998), 26 (4), 289-293 —
`“Tolterodine, A New Muscarinic Receptor Antagonist, ls 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 Pharrnacodynamics of Tolterodine, 63 CLIN.
`PHARMACOLOGY & THERAPEUTICS 529 (1998) (“Brynne 1998”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0006
`
`
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`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 af PNU-2005 77, a Major Metabolite af 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 efiicacy and safety of
`tolterodine in the treatment ofoveractive 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”).
`
`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”).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0007
`
`
`
`1023
`
`April 1, 2012 “Overactive Bladder Market: Managing the Future” —
`www. pm3 60online.cOm (“PM360”).
`
`1024
`
`“Toviaz® Label” — Pfizer Labs.
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`2006
`
`2007
`
`2018
`
`“FDA Approval Letter” —NDA20-77 1.
`
`Applications Covered by Section 505(b)(2) — October 1999 — FDA
`(CDER) (“FDA Guidance”).
`
`INTERNATIONAL JOURNAL OF PHARMACEUTICS (1986), 3, 201-217 —
`“Salt Sectionfor 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 —
`“DLIP 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.).
`
`Lisbeth Nilvebrant, Tolterodines A New Bladder-Selective Muscarinic
`
`Receptor Antagonist, LIFE SCIENCES 60:1 129-37 (1997).
`
`Ernesto Callegari et al., A Comprehensive Non—Clinical Evaluation of
`the CNS Penetration Potential of Antirnuscarinic Agents For the
`Treatment of Overactive Bladder, BRITISH JOURNAL OF CLINICAL
`PHARMACOLOGY, 72:2, 235-46 (201 1).
`
`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. 7,3 84,980.
`
`United States Patent No. 7,384,980.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0008
`
`
`
`Transcript of the Deposition of Steven Patterson, Ph.D., dated October
`4, 2016, Case IPR20l6-00510, Case IPR2016-00512, Case IPR20l6-
`
`00514, Case IPR20l6-00516, Case IPR20l6-00517 (“Patterson Tr.”).
`
`Inc. and
`Declaration of Leonard J. Chyall, Ph.D., Mylan Pharms.
`Mylan Labs. Ltd. v. UCB Pharma GmbH, Case IPR20l6-00510, Case
`IPR2016-00512, Case IPR20l6-00514, Case IPR20l6-00516, Case
`IPR2016-00517.
`
`Transcript of the Deposition of Culley C. Carson, III, M.D., dated
`August 25, 2016, C.A. No. 15-cv-0079 (“Carson Tr.”).
`
`Lisbeth Nilvebrant et al., Tolterodine — A New Bladder-Selective
`
`Antimuscarinic Agent, EUROPEAN JOURNAL OF PHARMACOLOGY 327
`(1997) (Nilvebrant II (1997)).
`
`2040
`
`Lisbeth Nilvebrant, Clinical Experiences with Tolterodine, 68 Life. Sci.
`2549 (2001) ("Nilvebrant 2001").
`
`2060
`
`C.V. of Scott A. MacDiarmid.
`
`2061
`
`2062
`
`2063
`
`2064
`
`Paul Abrams et al., The Standardisation of Terminology of Lower
`Urinary Tract Function, NEUROUROL. URO. 2l:167—78 (2002).
`
`Abrams P, Cardozo L, Khoury S, Wein A (eds), Incontinence,
`5”‘ International Consultation on Incontinence (5th Ed. 2013).
`
`Paul Abrams et al., Overactive Bladder Significantly Affects Quality of
`Life, AMERICAN JOURNAL OF MANAGED CARE 6:1 1, S580-S590 (2000).
`
`Walter F. Stewart et al., The prevalence and impact of overactive
`bladder in the U.S.: results from the NOBLE program, Neurourol
`Urodyn. at 406-8 (2001).
`
`Christopher Chapple & Lisbeth Nilvebrant, Tolterodine: Selectivity for
`the Urinary Bladder Over
`the Eye
`(as Measured by Visual
`Accommodation)
`in Healthy Volunteers, DRUGS R&D 3(2): 75-81
`(2002).
`
`Christopher Chapple, et al., The Effects of Antimuscarinic Treatments
`in Overactive Bladder: An Update of a Systematic Review and Meta-
`Analysis, EUROPEAN UROLOGY 54 at 558-559 (2008).
`
`Drugs@FDA.'Ditropan,
`FDA,
`https://wwwaccessdata. fda. gov/scripts/cder/drugsatfdal index. cfm (last
`visited Oct. 14, 2016).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0009
`
`
`
`2070
`
`2071
`
`2072
`
`2073
`
`Karl-Erik Andersson, Current Concepts in the Treatment of Disorders
`ofMicturition, DRUGS 352477-494, 481 (1988).
`
`M.M.S. Stahl, Urodynamic and Other Effects of Tolterodine: a Novel
`Antimuscarinic Drug for the Treatment of Detrusor Overactivity,
`NEUROUROL. URo. 14: 647-655 (1995).
`
`Detro1® LA Prescribing Information, Revised 08/2012.
`
`Bimal Malhotra et al. Thorough QT Study with Recommended and
`Supratherapeutic Doses of Tolterodine, CLINICAL PHARMACOLOGY &
`THERAPEUTICS 81:377-385 (2007).
`
`NDA 20-771 Approval Package.
`
`Martin C. Michel, Fesoterodine: A Novel Muscarinic Receptor
`Antagon ist for the Treatment of Overactive Bladder Syndrome, EXPERT
`OPIN. PHARMACOTHER. 9: 1787-96 (2008).
`
`Bimal Malhotra, et al., The Design and Development ofFesoterodine as
`a Prodrug of 5-Hydroxymethyl Tolterodine (5-Hll/IT),
`the Active
`Metabolite of Tolterodine, CURRENT MEDICINAL CHEMISTRY, 16:33,
`4481-89 (2009).
`
`Victor Nitti, et a1., Fesoterodine is an Eflective Antimuscarinic for
`Patients with Overactive Bladder (OAB): Results ofa Phase 2 Trial.
`
`a New Effective and Well-
`Christopher Chapple, Fesoterodine,
`Tolerated Antimuscarinic for the Treatment of Urgency-Frequency
`Syndrome: Results of a Phase 2 Controlled Study, NEUROUROL.
`URODYN., 23 (5-6) (2004) (hereinafter, “Chapple (2004).
`
`Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy,
`safety, and tolerability of once—daily fesoterodine in subjects with
`overactive bladder. EUR UROL. 52(4):1204—1212 (2007).
`
`safety and
`Nitti VW, Drnochowski R, Sand PK, et al. Efficacy,
`tolerability of_fesoterodine_for overactive bladder syndrome. J UROL.
`l78(6):2488-2494 (2007).
`
`Dmochowski RR, Peters KM, Morrow JD, et al. Randomized, double-
`
`blind, placebo-controlled study offlexible-dosefesoterodine in subjects
`with overactive bladder. UROLOGY. 75(]):62-68 (2010).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0010
`
`
`
`Sender Herschorn et al., Efficacy and Tolerability of Fesoterodine in
`Men With Overactive Bladder: A Pooled Analysis of 2 Phase III
`Studies, J. UROLOGY. 75 (5), 1149-1 155 (2010).
`
`2081
`
`2082
`
`Vik Khullar, et al., Fesoterodine Dose Response in Subjects with
`Overactive Bladder Syndrome, FEMALE UROLOGY (2008).
`
`Steve Chaplin and Adrian Wagg, Fesoterodine (Toviaz): New Option
`for
`Overactive
`Bladder,
`PRESCRIBER
`5,
`available
`at
`www.preScriber.C0.uk (Table 2) (2008).
`
`al., Thorough QT Study of the Effect of
`et
`Bimal Malhotra,
`Fesoterodine on Cardiac Repolarization, INT’L J. PHARMACOLOGY &
`THERAPEUTICS, 48:309-18 (2010).
`
`Gary Kay et al., Evaluation of Cognitive Function in Healthy Older
`Subjects Treated with Fesoterodine,
`POSTGRADUATE MEDICINE,
`Volume 124, Issue 3, 7-15 (May 2012).
`
`Chapple, C. et al., Superiority offesoterodine 8 mg vs 4 mg in reducing
`urgency urinary incontinence episodes in patients with overactive
`bladder: results of the randomised, double-blind, placebo-controlled
`EIGHT trial, BRIT. J. UROLOGY INT’L. 1142418-426 (2014).
`
`Wyndaele, J.J. et al., Flexible dosing with fesoterodine 4 and 8 mg: a
`systematic review ofdata from clinical trials, Int’l J. Clin. Prac. 68:7,
`830-840 (2014).
`
`Sender Herschorn, et al., Comparison of Fesoterodine and Tolterodine
`Extended Release for the Treatment of Overactive Bladder: A Head-to-
`Head Placebo-Controlled Trial, BJU INT’L, 105258-66 (2009).
`
`Steven A. Kaplan, et al., Superior Eflicacy of Fesoterodine over
`Tolterodine Extended Release with Rapid Onset: a Prospective, Head-
`to-Head Placebo-Controlled Trial, BRIT. J. URO. 107, 1432-40 (2010).
`
`al., Comparison of Fesoterodine and
`et
`Christopher Chapple,
`Tolterodine in Patients with Overactive Bladder, BJU INT’L, 102:1128-
`
`32 (2008).
`
`Steven A. Kaplan, et al., Eflicacy and Safety o_fFesoterodine 8 mg in
`Subjects with Overactive Bladder after a Suboptimal Response to
`Tolterodine ER, INT’LJ. CLIN. PRACTICE 68:9, 1065-1073 (2014).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0011
`
`
`
`4:446-451 (2003).
`
`Improving the Eflicacy of
`MacDiarmid, S. Overactive Bladder:
`Amficholinergics by Dose Escalation, CURRENT UROLOGY REPORTS.
`
`II.
`
`SUMMARY OF OPINIONS
`
`10.
`
`I have reviewed the Declaration of Steven E. Patterson, Ph.D.
`
`(the
`
`“Patterson Decl.”), 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
`
`‘650 patent and its associated file history, and the PTAB’s Decision on Institution
`
`of the ‘650 patent.
`
`I disagree with a number of the opinions expressed in the
`
`Patterson Declaration and the positions taken in the Petition.
`
`11. Based on my experience and expertise, I have been asked to describe
`
`and provide background on urinary incontinence and OAB, and the treatment of
`
`these conditions.
`
`In particular, I have been asked to describe how these conditions
`
`are treated with pharmaceuticals, including Toviaz®, both today and historically.
`
`A summary of this background is provided below.
`
`12.
`
`I have been asked to opine on whether fesoterodine satisfied any
`
`previously unmet need.
`
`Before the invention of fesoterodine,
`
`the primary
`
`pharmaceutical treatments for OAB available were oxybutynin and tolterodine in
`
`immediate release form. These treatments possessed similar efficacy and differed
`
`primarily in terms of tolerability. Fesoterodine satisfied a need for a treatment
`
`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0012
`
`
`
`with improved efficacy,
`
`excellent
`
`safety and tolerability,
`
`and a
`
`superior
`
`efficacy/tolerability/safety profile.
`
`In practice, fesoterodine met a long—felt unmet
`
`need for a treatment
`
`that offered “true” dose-escalation in incontinence drug
`
`therapy, meaning
`
`that
`
`fesoterodine’s
`
`excellent
`
`efficacy
`
`and
`
`favorable
`
`efficacy/safety/tolerability profile has been found to be dose—dependent. This
`
`breakthrough offered a clinical benefit for the millions of patients that could not, as
`
`a clinically practical matter, obtain relief or reach their treatment goal from the
`
`treatments available at that time.
`
`I am not aware of any prior art‘ that indicated
`
`that fesoterodine would satisfy this unmet need.
`
`13.
`
`I have been asked to opine on whether fesoterodine possesses any
`
`favorable or unexpected results as compared to the previously available OAB
`
`treatments. As above,
`
`fesoterodine offers a “true” dose-escalation treatment
`
`option, superior efficacy and/or an improved efficacy/tolerability/safety profile
`
`compared to the other treatments available at the time of its invention. These
`
`qualities were unexpected and could not have been predicted based on the prior art,
`
`including the prior art
`
`that concerns tolterodine and its active metabolite, 5-
`
`hydroxymethyl—tolterodine (“5—HMT").
`
`1 "Prior art" is defined below at fil 24.
`
`11
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0013
`
`
`
`III. LEGAL STANDARDS
`
`14.
`
`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.
`
`15.
`
`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 priority dates of the ‘980
`
`patent family and the ‘65O patent.
`
`16.
`
`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.
`
`12
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0014
`
`
`
`17.
`
`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.
`
`IV.
`
`THE CHALLENGED CLAIMS
`
`18.
`
`I understand that Petitioner has petitioned for review and cancellation of
`
`the following claims (collectively, the “challenged claims”):
`
`0 Claims 1-16 ofthe ’980 patent;
`
`0 Claims 1-5 ofthe ’230 patent;
`
`0 Claims 1-3, 5-8, and 10-12 ofthe ’478 patent;
`
`0 Claims 1, 3, 4, and 6-8 ofthe ’772 patent; and
`
`0 Claims 1-5 and 21-24 of the ‘650 patent.
`
`19.
`
`1 have reviewed the Declaration of Dr. Leonard Chyall and 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. Declaration of Leonard J. Chyall, Ph.D., Mylcm
`
`Pharms. Inc. and Mylcm Labs. Ltd. v. UCB Pharma GmbH, Nos. lPR20l6-00510,
`
`LPR2016-00512, LPR2016-00514, LPR2016-00516, IPR2016-00517 (Ex. 2024).
`
`I
`
`13
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0015
`
`
`
`am familiar with the drug Toviaz®, and I am knowledgeable about tolterodine, its
`
`metabolite 5—HMT, and fesoterodine.
`
`20.
`
`I understand that the dosages of fesoterodine used in Toviaz (4 and 8
`
`mg) are effective dosages, given that they are the F DA-approved dosage strengths
`
`for the drug. See Ex. 1024 (Toviaz Label).
`
`1 can also attest from my clinical
`
`experience that the dosages of fesoterodine used in Toviaz are effective dosages.
`
`21.
`
`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.
`
`22.
`
`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. Ex. 1003 (Patterson Decl.) at 1] 24. Except where expressly stated
`
`below, I have conducted my analysis as of that date as well, and I note where my
`
`opinion would change if the art were assessed as of November 16, 1999.
`
`23.
`
`I also understand that between July 20-26, 2016, the PTAB instituted
`
`inter partes review of the challenged claims on the following grounds:
`
`0
`
`Obviousness over the combination of Postlind (Exhibit 1010),
`
`the
`
`Bundgaard Publications (Exs. 1012 and 1020), the Detrol® Label (Ex.
`
`1009), and Berge (Ex. 1013); and
`
`14
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0016
`
`
`
`o
`
`Obviousness over the combination of Brynne 1998 (Ex. 1011),
`
`Bundgaard (Ex. 1012), and Johansson (Ex. 1005).
`
`Paper 12 (July 20, 2016) (‘“980 Decision”) at 29; Paper 12 (July 20, 2016) (“‘772
`
`Decision”) at 29; Paper 12 (July 20, 2016) (“‘650 Decision”) at 29; Paper 12 (July
`
`22, 2016) (“‘230 Decision”) at 29; Paper 12 (July 26, 2016) (“‘478 Decision”) at
`
`30.
`
`V.
`
`PERSON HAVING ORDINARY SKILL IN THE ART
`
`24.
`
`I understand that a patent claim is invalid for obviousness if, after
`
`consideration of the relevant knowledge that was publicly available as of the
`
`claim’s priority date (the “prior art”), a “person of ordinary skill in the art” would
`
`have found the differences between the prior art and the claimed invention to be
`
`obvious. My understanding is that the term “person of ordinary skill in the art”
`
`refers to a typical scientist or researcher having average skill in the technical field
`
`to which the patented inventions relate.
`
`25.
`
`In this case,
`
`the patents-in-suit
`
`relate to the field of treatment of
`
`overactive bladder with pharmaceuticals. As of the relevant dates, a person
`
`conducting research in that field would need knowledge of various technical
`
`disciplines, including medicinal chemistry, pharmacology, and pharmaceutics, as
`
`well as an understanding of the physiology of the bladder and the causes and
`
`symptoms of overactive bladder.
`
`15
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0017
`
`
`
`26.
`
`I have reviewed Petitioner’s definition of a person of ordinary skill in
`
`the art (Pet. at 6 (citing Ex. 1003 (Patterson Decl.) at W 22-23)) and I understand
`
`that
`
`the PTAB has accepted Petitioner’s definition for purposes of institution
`
`(Paper 12 (Decision) at 6.).
`
`I 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.
`
`VI. BACKGROUND
`
`A.
`
`Overview of Overactive Bladder (“DAB”)
`
`27. OAB is a symptom complex defined as urinary urgency with or without
`
`urgency incontinence, usually with urinary frequency and nocturia, in the absence
`
`of pathologic or metabolic factors that would explain these symptoms. See, e.g.,
`
`Paul Abrams et al., The Standardisation of Terminology of Lower Urinary Tract
`
`Function, NEUROUROL. URO. 2]:167—78 (2002) (Ex. 2061).
`
`28. OAB is associated with involuntary contractions of the bladder muscle
`
`before the bladder is full. These premature contractions may cause one or more of
`
`the following symptoms — intense urges to urinate (“urgency”), frequent urination
`
`(“frequency”),
`
`and/or
`
`unintentional
`
`leakage
`
`from the bladder
`
`(“urgency
`
`incontinence,” formerly known as “urge incontinence”). Patients with one or more
`
`of these three symptoms are diagnosed as suffering from OAB. See, e. g., Abrams
`
`P, Cardozo L, Khoury S, Wein A (eds),
`
`Incontinence, 5th International
`
`16
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0018
`
`
`
`Consultation on Incontinence (5th Ed. 2013) (Committee 4: Pathophysiology of
`
`Urinary Incontinence, Faecal Incontinence, and Pelvic Organ Prolapse) at 263-64
`
`(Ex. 2062).
`
`29. OAB significantly affects quality of life — socially, psychologically,
`
`occupationally, etc. Paul Abrams et al., Overactive Bladder Significantly Affects
`
`Quality QfLife, AMERICAN JOURNAL OF MANAGED CARE 6:11, S580-S590 at S581
`
`(2000) (hereinafter, “Abrams (2000)”) (Ex. 2063). OAB causes sufferers to miss
`
`life events in favor of staying confined to their homes or other well—known
`
`locations so that they always have reliable access to bathrooms. OAB may cause
`
`sufferers to experience embarrassing leakages or be forced to wear pads or diapers
`
`as an adult. The adverse effects of OAB may be generally broken down into four
`
`categories — coping, concern, adjusted social
`
`interaction, and loss of sleep.
`
`“Coping” may comprise decreased physical activity, the need to plan activities
`
`around the availability of bathrooms, limiting fluid intake, and the wearing of dark
`
`clothing.
`
`“Concern” may comprise fear, anxiety, worry, loss of self-esteem, or
`
`embarrassment about having leakage or other OAB symptoms. “Adjusted Social
`
`Interaction” may comprise limiting and planning travel around toilet accessibility,
`
`limiting social
`
`interactions, and frustrating family and friends.
`
`“Sleep” may
`
`comprise sleeplessness and fatigue when OAB symptoms interfere with the ability
`
`to obtain a full night’s rest.
`
`17
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0019
`
`
`
`30.
`
`In the United States alone, approximately sixteen percent (16%) of
`
`adults over the age of 18 years old have overactive bladder. Walter F. Stewart et
`
`al., The prevalence and impact of overactive bladder in the U.S..' resaltsfrom the
`
`NOBLE program, Neurourol Urodyn. at 406-8 (2001) (Ex. 2064).
`
`B. Muscarinic Receptors
`
`31. Both
`
`abnormal
`
`and
`
`normal
`
`bladder
`
`contractions
`
`occur when
`
`acetylcholine, a neurotransmitter, binds to muscarinic cholinergic receptors in the
`
`bladder. Several different subtypes of muscarinic receptors are known, classified
`
`as M1—M5. See, e.g., Karl—Erik Andersson, The Pharmacological Treatment of
`
`Urinary Incontinence, BJU INTERNATIONAL (1999)
`
`84:932—47
`
`(hereinafter,
`
`“Andersson (Review)”) (Ex. 1006).
`
`32. The various muscarinic receptor subtypes are found throughout the body
`
`in various tissues:
`
`M1
`
`Brain, Salivary glands
`
`- Brain, Heart, Bladder, Eyes
`
`M2
`
`
`
`Smoothmusclecells,includingbowel
`
`and bladder, and glands, including
`Salivary glands
`
`Brain, Salivary glands
`
`18
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0020
`
`
`
`33. The prevalence of the various muscarinic receptor subtypes varies from
`
`tissue to tissue. See, e. g., Lisbeth Nilvebrant et al., Tolterodine — A New Bladder-
`
`Selective Antimuscarinic Agent, EUROPEAN JOURNAL OF PHARMACOLOGY 327 at
`
`195-96 (1997) (hereinafier, “Nilvebrant II (l997)”) (Ex. 2032); Lisbeth Nilvebrant,
`
`Clinical Experiences with Tolterodine, LLFE SCIENCES 68, 2549-56 at 2549-50
`
`(2001) (hereinafter, “Nilvebrant (2001)”) (Ex. 2040); Christopher Chapple &
`
`Lisbeth Nilvebrant, Tolterodine: Selectivity for the Urinary Bladder Over the Eye
`
`(as Measured by Visual Accommodation) in Healthy Volunteers, DRUGS R&D
`
`2002, 3(2): 75-81 at 75-76 (hereinafter, “Chapple (2002)”) (Ex. 2065).
`
`34. An antimuscarinic compound, also known as
`
`an anticholinergic
`
`compound, may have no preference for the muscarinic receptors in the bladder
`
`over those present in other tissues and can cause significant side effects in patients.
`
`For example, antimuscarinic compounds can inhibit muscarinic receptors in the
`
`salivary glands, such as M3 receptors, and cause dryness of the mouth. See, e. g.,
`
`Ex. 2032 at 199-206; Ex. 2040 at 2549, 2552-53; see also Ex. 2065 at 80.
`
`Likewise, antimuscarinic compounds that inhibit muscarinic receptors in the gut
`
`can cause constipation, which has been shown to actually aggravate symptoms of
`
`OAB.
`
`See, e.g., Christopher Chapple, et al., The Effects of Antimuscarinic
`
`Treatments in Overactive Bladder: An Update of a Systematic Review and Meta-
`
`19
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2023 - 0021
`
`
`
`Anal
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