UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`
`ALEMBIC PHARMACEUTICALS LIMITED
`Petitioner
`
`v.
`
`UCB PHARMA GMBH
`Patent Owner
`
`
`Patent No. 6,858,650
`Filing Date: November 15, 2000
`Issue Date: February 22, 2005
`Title: STABLE SALTS OF NOVEL DERIVATIVES
`OF 3,3-DIPHENYLPROPYLAMINES
`
`_______________
`
`
`Inter Partes Review No. IPR2016-01596
`
`________________________________________________________________
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
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`SMRH:225668907.7
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
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`TABLE OF CONTENTS
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`Page
`
`I. 
`
`INTRODUCTION ........................................................................................... 1 
`
`II.  MANDATORY NOTICES ............................................................................. 2 
`
`A. 
`
`B. 
`
`C. 
`
`Real Party in Interest ............................................................................. 2 
`
`Related Matters ...................................................................................... 2 
`
`Fee ......................................................................................................... 4 
`
`D.  Designation of Lead Counsel and Request for Authorization .............. 4 
`
`E. 
`
`F. 
`
`Service Information ............................................................................... 4 
`
`Standing ................................................................................................. 5 
`
`III. 
`
`STATEMENT OF RELIEF REQUESTED .................................................... 5 
`
`IV.  SUMMARY OF THE ’650 PATENT AND CHALLENGED
`CLAIMS .......................................................................................................... 7 
`
`V. 
`
`CLAIM CONSTRUCTION ............................................................................ 8 
`
`VI.  TECHNICAL BACKGROUND AND STATE OF THE ART ...................... 8 
`
`A. 
`
`B. 
`
`The Person of Ordinary Skill in the Art of the ’650 Patent .................. 8 
`
`Before the Invention, Antimuscarinic Compounds Were Used
`to Treat Overactive Bladder Conditions ............................................... 8 
`
`C. 
`
`Prodrugs Were Known to Solve Active Compound Difficulties ........ 11 
`
`D.  Numerous Salt Forms Were Known for Compounds Similar to
`the Most Effective Overactive Bladder Drugs .................................... 15 
`
`VII.  SCOPE AND CONTENT OF THE PRIOR ART ......................................... 16 
`
`A. 
`
`Skilled Artisans Had Ample Motivation to Focus on
`Optimizing 5- HMT to Obtain an Overactive Bladder
`Compound ........................................................................................... 16 
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`1. 
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`2. 
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
`Postlind, the Detrol® Label, and Brynne 1998 Taught 5-
`HMT Was an Effective Compound for Overactive
`Bladder without Tolterodine ..................................................... 16 
`
`Skilled Artisans Would Immediately Recognize the
`Benefit to Starting with their Knowledge of 5-HMT and
`Tolterodine and Not Other Compounds ................................... 18 
`
`B. 
`
`Bundgaard Taught Predictable Modifications to Improve 5-
`HMT Delivery ..................................................................................... 20 
`
`C. 
`
`Berge and Johansson Taught Fumarate Salts ...................................... 23 
`
`VIII.  DETAILED GROUNDS FOR UNPATENTABILITY ................................ 24 
`
`A. 
`
`Claims 1 – 5 are Obvious Over the Postlind and Bundgaard
`Publications in view of the Detrol® Label and Berge ........................ 24 
`
`1. 
`
`2. 
`
`A Person of Ordinary Skill Would Have Been Motivated
`to Look at Improved 5-HMT Administration in View of
`Tolterodine ................................................................................ 25 
`
`Postlind and Bundgaard Publications in View of the
`Detrol® Label and Berge Would Have Led to Prodrug
`Optimization and Fumarate Salt Forms .................................... 28 
`
`3. 
`
`Summary of Proposed Rejection of Claims 1-5 ....................... 34 
`
`Claims 21-24 are Obvious over the Postlind and Bundgaard
`Publications in view of the Detrol® Label and Berge ........................ 43 
`
`Claims 1-5 and 21-24 Are Rendered Obvious by Brynne 1998,
`Bundgaard, and Johansson .................................................................. 48 
`
`1. 
`
`2. 
`
`A Person of Ordinary Skill Would Have Been Motivated
`to Look at Improved 5-HMT Administration in View of
`Tolterodine ................................................................................ 48 
`
`Brynne 1998 in View of Bundgaard and Johansson
`Would Have Led to Prodrug Optimization and Fumarate
`Salt Forms ................................................................................. 49 
`
`B. 
`
`C. 
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`IX.  EVEN IF CONSIDERED, SECONDARY CONSIDERATIONS
`FAIL TO OVERCOME THE EVIDENCE OF OBVIOUSNESS ................ 58 
`
`X. 
`
`THE PROPOSED REJECTIONS RAISE NEW ISSUES IN WHICH
`PETITIONER WILL LIKELY PREVAIL .................................................... 62 
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`Cases
`
`In re Applied Materials
`692 F.3d 1289 (Fed. Cir. 2012) .................................................................... 35, 59
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA Inc.
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 61
`
`Daiichi Sankyo Co. v. Matrix Labs.
`619 F.3d 1346 (Fed. Cir. 2010) .............................................................. 16, 26, 35
`
`In re Dillon
`919 F.2d 688 (Fed. Cir. 1990) ............................................................................ 16
`
`Eli Lilly & Co. v. Zenith Goldline Pharms., Inc.
`471 F.3d 1369 ............................................................................................... 16, 35
`
`Geo M. Martin Co. v. Alliance Machine Sys. Intʼl LLC
`618 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 60
`
`In re Kao
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 59, 62
`
`KSR Int’l Co. v. Teleflex Inc.
`550 U.S. 398 (2007) ...................................................................................... 16, 35
`
`McNeil-PPC, Inc. v. L. Perrigo Co.
`337 F.3d 1362 (Fed. Cir. 2003) .......................................................................... 59
`
`Merck & Co. v. Teva Pharms USA, Inc.
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 17
`
`Ormco Corp. v. Align Tech., Inc.
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 59
`
`Par Pharm, Inc. v. TWI Pharms, Inc.
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 17
`
`Pfizer, Inc. v. Apotex, Inc.
`480 F.3d 1348 (Fed. Cir. 2007) ........................................................ 23, 33, 34, 58
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`Takeda Chem. Indus. v. Alphapharm Pty.,
`492 F.3d 1350 (Fed Cir. 2007) ........................................................................... 33
`
`Tex. Instruments v. U.S. Int’l Trade Comm’n
`988 F.2d 1165 (Fed. Cir. 1993) .......................................................................... 62
`
`Statutes
`
`35 U.S.C. section 102(a) ............................................................................................ 6
`
`35 U.S.C. section 102(b) ........................................................................................ 5, 6
`
`35 U.S.C. section 103 .......................................................................................... 1, 63
`
`35 U.S.C. section 103(a) ............................................................................................ 5
`
`35 U.S.C. section 311 ................................................................................................ 5
`
`35 U.S.C. section 312(a)(1) ....................................................................................... 4
`
`35 U.S.C. section 314(a) .................................................................................... 62, 63
`
`Other Authorities
`
`37 Code of Federal Regulations section 42.10(b)...................................................... 4
`
`37 Code of Federal Regulations section 42.15 .......................................................... 4
`
`37 Code of Federal Regulations section 42.100(b) ................................................... 8
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`Ex. 1001:
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`Ex. 1002:
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`Ex. 1003:
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`Ex. 1004:
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`Ex. 1005:
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`Ex. 1006:
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`Ex. 1007:
`
`Ex. 1008:
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`Ex. 1009:
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`Ex. 1010:
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`Ex. 1011:
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
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`LIST OF EXHIBITS
`
`U.S.P.N. 6,858,650
`
`File History for U.S.P.N. 6,858,650
`
`Declaration of Dr. Steven Patterson, Ph.D.
`
`C.V. for Dr. Steven Patterson, Ph.D.
`
`“Johansson” – WO 94/11337 Filed 6 November 1992 – “Novel
`3,3-Diphenylpropylamines, Their Use and Preparation”
`
`“Andersson Review” – BJU International (1999), 84, 923-947 –
`“The Pharmacological Treatment of Urinary Incontinence”; K-E
`Andersson, R. Appell, L.D. Cardozo, C. Chapple, H.P. Drutz, A.E.
`Finkbeiner, F. Haab, and R. Vela Navarrete
`
`“Brynne 1997” – International Journal of Clinical Pharmacology
`and Therapeutics (1997), 35, 287-295 – “Pharmacokinetics and
`pharmacodynamics of tolterodine in man: a new drug for the
`treatment of urinary bladder overactivity”; N. Brynne, M.M.S.
`Stahl, B. Hallen, P.O. Edlund, L. Palmer, P. Hoglund, and J.
`Gabrielsson
`
`“Thomas” – 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
`
`”Detrol® Label” – Pharmacia & Upjohn
`
`“Postlind” – Drug Metabolism and Disposition (1998), 26 (4), 289-
`293 – “Tolterodine, A New Muscarinic Receptor Antagonist, Is
`Metabolized by Cytochromes P450 2D6 and 3A in Human Liver
`Microsomes”; H. Postlind, A. Danielson, A. Lindgren, and S.
`Andersson
`
`“Brynne 1998” – Clinical Pharmacology & Therapeutics (May
`1998), 63(5), 529-539 – “Influence of CYP2D6 polymorphism on
`the pharmacokinetics and pharmacodynamics of tolterodine”; N.
`Brynne, P. Dalen, G. Alvan, L. Bertilsson, and J. Gabrielsson
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`Ex. 1012:
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`Ex. 1013:
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`Ex. 1014:
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`Ex. 1015:
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`Ex. 1016:
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`Ex. 1017:
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`Ex. 1018:
`
`Ex. 1019:
`
`Ex. 1020:
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`Ex. 1021:
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`Ex. 1022:
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`“Bundgaard” – Elsevier 1985 – “Design of Prodrugs”
`
`“Berge 1977” – Journal of Pharmaceutical Sciences (1977), 66 (1),
`1-19 – “Pharmaceutical Salts”; S. Berge, L., Bighley, and D.
`Monkhouse
`
`“Andersson 1998” – Drug Metabolism and Disposition (1998),
`26(6), 528-535 – “Biotransformation of tolterodine, a new
`muscarinic receptor antagonist, in mice, rats, and dogs”; S.
`Andersson, A. Lindgren, and H. Postlind
`
`”Nilvebrant” – Pharmacology and Toxicology (1997), 81, 169-172
`– “Antimuscarinic Potency and Bladder Selectivity of PNU-
`200577, a Major Metabolite of Tolterodine”; L. Nilvebrant, P.
`Gillberg, and B. Sparf
`
`“DeMaagd” – P&T (2012), 37(6), 345-361 – “Management of
`Urinary Incontinence”; G. DeMaagd and T. Davenport
`
`“Appell” – Urology (1997), 50, 90-96 – “Clinical efficacy and
`safety of tolterodine in the treatment of overactive bladder: a
`pooled analysis”; R. Appell
`
`“Ashworth” – Home Care Provider (1997), 2(3), 117-120 – “Is My
`Antihistamine Safe?”; L. Ashworth
`
`“Lipinski” – Advanced Drug Delivery Reviews, 1997
`
`“Bundgaard PCT” – WO 92/08459 Filed 11 November 1991 –
`“Topical Compositions for Transdermal Delivery of Prodrug
`Derivatives of Morphine”
`
`“AUA Guideline” – American Urological Association Eductatio
`and Research (2014) – “Diagnosis and Treatment of Overactive
`Bladder (Non-Neorogenic) in Adults: AUA/SUFU Guideline”; E.
`Gormley, et al
`
`“Pfizer 2012 Press Release” – Aug. 2, 2012 “Study Shows Toviaz
`is Effective in Reducing Urge Urinary Incontinence in Patients
`with Overactive Bladder After Suboptimal Response to Detrol LA”
`– www.pfizer.com
`
`Ex. 1023:
`
`“PM360” – April 1, 2012 “Overactive Bladder Market: Managing
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`the Future” – www. pm360online.com
`
`“Toviaz® Label” – Pfizer Labs
`
`“FDA Approval Letter” – NDA20-771
`
`“FDA Guidance” – Applications Covered by Section 505(b)(2) –
`October 1999 – FDA (CDER)
`
`“Gould” – International Journal of Pharmaceutics (1986), 3, 201-
`217 – “Salt Section for Basic Drugs”; P. Gould
`
`“Alabaster” – Discovery & Development of Selective M3
`Antagonists for Clinical Use, 60 Life Science 1053 (1997)
`
`“Takeuchi” – 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)
`
`“Goldberg” – DuP 532, an angiotensin II receptor antagonist: First
`administration and comparison with losartan, Clinical
`Pharmacology & Therapeutics, January 1997
`
`“Begley” – The Blood-brain Barrier: Principles for TGargeting
`Peptides and Drugs to the Central Nervous System, J. Phar.
`Pharmacol. 1996, 48:136-146
`
`Dkt 6 2015-01-28 Summons Returned Executed, Case No. 1:15-
`cv-00079-GMS, Pfizer, et al v Mylan Pharmaceutical Inc. (Dist. of
`DE)
`
`Declaration of DeForest McDuff, Ph.D.
`
`CV for DeForest McDuff, Ph.D.
`
`Toviaz: Don’t Let Overactive Bladder Stop You In Your Tracks
`
`Toviaz U.S. and Worldwide Sales
`
`U.S. OAB Prescriptions and Shares by Drug (2008–2014)
`
`U.S. OAB Sales and Shares by Drug (2008–2014)
`
`Ex. 1024:
`
`Ex. 1025:
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`Ex. 1026:
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`Ex. 1027:
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`Ex. 1028:
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`Ex. 1029:
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`Ex. 1030:
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`Ex. 1031:
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`Ex. 1032:
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`Ex. 1033:
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`Ex. 1034:
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`Ex. 1035:
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`Ex. 1036:
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`Ex. 1037:
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`Ex. 1038:
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`U.S. OAB Market Share, Prescriptions, and Sales by Drug (2000–
`2007)
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`Prescription Path of Toviaz and Other OABs
`
`Sales Path of Toviaz and Other OABs
`
`Sales Path of Toviaz Compound to Pharmaceutical Industry
`Benchmarks
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`Comparison of Toviaz Sales to Compound to Pharmaceutical
`Industry Benchmarks
`
`Chart of Sales Path of Toviaz
`
`Present Value of Toviaz U.S. Sales
`
`Present Value of Toviaz Worldwide Sales
`
`Estimates of Expected R&D Costs
`
`U.S. OAB Detail Shares by Drug (2008–2015)
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`Consumer Price Index (CPI)
`
`Ex. 1039:
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`Ex. 1040:
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`Ex. 1041:
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`Ex. 1042:
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`Ex. 1043:
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`Ex. 1044:
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`Ex. 1045:
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`Ex. 1046:
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`Ex. 1047:
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`Ex. 1048:
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`Ex. 1049:
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
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`I.
`
`INTRODUCTION
`
`Through counsel, real party in interest Alembic Pharmaceuticals Limited
`
`(“Petitioner” or “Alembic”) hereby petitions for initiation of inter partes review of
`
`U.S. Patent No. 6,858,650 B1, entitled “STABLE SALTS OF NOVEL
`
`DERIVATIVES OF 3,3- DIPHENYLPROPYLAMINES” (“the ’650 patent”).
`
`Ex. 1001. The Patent Trial and Appeal Board (the “Board”) has already issued its
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`Decision Instituting Inter Partes Review (“Decision”) on all challenged claims of
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`the ’650 patent on the same grounds raised herein. Mylan Pharmaceuticals, Inc.et
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`al. v. UCB Pharma GmbH, Case IPR2016-00510 (“IPR 510”) (Paper 12). In its
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`Decision, the Board found that Petitioner Mylan Pharmaceuticals Inc. and Mylan
`
`Laboratories Limited (collectively “Mylan”) had demonstrated a reasonable
`
`likelihood that claims 1-5 and 21-24 of the ’650 patent are unpatentable for failing
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`to satisfy the non-obviousness requirement of 35 U.S.C. § 103. Id. The Board
`
`instituted IPR of the challenged claims on the following grounds:
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`(1) Claims 1-5 and 21-24 are invalid as obvious over the Postlind and
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`Bundgaard publications in view of the Detrol® label and Berge.
`
`(2) Claims 1-5 and 21-24 are invalid as obvious over the Byrnne 1998
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`and Bundgaard publications in view of Johansson.
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`IPR2016-00510 (Paper 12, p. 29).
`
`Petitioner Alembic hereby files its own petition on the same grounds and
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
`concurrently seeks joinder of this IPR petition to the instituted IPR proceeding on
`
`these challenged claims. A motion for Joinder with IPR2016-00510 is being filed
`
`concurrently with this Petition.
`
`For the sake of completeness and efficiency, the present Petition is a
`
`practical copy of the Corrected Petition in IPR2016-00510 (Paper 5). Specifically,
`
`the present Petition is tailored to the same claims, prior art, and grounds of
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`unpatentability that are the subject of IPR2016-00510.
`
`II. MANDATORY NOTICES
`A. Real Party in Interest
`The following real parties-in-interest are identified: Alembic
`
`Pharmaceuticals Limited, the Petitioner in this matter.
`
`B. Related Matters
`On July 20, 2016, the Board instituted inter partes review of claims 1-5 and
`
`21-24 of the ’650 patent in IPR2016-00510 filed by Mylan Pharmaceuticals Inc.
`
`and Mylan Laboratories Limited. (Paper 12). Torrent Pharmaceuticals Limited
`
`filed a petition for inter partes review of claims 1-5 and 21-24 of the ’650 Patent in
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`Torrent Pharmaceuticals Limited v. UCB Pharma GMBH, IPR2016-01636. In
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`addition, the ’650 patent is asserted in at least the following proceedings listed in
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`the chart below.
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`Description
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
`Docket Number
`
`Pfizer Inc. et al v. Dr. Reddy’s Labs., Ltd. et al
`
`1-15-cv-08226 (D.N.J)
`
`Pfizer Inc. et al v. Dr. Reddy's Labs., Ltd. et al
`
`1-15-cv-01067 (D. Del.)
`
`Pfizer Inc. et al v. Mylan Pharms. Inc.
`
`1-15-cv-00013 (N.D. W.Va.)
`
`Pfizer Inc. et al v. Mylan Pharms. Inc.
`
`1-15-cv-00079 (D. Del.)
`
`Pfizer Inc. et al v. Hetero USA Inc. et al
`
`1-13-cv-02021 (D. Del.)
`
`Pfizer Inc. et al v. Apotex Inc.
`
`1-13-cv-02022 (D. Del.)
`
`Pfizer Inc. et al v. Wockhardt Bio AG et al
`
`1-13-cv-01387 (D. Del.)
`
`Pfizer Inc. et al v. Lupin Ltd.
`
`1-13-cv-01153 (D. Del.)
`
`Pfizer Inc. et al v. Zydus Pharms. (USA), Inc.
`
`1-13-cv-01154 (D. Del.)
`
`Pfizer Inc. et al v. Accord Healthcare Inc. USA
`
`1-13-cv-01155 (D. Del.)
`
`Pfizer Inc. et al v. Amerigen Pharms. Inc., et al.
`
`1-13-cv-01156 (D. Del.)
`
`Pfizer Inc. et al v. Amneal Pharms. LLC
`
`1-13-cv-01157 (D. Del.)
`
`Pfizer Inc. et al v. Impax Labs. Inc.
`
`1-13-cv-01158 (D. Del.)
`
`Pfizer Inc. et al v. Alkem Labs. Ltd.
`
`1-13-cv-04628 (N.D. Ill.)
`
`Pfizer Inc. et al v. Sandoz Inc.
`
`1-13-cv-01111 (D. Del.)
`
`Pfizer Inc. et al v. Sandoz Inc., et al.
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`1-13-cv-01110 (D. Del.)
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`(IPR2016-01596)
`
`C.
`Fee
`This petition for inter partes review is accompanied by a payment of
`
`$23,000.00, charged to Deposit Account No. 50-4562, and requests review of
`
`9 claims of the ’650 patent. See 37 C.F.R. § 42.15. Thus, this petition meets the
`
`fee requirements under 35 U.S.C. § 312(a)(1). Should any further fees be required
`
`by the present Petition, the Board is hereby authorized to charge the above
`
`referenced Deposit Account.
`
`D. Designation of Lead Counsel and Request for Authorization
`
`Lead Counsel
`Manish K. Mehta
`Reg. No. 64,570
`mmehta@sheppardmullin.com
`Sheppard Mullin Richter & Hampton, LLP
`70 W. Madison St., 48th Floor
`Chicago, Illinois 60602
`T: (312) 499-6352
`F: (312) 499-4749
`
`Back-Up Counsel
`Laura Burson
`Reg. No. 40,929
`lburson@sheppardmullin.com
`Sheppard Mullin Richter &
`Hampton, LLP
`333 S. Hope St., 43rd Floor
`Los Angeles, California 90071
`T: (213) 617-5527
`F: (213) 443-2794
`
`
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`A power of attorney is being filed with the designation of counsel in
`
`accordance with 37 C.F.R. § 42.10(b).
`
`Service Information
`
`E.
`As identified in the attached Certificate of Service, a copy of the present
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`petition, in its entirety, is being served to the address of the attorney or agent of
`
`record. Alembic consents to service by e-mail, and may be served at its counsel,
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`Sheppard Mullin Richter & Hampton, LLP, at the e-mail addresses indicated
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`above.
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`F.
`Standing
`The Petitioner certifies that the ’650 patent is available for inter partes
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`review and that the Petitioner is not barred or estopped from requesting an inter
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`partes review challenging the patent claims on the grounds identified in this
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`petition.
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`III. STATEMENT OF RELIEF REQUESTED
`Pursuant to 35 U.S.C. § 311, this petition requests inter partes review and
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`cancellation of claims 1-5 and 21-24 of the ’650 patent, as follows.
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`(1) Claims 1-5 and 21-24 are invalid as obvious under 35 U.S.C. § 103(a)
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`over the Postlind and Bundgaard publications in view of the Detrol®
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`label and Berge.
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`(2) Claims 1-5 and 21-24 are invalid as obvious under 35 U.S.C. § 103(a)
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`over the Byrnne 1998 and Bundgaard publications in view of
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`Johansson.
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`The ’650 patent issued from patent application 10/130,214, filed as
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`PCT/EP00/11309 (“the PCT application”) on November 15, 2000, designating the
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`U.S. Ex. 1001. The PCT application claimed priority to German application
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`DE 119 55 190, filed November 16, 1999. Id. The effective filing date of the ‘650
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`patent is November 15, 2000 and the critical date under 35 U.S.C. § 102(b) is
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`November 15, 1999.
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`Postlind, Ex. 1010, was published in April 1998, was received February 11,
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`1997, and accepted January 9, 1998. It is prior art under 35 U.S.C. § 102(a)
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`and (b).
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`Bundgaard, Ex. 1012, was published in 1985 and thus is prior art under
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`35 U.S.C. § 102(a) and (b).
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`The Detrol® label, Ex. 1009, was approved for commercial distribution on
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`March 25, 1998, and thus is prior art under 35 U.S.C. § 102(b).
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`Johansson, WO 94/11337, Ex. 1005, was published May 1994 and thus is
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`prior art under 35 U.S.C. § 102(a) and (b).
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`Berge, Ex. 1013, was published in 1977 and thus is prior art under 35 U.S.C.
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`§ 102(a) and (b).
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`Brynne 1998, Ex. 1011, was presumed published on May 1, 1998, and
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`mailed before May 11, 1998, and thus is prior art under 35 U.S.C. § 102(a) and
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`§ 102(b).
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`Before the invention date, Postlind disclosed effective treatment of
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`overactive bladder by use of the 5-hydroxymethyl metabolite of tolterodine (“5-
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`HMT”). From both Postlind and the Detrol® label, the art was also aware that
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`tolterodine was quite effective, but not across all patients and with negative side-
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`effects, in part because catalysis of tolterodine varied across patients. Skilled
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`artisans would thus conclude that use of tolterodine could be improved. Given the
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`active metabolite was known, the catalytic activity was known, and the accepted
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`efficacy of the 5-HMT “prodrug-like” starting compound, the art demonstrates it
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`would have been obvious to a person of ordinary skill in the art at the time of
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`invention to make a single, suggested modification (Bundgaard) to the active
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`metabolite to achieve the claimed compound. All other aspects of the challenged
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`claims such as salt choice, etc., would naturally follow the development of a pro-
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`drug with a known, desired active metabolite.
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`The invalidity grounds set forth in this Petition are confirmed and supported
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`by the Declarations of Dr. Steven E. Patterson (Ex. 1003) and Dr. DeForest
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`McDuff (Ex. 1033).
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`IV. SUMMARY OF THE ’650 PATENT AND CHALLENGED CLAIMS
`The ʼ650 patent describes derivatives of 3,3-diphenylpropylamines and salt
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`forms. Ex. 1001, 1:10-14. Claim 1 provides a
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`generic structure for the covered molecule
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`reproduced here. According to the claim, “R denotes
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`C1- C 6 –alkyl, C3-C10-cycloaklyl, substituted or
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`unsubstituted phenyl and X- is the acid residue of a
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`physiological compatible inorganic or organic acid.” Id., Claim 1.
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`Claims 2-5 further specify the type of compatible acid (claims 2 and 4),
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`adding specific chirality (claim 3), and two specific substitutions and salt forms
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`(claim 5). Specifically, claim 5 lists R-(+)-2-(3-(diisopropylamino-1-
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`phenylpropyl)-4- hydroxymethl-phenylisobutyrate ester hydrogen fumarate. This
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`is commonly referred to as fesoterodine fumarate. Ex. 1003, ¶ 13. Claims 21-24
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`recite methods of use.
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`V. CLAIM CONSTRUCTION
`The claims in the ’650 patent are presumed to take on their ordinary and
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`customary meaning based on the broadest reasonable interpretation of the claim
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`language. 37 C.F.R. § 42.100(b).
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`VI. TECHNICAL BACKGROUND AND STATE OF THE ART
`A. The Person of Ordinary Skill in the Art of the ’650 Patent
`A person of ordinary skill in the art would have a Ph.D. in chemistry,
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`medicinal chemistry, pharmacology, or a related field, and at least one year of
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`industrial exposure to drug discovery, drug design, and synthesis. In lieu of an
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`advanced degree, the individual may have additional years of industry experience,
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`including, for example, in drug discovery, drug synthesis, and structure-activity
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`work. Ex. 1003, ¶ 23.
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`B.
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`Before the Invention, Antimuscarinic Compounds Were Used to
`Treat Overactive Bladder Conditions
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`Long before the invention, it was known muscarinic receptors play a role in
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`urinary bladder smooth muscle contractions and salivary activity. Ex. 1003, ¶¶ 26-
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`34; Ex. 1010, 289. The FDA had approved antimuscarinic agents for the treatment
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`of overactive bladder, including tolterodine tartrate marketed under the name
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`Detrol®. Ex. 1009. Detrol® was approved for commercial distribution on March
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`25, 1998 and its label described the oxidation of tolterodine by cyctochrome P450
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`2D6 to 5-HMT. Ex. 1025, 4. Detrol®’s label further states that “[b]oth tolterodine
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`and 5-HMT exhibit a high specificity for muscarinic receptors, since both show
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`negligible activity or affinity for other neurotransmitters . . . .” Ex. 1009, 2
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`(Clinical Pharmacology).
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`Tolterodine was the first drug specifically developed to treat overactive
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`bladder and thus distinguished itself from another prior art antimuscarinic
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`compound, oxybutynin. Ex. 1014, 528. Unlike tolterodine, oxybutynin led to dry
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`mouth because it had a higher selectivity for muscarinic receptors on salivary
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`glands over receptors in the bladder. Ex. 1015, 4. Tolterodine, and its primary,
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`beneficial metabolite 5-HMT, had selectivity for the bladder over receptors on
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`salivary glands and thus tolterodine exhibited a clinical advantage over
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`oxybutynin. Id.; Ex. 1017, 1; Ex. 1007, 287-88.
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`An antimuscarinic compound with selective affinity for the bladder naturally
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`garnered focus from skilled artisans.1 That focus was further sharpened given that
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`1 As explained infra, before the invention, other compounds that were not
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`antimuscarinic compounds – calcium antagonists, potassium channel antagonists,
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`tolterodine’s label revealed that a subset of the population had poor metabolism by
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`the cytochrome catalyst and thus negligible concentrations of 5-HMT in patient’s
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`plasma. Ex. 1009, 2. Artisans also knew tolterodine possessed its own activity
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`separate from the 5-HMT metabolite and, when present in the serum, could lead to
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`adverse events or negative drug-drug interactions. Id., 2, 7; Ex. 1007, 291
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`(“Tolterodine was associated with a dose-dependent increase in heart rate, the
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`onset of which was fairly rapid with time to maximal effect around 1.3 – 1.8 h.”).
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`Prior art identified the main metabolic pathways of tolterodine in human
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`liver microsomes. Ex. 1003, ¶¶ 36, 40, 44, and 48-50. Andersson described how
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`tolterodine undergoes stepwise oxidation of the 5-methyl group to yield the 5-
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`HMT metabolite. Ex. 1014, 534. Specifically, as shown, the cytochrome catalyst
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`(P450 2D6) oxidizes the 5-methyl to convert tolterodine into its structurally similar
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`active metabolite. Id., Fig. 6 (Andersson); Ex. 1003, ¶ 68-69.
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`and α-adrenoreceptors – were unproven as effective overactive bladder treatment.
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`See also, Ex. 1003, ¶¶ 26-34.
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`Postlind expressly noted that the identification of the metabolic catalyst and
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`mechanism “is of great importance to predict potential
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`drug interactions and genetic variations in drug
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`metabolism.”2 Ex. 1010, 289. It was known that
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`phenotypical differences arising from polymorphism of
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`the cyctochrome catalyst (i.e., CYP2D6) affect a
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`number of drugs including receptor antagonists and
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`lead to interpatient variability of the efficacy of drugs
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`that are acted on by this pathway. Ex. 1010, 2992;
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`Ex. 1003, ¶¶ 96-100. Postlind further confirmed that CYP2D6 is responsible for
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`the necessary oxidation to convert tolterodine to its active metabolite, 5-HMT. Id.
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`Prodrugs Were Known to Solve Active Compound Difficulties
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`C.
`Prodrug optimization of known active compounds has been considered an
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`industrially beneficial avenue of drug design for decades. Economic factors often
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`drive decisions which impact drug development. Those factors include market size
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`(number of compounds in a treatment field); medical use amount (number of
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`prescriptions likely to be written in the treatment field); and likelihood of
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`2 As explained infra, other compounds that may have shown overactive bladder
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`treatment efficacy had known issues or unproven pharmacologically relevant
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`characteristics. Ex. 1003, ¶¶ 85-91.
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`distinguishing a new product from existing compounds beyond non-inferiority.
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`Ex. 1003, ¶¶ 74-76 and 102. The ability to demonstrate required safety and
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`efficacy of an entirely new compound may require wholly independent data
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`collection that would be unneeded or at least limited if prodrug optimization were
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`pursued. Ex. 1026, 5.
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`Prodrug optimization thus focuses on active compounds already known
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`rather than examining compounds with untested, undemonstrated efficacy and
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`safety. Ex. 1003, ¶¶ 80, and 106-109. Indeed, skilled artisans were aware of many
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`examples of approved prodrugs of known active compounds that reused and
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`repurposed the underlying data of the active compound. Id. at ¶¶ 108-109. The
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`use of prodrugs was likewise long known to improve difficulties associated with
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`administering compounds. Id. at ¶ 80; Ex. 1012, 1-2. For example, a compound
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`that was too water soluble would lack sufficient lipophilicity to enter the gut wall
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`and be absorbed. Ex. 1003, ¶ 112- 113; Ex. 1012, 1-2. This was known to directly
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`impact bioavailability. Id.
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`Given the known characteristics of 5-HMT, namely its poor lipophilicity
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`(Ex. 1011, 538), as well as the knowledge of the skilled artisan of the use of
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`prodrug optimization to achieve better bioavailability through increasing
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`lipophilicity, the skilled artisan would have considered 5-HMT a good candidate
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`for prodrug optimization. Ex. 1003, ¶¶ 110-120.
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