UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`TORRENT 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. Unassigned
`
`
`_________________________________________________________________
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
`
`
`
`
`
`
`
`
`
`14018387.6
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`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ........................................................................................... 1 
`I. 
`II.  MANDATORY NOTICES ............................................................................. 1 
`A. 
`Real Party in Interest ............................................................................. 1 
`B. 
`Related Matters ...................................................................................... 1 
`C. 
`Fee ......................................................................................................... 2 
`D.  Designation of Lead Counsel and Request for Authorization .............. 2 
`E. 
`Service Information ............................................................................... 2 
`F. 
`Standing ................................................................................................. 3 
`III.  STATEMENT OF RELIEF REQUESTED .................................................... 3 
`IV.  SUMMARY OF THE ʼ650 PATENT AND CHALLENGED CLAIMS ....... 5 
`V. 
`CLAIM CONSTRUCTION ............................................................................ 6 
`VI.  TECHNICAL BACKGROUND AND STATE OF THE ART ...................... 6 
`A. 
`The Person of Ordinary Skill in the Art of the ʼ650 Patent .................. 6 
`B. 
`Before the Invention, Antimuscarinic Compounds Were Used to
`Treat Overactive Bladder Conditions. ................................................... 6 
`Prodrugs Were Known to Solve Active Compound Difficulties. ......... 9 
`C. 
`D.  Numerous Salt Forms Were Known for Compounds Similar to the
`Most Effective Overactive Bladder Drugs. ......................................... 12 
`VII.  SCOPE AND CONTENT OF THE PRIOR ART ......................................... 13 
`Skilled Artisans Had Ample Motivation to Focus on Optimizing 5-
`A. 
`HMT to Obtain an Overactive Bladder Compound. ........................... 14 
`Postlind, the Detrol® Label, and Brynne 1998 Taught 5-HMT
`1. 
`Was an Effective Compound for Overactive Bladder without
`Tolterodine. ............................................................................... 14 
`Skilled Artisans Would Immediately Recognize the Benefit to
`Starting with their Knowledge of 5-HMT and Tolterodine and
`Not Other Compounds. ............................................................. 16 
`
`2. 
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`B. 
`
`B. 
`
`C. 
`
`2. 
`
`2. 
`
`Bundgaard Taught Predictable Modifications to Improve 5-HMT
`Delivery. .............................................................................................. 17 
`Berge and Johansson Taught Fumarate Salts. ..................................... 20 
`C. 
`VIII.  DETAILED GROUNDS FOR UNPATENTABILITY ................................ 21 
`Claims 1-5 are Obvious Over the Postlind and Bundgaard
`A. 
`Publications in view of the Detrol® Label and Berge. ....................... 21 
`A Person of Ordinary Skill Would Have Been Motivated to
`1. 
`Look at Improved 5-HMT Administration in View of
`Tolterodine ................................................................................ 22 
`Postlind and Bundgaard Publications in View of the Detrol®
`Label and Berge Would Have Led to Prodrug Optimization and
`Fumarate Salt Forms. ................................................................ 25 
`Summary of Proposed Rejection of Claims 1-5 ....................... 31 
`3. 
`Claims 21-24 are Obvious over the Postlind and Bundgaard
`Publications in view of the Detrol® Label and Berge. ........................ 40 
`Claims 1-5 and 21-24 Are Rendered Obvious by Brynne 1998,
`Bundgaard, and Johansson. ................................................................. 44 
`A Person of Ordinary Skill Would Have Been Motivated to
`1. 
`Look at Improved 5-HMT Administration in View of
`Tolterodine. ............................................................................... 44 
`Brynne 1998 in View of Bundgaard and Johansson Would
`Have Led to Prodrug Optimization and Fumarate Salt Forms. 45 
`IX.  EVEN IF CONSIDERED, SECONDARY CONSIDERATIONS FAIL
`TO OVERCOME THE EVIDENCE OF OBVIOUSNESS. ......................... 53 
`THE PROPOSED REJECTIONS RAISE NEW ISSUES IN WHICH
`PETITIONER WILL LIKELY PREVAIL. ................................................... 58 
`
`X. 
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`FEDERAL CASES
`In re Applied Materials,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 32
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ...................................................................... 56, 57
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ........................................................ 13, 14, 23, 32
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) ............................................................................ 13
`
`Eli Lilly & Co. v. Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .......................................................................... 32
`
`Geo M. Martin Co. v. All. Machine Sys. Intʼl LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 55
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 54, 58
`
`KSR Intʼl Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 13, 32
`
`McNeil-PPC, Inc. v. L. Perrigo Co.,
`337 F.3d 1362 (Fed. Cir. 2003) .......................................................................... 55
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 15
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 54
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 14
`
`Pfizer Inc. and UCB Pharma GMBH v. Mylan Pharmaceuticals Inc.,
`No. 1:15-cv-00013-IMK (N.D. W. Va.) ............................................................... 1
`
`14018387.6
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`Pfizer, Inc. and UCB Pharma GMBH v. Mylan Pharmaceuticals, Inc.,
`No. 1:15-cv-00079-GMS (D. Del.) ........................................................... 1, 21, 30
`
`Pfizer, Inc. and UCB Pharma GMBH v. Sandoz, Inc., et al.,
`No. 1:13-cv-01110-GMS (D. Del.) ....................................................................... 1
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ........................................................ 21, 30, 31, 54
`
`Tex. Instruments v. U.S. Intʼl Trade Commsʼn,
`988 F.2d 1165 (Fed. Cir. 1993) .......................................................................... 57
`
`FEDERAL STATUTES
`
`35 U.S.C. §§ 102(a)-(b) ............................................................................................. 4
`
`35 U.S.C. § 103 ........................................................................................................ 58
`
`35 U.S.C. § 311 .......................................................................................................... 3
`
`35 U.S.C. § 312(a)(1) ................................................................................................. 2
`
`35 U.S.C. § 314(a) ................................................................................................... 58
`
`35 U.S.C. §§ 315 ........................................................................................................ 1
`
`REGULATIONS
`
`37 C.F.R. § 42.10(b) .................................................................................................. 2
`
`37 C.F.R. § 42.15 ....................................................................................................... 2
`
`37 C.F.R. § 42.100(b) ................................................................................................ 6
`
`
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`LIST OF EXHIBITS
`
`Ex. 1001: U.S.P.N. 6,858,650
`
`Ex. 1002: File History for U.S.P.N. 6,858,650
`
`Ex. 1003: Declaration of Dr. Steven Patterson, Ph.D.
`
`Ex. 1004: C.V. for Dr. Steven Patterson, Ph.D
`
`Ex. 1005:
`
`“Johansson” – WO 94/11337 Filed 6 November 1992 – “Novel 3,3-
`Diphenylpropylamines, Their Use and Preparation”
`
`Ex. 1006:
`
`Ex. 1007:
`
`“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
`
`Ex. 1008:
`
`“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
`
`Ex. 1009:
`
`“Detrol® Label” – Pharmacia & Upjohn
`
`Ex. 1010:
`
`“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
`
`Ex. 1011:
`
`“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
`
`Ex. 1012:
`
`“Bundgaard” – Elsevier 1985 – “Design of Prodrugs”
`
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`

`
`Ex. 1013:
`
`1013:
`
`EX.
`
`Ex. 1014:
`
`1014:
`
`EX.
`
`Ex. 1015:
`
`1015:
`
`EX.
`
`Ex. 1016:
`
`1016:
`
`EX.
`
`Ex. 1017:
`
`1017:
`
`EX.
`
`Ex. 1018:
`
`1018:
`
`EX.
`
`Ex. 1019:
`
`1019:
`
`EX.
`
`Ex. 1020:
`
`1020:
`
`EX.
`
`Ex. 1021:
`
`1021:
`
`EX.
`
`Ex. 1022:
`
`1022:
`
`EX.
`
`Ex. 1023:
`
`1023:
`
`EX.
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`“Berge 1977” – Journal of Pharmaceutical Sciences (1977), 66 (1), 1-
`“Berge 1977” — Journal ofPharmaceutical Sciences (1977), 66 (1), 1-
`19 – “Pharmaceutical Salts”; S. Berge, L., Bighley, and D.
`19 - “Pharmaceutical Salts”; S. Berge, L., Bighley, and D.
`Monkhouse
`Monkhouse
`
`“Andersson 1998” – Drug Metabolism and Disposition (1998), 26(6),
`“Andersson 1998” — Drug Metabolism and Disposition (1998), 26(6),
`528-535 – “Biotransformation of tolterodine, a new muscarinic
`528-535 — “Biotransformation of tolterodine, a new muscarinic
`receptor antagonist, in mice, rats, and dogs”; S. Andersson, A.
`receptor antagonist, in mice, rats, and dogs”; S. Andersson, A.
`Lindgren, and H. Postlind
`Lindgren, and H. Postlind
`
`“Nilvebrant” – Pharmacology and Toxicology (1997), 81, 169-172 –
`“Nilvebrant” — Pharmacology and Toxicology (1997), 81, 169-172 —
`“Antimuscarinic Potency and Bladder Selectivity of PNU-200577, a
`“Antimuscarinic Potency and Bladder Selectivity of PNU-200577, a
`Major Metabolite of Tolterodine”; L. Nilvebrant, P. Gillberg, and B.
`Major Metabolite of Tolterodine”; L. Nilvebrant, P. Gillberg, and B.
`Sparf
`Sparf
`
`“DeMaagd” – P&T (2012), 37(6), 345-361 – “Management of
`“DeMaagd” — P&T (2012), 37(6), 345-361 — “Management of
`Urinary Incontinence”; G. DeMaagd and T. Davenport
`Urinary Incontinence”; G. DeMaagd and T. Davenport
`
`“Appell” – Urology (1997), 50, 90-96 – “Clinical efficacy and safety
`“Appell” — Urology (1997), 50, 90-96 — “Clinical efficacy and safety
`of tolterodine in the treatment of overactive balder: a pooled
`of tolterodine in the treatment of overactive balder: a pooled
`analysis”; R. Appell
`analysis”; R. Appell
`
`“Ashworth” – Home Care Provider (1997), 2(3), 117-120 – “Is My
`“Ashworth” — Home Care Provider (1997), 2(3), 117-120 — “Is My
`Antihistamine Safe?”; L. Ashworth
`Antihistamine Safe?”; L. Ashworth
`
`“Lipinski” – Advanced Drug Delivery Reviews, 1997
`“Lipinski” — Advanced Drug Delivery Reviews, 1997
`
`“Bundgaard PCT” – WO 92/08459 Filed 11 November 1991 –
`“Bundgaard PCT” — WO 92/08459 Filed 11 November 1991 —
`“Topical Compositions for Transdermal Delivery of Prodrug
`“Topical Compositions for Transdermal Delivery of Prodrug
`Derivatives of Morphine”
`Derivatives of Morphine”
`
`“AUA Guideline” – American Urological Association Education and
`“AUA Guideline” — American Urological Association Education and
`Research (2014) – “Diagnosis and Treatment of Overactive Bladder
`Research (2014) — “Diagnosis and Treatment of Overactive Bladder
`(Non-Neorogenic) in Adults: AUA/SUFU Guideline”; E. Gormley, et
`(Non-Neorogenic) in Adults: AUA/SUFU Guideline”; E. Gormley, et
`al
`al
`“Pfizer 2012 Press Release” – Aug. 2, 2012 “Study Shows Toviaz® is
`“Pfizer 2012 Press Release” — Aug. 2, 2012 “Study Shows Toviaz® is
`Effective in Reducing Urge Urinary Incontinence in Patients with
`Effective in Reducing Urge Urinary Incontinence in Patients with
`Overactive Bladder After Suboptimal Response to Detrol LA” –
`Overactive Bladder After Suboptimal Response to Detrol LA” —
`www.pfizer.com
`www.pfizer.com
`
`“PM360” – April 1, 2012 “Overactive Bladder Market: Managing the
`“PM360” — April 1, 2012 “Overactive Bladder Market: Managing the
`Future” – www.pm360online.com
`Future” — www.pm360online.com
`
`140183876
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`
`Ex. 1024:
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`“Toviaz® Label” – Pfizer Labs
`
`Ex. 1025:
`
`“FDA Approval Letter” –NDA20-771
`
`Ex. 1026:
`
`“FDA Guidance” – Applications Covered by Section 505(b)(2) –
`October 1999 – FDA (CDER)
`
`Ex. 1027:
`
`“Gould” – International Journal of Pharmaceutics (1986), 3, 201-217
`– “Salt Section for Basic Drugs”; P. Gould
`
`Ex. 1028:
`
`“Alabaster” – Discovery & Development of Selective M3 Antagonists
`for Clinical Use, 60 Life Science 1053 (1997)
`
`Ex. 1029:
`
`Ex. 1030:
`
`Ex. 1031:
`
`“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 Targeting Peptides
`and Drugs to the Central Nervous System, J. Phar. Pharmacol. 1996,
`48:136-146
`
`Ex. 1032: Dkt 6 2015-01-28 Summons Returned Executed, Case No. 1:15-cv-
`00079-GMS, Pfizer, et al. v Mylan Pharmaceutical Inc. (D. Del.)
`
`Ex. 1033: Declaration of DeForest McDuff, Ph.D.
`
`Ex. 1034: CV for DeForest McDuff, Ph.D.
`Ex. 1035: Toviaz®: Donʼt Let Overactive Bladder Stop You In Your Tracks
`Ex. 1036: Toviaz® U.S. and Worldwide Sales
`
`Ex. 1037: U.S. OAB Prescriptions and Shares by Drug (2008–2014)
`
`Ex. 1038: U.S. OAB Sales and Shares by Drug (2008–2014)
`
`Ex. 1039: U.S. OAB Market Share, Prescriptions, and Sales by Drug (2000-
`2007)
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`Ex. 1040: Prescription Path of Toviaz® and Other OABs
`Ex. 1041: Sales Path of Toviaz® and Other OABs
`Ex. 1042: Sales Path of Toviaz® Compound to Pharmaceutical Industry
`Benchmarks
`Ex. 1043: Comparison of Toviaz® Sales to Compound to Pharmaceutical
`Industry Benchmarks
`Ex. 1044: Chart of Sales Path of Toviaz®
`Ex. 1045: Present Value of Toviaz® U.S. Sales
`Ex. 1046: Present Value of Toviaz® Worldwide Sales
`
`Ex. 1047: Estimates of Expected R&D Costs
`
`Ex. 1048: U.S. OAB Detail Shares by Drug (2008–2015)
`
`Ex. 1049: Consumer Price Index (CPI)
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`INTRODUCTION
`
`
`I.
`
`Through counsel, real party in interest Torrent Pharmaceuticals Limited
`
`(“Petitioner”) hereby petitions for initiation of inter partes review of U.S. Patent
`
`No. 6,858,650, entitled “STABLE SALTS OF NOVEL DERIVATIVES OF 3,3-
`
`DIPHENYLPROPYLAMINES” (“the ʼ650 patent”). Ex. 1001.
`
`II. MANDATORY NOTICES
`A. Real Party in Interest
`Torrent Pharmaceuticals Limited is the real party in interest. Torrent
`
`Pharmaceuticals Limited is related to Torrent Private Limited, which is also related
`
`to the Torrent Group. Out of an abundance of caution, Torrent Pharmaceuticals
`
`Limited identifies the foregoing entities, each of which agrees to be estopped under
`
`the provisions of 35 U.S.C. §§ 315 and/or 325 as a result of any final written
`
`decision in the requested IPR to the same extent as Petitioner, as real-parties-in-
`
`interest, solely to avoid disputes related to this Petition.
`
`B. Related Matters
`The ’650 patent is asserted in the actions styled: Pfizer, Inc. and UCB
`
`Pharma GMBH v. Mylan Pharmaceuticals, Inc., No. 1:15-cv-00079-GMS (D.
`
`Del.), Pfizer Inc. and UCB Pharma GMBH v. Mylan Pharmaceuticals Inc., No.
`
`1:15-cv-00013-IMK (N.D. W. Va.), and Pfizer, Inc. and UCB Pharma GMBH v.
`
`Sandoz, Inc., et al., No. 1:13-cv-01110-GMS (D. Del.). Petitioner is not a party to
`
`any of these actions, and Patent Owner has not asserted the ’650 patent against
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`Petitioner to date.
`
`The ’650 patent is the subject of a petition for inter partes review (IPR2016-
`
`00510) filed by Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited
`
`(collectively, “Mylan”) on February 2, 2016, which was instituted on July 20, 2016
`
`as to claims 1-5 and 21-24. Petitioner seeks joinder with that IPR for the reasons
`
`expressed in the concurrently-filed Motion for Joinder under 35 U.S.C. § 315(c),
`
`37 C.F.R. §§ 42.22 and 42.122(b).
`
`Fee
`
`C.
`This petition for inter partes review is accompanied by a payment of
`
`$23,000.00 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).
`
`D. Designation of Lead Counsel and Request for Authorization
`Petitioner designates lead and back-up counsel as noted below. Powers of
`
`attorney pursuant to 37 C.F.R. § 42.10(b) accompany this Petition.
`
`Lead Counsel
`Neal Seth, Reg. No. 67,075
`nseth@wileyrein.com
`
`Backup Counsel
`Lawrence Sung, Reg. No. 38,330
`lsung@wileyrein.com
`
`
`WILEY REIN LLP
`1776 K Street NW
`Washington, DC 20006,
`Phone: 202.719.7000 / Fax: 202.719.7049
`
`
`Service Information
`
`E.
`As identified in the attached Certificate of Service, a copy of the present
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`petition, in its entirety, is being served to the address of the attorney or agent of
`
`record. Torrent may be served at its counsel, Wiley Rein LLP, at the e-mail
`
`addresses indicated above.
`
`F.
`Standing
`Petitioner certifies that the ʼ650 patent is available for inter partes review
`
`and that the Petitioner is not barred or estopped from requesting an inter partes
`
`review challenging the patent claims on the grounds identified in this petition.
`
`III. STATEMENT OF RELIEF REQUESTED
`Pursuant to 35 U.S.C. § 311, this petition requests inter partes review and
`
`cancellation of claims 1-5 and 21-24 of the ʼ650 patent as follows.
`
`(1) Claims 1-5 and 21-24 are invalid as obvious over the Postlind and
`
`Bundgaard publications in view of the Detrol® label and Berge.
`
`(2) Claims 1-5 and 21-24 are invalid as obvious over the Brynne 1998 and
`
`Bundgaard publications in view of Johansson.
`
`The ʼ650 patent issued from patent application 10/130,214, filed as
`
`PCT/EP00/11309 (“the PCT application”) on November 15, 2000, designating the
`
`U.S. Ex. 1001. The PCT application claimed priority to German application DE
`
`119 55 190, filed November 16, 1999. Id. The effective filing date of the ʼ650
`
`patent is November 15, 2000 and the critical date under 35 U.S.C. § 102(b) is
`
`November 15, 1999.
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`Postlind, Ex. 1010, was published in April 1998, was received February 11,
`
`1997, and accepted January 9, 1998. It is prior art under 35 U.S.C. §§ 102(a)-(b).
`
`Bundgaard, Ex. 1012, was published in 1985 and thus is prior art under 35
`
`U.S.C. §§ 102(a)-(b).
`
`The Detrol® label, Ex. 1009, was approved for commercial distribution on
`
`March 25, 1998, and thus is prior art under 35 U.S.C. §§ 102(a)-(b).
`
`Johansson, WO 94/11337, Ex. 1005, was published May 1994 and thus is
`
`prior art under 35 U.S.C. §§ 102(a)-(b).
`
`Berge, Ex. 1013, was published in 1977 and thus is prior art under 35 U.S.C.
`
`35 U.S.C. §§ 102(a)-(b).
`
`Brynne 1998, Ex. 1011, was presumed published on May 1, 1998, and
`
`mailed before May 11, 1998, and thus is prior art under 35 U.S.C. §§ 102(a)-(b).
`
`Before the invention date, Postlind disclosed effective treatment of
`
`overactive bladder by use of the 5-hydroxymethyl metabolite of tolterodine (“5-
`
`HMT”). From both Postlind and the Detrol® label, the art was also aware that
`
`tolterodine was quite effective, but not across all patients and with negative side-
`
`effects, in part because catalysis of tolterodine varied across patients. Skilled
`
`artisans would thus conclude that use of tolterodine could be improved. Given the
`
`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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`IV. SUMMARY OF THE ʼ650 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
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`provides a generic structure for the
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`covered molecule
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`reproduced here.
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`According to the claim, “R denotes C1-
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`C6 –alkyl, C3-C10-cycloaklyl, substituted
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`or unsubstituted phenyl and X- is the
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`acid
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`residue of a physiologically
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`compatible inorganic or organic acid.”
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`Id. at 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).
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` Specifically, claim 5
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`lists R-(+)-2-(3-(diisopropylamino-1-
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`phenylpropyl)-4-hydroxymethyl-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 ʼ650 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 ʼ650 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 at 289. The FDA had approved antimuscarinic agents for the
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`treatment of overactive bladder, including tolterodine tartrate marketed under the
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`name Detrol®. Ex. 1009. Detrol® was approved for commercial distribution on
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`March 25, 1998, and its label described the oxidation of tolterodine by cytochrome
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`P450 2D6 to 5-HMT. Ex. 1025 at 4. Detrol®ʼs label further states that “[b]oth
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`tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for
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`muscarinic receptors, since both show negligible activity or affinity for other
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`neurotransmitter[s] . . . .” Ex. 1009 at 2.
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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 at 528. Unlike tolterodine, oxybutynin led to
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`dry mouth because it had a higher selectivity for muscarinic receptors on salivary
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`glands over receptors in the bladder. Ex. 1015 at 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
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`thus tolterodine exhibited a clinical advantage over
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`oxybutynin. Id.; Ex. 1017 at 1; Ex. 1007 at 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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`tolterodineʼs label revealed that a subset of the population had poor metabolism by
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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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`and α-adrenoreceptors – were unproven as effective overactive bladder treatment.
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`See also Ex. 1003 ¶¶ 26-34.
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`the cytochrome catalyst and thus negligible concentrations of 5-HMT in patients’
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`plasma. Ex. 1009 at 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. at 2, 7; Ex. 1007 at 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 at 534. Specifically, as shown, the cytochrome
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`catalyst (P450 2D6) oxidizes the 5-methyl to convert tolterodine into its
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`structurally similar active metabolite. Id. at Fig. 6 (Andersson); Ex. 1003 ¶¶ 68-69.
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`Postlind expressly noted
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`that
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`the
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`identification of the metabolic catalyst and
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`mechanism “is of great importance to predict
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`potential drug
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`interactions
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`and genetic
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`variations in drug metabolism.” Ex. 1010,
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`289.
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`
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`It was known
`
`that phenotypical
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`differences arising from polymorphism of the
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`cyctochrome catalyst (i.e., CYP2D6) affect a
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`of
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`drugs
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`including
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`receptor
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`antagonists and lead to interpatient variability
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`of the efficacy of drugs that are acted on by
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`this pathway. Ex. 1010 at 292; Ex. 1003 ¶ 95-
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`99. Postlind further confirmed that CYP2D6
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`
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`is responsible for the necessary oxidation to convert tolterodine to its active
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`metabolite, 5-HMT. Ex. 1010 at 292.
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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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`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 at 5.
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`Prodrug optimization thus focuses on active compounds already known
`
`rather than examining compounds with untested, undemonstrated efficacy and
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`safety. Ex. 1003 ¶¶ 80, 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. ¶¶ 108-109. The use
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`of prodrugs was likewise long known to improve difficulties associated with
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`administering compounds. Id. ¶ 80; Ex. 1012 at 1-2. For example, a compound
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`that was too water soluble would lack sufficient lipophilicity to enter the gut wall
`
`and be absorbed. Ex. 1003 ¶¶ 112-113; Ex. 1012 at 1-2. This was known to
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`directly impact bioavailability. Ex. 1003 ¶ 112.
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`Given the known characteristics of 5-HMT, namely its poor lipophilicity
`
`(Ex. 1011 at 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
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`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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`First, the skilled artisans would have known that 5-HMT had bioavailability
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`concerns. Tolterodine, the “prodrug-like” compound to 5-HMT was ten times
`
`more lipophilic than the active metabolite—5-HMT. Ex. 1011 at 538; Ex. 1003 ¶¶
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`55, 116-118. Skilled artisans also knew that the lipid solubility, and, hence
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`absorption of many polar drug molecules may be improved by forming esters with
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`short or long chain aliphatic acids. Ex. 1012, Ex. 1003 ¶¶ 56-62. Thus, skilled
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`artisans at the time of the invention would have understood from the relationship
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`between 5-HMT and its metabolic analog tolterodine that modifying 5-HMT
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`would likely provide the necessary protection for the prodrug to pass through the
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`gut and be acted on by enzymes for conversion to the desired active compound.
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`Ex. 1003 ¶¶ 110-119.
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`Second, skilled artisans would have known that such optimization of
`
`compounds
`
`for
`
`improved bioavailability by protecting compounds
`
`from
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`degradation or improvising gut absorption had been a routine and predictably
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`successful approach since the late 1990s. Id. As Bundgaard explained,
`
`Prodrug research matured as a branch of pharmaceutical research
`during the 1970s. Over the past decade this chemical approach to
`optimization of drug delivery has undergone considerable expansion,
`largely as a result of an increased awareness and understanding of the
`physicochemical factors that affect the efficacy of drug delivery and
`action. Several drugs are now used clinically in the form of prodrugs,
`and as the prodrug approach is becoming an integral part of the new
`drug design process one may expect that the new drugs in many cases
`will appear as prodrugs.
`
`Ex. 1012 at Preface. Even more relevant here, skilled artisans knew to create
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`prodrugs containing esters when the desired active metabolite possessed a
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`hydroxyl or carboxyl group. Id. at 2 (“In