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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.
`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.
`
`
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`TABLE OF CONTENTS
`
`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 ........................................................................................... 3 
`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 
`The Person of Ordinary Skill in the Art of the ʼ650 Patent ................. 6 
`A. 
`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 
`A. 
`Skilled Artisans Had Ample Motivation to Focus on
`Optimizing 5-HMT to Obtain an Overactive Bladder
`Compound ....................................................................................................... 13 
`1. 
`Postlind, the Detrol® Label, and Brynne 1998 Taught 5-
`HMT Was an Effective Compound for Overactive Bladder
`without Tolterodine ............................................................................. 13 
`Skilled Artisans Would Immediately Recognize the Benefit
`to Starting with their Knowledge of 5-HMT and Tolterodine
`and Not Other Compounds ............................................................... 15 
`
`2. 
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`B. 
`
`B. 
`
`C. 
`
`Bundgaard Taught Predictable Modifications to Improve 5-
`HMT Delivery ................................................................................................ 17 
`Berge and Johansson Taught Fumarate Salts ...................................... 20 
`C. 
`VIII.  DETAILED GROUNDS FOR UNPATENTABILITY ..................................... 21 
`A. 
`Claims 1 – 5 are Obvious Over the Postlind and Bundgaard
`Publications in view of the Detrol® Label and Berge ....................... 21 
`1. 
`A Person of Ordinary Skill Would Have Been Motivated to
`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 ........................................... 24 
`Summary of Proposed Rejection of Claims 1-5 .............................. 30 
`3. 
`Claims 21-24 are Obvious over the Postlind and Bundgaard
`Publications in view of the Detrol® Label and Berge ....................... 38 
`Claims 1-5 and 21-24 Are Rendered Obvious by Brynne 1998,
`Bundgaard, and Johansson ........................................................................ 43 
`1. 
`A Person of Ordinary Skill Would Have Been Motivated to
`Look at Improved 5-HMT Administration in View of
`Tolterodine ............................................................................................ 43 
`Brynne 1998 in View of Bundgaard and Johansson Would
`Have Led to Prodrug Optimization and Fumarate Salt
`Forms ..................................................................................................... 44 
`IX.  EVEN IF CONSIDERED, SECONDARY CONSIDERATIONS
`FAIL TO OVERCOME THE EVIDENCE OF OBVIOUSNESS .......... 53 
`X.  THE PROPOSED REJECTIONS RAISE NEW ISSUES IN
`WHICH PETITIONER WILL LIKELY PREVAIL .................................... 57 
`CERTIFICATE OF SERVICE .......................................................................................... 1 
`
`
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`2. 
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`2. 
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`
`Ex. 1001:
`
`Ex. 1002:
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`Ex. 1003:
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`Ex. 1004:
`
`Ex. 1005:
`
`Ex. 1006:
`
`Ex. 1007:
`
`Ex. 1008:
`
`Ex. 1009:
`
`Ex. 1010:
`
`Ex. 1011:
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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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.
`
`iii
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`Ex. 1012:
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`Ex. 1013:
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`Ex. 1014:
`
`Ex. 1015:
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`Ex. 1016:
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`Ex. 1017:
`
`Ex. 1018:
`
`Ex. 1019:
`
`Ex. 1020:
`
`Ex. 1021:
`
`Ex. 1022:
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`Brynne, P. Dalen, G. Alvan, L. Bertilsson, and J. Gabrielsson
`
`“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 balder: 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
`
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`Ex. 1023:
`
`Ex. 1024:
`
`Ex. 1025:
`
`Ex. 1026:
`
`Ex. 1027:
`
`Ex. 1028:
`
`Ex. 1029:
`
`Ex. 1030:
`
`Ex. 1031:
`
`Ex. 1032:
`
`Ex. 1033:
`
`Ex. 1034:
`
`Ex. 1035:
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`Overactive Bladder After Suboptimal Response to Detrol LA” –
`www.pfizer.com
`
`“PM360” – April 1, 2012 “Overactive Bladder Market: Managing
`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: Donʼt Let Overactive Bladder Stop You In Your Tracks
`
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`Ex. 1036:
`
`Ex. 1037:
`
`Ex. 1038:
`
`Ex. 1039:
`
`Ex. 1040:
`
`Ex. 1041:
`
`Ex. 1042:
`
`Ex. 1043:
`
`Ex. 1044:
`
`Ex. 1045:
`
`Ex. 1046:
`
`Ex. 1047:
`
`Ex. 1048:
`
`Ex. 1049:
`
`
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`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)
`
`U.S. OAB Market Share, Prescriptions, and Sales by Drug (2000–
`2007)
`
`Prescription Path of Toviaz and Other OABs
`
`Sales Path of Toviaz and Other OABs
`
`Sales Path of Toviaz Compound to Pharmaceutical Industry
`Benchmarks
`
`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)
`
`Consumer Price Index (CPI)
`
`
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`I.
`
`INTRODUCTION
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`Through counsel, real party in interest Mylan Pharmaceuticals Inc.
`
`(“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. The ʼ650 patent is
`
`currently asserted in a co-pending litigation, and this petition is being filed within one
`
`year of Petitioner being served with a complaint for infringement. See Ex. 1032. Thus,
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`the ʼ650 patent is eligible for inter partes review.
`
`II. MANDATORY NOTICES
`
`
`
`A.
`
`Real Party in Interest
`
`The following real parties-in-interest are identified: Mylan Pharmaceuticals Inc.
`
`and Mylan Laboratories Limited, which are the Petitioner in this matter and which are
`
`wholly owned subsidiaries of Mylan Inc.; Mylan Inc., which is an indirectly wholly
`
`owned subsidiary of Mylan N.V.; and Mylan N.V. It is noted that Pfizer, Inc. is not the
`
`patent owner but instead is the NDA holder as asserted in the related matters and is
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`thus identified as an interested party.
`
`
`
`
`
`B. Related Matters
`
`The ʼ650 patent is asserted against Petitioner in the action styled Pfizer, Inc. and
`
`UCB Pharma GMBH v. Mylan Pharmaceuticals, Inc., No. 1:15-cv-00079-GMS (D. Del.)
`
`and Pfizer Inc. and UCB Pharma GMBH v. Mylan Pharmaceuticals Inc., Case No. 1:15-cv-
`
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`00013-IMK (N.D. W.Va.) The following pending action also involves the ʼ650
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`patent: Pfizer, Inc. and UCB Pharma GMBH v. Sandoz, Inc., et al., No. 1:13-cv-01110-
`
`GMS (D. Del.).
`
`
`
`C.
`
`Fee
`
`This petition for inter partes review is accompanied by a payment of $23,000.00
`
`and requests review of 9 claims of the ʼ650 patent. See 37 C.F.R. § 42.15. Thus, this
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`petition meets the fee requirements under 35 U.S.C. § 312(a)(1).
`
`
`
`D. Designation of Lead Counsel and Request for Authorization
`
`Lead Counsel
`Mitchell G. Stockwell
`Reg. No. 39,389
`mstockwell@kilpatricktownsend.com
`Kilpatrick Townsend & Stockton
`LLP
`1100 Peachtree Street, NE
`Suite 2800
`Atlanta, Georgia 30309
`(404) 815 6500
`
`Back-Up Counsel
`D. Clay Holloway
`Reg. No. 58,011
`cholloway@kilpatricktownsend.com
`Kilpatrick Townsend & Stockton LLP
`1100 Peachtree Street, NE
`Suite 2800
`Atlanta, Georgia 30309
`(404) 815 6500
`
`Alyson L. Wooten
`Reg. No. 58,045
`awooten@kilpatricktownsend.com
`Kilpatrick Townsend & Stockton LLP
`1100 Peachtree Street, NE
`Suite 2800
`Atlanta, Georgia 30309
`(404) 815 6500
`A power of attorney is being filed with the designation of counsel in
`
`
`
`accordance with 37 C.F.R. § 42.10(b).
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`E.
`
`Service Information
`
`As identified in the attached Certificate of Service, a copy of the present
`
`
`
`
`
`petition, in its entirety, is being served to the address of the attorney or agent of
`
`record. Mylan may be served at its counsel, Kilpatrick Townsend & Stockton LLP, at
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`the e-mail addresses indicated above.
`
`
`
`F.
`
`Standing
`
`The 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
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`Bundgaard publications in view of the Detrol® label and Berge.
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`(2) Claims 1-5 and 21-24 are invalid as obvious over the Byrnne 198 and
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`Bundgaard publications in view of Johansson.
`
`The ʼ650 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 DE 119
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`55 190, filed November 16, 1999. Id. The effective filing date of the ʼ650 patent is
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`November 15, 2000 and the critical date under 35 U.S.C. § 102(b) is November 15,
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`1999.
`
`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) and (b).
`
`Bundgaard, Ex. 1012, was published in 1995 and thus is prior art under 35
`
`U.S.C. § 102(a) and (b).
`
`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).
`
`Johansson, WO 94/11337, Ex. 1005, was published May 1994 and thus is prior
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`art under 35 U.S.C. § 102(a) and (b).
`
`Berge, Ex. 1013, was published in 1977 and thus is prior art under 35 U.S.C. §
`
`102(a) and (b).
`
`Brynne 1998, Ex. 1011, was presumed published on May 1, 1998, and mailed
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`before May 11, 1998, and thus is prior art under 35 U.S.C. § 102(a) and § 102(b).
`
`Before the invention date, Postlind disclosed effective treatment of overactive
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`bladder by use of the 5-hydroxymethyl metabolite of tolterodine (“5-HMT”). From
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`both Postlind and the Detrol® label, the art was also aware that tolterodine was quite
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`effective, but not across all patients and with negative side-effects, in part because
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`catalysis of tolterodine varied across patients. Skilled artisans would thus conclude
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`that use of tolterodine could be improved. Given the active metabolite was known,
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`Petition
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`for Inter Paartes Revieww of U.S. PPatent 6,8588,650
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`the catallytic activitty was knowwn, and thee accepted
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`efficacy of f the 5-HMMT “prodrugg-
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`like” staarting comppound, the art demonnstrates it wwould have
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`rson
`been obvioous to a per
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`of ordinnary skill in the art at tthe time of f invention
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`modificaation (Bunddgaard) to the active mmetabolite
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`to make a
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`single, sugggested
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`to achieve
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`e the claimeed compouund.
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`All otheer aspects oof the challeenged claimms such as ssalt choice,, etc., woulld naturallyy
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`follow the developpment of a pro-drug wwith a knowwn, desired
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`active mettabolite.
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`Y OF THEIV. SSUMMARY
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`E ʼ650 PAATENT ANND CHALLLENGE
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`TThe ʼ650 paatent descriibes derivattives of 3,33-diphenylppropylamin
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`forms. Ex. 1001, 11:10-14. Cllaim 1 provvides a
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`D CLAIMMS
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`es and salt
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`generic
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`structure foor the coveered molecuule
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`reproduuced here. AAccording to the claimm, “R
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`cycloaklyl, denotes C1-C6 –alkkyl, C3-C10-c
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`substitutedd
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`of or unsubbstituted phhenyl and XX- is the accid residue o
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`physioloogical comppatible inorrganic or orrganic acidd.” Id., Claiim 1.
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`a
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` (claim 5).
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`CClaims 2-5 ffurther spe
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`cify the typpe of comppatible acid
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`(claims 2 aand 4), add
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`ing
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`specific chirality (cclaim 3), and two speccific substittutions and salt forms
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`Specific
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`ally, claim 5 lists R-(++)-2-(3-(diissopropylammino-1-pheenylpropyl)--4-
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`hydroxyymethl-phenylisobutyrrate ester hhydrogen fuumarate. TThis is commmonly refe
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`to as fessoterodine fumarate. Ex. 1003, ¶¶ 13. Claimms 21-24 reecite methoods of use.
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`CLAIM CONSTRUCTION
`
`
`V.
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`The claims in the ʼ650 patent are presumed to take on their ordinary and
`
`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
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`A person of ordinary skill in the art would have a Ph.D. in chemistry, medicinal
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`chemistry, pharmacology, or a related field, and at least one year of industrial exposure
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`to drug discovery, drug design, and synthesis. In lieu of an advanced degree, the
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`individual may have additional years of industry experience, including, for example, in
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`drug discovery, drug synthesis, and structure-activity 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, ¶¶ 26-34;
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`Ex. 1010, 289. The FDA had approved antimuscarinic agents for the treatment of
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`overactive bladder, including tolterodine tartrate marketed under the name Detrol®.
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`Ex. 1009. Detrol® was approved for commercial distribution on March 25, 1998 and
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`its label described the oxidation of tolterodine by cyctochrome P450 2D6 to 5-HMT.
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`Ex. 1025, 4. Detrol®ʼs label further states that “[b]oth tolterodine and 5-HMT
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`exhibit a high specificity for muscarinic receptors, since both show negligible activity
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`or affinity for other neurotransmitters . . . .” Ex. 1009, 2 (Clinical Pharmacology).
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`Tolterodine was the first drug specifically developed to treat overactive bladder
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`and thus distinguished itself from another prior art antimuscarinic compound,
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`oxybutynin. Ex. 1014, 528. Unlike tolterodine, oxybutynin led to dry mouth because
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`it had a higher selectivity for muscarinic receptors on salivary glands over receptors in
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`the bladder. Ex. 1015, 4. Tolterodine, and its primary, beneficial metabolite 5-HMT,
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`had selectivity for the bladder over receptors on salivary glands and thus tolterodine
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`exhibited a clinical advantage over 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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`tolterodineʼs 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 patientʼs
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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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`1 As explained infra, before the invention, other compounds that were not
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`antimuscarinic compounds – calcium antagonists, potassium channel antagonists, and
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`α-adrenoreceptors – were unproven as effective overactive bladder treatment. See also,
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`Ex. 1003, ¶¶ 26-34.
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`adverse events or nnegative drrug-drug intteractions.
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`(“Tolterrodine was associated with a dosse-depende
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` Id., 2, 7; EEx. 1007, 2991
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`nt increasee in heart raate, the onsset
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`of whichh was fairlyy rapid withh time to mmaximal effefect around 1.3 – 1.8 hh.”).
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`PPrior art ideentified the main metaabolic pathwways of tollterodine inn human livver
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`microsoomes. Ex. 11003, ¶¶ 366, 40, 44, annd 48-50. AAnderssonn described
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`how
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`tolteroddine underggoes stepwise oxidatioon of the 5--methyl grooup to yieldd the 5-HMMT
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`metabollite. Ex. 1014, 534. Sppecifically, as shown,
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`the cytochhrome catalyyst (P450 22D6)
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`oxidizess the 5-methyl to convvert tolteroodine into itts structuraally similar
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`active
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`metabollite. Id., Figg. 6 (Anderrsson); Ex. 1003, ¶ 688-69.
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`PPostlind exppressly noteed that the identificatiion of
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`the metaabolic catallyst and meechanism ““is of great
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`importaance to preddict potentiial drug intteractions aand
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`genetic vvariations iin drug mettabolism.”22 Ex. 10100, 289.
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`It was kknown that phenotypiccal differennces arisingg from
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`polymorrphism of tthe cyctochhrome catallyst (i.e.,
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`CYP2DD6) affect a number off drugs inclluding recepptor
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`2 As explained iinfra, other compoundds that mayy have showwn overactiive bladderr
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`treatmennt efficacy had knownn issues or unproven ppharmacollogically rellevant
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`85-91.
`characteeristics. Exx. 1003, ¶¶
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`antagonists and lead to interpatient variability of the efficacy of drugs that are acted
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`on by this pathway. Ex. 1010, 2992; Ex. 1003, ¶¶ 96-100. Postlind further confirmed
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`that CYP2D6 is responsible for the necessary oxidation to convert tolterodine to its
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`active metabolite, 5-HMT. Id.
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`C.
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`Prodrugs Were Known to Solve Active Compound Difficulties.
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`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. Ex.
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`1003, ¶¶ 74-76 and 102. The ability to demonstrate required safety and efficacy of an
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`entirely new compound may require wholly independent data collection that would be
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`unneeded or at least limited if prodrug optimization were pursued. Ex. 1026, 5.
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`Prodrug optimization thus focuses on active compounds already known rather
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`than examining compounds with untested, undemonstrated efficacy and safety. Ex.
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`1003, ¶¶ 80, and 106-109. Indeed, skilled artisans were aware of many examples of
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`approved prodrugs of known active compounds that reused and repurposed the
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`underlying data of the active compound. Id. at ¶¶ 108-109 The use of prodrugs was
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`likewise long known to improve difficulties associated with administering compounds.
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`Id. at ¶ 80; Ex. 1012, 1-2. For example, a compound that was too water soluble would
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`lack sufficient lipophilicity to enter the gut wall and be absorbed. Ex. 1003, ¶ 112-
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`113; Ex. 1012, 1-2. This was known to directly impact bioavailability. Id.
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`Given the known characteristics of 5-HMT, namely its poor lipophilicity (Ex.
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`1011, 538), as well as the knowledge of the skilled artisan of the use of prodrug
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`optimization to achieve better bioavailability through increasing lipophilicity, the
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`skilled artisan would have considered 5-HMT a good candidate for prodrug
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`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
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`lipophilic than the active metabolite – 5-HMT. Ex. 1011, 538; Ex. 1003, ¶¶ 55, 116-
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`118. Skilled artisans also knew that the lipid solubility, and, hence absorption of many
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`polar drug molecules may be improved by forming esters with short or long chain
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`aliphatic acids. Ex. 1012, , Ex. 1003, ¶¶ 56-62. Thus, skilled artisans at the time of
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`the invention would have understood from the relationship between 5-HMT and its
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`metabolic analog tolterodine that modifying 5-HMT would likely provide the
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`necessary protection for the prodrug to pass through the gut and be acted on by
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`enzymes for conversion to the desired active compound. Ex. 1003, ¶¶ 110-119.
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`Second, the skilled artisans would have known that such optimization of
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`compounds for improved bioavailability by protecting compounds from degradation
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`or improovising gutt absorptionn had beenn a routine aand predicttably succeessful approoach
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`for skilleed artisans since the laate 1990s. IId. As Bunndgaard expplained,
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`Prodrug research matuured as a brranch of phharmaceuticcal researchh during
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`hhe 1970s. OOver the past decade this chemiical approa
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`ch to optimmization
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`of drug delivvery has unndergone c
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`onsiderablee expansionn, largely a
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`eesult of an increased aawareness aand undersstanding of f the
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`ct the efficcacy of drugg delivery aand
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`cction. Seveeral drugs aare now useed clinicallyy in the forrm of proddrugs,
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`annd as the pprodrug appproach is b
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`ecoming ann integral ppart of the nnew
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`drug design process onne may exppect that thee new druggs in many
`cases
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`will appear aas prodrugs.
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`dw
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`Even more Ex. 10144, Intro. E
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`relevant heere, skilled
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`artisans knnew to creatte prodrug
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`containiing esters wwhen the deesired activve metaboliite possesseed a hydroxxyl or carbooxyl
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`group. IId. at 2 (“Inn the past, esters mostly have beeen consideered as pro
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`drug types,, and
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`in fact esteers of drugss containinng hydroxyll or carboxxyl
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`the bestt known proodrugs are
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`groups.””).
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`5-HMT wouuld have beeen an immmediate canndidate for pprodrug mmodificationn to
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`the skill
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`ed artisan bbecause “[tt]he populaarity of usinng esters as a prodrug
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`containiing carboxyyl or hydro
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`xyl functions
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`(or thioll groups) sttems primaarily from thhe
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`fact thatt the organiism is rich in enzyme
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`.” Id. at 4.
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`capable of hydrolyyzing esters
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`5-HMT
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`contains bboth a hydrroxyl and
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`type for drrugs
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`–OH grouups
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`11
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`carboxyyl group (as shown herre). Ex. 10010. In factt, the preseence of the
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`on the #2 and #5 carbons are the primary candidates for prodrug optimization
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`because when an ester group is hydrolyzed in the body, the result is an –OH group.
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`Ex. 1003, ¶ 110-12. As such, conversion of the –OH groups to esters as a prodrug
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`optimization are limited to the two –OH groups on 5-HMT. Id.
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`D. Numerous Salt Forms Were Known for Compounds Similar to the
`Most Effective Overactive Bladder Drugs.
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`Skilled artisans in 1998 knew that stabilizing compounds through the use of salt
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`forms was an iterative, routine process. Ex. 1027. The commercially available
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`administered compound for 5-HMT was a tartrate salt. Ex. 1009. Oxybutynin was
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`administered as a hydrochloride salt form. Ex. 1003, ¶ 27.
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`Likewise, multiple texts for drug development described how to select and
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`make salt forms of compounds for drug use. For example, Gould teaches how to
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`identify useful salts and prepare compounds including the hydrate forms. Ex. 1027.
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`Gould explains the benefits and outcomes of ester modification of a drug for prodrug
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`form explains that “[f]or a drug having ionizable functional groups, salt formation can
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`be a powerful tool in improving formulation properties. Salt formation is preferable
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`to covalent derivatization when the physiochemical property-related problem is one
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`affecting only the formulation, since salt formation is readily reversible upon
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`dissolution in vivo.” Id.
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`Finally, the number of approved salt forms was generally limited. Ex. 1013.
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`But, here, the candidate list was even smaller. The FDA approved label for
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`tolterodine disclosed an organic salt and other prior art publications disclosed a
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`substitutable genus that would have included the fumarate salt of 5-HMT. Ex. 1003,
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`¶¶ 131-132; Ex. 1005, 2:9-10.
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`VII. SCOPE AND CONTENT OF THE PRIOR ART
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`Under KSR Intʼl Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007), there can be no
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`rigid, formulary test to determine obviousness, instead it requires consideration of the
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`scope and content of the prior art as viewed by the person of ordinary skill in the art.
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`In chemical cases, “structural similarity between claimed and prior art subject matter,
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`proved by combining references or otherwise, where the prior art gives reason or
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`motivation to make the claimed compositions, creates a prima facie case of
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`obviousness.” In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990). “[I]t is the possession
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`of promising useful properties in a lead compound that motivates a chemist to make
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`structurally similar compounds.” Daiichi Sankyo Co. v. Matrix Labs., 619 F.3d 1346,
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`1354 (Fed. Cir. 2010). “[P]roving a reason to select a compound as a lead compound
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`depends on more than just structural similarity, but also knowledge in the art of the
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`functional propertie