`
`In the United States Patent and Trademark Office
`
`
`
`
`
`
`
`
`Before the Patent Trial and Appeal Board
`
`AMERIGEN PHARMACEUTICALS LIMITED,
`
`Petitioner
`
`v.
`
`UCB PHARMA GMBH
`
`
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`U.S. 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
`
`
`
`
`
`
`
`Title: COMPOSITIONS AND METHODS FOR TREATMENT OF BOWEL DISEASES
`
`Inter Partes Review No.: Unassigned
`WITH GRANULATED MESALAMINE
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.100 ET SEQ.
`
`
`1
`
`
`
`
`
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`
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`

`

`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ......................................................................................... 8
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 8
`
`A.
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) .....................................................8
`
`B.
`
`C.
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ..............................................................9
`
`Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ...........................................9
`
`D.
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)...................................................... 10
`
`III. GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 and 42.104)................10
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.103) .................................................11
`
`V. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ...........................................11
`
`VI. SUMMARY OF THE ‘650 PATENT AND CHALLENGED CLAIMS ......13
`
`VII. CLAIM CONSTRUCTION ..........................................................................14
`
`VIII. TECHNICAL BACKGROUND AND STATE OF THE ART .....................14
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Person of Ordinary Skill in the Art of the ‘650 Patent .......................................... 14
`
`Before the Invention, Antimuscarinic Compounds Were Used to Treat Overactive
`
`Bladder Conditions .................................................................................................... 14
`
`Prodrugs Were Known to Solve Active Compound Difficulties .................................. 17
`
`Numerous Salt Forms Were Known for Compounds Similar to the Most Effective
`
`Overactive Bladder Drugs .......................................................................................... 21
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART .........................................22
`
`A.
`
`Skilled Artisans Had Ample Motivation to Focus on Optimizing 5-HMT to Obtain
`
`an Overactive Bladder Compound .............................................................................. 22
`
`1.
`
`2.
`
`Postlind, the Detrol® Label, and Brynne 1998 Taught 5-HMT Was an
`Effective Compound for Overactive Bladder without Tolterodine. ........................ 22
`
`Skilled Artisans Would Immediately Recognize the Benefit to Starting with
`their Knowledge of 5-HMT and Tolterodine and Not Other Compounds. .............. 24
`
`Bundgaard Taught Predictable Modifications to Improve 5-HMT Delivery ................ 26
`
`Berge and Johansson Taught Fumarate Salts .............................................................. 29
`
`2
`
`B.
`
`C.
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`X. DETAILED GROUNDS FOR UNPATENTABILITY.................................30
`
`A.
`
`Claims 1-5 are Obvious Over the Postlind and Bundgaard Publications in view of
`
`the Detrol® Label and Berge ...................................................................................... 30
`
`1.
`
`2.
`
`A Person of Ordinary Skill Would Have Been Motivated to Look at Improved
`5-HMT Administration in View of Tolterodine. ..................................................... 31
`
`Postlind and Bundgaard Publications in View of the Detrol® Label and Berge
`Would Have Led to Prodrug Optimization and Fumarate Salt Forms. .................. 34
`
`3.
`
`Summary of Proposed Rejection of Claims 1-5. .................................................... 40
`
`B.
`
`Claims 21-24 are Obvious over the Postlind and Bundgaard Publications in view of
`
`the Detrol® Label and Berge. ..................................................................................... 48
`
`C.
`
`Claims 1-5 and 21-24 Are Rendered Obvious by Brynne 1998, Bundgaard, and
`
`Johansson ................................................................................................................... 53
`
`1.
`
`2.
`
`A Person of Ordinary Skill Would Have Been Motivated to Look at Improved
`5-HMT Administration in View of Tolterodine. ..................................................... 53
`
`Brynne 1998 in View of Bundgaard and Johansson Would Have Led to
`Prodrug Optimization and Fumarate Salt Forms. ................................................. 54
`
`XI. EVEN IF CONSIDERED, SECONDARY CONSIDERATIONS FAIL TO
`OVERCOME THE EVIDENCE OF OBVIOUSNESS .................................63
`
`XII. THE PROPOSED REJECTIONS RAISE NEW ISSUES IN WHICH
`PETITIONER WILL LIKELY PREVAIL ....................................................68
`
`
`
`
`
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`3
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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: “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
`
`
`Ex. 1007:
`
`“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),
`289293 – “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
`
`
`
`4
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`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”
`
`Ex. 1013:
`
`“Berge 1977” – Journal of Pharmaceutical Sciences (1977), 66
`(1), 1-19 – “Pharmaceutical Salts”; S. Berge, L., Bighley, and
`D. Monkhouse
`
`
`Ex. 1014:
`
`
`Ex. 1015:
`
`
`Ex. 1016:
`
`
`Ex. 1017:
`
`
`Ex. 1018:
`
`
`Ex. 1019:
`
`Ex. 1020:
`
`
`Ex. 1021:
`
`
`
`“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
`Education and Research (2014) – “Diagnosis and Treatment of
`Overactive Bladder (Non-Neorogenic) in Adults: AUA/SUFU
`Guideline”; E. Gormley, et al
`
`5
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`

`
`
`Ex. 1022:
`
`
`Ex. 1023:
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`“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
`
`“PM360” – April 1, 2012 “Overactive Bladder Market:
`Managing the Future” – www. pm360online.com
`
`“Toviaz® Label” – Pfizer Labs
`
`
`Ex. 1024:
`
`Ex. 1025: “FDA Approval Letter” –NDA 20-771
`
`Ex. 1026:
`
`“FDA Guidance” – Applications Covered by Section 505(b)(2)
`– October 1999 – FDA (CDER)
`
`
`Ex. 1027:
`
`
`Ex. 1028:
`
`
`Ex. 1029:
`
`
`Ex. 1030:
`
`“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. 1317, 1997)
`
`“Goldberg” – DuP 532, an angiotensin II receptor antagonist:
`First administration and comparison with losartan, Clinical
`Pharmacology & Therapeutics, January 1997
`
`
`Ex. 1031: “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-cv00079-GMS, Pfizer, et al v Mylan Pharmaceutical Inc.
`(Dist. of DE)
`
`
`Ex. 1033: Declaration of DeForest McDuff, Ph.D.
`
`
`
`
`6
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
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`Ex. 1034: CV for DeForest McDuff, Ph.D.
`
`Ex. 1035: Toviaz: Don’t 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)
`
`
`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)
`
`
`
`
`
`7
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`

`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`
`I.
`
`INTRODUCTION
`
`Through its counsel, real party in interest Amerigen Pharmaceuticals, Ltd.
`
`(“Petitioner”) requests that the Board institute inter partes review (“IPR”) of U.S.
`
`Patent No. 6,858,650, entitled “STABLE SALTS OF NOVEL DERIVATIVES OF
`
`3,3-DIPHENYLPROPYLAMINES” (“the ‘650 Patent”). Ex. 1001. The ‘650
`
`Patent was asserted against Petitioner in a prior federal district court litigation,
`
`Pfizer, Inc. and UCB Pharma GMBH v. Sandoz, Inc., et al., No. 1:13-cv-01110
`
`GMS (D. Del.). Inter partes review of claims 1, 2-5 and 21-24 of the ‘650 Patent
`
`was instituted in IPR2016-00510 on July 20, 2016, based on a petition filed by
`
`Mylan Pharmaceuticals Inc. Petitioner adopts and presents in this Petition each of
`
`the positions advanced in IPR2016-00510. For convenience and efficiency, each
`
`of arguments set forth in IPR2016-00510, is republished herein. A Motion for
`
`Joinder with IPR2016-00510 is being filed concurrently with this petition in
`
`accordance with 37 C.F.R. § 42.122(b) and 35 U.S.C. §315(c).
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`
`Petitioner provides the following mandatory notices under 37 C.F.R. §§
`
`42.8(a)(1) and 42.8(b).
`
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner hereby certifies that Amerigen
`
`Pharmaceuticals Limited (“Amerigen”) is the only real party in interest for this
`
`
`
`8
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`

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`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`petition. No other entity or person other than Petitioner has authority to direct or
`
`control Petitioner’s actions or decisions relating to this petition. Petitioner is
`
`funding all of the fees and costs of this petition for inter partes review. Petitioner
`
`submits that while Pfizer, Inc. (“Pfizer”) is not an owner of the ‘650 Patent, Pfizer
`
`is the NDA holder as asserted in related matters and Petitioner thus identifies
`
`Pfizer as an interested party here.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`
`Petitioner identifies the following related matters:
`
`The ‘650 Patent was earlier asserted against Petitioner in the action styled
`
`Pfizer, Inc. and UCB Pharma GMBH v. Sandoz, Inc., et al., No. 1:13-cv-01110
`
`GMS (D. Del.). The following pending actions also involve the ‘650 Patent:
`
`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 00013-IMK (N.D. W.Va.).
`
`C.
`
`Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`Lead Counsel
`William Hare
`(Reg. No. 44,739)
`McNeely Hare & War LLP
`12 Roszel Road, Suite C104,
`Princeton, NJ 08540
`Telephone: (202) 640-1801
`Fax: (202) 478-1813
`bill@miplaw.com
`
`
`
`Back-Up Counsel
`Renita S. Rathinam
`(Reg. No 53,502)
`McNeely Hare & War LLP
`5335 Wisconsin Avenue, NW
`Suite 440
`Washington D.C. 20015
`Telephone: (202) 253 4903
`Fax: (202) 478-1813
`rathinam@miplaw.com
`
`9
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`

`
`
`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`Gabriela Materassi
`(Reg. No. 47,774)
`McNeely Hare & War LLP
`12 Roszel Road, Suite C104,
`Princeton, NJ 08540
`Telephone: (347) 684-4154
`Fax: (202) 478-1813
`materassi@miplaw.com
`
`
`A power of attorney is being filed with the designation of counsel in
`
`accordance with 37 C.F.R. § 42.10(b).
`
`D.
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`
`Documents may be delivered by hand to the addresses of lead and back-up
`
`counsel as indicated above and in the attached Certificate of Service. Petitioner
`
`consents to electronic service by e-mail at the above listed email addresses of Lead
`
`and Back-Up Counsel (bill@miplaw.com, materassi@miplaw.com, and
`
`rathinam@miplaw.com).
`
`III. GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 and 42.104)
`
`Petitioner hereby certifies that IPR is available for the ‘650 Patent and that
`
`Petitioner is not barred or estopped from requesting an IPR challenging the patent
`
`claims on the instituted grounds identified in this Petition because a motion for
`
`joinder has been filed to join IPR2016-00510 no later than one month after
`
`institution in accordance with 37 C.F.R. § 42.122(b) and 35 U.S.C. §315(c).
`
`
`
`10
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`

`

`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`The required fees for this petition are submitted herewith via online
`
`payment. The Office is authorized to charge any fee deficiencies and credit
`
`overpayments to Deposit Acct. No. 502923, Customer ID No. 32687.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`
`Pursuant to 35 U.S.C. §311, this petition requests inter partes review and
`
`cancellation of claims 1-5 and 21-24 of the ‘650 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 ‘650 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 ‘650
`
`Patent is November 15, 2000 and the critical date under 35 U.S.C. § 102(b) is
`
`November 15, 1999.
`
`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) and
`
`(b).
`
`
`
`11
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`
`
`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
`
`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 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 before May 11, 1998, and thus is prior art under 35 U.S.C. § 102(a) and (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
`
`efficacy of the 5-HMT “prodrug-like” starting compound, the art demonstrates it
`
`would have been obvious to a person of ordinary skill in the art at the time of the
`
`invention to make a single, suggested modification (Bundgaard) to the active
`
`
`
`12
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`metabolite to achieve the claimed compound. All other aspects of the challenged
`
`claims such as salt choice, etc., would naturally follow the development of a prod-
`
`drug with a known, desired active metabolite.
`
`VI. SUMMARY OF THE ‘650 PATENT AND CHALLENGED CLAIMS
`
`The ‘650 Patent describes derivatives of 3,3-diphenylpropylamines and salt
`
`forms. Ex. 1001, 1:10-14. Claim provides a generic structure for the covered
`
`molecule reproduced here:
`
`
`
`According to the claim, “R denotes C1-C6 –alkyl, C3-C10 –cycloalkyl,
`
`substituted or unsubstituted phenyl and X- is the acid residue of physiological
`
`compatible inorganic or organic acid.” Id., Claim 1.
`
`Claims 2-5 further specify the type of compatible acid (claims 2 and 4),
`
`adding specific chirality (claim 3), and two specific substitutions and salt forms
`
`(claim 5). Specifically, claim 5 lists R-(+)-2-(3-(diisopropylamino- 1 -
`
`phenylpropyl)-4-hydroxymethyl-phenyliobutyrate ester hydrogen fumarate. This
`
`
`
`13
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`Petition for Inter Partes Review of U.S. Patent 6,858,650
`
`is commonly referred to as fesoterodine fumarate. Ex. 1003, ¶ 13. Claims 21-24
`
`recite methods of use.
`
`VII. CLAIM CONSTRUCTION
`
`The claims in the ‘650 Patent are presumed to take on their ordinary and
`
`customary meaning based on the broadest reasonable interpretation of the claim
`
`language. 37 C.F.R. § 42.100(b).
`
`VIII. 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,
`
`medicinal chemistry, pharmacology, or a related field, and at least one year of
`
`industrial exposure to drug discovery, drug design, and synthesis. In lieu of an
`
`advanced degree, the individual may have additional years of industry experience,
`
`including, for example, in drug discovery, drug synthesis, and structure-activity
`
`work. Ex. 1003, ¶ 23.
`
`B.
`
`Before the Invention, Antimuscarinic Compounds Were Used to
`Treat Overactive Bladder Conditions
`
`Long before the invention, it was known muscarinic receptors play a role in
`
`urinary bladder smooth muscle contractions and salivary activity. Ex. 1003, ¶¶ 26-
`
`34; Ex. 1010, 289. The FDA had approved antimuscarinic agents for the treatment
`
`of overactive bladder, including tolterodine tartrate marketed under the name
`
`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 cytochrome P450
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`2D6 to 5-HMT. Ex. 1025, 4. Detrol®ʼs 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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`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 patient’s
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`plasma. Ex. 1009, 2. Artisans also knew tolterodine possessed its own activity
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`1 As explained infra, before the invention, other compounds that were not
`antimuscarinic compounds – calcium antagonists, potassium channel antagonists,
`and α-adrenoreceptors – were unproven as effective overactive bladder treatment.
`See also Ex. 1003, ¶ 26-34.
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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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`Postlind expressly noted that the identification of the metabolic catalyst and
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`mechanism “is of great importance to predict potential drug interactions and
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`genetic variations in drug metabolism.”2 Ex. 1010, 289. It was known that
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`phenotypical differences arising from polymorphism of the cytochrome catalyst
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`(i.e., CYP2D6) affect a number of drugs including receptor antagonists and lead to
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`interpatient variability of the efficacy of drugs that are acted on by this pathway.
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`Ex. 1010, 2992; Ex. 1003, ¶¶ 96-100. Postlind further confirmed that CYP2D6 is
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`responsible for the necessary oxidation to convert tolterodine to its active
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`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.
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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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`2 As explained infra, other compounds that may have shown overactive
`bladder treatment efficacy had known issues or unproven pharmacologically
`relevant characteristics. Ex. 1003, ¶¶ 85-91.
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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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`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
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`more lipophilic than the active metabolite — 5-HMT. Ex. 1011, 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, the skilled artisans would have known that such optimization of
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`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 for skilled artisans since the late 1990s. Id. As Bundgaard
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`explained,
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`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.
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`Ex. 1014, Intro. Even more relevant here, skilled artisans knew to create prodrugs
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`containing esters when the desired active metabolite possessed a hydroxyl or
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`carboxyl group. Id. at 2 (“In the past, esters mostly have been considered as
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`prodrug types, and the best known prodrugs are in fact esters of drugs containing
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`hydroxyl or carboxyl groups.”).
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`5-HMT would have been an immediate candidate for prodrug modification
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`to the skilled artisan because “[t]he popularity of using esters as a prodrug type for
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`drugs containing carboxyl or hydroxyl functions (or thiol groups) stems primarily
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`from the fact that the organism is rich in enzymes capable of hydrolyzing esters.”
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`Id. at 4.
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`
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`5-HMT contains both a hydroxyl and carboxyl group (as shown here). Ex.
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`1010. In fact, the presence of the —OH groups on the #2 and #5 carbons are the
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`primary candidates for prodrug optimization because when an ester group is
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`hydrolyzed in the body, the result is an —OH group. Ex. 1003, ¶ 110-12. As such,
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`conversion of the —OH groups to esters as a prodrug optimization are limited to
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`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
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`salt 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.
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`1027. Gould explains the benefits and outcomes of ester modification of a drug for
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`prodrug form explains that “[f]or a drug having ionizable functional groups, salt
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`formation can be a powerful tool in improving formulation properties. Salt
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`formation is preferable to covalent derivatization when the physiochemical
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`property-related problem is one affecting only the formulation, since salt formation
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`is readily reversible upon 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.
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`1003, ¶¶ 131-132; Ex. 1005, 2:9-10.
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`IX. SCOPE AND CONTENT OF THE PRIOR ART
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`Under KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007), there can be
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`no rigid, formulary test to determine obviousness, instead it requires consideration
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`of the scope and content of the prior art as viewed by the person of ordinary skill in
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`the art. In chemical cases, “structural similarity between claimed and prior art
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`subject matter, proved by combining references or otherwise, where the prior art
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`gives reason or motivation to make the claimed compositions, creates a prima facie
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`case of obviousness.” In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990). “[I]t is the
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`possession of promising useful properties in a lead compound that motivates a
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`chemist to make structurally similar compounds.” Daiichi Sankyo Co. v. Matrix
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`Labs., 619 F.3d 1346, 1354 (Fed. Cir. 2010). “[P]roving a reason to select a
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`compound as a lead compound depends on more than just structural similarity, but
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`also knowledge in the art of the functional properties and limitations of the prior
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`art compounds.” Id. (emphasis added) (citing Eli & Co. v. Zenith Goldline
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`Pharms., Inc., 471 F.3d 1369, 1377-79).
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`A.
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`Skilled Artisans Had Ample Motivation to Focus on Optimizing 5-
`HMT to Obtain an Overactive Bla