UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`LIMITED,
`Petitioner,
`
`v.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case IPR2016-00510
`Patent 6,858,650 B1
`
`PATENT OWNER’S RESPONSE
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`IPR2016-00510
`Patent 6,858,650 B1
`
`
`TABLE OF CONTENTS
`
`I.
`Introduction .................................................................................................. 1
`Related Litigation ........................................................................................ 4
`II.
`III. The Petition .................................................................................................. 5
`IV. The ‘650 Patent and the ‘980 Patent Family ............................................... 6
`A.
`Specification and Claims of the ‘650 Patent ..................................... 6
`B.
`Critical Date for the ‘650 Patent ....................................................... 6
`C.
`Person of Ordinary Skill in the Art ................................................... 7
`D.
`Claim Construction for the ‘650 Patent ............................................ 7
`E.
`Prosecution of the ‘650 Patent .......................................................... 7
`F.
`The ‘980 Patent Family ..................................................................... 8
`G.
`Prosecution of the ‘980 Patent Family .............................................. 9
`
`V. Additional References Informing the Scope and Content of the Prior
`Art .............................................................................................................. 11
`A.
`Lin & Lu (Ex. 2028) ........................................................................ 11
`B.
`Brynne 1999 (Ex. 2029) .................................................................. 12
`C. Ashworth (Ex. 1018) ....................................................................... 13
`D.
`Bundgaard 1991 (Ex. 2015) ............................................................ 14
`
`VI. Claims 1-5 and 21-24 Are Not Invalid as Obvious Over the
`Combination of Postlind, the Bundgaard Publications, the Detrol®
`Label, and Berge ........................................................................................ 15
`A. Only Hindsight Explains Why a Skilled Artisan Would Have
`Selected Tolterodine and Then Set It Aside in Favor of 5-HMT ... 16
`
`1)
`2)
`
`3)
`
`Tolterodine Did Not Stand Out as a Lead Compound .......... 16
`Polymorphism Provided No Reason to Switch Focus
`from Tolterodine to 5-HMT .................................................. 18
`Any Adverse Events Associated with Detrol®
`(Tolterodine) Were, If Anything, Suggested as Tied to 5-
`HMT ...................................................................................... 23
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`IPR2016-00510
`Patent 6,858,650 B1
`B.
`Petitioner’s Own Prior Art Proves by a Preponderance That
`There Was No Expectation 5-HMT Would Have Insufficient
`Absorption or Bioavailability .......................................................... 26
`There Was No Reason for a Skilled Artisan to Pursue a Prodrug
`Design to Address the Alleged Bioavailability Problem ................ 31
`
`C.
`
`2)
`
`1)
`
`A Person of Ordinary Skill Would Have Known that
`Prodrug Design Is Disfavored ............................................... 32
`No Prodrug Teaching Existed in the Relevant Chemical,
`Biological, or Medical Classes of Compounds ..................... 34
`Petitioner’s References Neither Teach Nor Suggest the Specific
`Molecular Modifications to 5-HMT Resulting in Fesoterodine ..... 35
`
`1)
`
`2)
`
`3)
`
`Petitioner’s Suggestion to Synthesize and Test a Limited
`Number of “Simple” Alkyl Ester Prodrug Substituents Is
`Unsupported by the Prior Art ................................................ 37
`It Would Not Have Been Obvious for a Skilled Artisan to
`Modify the Phenolic 2-Position Carbon of 5-HMT .............. 41
`A Skilled Artisan Would Not Have Been Motivated To
`Use an Isobutyryl Ester and Would Have Had No
`Expectation of Success ......................................................... 44
`Postlind Does Not Teach the (R) Enantiomer of Fesoterodine ....... 49
`Berge’s General Disclosure Does Not Render the Claimed Salts
`of Fesoterodine, Especially the Hydrogen Fumarate Salt Form,
`Obvious ........................................................................................... 50
`The Prior Art Does Not Render Use of the Claimed Salts of
`Fesoterodine to Treat Overactive Bladder Obvious ........................ 54
`
`D.
`
`E.
`F.
`
`G.
`
`VII. Claims 1-5 and 21-24 Are Not Invalid as Obvious Over the
`Combination of Brynne 1998, the Bundgaard Publications, and
`Johansson ................................................................................................... 56
`A.
`Brynne 1998 Would Not Have Motivated a Person of Skill to
`Set Aside Tolterodine and Focus on 5-HMT .................................. 56
`The Bundgaard Publications Fail for the Same Reasons Stated
`Above .............................................................................................. 58
`Johansson’s Statement that Enantiomers Are Possible Does Not
`Teach the (R) Enantiomer of Fesoterodine ..................................... 58
`
`B.
`
`C.
`
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`IPR2016-00510
`Patent 6,858,650 B1
`D.
`Johansson’s Mention of a Fumarate Salt Does Not Render the
`Claimed Salts of Fesoterodine or Their Use To Treat
`Overactive Bladder Obvious ........................................................... 59
`
`VIII. Secondary Considerations Support a Finding of Nonobviousness ........... 61
`A.
`Fesoterodine Fumarate’s Unpredictable Properties Demonstrate
`the Non-Obviousness of Optimization ............................................ 61
`Fesoterodine Fumarate (Toviaz®) Has Several Unexpected
`Beneficial Properties and Met a Long Felt Need in the Field ......... 64
`
`B.
`
`IX. Conclusion ................................................................................................. 66
`
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`IPR2016-00510
`Patent 6,858,650 B1
`
`Table of Patent Owner’s Exhibits
`
`Ex. 2003
`
`Ex. 2004
`
`Ex. 2005
`
`Ex. 2001 Memorandum Opinion, Pfizer Inc. et al. v. Sandoz, Inc. et al, 13-cv-
`01110 (D. Del.).
`
`Ex. 2002 Declaration of William R. Roush.
`
`C.V. of William R. Roush.
`
`Lisbeth Nilvebrant et al., Tolterodine – A New Bladder Selective
`Muscarinic Receptor Antagonist: Preclinical Pharmacological and
`Clinical Data, 60 Life Sciences 1129 (1997) (“Nilvebrant 1997 II”).
`
`British Journal of Clinical Pharmacology (2011), 72(2), 235-246 – “A
`comprehensive non-clinical evaluation of the CNS penetration
`potential of antimuscarinic agents for the treatment of overactive
`bladder”; E. Callegari, B. Malhotra, P. Bungay, R. Webster, K.
`Fenner, S. Kempshall, J. LaPerle, M. Michel, G. Kay (“Callegari
`2011”).
`
`Trial Transcript, July 13-16, 2015, Pfizer Inc. et al. v. Sandoz, Inc. et
`al, 13-cv-01110 (D. Del.).
`
`The file history of United States Patent No. 7,384,980.
`
`Ex. 2008 Urodynamics: Principles, Practice and Application (1994), 43-70 –
`“Pharmacologic treatment of voiding dysfunction”; A.J. Wein, P.A.
`Longurst, R.M. Levin. (“Wein 1994”).
`
`Ex. 2009 Detrol® LA Label 2004.
`
`File History for U.S.P.N. 6,713,464.
`
`File History for U.S.P.N. 7,230,030.
`
`File History for U.S.P.N. 6,858,650.
`
`
`Ex. 2006
`
`Ex. 2007
`
`Ex. 2010
`
`Ex. 2011
`
`Ex. 2012
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`iv
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`
`Ex. 2017
`
`Ex. 2020
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`IPR2016-00510
`Patent 6,858,650 B1
`Ex. 2013
`Jeffrey P. Krise et al., Novel Prodrug Approach for Tertiary Amines:
`Synthesis and Preliminary Evaluation of N-Phosphonooxymethyl
`Prodrugs, 42 J. Med. Chem. 3094 (1999) (“Krise”).
`
`Ex. 2014 A.A. Sinkula et al., Rationale for Design of Biologically Reversible
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`
`Ex. 2015 Hans Bundgaard, Novel Chemical Approaches in Prodrug Design, 16
`Drugs of the Future 443 (1991) (“Bundgaard 1991”).
`
`Ex. 2016 Michael W. Jann et al., Clinical Pharmacokinetics of the Depot
`Antipsychotics, 10 Clinical Pharmacokinetics 315 (1985) (“Jann”).
`
`R. Beresford et al., Haloperidol Decanoate a Preliminary Review of
`Its Pharmacodynamic
`and Pharmacokinetic Properties
`and
`Therapeutic Use in Psychosis, 22 Drugs 31 (1987) (“Beresford”).
`
`Ex. 2018 United States Patent No. 7,384,980.
`
`Ex. 2019 United States Patent No. 6,858,650.
`
`Transcript of the Deposition of Steven Patterson, Ph.D., dated
`October 4, 2016, Case IPR2016-00510, Case IPR2016-00512, Case
`IPR2016-00514, Case
`IPR2016-00516, Case
`IPR2016-00517
`(“Patterson Tr.”).
`
`Ex. 2021 Declaration of Hans Maag, Sc.D.
`
`Ex. 2022 Declaration of William R. Roush, Ph.D.
`
`Ex. 2023 Declaration of Scott A. MacDiarmid, M.D., FRCPSC.
`
`Ex. 2024 Declaration of Leonard J. Chyall, Ph.D.
`
`Ex. 2025 Declaration of Claus O Meese, Ph.D.
`
`Transcript of the Deposition of Culley C. Carson III, M.D., dated
`August 25, 2016, C.A. No. 15-cv-0079 (D. Del.). (“Carson Tr.”)
`
`
`Ex. 2026
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`v
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`Ex. 2028
`
`Ex. 2030
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`IPR2016-00510
`Patent 6,858,650 B1
`Ex. 2027
`Transcript of the Deposition of David R. Janero, Ph.D., dated August
`16, 2016, C.A. No. 15-cv-0079 (D. Del.).
`
`Jiunn H. Lin & Anthony Y.H. Lu, Role of Pharmacokinetics and
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`
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`
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`
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`
`Lisbeth Nilvebrant et al., Tolterodine – A New Bladder-Selective
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`
`J. Andrew Fantl et al., Urinary Incontinence in Adults: Acute and
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`
`Ex. 2037
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`vi
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`Ex. 2040
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`Patent 6,858,650 B1
`Ex. 2038 H. Madersbacher et al., A Urodynamically Controlled Multicenter
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`Patent 6,858,650 B1
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`
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`
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`
`C.V. of Leonard J. Chyall, Ph.D.
`
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`
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`20, 1998.
`
`“Timetable of the development of Fesoterodine.”
`
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`10, 1998.
`
`“Chemical Development Plan, Incontinence Project,” dated February
`24, 1999.
`
`“Laborjournal: A. Cawello,” dated August 19, 1999.
`
`“NCE-Incontinence Meeting,” dated May 28, 1999.
`
`“Some information about SPM 8224” & “Some information about
`SPM 8272.”
`
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`
`
`Ex. 2098
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`Ex. 2100
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`Ex. 2101
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`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`C.R. Bard Inc. v. M3 Sys. Inc.,
`157 F.3d 1340 (1998) .......................................................................................... 42
`
`Circuit Check Inc. v. QXQ Inc.,
`795 F.3d 1331 (Fed. Cir. 2015) .................................................................... 35, 47
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .............................................................. 16, 30, 33
`
`Daiichi Sankyo Co. v. Mylan Pharm. Inc.,
`670 F. Supp. 2d 359 (D.N.J. 2009) ..................................................................... 33
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 30
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 51
`
`Ferrum Ferro Capital, LLC v. Allergan Sales, LLC,
`No. IPR2015-00858, 2015 Pat. App. LEXIS 12725 (P.T.A.B. Sept.
`21, 2015) ............................................................................................................. 25
`
`In re Applied Materials,
`692 F.3d 1284 (Fed. Cir. 2012) .......................................................................... 45
`
`In re Chapman,
`595 F.3d 1330 (Fed. Cir. 2010) .......................................................................... 30
`
`In re Deuel,
`51 F.3d 1552 (Fed. Cir. 1995) ............................................................................ 37
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ............................................................................ 37
`
`In re Rosuvastatin Calcium Patent Litig.,
`703 F.3d 511 (Fed. Cir. 2012) ................................................................ 37, 41, 61
`
`xiii
`
`
`
`

`
`IPR2016-00510
`Patent 6,858,650 B1
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 30
`
`Merck Sharp & Dohme v. Sandoz Inc.,
`No. 12-cv-03289-PGS, 2015 WL 5089543 (D.N.J. Aug. 27, 2015) .................. 33
`
`Monarch Knitting Mach. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 31
`
`Novartis Pharm. Corp. v. Watson Labs., Inc.,
`No. 2014-1799, 2015 U.S. App. LEXIS 8374 (Fed. Cir. May 21,
`2015) ................................................................................................................... 26
`
`Pfizer, Inc. and UCB Pharma GmbH v. Mylan Pharmaceuticals, Inc.,
`No. 1:15-cv-00013-IMK (N.D.W.Va.) ................................................................. 4
`
`Pfizer, Inc. and UCB Pharma GmbH v. Mylan Pharmaceuticals, Inc.,
`No. 1:15-cv-00079-GMS (D. Del.) ....................................................................... 4
`
`Pfizer Inc., et al. v. Mylan Pharm. Inc.,
`71 F. Supp.3d 458, 474 (D. Del. 2014) ............................................................... 52
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .............................................................. 51, 52, 55
`
`Pfizer Inc. v. Sandoz Inc.,
`2016 WL 1611377 (D. Del. Apr. 20, 2016) ................................................passim
`
`Pfizer Inc. v. Teva Pharm. U.S.A., Inc.,
`882 F. Supp. 2d 643 (D. Del. 2012) .................................................................... 59
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) .....................................................................passim
`
`Roche Palo Alto LLC v. Ranbaxy Labs. Ltd,
`No. 06-cv-2003, 2009 WL 3261252 (D.N.J. Sept. 30, 2009) ............................ 33
`
`Sanofi-Aventis Deutschland GmbH v. Glenmark Pharma. Inc.,
`748 F. 3d 1354 (Fed. Cir. 2014) ......................................................................... 49
`
`Sanofi-Synthelabo v. Apotex Inc.,
`492 F.Supp.2d 353 (S.D.N.Y. 2007), aff’d, 550 F.3d 1075 (Fed.
`Cir. 2008) ...................................................................................................... 50, 52
`
`xiv
`
`
`
`

`
`IPR2016-00510
`Patent 6,858,650 B1
`Shire LLC v. Amneal Pharms. LLC,
`802 F.3d 1301 (Fed. Cir. 2015) .................................................................... 53, 60
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ...................................................................passim
`
`UCB, Inc. v. Accord Healthcare, Inc.,
`13-cv-1206-LPS, 2016 WL 4376346 (D. Del. Aug. 15, 2016) .......................... 65
`
`Valeant Int’l (Barbados) SLR v. Watson Pharm. Inc.,
`No. 10-20526-CIV, 2011 WL 6792653 (S.D. Fla. Nov. 8, 2011),
`aff’d 534 F. App’x 999 (Fed. Cir. 2013) ............................................................ 52
`
`Winner Int’l Royalty Corp. v. Wang,
`202 F.3d 1340 (Fed. Cir. 2000) .......................................................................... 21
`
`Yamanouchi Pharm. Co. v. Danbury Pharm., Co.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 62
`
`STATUTES AND RULES
`
`37 C.F.R. § 42.65(a) ................................................................................................. 43
`
`37 C.F.R. § 42.104(b)(4),(5) ............................................................................ 2, 3, 54
`
`37 C.F.R. § 42.104(b)(5) .................................................................................... 31, 50
`
`35 U.S.C. § 103(a) ..................................................................................................... 7
`
`35 U.S.C. § 316(a)(8) ................................................................................................. 1
`
`35 U.S.C. § 316(e) ..................................................................................................... 3
`
`
`
`xv
`
`
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`

`
`
`
`
`
`I.
`
`Introduction
`
`On July 20, 2016, the Patent Trial and Appeal Board (the “Board”) instituted
`
`Petitioner Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited’s
`
`(collectively, “Mylan” or “Petitioner”) Petition for Inter Partes Review of claims
`
`1-5 and 21-24 of U.S. Patent No. 6,858,650 (the “‘650 Petition”). Paper 12.
`
`Pursuant to 35 U.S.C. §316(a)(8), UCB Pharma GmbH (“Respondent” or “UCB”)
`
`submits this Patent Owner Response.
`
`Petitioner’s challenge to U.S. Patent No. 6,858,650 (the “‘650 patent”)
`
`alleges that fesoterodine fumarate, a specific salt form of the compound
`
`fesoterodine, would have been obvious. Because the compound fesoterodine is not
`
`prior art to the ‘650 patent, Petitioner must first demonstrate that fesoterodine itself
`
`would have been obvious. This is a showing that Petitioner cannot make.
`
`As detailed in the Patent Owner’s Preliminary Response, Petitioner’s
`
`assertion of obviousness requires a person of ordinary skill to follow at least six
`
`steps to arrive at fesoterodine fumarate. Paper 9 at 2-6. Petitioner has not
`
`identified teachings in the prior art to support taking any of these suggested steps,
`
`much less all of them. Nor would a person of ordinary skill have had an
`
`expectation that performing Petitioner’s steps would have led to a successful
`
`compound. Petitioner has not carried its burden of showing where each element of
`
`the claimed invention is found in the prior art, nor has it identified specific portions
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`of the evidence that support its challenge. 37 C.F.R. §42.104(b)(4),(5). As
`
`described in greater detail herein, Petitioner fails to meet its burden at every step
`
`along its proposed path to fesoterodine. Several key shortcomings of its
`
`obviousness analysis are highlighted below:
`
`First, Petitioner’s proffered reason to lead with tolterodine’s metabolite, 5-
`
`HMT – tolterodine’s variable metabolism due to CYP2D6 polymorphism – was
`
`probed in the prior art clinical development of Detrol® (tolterodine). CYP2D6
`
`polymorphism was consistently found to be inconsequential for tolterodine,
`
`including in the Detrol® Label (Ex. 1009) and in Brynne 1998 (Ex. 1011), both
`
`relied on by Petitioner. If CYP2D6 polymorphism was not a problem for
`
`tolterodine it would not have prompted a shift in focus from tolterodine to its
`
`active metabolite, 5-HMT.
`
`Second, Petitioner’s proffered reason to modify 5-HMT – its purported poor
`
`oral absorption – is a fiction. 5-HMT’s oral absorption had never been measured,
`
`nor did the prior art even suggest it to be problematic. If anything, the prior art
`
`suggests that 5-HMT would be well-absorbed.
`
`Third, arriving at fesoterodine requires selecting and modifying the phenolic
`
`2-position on 5-HMT’s phenyl ring for substitution. The only prior art teaching
`
`specific to phenolic substitutions, Bundgaard 1991 (Ex. 2015), singles them out not
`
`
`
`2
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`for their success or ease, but rather as substitutions in need of additional research.
`
`If anything, the caution of Bundgaard 1991 would have prompted a person of
`
`ordinary skill to consider a substitution elsewhere.
`
`Fourth, the law requires that Petitioner be able to show that it would have
`
`been obvious to make the “specific molecular modifications” necessary to arrive at
`
`the claimed compound. See infra Sections VI.D.1; VI.D.3. The law also requires
`
`that Petitioner be able to specify where each claim element is disclosed in the prior
`
`art. 37 C.F.R. §42.104(b)(4),(5). Yet, Petitioner does not even attempt to show
`
`that the phenolic mono-isobutyryl substitution of 5-HMT (necessary to arrive at
`
`fesoterodine) is taught anywhere in the prior art. Petitioner instead proposes that a
`
`person of ordinary skill could have arrived at fesoterodine and its requisite prodrug
`
`properties, through “optimization.” ‘650 Petition at 19-20. Even if a person of
`
`ordinary skill had followed Petitioner’s proposed steps, those steps would only
`
`lead to analogs of the claimed compound with unknown properties, far short of the
`
`“specific molecular modifications” the law requires.
`
`The full record will show that Petitioner has not met its burden of proving
`
`unpatentability by a preponderance of the evidence as required under 35 U.S.C.
`
`§316(e). Accordingly, the Board should confirm patentability of claims 1-5 and
`
`21-24 of the ‘650 patent.
`
`
`
`3
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`IPR2016-00510
`Patent 6,858,650 B1
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`
`
`II.
`
`Related Litigation
`
`After receiving notice from Petitioner of an intent to launch a generic
`
`version of the overactive bladder treatment Toviaz®, UCB and its exclusive
`
`licensee, Pfizer Inc., asserted the ‘650 patent, as well as U.S. Patent Nos.
`
`7,384,980, 7,855,230, 7,985,772, and 8,338,478 (collectively, the “‘980 patent
`
`family”)1, against Petitioner in the actions 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., No. 1:15-cv-00013-IMK
`
`(N.D.W.Va.). The West Virginia action is stayed, while the Delaware action is
`
`scheduled for trial on January 23, 2017.
`
`Petitioner is not the first to challenge the Toviaz® patents. In July 2015,
`
`UCB and Pfizer asserted these patents at trial in the U.S. District Court for the
`
`District of Delaware against four other challengers (the “First-Filers”), who, like
`
`Petitioner, sought to invalidate the Toviaz® patents and market generic versions of
`
`Toviaz®. Petitioner essentially appropriates the First-Filers’ case, which relied on
`
`the Detrol® Label (Ex. 1009) and Brynne 1998 (Ex. 1011) to assert that tolterodine
`
`was an