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
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`PATENT OWNER PRELIMINARY RESPONSE
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`IPR2016-00510
`Patent 6,858,650 B1
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`TABLE OF CONTENTS
`I.
`Introduction .................................................................................................. 1
`The Petition .................................................................................................. 6
`II.
`III. The “First-Filer” Action .............................................................................. 7
`IV. The ‘650 Patent and the ‘980 Patent Family ............................................... 8
`A.
`Specification and Claims of the ‘650 Patent ..................................... 8
`B.
`Critical Date for the ‘650 Patent ....................................................... 9
`C.
`Person of Ordinary Skill in the Art ................................................... 9
`D.
`Claim Construction for the ‘650 Patent ............................................ 9
`E.
`Prosecution of the ‘650 Patent .......................................................... 9
`F.
`The ‘980 Patent Family ................................................................... 10
`G.
`Prosecution of the ‘980 Patent Family ............................................ 11
`
`V.
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`B.
`
`C.
`
`Claims 1-5 and 21-24 Are Not Obvious in View of Postlind and
`Bundgaard in view of the Detrol® Label and Berge ................................. 13
`A.
`Persons of Ordinary Skill Had No Reason to Set Aside
`Tolterodine and Seek to Focus on 5-HMT ...................................... 13
`5-HMT Possesses No Absorption or Bioavailability Problem
`That Requires Modification ............................................................ 17
`Persons of Ordinary Skill Would Have Had No Reason to
`Pursue a Prodrug Design to Address the Alleged Bioavailability
`Problem ........................................................................................... 21
`Even if Persons of Ordinary Skill Chose to Design a Prodrug of
`5-HMT, Petitioner’s Cited Prior Art Neither Teaches Nor
`Suggests the Specific Molecular Modifications to 5-HMT that
`Resulted in Fesoterodine ................................................................. 23
`
`D.
`
`1)
`
`2)
`
`3)
`
`Petitioner’s Suggestion to Synthesize and Test a Limited
`Number of Prodrug Substituents Is Unsupported by the
`Prior Art ................................................................................ 24
`A Person of Ordinary Skill Would Not Have Known to
`Modify the #2-Position Carbon of 5-HMT ........................... 27
`A Person of Ordinary Skill in the Art Would Have Had
`No Motivation to Use an Isobutyryl Ester and Would
`Have Had No Expectation of Success .................................. 29
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`Patent 6,858,650 B1
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`E.
`F.
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`G.
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`Postlind Does Not Teach the (R) Enantiomer of Fesoterodine ....... 32
`Fesoterodine’s Unpredictable Properties Compared to Other 5-
`HMT Candidate Prodrugs Demonstrate the Non-Obviousness
`of Optimization ................................................................................ 33
`Berge’s General Disclosure of Salts Does Not Render the
`Claimed Salts of Fesoterodine, and Especially the Fumarate
`Salt Form, Obvious.......................................................................... 35
`
`VI. Claims 1-5 and 21-24 Are Not Invalid as Obvious over the Brynne
`(1998) and Bundgaard Publications in View of Johansson ....................... 39
`A.
`Brynne 1998 Teaches Nothing to Motivate a Person of Skill to
`Set Aside Tolterodine and Focus on 5-HMT .................................. 39
`Bundgaard Fails for the Same Reasons Stated Above .................... 41
`Johansson’s Statement that Enantiomers Are Possible Does Not
`Teach the (R) Enantiomer of Fesoterodine ..................................... 41
`Johansson’s Mention of a Fumarate Salt Does Not Render
`Claim 5, and Claims Dependent Thereon, Unpatentable ................ 42
`
`B.
`C.
`
`D.
`
`VII. Pursuant to 35 U.S.C. §325(d), the Board Should Exercise Its
`Discretion and Deny The Petition Due to Prior Consideration by the
`USPTO ....................................................................................................... 43
`VIII. Conclusion ................................................................................................. 47
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`Patent 6,858,650 B1
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`Ex. 2001
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`Ex. 2002
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`Ex. 2003
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`Ex. 2004
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`Ex. 2005
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`Ex. 2006
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`Ex. 2007
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`Ex. 2008
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`Ex. 2009
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`Ex. 2010
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`Ex. 2011
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`Ex. 2012
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`Table of Exhibits
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`Memorandum Opinion, Pfizer Inc., et al. v. Sandoz Inc., et al.,
`No. 1:13-cv-01110-GMS (D. Del. Apr. 20, 2016), ECF No. 304
`
`Declaration of William R. Roush, Ph.D.
`
`C.V. for William R. Roush, Ph.D.
`
`“Nilvebrant 1997 II” – Life Sciences (1997), 60(13/14), 1129-
`1136 – “Tolterodine – A New Bladder Selective Muscarinic
`Receptor Antagonist: Preclinical Pharmacological and Clinical
`Data”; L. Nilvebrant, B. Hallen, G. Larsson
`
`“Callegari 2011” – 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
`
`Trial Transcripts, Pfizer Inc., et al. v. Sandoz Inc., et al., No.
`1:13-cv-01110-GMS (D. Del. July 13-16, 2015)
`
`File History for U.S.P.N. 7,384,980
`
`“Wein 1994” – Urodynamics: Principles, Practice and
`Application (1994), 43-70 – “Pharmacologic treatment of
`voiding dysfunction”; A.J. Wein, P.A. Longurst, R.M. Levin
`
`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
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`Ex. 2013
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`Ex. 2014
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`Ex. 2015
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`Ex. 2016
`
`Ex. 2017
`
`“Krise” – J. Med. Chem (1999), 42, 3094-3100 – “Novel
`Prodrug Approach
`for Tertiary Amines: Synthesis and
`Preliminary Evaluation of N-Phosphonooxymethyl Prodrugs”;
`J.P. Krise, J. Zygmunt, G.I. Georg, V.J. Stella
`
`“Sinkula” – Journal of Pharmaceutical Sciences (1975), 64(2),
`181-210 – “Rationale for Design of Biologically Reversible
`Drug Derivatives: Prodrugs”; A.A. Sinkula, S.H. Yalkowski
`
`“Bundgaard (1991)” – Drugs of the Future (1991), 16(5), 443-
`458 – “Novel Chemical Approaches in Prodrug Design”; H.
`Bundgaard
`
`“Jann” – Clinical Pharmacokinetics (1985), 10, 315-333 –
`“Clinical Pharmacokinetics of the Depot Antipsychotics”; M.J.
`Jann, L. Ereshefsky, S.R. Saklad
`
`“Beresford” – Drugs (1987), 33, 31-49 – “Haloperidol
`Decanoate a Preliminary Review of Its Pharmacodynamic and
`Pharmacokinetic Properties and Therapeutic Use in Psychosis”;
`R. Beresford, A. Ward
`
`Ex. 2018
`
`U.S.P.N. 7,384,980
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`Table of Authorities
`
`CASES
`C.R. Bard Inc. v. M3 Sys. Inc., 157 F.3d 1340 (1998) ............................................... 28
`
`Circuit Check Inc. v. QXQ Inc., 795 F.3d 1331 (Fed. Cir. 2015) ........................ 22, 31
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd., 619 F.3d 1346 (Fed. Cir. 2010) ...... 20
`
`Daiichi Sankyo Co. v. Mylan Pharm. Inc., 670 F. Supp. 2d 359 (D.N.J. 2009) ....... 22
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314 (Fed. Cir.
`2009) ..................................................................................................................... 20
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008) ...................... 36
`
`Ferrum Ferro Capital, LLC v. Allergan Sales, LLC, No. IPR2015-00858, 2015
`Patt. App. LEXIS 12725 (P.T.A.B. Sept. 21, 2015) ............................................. 17
`
`Fidelity Nat’l Info. Serv., Inc. v. DataTreasury Corp., IPR2014-00489 (P.T.A.B.
`Aug. 13, 2014) ...................................................................................................... 29
`
`In re Chapman, 595 F.3d 1330 (Fed. Cir. 2010) ....................................................... 20
`
`In re Deuel, 51 F.3d 1552 (Fed. Cir. 1995) ............................................................... 24
`
`In re O’Farrell, 853 F.2d 894 (Fed. Cir. 1988) ......................................................... 25
`
`In re Rosuvastatin Calcium Patent Litig., 703 F.3d 511 (Fed. Cir. 2012) .... 24, 27, 33
`
`Leo Pharm. Prods. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ...................................... 20
`
`Merck Sharp & Dohme v. Sandoz Inc., No. 12-cv-03289-PGS, 2015 WL 5089543
`(D.N.J. Aug. 27, 2015) .......................................................................................... 21
`
`Monarch Knitting Mach. v. Sulzer Morat GmbH, 139 F.3d 877 (Fed. Cir. 1998) .... 21
`
`Neil Ziegman, N.P.Z., Inc. v. Stephens, IPR2015-01860, 2016 WL 1084154
`(P.T.A.B. Feb. 24, 2016) ................................................................................. 44, 45
`
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`Novartis Pharm. Corp. v. Watson Labs., Inc., No. 2014-1799, 2015 U.S. App.
`LEXIS 8374 (Fed. Cir. May 21, 2015) ................................................................. 18
`
`Pfizer, Inc. and UCB Pharma GmbH v. Mylan Pharmaceuticals, Inc., No. 1:15-cv-
`00013-IMK (N.D.W.V.) ......................................................................................... 7
`
`Pfizer, Inc. and UCB Pharma GmbH v. Mylan Pharmaceuticals, Inc., No. 1:15-cv-
`00079-GMS (D. Del.) ............................................................................................. 6
`
`Pfizer Inc., et al. v. Mylan Pharm. Inc., 71 F. Supp.3d 458 (D. Del. 2014) .............. 36
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ................................ 36, 37
`
`Pfizer Inc. v. Teva Pharm. U.S.A., Inc., 882 F. Supp. 2d 643 (D. Del. 2012) ........... 42
`
`Prism Pharma Co., Ltd. v. Choongwae Pharma Corp., No. IPR2014-00315
`(P.T.A.B. July 8, 2014) ......................................................................................... 44
`
`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) ......................................................................................... 22
`
`Sanofi-Aventis Deutschland GmbH v. Glenmark Pharma. Inc., 748 F. 3d 1354
`(Fed. Cir. 2014) ..................................................................................................... 32
`
`Sanofi-Synthelabo v. Apotex Inc., 492 F.Supp.2d 353 (S.D.N.Y. 2007), aff’d, 550
`F.3d 1075 (Fed. Cir. 2008) ................................................................................... 36
`
`Shire LLC v. Amneal Pharms. LLC, 802 F.3d 1301 (Fed. Cir. 2015) ................. 38, 43
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir.
`2007) .............................................................................................................. passim
`
`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) ...... 36
`
`Winner Int’l Royalty Corp. v. Wang, 202 F.3d 1340 (Fed. Cir. 2000) ...................... 14
`
`Yamanouchi Pharm. Co. v. Danbury Pharm., Co.
`231 F.3d 1339 (Fed. Cir. 2000) ............................................................................ 34
`
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`STATUTES AND RULES
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`37 C.F.R. § 42.104(b) ................................................................................ 6, 21, 33, 38
`
`37 C.F.R. § 42.108(c) ............................................................................................. 6, 47
`
`35 U.S.C. § 103(a) ....................................................................................................... 9
`
`35 U.S.C. § 313 ............................................................................................................ 1
`
`35 U.S.C. § 325(d) ......................................................................................... 43, 44, 45
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`Pursuant to 35 U.S.C. § 313, Patent Owner UCB Pharma GmbH, (“UCB” or
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`“Respondent”) files its Preliminary Response to Mylan Pharmaceuticals Inc. and
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`Mylan Laboratories Limited’s (collectively, “Mylan” or “Petitioner”) Petition for
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`Inter Partes Review of U.S. Patent No. 6,858,650 (the “Petition”).
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`I.
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`Introduction
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`Petitioner’s obviousness challenge to U.S. Patent No. 6,858,650 (the “‘650
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`patent”) centers on whether fesoterodine fumarate, a specific salt form of the
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`compound fesoterodine, would have been obvious. Because the compound
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`fesoterodine is not prior art to the ‘650 patent, Petitioner must first demonstrate
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`that fesoterodine itself would have been obvious. In its attempt to meet its burden
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`as to both the compound and its fumarate salt form, Petitioner strings together two
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`combinations of prior art patents and publications, but neither presents any new or
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`unique obviousness theories.
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`For one, all of Petitioner’s references bearing any relation to Petitioner’s
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`lead compounds or the field of the invention were considered by the Patent Office,
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`and Petitioner recites them for the same reasons now or seeks to substitute a
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`different, also considered reference, to make substantially the same argument. The
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`Patent Office concluded once that fesoterodine and fesoterodine fumarate would
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`not have been obvious, Petitioner presents nothing new, and the Board should deny
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`the Petition.
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`Second, other companies, prior to Petitioner, sought to make generic
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`versions of Respondent’s Toviaz® product and challenged Respondent’s patents at
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`a trial in the U.S. District Court for the District of Delaware. Petitioner closely
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`followed the obviousness challenges previously tried at trial, and presents
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`substantially the same arguments and prior art in the Petition. On April 20, 2016,
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`the District Court found that all of the challenged claims would not have been
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`obvious and, in its written decision, rejected the contentions Petitioner offers now.
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`Ex. 2001.
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`The earlier decision by the Patent Office to grant the ‘650 claims and the
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`District Court’s decision to confirm their validity demonstrate the flaws in
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`Petitioner’s obviousness theory. In fact, Petitioner’s theory requires a person of
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`ordinary skill to start with the prior art drug tolterodine and take no less than six
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`necessary steps to reach the claimed compound fesoterodine fumarate. The prior
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`art as a whole would not direct a person of ordinary skill to perform the suggested
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`steps and Petitioner fails to supply a reason or motivation to move from one step to
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`the next.
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`Petitioner’s Step 1: In 1999, a person of ordinary skill would be motivated
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`to modify tolterodine’s metabolite, 5-HMT (‘650 Petition at 24). Petitioner’s first
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`step is that a person of ordinary skill would consider the prior art drug tolterodine
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`as a starting point but would then pivot to its metabolite, 5-HMT. The linchpin of
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`2
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`Petitioner’s first step is that its principal reference, Postlind, states that clinical
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`studies of drugs other than tolterodine have shown that patients that lack a
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`particular enzyme called CYP2D6 may develop adverse drug effects. According
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`to Petitioner, based on Postlind, a person of ordinary skill would seek to design a
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`drug based on tolterodine’s metabolite, 5-HMT, rather than tolterodine, in order to
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`avoid the effect of the CYP2D6 enzyme on tolterodine. Contrary to Petitioner’s
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`view, the prior art, such as the Detrol® (tolterodine) Label (Ex. 1009) and Brynne
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`1998 (Ex. 1011), taught that clinical results for tolterodine do not demonstrate any
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`side effect concern due to the CYP2D6 enzyme. A person of ordinary skill would
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`not follow a general caution about other drugs, when the prior art specific to the
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`drug-in-question found that the caution did not apply.
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`Petitioner’s Step 2: 5-HMT would need to be modified because a person of
`
`ordinary skill would know that it is poorly absorbed if administered orally (‘650
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`Petition at 10, 26). Petitioner argues that once a person of ordinary skill focused
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`on 5-HMT, poor absorption would provide the reason to modify it. There is no
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`prior art, and Petitioner cites none, for this critical proposition because 5-HMT’s
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`oral absorption was never tested or even hypothesized in the prior art. To the
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`contrary, Petitioner’s cited prior art actually shows that 5-HMT likely is well-
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`absorbed (see Lipinski (Ex. 1019) at 9) and would have no problems. Petitioner’s
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`justification for modifying 5-HMT is contrary to the prior art and constitutes a step
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`a person of ordinary skill would never take.
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`Petitioner’s Step 3: Persons of ordinary skill would modify 5-HMT into an
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`ester prodrug (‘650 Petition at 26-27). None of the prior art cited by Petitioner
`
`evidences any attempt to make a prodrug of any type in the relevant chemical (3,3-
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`diphenylpropylamines) or biological class of drugs (anti-muscarinic compounds),
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`or the relevant field of use (the treatment of overactive bladder). Because
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`Petitioner can point to no prodrugs of relevant compounds, it is left, in its
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`combinations of references, to rely on a general treatise on prodrugs – Bundgaard
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`(Ex. 1012). But Petitioner identifies nothing in the art that teaches a person of
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`ordinary skill to look to prodrugs in the first place and Bundgaard falls short of
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`providing the particularized showing necessary to demonstrate obviousness.
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`Petitioner’s Step 4: A person of ordinary skill would only need to test a
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`handful of compounds (‘650 Petition at 19, 29). Petitioner’s attempt to denigrate
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`the work of the inventors as a few simple choices is at odds with the options
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`available for substitution on the 5-HMT structure. 5-HMT has two different
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`hydroxyl (“OH”) groups that are each a candidate for substitution. Contrary to
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`Petitioner’s suggestion, these two OH positions alone, or in combination, present
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`thousands of possible ester prodrugs to synthesize and test, even after giving
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`Petitioner the benefit of the doubt that persons of ordinary skill would limit
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`themselves to small chain esters. If persons of ordinary skill considered other
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`commonly-used esters, and Petitioner presents no reason why they would not, the
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`number of possibilities multiplies into the millions.
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`Petitioner’s Step 5: A person of ordinary skill would “optimize” the
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`substitutions of 5-HMT and reach the isobutyryl substitution of fesoterodine (‘650
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`Petition at 19, 29). In neither of its two combinations of prior art does Petitioner
`
`cite a single reference with any mention of an isobutyryl substitution, or that such a
`
`substitution should only be at the 2-position of the phenyl ring, such as in
`
`fesoterodine. Suggesting that a person would “optimize” from a series of
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`compounds cannot fill the gaping hole in Petitioner’s argument that none of the
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`cited prior art suggests or contains the specific molecular modifications needed to
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`make fesoterodine, the claimed compound.
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`Petitioner’s Step 6: A person of ordinary skill would have known that the
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`free base form of fesoterodine needed to be stabilized, and would do so with a
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`fumarate salt (‘650 Petition at 29-30). To assert that salts of fesoterodine would
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`have been obvious, Petitioner argues only that the fumarate salt form of
`
`fesoterodine would have been obvious. Petitioner, however, points only to a
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`general reference on salts (Berge Ex. 1013), and a reference containing a list of
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`possible salt forms for compounds other than the compound in question,
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`fesoterodine (Johansson Ex. 1005). Neither reference suggests any need to make a
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`salt form of a prodrug like fesoterodine or any expectation that the fumarate salt
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`would successfully stabilize such a compound.
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`In sum, Petitioner proposes a path to the claimed compound comprising a
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`series of convenient steps. But the prior art does not support these steps, and the
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`path is constructed from hindsight. Fesoterodine fumarate, the compound at issue,
`
`lies nowhere in the descriptions (or even the margins) of the prior art, nor in the
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`imaginings of persons of ordinary skill. Petitioner falls short of carrying its burden
`
`of specifying where each element of the claimed invention is found in the prior art
`
`and the specific portions of the evidence that support its challenge. 37 C.F.R.
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`§42.104(b)(4), (5). Petitioner fails to demonstrate that there is a reasonable
`
`likelihood that at least one of the challenged claims is unpatentable and its Petition
`
`should be denied. 37 C.F.R. §42.108(c).
`
`II.
`
`The Petition
`
`After receiving notice from Petitioner that it intended to launch a generic
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`version of the OAB treatment Toviaz®, UCB and Pfizer Inc., the exclusive
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`licensee of the ‘650 patent, asserted the ‘650 patent, and U.S. Patent Nos.
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`7,384,980 (the “‘980 patent”), 7,855,230, 7,985,772, and 8,338,478 (collectively,
`
`the “‘980 patent family”), against Petitioner in the actions Pfizer, Inc. and UCB
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`Pharma GmbH v. Mylan Pharmaceuticals, Inc., No. 1:15-cv-00079-GMS (D. Del.)
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`and Pfizer, Inc. and UCB Pharma GmbH v. Mylan Pharmaceuticals, Inc., No.
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`1:15-cv-00013-IMK (N.D.W.V.).
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`Petitioner then filed the present Petition for inter partes review of the ‘650
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`patent challenging claims 1-5 and 21-24. Although the challenged claims possess
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`varying claim scope, Petitioner has made clear that its challenge rises or falls on
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`whether a single compound – fesoterodine fumarate, the active ingredient in
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`Toviaz® – would have been obvious. Petitioner asserts two different combinations
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`of prior art in support of its Petition:
`
`• Postlind (Ex. 1010) and Bundgaard (Ex. 1012) in view of the Detrol®
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`Label (Ex. 1009) and Berge (Ex. 1013).
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`• Brynne 1998 (Ex. 1011) and Bundgaard (Ex. 1012) in view of
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`Johansson (Ex. 1005).
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`See, e.g., ‘650 Petition at 3.
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`III.
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`The “First-Filer” Action
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`Petitioner is not the first to challenge the Toviaz® patent family. In July
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`2015, UCB and Pfizer asserted their patent rights at trial in the U.S. District Court
`
`for the District of Delaware against four other challengers (the “First-Filers”), who,
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`like Petitioner, sought to invalidate the ‘650 patent and market generic versions of
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`Toviaz®. Petitioner essentially reiterates the First-Filers’ case -- the First-Filers
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`relied on the Detrol Label® (Ex. 1009) and Brynne 1998 (Ex. 1011) to assert that
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`tolterodine was an obvious lead compound; on Bundgaard (Ex. 1012) to assert that
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`an ester prodrug was obvious to make; and on Johansson (Ex. 1005) and Berge
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`(Ex. 1013) to assert that the fumarate salt was an obvious salt choice. The District
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`Court decided against the First-Filers; finding none of the alleged steps obvious.
`
`See Ex. 2001. As described below, the District Court expressly rejected many of
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`Petitioner’s contentions as contrary to the teachings of the prior art.
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`IV.
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`The ‘650 Patent and the ‘980 Patent Family
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`A.
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`Specification and Claims of the ‘650 Patent
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`The ‘650 patent entitled “Stable Salts of Novel Derivatives of 3,3-
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`Diphenylpropylamines” issued on February 22, 2005. The ‘650 patent claims and
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`“concerns highly pure, crystalline stable compounds of novel derivatives of 3,3-
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`diphenylpropylamines in the form of their salts,” and methods of treating patients
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`by administering an effective amount of these compounds. See, e.g.,‘650 patent
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`(Ex. 1001), col. 1, ll. 10-14. All challenged claims encompass fesoterodine
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`fumarate or a method of treating a disease by administering fesoterodine fumarate.
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`Fesoterodine is also claimed in applications that were co-pending, co-owned, and
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`issued as the patents comprising the ‘980 patent family.
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`B.
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`Critical Date for the ‘650 Patent
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`For purposes of this Preliminary Response, Respondent assesses the state of
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`the art as of November 15, 1999, unless expressly stated otherwise below.1
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`C.
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`
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`Person of Ordinary Skill in the Art
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`Respondent does not dispute Petitioner’s definition of a person of ordinary
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`skill in the art. See ‘650 Petition at 6.
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`D.
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` Claim Construction for the ‘650 Patent
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`Respondent does not dispute Petitioner’s position that no claim terms require
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`construction. ‘650 Petition at 6.
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`E.
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`
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`Prosecution of the ‘650 Patent
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`During prosecution, then-pending claims 1-5 (which later issued as claims 1-
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`5 of the ‘650 patent) were provisionally rejected for obviousness-type double
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`patenting over claims of co-pending, and co-owned, U.S. Application No.
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`09/700,094 (the “‘094 application”) (Ex. 2010), the parent application of each
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`patent in the ‘980 patent family. Aug. 4, 2003 Office Action (Ex. 2012 at 792-
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`802). In the same rejection, the Examiner, Zachary Tucker, rejected other, then-
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`pending claims not directed to fesoterodine under 35 U.S.C. 103(a) as being
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`1 Petitioner states that the critical date for the ‘650 patent is November 15, 1999,
`(‘650 Petition at 4), yet its chemistry expert, Dr. Patterson, uses May 11, 1998
`as the critical date for his analysis. Patterson Decl. (Ex. 1003) at ¶24.
`Presumably Dr. Patterson has chosen this date because May 11, 1998 is the
`priority date for the ‘980 patent family.
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`unpatentable over Johansson (Ex. 1005). Id. The Examiner did not reject claims
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`1-5 over Johansson. Id.
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`
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`To overcome the obviousness-type double patenting rejection over claims 1-
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`5, applicants submitted a terminal disclaimer, which the Examiner acknowledged
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`by withdrawing the rejection. Nov. 5, 2003 Amendment (Ex. 2012 at 823-832).
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`Applicants also added method of treatment claims that ultimately issued as claims
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`21-24 of the ‘650 patent. Id. (Ex. 2012 at 822). Claims 1-5 and 21-24 of the ‘650
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`patent issued soon thereafter. Jan. 28, 2004 Notice of Allowance (Ex. 2012 at
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`834).
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`F.
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`The ‘980 Patent Family
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`The patents comprising the ‘980 patent family each disclose and claim a
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`genus of compounds, including fesoterodine, methods of making these compounds,
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`and/or methods of treating disease by administering these compounds. These
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`patents comprise the first disclosure of fesoterodine in the art.
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`None of the patents comprising the ‘980 patent family, or any related
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`application, are prior art to the ‘650 patent under any statutory section, and
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`fesoterodine is not prior art to the ‘650 patent. The only basis for rejection during
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`prosecution of the ‘650 patent related to the ‘980 patent family was the
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`obviousness-type double patenting rejection that was properly overcome by
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`terminal disclaimer.
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`G.
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`Prosecution of the ‘980 Patent Family
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`Each patent in the ‘980 patent family claims priority to the ’094 application,
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`the application considered during prosecution of the ‘650 patent that resulted in a
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`terminal disclaimer. The same Examiner who reviewed the ‘650 patent, Zachary
`
`Tucker, reviewed the ‘094 application (Ex. 2010).
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`In an Office Action, the Examiner stated that certain claimed compounds
`
`were expressly disclosed by Johansson (Ex. 1005) and Brynne 1997 (Ex. 1007).
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`February 6, 2003 Office Action (Ex. 2010 at 253-254). In the same office action in
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`which he modified the Election of Invention to remove these compounds, the
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`Examiner allowed a number of claims, including those that claimed “phenolic
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`monoesters,” such as fesoterodine, and pharmaceutical compositions comprising
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`such compounds and methods of treating disease with such compounds. Id. (Ex.
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`2010 at 256).
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` In the subsequent Notice of Allowance, the Examiner explained that
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`“[t]he compounds of the invention are novel derivatives of tolterodine” and that the
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`“state of the art as it pertains to tolterodine derivatives is exemplified by the
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`following four references” - Nilvebrandt 1997 (Ex. 1015), Nilvebrandt 1997 II (Ex.
`
`2004), Postlind (Ex. 1010), and Andersson (Ex. 1014). May 16, 2003 Notice of
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`Allowance (Ex. 2010 at 288-89). The Examiner continued:
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`• “The two Nilvebrandt et al references disclose that the 5-hydroxymethyl
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`metabolite of tolterodine contributes significantly to the therapeutic
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`efficacy of tolterodine;”
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`• “The Postlind et al reference explores the effects of concomitantly
`
`administered drugs on the metabolism of tolterodine in human liver
`
`microsomes;” and
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`• “The Andersson et al reference describes several distinct tolterodine
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`derivatives formed in the metabolism of that compound by mice, rats and
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`dogs.”
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`Id. (Ex. 2010 at 289). Upon review of these references, the Examiner concluded
`
`that “[n]one of the aforementioned references disclose an ester derivative of
`
`tolterodine, or that an ester derivative of tolterodine would be an effective
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`therapeutic agent.” Id. (Ex. 2010 at 289).
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`
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`On December 12, 2005, in conjunction with prosecution of U.S. Application
`
`No. 10/766,263 (Ex. 2011), a second application in the ‘980 patent family,
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`Applicants submitted an Information Disclosure Statement that included the 2004
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`edition of the Detrol® Label (Ex. 10092) and Brynne 1998 (Ex. 1011). See Dec.
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`12, 2005 Information Disclosure Statement (Ex. 2011 at 352-356). The Examiner
`
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`2 All portions of the 1998 Label relied on by the Petitioner are carried over in later
`versions of the Detrol® label, including the 2004 Label.
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`considered and then initialed each reference in connection with the Notice of
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`Allowance on July 12, 2006. See id., July 12, 2006 Notice of Allowance (Ex. 2011
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`at 2014-19).
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`V.
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`Claims 1-5 and 21-24 Are Not Obvious in View of Postlind and
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`Bundgaard in view of the Detrol® Label and Berge
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`Petitioner’s first combination relies upon four references to propose the six
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`steps that a person of ordinary skill would take that allegedly render the claims
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`obvious. Of these references, only two – Postlind (Ex. 1010) and the Detrol®
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`Label (Ex. 1009) – concern compounds structurally related to fesoterodine
`
`fumarate, the challenged compound. Petitioner’s other references, Bundgaard (Ex.
`
`1012) and Berge (Ex. 1013), are generic teachings regarding prodrugs and salts,
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`respectively, with no relation to any structurally related compound.
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`A.
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`
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`Persons of Ordinary Skill Had No Reason to Set Aside Tolterodine and Seek
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`to Focus on 5-HMT
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`A party arguing obviousness must establish a “reason or motivation” in the
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`prior art for a person of ordinary skill to arrive at the claimed invention. See, e.g.,
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`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1356 (Fed.
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`Cir. 2007). According to Petitioner, a person of ordinary skill would initially
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`consider tolterodine as a promising lead compound3 but then immediately pivot to
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`its active metabolite, 5-HMT, to avoid the CYP2D6 polymorphism of tolterodine.4
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`‘650 Petition at 22-25.
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`Petitioner’s sole reason for the switch to 5-HMT is Postlind’s statement that
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`there may be risks with drugs affected by CYP2D6 polymorphism. ‘650 Petition
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`at 23-24 citing Postlind (Ex. 1010) at 292. Postlind expresses a caution about any
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`drug subject to CYP2D6 polymorphism and this caution is based on a 1986
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`publication concerning experiences with drugs other than tolterodine, written years
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`before tolterodine was even discovered. Postlind (Ex. 1010) at 292 citing Smith
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`(1986). References in the prior art that actually described the effects of CYP2D6
`
`polymorphism on tolterodine itself (discussed below) found the g