UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC., MYLAN LABORATORIES LIMITED,
`ALEMBIC PHARMACEUTICALS LIMITED, TORRENT PHARMACEUTICALS
`LIMITED, AND AMERIGEN PHARMACEUTICALS LIMITED,
`
`Petitioners
`
`
`v.
`
`UCB PHARMA GMBH,
`
`Patent Owner
`
`
`
`Case IPR2016-00510
`
`Patent No. 6,858,650
`
`
`
`
`
`US2008 12345620 3
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC., MYLAN LABORATORIES LIMITED,
`ALEMBIC PHARMACEUTICALS LIMITED, TORRENT PHARMACEUTICALS
`LIMITED, AND AMERIGEN PHARMACEUTICALS LIMITED,
`
`Petitioners
`
`
`v.
`
`UCB PHARMA GMBH,
`
`Patent Owner
`
`
`
`Case IPR2016-00510
`
`Patent No. 6,858,650
`
`
`
`
`
`US2008 12345620 3
`
`
`
`
`
`
`
`PETITIONER MYLAN PHARMACEUTICALS INC.’S CORRECTED
`PETITION ER MYLAN PHARMACEUTICALS IN C.’S CORRECTED
`
`REPLY TO PATENT OWNER’S RESPONSE TO PETITION
`REPLY TO PATENT OWNER’S RESPONSE TO PETITION
`
`ii
`
`ii
`
`US2008 12345620 3
`
`US2008 12345620 3
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................................ 1
`
`II.
`
`RESPONSE TO PATENT OWNER’S ARGUMENTS ....................................... 2
`
`A. Ground I: Claims 1-5 and 21-24 are Obvious Over the Postlind
`
`and Bundgaard Publications in view of the Detrol® Label and
`
`Berge .................................................................................................................... 2
`
`C.
`
`Ground II: Claims 1-5 and 21-24 Are Rendered Obvious by
`
`Brynne 1998, Bundgaard, and Johansson .................................................... 23
`
`III. CONCLUSION ........................................................................................................... 26
`
`CERTIFICATE OF SERVICE .......................................................................................... 1
`
`
`
`i
`
`US2008 12345620 3
`
`
`
`
`
`
`
`LIST OF EXHIBITS
`
`U.S.P.N. 6,858,650
`File History for U.S.P.N. 6,858,650
`Declaration of Dr. Steven Patterson, Ph.D.
`C.V. for Dr. Steven Patterson, Ph.D
`“Johansson” – WO 94/11337 Filed 6 November 1992 – “Novel
`3,3-Diphenylpropylamines, Their Use and Preparation”
`“Andersson Review” – BJU International (1999), 84, 923-947 –
`“The Pharmacological Treatment of Urinary Incontinence”; K-E
`Andersson, R. Appell, L.D. Cardozo, C. Chapple, H.P. Drutz, A.E.
`Finkbeiner, F. Haab, and R. Vela Navarrete
`“Brynne 1997” – International Journal of Clinical Pharmacology
`and Therapeutics (1997), 35, 287-295 – “Pharmacokinetics and
`pharmacodynamics of tolterodine in man: a new drug for the
`treatment of urinary bladder overactivity”; N. Brynne, M.M.S. Stahl,
`B. Hallen, P.O. Edlund, L. Palmer, P. Hoglund, and J. Gabrielsson
`“Thomas” – British Heart Journal (1995), 74, 53-56 –
`“Concentration dependent cardiotoxicity of terodine in patients
`treated for urinary incontinence”; S. Thomas, P. Higham, K
`Hartigan-Go, F. Kamali, P. Wood, R. Campbell, and G. Ford
`“Detrol® Label” – Pharmacia & Upjohn
`“Postlind” – Drug Metabolism and Disposition (1998), 26 (4), 289-
`293 – “Tolterodine, A New Muscarinic Receptor Antagonist, Is
`Metabolized by Cytochromes P450 2D6 and 3A in Human Liver
`
`Ex. 1001:
`Ex. 1002:
`Ex. 1003:
`Ex. 1004:
`Ex. 1005:
`
`Ex. 1006:
`
`Ex. 1007:
`
`Ex. 1008:
`
`Ex. 1009:
`Ex. 1010:
`
`ii
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Microsomes”; H. Postlind, A. Danielson, A. Lindgren, and S.
`Andersson
`“Brynne 1998” – Clinical Pharmacology & Therapeutics (May
`1998), 63(5), 529-539 – “Influence of CYP2D6 polymorphism on
`the pharmacokinetics and pharmacodynamics of tolterodine”; N.
`Brynne, P. Dalen, G. Alvan, L. Bertilsson, and J. Gabrielsson
`“Bundgaard” – Elsevier 1985 – “Design of Prodrugs”
`“Berge 1977” – Journal of Pharmaceutical Sciences (1977), 66 (1),
`1-19 – “Pharmaceutical Salts”; S. Berge, L., Bighley, and D.
`Monkhouse
`“Andersson 1998” – Drug Metabolism and Disposition (1998),
`26(6), 528-535 – “Biotransformation of tolterodine, a new
`muscarinic receptor antagonist, in mice, rats, and dogs”; S.
`Andersson, A. Lindgren, and H. Postlind
`“Nilvebrant” – Pharmacology and Toxicology (1997), 81, 169-172
`– “Antimuscarinic Potency and Bladder Selectivity of PNU-200577,
`a Major Metabolite of Tolterodine”; L. Nilvebrant, P. Gillberg, and
`B. Sparf
`“DeMaagd” – P&T (2012), 37(6), 345-361 – “Management of
`Urinary Incontinence”; G. DeMaagd and T. Davenport
`“Appell” – Urology (1997), 50, 90-96 – “Clinical efficacy and safety
`of tolterodine in the treatment of overactive balder: a pooled
`analysis”; R. Appell
`“Ashworth” – Home Care Provider (1997), 2(3), 117-120 – “Is My
`
`Ex. 1011:
`
`Ex. 1012:
`Ex. 1013:
`
`Ex. 1014:
`
`Ex. 1015:
`
`Ex. 1016:
`
`Ex. 1017:
`
`Ex. 1018:
`
`iii
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Antihistamine Safe?”; L. Ashworth
`“Lipinski” – Advanced Drug Delivery Reviews, 1997
`“Bundgaard PCT” – WO 92/08459 Filed 11 November 1991 –
`“Topical Compositions for Transdermal Delivery of Prodrug
`Derivatives of Morphine”
`“AUA Guideline” – American Urological Association Eductatio
`and Research (2014) – “Diagnosis and Treatment of Overactive
`Bladder (Non-Neorogenic) in Adults: AUA/SUFU Guideline”; E.
`Gormley, et al
`“Pfizer 2012 Press Release” – Aug. 2, 2012 “Study Shows Toviaz is
`Effective in Reducing Urge Urinary Incontinence in Patients with
`Overactive Bladder After Suboptimal Response to Detrol LA” –
`www.pfizer.com
`“PM360” – April 1, 2012 “Overactive Bladder Market: Managing
`the Future” – www. pm360online.com
`“Toviaz® Label” – Pfizer Labs
`“FDA Approval Letter” –NDA20-771
`“FDA Guidance” – Applications Covered by Section 505(b)(2) –
`October 1999 – FDA (CDER)
`“Gould” – International Journal of Pharmaceutics (1986), 3, 201-
`217 – “Salt Section for Basic Drugs”; P. Gould
`“Alabaster” – Discovery & Development of Selective M3
`Antagonists for Clinical Use, 60 Life Science 1053 (1997)
`“Takeuchi” – 1,2,3,4-Tetrahydro-2-Isoquinolinecarboxylate
`
`Ex. 1019:
`Ex. 1020:
`
`Ex. 1021:
`
`Ex. 1022:
`
`Ex. 1023:
`
`Ex. 1024:
`Ex. 1025:
`Ex. 1026:
`
`Ex. 1027:
`
`Ex. 1028:
`
`Ex. 1029:
`
`iv
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Derivatives: A Novel Class of Selective Muscarinic Antagonists, III,
`in 213th ACS National Meeting, San Francisco, Abst. 046 (Apr. 13-
`17, 1997)
`“Goldberg” – DuP 532, an angiotensin II receptor antagonist: First
`administration and comparison with losartan, Clinical
`Pharmacology & Therapeutics, January 1997
`“Begley” – The Blood-brain Barrier: Principles for TGargeting
`Peptides and Drugs to the Central Nervous System, J. Phar.
`Pharmacol. 1996, 48:136-146
`Dkt 6 2015-01-28 Summons Returned Executed, Case No. 1:15-cv-
`00079-GMS, Pfizer,et al v Mylan Pharmaceutical Inc.(Dist. of DE)
`Declaration of DeForest McDuff, Ph.D.
`CV for DeForest McDuff, Ph.D.
`Toviaz: Donʼ t Let Overactive Bladder Stop You In Your Tracks
`Toviaz U.S. and Worldwide Sales
`U.S. OAB Prescriptions and Shares by Drug (2008–2014)
`U.S. OAB Sales and Shares by Drug (2008–2014)
`U.S. OAB Market Share, Prescriptions, and Sales by Drug (2000–
`2007)
`Prescription Path of Toviaz and Other OABs
`Sales Path of Toviaz and Other OABs
`Sales Path of Toviaz Compound to Pharmaceutical Industry
`Benchmarks
`Comparison of Toviaz Sales to Compound to Pharmaceutical
`
`Ex. 1030:
`
`Ex. 1031:
`
`Ex. 1032:
`
`Ex. 1033:
`Ex. 1034:
`Ex. 1035:
`Ex. 1036:
`Ex. 1037:
`Ex. 1038:
`Ex. 1039:
`
`Ex. 1040:
`Ex. 1041:
`Ex. 1042:
`
`Ex. 1043:
`
`v
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Industry Benchmarks
`Chart of Sales Path of Toviaz
`Present Value of Toviaz U.S. Sales
`Present Value of Toviaz Worldwide Sales
`Estimates of Expected R&D Costs
`U.S. OAB Detail Shares by Drug (2008–2015)
`Consumer Price Index (CPI)
`2009-2010 UBS U.S. Pharmaceuticals 8/24/201
`2011-2014 UBS U.S. Pharmaceuticals 1/4/2016
`2009-2011 Pfizer Form 10-K, 2012
`2012-2014 Pfizer Form 10-K 2015
`UBS U.S. Pharmaceuticals 11/26/2010
`UBS U.S. Pharmaceuticals 11/15/2013
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2001
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2002
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2003
`Cowen and Company, “Therapeutic Categories Outlook,” 3/2004
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2005
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2006
`Cowen and Company, “Therapeutic Categories Outlook,” 10/2007
`Cowen and Company, “Therapeutic Categories Outlook,” 9/2008
`Grabowski, Henry, John Vernon, and Joseph A. DiMasi (2002),
`“Returns on Research and Development for 1990s New Drug
`Introductions,” Pharmacoeconomics, 20(3):11-29
`
`Ex. 1044:
`Ex. 1045:
`Ex. 1046:
`Ex. 1047:
`Ex. 1048:
`Ex. 1049:
`Ex. 1050:
`Ex. 1051:
`Ex. 1052:
`Ex. 1053:
`Ex. 1054:
`Ex. 1055:
`Ex. 1056:
`Ex. 1057:
`Ex. 1058:
`Ex. 1059:
`Ex. 1060:
`Ex. 1061:
`Ex. 1062:
`Ex. 1063:
`Ex. 1064:
`
`vi
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Grabowski, Henry and Ronald Hansen, “Briefing Cost of
`Developing a New Drug,” Tufts Center for the Study of Drug
`Development, 11/18/2014
`Moore, Thomas and Curt Furberg (2014), “Development Times,
`Clinical Testing, Postmarketing Follow-up, and Safety Risks for the
`New Drugs Approved by the US Food and Drug Administration:
`The Class of 2008,” JAMA Intern Med. 174(1):90-95
`Adams, Christopher P. and Van V. Brantner (2006), “Estimating
`the Cost of New Drug Development: Is It Really Worth $802
`Million?,” Health Affairs 25(2):420-428
`Adams, Christopher Paul and Van Vu Brantner (2009), “Spending
`on New Drug Development,” Health Economics 19(2):130-141
`Novel Derivatives of 3,3-Diphenylpropylamines, European Patent
`No. 0,957,073 (filed 5/12/1998; issued 11/17/1999)
`ClinicalTrials.gov, Two Phase Extension Trial of SP668 to
`Investigate the Safety and Tolerability of Sustained Release
`Fesoterodine in Subjects with Overactive Bladder: A Double-Blind
`Phase Followed by an Open-Label Extension Phase,
`https://www.clinicaltrials.gov/ct2/show/NCT00220389?term=fes
`oterodine&rank=50
`FDA Approval Letter, NDA 22-030, 10/31/2008
`St. Louis Federal Reserve, U.S. CPI,
`https://research.stlouisfed.org/fred2/data/USACPIALLAINMEI.
`txt.
`
`Ex. 1065:
`
`Ex. 1066:
`
`Ex. 1067:
`
`Ex. 1068:
`
`Ex. 1069:
`
`Ex. 1070:
`
`Ex. 1071:
`Ex. 1072:
`
`vii
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Ex. 1073:
`Ex. 1073:
`Ex. 1074:
`Ex. 1074:
`Ex. 1075:
`Ex. 1075:
`Ex. 1076:
`Ex. 1076:
`
`Deposition Transcript of William Roush, dated September 9, 2016
`Deposition Transcript ofWi11iarn Roush, dated September 9, 2016
`Deposition Transcript of Hans Maag, dated August 16, 2016
`Deposition Transcript of Hans Maag, dated August 16, 2016
`Deposition of Leonard Chyall, dated August 23, 2016
`Deposition of Leonard Chyall, dated August 23, 2016
`Deposition of Claus Meese, dated January 20-21, 2015
`Deposition of Claus Meese, datedjanuary 20-21, 2015
`
`viii
`
`viii
`
`US2008 12345620 3
`
`US2008 12345620 3
`
`
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Through counsel, real party in interest Mylan Pharmaceuticals Inc.
`
`(“Petitioner”) submits this Reply to Patent Owner UCB Pharma GmbH (“Patent
`
`Owner”)’s Response (“the “Response,” Paper 20) to the Petition (the “Petition,”
`
`Paper 5) for Inter Partes Review (“IPR”) of U.S. Patent No. 6,858,650 (“the ʼ650
`
`patent,” Ex. 1001).
`
`In its Decision on Institution, the Board recognized there is a reasonable
`
`likelihood that claims 1-5 and 21-24 of the ’650 patent are unpatentable under two
`
`separate grounds. Paper 12 (the “Decision”). After Patent Owner requested
`
`rehearing, the Board upheld its decision to institute on both grounds. Paper 18, 7.
`
`The compounds at issue are unpatentable as obvious because a skilled artisan
`
`would seek to develop an overactive bladder treatment from the active 5-HMT
`
`metabolite of the prior art antimuscarinic compound tolterodine, following well-
`
`known drug development techniques to make a single, suggested ester modification at
`
`the #2 carbon to develop it as a prodrug, and ultimately formulate it as a salt.
`
`Petition, 4-5. Patent Owner argues such modifications were not obvious, attempting
`
`to portray each step as a confounding array of choices for the skilled artisan. A skilled
`
`artisan, however, with knowledge of the art regarding drug development and equipped
`
`1
`
`US2008 12345620 3
`
`
`
`
`
`
`
`with routine assays and techniques, would not have been confounded at any step, and
`
`would have found obvious prodrug compounds of 5-HMT.
`
`II. RESPONSE TO PATENT OWNER’S ARGUMENTS
`A. Ground I: Claims 1-5 and 21-24 are Obvious Over the Postlind and
`Bundgaard Publications in view of the Detrol® Label and Berge.
`a. Postlind, and the Detrol® Label Taught 5-HMT was an
`Effective Compound for Drug Development
`
`The Board found a reasonable likelihood the skilled artisan would have selected
`
`5-HMT as a lead compound. Decision, 17-19. Tolterodine was known as a treatment
`
`for overactive bladder, and its metabolism to the potent antimuscarinic compound 5-
`
`HMT was well characterized by Postlind and the Detrol® label. See Petition, 6-7.
`
`Tolterodine’s limitations were also known to skilled artisans, such as its undesirable
`
`metabolism in a subset of patients because of CYP2D6 polymorphism, and
`
`tolterodine’s leading to potential side effects.1 See Petition, 7-8, 13-14; Decision, 18-
`
`19. Therefore, a skilled artisan would focus on tolterodine’s active metabolite – 5-
`
`HMT – to take advantage of 5-HMT’s activity separate from tolterodine, and answer
`
`
`
`1 As discussed below, the prior art suggested that tolterodine, not 5-HMT, was
`responsible for these side effects. See infra Part II.A.a.ii.
`
`2
`
`US2008 12345620 3
`
`
`
`
`
`
`
`the obvious question of “how do I deliver 5-HMT without the complications of
`
`tolterodine?” Petition at 15.
`
`Patent Owner argues a skilled artisan would not have chosen 5-HMT because
`
`1) tolterodine was only one of many potential lead compounds, 2) the CYP2D6
`
`polymorphism would not have caused a skilled artisan to focus on 5-HMT instead of
`
`tolterodine, and 3) any adverse events associated with Detrol® were tied to 5-HMT.
`
`Response at 16-25. Each of these assertions fails.
`
`i. 5-HMT as a Lead Compound
`A skilled artisan would have understood the functional properties of
`
`tolterodine and 5-HMT, and would have understood 5-HMT to have been
`
`responsible for some of the activity of tolterodine. See Petition, 14-15, Ex. 1003, ¶¶
`
`40, 48, 66, 68, 71, 74, 95-102; Ex. 1073, 94:16-24, 95:8-18 (admitting skilled artisans
`
`would have been aware of the Detrol® label and understood its relationship to other
`
`OAB drugs). Likewise, even if there were other antimuscarinic compounds of
`
`interest, there is no evidence that 5-HMT was inferior or disfavored over these
`
`compounds. See Response, 17-18 (citing Patterson and Carson deposition transcripts,
`
`Exs. 2020 and 2026). Instead, Petitioner has presented evidence – unrebutted by
`
`Patent Owner – that the co-administration of tolterodine and its metabolite 5-HMT
`
`had advantages in tolerability and efficacy compared to other antimuscarinic therapies
`3
`
`US2008 12345620 3
`
`
`
`
`
`
`
`such as oxybutynin, as well as to other classes of compounds such as calcium
`
`antagonists. See Petition, 16-17; Ex. 1003, ¶¶ 85-102; Ex. 1008, 53; Ex. 1016, 53.
`
`These advantages would have motivated a skilled artisan to look at 5-HMT as a lead
`
`compound and given the unique situation of essentially dosing two compounds –
`
`tolterodine and 5-HMT – to get a single pharmacological activity, would have
`
`recognized an area for improvement over other prior art compounds.2 See Otsuka
`
`Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1293 (Fed. Cir. 2012) (affirming the district
`
`court’s conclusion that two prior art compounds were viable lead compounds).
`
`Accordingly, Patent Owner cannot show that a skilled artisan would not have started
`
`with 5-HMT to avoid dosing two actives when one would do. Petition, 15; Ex. 1003,
`
`¶¶ 95-102.
`
`ii. The Prior Art Taught a Skilled Artisan to Look to 5-
`HMT to Avoid Tolterodine’s Adverse Events
`
`
`
`2 Petitioner contends that Patent Owner’s application of lead compound analysis
`is overly rigid and inconsistent with KSR Int’l v. Teleflex, Inc., 550 U.S. 398 (2007). In
`fact, the continued viability of the lead compound analysis is questionable in light of
`KSR. See Eisai Co. v. Dr. Reddy’s Labs. Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008)
`(explaining that “[p]ost-KSR, a prima facie case of obviousness for a chemical
`compound still, in general, begins with the reasoned identification of a lead
`compound”) (emphasis added).
`
`4
`
`US2008 12345620 3
`
`
`
`
`
`
`
`The prior art taught the skilled artisan to select 5-HMT over tolterodine for
`
`further development to avoid the risk of drug interaction and adverse events
`
`associated with administering tolterodine. See Petition, 24; Ex. 1003, ¶¶ 42-43. A
`
`skilled artisan would have focused on 5-HMT to avoid these risks, which were
`
`suggested to be due to tolterodine’s physical properties, individual variations in the
`
`CYP2D6-mediated metabolism of tolterodine, and the dual activity of tolterodine and
`
`its 5-HMT metabolite. See Petition, 7-8, 14-15; Ex. 1003, ¶¶ 95-102, 111-112.
`
`The metabolic pathway and antimuscarinic activity of tolterodine are not in
`
`dispute. Postlind and the Detrol® label taught a skilled artisan that in a majority of
`
`the population, tolterodine is metabolized to 5-HMT via the CYP2D6 enzyme,
`
`whereas in individuals who are poor CYP2D6 metabolizers, tolterodine was instead
`
`metabolized to N-dealkylated tolterodine by the CYP3A4 enzyme pathway. See Ex.
`
`1010, 292; Ex. 1009, 2; Petition, 22-24; Response, 19-213; Decision, 17-18. Likewise,
`
`Patent Owner agrees both tolterodine and 5-HMT were known to be active
`
`antimuscarinic compounds. See Response, 20-23.
`
`
`3 Patent Owner’s assertion that CYP3A4 is not “relevant to tolterodine
`metabolism” is contradicted by the Detrol® label and Postlind. Compare Response, 21
`with Ex. 1009, 2 (“The identified pathway of metabolism for…poor metabolizers[] is
`dealkylation via cytochrome P450 3A4 to N-dealkylated tolterodine.”) and Ex. 1010,
`292.
`
`5
`
`US2008 12345620 3
`
`
`
`
`
`
`
`Patent Owner first contends that a skilled artisan would not be concerned
`
`about CYP2D6 polymorphism because it “made no difference to the therapeutic profile of
`
`tolterodine.” Response, 20-25 (second emphasis added). Postlind nevertheless
`
`cautioned a skilled artisan to avoid CYP2D6 because of “the possibility of clinical drug
`
`interaction…if tolterodine is administered at the same time as a compound that is
`
`preferentially metabolized by CYP2D6 or to individuals associated with the CYP2D6
`
`poor metabolizer phenotype.” Ex. 1010, 292 (emphasis added); see also id. (identifying
`
`diverse classes of “drugs identified as being affected by CYP2D6 polymorphism”).
`
`Petition, 22-23; Response, 19; Decision, 17-18.
`
`Patent Owner’s emphasis on the concurrent antimuscarinic activity of
`
`tolterodine and 5-HMT highlights a fundamental problem with tolterodine: A skilled
`
`artisan would have focused on 5-HMT to avoid dosing a compound with two active
`
`forms. The fact that tolterodine itself was active indicated a risk of adverse negative
`
`drug-drug interactions, and would have motivated a skilled artisan to focus on 5-HMT
`
`to reduce the number of metabolic steps and variables in pharmacology. See Petition,
`
`14-15; Ex. 1003, ¶ 97 (drug developers knew that reducing metabolic steps was
`
`preferable to reduce pharmacological variables); id., ¶¶ 95-102. Further, a skilled
`
`artisan would have understood that tolterodine’s alternative metabolism through
`
`CYP3A4 resulted in an inactive metabolite, exposing a subset of patients to reduced
`6
`
`US2008 12345620 3
`
`
`
`
`
`
`
`therapeutic dose, and side effects of having too much unmetabolized tolterodine. See,
`
`e.g., Ex. 1009, 7 (capping dosage “[f]or patients with significantly reduced hepatic
`
`function or who are currently taking drugs that are inhibitors of cytochrome P450
`
`3A4.”); Ex. 1003, ¶¶ 95-102; Petition, 24. As Patent Owner’s chemistry expert
`
`explained, “tolterodine is not actually a very good product because it doesn’t get
`
`converted completely to 5-HMT.” Ex. 1074, 77:11-19.
`
`Finally, a skilled artisan would have turned to 5-HMT to avoid adverse events
`
`suggested to be caused by tolterodine, not 5-HMT. First, Patent Owner
`
`mischaracterizes the Detrol® Label’s teachings. Far from failing to “parse between 5-
`
`HMT and tolterodine in its attribution of adverse events” (see Response, 23), the
`
`Detrol® Label taught a skilled artisan that administering too much tolterodine, but
`
`not 5-HMT, was undesirable by capping the dose when the inactivation by CYP3A4 is
`
`blocked. Specifically, the Detrol® Label taught that in poor CYP2D6 metabolizers,
`
`the alternative metabolic pathway through CYP3A4 resulted in “significantly higher
`
`serum concentrations of tolterodine and in negligible concentrations of [5-HMT].”
`
`Ex. 1009, 2; Petition, 24; Ex. 1003, ¶ 38. The Detrol® label then instructed patients
`
`with blocked 3A4 pathways should receive a reduced dose of 1 mg daily to prevent
`
`adverse events in these patients. Ex. 1009, 5, 7; Petition, 24. Accordingly, the
`
`Detrol® label suggested to a skilled artisan that tolterodine was responsible for
`7
`
`US2008 12345620 3
`
`
`
`
`
`
`
`adverse events that could be avoided with 5-HMT. Ex. 1009, 2, 5, 7; Petition, 24; Ex.
`
`1003, ¶ 111.
`
`Second, Patent Owner mischaracterizes the teachings of the Brynne 1998
`
`reference, which suggested to the skilled artisan that tolterodine, not 5-HMT, was
`
`responsible for the majority of side effects. For example, while Patent Owner
`
`correctly notes Brynne found that only extensive metabolizers reported an increased
`
`heart rate, Brynne taught that “the most likely explanation for this finding is the
`
`higher fluctuation of drug concentrations as a result of the larger extraction rate.” Ex.
`
`1011, 538. Thus, Brynne taught that fluctuating tolterodine concentrations adversely
`
`elevated heart rate, not the presence or any action of 5-HMT. Id. Likewise, Brynne
`
`explained the abnormal vision experienced by poor metabolizers was likely due to
`
`tolterodine being “tenfold more lipophilic than 5-HM[T],” thereby crossing the
`
`blood-brain barrier more readily and causing visual accommodation. See id.; see also
`
`Ex. 1003, ¶ 117 (“5-HMT would be less likely to generate neurological adverse events
`
`compared to tolterodine” because “[a]n increase in lipophilicity results in an increase
`
`in the likelihood of passive blood brain barrier penetration”); Ex. 1031; see also Ex.
`
`1011, 536 (both tolterodine and 5-HMT affected salivation at different stages of
`
`administration). A skilled artisan would have also understood that the increased
`
`incidence of headaches in poor metabolizers was also likely caused by tolterodine
`8
`
`US2008 12345620 3
`
`
`
`
`
`
`
`crossing the blood-brain barrier. See Ex. 1011. Thus, Brynne 1998 would have
`
`motivated a skilled artisan to consider 5-HMT in the absence of tolterodine because it
`
`taught the opposite of what Patent Owner asserts: Tolterodine, not 5-HMT, was the
`
`likely culprit for undesirable side effects.
`
`Accordingly, a skilled artisan would have been motivated by the teachings of
`
`the prior art to focus on 5-HMT instead of tolterodine to avoid the complication of
`
`dosing two active moieties, complications from CYP2D6 metabolism, and undesirable
`
`side effects, all of which were associated with tolterodine, but not for 5-HMT.4
`
`b. The Prior Art Suggested 5-HMT May Have Had
`Bioavailability Concerns
`
`Although 5-HMT would address the side effect issues associated with the
`
`presence of tolterodine, a skilled artisan would have looked to make an improved
`
`derivative of 5-HMT rather than orally dosing 5-HMT itself. Patent Owner does not
`
`dispute that a skilled artisan would have known that 5-HMT was described in another
`
`
`
`4 Patent Owner also asserts with respect to claims 3-5 that there is no teaching of
`the (R) enantiomer of the claimed compounds. The prior art taught that “tolterodine
`is an (R) enantiomer.” Response, 49 (citations omitted). 5-HMT is also an (R)
`enantiomer. Ex. 1074, 202:10-18 (admitting Postlind discloses the R-enantiomer of 5-
`HMT because it discloses tolterodine). Because 5-HMT and tolterodine are (R)
`enantiomers, a skilled artisan would have no reason to develop anything other than an
`(R) enantiomer.
`
`9
`
`US2008 12345620 3
`
`
`
`
`
`
`
`patent not owned by Schwarz as of November 1997, and therefore would have been
`
`discouraged from seeking to use orally-administered 5-HMT. See Petition, 45 n. 4; Ex.
`
`1003, ¶ 136; Ex. 1074, 116:20-118:11 (Patent Owner’s chemistry expert testifying that
`
`whether one can obtain patent protection is an important consideration in driving
`
`drug development). Accordingly, because 5-HMT was patented, a skilled artisan
`
`seeking to improve upon 5-HMT would not have sought to use it directly, but would
`
`have pursued a 5-HMT derivative.
`
`In addition, the Board found a reasonable likelihood the skilled artisan would
`
`have recognized the poor bioavailability of 5-HMT from “lipophilicity of profile of 5-
`
`HMT, and/or the Brynne [1998] reference.” Decision, 20-22. Brynne 1998 expressly
`
`taught that “[t]olterodine is tenfold more lipophilic than 5-HM[T], and consequently
`
`tolterodine penetrates membranes more rapidly.” Ex. 1011, 538; see also Decision, 20;
`
`Petition, 10, 26. Likewise, Dr. Patterson explained the structure of 5-HMT suggested
`
`that it was significantly less bioavailable than tolterodine, and “[i]mproving the
`
`lipophilicity properties of 5-HMT was a matter of routine, but extremely predictable
`
`optimization.” Ex. 1003, ¶¶ 115, 119; see also Petition, 9-10, 18-19, 26-28; Ex. 1012, 4
`
`10
`
`US2008 12345620 3
`
`
`
`
`
`
`
`(teaching esterification can “obtain derivatives with almost any desirable
`
`hydrophilicity or lipophilicity as well as in vivo lability”). 5
`
`Patent Owner does not dispute Brynne’s conclusion, but instead asserts that
`
`actual oral bioavailability data was necessary for a skilled artisan to understand
`
`bioavailability. Response, 26-27. Patent Owner cites no prior art reference or
`
`authority supporting this proposition. See Response, 26-27; cf. Ex. 1074, 26:8-16
`
`(Patent Owner’s chemistry expert testifying that administering a compound “in
`
`exactly the same form as it needs to be whenever it reaches the target system or
`
`organ” is “something of a[n] ideal situation which, in my mind, never occurs”);
`
`Novartis Pharm. Corp. v. Watson Labs., Inc., 611 F. App'x 988, 996 (Fed. Cir. 2015)
`
`(unpublished) (article did not teach patented compound’s general susceptibility to
`
`oxidative degradation because it only taught the compound was more stable than
`
`another compound with a known susceptibility to oxidative degradation); Pfizer Inc. v.
`
`Sandoz Inc., No. CV 13-1110-GMS, 2016 WL 1611377, at *9 (D. Del. Apr. 20, 2016)
`
`(noting “5-HMT's oral absorption properties were, and still are unknown”). Instead, a
`
`
`5 As the Board correctly noted, Petitioner inadvertently stated 5-HMT was “too
`lipophilic,” when Petitioner intended to say “too hydrophilic.” See Petition, 26;
`Decision, 20; cf. Petition at 10 (noting “poor lipophilicity” of 5-HMT); Ex. 1003, ¶ 112
`(noting 5-HMT would be likely to be less bioavailable than tolterodine “because of its
`hydrophilicity and thus lower than acceptable lipophilicity”).
`
`11
`
`US2008 12345620 3
`
`
`
`
`
`
`
`skilled artisan is not an automaton, and is capable of making inferences and analytical
`
`steps known in the field. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 401 (2007) (“[A]
`
`court can consider the inferences and creative steps a person of ordinary skill in the
`
`art would employ.”).
`
`Here, many teachings in the prior art allowed a skilled artisan to make
`
`inferences about 5-HMT’s bioavailability. First, Brynne 1998 would have taught a
`
`skilled artisan to be concerned about 5-HMT’s bioavailability because a skilled artisan
`
`would have understood that a compound’s lipophilicity was an important predictor of
`
`its bioavailability. See Petition, 10, 26; Ex. 1003, ¶¶ 54-55, 116, 119; Ex. 1012, 2-3; Ex.
`
`1019, 5 (“Lipophilicity…appears in some form in almost every analysis of physico-chemical
`
`properties related to absorption.”) (emphasis added). Patent Owner’s chemistry experts
`
`likewise agreed that lipophilicity of a given compound was a predictor of its
`
`bioavailability, and that 5-HMT was likely to have less absorption and bioavailability
`
`than tolterodine. See Ex. 1074, 52:9-21 (Patent Owner’s chemistry expert agreeing
`
`that a skilled artisan “would have understood that tolterodine was likely to have better
`
`absorption and bioavailability than 5-HMT”), 151:15-152:3 (agreeing additional
`
`hydroxyl group on 5-HMT causes increased hydrophilicity (i.e., reduced lipophilicity)
`
`over tolterodine), 153:7-12 (agreeing skilled artisan would expect “5-HMT would be
`
`less bioavailable than tolterodine because of its hydrophilicity”); Ex. 1073, 66:10-25
`12
`
`US2008 12345620 3
`
`
`
`
`
`
`
`(skilled artisan would have assessed lipophilicity and agreed 5-HMT was more
`
`hydrophilic than tolterodine); 71:16-24 (agreeing skilled artisan would have looked at
`
`lipophilicity of a drug in assessing oral availability). Accordingly, a skilled artisan
`
`would have understood from Brynne 1998’s teachings about the lipophilicity of 5-
`
`HMT that it may have bioavailability concerns.
`
`In addition, Patent Owner does not address Dr. Patterson’s opinion that the
`
`structure of 5-HMT “would have suggested that 5-HMT could have significantly less
`
`bioavailability than its parent.” Ex. 1003, ¶¶ 110-115. Instead, Patent Owner
`
`contends the “Rule of 5” demonstrated 5-HMT had no bioavailability problems
`
`because 5-HMT did not violate the four Rule of 5 properties.6 Response, 28-29. The
`
`Rule of 5, however, is not a strict threshold of bioavailability; instead, it only identifies
`
`a class of compounds at risk for having poor absorption. Ex. 1019, 7; Ex. 1003, ¶¶
`
`121-122. Likewise, Dr. Patterson based his opinion on the bioavailability of 5-HMT
`
`on an examination of its structure, using the Rule of 5 as a skilled artisan would,
`
`namely, as a “set of guiding principles.” Ex. 1003, ¶¶ 121-122. Accordingly, a skilled
`
`artisan would have been motivated to modify 5-HMT based on the teachings of the
`
`
`6 The 2011 discovery that “5-HMT is a substrate for the transporter P-
`glycoprotein” is irrelevant to the knowledge of a skilled artisan. See Response, 28 n.
`13 (citing Ex. 2005, 243).
`
`13
`
`US2008 12345620 3
`
`
`
`
`
`
`
`prior art that suggested that it may have limited bioavailability and to obtain a
`
`commercially viable, e.g. protectable, drug product.
`
`c. Bundgaard Taught Predictable Ester Prodrug Modifications
`to Improve 5-HMT Delivery
`
`The Board found there was a reasonable likelihood a skilled artisan “would
`
`have reason to pursue a prodrug approach to modifying 5-HMT, and arrive at a
`
`mono-ester derivative within the scope of the claimed invention.” Decision, 24-25.
`
`As Petitioner explained, prodrugs, and particularly small chain ester prodrugs, were
`
`conventional tools in a skilled artisan’s drug development kit at the time of the
`
`invention, and their formulation and optimization was the predictable use of prior art
`
`ingredients according to their known functions. See Petition, 17-18, 25-27. Guided by
`
`the teachings of Bundgaard, the structure of 5-HMT, and using routine testing and
`
`optimization, a skilled artisan would have been motivated to prepare an isobutyl ester
`
`at the #2 carbon of 5-HMT, and had a reasonable expectation of success in doing so.
`
`See Petition, 25-30; Ex. 1003, ¶¶ 119-130.
`
`Patent Owner first contends that prodrugs were generally disfavored and
`
`difficult approach to drug development. Response, 32-33 (citing Exs. 2021 and 2022).
`
`Patent Owner’s position is undermined by the testimony of its experts, who both
`
`admitted that prodrug development, and in particular ester prodrugs were within the
`
`14
`
`US2008 12345620 3
`
`
`
`
`
`
`
`capabilities of a skilled artisan. See Ex. 1074, 102:6-103:6 (admitting that the chemistry
`
`of adding an isobutyl ester to make fesoterodine from 5-HMT was “a procedure
`
`known in the literature, and if a person of ordinary skill has a degree in chemistry,
`
`they should be able to do it”); Ex. 1073, 110:20-111:7, 112:7-113:7 (confirming
`
`Petitioner’s assertion that prodrugs are part of the drug developer’s tool kit); see also
`
`Pfizer v. Apotex, 480 F.3d 1348, 1368 (Fed. Cir. 2007).
`
`Moreover, Bundgaard explicitly characterized ester prodrugs – particular
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
