IPR2017-00011
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`v.
`
`SHIRE LLC,
`
`Patent Owner.
`____________________
`
`Case IPR2017-00011
`US Patent No. RE41,148
`____________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`TABLE OF CONTENTS
`
`Introduction ....................................................................................................... 1
`I.
`II. The Petition Fails To Make A New Prior Art Argument ............................... 5
`III. The ‘148 Reissue Patent .................................................................................... 7
`A. Related IPR2015-02009 and IPR2016-01033 .............................................. 7
`B. Technical Background ................................................................................... 8
`C. The ‘148 Reissue Specification ................................................................... 10
`D. The ‘148 Claims and Prosecution ............................................................... 12
`IV. Claim Construction ......................................................................................... 16
`A. Mixture of amphetamine base salts (Claims 1-20) ................................... 16
`B. Delayed enteric release dosage form (Claims 1-20) .................................. 19
`C. “About” for pharmacokinetic values (claims 1-11, 15-20). ...................... 20
`V. The Prior Art Cited in Petitioner’s Alleged Grounds for the IPR ............. 21
`A. Mehta, US 5,837,284 (EX1005) ................................................................... 23
`B. The 1997 PDR (EX1009) ............................................................................. 26
`C. Brown (EX1011) ........................................................................................... 26
`D. Amidon, US 5,229,131 (EX1004) ................................................................ 28
`E. Slattum (EX1031) ......................................................................................... 32
`VI. The ‘148 Claims Are Non-Obvious And Patentable .................................... 34
`A. Claims 1-20 Are Not Obvious ..................................................................... 35
`1.
`Independent Claim 1 is not Obvious from the Prior Art ............... 39
`a) mixture of amphetamine base salts in an ADHD formulation
`release dosage form, and a carrier ........................................................ 39
`b) Effective ≥8-hour amphetamine levels and a second peak
`amphetamine level higher than a first amphetamine level ................. 42
`c) The formulation, when containing a total dose of 20mg, has an AUC
`of about 467 to about 714ng·hr/ml ........................................................ 46
`d) There was no reasonable expectation of success; the references are
`not enabling ............................................................................................. 49
`
`comprising an immediate release dosage form, a delayed enteric
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`Claim 6 is not Obvious (AUC ~714ng·hr/ml; Tmax ~7 hrs; Cmax
`
`Claim 2 is not Obvious (Cmax) ........................................................ 51
`2.
`Claims 3 and 4 are not Obvious (Tmax) .......................................... 53
`3.
`Claim 5 is not Obvious (AUC ~714ng·hr/ml) .................................. 54
`4.
`5.
`~40ng/ml) ............................................................................................ 55
`Claim 7 is not Obvious (Cmax ~40ng/ml). ...................................... 55
`6.
`Claim 8 is not Obvious (Tmax ~7 hours) ......................................... 56
`7.
`Claim 9 is not Obvious (equal amounts of amphetamine salts) .... 56
`8.
`Claims 10 and 11 are not Obvious (polymer and thickness) ......... 57
`9.
`10. Claims 15 and 16 are not Obvious (20mg total dose) ..................... 59
`11. Claims 17 and 18 are not Obvious (proportional AUC; Cmax) .... 59
`12. Claims 19 and 20 are not Obvious (pH-independent release;
`Protective Coating) ............................................................................ 60
`13.
`Independent Claim 12 and Claims 13-14 are not Obvious............ 60
`VII. Objective Evidence That The ‘148 Claims Are Not Obvious .................. 61
`A. Long-Felt Need, Failure By Others, and Unexpected Results ................. 61
`B. Skepticism, Praise & Commercial Success ............................................... 63
`CONCLUSION .................................................................................. 64
`VIII.
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`LIST OF EXHIBITS
`
`
`Exhibit Description
`2001
`DECLARATION OF BERNHARDT L. TROUT, Ph.D.
`2002
`Curriculum Vitae of Bernhardt L. Trout, Ph.D.
`2003
`FDA Orange Book Listing for Shire’s Adderall XR
`2004
`FDA Approved Product Label for Shire’s Adderall XR
`2005
`Excerpts from File History of Burnside, U.S. Patent No. 6,322,819
`2006
`Excerpts from File History of Burnside, U.S. Patent No. RE42,096
`2007
`Excerpts from File History of Burnside, U.S. Patent No. 6,605,300
`2008
`Barr’s Para IV Letter, IDS No. 1 (March 15, 2005), Exhibit 26 in File
`History of Burnside, US Patent No. RE 41,148
`Excerpts from Chambliss Expert Report, IDS No. 2 (Nov. 23, 2005), in
`File History of Burnside, US Patent No. RE 41,148
`Excerpts from Klibanov Expert Report, IDS No. 2 (April 25, 2005), in
`File History of Burnside, US Patent No. RE 41,148
`2011 William E. Pelham, Jr. et al., Sustained Release and Standard
`Methylphenidate Effects on Cognitive and Social Behavior in Children
`with Attention Deficit Disorder, 80 Pediatrics 491 (1987)
`James M. Swanson et al., Letter, More Frequent Diagnosis of Attention
`Deficit-Hyperactivity Disorder, 333 New England J. of Med. 944
`(1995)
`Paul J. Ambrosini et al., A Community Assessment, Open-Label Study
`of the Safety, Tolerability, and Effectiveness of Mixed Amphetamine
`Salts Extended Release in School-Age Children With ADHD, 22
`Current Med. Res. & Opinion 427 (2006)
`Joseph Biederman et al., A Randomized, Double-Blind, Placebo-
`Controlled, Parallel- Group Study of SLI381 (Adderall XR) in Children
`With Attention-Deficit/Hyperactivity Disorder, 110 Pediatrics 258
`(2002)
`
`2014
`
`
`
`iii
`
`2009
`
`2010
`
`2012
`
`2013
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`Patent Owner’s Preliminary Response
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`2015
`
`2019
`
`2020
`2021
`
`J.M. Swanson et al., The Use of Laboratory School Protocol to
`Evaluate Concepts About Efficacy and Side Effects of New
`Formulations of Stimulant Medications, 6 J. Attention Disorders S-73
`(2002)
`2016 William E. Pelham, Jr. et al., Pemoline Effects on Children with
`ADHD: A Time-Response by Dose-Response Analysis on Classroom
`Measures, 34 J. Am. Acad. Child & Adolescent Psychiatry 1504 (1995)
`Excerpts from File History of Burnside, US RE 41,148
`2017
`2018 Kennerly S. Patrick & John S. Markowitz, Pharmacology of
`Methylphenidate, Amphetamine Enantiomers and Pemoline in
`Attention-Deficit Hyperactivity Disorder, 12 Human
`Psychopharmacology 527 (1997)
`Richard H. Weisler, Safety, Efficacy and Extended Duration of Action
`of Mixed Amphetamine Salts Extended-Release Capsules for the
`Treatment of ADHD, 6 Expert Opin. Op. in Pharmacotherapy 1003
`(2005)
`FDA Approved Product Label for Shire’s Adderall
`Thomas Spencer et al., Efficacy of a Mixed Amphetamine Salts
`Compound in Adults with Attention-Deficit/Hyperactivity Disorder, 58
`Arch. Gen. Psych. 775 (2001)
`James J. McGough et al., Pharmacokinetics of SLI381 (ADDERALL
`XR), an Extended-Release Formulation of Adderall, 42 J. Am. Acad.
`Child Adolesc. Psychiatry 684 (2003)
`Steven R. Pliszka, The Use of Psychostimulants in the Pediatric
`Patient, 45 Pediatric Clinics of North America 1085 (1998)
`SUPAC-MR: Modified Release Solid Oral Dosage Forms (Sept. 1997)
`(“1997 FDA Guidance”)
`Institution Decision, IPR2016-01033
`Shire v. Abhai, Claim Construction Decision, DI 85
`Burnside, US RE 42096
`Food Effect Bioavail and Fed Bioequiv Studies (2002)
`
`2022
`
`2023
`
`2024
`
`2025
`2026
`2027
`2028
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`Selected Portions of Donald N. Franz, Sympathomimetic Drugs, In:
`REMINGTON, THE SCIENCE AND PRACTICE OF PHARMACY,
`Chapter 57, 981, 987, 19th Edition (1995)
`Burnside, U.S. Patent No. 6,322,819
`Gerald L. Brown, et. al., Clinical Pharmacology of d-Amphetamine in
`Hyperactive Children. In: PHARMACOKINETICS OF
`PSYCHOACTIVE DRUGS FURTHER STUDIES, Ed. L. A.
`Gottschalk. New York: Spectrum, pp. 137-153 (1979) (“Brown
`1979b”)
`Gerald L. Brown, et al., Plasma Levels of d-Amphetamine in
`Hyperactive Children, 62 Psychopharmacology 133 (1979) (“Brown
`1979a”)
`23 USP-NF 18 for Propranolol
`Shire Motion to Amend, IPR2015-02009, Paper 14
`Orange Book re Mylan ANDA 206721
`Excerpts from Langer Expert Report
`Adrienne Rains & Lawrence Scahill, 17 J. Child & Adolescent Psych.
`Nursing 177 (2004)
`1964 PDR for Ritalin
`Excerpts from MERCK INDEX, 11th Edition
`William E. Pelham, Jr. et al., Relative Efficacy of Long-Acting
`Stimulants on Children with Attention Deficit-Hyperactivity Disorder:
`A Comparison of Standard Methylphenidate, Sustained-Release
`Methylphenidate, Sustained-Release Dextroamphetamine, and
`Pemoline, 88 Pediatrics 226 (1990)
`DECLARATION OF SARA E. ROSENBAUM, PhD
`Curriculum Vitae of Sara E. Rosenbaum, Ph.D
`Shargel, Applied Bio & Pharmacokinetics (1999)
`FDA Patent Exclusivity for Ritalin LA
`Polymethacrylates, Handbook of Pharm. Excipients (1994)
`
`v
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`2029
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`2030
`2031
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`2032
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`2033
`2034
`2035
`2036
`2037
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`2038
`2039
`2040
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`2041
`2042
`2043
`2044
`2045
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`Bodmeier (1996)
`Lehninger, Principles of Biochemistry, Excerpt (1993)
`Khankari,Pharmaceutical Hydrates, Thermochimica Acta, Vol. 248, pp.
`61-79 (1995)
`Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Chapter 1
`(1991)
`Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Chapter 5
`(1991)
`IPR2015-02009 Decision Denying Amerigen Request for Rehearing,
`Paper 33
`Rowland, Clinical Pharmacokinetics 2d, Ch. 4 (1989)
`2053 Winters, Basic Clinical Pharmacokinetics, Excerpt (1994)
`Benet, Transplantation Proc., 31 (Suppl 3A), 75-9S (1999)
`
`
`2046
`2047
`2048
`
`2049
`
`2050
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`2051
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`2052
`2053
`2054
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`IPR2017-00011
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`TABLE OF AUTHORITIES
`
`Page(s)
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`
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`CASES
`
`3M v. Chemque, Inc., 303 F.3d 1294 (Fed. Cir. 2002) ...................................... 42, 49
`
`Amgen Inc. v. Hoechst Marion Roussel, 314 F. 3d 1313 (Fed. Cir.
`2003) ................................................................................................................... 42
`
`Aventis Pharm. Inc. v. Amino Chem. Ltd., 715 F.3d 1363 (Fed. Cir.
`2013) ................................................................................................................... 18
`
`BioDelivery Sciences Int’l, Inc. v. Monosol RX, LLC, IPR2015-00169,
`Paper 69 (PTAB Mar. 24, 2016) ........................................................................... 5
`
`Biomarin Pharm. Inc. v. Genzyme Therapeutic Prods. Ltd. P’ship,
`IPR2013-00534, Paper 81 (PTAB Feb. 23, 2015) ....................................... 22, 55
`
`Brown & Williamson Tobacco Corp. v. Philip Morris, Inc., 229 F.3d
`1120 (Fed. Cir. 2000) .......................................................................................... 63
`
`Crocs, Inc. v. ITC, 598 F.3d 1294 (Fed. Cir. 2010) ........................................... 58, 63
`
`Depuy Spine, Inc v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314
`(Fed. Cir. 2009) ................................................................................................... 38
`
`Galderma Labs L.P. v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir. 2013) ........................ 59
`
`Graham v. John Deere Co., 383 U.S. 1 (1966) ....................................................... 36
`
`Howmedica Osteonics Corp. v. Zimmer, Inc., 640 Fed. Appx. 951
`(Fed. Cir. 2016) ................................................................................................... 22
`
`Hulu LLC v. Intertainer, Inc., IPR2014-01456, Paper 8 (PTAB Mar. 6,
`2015) ..................................................................................................................... 5
`
`In re Aller, 220 F.2d 454 (CCPA 1955)…………………………………………...58
`
`In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991) .................................... 21
`
`In re Cuozzo Speed Techs., LLC, 793 F.3d 1268 (Fed. Cir. 2015) ........................... 16
`
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`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) ..................................................... 60
`
`In re Dembiczak, 175 F.3d 994 (Fed. Cir. 1999) ..................................................... 36
`
`In re Dow Chem. Co., 837 F.2d 469 (Fed. Cir. 1988) ............................................. 37
`
`In re Fritch, 972 F.2d 1260 (Fed. Cir. 1992) ........................................................... 51
`
`In re Huai-Hung Kao, 639 F.3d 1057 (Fed. Cir. 2011) ............................... 21, 46, 47
`
`In re Magnum Oil Tools Int'l, Ltd., 829 F.3d 1364 (Fed. Cir. 2016) ....................... 36
`
`In re Napier, 55 F.3d 610 (Fed. Cir. 1995) .............................................................. 22
`
`In re Reed, 297 F.2d 251 (CCPA 1962) .................................................................. 21
`
`In re Soni, 54 F.3d 746 (Fed. Cir. 1995) .................................................................. 62
`
`In re Wands, 858 F.2d 731 (Fed. Cir. 1988) ................................................ 42, 49, 50
`
`Institut Pasteur v. Focarino, 738 F.3d 1337 (Fed. Cir. 2013) ................................. 39
`
`Intendis GmbH v. Glenmark Pharms., Inc., 822 F.3d 1355 (Fed. Cir.
`2016) ................................................................................................................... 37
`
`KSR Int’ Co. v. Teleflex Inc., 550 US 398 (2007)............................................. 37, 38
`
`Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804 (Fed. Cir.
`1989) ................................................................................................................... 38
`
`Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364 (Fed. Cir.
`2005) ................................................................................................................... 63
`
`Microboards Technology, LLC v. Stratasys Inc., IPR2015-00287,
`Paper 13 (PTAB May 25, 2015) ........................................................................... 5
`
`Microprocessor Enhancement Corp. v. Tex. Instruments, Inc., 520 F.3d
`1367 (Fed. Cir. 2008) .......................................................................................... 18
`
`Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292 (Fed. Cir. 2015) ...................... 16
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877
`(Fed. Cir. 1998) ................................................................................................... 63
`
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`Mylan Pharm. Inc. v. Eurand, Inc., 133 S. Ct. 933 (2013) ...................................... 62
`
`Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359 (Fed. Cir. 2008) ...................... 42
`
`Nora Lighting, Inc. v. Juno Mfg., LLC, IPR2015-00601, Paper 13
`(PTAB Aug. 12, 20015) ........................................................................................ 5
`
`Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186 (Fed. Cir. 2014) ................. 22
`
`Para-Ordance Mft. V. SGS Importers Int’l, Inc., 73 F.3d 1085 (Fed.
`Cir. 1995) ............................................................................................................ 45
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ............................. 37, 38
`
`Pfizer, Inc. v. Mylan Pharms Inc., 71 F. Supp. 3d 458 (D. Del. 2014) ................... 38
`
`Power-One, Inc. v. Artesyn Techns., Inc., 599 F.3d 1343 (Fed. Cir.
`2010) ................................................................................................................... 63
`
`Prolitec, Inc. v. ScentAir Techs., Inc., 807 F.3d 1353 (Fed. Cir. 2015) .................... 16
`
`Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568
`(Fed. Cir. 1996) ................................................................................................... 37
`
`Redline Detection, LLC v. Star Envirotech, Inc., 811 F.3d 435 (Fed.
`Cir. 2015) ............................................................................................................ 38
`
`Regent Jack Mfg. Co. v. United States, 155 Ct. Cl. 222 (Ct. Cl. 1961) ................... 45
`
`Rolls-Royce, PLC v. United Techs. Corp., 603 F.3d 1325 (Fed. Cir.
`2010) ................................................................................................................... 61
`
`Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012) ........................ 21
`
`Shire LLC v. Abhai, LLC, No. 15-cv-13909 (D. Mass.) .......................................... 20
`
`Straight Path IP Group, Inc. v. Sipnet EU S.R.O., 806 F.3d 1356 (Fed.
`Cir. 2015) ............................................................................................................ 16
`
`Therasense, Inc. v. Becton, Dickinson & Co., 593 F. 3d 1325 (Fed. Cir.
`2010) ................................................................................................................... 42
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling
`USA, Inc., 699 F.3d 1340 (Fed. Cir. 2012) ......................................................... 63
`
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`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795 (Fed. Cir.
`1999) ................................................................................................................... 16
`
`W.L. Gore & Assocs. v. Garlock, Inc., 721 F.2d 1540 (Fed. Cir. 1983) ................. 36
`
`STATUTES
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`35 U.S.C. § 314(a) ..................................................................................................... 4
`
`35 U.S.C. § 325(d) ..................................................................................................... 5
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`35 U.S.C. § 103 ........................................................................................................ 36
`
`REGULATIONS
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`37 C.F.R. § 42.108(c) ................................................................................................. 4
`37 C.F.R. § 42.100(b) .............................................................................................. 16
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`PATENT OWNER’S PRELIMINARY RESPONSE
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`I. Introduction
`Shire’s U.S. Patent RE41,148 (“the ‘148 patent”) was reissued from U.S.
`
`Patent 6,605,300 (“the ‘300 patent”) and is a continuation-in-part of RE42,096
`
`(“the ‘096 patent”). EX1001; EX2007; EX2027. Both are listed in the FDA
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`“Orange Book” for Adderall XR®. EX2003.
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`Adderall XR® is an extended release formulation of mixed amphetamine
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`salts, indicated for Attention Deficit Hyperactivity Disorder (“ADHD”). EX2001,
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`¶29; EX2004. Mylan markets generic immediate release Adderall®. EX2035.
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`Mylan has not given notice that it seeks FDA approval for generic Adderall XR®,
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`and has no litigation with Shire over these patents.
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`The ‘148 patent provides “an oral multiple unit pulsed dose delivery system
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`for amphetamine salts and mixtures thereof,” having a specified pharmacokinetic
`
`(“PK”) profile, “over
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`the course of about 8 hours with a single oral
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`administration.” EX1001, 3:35-40, 10:19-20. Example 5 shows “typical profiles of
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`plasma amphetamine concentration after administration of a composite capsule
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`containing the immediate-release pellets” of Example 1 and “delayed-release
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`pellets” of Example 2 or 3, using a “10mg dose” of each pellet (20mg total).
`
`EX1001, 12:26-48 and Figs. 7-8.
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`IPR2017-00011
`Patent Owner’s Preliminary Response
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`The ‘148 claims focus on the plasma concentration profile. EX1001, claims
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`1, 12. It was not routine to design an extended release amphetamine formulation,
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`with suitable PK for ADHD over 8+ hours. One way to achieve this PK profile is
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`to provide an “immediate release of drug and enteric release of drug wherein the
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`enteric release is a pulsed release” Id., 3:66-4:3. This was not routine. “Particularly
`
`challenging for formulation scientists has been overcoming two conflicting hurdles
`
`for pulsatile formulation development, i.e., lag time and rapid release.”Id., 2:13-16;
`
`EX2001, ¶24; EX2041, ¶¶28-57.
`
`This is the third inter partes review (“IPR”) challenging this patent family
`
`and is Mylan’s second. Amerigen’s IPR2015-02009 challenged selected ‘096
`
`patent claims. Mylan’s IPR2016-01033 challenged all of the ‘096 claims. Both
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`IPRs cited Mehta (EX1005) and the 1997 PDR (EX1009). Mylan’s IPR added
`
`Amidon (EX1004) and Brown (EX1011). Each time, the Board declined to
`
`institute ‘096 claims 1-17, comprising a delayed enteric release of essentially all of
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`the amphetamine dose within a pulse of about 60 minutes. Mylan now adds
`
`Slattum (EX1031) to challenge the ‘148 patent. All five references were considered
`
`during prosecution. Petition, 10, 13, 14, 15.
`
`The ‘148 claims provide a dual-release oral formulation for ADHD
`
`comprising specific amphetamine base salts; effective drug levels for 8+ hours; a
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`second peak plasma concentration that exceeds an earlier peak, and quantitative
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`PK parameters. These include an area under the curve (“AUC”) of about 467-
`
`714ng·hr/ml; a maximum plasma concentration (“Cmax”) of about 22.5-40ng/ml;
`
`and a time to peak plasma concentration (“Tmax”) of about 7-10 hours. EX1001,
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`Claims 1-20. Claims 10-14 provide an enteric coating that is greater than about
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`20µm thick, is soluble at a pH ≥5.5, and is a dried aqueous dispersion of a
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`particular copolymer.
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`The references are remote from the claimed amphetamine formulation and
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`its PK and coating requirements. Mehta (concerning methylphenidate) and Amidon
`
`(concerning propranolol) cannot be combined to provide all the claimed features,
`
`despite amphetamine salts from the PDR and Brown’s description of sustained
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`release d-amphetamine. Slattum with sustained release d-amphetamine. Slattum
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`studied IR d-amphetamine co-administered with a urinary acidification agent
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`(EX1031, 4). This artificially causes “lower blood levels and efficacy of
`
`amphetamines” (EX1009, 5). Such abnormal results are useless for designing an
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`effective ADHD formulation. EX2001, ¶¶70-200; EX2041, ¶¶28-57.
`
`The Board previously found that Mehta could not be modified to deliver a
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`rapid release sufficient to simulate a second immediate release of methylphenidate
`
`or amphetamine. EX1022, 23-25, 33-34; EX2025, 28-30. Amidon’s equations and
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`different dosage forms for propranolol showed unpredictability. EX2025, 30-31.
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`Brown made no difference. Id., 31.
`
`Shire’s experts, Drs. Trout and Rosenbaum, agree with the Board’s findings
`
`in the prior IPRs. EX2001, ¶¶ 61-68; EX2041, ¶¶54, 80. They also explain why the
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`references cannot be transformed into a workable formulation of the ‘148 claims.
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`Petitioner’s Dr. Auslander repackages a failed argument that Mehta led the
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`way, from an unrealized quick-release goal, to a suitable pulsed formulation that
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`this time can provide all of the ‘148 PK and formulation requirements. EX1002,
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`¶¶73, 78 (citing EX1005, 6:8-16); EX1022, 23-24. He opines that overcoming “any
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`difficulty” was only “a matter of routine” given Amidon. EX1002, ¶114. He argues
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`“motivation” (the PDR) to try for once-daily amphetamine, despite unsuccessful
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`sustained release experiments (Brown). Id., ¶¶97-100. He relies on Dr. Palmieri to
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`pluck pharmacokinetic goals from Slattum. Id., ¶115. But Slattum’s results from
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`subjects with acidified urine are inapplicable. EX2041, ¶¶88-89; EX1009, 5. The
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`evidence is conspicuously missing any “why” and “how to,” by which the
`
`references are combinable. Indeed the references are all over the place and did not
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`prompt the ‘148 claims, which set forth an unexpected improvement in an
`
`unpredictable art.
`
`The Petition fails to show a reasonable likelihood that it can prevail; it
`
`should be denied. 35 U.S.C. § 314(a); 37 C.F.R. § 42.108(c).
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`IPR2017-00011
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`II. The Petition Fails To Make A New Prior Art Argument
`The Petition depends on the same arguments that failed in IPR2016-01033.
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`According to Mylan, Brown supposedly motivated “optimizing” Mehta to make a
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`delayed rapid-pulse formulation for amphetamine salts from the PDR, using
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`guidance from Amidon. That formulation supposedly would match
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`the
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`pharmacokinetics in Slattum, and coincide with the ‘148 claims, as a latent or
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`routinely adjustable result. Petition, 17-25. However, the references do not enable a
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`successful pulsatile formulation. EX2025, 29-31. They consequently cannot enable
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`the claimed pharmacokinetics either. The artisan furthermore would not try to
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`match Slattum’s PK results in subjects with acidified urine. EX2001, ¶¶99-101,
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`107; EX2041, ¶¶65-69. “Optimizing” Mehta has repeatedly been considered and
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`overcome in this patent family, including two reissues and two IPRs. There is no
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`good reason to address this argument again.
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`The Petition does not make a new argument and should be dismissed. 35
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`U.S.C. § 325(d). See Hulu LLC v. Intertainer, Inc., IPR2014-01456, Paper 8, 7-8
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`(PTAB Mar. 6, 2015) (same prior art and argument); Microboards Technology, LLC
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`v. Stratasys Inc., IPR2015-00287, Paper 13, 11-12 (PTAB May 25, 2015) (same
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`prior art); Nora Lighting, Inc. v. Juno Mfg., LLC, IPR2015-00601, Paper 13, 11-12
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`(PTAB Aug. 12, 20015) (cumulative prior art); BioDelivery Sciences Int’l, Inc. v.
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`Monosol RX, LLC, IPR2015-00169, Paper 69, 16 (PTAB Mar. 24, 2016) (issue
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`preclusion is appropriate when forum is the same).
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`The parent ‘096 patent was allowed over Mehta’s so-called “pulsatile dosage
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`form comprising a methylphenidate salt.” EX2005, 52-53, 96. Mehta disclosed
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`only “a gradual release of the methylphenidate” after a delay. Id., 56. “[T]he prior
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`art does not teach or fairly suggest that essentially all of the enteric coated drug is
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`released within 60 minutes from the initiation of the delayed pulsed enteric
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`release.” Id., 96 (Allowance). During reissue, the Examiner was given arguments
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`for optimizing Mehta that were made by litigation adversaries. EX2017, 17, 30,
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`36-38, 47-48, 64-72, 103-111; EX2008, 4-6; EX2009, 2-6. The Board agreed that
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`Mehta and the PDR did not make the invention obvious, and agreed that Amidon
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`and Brown do not help. EX1022, 23-25, 32-34, 37-38; EX2025, 29-31.
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`The parent ‘300 patent also confronted optimizing Mehta. EX2007, 56. The
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`claims were distinguished because (1) they “define that the second maximum
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`[amphetamine] concentration is greater than the first, whereas Mehta discloses the
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`opposite;” and (2) Mehta did not teach how “amphetamines can be effectively used
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`for ADHD by a single administration over eight hours ….” Id., 61. The PDR was
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`cited for the “four amphetamine salts.”Id., 115. Third-party litigation arguments
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`were submitted to the Examiner, including that the claimed PK parameters (relative
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`peaks, AUC, etc.) could have been optimized from Mehta and the PDR. Brown,
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`Amidon and Slattum are cumulative and gratuitous at best; they do not make for a
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`new argument.
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`The Petition covers old ground and should be denied.
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`III. The ‘148 Reissue Patent
`The ‘148 patent (EX1001) is a reissue of U.S. Patent 6,605,300 (EX2001, 1)
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`and a child of U.S. Patent 6,322,819 (EX2030), now RE42,096 (EX2027).
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`A. Related IPR2015-02009 and IPR2016-01033
`IPR2015-02009 was brought by Amerigen against the ‘096 patent. Trial was
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`not instituted for any of claims 1-17. EX1022, 38. The Board found: “[t]here is no
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`pulse in Mehta that releases ‘essentially all’ (~80 %) of the methylphenidate ...
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`from a delayed release coating within about 60 minutes.” Id., 23. “Mehta does not
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`provide … a reasonable expectation of success” or any adequate guidance. Id., 33.
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`This is true for “Mehta’s methylphenidate, or Adderall’s amphetamine salts.” Id.,
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`34. Amerigen’s rehearing request was denied. EX2051, 2, 7-9. Shire’s motion to
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`cancel instituted claims is pending. EX2034.1
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`1 Instituted claims 18-21, 23, and 25 (via claims 18-20) omit releasing
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`“essentially all” the drug as a pulse, deemed to include releasing any amount.
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`EX1022, 26, 34. Shire disagreed, but anyway seeks to cancel the instituted claims.
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`EX2034.
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`In IPR2016-01033, Mylan challenged all of the ‘096 claims. Mylan cited
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`obviousness over Mehta and the PDR, “optimization” from Amidon (EX1004), and
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`a motivating teach-away by Brown (EX1011). The Board again declined to
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`institute claims 1-17. EX2025, 32-33. Mehta did not release methylphenidate
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`“anywhere near the required time period” and failed to offer “adequate guidance
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`for one of ordinary skill in the art to achieve such a dosage form.” Id., 30.
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`“Amidon itself provides evidence of the unpredictability of formulating dosage
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`forms with particular delay and release parameters.” Id., 31.
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`Here, Mylan argues again that Mehta, when enhanced by Amidon, the PDR,
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`Brown, and Slattum, would provide the rapid-pulse formulation described in the
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`‘148 patent, and would thereby achieve the claimed ‘148 pharmacokinetics,
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`“inherently”. Petition, 19-25. Since Mehta is not configurable to enable a pulsed
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`release, it cannot enable the claimed ‘148 formulation and its PK requirements.
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`EX1022, 23-25, 33-34; EX2025, 29-31; EX2001, ¶¶187-200, 247; EX2041, ¶¶54,
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`80-81.
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`B. Technical Background
`When a drug is orally administered, it is (1) released from its dosage form,
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`e.g. in the stomach or intestines; (2) absorbed into the blood by crossing the
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`gastrointestinal membrane; and (3) distributed to its site of action. If the drug is
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`given as a salt, the effective dose is the percentage of the salt that is present as a
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`pharmaceutically active base. This
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`is called
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`the salt factor (“S”). The
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`bioavailability factor (“F”) of the drug is the fraction of the effective dose that is
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`absorbed and reaches the bloodstream. This is usually less than 100%, because of
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`incomplete absorption, and depends on the drug and its dosage form. EX2041,
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`¶¶39-41.
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`Upon absorption, the drug may or may not be (4) metabolized on its first
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`pass through the liver, before entering the circulation. Upon entering the circulation
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`the drug is (5) subject to elimination via the liver and kidneys. The clearance (“Cl”
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`or “CL”) of a drug represents its removal of the drug from a volume of plasma in a
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`given unit of time, generally L/hr. EX1032, 1, EX2041, ¶34.
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`Plasma concentration can be measured over time and plotted on a curve. As
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`a drug is released from a formulation, it is absorbed and enters the circulation. Its
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`concentration rises to a high over time and then falls off. The maximum
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`concentration is Cmax. The time at which Cmax occurs is Tmax. For two doses or
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`releases there is still one Cmax at one Tmax over the course of the plasma
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`concentration curve. If the curve has two peaks, C1 and C2 at T1 and T2, one of
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`them will be Cmax at Tmax. The area under the plasma concentration curve
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`(“AUC”) represents the drug exposure to the bloodstream over time. A therapeutic
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`window for the drug is a plasma concentration that is between a minimum effective
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`concentration over time, and a maximum toxic concentration. These PK concepts
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`are illustrated schematically below. EX2043, 7; EX2041, ¶¶37-43.
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`C. The ‘148 R