IPR2018-00293
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`KVK-TECH, INC.,
`
`Petitioner,
`
`v.
`
`SHIRE LLC,
`
`Patent Owner.
`
`____________________
`
`Case IPR2018-00293
`US Patent No. 9,173,857
`____________________
`
`
`
`
`PATENT OWNER RESPONSE
`
`
`
`
`
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`TABLE OF CONTENTS
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`
`Page
`
`LIST OF EXHIBITS ......................................................................................... iv
`
`PATENT OWNER’S RESPONSE...................................................................... 1
`
`I.
`
`INTRODUCTION.................................................................................... 1
`
`A.
`
`B.
`
`Summary of Patent Owner’s Argument ........................................... 1
`
`The Posture of This IPR .................................................................. 6
`
`II.
`
`SHOJAEI– A THREE COMPONENT, THREE DELIVERY (IR-
`DPR-SR) AMPHETAMINE DOSAGE SYSTEM ..................................... 8
`
`A.
`
`B.
`
`C.
`
`The Invention and Its Technical Background ................................... 8
`
`Person Of Ordinary Skill In The Art .............................................. 15
`
`The Shojaei Specification.............................................................. 17
`
`D. Claim Construction ....................................................................... 18
`
`III. PETITIONER’S PRIOR ART................................................................. 19
`
`A. Burnside – Two Beads ONLY, No SR Combination ...................... 19
`
`B. ADDERALL XR – Two Beads ONLY; No SR at All..................... 21
`
`C. No References Motivated Three Beads And SR Amphetamine ....... 22
`
`1.
`
`Kratochvil – A Problem and a Teach-Away ......................... 22
`
`2. Mehta – No Pulses, No Amphetamine .................................. 22
`
`3. Midha – Triple-Pulse Methylphenidate; Avoid SR............... 23
`
`4.
`
`5.
`
`Couch – No Leap to Three-Bead SR Combinations .............. 24
`
`Rudnic, Burnside ‘776, and Wilson – Different Drugs,
`Different Combinations ....................................................... 25
`
`IV. BURNSIDE DOES NOT ANTICIPATE ANY CLAIMS (GROUND
`1)........................................................................................................... 25
`
`A. Claim 1 Is Not Anticipated ............................................................ 25
`
`B.
`
`Claims 2-4, 13-18 and 29 Are Not Anticipated ............................... 26
`
`C. Claims 5-12 and 19 Are Not Anticipated (PK Claims).................... 27
`
`V. CLAIM 1 IS NOT OBVIOUS OVER BURNSIDE AND XR ................... 29
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`TABLE OF CONTENTS
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`A. No Motivation to Combine Burnside Example 4 with Example
`5 or ADDERALL XR ................................................................... 29
`
`B. Other References Did Not Point from Burnside to Shojaei. ............. 32
`
`1. Mehta, Rudnic, And Burnside ‘776 – No Pulse, Different
`Drugs ................................................................................. 34
`
`2.
`
`Couch – No Reason to Add Late SR after a Pulse ................. 35
`
`3. Wilson and Midha – SR Was Unsuitable .............................. 37
`
`C. Burnside’s SR Bead Was Not “Obvious to Try” ............................. 38
`
`D. No Reasonable Expectation of Success .......................................... 40
`
`1.
`
`Burnside’s In Vitro Release Profile Did Not Predict
`Therapeutic Success ............................................................ 41
`
`(a) Petitioner’s In Vitro to In Vivo Predictions Are
`Unsound.................................................................... 42
`
`(b) Predictability Needs Data that Was Unavailable .............. 50
`
`2.
`
`The Prior Art Taught Away From The Invention .................. 52
`
`(a) Acute Tolerance Discredited SR Amphetamine .......... 53
`
`(b)
`
`Pharmacodynamics Discouraged SR Amphetamine .... 57
`
`VI. CLAIMS 2-4, 13-18, AND 19-20, AND 31 ARE NOT OBVIOUS
`OVER BURNSIDE ALONE WITH ADDERALL XR (COATINGS,
`CORES, AND SALTS) .......................................................................... 59
`
`VII. CLAIMS 5-12 AND 19 ARE NOT OBVIOUS OVER BURNSIDE
`ALONE OR WITH ADDERALL XR (“PK CLAIMS”)........................... 59
`
`A. Claims 5-12 Are Not Inherently Obvious (PK Claims) ................... 60
`
`1.
`
`2.
`
`Different Bead Ratios and Coatings of Burnside Make
`Different Compositions and Results ..................................... 60
`
`Expectation from Shojaei Is Not Inherency from
`Burnside ............................................................................. 63
`
`B.
`
`Claim 19 Is Not Inherently Obvious (No Food Effect) .................... 64
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`TABLE OF CONTENTS
`(continued)
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`Page
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`VIII. CLAIMS 20-28 ARE NOT OBVIOUS OVER BURNSIDE ALONE
`OR WITH ADDERALL XR (“DOSAGE CLAIMS”) .............................. 65
`
`IX. OBJECTIVE EVIDENCE THAT THE CLAIMS ARE NOT
`OBVIOUS ............................................................................................. 67
`
`X. CONCLUSION ...................................................................................... 69
`
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`IPR2018-00293
`Patent Owner’s Response
`
`LIST OF EXHIBITS
`
`2001 DECLARATION OF BERNHARDT L. TROUT, Ph.D. (with CV)
`
`2002 DECLARATION OF SARA ROSENBAUM, Ph.D. (with CV)
`
`2003 FDA Orange Book Listing for MYDAYIS® (NDA N022063)
`
`2004 MYDAYIS® FDA Label (06-2017)
`
`2005 MYDAYIS® Website Pages
`
`2006 Amidon, U.S. Patent No. 5,229,131
`
`2007 Mehta, U.S. Patent No. 5,837,284
`
`2008 IPR2017-00011 Decision Denying Institution (RE41, 148 (300 Patent)
`
`2009 Excerpts from Merck, 11th Ed
`
`2010 Ansel, Popovich & Allen 6th, Ch. 3-5 (1995)
`
`2011 Sonsalia, Remington Ch. 74, - CNS Stimulants (1995)
`
`2012 Robinson, Remington, Ch. 94 - Sustained Release (1995)
`
`2013 Porter, Remington, Ch. 93 – Coating (1995)
`
`2014 Franz, Remington Vol. II, Ch. 57 - Sympathomimetic Drugs (1995)
`
`2015 Malinowsi, Remington, Ch. 53 – Bioequivalence (2000)
`
`2016 Stempel, 7th Ed. - Dispensing of Medication (1971)
`
`2017 USP 23 NF 18 - Uniformity Sec. 905 (1955)
`
`2018 USP 23 NF 18 1995 - Excerpts (1955)
`
`2019 Patrick, Human Psychopharmacology, 12:527-546 (1997)
`
`2020 Spencer, Arch Gen Psych, 58:775-78 (2001 Aug)
`
`2021 Lehninger, Principles of Biochemistry, Excerpt (1993)
`
`2022 Benet, Toxicologic Pathology, 23:115-123 (1995)
`
`2023 Shargel, Applied Bio & Pharmacokinetics, Ch. 2, 10 (1999)
`
`2024 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch.1 (1991)
`
`2025 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch.5 (1991)
`
`2026 Chiao, Remington, Ch. 94 – Sustained Release (1995)
`
`2027 Hinsvark, J. Pharmacokin. Biopharm., 1:319-328 (1973)
`
`2028 Benet, Transplantation Proc., 31 (Suppl 3A), 7S-9S (1999)
`
`2029 Winters, Basic Clinical Pharmacokinetics (1994)
`
`2030 Rowland, Clinical Pharmacokinetics 2d (1989)
`
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`2031 Mircioiu, Basic & Clinical Pharmacology & Toxicology, 96:262–264 (2005)
`
`2032 Booijink, Future Microbiol. 2(3), 285-295 (2007)
`
`2033 Fischer, Pharm. Res., 4:480-485 (1987)
`
`2034 Gupta and Robinson, Controlled Release Delivery (1992)
`
`2035 Macheras, Oral Drug Absorption, Ch. 6 - Modeling Biopharm. (2006)
`
`2036 Schug, European J. Pharm. Sci., 15:279-285 (2002)
`
`2037 Hendeles, J. Allergy Clin. Immunol., 72:7:43-751 (1986)
`
`2038 FDA Use & Limitations of In Vitro Testing (Excerpts)
`
`2039 Guidance for Industry ER Formulations IVIVC (1997)
`
`2040 Amidon, Mol. Pharm., 7:1361 (2010)
`
`2041 Khan, International Journal of Pharmaceutics 140:131-143 (1996)
`
`2042 Koziolek, Advanced Drug Delivery Reviews 101:75–88 (2016)
`
`2043 Chasseaud, Ann. Rev. Pharmacol., 14:35-46 (1974)
`
`2044 Greenhill, J. Am. Acad. Child Adolesc. Psychiatry, 42:1234-1241 (2003)
`
`2045 Swanson, Clin. Pharmacol. Therap., 66:95-305 (1999)
`
`2046 Spencer, Current Diagn & Treatment Psych., Ch 35 – ADHD (2008)
`
`2047 Decision re Institution of IPR2015-02009
`
`2048 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch. 7 – (1991)
`
`2049 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Appendix II (1991)
`
`2050 Percel, US 2003-0157173A1
`
`2051 Couch, WO 2004-028509A1
`
`2052 Shire, Q3 2017 MYDAYIS Results (Excerpts)
`
`2053 Brauer, J. Clin. Pharm. 16-1, 72-76 (1996)
`
`2054 Shire, ER and IR Utilization in Adult ADHD [CONFIDENTIAL]
`
`2055 Shire, MYDAYIS Performance [CONFIDENTIAL]
`
`2056 Auiler, Curr. Med. Res. Opin., 18:311-316 (2002)
`2058 Ansel, Popovich & Allen 6th, Ch. 3-5 (1995) (adds pages 17-25 to EX2010)
`2059 Brauer J. Clin. Pharm. 16-1 72-76 (1996) (replaces missing p.74 of EX2053)
`2060 DECLARATION OF JAMES POLLI (with CV)
`2061 Swanson, Canadian Child Adolesc. Psych. Re. 1 4-3 (2005)
`2062 Goodman & Gilman, 9th ed. (1996), Preface
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`2063 Remington, 20th ed. (2000), Pharmaceutical Care
`2064 Handbook of Pharmaceutical Excipients, 4th ed. (2003), Preface
`2065 Brown, J. Am. Acad. Child Psych. (19) 225-239 (1980)
`2066 Jusko Deposition Exhibit. 304, Levy, Case History of a Pharmaceutical
`Formulation Failure, Clinical Pharmacology & Therapeutics, 8(6)
`2067 Jusko Deposition Exhibit 305, Findling, First-Dose Pharmacokinetics of
`Lithium Carbonate in Children and Adolescents, Journal of
`Psychopharmacology, 30(4):404-410 (2010)
`2068 Jusko Deposition Exhibit 307, Jusko, SYSTEMS PHARMACOLOGY AND
`PHARMACODYNAMICS, Foundations of Pharmacodynamic Systems
`analysis, 161-175 (2016)
`2069 Jusko Deposition Exhibit 309, Applied Pharmacokinetics & Pharmaco-
`dynamics: Principles of Therapeutic Drug Monitoring, Guidelines for
`Collection and Analysis of Pharmacokinetic Data, 8-29 (2006)
`2070 JUSKO DEPOSITION TRANSCRIPT (September 27, 2018)
`2071 BURGESS DEPOSITION TRANSCRIPT (September 24, 2018)
`2072 Burgess Deposition Exhibit 200 (Statement regarding drug doses)
`2073 Jusko Deposition Exhibit 303, Levy et al., Multicompartment Pharmacokinetic
`Models and Pharmacologic Effects, Journal of Pharmaceutical Sciences, 58(4)
`(1969)
`2074 Jusko Deposition Exhibit 306, Mager et al., Scaling Pharmacodynamics from in
`Vitro and Preclinical Animal Studies to Humans, Drug Metabolism
`Pharmacokinetics, 24(1): 16-24 (2009)
`2075 Jusko Deposition Exhibit 308, Sharma et al., Characterization of Four Basic
`Models of Indirect Pharmacodynamic Responses, Journal of Pharmacokinetics
`and Biopharmaceutics, 24(6): 611-635
`2076 Jusko Deposition Exhibit 310, Jusko, W. J., Pharmacokinetic Principles in
`Pediatric Pharmacology, Symposium on Pediatric Pharmacology, Pediatric
`Clinics of North America, 19(1) (1972)
`2077 Shen and Burgess, J. Control Release, 2015 December 10; 219, 644-51
`2078 AstraZeneca Pharms. LP v. Anchen Pharms., 2012 US Dist LEXIS 43989
`(2012)(unpublished)
`2079 Mendyk et al., How-To: Empirical IVIVR without Intravenous Data –
`Dissolution Technologies May 2015
`2080 U.S. Pharmacopeia 24, pp. 1629-1631 (2000)
`2081 Dokoumetzidis, International J. Pharm., 321, 1-11 (2006)
`
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Abbott Labs., Inc. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2009) ..................................................................... 40
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ................................................................. 40, 57
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ..................................................................... 28
`
`Amgen, Inc. v. F. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) ............................................................... 40, 53
`
`Aqua Products v. Matal,
`872 F.3d 1290 (Fed. Cir. 2017) ..................................................................... 29
`
`Arctic Cat Inc. v. Bombardier Recreational Prods.,
`876 F.3d 1350 (Fed. Cir. 2017) ..................................................................... 68
`
`AstraZeneca Pharms. LP v. Anchen Pharms., Inc.,
`2012 U.S. Dist. LEXIS 43989 (D.N.J. 2012) aff’d, 498 Fed. Appx.
`999 (Fed. Cir. 2013) .............................................................................. passim
`
`Becton Dickinson v. Braun,
`IPR2017-08516, Paper 8, 27 (2018) ........................................................ 28, 33
`
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) ..................................................................... 26
`
`Cheese Sys. v. Tetra Pak Cheese & Powder Sys.,
`725 F.3d 1341 (Fed. Cir. 2013) ..................................................................... 33
`
`Demaco Corp. v. F. Von Langsdorff Licensing, Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) ..................................................................... 68
`
`In re Dembiczak,
`175 F.3d 994 (Fed. Cir. 1999) ....................................................................... 49
`
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`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................... 32, 40, 53
`
`In re Dow Chem. Co.,
`837 F.2d 469 (Fed. Cir. 1988) ............................................................ 42, 49, 63
`
`Endo Pharm. Sols., Inc. v. Custopharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) ..................................................................... 60
`
`Eurand, Inc. v. Mylan Pharms., Inc. (In re Cyclobenzaprine
`Hydrochloride Extended-Release Capsule Patent Litig.),
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. passim
`
`Generation II Orthotics Inc. v. Med. Tech. Inc.,
`263 F.3d 1356 (Fed. Cir. 2001) ............................................................... 18, 67
`
`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) ....................................................................... 68
`
`Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A. De C.V.,
`865 F.3d 1348 (Fed. Cir. 2017) .......................................................... 40, 53, 66
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ............................................................... 28, 64
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) ..................................................................... 26
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................... 26, 33, 38, 40
`
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................... 40, 57
`
`Life Techs. Inc. v. Clontech Labs,
`224 F.3d 1320 (Fed. Cir. 2000) .................................................... 16, 40, 42, 43
`
`Litton Indus. Prods. v. Solid State Sys. Corp.,
`755 F.2d 158 (Fed. Cir. 1985) ....................................................................... 16
`
`Medichem S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................... 29, 52, 53
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`Millenium Pharms. v. Sandoz,
`862 F.3d 1356 (Fed. Cir. 2017) ............................................................... 64, 67
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ................................................................. 52, 53
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) ............................................................... 27, 28
`
`Mylan Labs. Ltd. v. Aventis Pharma S.A.,
`IPR2016-00712, Paper 9, 17-18 (2016) ......................................................... 60
`
`Mylan Pharms. Inc.. v. Shire Labs., Inc.
`IPR2017-00011, Paper 7 (2017).................................................................... 54
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) ..................................................................... 26
`
`Newell Co., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ....................................................................... 51
`
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) ..................................................................... 16
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ..................................................................... 67
`
`Par Pharm. Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................... 47, 60, 64
`
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993)................................................................... 49, 63
`
`In re Spada,
`911 F.2d 705 (Fed. Cir. 1990) ....................................................................... 27
`
`Therasense, Inc. v. Becton Dickinson & Co,
`593 F.3d 1325 (Fed. Cir. 2010) ............................................................... 25, 26
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ............................................................... 34, 57
`
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`Upjohn Co. v. MOVA Pharm. Corp.,
`225 F.3d 1306 (Fed. Cir. 2000) .......................................................... 29, 43, 64
`
`Velander v. Garner,
`348 F.3d 1359 (Fed. Cir. 2003) ............................................................... 43, 64
`
`W.L. Gore & Assocs. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .................................................... 28, 42, 49, 63
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) ..................................................................... 29
`
`Statutes
`
`35 U.S.C. § 102 ................................................................................................ 49
`
`35 U.S.C. § 316(e) ............................................................................................ 29
`
`Other Authorities
`
`47 C.F.R. § 42.13(d) ......................................................................................... 30
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`IPR2018-00293
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`PATENT OWNER’S RESPONSE
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`I.
`
`INTRODUCTION
`
`This is Shire’s Response to KVK’s Petition for inter partes review,
`
`challenging all claims of Shojaei, U.S. Patent No. 9,173,857 (EX1001). The
`
`invention concerns an exceptionally long-acting three-bead pharmaceutical
`
`treatment for ADHD comprising amphetamine. The beads provide an immediate
`
`release (“IR”), a delayed pulse release (“DPR”), and a double-coated sustained
`
`release (“SR”). The SR bead has a pH-independent coating layered over an enteric
`
`coating in an “inside-out” configuration. EX1001, 4:40-63, Figs. 2-3.
`
`Petitioner asserts that Burnside (EX1002) anticipated Shojaei (Ground 1), or
`
`made it obvious to combine one Burnside bead with two others (Ground 2), or with
`
`ADDERALL XR® (EX1003, EX1031) (Ground 3). Petition, 4-5.
`
`A.
`
`Summary of Patent Owner’s Argument
`
`Shojaei’s claims are not anticipated or obvious. The prior art does not
`
`disclose a three-bead (IR-DPR-SR) amphetamine treatment. There was no
`
`motivation with a reasonable expectation of success to make one for the intended
`
`therapeutic purpose.
`
`Drug performance and efficacy are formulation-specific. In vitro release
`
`does not indicate in vivo results. Amphetamine in particular displays acute
`
`tolerance, which meant that sustained release was contraindicated by a therapeutic
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`need for fast dosing. Later on-going release also implicated unpredictable
`
`absorption in the colon. Dose linearity and superposition are inappropriate when
`
`acute tolerance and variable gastrointestinal absorption are in play, and they say
`
`nothing about pharmacodynamics and therapeutic efficacy. Motivation with a
`
`reasonable expectation of success cannot come without germane data, meaningful
`
`analysis, and regard for key obstacles. Obviousness cannot be misappropriated, by
`
`hindsight, from Shojaei’s success.
`
`Each of Petitioner’s Grounds must be denied.
`
`•
`
`Burnside alone or in combination with ADDERALL XR does not
`
`disclose any amphetamine three bead combination. Decision, 33-34;
`
`EX2001, ¶¶63-75; EX2060, ¶¶70, 82.
`
`•
`
`There was no motivation to make an IR-DPR-SR (double-coated
`
`inside-out) amphetamine pharmaceutical composition. Petitioner
`
`cannot establish and is incorrect that (a) any type of longer dosing
`
`means longer therapy and (b) any sustained release would predictably
`
`function by superposition. The prior art taught away from SR
`
`amphetamine, because of acute tolerance and failed SR treatments.
`
`EX2001, ¶¶153-154; EX2002, ¶¶128-129; EX2060, ¶¶155-167;
`
`EX2061, 2, 4-6; EX2044, 7 (hysteresis); EX2045, 2 (“acute
`
`tolerance”); EX2046, 8 (“pulsing-pharmacokinetic profiles for
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`ADHD”); EX2053, 3 (“plasma levels and drug effects ... are
`
`dissociable”).
`
`•
`
`Petitioner’s experts overlooked acute tolerance. Dr. Burgess was
`
`ignorant. EX2071, 125:21-25 (“I don't believe that acute tolerance has
`
`been reported”). From pulsatile ADDERALL XR, Dr. Jusko
`
`speculated that tolerance “would not be expected” (EX2070, 28:10-
`
`24), while admitting that “[o]ne would need the sustained release
`
`formulation data” (id., 30:8-10). From irrelevant “generalities” he
`
`misstated that a “delayed pulse release could be considered sustained
`
`release” (id., 30:19-20). He admitted that amphetamine demonstrates
`
`complicated hysteresis, showing “a discordance between the time
`
`course of effect and the time course of plasma concentration,” i.e.,
`
`acute tolerance. Id., 13:11-14:10.
`
`•
`
`There was no reasonable expectation of success, because Burnside’s
`
`individual beads and conventional filling of capsules did not forecast a
`
`combination suitable for the intended purpose of treating disease,
`
`particularly longer-day amphetamine for ADHD. Success was not
`
`likely just from in vitro dissolution profiles of individual beads, e.g.,
`
`Burnside Fig.6, without pharmacokinetic (PK) data, in vitro-in vivo
`
`correlations (“IVIVC”), and analysis predictive of pharmacodynamic
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`(“PD”) and therapeutic results. As Dr. Burgess explained, it is
`
`“[t]hrough the successful development and application of a
`
`meaningful IVIVC” that the “in vivo performance may be accurately
`
`predicted from the in vitro performance of drug products” (EX2077,
`
`3). EX2001, ¶¶134-135; EX2002, ¶¶60-70, 125-130; EX2060, ¶¶91,
`
`109.
`
`•
`
`The PK properties in claims 5-12 are not inherent in the asserted prior
`
`art. Dr. Jusko presumed IR-DPR-SR beads in a fixed ratio. “So if one
`
`adds another component and it is the same amount as the other two
`
`components, one-to-one-to-one, yes, it should produce this -- this
`
`behavior” (EX2070, 96:1-7).1 However, the references are silent
`
`about ratios or amounts for hypothetically adding a third Burnside
`
`bead. Petitioner cannot show that the proposed prior art modifications
`
`would necessarily produce the claimed parameters. Distributing the
`
`dose differently among different beads would produce different
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`results. EX2002, ¶¶6-7, 79-84; EX2060, ¶¶195-206. Different coating
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`thicknesses also furnish different results. EX2060, ¶¶207-210.
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`1 Emphases are added unless otherwise indicated.
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`•
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`“No food effect” in claim 19 is not inherent in amphetamine. EX2002,
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`¶¶90-92; EX2060, ¶¶212-218. Dr. Jusko spoke of “probability,” not a
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`necessary result. EX2070, 81:9-10; see EX2002, ¶¶85-92, 133-141;
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`EX2036, 1 (“not predictable”); EX2037, 5 (SR susceptible to food);
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`EX2048, 13-15 (cannot predict from prolonged-release).
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`•
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`The therapeutic action of amphetamines is poorly understood
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`(EX1031, 1), a significant factor in making any prediction of success.
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`EX2060, ¶¶181-182. According to Dr. Jusko, “modeling of
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`pharmacokinetic-pharmacodynamic data should, if possible, be based
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`on the mechanism by which a drug produces its response.” EX2075,
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`1. Acute tolerance complicates this equation. EX2002, ¶¶128-130;
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`EX2060, ¶¶155-167.
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`•
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`A dosage form “can have a significant effect on bioavailability, and
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`indeed make a difference between success and failure of therapy.”
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`EX2034, 30. Long-acting drugs may be “severely limited due to a
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`short GI-transit time” and are “variable and unpredictable.” Id., 47.
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`Thus, “most oral dosage form[s] are limited to a 12-hour period.” Id.
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`Shojaei unexpectedly prolonged ADHD therapy to 16 hours, essential
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`for longer work days. Decision 4 (citing EX1001, 3:34-49); EX2001,
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`¶¶23, 140-156; EX2002, ¶¶116-117, 130-132; EX2060, ¶12.
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`Petitioner uses guesswork and hindsight to argue superficial paradigms that
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`its experts knew were not universal and were unpredictable for amphetamine.
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`Artisans were motivated away from sustained release and would not expect
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`success, especially using untried double-coated inside-out SR beads, combined
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`with IR and DPR beads, for tolerance-prone amphetamine.
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`B.
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`The Posture of This IPR
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`The Board is considering whether Shojaei’s claims are unpatentable, under a
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`post-institution standard, in light of additional and uncontroverted evidence.
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`Petitioner relies on Burnside (EX1002), the primary reference during prosecution,
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`with or without ADDERALL XR (EX1003, EX1031). Decision, 5. The Board is
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`also considering whether PK parameters in claims 5-12 and “no food effect” in
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`claim 19 are inherently obvious. Id., 27-29.
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`Regarding Ground 1, no claim is expressly or inherently anticipated because
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`Shojaei’s three-bead, three-mode, IR-DPR-SR formulation is missing from
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`Burnside. Decision, 33-34.
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`Regarding Ground 2, Burnside used IR and DPR beads, and rejected SR
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`release as “not suitable,” because of obstacles like “biological tolerance” (EX1002,
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`1:21-2:1). Amphetamine’s effects “may rapidly dissipate, even though plasma
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`levels of the drug are still increasing.” EX2059, 1. Burnside’s inside-out SR bead
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`was unconventional in structure and untried in function. It had no ordinary purpose
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`or predictable in vivo or therapeutic results alone or in combination. Artisans had
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`no motivation to rearrange Burnside, combine it with ADDERALL XR, or use a
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`discarded SR bead. They had no reasonable expectation of success.
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`Regarding Ground 3, ADDERALL XR (EX1003, EX1031) did not add
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`substance to Burnside. No longer-day therapy, SR bead, or three-bead results were
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`contemplated.
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`The PK parameters in claims 5-12 are not inherently obvious. Burnside does
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`not disclose any IR-DPR-SR bead ratios. Different coating thicknesses, and doses
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`or ratios of beads yield different, not necessarily identical, PK results. EX1001,
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`4:64-5:18; EX2070, 42:4-9, 96:1-7; EX2002, ¶¶6-7, 79-84; EX2060, ¶¶195-210.
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`“No food effect” in claim 19 is not an inherent amphetamine property and
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`formulation results were unpredictable. EX2002, ¶¶85-92, 133-141; EX2060,
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`¶¶212-218.
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`Shojaei’s claims are patentable. In addition to pre-trial evidence, Patent
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`Owner provides: (1) a Declaration of Dr. James Polli (EX2060); (2) Exhibits 2058-
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`2081; and (3) cross-examination testimony of Drs. Jusko and Burgess (EX2070;
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`EX2071). Dr. Polli has hands-on experience with amphetamines. EX2060, ¶7. Drs.
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`Jusko and Burgess have none. EX2070, 15:17-16:1 (“No, I have not”); EX2071,
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`37:5-22 (“I do not think that I have”).
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`II.
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`SHOJAEI– A THREE COMPONENT, THREE DELIVERY (IR-DPR-
`SR) AMPHETAMINE DOSAGE SYSTEM
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`The Shojaei patent was applied for on May 12, 2006. It covers Shire’s
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`Orange Book-listed MYDAYIS® product, approved for a once-daily 16-hour
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`treatment for ADHD. EX2003, 1-3, 6; EX2005, 2. Claim 1 provides a three-bead
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`amphetamine pharmaceutical treatment, comprising “an immediate release
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`component, a delayed pulsed release component and a delayed sustained release
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`component.” EX1001, claim 1, 3:61-64, 5:19-28, 18:64-21:40. The SR component
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`has unusual reversed layers disclosed in Burnside but not tried until Shojaei – a
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`pH-independent coating surrounds an enteric coating. Id., 4:16-55. Nobody could
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`predict how that structure would perform in vivo.
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`The result was a non-obvious treatment that met “therapeutic needs for
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`ADHD patients with longer-day demands” Decision, 3 (quoting EX1001, 3:61-65).
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`This encompassed a 16-hour treatment. Decision, 3-4 (quoting EX1001, 3:54-57);
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`EX1001, 6:42-46, 17:45-50. The invention went against the state of the art and was
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`surprisingly effective.
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`A. The Invention and Its Technical Background
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`An oral pharmaceutical treatment must send its drug into the gastrointestinal
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`(“GI”) tract (release), then into the bloodstream (absorption), then to targeted tissue
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`(disposition), and must yield an effective treatment (results). The pharmacokinetics
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`(PK) of a drug describe its rise and fall in the bloodstream. Disposition and
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`physiological effects are called pharmacodynamics (PD). Therapeutic efficacy is
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`the desired result. EX2001, ¶48; EX2002, ¶¶41, 73; EX2023, 4-5.
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`Separate amphetamine doses from three types of beads, each with a different
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`mode of release, act sequentially to achieve Shojaei’s extra-long-acting purpose.
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`IR starts in the stomach, is rapid, and is first to reach the small intestine for
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`absorption. DPR is next and also rapid, but has a lag time before commencing. SR
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`has a lag time and then slowly releases to finish last. The onset, rate, and duration
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`of each release occurs at different times, pHs, and locations in the GI tract. This
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`has a profound effect on amphetamine absorption and therapeutic results. EX2001,
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`¶¶32-37, 52, 135; EX2002, ¶¶44-48, 63-65, 73; EX2060, ¶¶43, 48, 50, 64, 127,
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`142, 145, 183, 184.
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`Everyone working with amphetamine knew that it produces acute tolerance
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`when treating ADHD. EX2053, 3; EX2044, 7; EX1031, 9. As Dr. Polli explains,
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`acute tolerance is the rapid dissipation of the clinical effects of amphetamines after
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`the drug produces its initial effects, even though plasma concentration is level.
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`EX2060, ¶156 (citing EX1018, 2:43-44; EX 2053, 1; EX2044, 7; EX2045, 2).
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`There is a dissociation between the time course of plasma levels and
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`amphetamine’s effects. Id. (citing EX2053, 3). Acute tolerance causes “reduced
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`efficacy of sustained-release preparations.” EX2045, 2. Thus, controlled-release
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`once-daily formulations must provide a tolerance-avoiding plasma profile.
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`EX2033, 1. This made pulsatile release the state of the art. Because of acute
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`tolerance (a/k/a tachyphylaxis), “[i]ncreasing blood levels with a delayed drug
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`burst is intended to provide sustained therapeutic benefit” for stimulants. EX1010,
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`2; EX1022, 10; EX2045, 2. A component that induces tachyphylaxis would rob a
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`pharmaceutical treatment of its ability to treat disease. This taught away from any
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`motivation to combine an SR bead with IR and DPR beads according to Shojaei’s
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`claims, and forestalled any expectation of success. EX2060, ¶¶156, 159, 162-166,
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`179-180; EX2061, 2; EX2046, 8.
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`Despite its pervasive presence in the literature, Dr. Burgess did not know
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`about acute amphetamine tolerance. EX2071, 125:7-8, 13-14, 20-23. Dr. Jusko
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`unaccountably misstated that amphetamine does not display tolerance in relation to
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`ADHD. EX2070, 26:11-14. Both experts erroneously relied on limited in vitro
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`drug release tests, without considering any in vivo human consequences. There was
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`no in vivo data in the prior art by which to make any comparisons and predictions
`
`leading to a successful longer-acting ADHD therapy based on SR amphetamine,
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`especially using an atypical inside-out coating structure. Absorption and PK are
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`not foreseeable from dissolution testing. Even without complications from
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`tolerance:
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`Although scientists wish to establish in vitro–in vivo correlations
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`between release of drug from the formulation and drug
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`absorption, the limited knowledge of the