`
`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 IPR2018-00290
`US Patent No. 8,846,100
`____________________
`
`
`
`PATENT OWNER SUR-REPLY
`
`
`
`
`
`
`
`
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`TABLE OF CONTENTS
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`Page
`
`
`Summary of Patent Owner’s Argument ......................................................... 1
`I.
`II. No Motivation or Reasonable Expectation of Success .................................. 2
`A.
`Petitioner Has Not Shown that Acute Tolerance Would Be
`Disregarded by a POSA Faced With Shojaei’s Objectives.................. 2
`Petitioner Has Not Shown that GI Barriers Would Be
`Disregarded by a POSA Faced With Shojaei’s Objectives.................. 9
`The Prior Art Taught Away from the Invention ................................ 12
`C.
`III. No Claims are Inherently Obvious ............................................................... 13
`IV. Two Points: Dosage Claims and Objective Evidence .................................. 15
`
`B.
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`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)
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`2030 Rowland, Clinical Pharmacokinetics 2d (1989)
`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)
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`2062 Goodman & Gilman, 9th ed. (1996), Preface
`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)
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`2081 Dokoumetzidis, International J. Pharm., 321, 1-11 (2006)
`2082 McCRACKEN DEPOSITION TRANSCRIPT (February 27, 2019)
`2083 290-2083 Swanson, J. Child Psychol. Psych. 50, 1-2, 180-193 (2009)
`2084 McCracken Exhibit 612; Enlarged Page from EX1059.
`2085 McCracken Exhibit 615; U.S. Patent No. 8,846,100 (the “‘100 patent”) (Marked)
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Copaxone,
`906 F.3d 1013 (Fed. Cir. 2018) .................................................................... 11, 14
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 11
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ............................................................................ 6
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 13
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 12
`Par Pharm., Inc. v. Twi Pharms., Inc.,
`773 F.3d (Fed. Cir. 2014) ................................................................................... 14
`In re Rijckaert,
`9 F.3d at 1533-34 ................................................................................................ 14
`Santarus, Inc. v. Par Pharmaceutical, Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 14
`
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`IPR2018-00290
`Patent Owner’s Sur-Reply
`PATENT OWNER’S SUR-REPLY
`
`I. SUMMARY OF PATENT OWNER’S ARGUMENT
`Petitioner’s Reply is plagued by pervasive hindsight and dispositive errors.
`
`First, Petitioner repeatedly misuses the challenged patent itself (Shojaei) and
`
`the success of the invention, as prior art. A POSA’s “motivation” cannot come from
`
`Shojaei’s “intent” to use IR-DPR-SR beads. Reply, 2-4. Shojaei cannot be the prior
`
`art basis for a “reasonable expectation” of a POSA’s success. Id., 6. Contrary to
`
`Petitioner’s post-hoc assertions, gastrointestinal and acute tolerance barriers were
`
`not fictional to a POSA. That would be convenient for Petitioner, but the evidence
`
`proves otherwise. Reply, 6, 11-12. Shojaei’s discoveries of a PK profile goal, and a
`
`formulation to meet the goal, are evidence of invention, not obviousness. EX1001,
`
`Fig. 9. Likewise, effective PK parameters are not obviously inherent because of
`
`dose and bead ratios found only in Shojaei’s examples. Reply, 22. “No food effect”
`
`is not inherent in amphetamine per se, or in Shojaei’s formulation. Petitioner’s
`
`assertions about different products are irrelevant, and different results for different
`
`products are admittedly possible. EX2082, 208:4-209:8; Reply, 17. The problems
`
`were real. Shojaei’s unpredictable solution was not in the prior art.
`
`Second, Petitioner’s new expert, Dr. McCracken, is unreliable and not
`
`credible. He testified that “[t]here was not evidence [of amphetamine acute
`
`tolerance] in the literature, to my knowledge, as best as I can recall, prior to 2003,
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`IPR2018-00290
`Patent Owner’s Sur-Reply
`nor since.” EX2082, 18:23-25. However, Dr. McCracken himself, his co-authors,
`
`and others, reported it repeatedly. EX1014, 11; EX2046, 8; EX2045, 2; EX2044, 7;
`
`EX2061, 1-2. He finally admitted on cross-examination that acute tolerance “has
`
`been invoked” for amphetamine. EX2082, 29:5-9.
`
`II. NO MOTIVATION OR REASONABLE EXPECTATION OF SUCCESS
`Petitioner says all obstacles between drug release and prolonged treatment
`
`are fiction; this is contrary to the prior art and to Dr. McCracken. A POSA would
`
`not reasonably expect success.
`
`A. Petitioner Has Not Shown that Acute Tolerance Would Be
`Disregarded by a POSA Faced With Shojaei’s Objectives
`Dr. Polli explained that SR dosing was unlikely to yield effective brain
`
`stimulation and prolong ADHD treatment, because of acute tolerance. EX2060,
`
`¶¶156-166, 138, 142, 146, 151-154; EX1046, 23, 39, 42, 57. Drs. Trout and
`
`Rosenbaum concur. EX2001, ¶¶111, 128, 146-152; EX2002, ¶¶128-129. Dr.
`
`Burgess maintained ignorance. EX2071, 24, 125. Dr. Jusko backpedaled. EX2070,
`
`13-14 (yes to hysteresis), 29 (no data). Despite a POSA’s perspective, Dr.
`
`McCracken says he personally doesn’t believe in acute tolerance, because
`
`ADDERALL XR overcame it. EX2082, 37:5-10, 38:4-18, 29:5-9, 30:16-31:18.
`
`Amphetamine is known to lose efficacy because of acute tolerance. EX2053,
`
`3; EX2044, 7; EX1031, 9. There is “discordance” between the time course of
`
`effect and plasma concentration, called hysteresis. EX2070, 13:11-14:10; EX2060,
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`¶160-161. Even Dr. McCracken acknowledged this. EX2082, 154:9-16. Acute
`
`tolerance is a formulation/delivery problem; efficacy declines during or between
`
`doses, not immediately or totally. See EX2070, 29 (“hours”); EX2045, 8; EX2082,
`
`25:4-10 (“course of a day”); EX2061, 6 (medication interval). Thus, Dr.
`
`McCracken misrepresented Spencer, Kratochvil, and Swanson 1999 as calling for
`
`“sudden” and therapeutically complete decline “shortly after administration,”
`
`which no references say. EX2082, 155:7-156:15; 160:6-163:13; 54:20-55:5.
`
`Petitioner argues “no such thing as acute tolerance” because the “two
`
`pulses” of XR work and “superposition” by earlier pulsatile doses would protect a
`
`later SR dose. However, XR was unique; its pulses in the small intestine are within
`
`4 hours. It targeted rapidly ascending absorption to overcome tolerance, and it is
`
`therapeutic for 12 hours. EX1031, 9; EX2070, 13:11-14:10; 27:4-29:4; EX1002,
`
`1:21-23, 31-35; EX1018, 1:42-46, 2:43-47; EX2044, 7. It avoided tolerance with
`
`pulses (not SR), as designed, and was a “home run.” EX2082, 104:11-25.
`
`Petitioner now claims that XR provided “tolerance protection” for an
`
`additional, later SR dose. This notion is not in the prior art; it is new and wholly
`
`unsubstantiated. It improperly relies on a post-hoc and untested 2019 interpretation
`
`of a PK profile taken from the patent. EX1001, Fig. 9. For example, if Shojaei
`
`overcame tolerance because of Dr. McCracken’s idea that the “cumulative PK
`
`curve” for IR-DPR-SR composition in Fig. 9 of the patent “is unrecognizable as
`
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`Patent Owner’s Sur-Reply
`having a separate sustained release component,” that curve (and conclusion) was
`
`not in the prior art. EX1058, ¶73. Moreover, Dr. McCracken admitted that the 80-
`
`hour scale in Fig. 9 obscures the SR contribution. EX2082, 188:8-22. Artisans
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`never expected, and the prior art provides no basis for expecting, two pulses to
`
`“smoothly” protect a later SR from tolerance. EX1058, ¶¶71, 74. There was no
`
`expectation, from “superposition” or otherwise, that XR would continuously
`
`counteract tolerance and would protect additional SR dosing. There is no evidence
`
`that this is how Shojaei’s invention even works. EX2060, ¶¶156-166; EX2002,
`
`¶¶129-132; EX2045, 2; EX2053, 3; EX2046, 8; EX2061, 2.
`
`Longer ADHD treatment is not reasonably predictable from a hypothetical
`
`or post-hoc “superposition” of amphetamine doses, where successive amphetamine
`
`releases are effective, regardless of tolerance or any other variables. Reply 10-11;
`
`EX1058, ¶¶68-78; EX2082, 41:23-24. Tolerance in particular actively thwarts
`
`superposition by disconnecting absorption and efficacy. The time course of PK and
`
`clinical results do not predictably correspond. EX2060, ¶¶151-156, 161. Here,
`
`results were especially unpredictable because combinations involving pulses and
`
`SR were previously unknown, and inside-out SR beads were untried.
`
`Petitioner’s claim that Dr. McCracken’s 2003 study (EX1037, EX1057)
`
`disproved tolerance is simply untrue. He conceded that “There is nothing about
`
`acute tolerance” in his study design. EX2082, 77:7-9, 66:18-20; EX1057, 691.
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`Precise PK and PD relationships were “beyond the scope of this article.” EX1037,
`
`11. Comparison to other studies was difficult. Id. His two articles did not report
`
`any findings about an absence of amphetamine acute tolerance, especially for an
`
`SR product. They could not, because they studied pulsatile ADDERALL XR, not
`
`SR for longer-day therapy. Indeed, his “highly cited” work was never cited to
`
`disprove tolerance or to ratify SR amphetamine. EX2082, 66:6-17.
`
`Sixteen years ago, Dr. McCracken wrote that, given his 2003 study’s “high
`
`variability and relatively few subjects …, further analyses of the relationship
`
`between blood concentrations and response were not feasible.” EX1057, 8. This
`
`relationship is the essence of tolerance. 1 Then, just weeks ago, the unfeasible
`
`became feasible. He reinterpreted his study to conclude that, because double-pulse
`
`ADDERALL XR (IR+DPR beads) avoided acute tolerance, amphetamines in any
`
`form never displayed tolerance and never would. He testified that even a person
`
`more qualified than a POSA was not qualified to do this recalculations; only he
`
`could. EX2082, 184:19-22, 187:3-20. A POSA could not reach his conclusion.
`
`
`1 In each experimental cohort (dosage form and dose) he relied on no more than
`
`9 subjects, from a pre-randomization pool of 51 subjects. His criticism of other
`
`studies as underpowered would apply to his own work. EX1058, ¶¶48, 55; Reply,
`
`13; EX1057, 5, Table 3; EX2082, 124:2-24, 128:10-14; 176:7-13.
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`Indeed, Dr. McCracken’s 2003 study shows XR’s loss of efficacy over time
`
`versus placebo, but this indicates XR was a successful anti-tolerance product, not
`
`that amphetamine is tolerance-free. EX1058, ¶¶71-78; EX1014, 11; EX2046, 8.
`
`Petitioner suggests unpredictability from complicating factors, like patient fatigue,
`
`instead or in addition to tolerance, to no avail. EX2044, 7; EX2053, 3. See Depuy
`
`Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326-1327 (Fed. Cir.
`
`2009). Amphetamine’s long half-life in the blood does not dispose of tolerance or
`
`unpredictability either, because amphetamine nonetheless has a relatively short
`
`efficacy. Artisans understood that efficacy depends on a unique, steep pace for
`
`absorption, not an anti-tolerance half-life. EX2082, 20:4-18; 23:3-13.
`
`Petitioner reacts to all of the prior art obstacles by casting the literature and
`
`Dr. Polli as naïve. Reply, 9-12. However, Dr. Polli studied XR; he “perform[ed]
`
`the IVIVC analysis for Shire.” EX1046, 114. The evidence shows clearly that the
`
`literature was not wrong and persistently warned of acute amphetamine tolerance.
`
`For example, Brown’s SR results showed acute tolerance, because duration
`
`of efficacy was “not correlated with specific plasma levels of d-amphetamine.”
`
`EX2065, 13. Amphetamine is short-acting despite a long half-life (id., 10),
`
`indicating a “behavioral half-life,” where “clinical effect from both stimulants is
`
`related to the absorption phase” (id., 11). SR results “would not lead one to predict
`
`a prolonged response.” Id., 13; EX2082, 111:6-13; 347:12-19; EX2060, ¶¶178-180.
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`Petitioner misapplies a few articles to suggest tolerance was a myth, but the
`
`record shows it was a real issue that artisans took seriously. For example, Pelham
`
`is cited for some SR effects, but “the prevailing belief” in a need for rapid
`
`absorption to overcome tolerance was still “a reasonable hypothesis.” EX1052, 4,
`
`11. Likewise, James had results for unspecified SR spansules, but his study “was
`
`marginal for fully exploring drug-drug differences.” EX1053, 8. He “may have
`
`missed the peak efficacy” (id., 7), so post-peak decline and tachyphylaxis could not
`
`be studied. EX2060, ¶¶146, 151, 161-162; EX1058, ¶¶62. Worse, Dr. McCracken
`
`says James used an actometer that “doesn’t really have any clinical application or
`
`meaning” (EX2082, 162:10-163:25), but his opinion uses it to question tolerance
`
`(id., 168:4-11). Contrary to Petitioner, these references did not disprove tolerance.
`
`At the very least, they added confusion.2 Overall, Brown had PK profiles and
`
`direct comparison to clinical effects. EX2065, 6, 7. Pelham and James did not.
`
`EX2082, 165:19-166:13. The literature did not provide any predictable tolerance-
`
`free path to successful longer-day SR for amphetamine and ADHD.
`
`Tolerance could not be assessed, because the results “did not identify a clear
`
`relationship between drug concentration levels and behavioral response.” EX1057,
`
`
`2 The spansules in Brown, Pelham, and James may or may not be the same,
`
`making predictions improbable. EX2082, 159:8-19, 160:16-22.
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`IPR2018-00290
`Patent Owner’s Sur-Reply
`7. In McGough, Dr. McCracken cited Brown to highlight “individual variability in
`
`response to amphetamine.” EX1057, 1, 6. Like Brown, McGough linked “the
`
`sustained absorption phase of [ADDERALL XR]” to its efficacy. EX1057, 6
`
`(emphasis added). Notably, “further analyses … were not feasible” beyond a single
`
`dose Id., 8. “Additional work is required to assess the pharmacokinetic and
`
`pharmacodynamic relationships” (id.).
`
`Shojaei’s invention was also unpredictable because the literature described
`
`tachyphylaxis for stimulants, including amphetamine, and warned against SR
`
`dosing for longer-day treatment. Brauer reported the same dissociation between
`
`plasma amphetamine and efficacy noted by Dr. Jusko, which made acute tolerance
`
`“the most likely explanation,” even without placebo. EX2053, 2, 3; EX2070,
`
`13:11-14:10. Tulloch described “little correlation between serum levels and
`
`behavioral effects.” EX1014, 11. XR replicated “ascending” PK results, probably
`
`by “extending the absorption phase.” Id. Spencer taught “ascending or pulsing” PK
`
`profiles for ADHD efficacy, which XR used “to overcome acute tolerance.”
`
`EX2046, 8. Swanson 1999 reported tolerance explicitly for amphetamine. EX2045,
`
`2. Greenhill explained a post-peak decline in efficacy (hysteresis) as “the presence
`
`of tolerance,” with complicating factors. EX2044, 7. Swanson 2005 explained that
`
`maintaining peak amphetamine falters therapeutically. EX2061, 1. “Acute
`
`tolerance” was the predictable culprit. Id., 5.
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`IPR2018-00290
`Patent Owner’s Sur-Reply
`In 2009, after Shojaei, Swanson reported the “consensus opinion,” namely
`
`“a PK profile with peaks and valleys to produce and maintain clinical efficacy,
`
`which implied an inherent limitation on CR [controlled release] formulations.”
`
`EX2083, 3. Acute tolerance was implicated. Id., 3, 4.
`
`Greenhill, Tulloch, Spencer, and Swanson are Dr. McCracken’s co-authors.
`
`EX1037; EX1057; EX2082, 64:2-65:4. But Dr. McCracken, now considers them,
`
`and everyone else, somehow unqualified and totally wrong. EX2082, 184:19-22,
`
`187:3-20 (Swanson); EX1058, ¶¶57-63. From vague statistical rigmarole, Dr.
`
`McCracken now reinterprets 2003 work to argue conclusions impossible earlier or
`
`unavailable to anyone else even today. EX2082, 30:16-21, 91:15-97:17. He now
`
`claims superior knowledge, beyond the prior art and beyond a POSA. Decision, 9-
`
`10; Response, 15-17. For a POSA at the time of Shojaei, there was no reasonable
`
`expectation of success.
`
`B. Petitioner Has Not Shown that GI Barriers Would Be Disregarded
`by a POSA Faced With Shojaei’s Objectives
`Dr. Polli explained that effective late absorption of SR amphetamine was
`
`improbable because of GI obstacles – absorptions worsens along the way, especially
`
`in the colon. EX2060, ¶¶48-50, 64-65, 88, 142, 146, 221; EX1046, 23-24, 27, 30, 36-
`
`38. Drs. Trout and Rosenbaum concur. EX2001, ¶¶36, 40, 47, 52, 126-137, 147, 162,
`
`165; EX2002, ¶¶26-28, 43-45, 120-127. Dr. Jusko was blind to problems. EX1006,
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`IPR2018-00290
`Patent Owner’s Sur-Reply
`¶¶39-41; EX2060, ¶127. Dr. Burgess put her faith in Dr. Jusko. EX1004, ¶¶87, 141.
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`Dr. McCracken opined on tolerance and food effect, not GI issues. EX1058, ¶5.
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`“Too slow, too little, too late” is a tough problem, particularly for SR, and
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`SR amphetamine “can cause problems given late in the day.” EX2082, 34:2-15.
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`Thus, no automatic “positive effect” is conflated with a mere release of drug “into
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`the circulatory system,” regardless of all other factors. Reply, 7. A dose will be
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`therapeutic only if, when, and to the extent absorption is effective. To a POSA, this
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`was unpredictable. EX2060, ¶¶43-47.
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`True to form, Petitioner discounts GI barriers by disregarding the prior art in
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`favor of improper hindsight from Shojaei’s success. Reply, 5-6, 8; EX1058, ¶¶107-
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`108. Artisans had no such guidance. Burnside’s “inside-out” SR bead was untried
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`and doubtful. EX2060, ¶88. No in vivo or PK data were available. Nothing enabled
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`artisans to translate bare in vitro release into a prediction of prolonged efficacy.
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`EX2034, 47; EX1001, 3:34-49; EX2001, ¶23, 140-156; EX2002, ¶¶116-117, 130-
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`132; EX2060, ¶¶46, 54-55, 59-61, 64-66, 88. For example, PULSINCAP, cited by
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`Petitioner, had a late pulsatile release in the “e.g., colon” (EX1058, ¶108), but
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`produced “no measurable amounts” of circulating drug, likely from poor distal GI
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`absorption. EX1001, 2:58-3:5; EX2060, ¶176. “Compensation for changing
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`absorption characteristics in the gastrointestinal tract” was unpredictably difficult,
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`especially after 12 hours. EX1001, 1:44-52; EX2034, 47.
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`Burnside did not teach SR “in combination with other bead types.” Reply, 9.
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`See Inst. Dec., 32-33; EX2001, ¶¶63-70; EX2060, ¶70. Dr. McCracken proclaims
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`incredibly that SR was Burnside’s “heart and soul” (EX2082, 204:15-23), but cites
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`“delayed release” in Fig. 6 (DPR not SR) as support. Id., 204:15-205:23. He admits
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`a combination with Example 4 “is not described.” Id. 206:10-17.
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`Burnside did review formulation issues in a disclosure all about amphetamine.
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`Contrary to Petitioner, artisans would not ignore such warnings as “general” and not
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`for amphetamines. Reply, 9. Artisans would heed what Burnside told them.
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`EX2001, ¶¶40, 73, 91, 110, 135; EX2060, ¶¶41, 82, 165. Burnside also disclosed
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`optional protective layers (EX1002, 3:65) to accomplish “delayed pulsed release”
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`(id., 5:60-63; 5:43-45), i.e. DPR, not SR, as Petitioner contends. EX2082, 207:8-21.
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`Petitioner’s prior art had no helpful PK and bioequivalence data, no PK/PD
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`correlation, and no mechanism of action. It consequently cannot support
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`Petitioner’s obviousness arguments. In re Cyclobenzaprine, 676 F.3d 1063, 1070
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`(Fed. Cir. 2012). Petitioner’s use of In re Copaxone, 906 F.3d 1013, 1028-29 (Fed.
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`Cir. 2018) is inapposite, because no clinical studies guided artisans to Shojaei’s
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`invention. On the contrary, “double-pulsed” XR has a rapidly rising PK curve; not
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`sustained. EX1031, 1-2, Fig. 1. Dr. McCracken noted DEXEDRINE SR Spansules,
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`but no data or details informed a POSA what is meant by the statement, “an initial
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`dose is released promptly and the remaining medication is released gradually.”
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`EX1054, 1. Dr. McCracken agreed there is no record of what Spansules were, how
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`they worked, or their release or PK properties. EX2082, 160:16-22. A POSA
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`understood that Spansules (1) “can cause problems given late in the day.” EX2082,
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`34:2-15; and (2) high amphetamine blood levels from a long half-life do not
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`prolong efficacy. Reply, 7-8; EX2061, 5; EX1031, 2 (Fig. 1). No barrier-busting,
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`late-day IR-DPR-SR combination was suggested by the prior art.
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`C. The Prior Art Taught Away from the Invention
`The references also “teach away” from the invention. The art emphasized,
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`and a POSA knew, that pulses were needed; SR would fail. This included Burnside
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`and ADDERALL XR. Prevailing wisdom was strongly “divergent from [Shojaei’s]
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`path.” Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877, 885
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`(Fed. Cir. 1998).
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`Couch (EX1023) did not supplant the prior art and lead artisans to Shojaei.
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`For example, Dr. McCracken deliberately confounded pulses with SR, while
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`saying Couch showed “the ability of the dual beaded formulation within Adderall
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`XR to [mimic] BID dosing of IR,” not SR. EX2082, 40:17-41:18. Dr. Burgess was
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`contradictory, saying Couch taught one SR bead. EX2071, 90:21-91:2. Dr. Jusko
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`was silent. Drs. Polli and Trout explained why Couch did not overturn the anti-SR
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`wisdom. EX2060, ¶¶84,163, 169-175, 180; EX2001, ¶¶130, 134.
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`III. NO CLAIMS ARE INHERENTLY OBVIOUS
`The food effect and PK claims are not inherently obvious. Express prior art
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`teachings must detail everything needed for inherent success; extrinsic guidance
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`and hindsight are prohibited. In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011).
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`Inherency is not “presumed” or “assumed,” as Dr. McCracken used the term.
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`EX2082, 47:25-50:9. It means proven immutability, not being “struck” by absent
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`exceptions, as Dr. McCracken said he was. Id., 208:4-209:1; EX1058, ¶¶99-100.
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`Amphetamine as a compound is not inherently food-friendly merely because
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`Petitioner says that MYDAYIS joined other FDA-approved products. Reply, 16-
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`17. FDA would not need tests for a “given” property. Also, “no food effect”
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`mitigates side effects. EX1058, ¶92. Marketing other products with this peripheral
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`advantage cannot prove inherency. ADDERALL XR was different and double-
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`pulsed. Dexedrine, Dyanavel, and Adzenys are of unspecified date, composition,
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`and lack PK data. Each formulation was tested, not plain amphetamine. EX1031,
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`2; EX1054, 1-2; EX1055, 9-10; EX1056, 17-18. Worse, Petitioner purports to
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`establish “no food effect” by questioning the scope of Shojaei’s claims under §112
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`(Reply, 17), which is out of bounds in an IPR, and cannot prove facts about
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`amphetamine. No evidence establishes an inherent “no food effect.”
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`The claimed PK values are not inherent, either. They are therapeutically
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`consequential. The prior art lacks the required explicit means to always provide
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`them. Par Pharm., Inc. v. Twi Pharms., Inc., 773 F.3d, 1186, 1196 (Fed. Cir. 2014).
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`Dose, bead ratio, and coating thickness combinations to provide the claimed results
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`are missing from the prior art. Petitioner’s extraneous and hindsight manipulations
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`to reach the right results are prohibited. In re Rijckaert, 9 F.3d at 1533-34.
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`Petitioner’s references did not “expressly teach” dosages and ratios to assure
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`claimed results. Cf. Santarus, Inc. v. Par Pharmaceutical, Inc., 694 F.3d 1344,
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`1353-1354 (Fed. Cir. 2012). There were no admissions about inherent properties of
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`an explicit formulation. Cf. In re Copaxone, 906 F.3d 1013, 1030 (Fed. Cir. 2018).
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`By saying “if” the right 37.5 mg dosage is “arbitrarily” used (Reply, 22),
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`Petitioner admits no inherency; this feature was undisclosed and makes a
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`difference, regardless of “other claimed dosages” (id., 20-21). FDA’s use of
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`bioequivalent PK data for generic drug approval is similarly irrelevant. Id. Shojaei
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`achieved surprising bioequivalence. His new PK results, and his confidence in late-
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`day efficacy, do not prove a POSA’s expectations. Id. Whether the patent includes
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`data from clinical efficacy trials does not prove a POSA’s expectations, either. It
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`cannot be of “no advantage” (id., 20) or insufficiently “unique” (id., 21) that
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`Shojaei tackled and solved this problem (EX1001, 3:53-62), which Petitioner cites
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`for motivation and success (Reply, 2, 4) but devalues here (id., 20-21).
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`Ratios for a three-bead composition are missing from the art, and matter for
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`the outcome. Tmax and Cmax vary, with different doses in different beads
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`releasing at different times and rates. EX2070, 96:1-6. AUC varies, with different
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`beads absorbing differently at different GI locations. EX2060, ¶¶204-205. Trying
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`different things that are not explicit in references is the antithesis of inherency. A
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`hindsight process of elimination compounds the error. Reply, 27. By arguing in
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`circles that “obvious to try” proves inherency, and inherency proves obviousness,
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`Petitioner disproves its own case. Reply, 21-22.
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`Petitioner has no expert support for its PK arguments. Dr. Jusko admitted the
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`art is deficient and results are variable. EX2070, 43:4-13, 96:1-6, 97:25-98:10. Dr.
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`Polli was blatantly misapplied. EX1046, 123-124. Dr. McCracken contemplated
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`XR and tolerance, not doses and bead ratios. EX1058, ¶¶5, 34-44. No one else
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`helped. Reply, 19-22. A missing dose and ratio of IR-DPR-SR beads, plus
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`thicknesses, cannot be imposed on the references, to reach missing PK parameters.
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`IV. TWO POINTS: DOSAGE CLAIMS AND OBJECTIVE EVIDENCE
`• Hindsight overlap with XR doses cannot make Shojaei’s doses predictable.
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`• A POSA’s long-felt need for longer-acting ADHD therapy is not rebutted
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`by hearsay “business reasons” to delay MYDAYIS. Reply, 15. And MYDAYIS had
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`rapid sales at launch, despite XR + IR, which no exclusivity blocks. EX2055, 2, 4.
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`* * * * *
`Petitioner has failed to establish that any challenged claim is unpatentable.
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` Respectfully submitted,
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`/Joseph R. Robinson/ (Reg. No. 33,448)
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`Dated: March 7, 2019
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`CERTIFICATE OF SERVICE
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`The undersigned hereby certifies that a