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
`
`_______________________
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S SUR-REPLY
`
`
`
`
`
`
`
`
`
`______________________
`
`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
`
`_______________________
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S SUR-REPLY
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`MOTIVATION AND REASONABLE EXPECTATION OF SUCCESS ......................... 1
`THERE IS NO ACUTE TOLERANCE WITH AMPHETAMINE PRODUCTS ........... 3
`A.
`McCracken’s 2003 Paper Showed that Loss of Therapeutic Efficacy in
`Amphetamine ADHD Medications was due to Late-Day Fatigue, not Acute
`Tolerance................................................................................................................. 3
`
`B.
`The Acute Tolerance Hypothesis was Based on Weak Studies .............................. 7
`C. Methylphenidate is Different from Amphetamine ........................................... 11
`
`INHERENCY OF FOOD EFFECT .................................................................................. 12
`
`INHERENCY OF PK CLAIMS ....................................................................................... 14
`
`i
`
`
`
`
`
`UPDATED EXHIBIT LIST
`
`1007
`
`1009
`
`1001 U.S. Patent No. 9,173,857 (the “‘857 patent”)
`1002 U.S. Patent No. 6,605,300 (“Burnside”)
`1003 PHYSICIANS’ DESK REFERENCE® 3144-3146 (58th ed. 2004)
`(“2004 PDR”)
`1004 Declaration of Diane J. Burgess, Ph.D.
`1005 Prosecution History of the ‘100 Patent
`1006 Declaration of William J. Jusko, Ph.D.
`Rong-Kun Chang et al., A Review of Aqueous Coating Techniques and
`Preliminary Data on Release from a Theophylline Product, 11 Pharm.
`Tech. 3, 56-68 (1987)
`1008 FDA: Center for Drug Evaluation and Research, Application No. 11-
`522, Approval Letter (Feb. 13, 1996)
`ORANGE BOOK: APPROVED DRUG PRODUCTS WITH
`THERAPEUTIC EQUIVALENCE EVALUATIONS, ADDERALL®,
`https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm. (last
`visited Aug. 16, 2017)
`1010 Christopher J. Kratochvil, MD, ADHD: Treatment and Outcome, 4
`Managing ADHD 3A, 1-4 (2004)
`David J. Heal et al., Amphetamine, Past and Present - a
`Pharmacological and Clinical Perspective, 27 J. Psychopharmacology
`6, 479-496 (2013)
`1012 C. Bradley, The Behavior of Young Children Receiving Benzedrine, 94
`Am. J. Psychiatry 1, 154-162 (1937)
`Drugs@FDA U.S. Food and Drug Administration, FDA Approved
`Drugs, Adderall XR®,
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overvi
`ew.process&ApplNo=021303 (last visited Aug. 16, 2017).
`Simon J. Tulloch et al., SLI381 (Adderall XR), a Two-Component,
`Extended-Release Formulation of Mixed Amphetamine Salts:
`Bioavailability of Three Test Formulations and Comparison of Fasted,
`Fed, and Sprinkled Administration, 22 Pharmacotherapy 11, 1405-
`1415 (2002)
`1015 U.S. Patent No. 4,728,512
`1016 U.S. Patent No. 5,326,570
`
`1011
`
`1013
`
`1014
`
`ii
`
`
`
`1021
`
`1025
`
`1017 U.S. Patent No. 8,313,776
`1018 U.S. Patent No. 6,555,136
`1019 U.S. Patent No. 6,322,819
`1020 U.S. Food and Drug Administration, Clinical Pharmacology and
`Biopharmaceutics Review, Application No. 21-303/S-001
`ORANGE BOOK: APPROVED DRUG PRODUCTS WITH
`THERAPEUTIC EQUIVALENCE EVALUATIONS, ADDERALL
`XR®, https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm.
`(last visited Aug. 25, 2017)
`1022 THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 62-83
`(Alfred Goodman Gilman et al. eds., 8th ed. 1990)
`1023 U.S. Patent Application Publication No. US2004/0059002
`1024 Agyilirah, G.A. and Banker, G.S., POLYMERS FOR CONTROLLED
`DRUG DELIVERY 39-66 (Peter J. Tarcha ed., 1991)
`Walter G. Chambliss, “The forgotten dosage form: enteric-
`coated tablets,” Pharmaceutical Technology, 7: 124-132, 138-
`140 (1983)
`1026 BIOPHARMACEUTICS AND RELEVANT PHARMACOKINETICS
`(John G. Wagner et al. eds., 1st ed. 1971)
`1027 REMINGTON THE SCIENCE AND PRACTICE OF PHARMACY
`(Limmer, 20th ed., 2000)
`1028 HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Ainley Wade
`& Paul J. Weller eds., 2d ed. 1994)
`1029 HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Arthur H.
`Kibbe ed., 3d ed. 2000)
`1030 INTENTIONALLY LEFT BLANK
`1031 FDA Adderall XR® Label, 2004 (Published August 2004)
`1032 FDA Adderall IR® Label, 2005 (Published June 2005)
`Susan B. Clausen et al., Single- and Multiple-Dose Pharmacokinetics of
`an Oral Mixed Amphetamine Salts Extended-Release Formulation in
`Adults, 10 CNS Spectrums 12 (Suppl 20), 6 (2005)
`1034 WO 99/66904
`1035 WO 98/27967
`1036 Pltff.’s Reply Claim Construction Brief, Shire LLC et al. v. Abhai, LLC,
`1:15-cv-13909-WGY (D. Mass. July 21, 2016), D.I. 73
`1037 James T. McCracken et al., J. Am. Acad. Child Adoles. Psych. (2003)
`Clive G. Wilson, GASTROINTESTINAL TRANSIT AND
`DRUG ABSORPTION, in DRUGS AND THE
`PHARMACEUTICAL SCIENCE: ORAL DRUG ABSORPTION
`
`1038
`
`1033
`
`iii
`
`
`
`1040
`
`PREDICTION AND ASSESSMENT (Jennifer Dressman & Hans
`Lennernäs, Vol. 106, 2000.)
`1039 J. Fallingborg, Intraluminal pH of the Human Gastrointestinal Tract, 46
`J. Health Sci. 183 (1999)
`J. Fallingborg et al., Measurement of Gastrointestinal pH and
`Regional Transit Times in Normal Children, 11 J. Pediatric
`Gastroenterology & Nutrition 211 (1990)
`1041 INTENTIONALLY LEFT BLANK
`1042 INTENTIONALLY LEFT BLANK
`1043 INTENTIONALLY LEFT BLANK
`1044 INTENTIONALLY LEFT BLANK
`1045 Declaration of James McCracken, M.D.
`1046 POLLI DEPOSITION TRANSCRIPT (January 17, 2019)
`Polli Deposition Exhibit 100, “Clinical
`Pharmacology/Biopharmaceutics Review” for Adderall XR (FDA
`April 2007).
`1048 Polli Deposition Exhibit 101, U.S. Patent No. RE41,148
`1049 FDA Review of Chemistry, Manufacturing, and Controls for
`Adderall XR (2000)
`1050 FDA Approvable Letter for Mydayis (2007)
`1051 FDA Summary Review for Mydayis (2017)
`Pelham 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,” Pediatrics, 86:2
`(August 1990)
`James et al., “Double-Blind, Placebo-Controlled Study of Single-Dose
`Amphetamine Formulations in ADHD,” J. Am. Acad. Child Adolesc.
`Psychiatry, 40:11 (November 2001)
`1054 Dexedrine® Spansule® Sustained Release Product Label 2007
`1055 Dyanavel XR® Product Label (2017)
`1056 Adzenys ER® Product Label (2017)
`McGough et al., “Pharmacokinetics of SLI381 (ADDERALL XR), an
`Extended-Release Formulation of Adderall,” J. Am. Acad. Child
`Adolesc. Psychiatry, 42:6 (June 2003)
`1058 Corrected Declaration of James McCracken, M.D., Feb. 26, 2019
`
`1057
`
`iv
`
`1047
`
`1052
`
`1053
`
`
`
`KVK-Tech, Inc. (Petitioner) submits its Response to the Sur-Reply of Patent
`
`Owner, Shire LLC regarding U.S. Patent No. 9,173,857 (“the ‘857 Patent”).
`
`I. Motivation and Reasonable Expectation of Success
`
`One of ordinary skill in the art in April 2006 (POSA) would have expected
`
`that the addition of SR beads from Burnside’s Example 4 to the IR + DR beads of
`
`Adderall XR (or Burnside Example 5) would release a third dose of amphetamine,
`
`after the initial IR and DR pulsed doses of Adderall XR are released. (Jusko
`
`EX.1006, ¶¶34-41,48; Burgess EX.1004, ¶66.)
`
`Patentee’s expert, Dr. Polli, agrees that “[t]he SR beads are releasing later
`
`and further along the GI tract than the IR and DPR beads.” (EX.2060, ¶204.) Dr.
`
`Trout, another one of Patent Owner’s experts, also stated that the SR beads would
`
`have been expected to release amphetamine in the intestines - later than the IR and
`
`DR beads (EX.2001, ¶165).
`
`Patent Owner now argues, however, that even if the amphetamine from the
`
`SR bead is released later, it may not necessarily translate to longer therapeutic
`
`effect due to absorption barriers in the colon. (Sur-Reply, pp. 9-12.)
`
`Dr. McCracken testified that a POSA would have understood that Burnside’s
`
`SR beads was specifically designed to release a majority of its amphetamine into
`
`the small intestine, where it is both readily absorbed and would avoid side effects.
`
`(EX.2082 41:25- 42:7; EX1058 ¶¶107-109.)
`
`
`
`
`
`Patent Owner’s expert, Dr. Polli, conceded that even though absorption is
`
`more difficult in the colon, “amphetamine is absorbed from the SR dose when it
`
`releases some or all of its dose in the lower small intestine and in the colon,”
`
`(EX.2060, ¶202), and once absorbed in the small intestines and colon, Dr. Polli
`
`conceded that “it could address that goal of extending the duration of therapy
`
`relative to Adderall XR.” (EX.1046, Polli Tr. 30:7-12.)
`
`In view of these admissions, Patent Owner should agree that adding the SR
`
`beads to Adderall XR would have been expected to extend efficacy. It certainly
`
`was what Patent Owner intended to happen when it added the SR beads to
`
`Adderall XR. (See EX.1046, p. 20:20-25; EX.1047, p. 1.)
`
`The clinical studies demonstrate that the longer amphetamine blood levels
`
`are sustained, the longer the amphetamine is effective to treat ADHD. For
`
`example, while Adderall IR has a Tmax of 3 hours and efficacy for 9-10 hours,
`
`Adderall XR has a Tmax of 7 hours and efficacy for at least 12 hours. (EX.1031, p
`
`1; EX.1058 (McCracken), ¶¶ 35-39.) Dexedrine IR v. SR also demonstrates that a
`
`later Tmax prolongs efficacy. (Dexedrine Label, EX.2084, p.3; McCracken,
`
`EX.1058, ¶52.)
`
`Accordingly, Adding the SR bead to Adderall XR would have been expected
`
`to extend efficacy.
`
`2
`
`
`
`II. There is no Acute Tolerance with Amphetamine Products
`
`Patent Owner devotes well over half of its 15-page sur-reply to one topic:
`
`acute tolerance; a topic Patent Owner didn’t argue during the original prosecution
`
`of the ‘100 and ‘857 patents (See EX.1005). Dr. McCracken is the only ADHD
`
`expert in this case, and his 2003 clinical study proves that amphetamine does not
`
`have an acute tolerance problem.
`
`A. McCracken’s 2003 Paper Showed that Loss of Therapeutic
`Efficacy in Amphetamine ADHD Medications was due to Late-
`Day Fatigue, not Acute Tolerance
`In 2003, Dr. McCracken published the results of his Adderall XR® study
`
`(EX.1037). This was the largest study at the time – investigating the therapeutic
`
`efficacy of Adderall XR® in 51 subjects. This study was motivated by the
`
`“surprising paucity of studies on the pharmacokinetic (PK) and behavioral time
`
`course of effects of low-dose amphetamine administration for ADHD (Brown et
`
`al., 1979, 1980; Pelham et al., 1999; Swanson et al., 1998).” (EX.1037 pp. 674,
`
`681; EX.1058 ¶¶ 31-32.)
`
`Patent Owner now relies on the same Brown (EX.2065) and Swanson
`
`(EX.2045) references, cited as inadequate by McCracken in 2003, to argue that
`
`acute tolerance is still a viable hypothesis. However, Dr. McCracken’s study shows
`
`that acute tolerance was never “the predictable culprit” causing the gradual
`
`3
`
`
`
`decrease in late-day therapeutic efficacy of amphetamine (Sur-Reply p. 8); rather,
`
`factors wholly unrelated to amphetamine are to blame.
`
`Dr. McCracken’s study showed that Adderall XR® exhibited robust, dose-
`
`dependent and statistically significant therapeutic efficacy that extended for at least
`
`12 hours (the final measurement time) for the Adderall XR® 20 and 30 mg doses
`
`when compared to placebo. (EX.1058 ¶34.) Dr. McCracken testified that the study
`
`confirmed robust 12-hour clinical efficacy lasting at least 5 to 7 hours beyond the
`
`point at which amphetamine plasma levels reach Cmax, which is not indicative of
`
`a rapid loss of efficacy that one would see with acute tolerance. (EX.2082 187:3-
`
`20.)
`
`While this alone would be sufficient to disprove the acute tolerance
`
`hypothesis, the data showed that the placebo group displayed a significant decline
`
`in SKAMP and PERMP rating scores1 between 4.5 and 12 hours. This decrease in
`
`efficacy for the placebo group was commensurately reflected in each and every
`
`dosage group receiving Adderall XR®. This can be seen below in Fig. 2 of
`
`EX.1037 (copied below), and in the enlarged section to the right that is marked to
`
`show the corresponding decline of therapeutic efficacy in patients treated with both
`
`placebo and 10mg of drug:
`
`
`1 These are standard assessment protocol used for evaluating the time-efficacy
`effects of ADHD drugs (EX.1058 ¶33).
`
`4
`
`
`
`
`
`
`
`
`
`Dr. McCracken concluded that “the respective slopes (i.e. rates) of declining
`
`SKAMP and PERMP scores from 6 hours to 10.5 hours are similar in the placebo
`
`and drug curves. Acute tolerance would predict loss of efficacy at a much faster
`
`rate than the placebo responses. Yet this was not the case for the 20 and 30 mg
`
`conditions until at least 12 hours after administration.” (EX.1058 ¶¶ 37-38.)
`
`
`
`This study underscored the importance of including a placebo group in time-
`
`efficacy studies of ADHD drugs. As Dr. McCracken explained, “[t]his repeated
`
`deterioration in placebo performance scores demonstrates the lack of clinically
`
`significant acute tolerance issues in amphetamines, instead confirming that any late
`
`day deterioration in therapeutic efficacy is likely attributable to normal common
`
`fatigue and decreased afternoon arousal,” and “[s]uch rigorous data from the
`
`largest pharmacodynamic study of amphetamines is a powerful rebuttal of the
`
`poorly substantiated and largely outdated (since well before 2006) claims of Dr.
`
`Polli.” (EX.1058 ¶¶39, 42.)
`
`5
`
`
`
`Patent Owner argues that this study is not relevant because it did not
`
`explicitly study acute tolerance in amphetamines as an endpoint. (Sur-Reply pp. 4-
`
`5.) To the contrary, Dr. McCracken testified that “this is exactly the kind of study
`
`one would need to do if you were wanting to identify acute tolerance.” (EX.2082
`
`66:18-67:2.)
`
`Moreover, the presence of acute tolerance in amphetamines was never tested
`
`in a large and sufficiently-powered, placebo controlled, clinical study like Dr.
`
`McCracken’s. Rather, it was an untested hypothesis proffered to explain the
`
`decline of stimulant performance in the afternoon, that Dr. McCracken showed was
`
`due to common fatigue, not acute tolerance. Dr. McCracken testified that acute
`
`tolerance as it relates to amphetamine was “just simulation and hypothesis.”
`
`(EX.2082 150:5-21.)
`
` In fact, though Patent Owner funded Dr. McCracken’s 2003 study (EX.
`
`2082 12:2-14), it never had any interest in studying whether acute tolerance exists
`
`for amphetamines, or how Adderall XR® may have allegedly overcome it: “[t]here
`
`is nothing about acute tolerance that Shire was wanting to study in my 2003
`
`research.” (EX.2082 77:4-9.)
`
`Patent Owner also suggests that the 2003 study does not refute acute
`
`tolerance because Adderall XR® “was unique” in that it “targeted rapidly
`
`ascending absorption to overcome tolerance.” (Sur-Reply pp. 3,8.) While Patent
`
`6
`
`
`
`Owner argues that “rapidly ascending absorption” is necessary to overcome acute
`
`tolerance, Patent Owner fails to explain why clinical efficacy continued 5-7 hours
`
`after amphetamine blood levels were no longer “rapidly ascending” – in fact, blood
`
`levels were plateauing and then declining. (EX.1058 ¶¶ 27-30, 35.)
`
`In one of the more audacious arguments, Patentee submitted a new exhibit
`
`with its sur-reply (EX.2083) (which Petitioner has moved to exclude) that
`
`mischaracterizes a “consensus opinion” as late as 2009 implicating acute tolerance.
`
`(Sur-Reply, p. 9.) The quoted phrase – on the first full paragraph on page 3 of
`
`EX.2083 – does not refer to a 2009 consensus opinion, but rather a 1980s
`
`consensus opinion. Moreover, the article explains that this 1980s consensus
`
`opinion was debunked, recognizing the “widespread acceptance of second-
`
`generation CR formulations of MPH and AMP starting in 2000” (Id. p. 4), because
`
`the “fundamental principle of acute tolerance is not understood or recognized by
`
`all” as scientists developed “new CR formulations without an ascending drug
`
`delivery profile.” (Id. p. 11.)
`
`The Acute Tolerance Hypothesis was Based on Weak Studies
`B.
`Patent Owner relies on Dr. Polli – who admittedly is not an expert in ADHD
`
`(EX. 1046 4:10-23) – to offer his unqualified opinion that “SR dosing was unlikely
`
`to yield effective brain stimulation and prolong ADHD treatment, because of acute
`
`tolerance.” (Sur-Reply at p. 2.) Patent Owner did not retain an ADHD expert, so its
`
`7
`
`
`
`positions on ADHD treatment, and whether acute tolerance affects such treatment,
`
`are unsupportable.
`
`Moreover, of the thousands of references and scientific studies addressing
`
`ADHD treatment in the literature, Patent owner could find only a handful of
`
`references – five total – that discuss acute tolerance as a hypothesis to explain late-
`
`day decrease in therapeutic efficacy of amphetamines. Patent Owner’s other
`
`references do not address acute tolerance in amphetamines, but other drugs: see,
`
`e.g., Swanson EX.2045 (methylphenidate); Patrick EX.2019 (methylphenidate);
`
`Limmer EX. 1027 (nitroglycerin); EX.1058 ¶45.
`
`Of the Patent Owner’s five references that discuss the hypothesis of acute
`
`tolerance in amphetamines – only three present data from actual studies:2
`
`Exhibit First Author Amphetamine Study Study Size Placebo
`
`EX2044 Greenhill
`
`EX2046
`
`Spencer
`
`EX2053
`
`Brauer
`
`EX2061
`
`Swanson
`
`EX2065
`
`Brown
`
`Yes
`
`No
`
`Yes
`
`No
`
`Yes
`
`12 subjects
`
`No
`
`6 subjects
`
`No
`
`No
`
`No
`
`No
`
`No
`
`9 subjects
`
`Yes
`
`
`2 Spencer (EX.2046) mentions acute tolerance without support, and Swanson
`(EX.2061) cites to Greenhill (EX.2044) for support. They add nothing new.
`
`8
`
`
`
`
`
`As the authors themselves conceded, these studies were grossly
`
`underpowered, and only Brown included a placebo control. See, e.g., EX.1058 ¶¶
`
`48-60.
`
`
`
`First, Greenhill recognized that his study was underpowered. “[T]he study
`
`has only 12 subjects, which severely limits the ability to address the apparent
`
`intersubject variability . . . .” (EX.2044 p. 1240.) Greenhill also recognized the
`
`study’s fatal flaw of not including a placebo to account for the effects of late day
`
`fatigue, circadian differences in arousal, or other external sources: “there was no
`
`placebo condition, so our interpretation of what might have occurred on placebo in
`
`the afternoon relies on a theoretical PD placebo profile derived from prior studies.
`
`This imposes a weakness in the design and interpretation of PK/PD relationships
`
`that may exist . . . we do not know if the need for a greater amount of medication to
`
`maintain concentration and control of behavior represents the natural onset of
`
`fatigue or boredom, or represents a habituation or tolerance at the receptor level.”
`
`(EX.2044 p. 1240; EX.1058 ¶¶ 57-58.) (emphasis added)
`
`
`
`Second, the Brauer study was even more underpowered, examining only 6
`
`healthy subjects, and also acknowledged its lack of placebo as an incurable flaw:
`
`“[a]lthough the results of this study are suggestive of . . . acute tolerance to some of
`
`the effects of d-amphetamine, the absence of a placebo control condition makes it
`
`9
`
`
`
`difficult to rule out other possible interpretations of the data . . . such as
`
`uncontrolled variations related to circadian rhythms or to environmental events . .
`
`. [t]hese Issues can only be addressed by subsequent studies including a placebo
`
`control condition.” (EX.2053 p. 4; EX1058 ¶60.) (emphasis added)
`
`
`
`Third, while Brown (EX.2065) was the only study to include a placebo
`
`control, it was widely criticized by other papers as underpowered and flawed.
`
`“Brown et al . . . has several limitations, . . . including an N of only 9 and the fact
`
`that the dependent behavioral measures included only an activity monitor and the
`
`blood technician's ratings of the subjects’ behavior during blood draws.” (Pelham
`
`EX.1052 p. 227.) See also, McGough (EX.1057 at 689) “[i]t is likely that small
`
`subject number with a large standard deviation led to the failure in [Brown] to
`
`demonstrate a significantly increased time to Tmax in sustained- versus
`
`immediate-release dextroamphetamine.” (EX.1058 ¶ 49.)
`
`Indeed, subsequent studies showed Brown to be entirely wrong concerning
`
`the efficacy of SR amphetamine formulations, and even encouraged the
`
`combination of immediate and sustained release amphetamine formulations to
`
`prolong therapeutic efficacy: “the clinical practice of combining immediate-release
`
`dextroamphetamine with Spansules may be appropriate in some cases, and it
`
`should be explored in controlled trials.” (James EX.1053 p. 1275.)
`
`10
`
`
`
`C. Methylphenidate is Different from Amphetamine
` Most of Patent Owner’s acute tolerance references relate to
`
`Methylphenidate, which is a different drug with significantly different
`
`characteristics than amphetamine. (EX.2082 154:5-8.) Patent Owner has
`
`acknowledged this before the PTAB in Mylan Phama., Inc. v. Shire Labs., Inc.
`
`(IPR2017-00011) arguing that the two drugs are “significantly different” and their
`
`mechanisms of action “are known not to be the same.” (EX.2008 pp. 26-27.)
`
`Patent Owner repeatedly mischaracterizes Dr. McCracken’s testimony by
`
`conflating amphetamines and methylphenidate. For example, Dr. McCracken did
`
`not state that acute tolerance “has been invoked” for amphetamine. (Sur-Reply p.
`
`2.) In fact, he explicitly stated that “I don’t believe acute tolerance exists with
`
`respect to amphetamines . . . . I don’t believe that’s ever been established in the
`
`literature . . . [p]rimarily acute tolerance has been invoked with regards to
`
`stimulants, but most – mostly with respect to methylphenidate-containing products,
`
`less so amphetamines.” (EX.2082, 28:21-29:9.) Patent Owner also misrepresents
`
`that “Dr. McCracken himself . . . reported [acute tolerance in amphetamines]
`
`repeatedly.” (Sur-Reply at p. 2.) Dr. McCracken is not quoted in, or an author of,
`
`any of the references that Patent Owner attributes to him. (see, e.g., Exhibits 1014;
`
`2046; 2045; 2044; and 2061.)
`
`11
`
`
`
`III.
`
`Inherency of Food Effect
`
`The absence of a food effect is inherent in the extended release amphetamine
`
`composition that has the IR, DR and SR beads of claim 1. (Jusko EX.1006, ¶¶30-
`
`33; McCracken EX.1058, pp. 46-56.) In particular, Dr. McCracken opined that (a)
`
`in his clinical thirty-plus years of experience, no amphetamine formulations have
`
`shown signs of a clinically significant food effects (EX.1058, ¶92, ¶100); (b)
`
`amphetamine literature as well indicates no food effect (Id., ¶103); (c) the addition
`
`of the SR bead to a formulation that already has no food effect (Adderall XR)
`
`would not create a food effect (Id., ¶¶93-94); and (d) the SR beads in particular are
`
`designed to release within 8 hours from ingestion, which is mostly in the small
`
`intestines and the remaining amount in the colon, resulting in nearly all the
`
`amphetamine being released and absorbed, regardless of food. (Id., ¶¶107-113.)
`
`Dr. Jusko also testified that the release of SR beads added to Adderall XR
`
`(already exhibiting no food effect) would not be affected by food because “the
`
`release is happening well beyond where the food effect is relevant.” (EX.2070,
`
`Jusko Tr. pp. 79:9-82:11.) He further explained that once the SR bead enters the
`
`small intestines where the pH is sufficiently high to dissolve the SR coating, the
`
`food effect is no longer relevant. (Id. at 81-82.)
`
`Patent Owner argues that food effect is formulation dependent. But no food
`
`effect is inherent in all amphetamine products, regardless of formulation.
`
`12
`
`
`
`(EX.1058, ¶¶101-102.) See, e.g., Adderall XR (EX.1031, p.2); Dexedrine SR
`
`(EX.1054 p.2, EX.2084, p.3); Mydayis (EX.2004, p.15); Dyanavel XR (EX.1055,
`
`p.10); and Adzenys ER (EX.1056, p.18).3
`
`Patent Owner argues that when Dr. McCracken was asked in deposition
`
`what he meant by the term “inherent,” he responded with the ambiguous terms
`
`“assumed” or “presumed” (Sur-Reply, p. 13). Patent Owner left it up to Petitioner
`
`to follow-up, and Petitioner clarified on re-direct that Dr. McCracken understood
`
`“inherent” to mean an “integral characteristic,” and when pressed to be even more
`
`specific, he testified that it means “amphetamine as a chemical entity do[es] not
`
`possess differences influenced by fed versus fasting in their absorption and PK
`
`properties.” (McCracken Dep. EX.2082, p. 219.)
`
`In addition, as discussed in the Reply, even though claim 19 covers “no food
`
`effect” for all formulations within claim 1, the ‘857 patent specification
`
`demonstrated no food effect (AUC/Cmax) with only one formulation: SPD465.
`
`(EX.1001; Example 9.) Patent Owner argues that the claim “scope” is “out of
`
`bounds in an IPR.” (Sur-Reply, p. 13.) Assuming there is such a rule (and none is
`
`
`3 Petitioner explained in its Opposition to Patent Owner’s Motion to Exclude that
`evidence of an inherent property of an obvious formulation may post-date the
`patent application.
`
`13
`
`
`
`cited), Petitioner is not trying to change the scope of the claims; only demonstrate
`
`that all formulations within claim 1 inherently have no food effect.
`
`IV.
`
`Inherency of PK Claims
`
`Petitioner demonstrated in its Reply that the formulation of the three beads
`
`in SPD465 as described in the ‘857 patent are insubstantially different from the
`
`three bead types in Examples 1, 2 and 4 of Burnside, and therefore, if the
`
`combination of the Burnside beads is obvious, the bioavailability elements are
`
`inherent in that combination. (Jusko EX.1006, ¶¶23-29.)
`
`Patent Owner argues that for inherency, the 37.5 mg dose, the (1:1:1) bead
`
`ratio and the coating thickness are variables affecting PK parameters. Petitioner, in
`
`its Reply (pp. 19-27), demonstrated that (1) the 37.5 mg dosage was an arbitrary
`
`amount known to be effective (Adderall XR included that amount), which has no
`
`advantage over the other dosage amounts; (2) the coating amounts in the ‘857
`
`patent are substantially the same as in Burnside; and (3) the 1:1:1 ratio was an
`
`obvious choice.
`
`Patent Owner argues that there must be an explicit disclosure of the 37.5 mg
`
`dosage amount, the 1:1:1 ratio and the coating thicknesses in the same formulation.
`
`(Sur-Reply, pp. 13-14.) Patent Owner is confusing an obvious formulation, on the
`
`one hand, with the inherent properties of an obvious formulation, on the other
`
`hand.
`
`14
`
`
`
`Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) is
`
`on point. The patent at issue claimed an omeprazole formulation; and further
`
`claimed certain levels of blood concentration upon administration to a patient. The
`
`Federal Circuit affirmed obviousness because the formulation was obvious over
`
`the prior art, and the blood concentration claimed is inherent in the obvious
`
`formulation. See, also, In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011) (food
`
`effect inherent in an obvious formulation); Monsanto Tech LLC v. E.I. DuPont de
`
`Nemours & Co. 878 F.3d 1336, 1346-1348 (Fed. Cir., 2018) (composition of
`
`claimed soy bean plant inherent in obvious method of making the plant).
`
`Patent Owner cites to In re Rijckaert, 9 F.3d 1531 (Fed. Cor. 1993), but it is
`
`inapplicable. The Federal Circuit held that the product itself (a recording
`
`apparatus) was not obvious from the prior art (Id. at 1533), which is a very
`
`different situation from the present one, wherein, if the claimed composition is
`
`obvious, the PK elements are inherent in the obvious composition.
`
`
`
`Dated: March 15, 2019 Respectfully submitted,
`
`By: /s/ Steven Roth
`Steven Roth, PTO Reg No. 47,039
`David J. Galluzzo, Pro Hac Vice
`Tom Vetter, PTO Reg No. 30,597
`
`
`
`Counsel for Petitioner, KVK-Tech, Inc.
`
`
`
`
`
`
`15
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e)(4), the undersigned certifies that a true and
`
`correct copy of this document (Petitioner Response to Patent Owner’s Sur-Reply)
`
`was served electronically via email on March 15, 2019, in its entirety on each of
`
`the following:
`
`Joseph R. Robinson
`Troutman Sanders LLP
`875 Third Avenue
`New York, NY 10022
`joseph.robinson@troutmansander
`s.com
`
`Robert Schaffer
`Troutman Sanders LLP
`875 Third Avenue
`New York, NY 10022
`robert.schaffer@troutmansanders.
`com
`
`Dustin B. Weeks
`Troutman Sanders LLP
`Bank of America Plaza
`600 Peachtree Street NE, Suite
`5200 Atlanta, GA 30308-2231
`dustin.weeks@troutmansanders.c
`om
`
`
`
`
`
`
`Patent Owner has consented to Electronic Service.
`
`
`
`Dated: March 15, 2019
`
`By: /s/Steven Roth
`Steven Roth
`Reg. No. 47,039
`sroth@lmiplaw.com
`
`
`
`16
`
`
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