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 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 REPLY
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`CLAIM 1 IS OBVIOUS OVER BURNSIDE WITH/WITHOUT
`ADDERALL XR. ............................................................................................ 1
`A. Motivation to Combine ......................................................................... 2
`B.
`Reasonable Expectation of Success ...................................................... 4
`C.
`Teaching Away ...................................................................................... 8
`D.
`Secondary Considerations ................................................................... 14
`CLAIMS 2-4, 13-18 AND 29 ARE OBVIOUS OVER BURNSIDE ........... 16
`II.
`III. CLAIM 19 IS OBVIOUS OVER BURNSIDE ............................................. 16
`IV. CLAIMS 20-28 ARE OBVIOUS OVER BURNSIDE
`AND ADDERALL XR ................................................................................. 18
`CLAIMS 5-12 ARE OBVIOUS OVER BURNSIDE
`AND ADDERALL XR ................................................................................. 19
`A.
`The 37.5 mg Dosage Amount ............................................................. 20
`B.
`The 1:1:1 Ratio .................................................................................... 21
`C.
`The Formulation and Coating Thickness ............................................ 22
`D.
`Summary of Obviousness of the PK Claims ....................................... 27
`
`V.
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .............................................................................. 14
`In re Copaxone,
`906 F.3d 1013 (Fed.Cir.,2018) ........................................................................ 7, 22
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................................. 7
`In re Gurley,
`27 F.3d 551 (Fed.Cir.1994) .................................................................................... 9
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) .............................................................................. 15
`In re O'Farrell,
`853 F.2d 894 (Fed.Cir.1988) .................................................................................. 4
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 420 (2007) ....................................................................................... 4
`LizardTech, Inc. v. Earth Resource Mapping, Inc.
`424 F.3d 1336 (Fed. Cir. 2005) ............................................................................ 17
`Merck v. Teva,
`395 F.3d 1364 (Fed. Cir. 2005). ........................................................................... 16
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed.Cir.2012) ....................................................................... 19, 21
`
`STATUTES
`21 U.S.C. 355(j)(2)(A)(iv) ....................................................................................... 20
`
`
`ii
`
`
`
`UPDATED EXHIBIT LIST
`
`1007
`
`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
`1017 U.S. Patent No. 8,313,776
`1018 U.S. Patent No. 6,555,136
`1019 U.S. Patent No. 6,322,819
`
`1014
`
`1009
`
`1011
`
`1013
`
`iii
`
`
`
`1021
`
`1025
`
`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
`PREDICTION AND ASSESSMENT (Jennifer Dressman & Hans
`Lennernäs, Vol. 106, 2000.)
`1039 J. Fallingborg, Intraluminal pH of the Human Gastrointestinal Tract, 46
`
`1033
`
`1038
`
`iv
`
`
`
`1047
`
`1052
`
`1053
`
`1040
`
`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)
`
`1057
`
`
`
`v
`
`
`
`KVK-Tech, Inc. (Petitioner) submits its Reply to the Response of Patent
`
`Owner, Shire LLC (Shire or Patentee), regarding U.S. Patent No. 9,173,857 (“the
`
`‘857 Patent”).
`
`I.
`
`Claim 1 is Obvious over Burnside with/without Adderall XR.
`
`Claim 1 covers an immediate release bead (IR bead), a first delayed, pulsed
`
`release bead (DR bead), and a second delayed, sustained release bead comprising a
`
`delayed release coating layered onto a core, and a pH independent sustained
`
`release coating layered onto the delayed release coating (SR bead).
`
`There is no dispute that Burnside (EX.1002) discloses the IR, DR and SR
`
`beads claimed in the ‘857 patent:
`
`
`
`“Burnside Example 1 prepared immediate release pellets (beads).”
`
`(Polli Dec. EX.2060, ¶99.) (Burgess Dec. EX.1004, ¶¶63-64.)
`
`
`
`“Burnside Example 2 [and Example 3] prepared delayed pulsatile
`
`release pellets (beads) . . .” (EX.2060, ¶¶100-101.) (EX.1004, ¶¶63-64.)
`
`
`
`“Burnside Example 4 prepared two different sustained release pellets
`
`(beads) . . . having an enteric coating layered over an amphetamine-loaded core,
`
`and pH independent SURELEASE layered coating over the enteric coating.”
`
`(EX.2060, ¶102.) (EX.1004, ¶¶63-64.)
`
`1
`
`
`
`Patentee disputes whether it was obvious to combine the first two pulsatile
`
`beads of Burnside (Example 5) or Adderall XR, on the one hand, with the SR bead
`
`of Example 4, on the other. Petitioner contends that it was obvious as shown by a
`
`motivation to combine and a reasonable expectation of success.
`
`A. Motivation to Combine
`The motivation to combine derives from the need for a longer acting
`
`amphetamine formulation than Adderall XR. Prior to 2006, doctors often
`
`prescribed a morning dose of Adderall XR followed by a booster dose of Adderall
`
`IR taken 8-10 hours later. See, Kratochvil (EX.1010, p.2) (“Adderall XR early and
`
`IR around 6 pm.”) The ‘857 patent also describes this well-known practice:
`
`“Long acting stimulant preparations, such as ADDERALL XR … are
`designed to provide a duration of effect up to 12 hours … For patients
`… who require duration of clinical benefit beyond 10-12 hours,
`clinicians have augmented the morning long-acting formulation,
`typically at 8-10 hours post-dose, with a dose of the same immediate-
`release (IR) medication.” (EX.1001:3:39-49)
`
`See also EX.1047, p.1(“[t]he rationale for the development of SPD465 (Long
`
`Acting Adderall XR) is to enable primary adult and adolescent ADHD patients to
`
`benefit from ADHD symptom control throughout the entire day and extend those
`
`benefits into the early evening hours ….”)
`
`2
`
`
`
`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 and DR beads
`
`of Adderall XR would prolong therapeutic efficacy. This is in part because a
`
`POSA would understand that the SR beads 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.)
`
`Indeed, Dr. Polli admitted that the SR bead was added with the “intent” to allow
`
`later day treatment of ADHD:
`
`So given those definitions of those three beads,
`Q.
`given your statement in your report that we've been discussing
`[the statement above in ¶204] do you have an expectation that
`the SR bead would be expected to release later, slower and
`further down the GI tract than the IR and DPR beads?
`
`I mean, you know, I am thinking about the '100
`A.
`patent, and the SR bead did have that intent to allow for
`treatment of ADHD for later day to prolong the duration of
`therapy via the SR bead. So in that regard, I would say, yes, I
`think there's some SR beads that had that intent.
`
`(Polli EX.1046, p.20.)
`
`3
`
`
`
` Accordingly, a POSA would be motivated to combine the SR bead of
`
`Burnside’s Example 4 with the IR + DR beads of Adderall XR (as disclosed in
`
`Burnside’s Example 5) to prolong therapeutic efficacy, because the SR bead
`
`provides a later release of a third dose of amphetamine into the gastro-intestinal
`
`tract.
`
`B. Reasonable Expectation of Success
`First, the expectation of success need only be reasonable; not a certainty. In
`
`re O'Farrell, 853 F.2d 894, 903–04 (Fed.Cir.1988). Second, “success” does not
`
`mean that one of ordinary skill in the art reasonably expects every advantage of the
`
`invention touted by the inventors; indeed, the reason to combine does not even
`
`have to be the same as the inventors. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`420 (2007) (“[t]he question is not whether the combination was obvious to the
`
`patentee … [u]nder the correct analysis, any need or problem known in the field of
`
`the endeavor at the time of the invention and addressed by the patent can provide a
`
`reason for combining the elements in the claimed manner.”)
`
`In this case, the reason to combine the SR beads with the IR+DR beads was
`
`to prolong treatment of ADHD over that provided by of the IR and DR beads alone
`
`(Adderall XR). The evidence demonstrates that a POSA would have reasonably
`
`expected that the SR bead would achieve that goal.
`
`4
`
`
`
`Dr. Jusko stated that a POSA would have expected the SR bead to continue
`
`releasing for many hours after the IR and DR beads were depleted providing many
`
`more hours of efficacy. (EX.1006, ¶37.) Dr. Polli agrees, stating in his Declaration
`
`(EX.2060, ¶144), that the Example 4 bead “probably would release some
`
`amphetamine after the IR and DPR beads are finished.” And, as quoted above,
`
`Dr. Polli also stated in his declaration that “the SR beads are releasing later and
`
`further along the GI tract than the IR and DPR beads.” (EX.2060, ¶204.)
`
`Dr. Polli admitted that there would be a reasonable expectation of success if
`
`the amphetamine from the third bead would be absorbed later:
`
`“I mean, it is true, even though there's several negatives, that if you
`are somehow able to get more drug absorbed later, it could address
`that goal of extending the duration of therapy relative to Adderall
`XR.”
`
`(Polli Tr. 30, emphasis added).
`
`Other than conclusory speculation, Patentee provides no evidence that
`
`amphetamine from the SR bead would not have been expected to be absorbed in
`
`the small intestine and colon. To the contrary, two of Patentee’s experts admitted
`
`that amphetamine from the SR beads would be released and absorbed in the
`
`intestines and colon. Dr. Trout stated that the SR beads would have been expected
`
`to release amphetamine in “the intestine.” (EX.2001, ¶165.) And Dr. Polli
`
`5
`
`
`
`admitted that “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, where absorption is
`
`more difficult.” (EX.2060, ¶202.) Moreover, Dr. MacCracken opined that most of
`
`the amphetamine from the SR bead would be released in the small intestines
`
`(EX.1045, ¶¶107-108) where it can it can be readily absorbed. (Burnside,
`
`EX.1002:1:55-57.)
`
`Also contrary to Patentee’s speculation, they in fact demonstrated that little
`
`or no amphetamine from the SR bead of Example 4 is lost. Patentee compared
`
`Adderall IR with the SR bead from Example 4 of the ‘857 patent (which has the
`
`same SR coating in the same percentage as in Example 4 of Burnside), in a
`
`bioavailability study on 12 subjects, and demonstrated that AUC and Cmax were
`
`equivalent. (EX.1001, 20:62-21:38 and Table 5.) Thus, an equivalent amount of
`
`amphetamine from the IR and SR formulations was absorbed into the blood
`
`stream.
`
`Patentee also argues that a POSA could not have predicted whether
`
`amphetamine SR would work to extend treatment of ADHD. But Couch explicitly
`
`states that SR works to control ADHD, and avoids any acute tolerance issues
`
`(discussed further below):
`
`“The SR formulations of this invention will be effective to treat, e.g.,
`ADHD, in the same manner as ADDERALL® XR. ... They will also
`
`6
`
`
`
`be effective to treat ADHD with low incidence of side effects,
`including substance abuse, addiction, tolerance, tachyphylaxis, etc.”
`
`(EX.1023, p.2 [0006].)
`Patentee relies on In re Cyclobenzaprine, 676 F.3d 1063 (Fed. Cir. 2012) for
`
`the proposition that obviousness of efficacy claims requires a PK/PD correlation
`
`and a known mechanism of action. This case is inapposite as subsequent cases
`
`distinguished In re Cyclobenzaprine on the grounds that obviousness was based on
`
`PK data alone; i.e., there was “no prior art clinical studies to suggest what would
`
`be a therapeutically effective formulation.” In re Copaxone, 906 F.3d 1013, 1028-
`
`29 (Fed.Cir.,2018). By contrast, the court in Copaxone invalidated a patent as
`
`obvious based on clinical efficacy studies, without any finding of a PK/PD
`
`correlation or mechanism of action.
`
`Here, clinical data demonstrates that once amphetamine is released into the
`
`circulatory system, it can have a positive therapeutic effect on controlling ADHD.
`
`(McCracken EX.1045, ¶99; Jusko EX.1006, ¶40-41.) The clinical studies
`
`demonstrate that sustaining amphetamine blood levels, sustains efficacy. 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. (McCracken,
`
`EX.1045, ¶¶ 35-39, EX.1031, p.1; EX.1037, pp.677-79.) Moreover, while
`
`Dexedrine IR (dextroamphetamine) has a Tmax of 3 hours and efficacy 3-6 hours,
`
`Dexedrine SR has a Tmax of 8 hours and efficacy for at least 9-12 hours.
`
`7
`
`
`
`(McCracken, EX.1045, ¶52, Dexedrine Label, EX.1054; James, EX.1053, p.1275;
`
`Pelham, EX.1052, p.232.) Thus, the clinical data demonstrates that extending
`
`amphetamine blood levels, extends treatment of ADHD.
`
`In the present IR-DR-SR composition, the SR beads provide an added dose
`
`of amphetamine superimposed on the IR and DR dose, which increases plasma
`
`levels of amphetamine for a longer period of time, and thus prolongs efficacy.
`
`(Jusko, EX.1006, ¶¶40-41; McCracken EX.1045, ¶¶71-74.)
`
`Ironically, the ‘857 patent provides no clinical efficacy data, let alone
`
`PK/PD data, as confirmed by Dr. Polli. (EX.1046, p.123.) Evidently, Patentee had
`
`no trouble claiming efficacy for ADHD based solely on in-vitro and
`
`pharmacokinetic data, without any supporting efficacy data.
`
`Accordingly, a POSA in 2006 would have reasonably expected (i) the SR
`
`beads to continue to release amphetamine later and over a longer period of time
`
`than the IR and DR beads, (ii) that amphetamine released from the SR beads in the
`
`small intestines and colon would be absorbed into the circulatory system, and (iii)
`
`once in the bloodstream, amphetamine would provide prolonged efficacy for
`
`ADHD.
`
`C. Teaching Away
`A reference teaches away when a POSA, upon reading the reference, “would
`
`be discouraged from following the path set out in the reference, or would be led in
`
`8
`
`
`
`a direction divergent from the path that was taken by the applicant.” In re
`
`Gurley, 27 F.3d 551, 553 (Fed.Cir.1994). Moreover, “a known or obvious
`
`composition does not become patentable simply because it has been described as
`
`somewhat inferior to some other product for the same use.” Id.
`
`Patentee argues that acute tolerance issues with amphetamine formulations
`
`made it “impossible” to have any reasonable expectation of success using the SR
`
`bead of Burnside to treat ADHD. Patentee even suggests that Burnside which
`
`explicitly teaches the use of SR amphetamine beads in combination with other
`
`bead types – somehow teaches away from SR beads in ADHD amphetamine
`
`formulations.
`
`Patentee argues that the background section of Burnside (EX.1002, 1:14-
`
`2:12), and, in particular, the following statement, teaches away from using SR
`
`beads:
`
`“Continuous release drug plasma profiles are often accompanied by a
`decline in the pharmacotherapeutic effect of the drug, e.g., biological
`tolerance of transdermal nitroglycerin.”
`
`(Id. 1:31-34, emphasis added). Amphetamine is not mentioned once in this
`
`section, nor are any alleged effects of acute tolerance on amphetamines. This
`
`section only discusses problems that inventors may generally encounter
`
`when designing formulations. Burnside explicitly teaches an SR formulation
`
`in the detailed description of the invention (EX.1002, 9:1-22) and
`
`9
`
`
`
`exemplifies it in Example 4. (Id. 6:58-61.) Burnside states that
`
`Figure 6 “illustrates the drug release profile of coated pellets described in
`
`Example 4 which exemplifies … the present invention.” (Id. 6:58-62.)
`
`Burnside also discloses a preferred embodiment where SR beads are
`
`combined with IR beads in a formulation for treating ADHD. (EX.1045,
`
`¶83; EX.1002, 3:38-52, 4:19-28, 9:1-17.) Burnside thus teaches towards SR
`
`beads, not away.
`
`Patentee – relying on witnesses without ADHD or amphetamine expertise
`
`(EX.1046, Polli Tr. 4, 114-15) – argues that a few prior art references suggesting
`
`acute tolerance taught away from an SR amphetamine formulation for ADHD.
`
`However, most of the references do not relate to amphetamine, and those that
`
`relate to amphetamine, don’t teach away from SR amphetamine. Patentee also
`
`ignores a host of other prior art references teaching that acute tolerance is not an
`
`issue with amphetamine formulations for ADHD.
`
`First, as discussed above, sustained release amphetamine formulations were
`
`known to extend efficacy without acute tolerance issues. Couch discloses SR
`
`amphetamine formulations for treating ADHD, explicitly stating that they do not
`
`display acute tolerance issues. (EX.1023, p.2 [0006].) Other sustained release
`
`formulations were also shown to be advantageous over immediate release
`
`formulations; James et al. (EX.1053) compared the efficacy of Adderall® to
`
`10
`
`
`
`sustained release Dexedrine® Spansules in 35 children and concluded that
`
`sustained release provided superior clinical efficacy over immediate release.
`
`(EX.1045, ¶¶ 53-54.) Pelham also found sustained release Dexedrine Spansules to
`
`prolong efficacy without signs of acute tolerance. (EX.1045, ¶55 citing Pelham
`
`EX.1052.)
`
`Second, a POSA would not expect an acute tolerance issue from a mixed
`
`“IR-DR-SR” amphetamine formulation that employs two pulsatile doses. Indeed,
`
`Patentee cites to no pulsatile, SR, or pulsatile+SR combination amphetamine
`
`formulation for treating ADHD that display a “rapid” decrease in therapeutic
`
`efficacy suggestive of acute tolerance issues. (EX.1045, ¶¶ 68-78.)
`
`Third, regardless of formulation type, amphetamines do not display an acute
`
`tolerance problem. (EX.1045, ¶¶ 24-67.) For example, Dr. McCracken reported in
`
`his 2003 study that even though amphetamine blood levels for Adderall XR peaked
`
`between 5 and 7 hours, efficacy continued for at least another 5 to 7 hours for a
`
`total of 12 hours of efficacy (EX.1045, ¶27; citing EX.1037.) Drs. Polli and
`
`McCracken agree that acute tolerance results in the rapid decline in efficacy.
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`(EX.2060, ¶156; EX.1045, ¶24.) But here, efficacy continued well after blood
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`levels began to decline, which is inconsistent with acute tolerance. (EX.1045,
`
`¶¶27-30.)
`
`11
`
`
`
`Dr. McCracken definitively supports his position for no acute tolerance by
`
`showing that decreases in therapeutic efficacy in the afternoon occurs in tandem
`
`with plasma levels and placebo patients; if acute tolerance were an issue with
`
`amphetamines, loss of therapeutic efficacy would occur faster than plasma levels
`
`and placebo patients. (Id., ¶¶35-38, 41-42.)
`
`Fourth, the prior art Patentee relies on does not teach away; indeed, most of
`
`it has no relation to alleged amphetamine acute tolerance issues at all (see, e.g.,
`
`EXS.2045, 2019, 2013, 2026, 2043, 2034), with several discussing
`
`methylphenidate, which is a different drug substance with a different biological
`
`action (EX.1045, ¶¶45-46.) Similarly, Spencer (EX.2046), Patrick (EX.2019) and
`
`Swanson (EX.2061), do not provide any studies or data on acute tolerance for
`
`amphetamine, only methylphenidate. (EX.1045, ¶¶ 61, 63) Patentee argues that
`
`Kratochvil (EX.1010, p.2) teaches away by stating that a drug burst avoids acute
`
`tolerance (Response, p.22.) But the statement was made with regard to
`
`methylphenidate, not amphetamine. Moreover, the statement does not teach away
`
`from adding the SR bead to the IR+DR combination.
`
`Patentee’s main reference in support of acute tolerance teaching away from
`
`sustained release is Brown (EX.2065.) Brown studied the effects of an SR
`
`formulation on 9 children and reported no evidence of prolonged clinical response
`
`beyond the absorption phase (after 4 hours). (EX.2065, 13.)
`
`12
`
`
`
`
`
`While blood plasma (left ascending curve) rises until about 4 hours, efficacy
`
`curves show that “Sustained Release” has better (i.e. lower) scores than placebo at
`
`each timepoint, suggesting prolonged efficacy beyond 4 hours. Despite this trend,
`
`Brown could only report statistical significance at hour 2 (not even at peak plasma
`
`concentrations at hours 3 and 4). (EX.2065, p.6; EX.1045, ¶50.) Several studies
`
`criticized Brown for being underpowered and using flawed methodologic methods.
`
`(EX.1045, ¶49, citing Pelham Ex.1052 p.227 and McGough Ex.1057, p.689.)
`
`Moreover, subsequent studies proved Brown’s hypothesis of acute tolerance
`
`in SR formulations wrong; in 2001, James et al. compared the efficacy of sustained
`
`release amphetamine to Adderall IR and found that the sustained release provided
`
`superior clinical efficacy over the immediate release doses. (EX.1045, ¶¶52-54,
`
`citing James EX.1053, p.1275.) Another study in 1990 by Pelham et al. reported
`
`that sustained release amphetamine prolonged efficacy measures for 9 hours after
`
`13
`
`
`
`morning dosing. (EX.1045, ¶55 citing Pelham EX.1052, p.232.) If acute tolerance
`
`were an issue in sustained release amphetamine formulations, this study would
`
`have shown a rapid deterioration of efficacy shortly after dosing.
`
`Patentee also relies on Greenhill (EX.2044) and Brauer (EX.2053) to show
`
`acute tolerance affecting immediate release (not SR) amphetamine formulations,
`
`but these studies are fatally flawed because they were underpowered and failed to
`
`include placebos. The authors note these weaknesses in their respective studies,
`
`and further note that fatigue, circadian rhythms, or other external factors may cause
`
`late-day deterioration in drug efficacy. (EX.1045, ¶¶ 57-60 citing Greenhill
`
`EX.2044, p.1240 and Brauer EX.2053, p.75.)
`
`Finally, Patentee argues that Tulloch (EX.1014) teaches away from SR
`
`beads, but Tulloch reports the results of a PK study on Adderall XR; it says
`
`nothing about acute tolerance or SR and does not provide any efficacy data.
`
`D.
`Secondary Considerations
`Patentee argues unexpected results, long felt need and commercial success.
`
`(Response, pp.67-69.) All of these require nexus to the patent claims. Allergan,
`
`Inc. v. Apotex Inc., 754 F.3d 952, 965 (Fed. Cir. 2014) (“objective evidence of
`
`non-obviousness must be commensurate in scope with the claims which the
`
`evidence is offered to support.”)
`
`14
`
`
`
`Patentee argues that there was a long felt need for a “longer acting
`
`amphetamine,” and that the ‘857 patent invention unexpectedly achieved this
`
`result. However, none of the claims of the ‘857 patent include prolonged efficacy
`
`as an element. And, in any event, as discussed above, the prolonged efficacy of
`
`adding the SR bead was very much expected.
`
`With respect to long felt need, the original application for Mydayis was filed
`
`in 2006, and FDA issued an Approvable Letter in 2007. (EX.1050.) After the
`
`Approvable Letter, Shire dropped the application, and then re-applied in 2016, nine
`
`(9) years later. Shire told FDA that the nine-year hiatus was for “business
`
`reasons,” which is incongruous with its present claim of long felt need. (EX.1051,
`
`pp.1-2.) Why abandon the product for nine years for business reasons if there was
`
`such a long-felt need for it?
`
`Commercial success fails for the same reasons. There can be no nexus to the
`
`claims when there are no claims to prolonged efficacy. Commercial success also
`
`requires Patentee to prove a substantial market share growth attributable to the
`
`patented features. See, In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996). Shire has
`
`submitted no such evidence, and whatever data Shire has provided show low
`
`market share for Mydayis (EX.2055, pp.6-8.) Also, competition is blocked by FDA
`
`New Product (“NP”) exclusivity until June 20, 2020 (EX.2003, p.6), allowing
`
`15
`
`
`
`Shire to increase sales unhindered by competition, for reasons having nothing to do
`
`with the ‘857 patent. See, Merck v. Teva, 395 F.3d 1364, 1377 (Fed. Cir. 2005).
`
`II. Claims 2-4, 13-18 and 29 are Obvious over Burnside
`
`Petitioner has previously demonstrated that these claims are anticipated or
`
`obvious. (Petition, pp.27-28, 30-33; EX.1004, Burgess pp.35-38, 40-46.)
`
`In its Response, Patentee merely links the obviousness of these claims to
`
`claim 1:
`
` “No dependent claim can be anticipated because claim 1 is not
`
`anticipated.” (Response, p.26.)
`
` “Claims 2-4, 13-18, and 29 are not obvious at least because claim 1 is
`
`not obvious. (Response, p.59.)
`
`Accordingly, if claim 1 is obvious, so are these claims.
`
`III. Claim 19 is Obvious over Burnside
`
`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.)
`
`Patentee argues that food effect is formulation dependent, but no food effect
`
`is inherent in all amphetamine ADHD formulations, regardless of formulation type
`
`(e.g. sustained or pulsed release) or characteristics. (EX.1045, ¶¶101-102.) See,
`
`16
`
`
`
`e.g., Adderall XR (EX.1031, p.2); Dexedrine SR (EX.1054 p.2); Dyanavel XR
`
`(EX.1055, p.10); and Adzenys ER (EX.1056, p.18.)
`
` Dr. Polli testified that he is unaware of any specific amphetamine
`
`formulation having a food effect. (EX.1046, p.84.) So long as the formulation
`
`releases amphetamine into the GI tract, it will be absorbed into the blood stream.
`
`(EX.1045, ¶99.)
`
`In addition, claim 19 depends from claim 1, and thus does not claim a
`
`specific formulation; only the IR-DR-SR structure. The ‘857 patent specification,
`
`however, demonstrated no food effect (AUC/Cmax) with only one formulation:
`
`SPD465 (EX.1001; Example 9.) If, as Patentee now argues, only the precise
`
`formulation of SPD465 has no food effect, the specification fails to support and
`
`enable the breadth of claim 21. See, LizardTech, Inc. v. Earth Resource Mapping,
`
`Inc. 424 F.3d 1336, 1346 (Fed. Cir. 2005) (“we hold that the description of one
`
`method . . . does not entitle the inventor . . . to claim any and all means for
`
`achieving that objective”)1.
`
`
`1 This is not a new argument of invalidity. But, if, as Patentee now argues, no food
`effect is formulation specific, it raises the issue of whether the breadth of that claim
`is supported and enabled by the disclosure, which only discloses that SPD465 has
`no food effect.
`
`17
`
`
`
`IV. Claims 20-28 are Obvious over Burnside and Adderall XR
`
`Claims 20-28 depend from claim 1, and further claim dosage amounts of
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`about 12.5mg to 75mg. The claim term “about” encompasses a variance of 20%
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`according to Dr. Burgess. (EX.1004, p.20.) Dr. Polli opines that it encompasses
`
`dose uniformity which is up to ±6%. (EX.1046, p.66-67.)
`
`Clinical studies on Adderall XR demonstrated that doses ranging from 10mg
`
`up to 60mg were proven effective as compared with a placebo. (EX.1031, p.3.)
`
`The package insert did not state that the doses tested had any serious safety issues.
`
`A POSA in May 2006, would have expected that dosages of 62.
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