Paper No. __
`Filed: December 11, 2017
`
`Filed on behalf of: KVK-Tech, Inc.
`
`By: Jonathan A. Harris (jharris@axinn.com)
` James T. Evans (jevans@axinn.com)
` Axinn, Veltrop & Harkrider LLP
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`KVK-TECH, INC.
`Petitioner
`
`v.
`
`SHIRE PLC
`Patent Owner
`
`____________________
`
`Case IPR2018-00290
`Patent No. 8,846,100
`____________________
`
`CORRECTED PETITION FOR INTER PARTES REVIEW
`
`

`

`TABLE OF CONTENTS
`EXHIBIT LIST ........................................................................................................ vi
`Introduction ..................................................................................................... 1
`I.
`II. Mandatory Notices under 37 C.F.R. § 42.8 .................................................... 3
`Real Parties-in-Interest 37 C.F.R. § 42.8(b)(1) .................................... 3
`Related Matters ..................................................................................... 3
`Lead and Back-Up Counsel 37 C.F.R. § 42.8(b)(3)-(4) ...................... 3
`Payment of Fees 37 C.F.R. §§ 42.15(a) and 42.103 ....................................... 4
`III.
`IV. Grounds for Standing 37 C.F.R. § 42.104(a) ................................................. 4
`Identification of Challenge - Proposed grounds ............................................. 4
`V.
`State of the Prior Art as of 2006 ..................................................................... 4
`VI.
`Amphetamine Was a Well-Known ADHD Treatment ........................ 5
`Drug Coating Release Timings and Characteristics Were Well-
`Known in the Prior Art ......................................................................... 6
`Adderall IR® and Adderall XR® ........................................................... 7
`Amphetamine Formulations with Sustained Release Beads ................ 8
`VII. The ‘100 Patent ............................................................................................... 9
`Summary of the ‘100 Patent Specification ........................................... 9
`Summary of the ‘100 Patent Claims .................................................. 11
`Summary of the ‘100 Patent Prosecution History .............................. 12
`VIII. Level of Ordinary Skill in the Art ................................................................ 15
`IX. Claim Construction ....................................................................................... 16
`Detailed Explanation of Grounds ................................................................. 16
`X.
`Ground 1: Burnside Anticipates Claims 1-21 and 31 ........................ 17
`Independent Claim 1 ................................................................ 18
`1.
`2.
`Claims 2-4 ................................................................................ 27
`3.
`Claims 5-12 .............................................................................. 29
`ii
`
`

`

`
`
`4. 
`Claims 13-18 and 31 ................................................................ 30 
`Claims 19-20 ............................................................................ 32 
`5. 
`Claim 21 ................................................................................... 33 
`6. 
`The Obviousness Grounds - Ground 2 (Burnside alone) ................... 34 
` 
`and Ground 3 (Adderall XR® in view of Burnside) ..................................... 34 
`1. 
`Scope and Content of the Prior Art .......................................... 35 
`2. 
`Limitation-by-Limitation Analysis .......................................... 35 
`3. 
`Rationales for Combination ..................................................... 51 
`Reasonable Expectation of Success (Grounds 2 and 3) ..................... 59 
` 
`  Alleged Evidence of Secondary Considerations Does Not
`Support Non-Obviousness (Grounds 2 and 3) ................................... 61 
`XI.  The Board Should Adopt All Proposed Grounds ......................................... 62 
`XII.  Section 325(d) Does Not Apply here ........................................................... 63 
`XIII.  Conclusion .................................................................................................... 65 
`
` 
`
` 
`
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`
` 
`
`
`
`iii
`
`
`
`

`

`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ............................................................................ 37
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 37
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) .......................................................................... 26
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 16
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 55
`In re Harza,
`274 F.2d 669 (C.C.P.A. 1960) ............................................................................ 46
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .............................................................. 33, 36, 61
`In re Nomiya,
`509 F.2d 566 (C.C.P.A. 1975) ............................................................................ 10
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 62
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 58, 59
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 36
`Shire LLC et al. v. Abhai, LLC,
`1:15-cv-13909-WGY (D. Mass. Nov. 20, 2015) ................................................ 14
`In re Spada,
`911 F.2d 705 (Fed. Cir. 1990) ............................................................................ 29
`
`iv
`
`
`

`

`Statutes
`35 U.S.C. § 102(b) ................................................................................................. 5, 8
`35 U.S.C. § 325(d) ............................................................................................... 2, 63
`Other Authorities
`37 C.F.R. § 42.8 ......................................................................................................... 3
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 3
`37 C.F.R. § 42.8(b)(3)-(4) .......................................................................................... 3
`37 C.F.R. § 42.10(b) .................................................................................................. 3
`37 C.F.R. §§ 42.15(A) and 42.103 ............................................................................. 4
`37 C.F.R. § 42.100(b) .............................................................................................. 16
`37 C.F.R. § 42.104(A)................................................................................................ 4
`
`v
`
`

`

`EXHIBIT LIST
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Exhibit Reference
`1001
`U.S. Patent No. 8,846,100 (the “‘100 patent”)
`1002
`U.S. Patent No. 6,605,300 (“Burnside”)
`PHYSICIANS’ DESK REFERENCE® 3144-3146 (58th ed. 2004) (“2004
`1003
`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)
`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)
`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)
`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)
`U.S. Patent No. 4,728,512
`U.S. Patent No. 5,326,570
`U.S. Patent No. 8,313,776
`U.S. Patent No. 6,555,136
`
`1015
`1016
`1017
`1018
`
`1013
`
`1014
`
`vi
`
`

`

`1021
`
`1022
`1023
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`Exhibit Reference
`1019
`U.S. Patent No. 6,322,819
`U.S. Food and Drug Administration, Clinical Pharmacology and
`1020
`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)
`THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 62-83 (Alfred
`Goodman Gilman et al. eds., 8th ed. 1990)
`U.S. Patent Application Publication No. US2004/0059002
`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)
`BIOPHARMACEUTICS AND RELEVANT PHARMACOKINETICS (John G.
`Wagner et al. eds., 1st ed. 1971)
`REMINGTON THE SCIENCE AND PRACTICE OF PHARMACY (Limmer, 20th
`ed., 2000)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Ainley Wade & Paul J.
`Weller eds., 2d ed. 1994)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Arthur H. Kibbe ed., 3d
`ed. 2000)
`Prosecution History of the ‘857 Patent
`FDA Adderall XR® Label, 2004 (Published August 2004)
`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)
`WO99/66904
`WO98/27967
`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
`James T. McCraken et al., Analog Classroom Assessment of a Once-
`Daily Mixed Amphetamine Formulation, SLI381 (ADDERALL XR),
`in Children With ADHD J. AM. ACAD. CHILD ADOLESC.
`PSYCHIATRY, 42:6, June (2003)
`
`1029
`1030
`1031
`1032
`
`1033
`
`1034
`1035
`1036
`
`1037
`
`
`
`vii
`
`

`

`1038
`
`Exhibit Reference
`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.)
`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)
`Declaration of Chad Landmon in Support of Motion for Admission Pro
`Hac Vice
`Declaration of Thomas Hedemann in Support of Motion for Admission
`Pro Hac Vice
`
`1039
`
`1040
`
`1041
`
`1042
`
`
`
`viii
`
`

`

`KVK-Tech, Inc. (“Petitioner”) hereby submits this petition for inter partes
`
`review (“Petition”) of U.S. Patent No. 8,846,100 (“the ‘100 patent”) (Ex. 1001).
`
`The Petition shows a reasonable likelihood that claims 1-31 of the ‘100 patent (the
`
`“Challenged Claims”) are unpatentable on three grounds.
`
`I.
`
`INTRODUCTION
`
`This case is about a controlled release composition already disclosed within
`
`the experimental examples of a prior patent issued to the same alleged patent
`
`owner. The Challenged Claims covering that alleged invention boil down to an
`
`amphetamine salt composition comprising three beads: (1) immediate release
`
`beads; (2) delayed pulsed release beads; and (3) delayed sustained release
`
`beads. Importantly, the delayed sustained release beads served as the basis for
`
`allowance of all Challenged Claims.
`
`Yet, the above-mentioned prior art patent – U.S. Patent No. 6,605,300 to
`
`Burnside et al. (“Burnside”) (Ex. 1002)1 – teaches each and every single limitation
`
`of nearly all Challenged Claims, including the delayed sustained release beads.
`
`Indeed, there can be no dispute that Burnside teaches mixed amphetamine salts,
`
`which were known 80 years ago. Nor can there be any dispute that Burnside
`
`teaches the immediate and delayed release pulsed beads. Finally, Burnside teaches
`
`1 Burnside reissued as RE41,148 on February 23, 2010.
`
`1
`
`

`

`
`
`the delayed sustained release beads, which it dedicates to the public. In fact,
`
`Burnside’s experimental examples, which teach both delayed pulsed and sustained
`
`release beads were largely copied into the ‘100 patent and serve as the basis of the
`
`Challenged Claims. As such, Burnside anticipates the Challenged Claims.
`
`Although the Patent Office withdrew rejections of these claims based on
`
`Burnside during prosecution, it did so in view of Applicants’ inaccurate
`
`representations that Example 4 of Burnside does not teach delayed sustained
`
`release beads or a sustained release coating on top of an enteric coating. Shire
`
`LLC, the alleged assignee of the ‘100 patent, has itself demonstrated these
`
`representations are inaccurate by admitting in federal court that the formulation of
`
`Example 4, “shows a sustained enteric release, occurring over the course of six
`
`hours.” (Ex. 1036 at 12). In addition, and significantly, Petitioner presents new,
`
`additional prior art not considered during prosecution. The Challenged Claims
`
`thus warrant a fresh look by this tribunal and 35 U.S.C. § 325(d) does not apply
`
`here.
`
`At the very least, Burnside alone, or Adderall XR®, in combination with
`
`Burnside, renders these claims obvious. Both Burnside and Adderall XR® teach a
`
`two-bead system comprising immediate release beads and delayed pulsed release
`
`beads, each comprising mixed amphetamine salts. The prior art motivates a person
`
`of ordinary skill (“POSA”) to add Burnside’s sustained release beads to this two-
`
`2
`
`

`

`
`
`bead system to prolong the action of the amphetamine actives in patient
`
`populations for which the duration of therapeutic efficacy was insufficient.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
` Real Parties-in-Interest 37 C.F.R. § 42.8(b)(1)
`The real parties-in-interest are KVK-Tech, Inc. and Abhai LLC.
`
` Related Matters
`Amerigen Pharmaceuticals Limited (“Amerigen”) previously petitioned for
`
`inter partes review of claims 1-31 of the ‘100 patent on January 13, 2017 (Case
`
`No. IPR2017-00665.) Amerigen withdrew its Petition prior to the deadline for
`
`Patent Owner’s Preliminary Response. Petitioner is also concurrently filing a
`
`second petition for inter partes review of U.S. Patent No. 9,173,857 based on
`
`similar grounds.
`
` Lead and Back-Up Counsel 37 C.F.R. § 42.8(b)(3)-(4)
`Petitioner designates the following as lead and back-up counsel, both with
`
`Axinn, Veltrop & Harkrider LLP:
`
`Lead Counsel
`Jonathan A. Harris, Reg. No. 44,744
`90 State House Square, 9th Floor
`Hartford, CT 06103
`Tel: (860) 275-8100
`Fax: (860) 275-8101
`jharris@axinn.com
`
`Back-up Counsel
`James T. Evans, Reg. No. 64,377
`114 West 47th Street, 22nd Floor
`New York, NY 10036
`Tel:(212) 728-2231
`Fax: (212) 728-2201
`jevans@axinn.com
`
` 
`
`A power of attorney is submitted herewith pursuant to 37 C.F.R. § 42.10(b).
`
`3
`
`

`

`
`
`III. PAYMENT OF FEES 37 C.F.R. §§ 42.15(A) AND 42.103
`
`Petitioner submits the required fees with this Petition. Please charge any
`
`additional fees to Deposit Account No. 013050.
`
`IV. GROUNDS FOR STANDING 37 C.F.R. § 42.104(A)
`
`Petitioner certifies that the ‘100 patent is available for inter partes review,
`
`and that Petitioner is not barred or estopped from requesting such review.
`
`V.
`
`IDENTIFICATION OF CHALLENGE - PROPOSED GROUNDS
`
`Petitioner challenges claims 1-31 of the ‘100 patent and requests these
`
`claims be found unpatentable in view of the following grounds:
`
` Ground 1: Claims 1-21 and 31 are anticipated by Burnside (Ex. 1002).
`
` Ground 2: Claims 1-31 are obvious in view of Burnside (Ex. 1002).
`
` Ground 3: Claims 1-31 are obvious over: (1) Adderall XR® (Ex. 1003 or
`
`Ex. 1031)2 in view of (2) Burnside (Ex. 1002).
`
`VI. STATE OF THE PRIOR ART AS OF 2006
`All aspects of the Challenged Claims were known in the prior art long before
`
`the filing of the ‘100 patent. In fact, mixed amphetamine salts as well as
`
`immediate release, delayed pulsed release and delayed sustained release beads
`
`                                                            
`2 Exhibit 1003 and Exhibit 1031 are alternatives supporting the teachings of
`
`Adderall XR®. (Ex. 1004 at ¶¶34-36.)
`
`4
`
`

`

`
`
`were known in the art well before the ‘100 patent. The following prior art
`
`published more than one year before the May 12, 2006 filing date of the ‘100
`
`patent.
`
` Amphetamine Was a Well-Known ADHD Treatment
`By May 12, 2006, amphetamine salts had been used to treat attention deficit
`
`disorder (“ADHD”) for about 80 years. (See, e.g., Ex. 1011 at 3; Ex. 1012 at 14.)
`
`The specific mixed amphetamine salts (“MAS”) of Adderall® –
`
`dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate
`
`monohydrate, and amphetamine sulfate – were approved by FDA on February 13,
`
`1996 in an immediate release formulation. (Ex. 1008; Ex. 1004 at ¶¶30-31.) This
`
`formulation became known as Adderall IR®. (See Ex. 1004 at ¶¶30-31.) In
`
`response to industry desire for a longer-acting dosage form, an immediate release
`
`bead was combined with a delayed release bead to produce Adderall XR®. (See id.
`
`at ¶32.) Adderall XR®, approved by FDA on October 11, 2001, contained the
`
`same amphetamine salts as Adderall IR®. (Ex. 1013 at 1-4; Ex. 1004 at ¶32.)
`
`According to the 2004 PDR® for Adderall XR®, “[f]ood does not affect the extent
`
`of absorption of [ADDERALL XR®] . . . .” (Ex. 1003 at 5; see also Ex. 1014 at
`
`12.) The 2004 PDR® and Label for Adderall XR® are prior art under 35 U.S.C. §
`
`102(b).
`
`
`
`5
`
`

`

`
`
` Drug Coating Release Timings and
`Characteristics Were Well-Known In the Prior Art
`The use of coating agents to modulate the release time and rate of active
`
`drugs, as in Adderall XR®, was also well-known. (Ex. 1004 at ¶¶23-29; Ex. 1024
`
`at 4; Ex. 1025 at 2; Ex. 1026 at 4.) It was known as of at least 2000 that coating
`
`agents used for delayed pulsed or sustained release could be applied to subunits of
`
`dosage forms to achieve desired drug-release profiles. (Ex. 1027 at 8-9.) Enteric
`
`coating agents (e.g., EUDRAGIT® L 30-D-55), for triggering delayed pulsed
`
`release, and sustained release coating agents (SURELEASE®), for triggering
`
`sustained release of active pharmaceutical agents are extremely old in the art. (Ex.
`
`1004 at ¶¶27-29 (citing Ex. 1024 at 4, Ex. 1028 and Ex. 1029).)
`
`The prior art reports numerous triple-bead systems containing these types of
`
`coating agents, especially for active drugs traditionally administered multiple times
`
`per day, but modified for once-daily administration. This is especially true for
`
`drugs requiring an extended duration of action. (See, e.g., Ex. 1015 at 1:68-2:8.)
`
`In the case of propranolol HCl, for example, U.S. Patent No. 4,728,512 (“Mehta”)
`
`taught a once-daily dosage form comprising (i) “uncoated” beads (immediate
`
`release beads), (ii) beads “coated with a pH sensitive coat” (pulsed release beads
`
`with an enteric coating) and (iii) beads “coated with a pH independent coat”
`
`(sustained release beads). (Ex. 1015 at [57]; (Abstract).) The prior art taught
`
`6
`
`

`

`
`
`similar dosage forms for various other active drugs. (See, e.g., Ex. 1016;
`
`Ex. 1017.)
`
` Adderall IR® and Adderall XR®
`The prior art taught these same types of systems for mixed amphetamine
`
`salts.
`
`Some brief history may be helpful here. As previously mentioned, FDA
`
`approved the commercial manufacture and sale of Adderall IR® for the treatment
`
`of ADHD on February 13, 1996. (Ex. 1008; Ex. 1004 at ¶31.) Clinicians
`
`recognized the need for an extended duration of action for the treatment of ADHD
`
`so children could forego a second dose during the school day. (See, e.g., Ex. 1002
`
`at 3:13-28; Ex. 1004 at ¶32.) In response, FDA approved Adderall XR® on
`
`October 11, 2001. (Ex. 1004 at ¶32; Ex. 1013.) Adderall XR® combined
`
`immediate release beads with delayed pulsed release beads containing enteric
`
`coatings so the children would not be required to take a second dose of Adderall
`
`IR® during the school day. (See, e.g., Ex. 1002 at 3:13-28; Ex. 1010 at 2; see also
`
`Ex. 1004 at ¶¶32, 37-38.)
`
`Clinicians recognized, however, that a proportion of patients treated with
`
`Adderall XR®, especially adolescents and adults, still required additional treatment
`
`to extend the daily therapeutic effect. (Ex. 1001 at 3:26-45.) In many cases,
`
`clinicians instructed those patients to augment Adderall XR® with a later dose of
`
`7
`
`

`

`
`
`Adderall IR®. (Id.) A prior art article by Kratochvil described this same problem
`
`and solution. (Ex. 1010 at 2) (“Give . . . Adderall XR early and IR around 6 PM”).
`
` Amphetamine Formulations with Sustained Release Beads
`
`The prior art disclosed a solution to the Adderall XR®-Adderall IR® dosing
`
`regimen: a sustained release system. (Ex. 1004 at ¶¶40-45.) Burnside, issued
`
`August 12, 2003, is prior art under 35 U.S.C. § 102(b).3 (Ex. 1002 at [45].)
`
`Burnside teaches immediate release, delayed pulsed release and delayed sustained
`
`release beads in its experimental examples. Example 1 of Burnside teaches
`
`immediate release beads containing mixed amphetamine salts. (Ex. 1002 at
`
`10:30-57.) Each of Examples 2 and 3 of Burnside teach delayed pulsed release
`
`beads containing these same amphetamine salts coated with enteric polymers (i.e.,
`
`EUDRAGIT® L 30D-55 and EUDRAGIT® 4110D, respectively). (Id. at 10:58-
`
`11:57.) And Example 4 of Burnside teaches delayed sustained release beads,
`
`building on either Examples 2 or 3 by adding a sustained release coating (i.e.,
`
`SURELEASE®) over the enteric coating. (Id. at 11:58-12:26; see also id. at Figure
`
`6 (illustrating the sustained release profile); Ex. 1001 at 7:36-40.) Burnside also
`
`teaches that “[t]he drug delivery system . . . comprises one or a number; of beads
`
`                                                            
`3 Burnside is a continuation in-part of and claims priority to U.S. Patent No.
`
`6,322,819 (“the ‘819 patent”), issued November 27, 2001 (Ex. 1019.)
`
`8
`
`

`

`
`
`or beadlets in a dosage form . . . .” (Id. at 6:32-35; Abstract (“The product can be
`
`composed of either one or a number of beads in dosage form . . . .”) Example 5 of
`
`Burnside describes a non-limiting embodiment combining the beads of Example 1
`
`with those of Examples 2 or 3. (Id. at 12:27-48.) Petitioner provides further
`
`teachings from Burnside below in Section X.
`
`U.S. Patent Application Publication No. US2004/0059002 by Couch et al.
`
`(“Couch”) also teaches formulations containing immediate and sustained release
`
`beads of mixed amphetamine salts. (Ex. 1023 at ¶¶10, 19-20.)
`
`VII. THE ‘100 PATENT
`
`
`
`Summary of the ‘100 Patent Specification
`
`The ‘100 patent relates to a multi-dose composition comprising
`
`pharmaceutically active amphetamine salts for the treatment of ADHD. (Ex. 1004
`
`¶50.) The Background of the ‘100 patent describes Adderall XR® as prior art.
`
`According to admitted prior art in the Background of the ‘100 patent, Adderall
`
`XR® was designed to “me[e]t the need for a dosage form, which c[ould] be
`
`administered once, in place of the two oral doses which are needed using the
`
`conventional drug delivery formulations of the prior art.” (Ex. 1001 at 3:27-30.)
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`“However, clinicians have noted that a proportion of patients treated with these
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`formulations require additional treatment with a short-acting stimulant to extend
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`the daily therapeutic effect.” (“Admitted Prior Art”).4 (Id. at 3:31-41.)
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`The specification of the ‘100 patent describes the alleged invention as
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`comprising “an immediate release amphetamine component, a delayed pulsed
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`release amphetamine component and a sustained release amphetamine component.
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`. . .” (Id. at 5:20-22.) This composition is allegedly bioequivalent to
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`“ADDERALL XR® followed by an immediate release amphetamine formulation
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`administered 8 hours later[.]” (Id. at 4:9-11.)
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`The experimental examples of the ‘100 patent describe various
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`configurations of these three components, typically in the form of beads or
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`beadlets, as well as certain pharmacokinetic studies. Example 1 teaches immediate
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`release beads. (Id. at 18:60-19:22.) Example 3 teaches delayed pulsed release
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`beads. (Id. at 19:62-20:30.) And Example 4, building on Example 2, teaches
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`sustained release beads. (Id. at 20:31-21:38.) The combination of these three
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`beads in a capsule appears in Example 6. (Id. at 22:15-33.) Example 8 is a study
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`in humans comparing the pharmacokinetics of (1) the 37.5 mg capsule of Example
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`6 with (2) a single 25 mg dose of Adderall XR® followed by a 12.5 mg immediate
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`release dose of Example 1 eight hours later. (Id. at 23:1-26:10.) The
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`                                                            
`4 The statement constitutes admitted prior art. See In re Nomiya, 509 F.2d 566,
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`571 n.5 (C.C.P.A. 1975).
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`pharmacokinetic data, i.e., AUC, Cmax, Tmax, as measured in Example 8, appears at
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`Table 10. (Id. at 25:36-26:6.)
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`Summary of the ‘100 Patent Claims
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`Claim 1, the lone independent claim of the ‘100 patent, recites:
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`1. A pharmaceutical composition comprising: (a) an immediate release
`bead comprising at least one amphetamine salt; (b) a first delayed
`release bead comprising at least one amphetamine salt; and (c) a second
`delayed release bead comprising at least one amphetamine salt; wherein
`the first delayed release bead provides pulsed release of the at least one
`amphetamine salt and the second delayed release bead provides
`sustained release of the at least one amphetamine salt; wherein the
`second delayed release bead comprises at least one amphetamine salt
`layered onto or incorporated into a core; a delayed release coating
`layered onto the amphetamine core; and a sustained release coating
`layered onto the delayed release coating, wherein the sustained release
`coating is pH-independent; and wherein the first delayed release bead
`and the second delayed release bead comprise an enteric coating.
`(Ex. 1001 at 31:59-32:37.) The beads of claim 1 look like this (Ex. 1004 at ¶52.):
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`Dependent claims 2-31 recite various additional characteristics of the
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`composition, including features of the enteric coating, pharmacokinetic data, use of
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`a protective layer, specific amphetamine salts, lack of food effect and dosage
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`strength. (Ex. 1001 at 32:38-34:27; Ex. 1004 at ¶53.)
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`
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`Summary of the ‘100 Patent Prosecution History
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`The ‘100 patent was filed as application serial no. 11/383,066 (“the ’066
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`application”) on May 12, 2006. (Ex. 1005 at 1, 51-58.) The original independent
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`claim of the ‘066 application recited immediate release, delayed release and
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`sustained release beads. (Id. at 51.)
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`The Examiner initially rejected all claims as anticipated and obvious based
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`on Burnside. The Examiner explained: “[Burnside] teaches an oral pulsed release
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`formulation comprising a combination of immediate release and delayed release
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`amphetamine beads (abstract),” and cited the experimental examples for the
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`sustained release beads. (Id. at 480-485, 482.) The Examiner asserted that the
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`claimed physiological effects of the dosage form (Tmax, Cmax, and AUC of a 37.5
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`mg dose) are “merely functional limitations that are the result of the instant
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`compositional components.” (Id. at 483.) The Examiner also rejected all claims
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`as obvious in view of Burnside. (Id. at 483-485, 484.)
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`In response, Applicants argued that “[Burnside] discloses immediate release
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`beads and delayed pulsed release beads, but not sustained release beads.” (Id. at
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`535, 536.) Applicants further argued Burnside teaches use of a delayed pulsed
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`release formulation as opposed to a sustained release formulation. (Id. at 536.)
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`Applicants’ characterization, however, was false. The ‘066 application states that
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`the “sustained release” coating is a polymer or combination of polymers and
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`provides a list of suitable polymers, including SURELEASE®. (Id. at 23.)
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`Example 4 of Burnside discloses a bead coated with amphetamine salts, followed
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`by an enteric coating and then SURELEASE®. (Ex. 1002 at 11:58-12:26; Ex.
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`1004 at ¶¶46-47.) As mentioned, the assignee on the ‘100 patent, admitted in
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`federal court that Burnside Figure 6, which provides the release profile for the
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`formulation of Example 4, “shows a sustained enteric release, occurring over the
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`course of six hours.”5 (Shire LLC et al. v. Abhai, LLC, 1:15-cv-13909-WGY
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`(D. Mass. July 21, 2016), D.I. 73 (Ex. 1036 at 12).)
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`In the second Office Action, the Examiner maintained the same rejections.
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`(Ex. 1005 at 551-557.) In response, Applicants acknowledged Example 4 of
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`Burnside teaches coating the beads of Examples 2 or 3 with SURELEASE®. (Id.
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`at 569-570.) Applicants failed, however, to inform the Examiner that the release
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`profile of Example 4 (shown in Figure 6) was, as Patent Owner later admitted, that
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`of a sustained release bead.
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`In the third Office Action, the Examiner again maintained the same
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`rejections. (Id. at 587-588.) Applicants asserted that the claimed “second delayed
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`release bead” has an “atypical construction,” not taught in Burnside, and amended
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`claim 1 to recite “wherein the second delayed release bead comprises at least one
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`amphetamine salt layered onto or incorporated into a core; a delayed release
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`coating layered onto the amphetamine core; and a sustained release coating
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`layered onto the delayed release coating.” (Id. at 645-646.)
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`Here again, Applicants mischaracterized the teachings of Burnside, stating
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`that the bead of Example 4 did not have a sustained release coating over the
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`                                                            
`5 Shire was citing to Figure 6 in RE41148, the reissued ‘100 patent. The Figure is
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`the same in the ‘100 patent.
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`enteric coating. Applicants’ statement was misleading because Example 4 of
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`Burnside teaches this very construction. That is, Example 4 teaches a core, coated
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`with amphetamine, followed by an enteric coating, and then a sustained release
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`coating. (Id. at 646; Ex. 1002 at 11:58-12:26.)
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`In the fourth Office Action, in response to Applicants’ false representation
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`that Burnside did not teach the second delayed sustained release bead recited by
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`the pending claims, the Examiner withdrew the anticipation rejection and
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`maintained obviousness rejections against some of the claims based on additional
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`art. (Ex. 1005 at 663-670.)
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`After another rejection and Interview, a Notice of Allowance was mailed
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`with an Examiner’s Amendment that included the following additional limitation
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`to claim 1: “wherein the sustained release coating is pH-independent.” (Id. at
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`784-786, 785.) The ‘100 patent issued on September 30, 2014. (Ex. 1001 at
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`[45].)
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`VIII. LEVEL OF ORDINARY SKILL IN THE ART
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`A POSA to whom the patent is addressed has at least a Bachelor of Science
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`Degree in Pharmacy, Chemistry, or Chemical Engineering, or similar field, and
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`experience in the field of pharmaceutics (including pharmaceutical formulation or
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`pharmacokinetics or a similar technical field of study). (Ex. 1004 ¶21.) This
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`person also has access to and may consult with a pharmacologist with experience
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`in pharmacokinetics and/or an M.D. with experience with ADHD and
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`pharmacological treatments for ADHD. (Id. at ¶21.) Declarations from Dr.
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`Burgess (Ex. 1004), an exper