IPR2018-00293
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`
`KVK-TECH, INC.,
`
`Petitioner,
`
`v.
`
`SHIRE LLC,
`
`Patent Owner.
`____________________
`Case IPR2018-00293
`US Patent No. 9,173,857
`____________________
`
`
`
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`DECLARATION OF BERNHARDT L. TROUT, Ph.D.
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`SHIRE EX. 2001
`KVK v. SHIRE
`IPR2018-00293
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`TABLE OF CONTENTS
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`IPR2018-00293
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`Page
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`I.
`II.
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`INTRODUCTION .......................................................................................... 1
`EXPERIENCE AND QUALIFICATIONS .................................................... 1
`A.
`Professional Background ...................................................................... 1
`B. Materials Considered for This Declaration .......................................... 4
`III. Legal Principles .............................................................................................. 6
`IV. THE PERSON OF ORDINARY SKILL IN THE ART ................................ 8
`V.
`THE ‘857 PATENT CLAIMS A METHOD FOR TREATING ADHD
`USING A THREE AMPHETAMINE COMPONENT (IR-DPR-SR)
`DOSAGE SYSTEM RESULTING IN 14-16 HOUR THERAPY ................ 8
`VI. TECHNICAL BACKGROUND HELPFUL IN UNDERSTANDING
`THE NOVELTY AND NON-OBVIOUSNESS OF THE ‘857
`PATENT METHOD OF USING A THREE AMPHETAMINE
`COMPONENT (IR-DPR-SR) DOSAGE SYSTEM .................................... 10
`A. Amphetamines .................................................................................... 10
`B. Drug Release from Oral Dosage Forms ............................................. 11
`a.
`The GI Tract – A Varying Environment .................................. 12
`b.
`The Method of the ‘857 Patent Combines Three Different
`Types of Amphetamine Delivery in a Single (IR-DPR-
`SR) Dosage System .................................................................. 14
`Pharmacokinetics and Pharmacodynamics – The Importance of
`In Vivo and the Unpredictability of In Vivo from In Vitro and
`ViceVersa ........................................................................................... 17
`VII. THE ‘857 PATENT ...................................................................................... 21
`A.
`The ‘857 Patent Dosage System Method Claims ............................... 21
`B.
`The ‘857 Patent Dose Claims ............................................................. 23
`VIII. CLAIMS 1-19 AND 29 ARE NOT ANTICIPATED BY OR
`OBVIOUS OVER BURNSIDE.................................................................... 23
`A. None of the ‘857 Patent Claims Are Anticipated .............................. 23
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`C.
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`-i-
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`TABLE OF CONTENTS
`(continued)
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`IPR2018-00293
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`
`a.
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`B.
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`Page
`Claim 1 Is not Anticipated ....................................................... 24
`i.
`There Is No Three Bead Combination in Burnside ....... 24
`Claims 2-4 Are Not Anticipated .............................................. 30
`b.
`Claims 13-16 and 29 Are Not Anticipated .............................. 31
`c.
`Claims 17 and 18 Are Not Anticipated .................................... 31
`d.
`The Prosecution History Establishes that: (a) The Examiner
`Correctly Understood Burnside to Disclose Two-Bead
`Pharmaceutical Compositions and (b) The Examiner Was Not
`Mislead ............................................................................................... 32
`C. None of the ‘857 Patent Claims Are Obvious .................................... 33
`a.
`The Dosage System Method Claims (claims 1-4, 13-18,
`and 29) and the Dose Claims (claims 20-28) Are Non-
`Obvious .................................................................................... 34
`i.
`Claim 1 is Non-Obvious ................................................ 34
`(1) Nether Burnside nor ADDERALL XR
`Disclose or Suggest the ‘857 Patent
`Amphetamine Three Bead IR-DPR-SR
`Combination ........................................................ 34
`(2) The Prior Art Did Not Motivate the ‘857
`Patent Amphetamine Three Bead IR-DPR-
`SR Combination .................................................. 43
`(3) There was No Reasonable Expectation of
`Success in Making the ‘857 Patent
`Amphetamine Three Bead IR-DPR-SR
`Combination ........................................................ 45
`(4) The ‘857 Patent Invention Gave Surprising
`and Unexpected Results ...................................... 58
`Claims 2-4, 13-20, and 31 Are Non-Obvious ............... 64
`ii.
`The Dose Claims Are Non-Obvious ........................................ 65
`b.
`APPENDIX A CURRICULUM VITAE
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`-ii-
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`I.
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`IPR2018-00293
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`DECLARATION OF BERNHARDT L. TROUT, Ph.D.
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`I, Bernhardt L. Trout, Ph.D., do hereby declare and say as follows:
`INTRODUCTION
`I am a citizen of the United States of America and am more than
`1.
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`twenty-one (21) years of age. I have been retained by counsel for Patent Owner
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`Shire LLC as an expert in drug delivery and pharmaceutical formulation to address
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`topics relevant to the subject matter of KVK-Tech, Inc. v. Shire LLC, IPR2018-
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`00293, involving the claims of U.S. Patent No. 9,173,857 (the “ʼ857 patent”). EX.
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`1001. I am being compensated at my usual rate for consultation on patent matters,
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`and I am being provided with, or reimbursed for, my expenses. My compensation
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`is in no way dependent on the outcome of this case.
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`II. EXPERIENCE AND QUALIFICATIONS
`Professional Background
`A.
`2.
`I am currently a Professor of Chemical Engineering at
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`the
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`Massachusetts Institute of Technology (MIT) and the Director of the Novartis-MIT
`
`Center for Continuous Manufacturing. I am also Director of the MIT Benjamin
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`Franklin Project of the Advancement of the Arts and Sciences, which is also
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`known as Engineering, Ethics, and Entrepreneurship.
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`3.
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`I received my S.B. and S.M. degrees from MIT (1990) and my Ph.D.
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`from the University of California at Berkeley (1996), all in chemical engineering. I
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`performed post-doctoral research at the Max-Planck Institute, Stuttgart, in solid-
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`IPR2018-00293
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`state physics. In 1998, I became an Assistant Professor of Chemical Engineering at
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`MIT. I was promoted to Associate Professor of Chemical Engineering in 2003, and
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`I was promoted to full Professor of Chemical Engineering at MIT in 2008. I hold
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`the Raymond F. Baddour, ScD, (1949) Chair as Professor of Chemical
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`Engineering.
`
`4.
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`I am a member of various scientific societies including the American
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`Institute of Chemical Engineering, the American Association of Pharmaceutical
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`Scientists, and the American Chemical Society.
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`5.
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`I have been a reviewer for several journals including Proceedings of
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`the National Academy of Sciences, The Journal of Physical Chemistry, Chemical
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`Physics Letters, Pharmaceutical Research, Journal of the American Chemical
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`Society, Biochemistry, Journal of Pharmaceutical Sciences, Biophysical Journal,
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`The Journal of Organic Chemistry, Analytical Biochemistry, Research Letters in
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`Physical Chemistry, Nature Materials, Molecular Pharmaceutics, Chemical Physics
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`Letters, Angewandte Chemie, Crystal Growth & Design, The Journal of
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`Chromatography A, and Crystal Engineering Communications.
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`6.
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`I have given more than 100 invited talks on pharmaceuticals and
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`pharmaceutical processing, including at the FDA, the American Association of
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`Pharmaceutical Sciences, The Industrial Society of Pharmaceutical Engineering,
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`IPR2018-00293
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`the American Chemical Society, PEP Talk, and several companies.
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`7.
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`I have published more than 190 papers in refereed journals and have
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`28 patents pending or issued.
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`8. My current research group at MIT consists of approximately 8 Ph.D.
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`students, Post-Doctoral Associates, and technical research staff. My research
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`consists of a wide-range of areas
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`in pharmaceutical development and
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`manufacturing, including pharmaceutical and biopharmaceutical formulation,
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`continuous pharmaceutical manufacturing, and crystallization and polymorphism
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`of pharmaceuticals. This research
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`investigates
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`the underlying science of
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`pharmaceutical development and manufacturing and aims to develop new
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`technologies in those areas. I also consult for industry and for the FDA. This
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`consulting consists of a range of endeavors from technical problem solving to
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`strategy. My work includes developing targeted release profiles, i.e. dosage forms
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`that exhibit targeted dissolution and pharmacokinetic properties. In doing so, my
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`group studies a wide range of standard and non-standard excipients, including
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`polymer and non-polymer coating materials.
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`9. My curriculum vitae is attached hereto as Appendix A.
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`IPR2018-00293
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`B. Materials Considered for This Declaration
`In making this Declaration, I have studied and considered: (a) the ‘857
`10.
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`patent (EX1001) and its file history (EX1030) (b) KVK’s Petition and Exhibits in
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`this IPR (EX1001-1042), including the declarations of its experts (EX1004 and
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`EX1006) and its grounds for this IPR (EX1002, EX1003, EX1031, EX1015-1018);
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`(c) KVK’s Petition and Exhibits in related IPR2018-00290; and (d) each of the
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`documents I cite in the body of this Declaration. This includes U.S. Patent
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`8,864,100 (“the ‘100 patent”), which is EX1001 in the related IPR, and its file
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`history (EX1005 here). I am also submitting a Declaration in IPR2018-00290.
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`11.
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`I understand that this is an inter partes review (“IPR”) proceeding
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`conducted before the Patent Trial and Appeal Board (“Board”) of the U.S. Patent
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`and Trademark Office (“USPTO”) to determine if claims 1-29 of the ‘857 patent
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`(the challenged claims) should be cancelled as unpatentable, in view of certain
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`prior art grounds asserted in the Petition. I understand that Petitioner requested
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`institution of this proceeding through a Corrected Petition dated December 11,
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`2017, and that the Petition asserted that:
`
`i.
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`claims 1-19 and 29 of the ‘100 patent are invalid as anticipated by
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`U.S. Patent No. 6,605,300 (“Burnside”);
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`ii.
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`claims 1-29 are obvious over Burnside; and
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` iii. claims 1-29 are obvious over ADDERALL XR® (based on
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`IPR2018-00293
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`Physicians’ Desk Reference 3144-46 (58th ed. 2004) (EX1003) or the
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`2004 Label for ADDERALL XR (EX1031)) in view of Burnside.
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`The Petition was accompanied by Declarations of Diane J. Burgess, Ph.D.
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`(EX1004) and William J. Jusko, Ph.D. EX1006.
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`12. Contrary to the Petitioner, neither Burnside nor ADDERALL XR
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`disclose a method for treating ADHD using a three component, three dose
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`immediate release (IR)-delayed pulse release (DPR)-sustained release (SR)
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`amphetamine dosage system providing significantly longer (i.e., up to 16 hours)
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`therapeutic effect from a single administration than did the prior art. Both
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`Burnside and ADDERALL XR are
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`two component,
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`two dose IR-DPR
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`amphetamine dosage systems that provide only up to 12 hours of ADHD therapy.
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`The only other amphetamine product was an earlier single component, single dose
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`ADDERALL IR which required twice daily administration for the coverage that
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`ADDERALL XR addressed.
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`13. Nor does any prior art relied upon by Petitioner motivate making such
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`an amphetamine dosage system from a disclosure of a disparate third bead that was
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`never used by Burnside or others to make a long-acting three component, three
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`dose dosage form.
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`III. Legal Principles
`I am not an attorney. However, I have been advised of the following
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`legal principles, and they have helped to form my conclusions in this report.
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`15.
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`I understand that, in an IPR, patent claims are given their broadest
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`reasonable interpretation, according to ordinary meaning, in the context of the
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`patent and its prosecution history. Ordinary meaning is what artisans would have
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`understood at the time of invention. An explicit definition guides the artisan to the
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`correct meaning of a claim term.
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`16. An invention that is patentable in the United States must not be, inter
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`alia, anticipated or obvious. 35 U.S.C. §§ 102 and 103.
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`17. The test for anticipation under § 102 is whether each and every
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`element as set forth in a patent claim is found, either expressly or inherently, in a
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`single prior art reference. An anticipatory reference must be considered together
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`with the knowledge of one of ordinary skill in the pertinent art, which includes art-
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`recognized knowledge that may be not be explicit in the reference. A characteristic
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`is inherent in a reference when evidence makes it clear that the missing descriptive
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`matter is necessarily present and would be so-recognized by persons of ordinary
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`skill in the art, whether before or after the patent-at-issue was first applied for.
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`18. Obviousness is a question of law based upon factual inquiries
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`concerning: (1) the scope and content of the prior art; (2) differences between the
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`prior art and the claims at issue; (3) the level of ordinary skill in the art; and (4)
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`IPR2018-00293
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`objective evidence of non-obviousness.
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`19.
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`To establish obviousness in view of a combination of references,
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`Petitioner must set forth sufficiently articulated reasoning, with rational
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`underpinnings, explaining why one skilled in the art would have been motivated to
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`combine the teachings of those references to derive the claimed subject matter and
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`would have had a reasonable expectation of success in doing so. Furthermore, a
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`reference may teach away from a claimed invention when a person of ordinary
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`skill, upon reading the reference, would be discouraged from following the path set
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`out in the reference or would be led in a direction divergent from the path taken by
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`the patent applicant.
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`20.
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`Inherency in the context of obviousness may not be established by
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`probabilities or possibilities. The mere fact that a certain thing may result from a
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`given set of circumstances is not enough.
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`21.
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`The ‘857 patent must be read from the perspective of a person of
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`ordinary skill in the relevant art at the time the invention was made, which here is
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`no later than May 2006. The earliest filing date listed on the face of the ‘857 patent
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`is May 12, 2006. EX1001, cover page (22). I understand the person of ordinary
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`skill in the art is a hypothetical person who is presumed to know the relevant art at
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`the time of the invention.
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`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`22. A person of ordinary skill in the art to which the ‘857 patent pertains
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`IPR2018-00293
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`would have a Bachelor of Science degree in pharmacy, chemistry, chemical
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`engineering, or a similar field, and three years of experience in the field of
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`pharmaceutics (including pharmaceutical formulation, pharmacokinetics or a
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`similar technical field of study). A person of ordinary skill in the art in
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`pharmaceutics may work as part of a team. However, Drs. Burgess and Jusko are
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`incorrect if they imply that a person of ordinary skill in the art would have the all
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`of the attributes of all of their teammates and of those with whom they might
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`consult. See EX1004, ¶21; EX 1006, ¶17. Rather, each individual on that team
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`would have her own individual skills, experience, and educational levels.
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`Colleagues may share information, but no single individual would have all of this.
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`Regardless, my opinions regarding the lack of obviousness or anticipation would
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`not change based on KVK-Tech’s definition of a POSA.
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`V. THE ‘857 PATENT CLAIMS A METHOD FOR TREATING ADHD
`USING A THREE AMPHETAMINE COMPONENT (IR-DPR-SR)
`DOSAGE SYSTEM RESULTING IN 14-16 HOUR THERAPY
`23. The ‘857 patent is directed to a method of treating ADH comprising an
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`orally delivered amphetamine salt pharmaceutical composition or system. EX1001,
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`Abstract, claim 1. This composition is “a long acting amphetamine pharmaceutical
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`composition, which includes an immediate release [“IR”] component, a delayed
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`pulse release [“DPR”] component and a sustained release [“SR”] component.” Id.,
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`3:61-65. This system is effective for treating Attention Deficit Hyperactivity
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`Disorder (“ADHD”) in patients who require effective treatment for longer days of
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`14-16 awake hours. Id., 3:54-57. The ‘857 patent explains that ADDERALL XR
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`(a two component IR-DPR dosage system disclosed in Burnside (EX1002)) did not
`
`address the needs of a patient population that required duration of clinical benefit
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`beyond 10-12 hours, such as adolescents and adults rather than school age,
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`pediatric patients. EX1001, 3:39-45, 52-53.
`
`24. The ‘857 patent claims can be divided into four groups – those
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`without pharmacokinetics limitations (e.g., AUC, Tmax, and Cmax limitations),
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`food effect limitations, or dose limitations (claims 1-4, 13-18, and 29, the “dosage
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`system method claims”), those with PK limitations (i.e., AUC, Tmax, and Cmax)
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`(claims 5-12, the “PK method claims”), a claim with a food effect limitation (claim
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`19, the “food effect claim”), and those with dose limitations (claims 20-28, the
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`“dose method claims”).
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`25.
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`I have been asked to address the novelty and non-obviousness of the
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`dosage system method claims and the dose method claims.
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`26. A diagnosis of ADHD (“attention deficit-hyperactivity disorder”)
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`(DSM-IV®)
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`implies
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`the presence of hyperactive-impulsive or
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`inattentive
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`symptoms that caused impairment and were present before age 7 years. The
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`symptoms must cause clinically significant impairment, e.g., in social, academic,
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`IPR2018-00293
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`or occupational functioning, and be present in two or more settings, e.g., school (or
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`work) and at home. The symptoms must not be better accounted for by another
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`mental disorder. EX1003, 5.
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`VI. TECHNICAL BACKGROUND HELPFUL IN UNDERSTANDING
`THE NOVELTY AND NON-OBVIOUSNESS OF THE ‘857 PATENT
`METHOD OF USING A THREE AMPHETAMINE COMPONENT
`(IR-DPR-SR) DOSAGE SYSTEM
`A. Amphetamines
`27. The ‘857 patent claims dosage systems for “amphetamine salts”. See,
`
`e.g., EX1001, claim 1.
`
`28.
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`“Amphetamines are non-catecholamine sympathomimetic amines
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`with CNS stimulant activity. The mode of therapeutic action in Attention Deficit
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`Hyperactivity Disorder (ADHD) is not known.” EX1003, 4. It has two
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`enantiomers and often is found as a racemic mixture of two enantiomers of α-
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`methylphenethylamine: “levo” or l-amphetamine and “dextro” or d-amphetamine.
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`EX1003, 4-5; EX2019, 10 (racemic; dextro-amphetamine is more potent than levo-
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`amphetamine); EX2020, 1; see also EX2021, 6-7. There is a difference in the
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`effects of the two amphetamine enantiomers. EX2011, 3.
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`29.
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`If a compound that has enantiomers is named without a prefix (e.g.,
`
`without dextro-(d) or levo- (l)), it is a racemate (i.e., a 50/50 mixture of the two
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`enantiomers). EX2021, 8.
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`IPR2018-00293
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`30. A salt of amphetamine can be formed by reacting the free base (e.g.,
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`dextro- or levo-amphetamine) with an acid. See EX2010, 10.
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`31. For example, dextroamphetamine sulfate is a salt made from
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`dextroamphetamine
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`free
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`base
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`and
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`sulfuric
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`acid. EX2014,
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`8,
`
`9.
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`Dextroamphetamine saccharate is the saccharate salt of the dextro-enantiomer of
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`amphetamine. Amphetamine aspartate monohydrate is the monohydrate of the
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`aspartate salt of racemic amphetamine. Amphetamine sulfate is the sulfate salt of
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`racemic amphetamine. Id.; EX2009, 4; EX2019, 10, 11.
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`B. Drug Release from Oral Dosage Forms
`32. The ‘857 patent method claims require a combination of three
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`amphetamine-containing components, each with a different method of releasing
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`the amphetamine after administration, i.e., immediate release (“IR”), delayed pulse
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`release (“DPR”), and sustained release (“SR”). See, e.g., EX1001, claim 1. Each
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`of these releases drug in a different manner, at a different time, and in a different
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`place in the gastrointestinal (“GI”) tract. Understanding these differences and why
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`they are important are helpful in understanding the novelty and non-obviousness of
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`‘857 patent claims.
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`33. There are many
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`types of dosage forms and many different
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`formulations of each type of dosage form. Each has a large range of potential
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`mixtures of active pharmaceutical
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`ingredients and
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`inactive components
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`(excipients) in particular configurations and apportioned into particular doses.
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`34. Oral dosage forms include many kinds of liquid, solid, and semisolid
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`dosage forms (e.g., tablets, capsules, sachets, drinks, or syrups). EX1001, 9:57-64;
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`EX2010, 37 (Table 3-6), 19. The drug in an oral dosage form is usually only a
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`portion of the dosage form. Excipients (e.g., diluents, lubricants, binders,
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`antioxidants, preservatives, colorants, flavorings, etc.) (EX2010, 37-42) are often
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`included in the formulation such as those required to deliver or manufacture the
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`dosage form, to achieve desirable characteristics of the finished product (e.g.,
`
`stability, etc), and to assure or potentiate the therapeutic effect of the drug. EX2018,
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`26.
`
`The GI Tract – A Varying Environment
`a.
`35. An orally delivered solid drug must dissolve in the GI tract before it
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`can be absorbed. Once an oral dosage form is swallowed, it travels to the stomach
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`and then through the intestines.
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`IPR2018-00293
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`EX2010, 5, 11; EX2043, 2; see also, EX2032, 2.
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`36. The formulation may be designed to release drug initially in the
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`stomach, to delay release until various portions of the intestine, or both. EX2048, 6.
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`After release commences, the release can take place over various amounts of time.
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`The design of the dosage form (including excipients) must take into account the
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`environment for release and the properties of the drug itself which may facilitate or
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`impede the release of drug from the dosage form. EX1001, 1:10-3:11, 12:24-52;
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`EX1027, 17; EX2010, 60-61, 65; EX2012, 3; EX2015, 5; EX2043, 2, 5-8; EX2042,
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`10-11.
`
`37. When the drug is released from the dosage form and is dissolved in the
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`gastrointestinal fluid, it has the opportunity to pass across the epithelial cell lining of
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`the gastrointestinal membrane and to be taken up into the blood, where it enters the
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`circulatory system. EX2010, 5; EX2043, 2.
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`b.
`
`The Method of the ‘857 Patent Combines Three Different
`Types of Amphetamine Delivery in a Single (IR-DPR-SR)
`Dosage System
`38. The dosage system of the ‘857 method patent is a three component,
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`three dose IR-DPR-SR amphetamine dosage system. See EX1001, claim 1.
`
`39. The ‘857 patent defines “sustained release” (i.e., SR) to mean “that
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`the delivery of drug goes on (it continues or is sustained) for an extended period of
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`time after initial onset, typically more than one hour, whatever the shape of the
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`dose release profile.” EX1001, 11:33-37.
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`40. A pulsed release is rapid, not gradual or sustained. EX1001, 2:4-6,
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`11:17-65; EX2010, 58-60; EX2006, 7:1-6. A “constant/sustained drug output [has]
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`the objective of minimizing peaks and valleys of drug concentrations in the body to
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`optimize drug efficacy and to reduce adverse effects” (EX1002, 1:14-17).
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`“However, for certain drugs, sustained release delivery is not suitable,” for various
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`reasons (id., 1:21-63), including “[d]rug absorption differences in various
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`gastrointestinal segments.” Id., 1:54-55. It is rational to “pump out the drug much
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`faster when the system reaches the distal segment of the intestine, to avoid the
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`entombment of the drug in the feces.” Id., 1:59-63.
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`41. All of the claims of the ‘857 patent use the terms “immediate release”
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`(i.e., IR), “delayed release”, “pulsed release” (i.e, together with delayed, DPR), and
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`“sustained release” (i.e., SR) to describe the release of the drug from the dosage
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`form after administration. See, e.g., EX1001, claim 1.
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`42. The ‘857 patent defines “immediate release” (i.e., IR) to mean “that
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`the release of drug begins very soon, within a relatively short time after
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`administration, e.g. a few minutes or less.” EX1001, 11:17-21. This means that it
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`would be released in the stomach, which has a low pH and is highly acidic, as
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`shown in the figure above.
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`43. The ‘857 patent defines “delayed release” to mean “that the release of
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`drug is postponed, and begins or is triggered some period of time after
`
`administration (e.g., the lag time), typically a relatively long period of time, e.g.
`
`more than one hour.” EX1001, 11:21-24; see also EX1002, 2:13-17.
`
`44. The ‘857 patent defines “pulsed release” to mean “that a drug is
`
`delivered in one or more doses that fluctuate between a maximum and minimum
`
`dose over a period of time. This can be represented by a dose release profile having
`
`one or more distinct peaks or valleys.” EX1001, 11:50-53. “Typically, pulsed
`
`release results in release of essentially all of a drug within about 60 minutes or
`
`less.” EX1001, 11:58-59. Delayed pulsed release is DPR.
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`45. The ‘857 patent and the prior art relied upon in the Petition include
`
`Figures that illustrate in vitro drug release. See, e.g., EX1001, Figs. 1, 4-8;
`
`EX1002, Figs. 3-6. Understanding how drug release is measured in vitro and the
`
`limitations on the usefulness of these experiments in drug system design are
`
`helpful in understanding the novelty and non-obviousness of the ‘857 patent
`
`claims.
`
`46. The in vitro release of a drug from a formulation or dosage form under
`
`test conditions can be shown by a curve representing amount of drug dissolved as a
`
`function of time in a various media. EX1001, 4:30-33 (Fig. 1), 9:54-56 (Figs. 4-7);
`
`EX2018, 17-18; EX2034, 25; EX2041, 1, 4. Dissolution is product-specific.
`
`EX2010, 18; EX2038, 4; EX2040, 1; EX2043, 6-7. For example, two release
`
`curves are illustrated in Figure 1 of the ‘857 patent, reproduced below.
`
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`16
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`This is different from a plasma concentration profile and its curve, which is the
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`concentration of drug in the bloodstream over time. See ¶¶49-50, infra.
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`C.
`
`Pharmacokinetics and Pharmacodynamics – The Importance of
`In Vivo and the Unpredictability of In Vivo from In Vitro and
`ViceVersa
`47. The goal of oral drug delivery is to release the drug from the dosage
`
`form, to dissolve the drug in the GI tract, and to have the drug absorbed from the
`
`GI tract into the bloodstream. This is a complex process, and success at one stage
`
`does not predict or correlate with success at another. Nor does one successful drug
`
`formulation predict success for a different drug formulation. Understanding the
`
`failure of scientists to be able to correlate in vitro and in vivo information and data
`
`is helpful in understanding the novelty and non-obviousness of the ‘857 patent
`
`dosage system method and dose method claims. This involves preliminary
`
`pharmacokinetics and pharmacodynamics.
`
`48. After a drug is administered, what it does in the body can be described
`
`in terms of: (1) pharmacokinetics (“PK”), which is what the body does to the drug,
`
`including dissolution, adsorption, and clearance generally measured as the
`
`concentration of drug in the bloodstream as a function of time, and (2)
`
`pharmacodynamics, which encompasses the biological response to the drug.
`
`EX2022, 1, 8; EX2023, 4-5; EX2034, 24.
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`49. The “plasma concentration” of a drug is the amount of drug present in
`
`its soluble form per unit of plasma volume. EX1027, 14; EX2023, 7. Plasma
`
`concentration can be plotted as a function of time. For example, two plasma
`
`concentration curves are illustrated in ‘857 patent Figure 9 reproduced below (one
`
`curve from shaded circles and one curve from unshaded diamonds).
`
`
`
`See also EX2015, 7-8; EX2022, 5 (Fig. 2); EX2023, 6-7 (Figs. 2-2, 2-3); EX2027,
`
`8 (Fig. 2). The area under the curve (“AUC”) for a plasma concentration curve is
`
`an expression of the total amount of drug absorbed (its total exposure to the
`
`bloodstream). EX1001, 12:57-61; EX2015, 7-8; EX2022, 4; EX2023, 6-7, 26.
`
`50. The maximum concentration (“Cmax”) is the maximum plasma
`
`concentration after oral administration. EX1001, 12:6-67. Cmax is dependent on
`
`the drug, dose, extent of absorption, rate of absorption, rate of drug elimination,
`
`environment in the body, and dosage form. EX1001, 12:62-67; EX2015, 7;
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`EX2023, 6-7, 26, 39; EX2010, 5-6; EX2030, 5. Tmax” is the amount of time
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`necessary to reach Cmax after oral administration. EX1001, 13:1-3; EX2015, 7;
`
`EX2023, 26. Tmax depends on multiple factors, as does Cmax. See id.; EX2030,
`
`5. Tmax, like Cmax, cannot be determined from release or dissolution profile,
`
`either. EX2015, 7, 8 (Fig. 53-7); EX2023, 6; EX2030, 10.
`
`51.
`
` Drugs may be metabolized after absorption. EX1027, 19, 20;
`
`EX2024, 16; EX2010, 5, 6-7.
`
`52. Drug absorption
`
`is complex and unpredictable.
`
`
`
`In vivo
`
`pharmacokinetics and pharmacodynamics, including plasma concentration profiles,
`
`are often difficult to determine from in vitro dissolution or release testing and vice
`
`versa. See EX1027, 16 ( “difficult to predict the [pharmacodynamic] effect of a
`
`drug based only on pharmacokinetic data.”); EX2023, 12; EX2034, 4
`
`(“Unpredictable and poor in-vitro/in-vivo correlations ..., especially when the drug
`
`release rate is very low or drug absorption from the colon is involved.”); EX1024,
`
`25 (“current in vitro tests do not adequately predict in vivo performances.”);
`
`EX2040, 1361 (estimating in vivo PK results from in vitro dissolution testing is
`
`“empirical art or mystery,”); EX2043, 2 (“In vitro tests ... cannot be presumed to
`
`predict in vivo drug availability,” In vitro and in vivo systems must be compared
`
`“for every formulation type”); EX2031, 1, 7 (lack of IVIVC (i.e., in vitro/in vivo)
`
`correlation).
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`53. Although one may see correlations based on experiments already
`
`performed, they cannot be predicted beforehand. EX2039, 6-7, 9; EX2038, 4
`
`(“Demonstration of in vitro in vivo correlations (IVIVC) is necessary.”); id., 11
`
`(Correlations cannot be presumed. They are observed only after “proven
`
`efficacy”); id, 5 (testing and results “[p]redictive of in vivo performance” were still
`
`a “Desired Future State”); id., 8 (“Meaningful in vitro test methods that accurately
`
`reflect and predict oral bioperformance would revolutionize oral formulation
`
`development.”).
`
`54.
`
`In vitro models accurately predictive of drug absorption in vivo have
`
`been shown to be difficult. Problems include in vitro performance requirements,
`
`dosage form delivery rate, and complex and dynamic in vivo conditions. EX2035,
`
`19; EX2041, 1, 2, 5, 10. Parameters are often unknown. See, e.g., EX2031, 1;
`
`EX2038, 15. “[C]ompendial dissolution testing in 900 ml with a paddle (or rotating
`
`basket) doesn't really capture it.” EX2038, 19. “Meaningful in vitro test methods
`
`that accurately reflect and predict oral bioperformance would revolutionize oral
`
`formulation development.” Id., 8.
`
`55. Simply extending the release period for a drug from a dosage form
`
`does not mean similar in vivo performance. EX2041, 9; EX2048, 6. Predicting
`
`“expected bioavailability characteristics for an ER product from dissolution profile
`
`characteristics is a long sought after goal.” EX2039, 4; EX2040, 1; EX2041,8.
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`56. Accordingly, various formulations and dosage forms may exist for a
`
`particular drug, and their release profiles and plasma concentration profiles will
`
`vary. See EX2043, 2 (different formulations affect absorption, “and thereby cause
`
`differences in the onset, extent, and duration of pharmacologic effect.”); EX2048,
`
`6.
`
`VII. THE ‘857 PATENT
`A. The ‘857 Patent Dosage System Method Claims
`57. The only independent claim of the ‘857 patent, dosage system method
`
`claim 1, reads as follows:
`
`thereof, a
`
`A method for treating attention deficit hyperactivity
`disorder (ADHD) which comprises::
`administering
`to a patient
`in need
`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