IPR2018-00290
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`KVK-TECH, INC.,
`
`Petitioner,
`
`v.
`
`SHIRE LLC,
`
`Patent Owner.
`____________________
`Case IPR2018-00290
`US Patent No. 8,846,100
`____________________
`
`DECLARATION OF JAMES E. POLLI, Ph.D.
`
`SHIRE EX2060
`KVK v. SHIRE
`IPR2018-00290
`
`36748898v1
`
`

`

`TABLE OF CONTENTS
`
`IPR2018-00290
`
`Page
`LIST OF EXHIBITS ............................................................................................... iii
`I.
`INTRODUCTION .......................................................................................... 1
`II.
`EXPERIENCE AND QUALIFICATIONS .................................................... 1
`A.
`Professional Background ...................................................................... 1
`B. Materials Considered for This Declaration .......................................... 3
`III. SUMMARY OF MY OPINION..................................................................... 4
`IV. LEGAL PRINCIPLES .................................................................................... 5
`A.
`Claim Construction............................................................................... 5
`B. Anticipation and Obviousness .............................................................. 7
`C.
`Person of Ordinary Skill in the Art .................................................... 10
`THE CHALLENGED PATENT .................................................................. 11
`V.
`VI. PRINCIPLES OF DRUG DELIVERY ........................................................ 16
`A. Dissolution, Absorption, Distribution and Therapy ........................... 17
`B.
`Predictability in Drug Formulation Requires Observed Data-
`Based Modeling .................................................................................. 21
`VII. THE PTAB DECISION TO INSTITUTE THESE PROCEEDINGS ......... 31
`VIII. THERE IS NO PRIOR ART IN VITRO/IN VIVO CORRELATION
`OR PK/PD MODEL IN EVIDENCE – THERE CANNOT BE ANY
`REASONABLE EXPECTATION OF SUCCESS FOR THE
`INTENDED PURPOSE ............................................................................... 41
`A.
`Burnside’s In Vitro Dissolution Test Did Not Indicate In Vivo
`Results ................................................................................................ 41
`The Prior Art Discloses No Information or Data that Would
`Motivate a Three Bead IR-DPR-SR Amphetamine Combination
`Formulation with any Reasonable Expectation of Success ............... 45
`1.
`Burnside Discloses No Information or Data that Would
`Motivate a Three Bead IR-DPR-SR Combination
`Formulation with any Reasonable Expectation of Success ..... 45
`
`B.
`
`-i-
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`IPR2018-00290
`
`Page
`
`2.
`
`3.
`
`The ADDERALL XR PDR and Label Disclose No
`Information or Data that Would Motivate a Three Bead
`IR-DPR-SR Combination Formulation with any
`Reasonable Expectation of Success ......................................... 54
`Speculation from the Principle of Superposition Would
`Not Yield a Reasonable Expectation of Success from a
`Hypothetical Burnside Combination ....................................... 58
`IX. THE PRIOR ART TAUGHT AWAY FROM SUSTAINED
`RELEASE FOR A THERAPEUTIC AMPHETAMINE
`COMPOSITION ........................................................................................... 74
`A. Acute Tolerance Made It Impossible to Have any Reasonable
`Expectation of Success in Using an SR Bead with
`Amphetamines to Treat Disease ......................................................... 74
`Collectively, Other References Relied on by Petitioner Support
`an Expectation that Sustained Release Would Likely Fail ................ 83
`C. Additional References Support an Expectation that Sustained
`Release Would Likely Fail ................................................................. 89
`CLAIMS 5-12 AND 21 ARE NOT OBVIOUS OVER BURNSIDE
`ALONE OR WITH ADDERALL XR (“THE PK CLAIMS”) .................... 93
`A.
`Claims 5-12 Are Not Obvious over Burnside Alone or with
`Adderall XR ("The PK Claims") ........................................................ 94
`1.
`Different Bead and Dose Ratios Produce Different
`Results ...................................................................................... 94
`2. Different Coating Thicknesses Produce Different Results ........... 98
`Claim 21 (No Food Effect) ............................................................... 100
`B.
`XI. CLAIMS 22-30 ARE NOT OBVIOUS ("DOSAGE CLAIMS") .............. 103
`APPENDIX A CURRICULUM VITAE
`
`B.
`
`X.
`
`-ii-
`
`

`

`IPR2018-00290
`
`LIST OF EXHIBITS
`
`2001 DECLARATION OF BERNHARDT L. TROUT, Ph.D. (with CV)
`2002 DECLARATION OF SARA ROSENBAUM, Ph.D. (with CV)
`2003 FDA Orange Book Listing for MYDAYIS® (NDA N022063)
`2004 MYDAYIS® FDA Label (06-2017)
`2005 MYDAYIS® Website Pages
`2006 Amidon, U.S. Patent No. 5,229,131
`2007 Mehta, U.S. Patent No. 5,837,284
`2008 IPR2017-00011 Decision Denying Institution (RE41, 148) (300 Patent)
`2009 Excerpts from Merck, 11th Ed
`2010 Ansel, Popovich & Allen 6th, Ch. 3-5 (1995)
`2011 Sonsalia, Remington Ch. 74, - CNS Stimulants (1995)
`2012 Robinson, Remington, Ch. 94 - Sustained Release (1995)
`2013 Porter, Remington, Ch. 93 – Coating (1995)
`2014 Franz, Remington Vol. II, Ch. 57 - Sympathomimetic Drugs (1995)
`2015 Malinowsi, Remington, Ch. 53 – Bioequivalence (2000)
`2016 Stempel, 7th Ed. - Dispensing of Medication (1971)
`2017 USP 23 NF 18 - Uniformity Sec. 905 (1955)
`2018 USP 23 NF 18 1995 - Excerpts (1955)
`2019 Patrick, Human Psychopharmacology, 12:527-546 (1997)
`2020 Spencer, Arch Gen Psych, 58:775-78 (2001 Aug)
`2021 Lehninger, Principles of Biochemistry, Excerpt (1993)
`2022 Benet, Toxicologic Pathology, 23:115-123 (1995)
`2023 Shargel, Applied Bio & Pharmacokinetics, Ch. 2, 10 (1999)
`2024 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch.1 (1991)
`2025 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch.5 (1991)
`2026 Chiao, Remington, Ch. 94 – Sustained Release (1995)
`2027 Hinsvark, J. Pharmacokin. Biopharm., 1:319-328 (1973)
`
`-iii-
`
`36748898v1
`
`

`

`IPR2018-00290
`
`2028 Benet, Transplantation Proc., 31 (Suppl 3A), 7S-9S (1999)
`2029 Winters, Basic Clinical Pharmacokinetics (1994)
`2030 Rowland, Clinical Pharmacokinetics 2d (1989)
`2031 Mircioiu, Basic & Clinical Pharmacology & Toxicology, 96:262–264 (2005)
`2032 Booijink, Future Microbiol. 2(3), 285-295 (2007)
`2033 Fischer, Pharm. Res., 4:480-485 (1987)
`2034 Gupta and Robinson, Controlled Release Delivery (1992)
`2035 Macheras, Oral Drug Absorption, Ch. 6 - Modeling Biopharm. (2006)
`2036 Schug, European J. Pharm. Sci., 15:279-285 (2002)
`2037 Hendeles, J. Allergy Clin. Immunol., 72:7:43-751 (1986)
`2038 FDA Use & Limitations of In Vitro Testing (Excerpts)
`2039 Guidance for Industry ER Formulations IVIVC (1997)
`2040 Amidon, Mol. Pharm., 7:1361 (2010)
`2041 Khan, International Journal of Pharmaceutics 140:131-143 (1996)
`2042 Koziolek, Advanced Drug Delivery Reviews 101:75–88 (2016)
`2043 Chasseaud, Ann. Rev. Pharmacol., 14:35-46 (1974)
`2044 Greenhill, J. Am. Acad. Child Adolesc. Psychiatry, 42:1234-1241 (2003)
`2045 Swanson, Clin. Pharmacol. Therap., 66:95-305 (1999)
`2046 Spencer, Current Diagn & Treatment Psych., Ch 35 – ADHD (2008)
`2047 Decision re Institution of IPR2015-02009
`2048 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Ch. 7 – (1991)
`2049 Gibaldi, Biopharmaceutics & Clinical Pharmacokinetics, Appendix II (1991)
`2050 Percel, US 2003-0157173A1
`2051 Couch, WO 2004-028509A1
`2052 Shire, Q3 2017 MYDAYIS Results (Excerpts)
`2053 Brauer, J. Clin. Pharm. 16-1, 72-76 (1996)
`2054 Shire, ER and IR Utilization in Adult ADHD [CONFIDENTIAL]
`2055 Shire, MYDAYIS Performance [CONFIDENTIAL]
`2056 Auiler, Curr. Med. Res. Opin., 18:311-316 (2002)
`-iv-
`
`36748898v1
`
`

`

`IPR2018-00290
`
`2058 Ansel, Popovich & Allen 6th, Ch. 3-5 (1995) (EX2010 CORRECTED)
`2059 Brauer J. Clin. Pharm. 16-1 72-76 (1996) (EX2053 CORRECTED)
`2060 DECLARATION OF JAMES POLLI (with CV)
`2061 Swanson, Canadian Child Adolesc. Psych. Re. 1 4-3 (2005)
`2062 Goodman & Gilman, 9th ed. (1996), Preface
`2063 Remington, 20th ed. (2000), Pharmaceutical Care
`2064 Handbook of Pharmaceutical Excipients, 4th ed (2003), Preface
`2065 Brown, J. Am. Acad. Child Psych. (19) 225-239 (1980)
`2066 Jusko Deposition Exhibit. 304, Levy, Case History of a Pharmaceutical
`Formulation Failure, Clinical Pharmacology & Therapeutics, 8(6)
`2067 Jusko Deposition Exhibit 305, Findling, First-Dose Pharmacokinetics of Lithium
`Carbonate in Children and Adolescents, Journal of Psychopharmacology,
`30(4):404-410 (2010)
`2068 Jusko Deposition Exhibit 307, Jusko, SYSTEMS PHARMACOLOGY AND
`PHARMACODYNAMICS, Foundations of Pharmacodynamic Systems analysis,
`161-175 (2016)
`2069 Jusko Deposition Exhibit 309, Applied Pharmacokinetics & Pharmaco-dynamics:
`Principles of Therapeutic Drug Monitoring, Guidelines for Collection and
`Analysis of Pharmacokinetic Data, 8-29 (2006)
`2070 JUSKO DEPOSITION
`2071 BURGESS DEPOSITION
`2072 Burgess Deposition Exhibit 200 (Statement regarding drug doses)
`2073 Jusko Deposition Exhibit 303, Levy et al., Multicompartment Pharmacokinetic
`Models and Pharmacologic Effects, Journal of Pharmaceutical Sciences, 58(4)
`(1969)
`2074 Jusko Deposition Exhibit 306, Mager et al., Scaling Pharmacodynamics from in
`Vitro and Preclinical Animal Studies to Humans, Drug Metabolism
`Pharmacokinetics, 24(1): 16-24 (2009)
`2075 Jusko Deposition Exhibit 308, Sharma et al., Characterization of Four Basic
`Models of Indirect Pharmacodynamic Responses, Journal of Pharmacokinetics
`and Biopharmaceutics, 24(6): 611-635
`
`-v-
`
`36748898v1
`
`

`

`IPR2018-00290
`
`2076 Jusko Deposition Exhibit 310, Jusko, W. J., Pharmacokinetic Principles in
`Pediatric Pharmacology, Symposium on Pediatric Pharmacology, Pediatric
`Clinics of North America, 19(1) (1972)
`2077 Shen and Burgess, J. Control Release, 2015 December 10; 219, 644-51
`2078 AstraZeneca Pharms. LP v. Anchen Pharms., 2012 US Dist LEXIS 43989 (2012)
`(unpublished)
`2079 Mendyk et al., How-To: Empirical IVIVR without Intravenous Data – Dissolution
`Technologies May 2015.
`2080 U.S. Pharmacopeia 24, pp. 1629-1631 (2000)
`2081 Dokoumetzidis and Macheras, “A century of dissolution research : From Noyes
`and Whitney to the Biopharmaceutics Classification System,” Int’l. J.
`Pharmaceutics, 321 (2006) 1-11
`
`-vi-
`
`36748898v1
`
`

`

`IPR2018-00290
`
`DECLARATION OF JAMES POLLI, Ph.D.
`
`I.
`
`I, James E. Polli, Ph.D., do hereby declare and say as follows:
`INTRODUCTION
`1. I am a citizen of the United States of America and am more than twenty-one
`
`(21) years of age. I have been retained by counsel for Patent Owner Shire LLC as
`
`an expert in pharmaceutical science to address topics relevant to the subject matter
`
`of KVK-Tech, Inc. v. Shire LLC, IPR2018- 00290, involving the claims of U.S.
`
`Patent No. 8,846,100 (“Shojaei”). EX. 1001. I am being compensated at my usual
`
`rate for consultation on patent matters, and I am being provided with, or
`
`reimbursed for, my expenses. My compensation is in no way dependent on the
`
`outcome of this case.
`
`II.
`
`EXPERIENCE AND QUALIFICATIONS
`A. Professional Background
`2. I am a Professor and the Ralph F. Shangraw/Noxell Endowed Professor in
`
`Industrial Pharmacy and Pharmaceutics at the University of Maryland School of
`
`Pharmacy in Baltimore, Maryland. I received a BS in Pharmacy from the
`
`Philadelphia College of Pharmacy and Science in 1989 and received a Ph.D. in
`
`pharmaceutics from the University of Michigan in 1993.
`
`1
`
`36748898v1
`
`

`

`IPR2018-00290
`
`3. I am co-director of the University of Maryland Center of Excellence in
`
`Regulatory Science and Innovation (M-CERSI), a U.S. Food and Drug
`
`Administration (“FDA”)-funded collaborative agreement with the agency, and am
`
`the director of the University of Maryland online MS in Regulatory
`
`Science program. I teach professional pharmacy students and graduate students
`
`and serve as an advisor to Ph.D. students.
`
`4. I am a fellow of the American Association of Pharmaceutical Scientists, an
`
`editorial board member of several journals, an editor of Pharmaceutical Research,
`
`and a member of the FDA Pharmaceutical Science and Clinical Pharmacology
`
`Advisory Committee.
`
`5. I have given numerous invited talks throughout the world on pharmaceuticals
`
`and pharmaceutical processing, including at the FDA and the American
`
`Association of Pharmaceutical Sciences.
`
`6. I have published more than 150 papers and book chapters and have several
`
`patents pending or issued.
`
`7. My main research interests are: (1) maximizing oral bioavailability through
`
`formulation and chemical approaches and (2) developing public quality standards
`
`for oral dosage forms. I have published in the areas of dissolution, drug intestinal
`
`permeability, transporter substrate requirements, prodrug design, oral
`
`2
`
`36748898v1
`
`

`

`IPR2018-00290
`
`bioavailability, in vitro – in vivo correlation (IVIVC), and bioequivalence. My
`
`work has included IVIVC analyses of amphetamine dosage forms.
`
`8. My curriculum vitae is attached hereto as Appendix A.
`
`B. Materials Considered for This Declaration
`9. In making this Declaration, I have studied and considered: (a) U.S. Patent
`
`No. 8,846,100 in IPR2018-00290 (EX1001) and U.S. Patent No. 9,173,857 in
`
`IPR2018-00293 (EX1001), respectively, and their file histories (EX1005,
`
`EX1030); (b) KVK’s Petition and Exhibits in each IPR (EX1001-1042), including
`
`the declarations and cross-examinations of its experts (EX1004; EX1006; EX2070;
`
`EX2071), and its grounds and highlighted references (EX1002, EX1003, EX1031,
`
`EX1015-1018); (c) Patent Owner’s Preliminary Response and Exhibits in each
`
`IPR, including the declarations of its experts (EX2001 and EX2002); (d) the July 6,
`
`2018, Decisions in the IPRs; and (e) each of the documents I cite in the body of
`
`this Declaration. I am submitting a Declaration in both IPRs.
`
`10. I understand that this is an IPR proceeding conducted before the Patent Trial
`
`and Appeal Board (“Board” or “PTAB”) of the U.S. Patent and Trademark Office
`
`(“USPTO”) to determine if claims 1-31 of Shojaei (the challenged claims) should
`
`be cancelled as unpatentable, in view of certain prior art grounds asserted in the
`
`3
`
`36748898v1
`
`

`

`IPR2018-00290
`
`Petition. I understand that Petitioner requested institution of this proceeding
`
`through a Corrected Petition dated December 11, 2017, and asserted that:
`
`1) claims 1-21 and 31 of Shojaei are invalid as anticipated by U.S.
`
`Patent No. 6,605,300 (“Burnside”) (EX1002);
`
`2) claims 1-31 are obvious over Burnside; and
`
`3) claims 1-31 are obvious over ADDERALL XR® (based on
`
`Physicians’ Desk Reference 3144-46 (58th ed. 2004) (EX1003) or
`
`the 2004 Label for ADDERALL XR (EX1031)) in view of
`
`Burnside.
`
`The Petition was accompanied by Declarations of Diane J. Burgess, Ph.D.
`
`(EX1004) and William J. Jusko, Ph.D. EX1006. I further understand that the
`
`PTAB issued Decisions to Institute trials on all of the claims of the patents in this
`
`IPR and in the related IPR, respectively.
`
`SUMMARY OF MY OPINION
`III.
`11. I am submitting a declaration in IPR2018-00293, concurrently.
`
`12. Briefly, it is my opinion that the challenged claims are not anticipated,
`
`because there was no three-bead composition in Burnside. The claims are not
`
`obvious because and a person of ordinary skill in the art would not have been
`
`motivated to combine Burnside’s beads with a reasonable expectation of
`
`4
`
`36748898v1
`
`

`

`IPR2018-00290
`
`successfully making a three bead immediate, pulsed, and sustained release (IR-
`
`DPR-SR) combination that would work for its intended purpose, i.e., to treat
`
`disease and, particularly, to provide “a once-daily, long-acting amphetamine
`
`pharmaceutical composition that provides effective treatment of ADHD, without
`
`supplementation, for patients with longer day demands (e.g., 14-16 awake
`
`hours).” EX1001, 3:46-49. This is unexpected and surprising. I explain below the
`
`detailed bases for my opinions and provide references in support of my opinions.
`
`IV. LEGAL PRINCIPLES
`13. I am not an attorney. However, I have been advised of the following legal
`
`principles, and they have helped to form my conclusions in this report.
`
`A. Claim Construction
`14. I understand that prior to November 13, 2018, in an IPR, patent claims were
`
`given their broadest reasonable interpretation, according to ordinary meaning, in
`
`the context of the patent and its prosecution history. Ordinary meaning is what
`
`artisans would have understood at the time of invention. An explicit definition in
`
`the patent guides the artisan to the correct meaning of a claim term.
`
`15. I understand that subsequent to November 13, 2018, in an IPR, claims will
`
`be construed under the different standard currently used by U.S. district
`
`courts. Claim construction begins with the language of the claims. The words of
`
`5
`
`36748898v1
`
`

`

`IPR2018-00290
`
`a claim are generally given their ordinary and customary meaning, which is the
`
`meaning that the term would have to a person of ordinary skill in the art in
`
`question at the time of the invention. Extrinsic evidence, such as expert testimony
`
`and dictionaries, may be useful in educating the court regarding the field of the
`
`invention or helping determine what a person of ordinary skill in the art would
`
`understand claim terms to mean. Claims will be construed, if possible, to preserve
`
`their validity.
`
`16. A pharmaceutical composition is a drug formulation used to prevent,
`
`diagnose, treat, or cure disease. Pharmaceutical compositions comprise active
`
`compounds plus formulation excipients. EX2062, 3; EX2063, 3; EX2064, 3.
`
`17. I understand that the PTAB decided the terms “about” and “no food effect”
`
`have the meanings set forth in the patent, at EX1001, 11:59-12:11. Decision, 10-
`
`12. I have used these definitions in my analysis.
`
`18. However, I understand that Petitioner applied a “broadest reasonable
`
`interpretation” to find that “about” means ± 20%, in connection with the dosage
`
`amounts in claims 22-30. EX1004, ¶55; EX1006, ¶46. I disagree. A POSA would
`
`not apply an unqualified 20% variation to a stated effective dose according to the
`
`express definition of “about” in the patent. The PTAB has rejected Petitioner’s
`
`20% definition in favor of the definition in the patent. That definition defines
`
`6
`
`36748898v1
`
`

`

`IPR2018-00290
`
`“about” to account for “an acceptable error range for the particular value as
`
`determined by one of ordinary skill in the art, which will depend in part on how the
`
`value is measured or determined; i.e., the limitations of the measurement system,
`
`i.e. the degree of precision required for a particular purpose, such as a
`
`pharmaceutical formulation.” EX1001, 11:65-12:11. Examples follow, of which ±
`
`20% is the broadest, but that is not what a POSA would consider an ordinary and
`
`customary error range for a therapeutic dose of a pharmaceutical formulation or
`
`treatment. A POSA would understand that “about” refers to dose uniformity,
`
`according to an acceptable frequency of variation within an acceptable range. See,
`
`e.g., EX1017, 3-4 (USP entry for “Dose Uniformity”).
`
`B. Anticipation and Obviousness
`19. An invention that is patentable in the United States must not be, inter alia,
`
`anticipated or obvious. 35 U.S.C. §§ 102 and 103.
`
`20. The test for anticipation under § 102 is whether each and every element as
`
`set forth in a patent claim is found, either expressly or inherently, in a single prior
`
`art reference. An anticipatory reference must be considered together with the
`
`knowledge of one of ordinary skill in the pertinent art, which includes art-
`
`recognized knowledge that may be not be explicit in the reference. A characteristic
`
`is inherent in a reference when evidence makes it clear that the missing descriptive
`
`7
`
`36748898v1
`
`

`

`IPR2018-00290
`
`matter is necessarily present and would be so-recognized by persons of ordinary
`
`skill in the art, whether before or after the patent-at-issue was first applied for.
`
`21. Obviousness is a question of law based upon factual inquiries concerning:
`
`(1) the scope and content of the prior art; (2) differences between the prior art and
`
`the claims at issue; (3) the level of ordinary skill in the art; and (4) objective
`
`evidence of non-obviousness such as surprising and unexpected results,
`
`commercial success, long-felt need, and failure of others.
`
`22. To establish obviousness in view of a combination of references or prior art
`
`components, Petitioner must set forth sufficiently articulated reasoning, with
`
`rational underpinnings, explaining why one skilled in the art would have been
`
`motivated to combine the components or teachings of those references to derive
`
`the claimed subject matter, and would have had a reasonable expectation of both
`
`making the claimed invention and that it would successfully work for its intended
`
`purpose. I understand that this involves considering the prior art as a whole, not
`
`just the references and teaches that are proposed for combination. Also, one should
`
`not use an inventor’s success as an indication of obviousness.
`
`23. When there is a design need or market pressure to solve a problem, and
`
`there is a finite number of identified, predictable solutions, a combination of these
`
`options may be obvious to try. A combination is obvious to try only if a person of
`
`8
`
`36748898v1
`
`

`

`IPR2018-00290
`
`ordinary skill in the art has good reason to pursue that combination from among
`
`those known limited options.
`
`24. A reference may teach away from a claimed invention when a person of
`
`ordinary skill, upon reading the reference, would be discouraged from following
`
`the path set out in the reference or would be led in a direction divergent from the
`
`path taken by the patent applicant. This includes consideration of known
`
`disadvantages of prior art components that discouraged the combination.
`
`25. When an applicant demonstrates substantially improved results and states
`
`that the results were unexpected, this should suffice to establish unexpected results
`
`in the absence of evidence to the contrary.
`
`26. Inherency of a claimed component or feature may not be established by
`
`probabilities or possibilities. The mere fact that a certain thing may result from a
`
`given set of circumstances is not enough. I understand that this is true for
`
`anticipation and also in the content of “inherent obviousness”.
`
`27. Inherent obviousness can supply a missing limitation that is “necessarily
`
`present” in a given combination of elements explicitly disclosed by the prior art.
`
`Inherency is not be established by probabilities or possibilities. The mere fact that
`
`a missing limitation may result from a given set of elements under some
`
`circumstances but not others is not sufficient. A retrospective view of inherency is
`
`9
`
`36748898v1
`
`

`

`IPR2018-00290
`
`not a substitute for some teaching in the prior art. Optimization of the prior art is
`
`not a substitute for some teaching in the prior art.
`
`28. The patent must be read from the perspective of a person of ordinary skill in
`
`the relevant art at the time the invention was made, which here is no later than May
`
`2006. The earliest filing date listed on the face of the patent is May 12, 2006.
`
`EX1001, cover page (22). I understand the person of ordinary skill in the art is a
`
`hypothetical person who is presumed to know the relevant art at the time of the
`
`invention.
`
`C. Person of Ordinary Skill in the Art
`29. A person of ordinary skill in the art (“POSA” or “artisan”) to which the
`
`patent pertains would have a Bachelor of Science degree in pharmacy, chemistry,
`
`chemical engineering, or a similar field, and three years of experience in the field
`
`of pharmaceutics (including pharmaceutical formulation, pharmacokinetics or a
`
`similar technical field of study).
`
`30. A person of ordinary skill in the art in pharmaceutics may work as part of a
`
`team. However, the artisan would not have all the knowledge, experience, and
`
`attributes of all of their teammates, and of those they might consult. Rather, each
`
`individual on a team would have individual skills, experience, and educational
`
`levels. Colleagues may share information, but no single individual would have all
`
`10
`
`36748898v1
`
`

`

`IPR2018-00290
`
`of their skill, merged into a single artisan. Such a hypothetical person would have
`
`extra-ordinary skill, nor ordinary skill.
`
`31. I understand that Petitioner has proposed a POSA having “at least a
`
`Bachelor of Science degree,” and no upper level of experience. EX1004, ¶21; EX
`
`1006, ¶17. In my opinion, “at least” is vague, and if meant to encompass any skill
`
`level above a Bachelor, I disagree, because a person of “ordinary” skill would not
`
`have completed a Ph.D. Ordinary skill would also include about three years of
`
`experience. Thus, I agree with testimony by Dr. Burgess that a POSA “would have
`
`some skill but not extensive skill. If a person has got a B.S. Degree and a couple of
`
`years of experience working in the field, so I would agree with that.” EX2071,
`
`170:14-17.
`
`32. I understand that the Board considers both definitions to be substantially the
`
`same. Decision, 9-10. On that basis, my opinions in this report are from the
`
`perspective of a POSA having the level of skill articulated in ¶31, above. Although
`
`I find Petitioner’s definition to be ambiguous, I do not believe my opinions would
`
`change under that definition.
`
`V.
`
`THE CHALLENGED PATENT
`33. The only independent claim of Shojaei, dosage system claim 1, reads as
`
`follows:
`
`36748898v1
`
`11
`
`

`

`IPR2018-00290
`
`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.
`
`12
`
`36748898v1
`
`

`

`IPR2018-00290
`
`34. The Shojaei patent claims a pharmaceutical composition having three
`
`amphetamine-containing components - “an immediate release [IR] component, a
`
`delayed pulsed release [DPR] component and a delayed sustained release [SR]
`
`component.” EX1001, claim 1, 3:53-56, 5:11-20, 18:56-21:34.
`
`35. Claims 2-19 and 21-31 depend directly from claim 1; claim 20 depends
`
`from claim 19. The dependent claims provide a pH-dependent enteric coating
`
`(claim 2); delayed release beads with the same or different enteric coatings (claims
`
`3-4); PK parameters (claims 5-12); amphetamine placement (claims 13-16);
`
`protective coatings (claims 17-18 and 31); amphetamine salts (claims 19-20); no
`
`food effect (claim 21); and dosage amounts (claims 22-30).
`
`36. The challenged patent is listed in the FDA Orange Book for Shire’s product
`
`MYDAYIS®. I understand this means that MYDAYIS is an embodiment of the
`
`patent. MYDAYIS is approved for patients 13 years and older as a once-daily
`
`treatment for ADHD that lasts for up to 16 hours. EX2003, 1-3, 6; EX2005, 2.
`
`37. The composition is bioequivalent to an equal dosage of ADDERALL XR®
`
`followed by an IR amphetamine composition 8 hours later.” EX1001, 3:57–62.
`
`Claim 1 of the patent includes three components, each having at least one
`
`amphetamine salt. The first component is an immediate release amphetamine salt
`
`bead. The second component is a first delayed release bead that includes
`
`13
`
`36748898v1
`
`

`

`IPR2018-00290
`
`amphetamine coated with an enteric coating, which release a rapid pulse of drug.
`
`The third component includes amphetamine coated with an enteric coating and a
`
`pH-independent sustained release coating over that, which provides a sustained
`
`release.
`
`38. The patent defines “immediate release” to mean “that the release of drug
`
`begins very soon, within a relatively short time after administration, e.g. a few
`
`minutes or less.” EX1001, 11:5-9. This means that it would be released in the
`
`stomach, which has a low (acidic) pH. EX1024, 5. For convenience, I refer to this
`
`release as “IR”.
`
`39. The patent defines “delayed release” to mean “that the release of 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, 11:9-12; See also EX1002, 2:13-17. The 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, 11:38-41. “Typically, pulsed release results in release of essentially all of
`
`a drug within about 60 minutes or less.” EX1001, 11:46-47. A pulsed release is
`
`14
`
`36748898v1
`
`

`

`IPR2018-00290
`
`rapid, not gradual or sustained. EX1001, 1:65-67, 11:5-53; EX2010, 58-60;
`
`EX2006, 7:1-6. For convenience, I refer to this release as “DPR”.
`
`40. The ‘patent defines “sustained release” to mean “that the delivery of drug
`
`goes on (it continues or is sustained) for an extended period of time after initial
`
`onset, typically more than one hour, whatever the shape of the dose release
`
`profile.” EX1001, 11:21-25. For convenience, I refer to this release as “SR”.
`
`41. SR is for drugs that require “reasonably constant blood levels over a long
`
`period of time.” EX2013, 5; EX2026, 1-2 (“insignificant” absorption phase).
`
`EX2001, ¶¶39-44; EX2002, ¶¶33-36; EX2010, 58-60; EX1001, 11:5-53. A
`
`“constant/sustained drug output [has] the objective of minimizing peaks and
`
`valleys of drug concentrations in the body to optimize drug efficacy and to reduce
`
`adverse effects.” EX1002, 1:14-17. “However, for certain drugs, sustained release
`
`delivery is not suitable,” for various reasons (id., 1:21-63), including “biological
`
`tolerance” and “[d]rug absorption differences in various gastrointestinal segments.”
`
`Id. Instead of SR, it is rational to “pump out the drug much faster when the system
`
`reaches the distal segment of the intestine, to avoid the entombment of the drug in
`
`the feces.” Id., 1:59-63.
`
`42. There are many mechanisms that can provide a sustained release of drug
`
`from a formulation, such as, for example, coatings, matrices (coating not required),
`
`15
`
`36748898v1
`
`

`

`IPR2018-00290
`
`and osmotic systems. There is virtually no limit to the combinations and materials
`
`that can be combined to make and achieve a sustained release. For example, there
`
`are numerous coating arrangements and coating materials, which may be polymers
`
`combined in one coating, or layers, or combines with a matrix. EX1002, 9:1-22;
`
`EX1023, ¶¶0009-20; EX1027, 9; EX2010, 61-65. I understand that Dr. Burgess
`
`agrees. EX2071, 146:17-149:12.
`
`VI. PRINCIPLES OF DRUG DELIVERY
`43. The goal of oral drug delivery is to release the drug from the dosage form,
`
`to dissolve the drug in the gastro-intestinal (“GI”) tract, to have the drug absorbed
`
`from the GI tract into the bloodstream, and to elicit the desired therapeutic effect in
`
`the patient. This is complex. A dosage form first passes through the stomach and
`
`then to the gastrointestinal (GI) tract, including the upper (proximal) and lower
`
`(distal) small intestine, and then the large intestine or colon. The length of the GI
`
`tract is limited. The transit time along this route is variable. EX2010, 12, 13;
`
`EX2033, 5; EX2048, 13. The pH varies along this route. EX1039, 4; EX2010, 5,
`
`11; EX2032, 1-2. Absorption varies also. EX2034, 5. So does the half-life of the
`
`drug, depending on the dosage form (EX2024, 6-7), which represents how rapidly
`
`absorbed drug is eliminated or cleared from blood circulation. EX1027, 20;
`
`EX2016, 18; EX2022, 1; EX2023, 22.
`
`16
`
`36748898v1
`
`

`

`IPR2018-00290
`
`A. Dissolution, Absorp