`
`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 SARA ROSENBAUM, Ph.D.
`
`
`
`
`
`
`
`SHIRE EX. 2002
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`TABLE OF CONTENTS
`
`IPR2018-00290
`
`Page
`
`I.
`II.
`
`INTRODUCTION .......................................................................................... 1
`EXPERIENCE AND QUALIFICATIONS .................................................... 1
`A.
`Professional Background ...................................................................... 1
`B. Materials Considered for This Declaration .......................................... 2
`III. LEGAL PRINCIPLES .................................................................................... 4
`IV. THE PERSON OF ORDINARY SKILL IN THE ART ................................ 6
`V.
`THE ‘100 PATENT CLAIMS ARE DIRECTED TO A THREE-
`COMPONENT (IR-DPR-SR) AMPHETAMINE DOSAGE SYSTEM
`WITH SPECIFIC PHARMACOKINETICS AND WITHOUT A
`FOOD EFFECT .............................................................................................. 7
`A. Amphetamines ...................................................................................... 8
`B. Drug Release from an Oral Dosage Form ............................................ 8
`a.
`The GI Tract Is a Complex Environment .................................. 9
`b.
`The ‘100 Patent Dosage System Combines Three
`Different Types of Amphetamine Delivery - IR-DPR-SR ...... 11
`Pharmacokinetics, Pharmacodynamics, and the Unpredictability
`of In Vivo from In Vitro and Vice Versa ........................................... 13
`a.
`Pharmacokinetics ..................................................................... 14
`b.
`Pharmacodynamics .................................................................. 24
`VII. THE ‘100 PATENT PK CLAIMS AND FOOD EFFECT CLAIM ............ 25
`VIII. THE PK CLAIMS AND THE FOOD EFFECT CLAIM ARE NOT
`ANTICIPATED BY BURNSIDE; NOR ARE THEY OBVIOUS
`OVER BURNSIDE OR ADDERALL XR IN VIEW OF BURNSIDE....... 27
`A.
`The PK Claims Are Not Anticipated ................................................. 27
`B.
`The Food Effect Claim Is Not Anticipated ........................................ 29
`C.
`The PK Claims Are Not Obvious over Burnside Alone or
`ADDERALL XR in view of Burnside ............................................... 32
`
`C.
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`-i-
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`D.
`
`THE FOOD EFFECT CLAIM (CLAIM 21) IS NOT
`OBVIOUS OVER BURNSIDE OR ADDERALL XR IN
`VIEW OF BURNSIDE ...................................................................... 46
`APPENDIX A CURRICULUM VITAE .................................................................. 1
`
`-ii-
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`IPR2018-00290
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`DECLARATION OF SARA ROSENBAUM, Ph.D.
`
`I.
`
`I, Sara Rosenbaum, 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 pharmacokinetics 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 (the “ʼ100 patent”). 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 tenured Professor of Pharmacokinetics in the Department of
`
`Biomedical and Pharmaceutical Sciences at the University of Rhode Island College
`
`of Pharmacy. I am also an Adjunct Professor of Molecular Pharmacology,
`
`Physiology, and Biotechnology at Brown University. I received my Ph.D. (1980)
`
`in Pharmacology from Liverpool University. I have
`
`taught courses
`
`in
`
`biopharmaceutics, pharmacokinetics, and pharmacodynamics. I have published
`
`more than 40 books and peer-reviewed publications in the field, and have
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`IPR2018-00290
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`presented at conferences around the world. I have been Editor-in-Chief and Editor
`
`Emeritus of Clinical Research and Regulatory Affairs and am a reviewer for
`
`Annals of Clinical Pharmacology and Clinical Pharmacokinetics. Over the course
`
`of my career, I have more than three decades of experience in the study of
`
`pharmacokinetics.
`
`3.
`
`My curriculum vitae is attached as Appendix A.
`
`B. Materials Considered for This Declaration
`4.
`In making this Declaration, I relied on over three decades of
`
`experience in pharmaceutical studies and have studied and considered: (a) the ‘100
`
`patent (EX1001) and its file history (EX1005); (b) KVK’s Petition and Exhibits in
`
`this IPR (EX1001-1042), including the declarations of its experts (EX1004 and
`
`EX1006) and its grounds for this IPR (EX1002, EX1003, EX1031, EX1015-1018);
`
`(c) KVK’s Petition and Exhibits in related IPR2018-00293; and (d) each of the
`
`documents I cite in the body of this Declaration. This includes U.S. Patent
`
`9,173,857 (“the ‘857 patent”), which is EX1001 in the related IPR, and its file
`
`history (EX1030 here). I am also submitting a Declaration in IPR2018-00293.
`
`5.
`
`I understand that this is an inter partes review (“IPR”) proceeding
`
`conducted before the Patent Trial and Appeal Board (“Board”) of the U.S. Patent
`
`and Trademark Office (“USPTO”) to determine if claims 1-31 of the ‘100 patent
`
`(the challenged claims) should be cancelled as unpatentable, in view of certain
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`IPR2018-00290
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`prior art grounds asserted in the Petition. I understand that Petitioner requested
`
`institution of this proceeding through a Corrected Petition dated December 11,
`
`2017, and that the Petition asserted that:
`
`i.
`
`claims 1-21 and 31 of the ‘100 patent are invalid as anticipated by
`
`U.S. Patent No. 6,605,300 (“Burnside”);
`
`ii.
`
`claims 1-31 are obvious over Burnside; and
`
`iii.
`
`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).
`
`6.
`
`It
`
`is my opinion
`
`that
`
`the
`
`‘100 patent claims
`
`that
`
`recite
`
`pharmacokinetic (PK) parameters (claims 5-12) and the ‘100 patent claim that
`
`recites the absence of a food effect (claim 21) are not expressly or inherently
`
`disclosed in Burnside or ADDERALL XR. In vivo PK parameters of a dosage
`
`form as claimed in ‘100 patent claims 5-12 cannot be determined in advance from
`
`in vitro data from another dosage form, from in vitro data from individual
`
`components of a dosage form, or from in vivo data from a different dosage form,
`
`particularly when these other dosage forms relate to two component systems while
`
`the claimed invention relates to a three component system. There is no way to
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`IPR2018-00290
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`determine whether the PK parameters claimed in the ‘100 patent would necessarily
`
`have been those of any combination of beads the Petitioner may propose in the
`
`absence of hard data. Neither Petitioner nor the prior art presents that PK data.
`
`7.
`
`The same can be said of the presence or absence of a food effect in a
`
`dosage form. Food effect is drug and formulation dependent. Neither Petitioner
`
`nor the prior art presents food effect data for the ‘100 patent three component,
`
`three dose amphetamine composition.
`
`III. Legal Principles
`8.
`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.
`
`9.
`
`I understand that, in an IPR, patent claims are 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 guides the artisan to the
`
`correct meaning of a claim term.
`
`10. An invention that is patentable in the United States must not be, inter
`
`alia, anticipated or obvious. 35 U.S.C. §§ 102 and 103.
`
`11.
`
`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
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`IPR2018-00290
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`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
`
`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.
`
`12. 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.
`
`13.
`
`To establish obviousness in view of a combination of references,
`
`Petitioner must set forth sufficiently articulated reasoning, with rational
`
`underpinnings, explaining why one skilled in the art would have been motivated to
`
`combine the teachings of those references to derive the claimed subject matter and
`
`would have had a reasonable expectation of success in doing so. Furthermore, 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.
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`14.
`
`Inherency in the context of obviousness 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.
`
`15.
`
`The ‘100 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 ‘100 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.
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`16. A person of ordinary skill in the art to which the ‘100 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 or pharmacokinetics or a
`
`similar technical field of study). A person of ordinary skill in the art in
`
`pharmaceutics may work as part of a team. Drs. Burgess and Jusko are mistaken to
`
`the extent they imply that a person of ordinary skill in the art would have the all of
`
`the attributes of all of their teammates and of those with whom they might consult.
`
`See EX1004, ¶21; EX 1006, ¶17. It is my opinion that each individual on that team
`
`would have her own individual skills, experience, and educational levels. In
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`IPR2018-00290
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`practice, colleagues may share information, but no single individual has all of the
`
`attributes of the entire team. Regardless, my opinions regarding the lack of
`
`obviousness or anticipation would not change based on KVK-Tech’s definition of a
`
`person of ordinary skill in the art.
`
`V.
`
`THE ‘100 PATENT CLAIMS ARE DIRECTED TO A THREE-
`COMPONENT (IR-DPR-SR) AMPHETAMINE DOSAGE SYSTEM
`WITH SPECIFIC PHARMACOKINETICS AND WITHOUT A FOOD
`EFFECT
`17.
`The ‘100 patent concerns an orally delivered amphetamine salt
`
`pharmaceutical system or composition. EX1001, Abstract, claim 1. The composition
`
`is “a long acting amphetamine pharmaceutical composition, which includes an
`
`immediate release [“IR”] component, a delayed pulse release [“DPR”] component
`
`and a sustained release [“SR”] component.” Id., 3:53-57. It is effective for treating
`
`Attention Deficit Hyperactivity Disorder (“ADHD”) patients who require effective
`
`treatment for longer days of 14-16 awake hours. Id., 3:46-49. The patent explains
`
`that ADDERALL XR (a two component IR-DPR dosage system disclosed in
`
`Burnside (EX1002)) did not meet the needs of a patient population that required
`
`clinical benefit longer than 10-12 hours, such as adolescents and adults rather than
`
`school age, pediatric patients. EX1001, 3:14-37, 43-45.
`
`18.
`
`The ‘100 patent claims can be divided into four groups – those
`
`without express pharmacokinetics (e.g., AUC, Tmax, and Cmax) limitations, food
`
`effect limitations, or dose limitations (claims 1-4, 13-20, and 31, the “dosage
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`IPR2018-00290
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`system claims”), those with express PK limitations (i.e., AUC, Tmax, and Cmax)
`
`(claims 5-12, the “PK claims”), a claim with a food effect limitation (claim 21, the
`
`“food effect claim”), and those with express dose limitations (claims 22-30, the
`
`“dose claims”) .
`
`19.
`
`I address in detail the novelty and non-obviousness of the PK claims
`
`(claims 5-12) in this declaration.
`
`20.
`
`I also address in detail the novelty and non-obviousness of food effect
`
`claim 21 in this declaration.
`
`VI. TECHNICAL BACKGROUND HELPFUL IN UNDERSTANDING
`THE NOVELTY AND NON-OBVIOUSNESS OF THE ‘100 PATENT
`PK AND FOOD EFFECT CLAIMS
`A.
`Amphetamines
`21.
`The ‘100 patent claims dosage systems include “amphetamine salts.”
`
`See, e.g., EX1001, claim 1.
`
`22.
`
`“Amphetamines are non-catecholamine sympathomimetic amines
`
`with CNS stimulant activity. The mode of therapeutic action in ADHD is not
`
`known.” EX1003, 4.
`
`B.
`23.
`
`Drug Release from an Oral Dosage Form
`The ‘100 patent claims call for a combination of three amphetamine-
`
`containing components. Each component has a different mode of releasing the
`
`amphetamine after administration, i.e., immediate release (“IR”), delayed pulse
`
`release (“DPR”), and sustained release (“SR”). See, e.g., EX1001, claim 1. Each
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`IPR2018-00290
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`of these modes releases drug in a different manner, at a different time, and in a
`
`different place in the gastrointestinal (“GI”) tract.
`
`24.
`
`There are many types of dosage forms. Each may have a specific
`
`mixture of active pharmaceutical ingredients and excipients (i.e., inactive
`
`components) in its own particular configuration and its own dose.
`
`25. Oral dosage forms include many different kinds of liquid, solid, and
`
`semisolid dosage forms (e.g., tablets, capsules, sachets, elixirs, syrups, etc.).
`
`EX1001, 9:50-57; EX2010, 7 (Table 3-6), 19. The drug in an oral dosage form
`
`usually makes up only a small portion of the dosage form. Other active or inactive
`
`ingredients are often added to the formulation such as those for delivering or
`
`manufacturing the dosage form, for achieving desirable characteristics of the
`
`finished product and for assuring or potentiating the drug’s therapeutic effect.
`
`EX2010, 37-42; EX2018, 26.
`
`The GI Tract Is a Complex Environment
`a.
`26. Only after a drug is released from an oral dosage form and is dissolved,
`
`can it be absorbed. After an oral dosage form is swallowed, it goes to the stomach
`
`and then through the intestines as illustrated below.
`
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`IPR2018-00290
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`EX2010, 5, 11; EX2043, 2; see also, EX2032, 2.
`
`27.
`
`The formulation may release the drug initially in the stomach, delay
`
`release until various portions of the intestine, or both, depending upon its design.
`
`EX2048, 6. After release commencement, release can take place over various
`
`periods of time. Dosage form design (including excipients) must take into account
`
`the release environment and the properties of the drug itself which may help or
`
`hinder drug release from the dosage form. EX1001, 1:5-3:5, 12:12-40; EX1027, 17;
`
`EX2010, 60-61, 65; EX2012, 3; EX2015, 5; EX2016, 17; EX2043, 2, 5-8; EX2042,
`
`10-11.
`
`28. When the drug is released from the dosage form and is dissolved in the
`
`GI fluid, it may pass across the epithelial cell lining of the GI membrane and may be
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`IPR2018-00290
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`taken up into the blood, where it enters the circulatory system. EX2010, 5; EX2043,
`
`2.
`
`b.
`
`The ‘100 Patent Dosage System Combines Three Different
`Types of Amphetamine Delivery - IR-DPR-SR
`The ‘100 Patent composition employs a three component, three dose
`
`32.
`
`IR-DPR-SR amphetamine dosage system. See EX1001, claim 1.
`
`33.
`
`The ‘100 patent defines “immediate release” (i.e., IR) 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 pH and is highly acidic. See
`
`¶¶26-27, supra.
`
`34.
`
`The ‘100 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.
`
`35.
`
`The ‘100 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. Delayed pulsed release is DPR.
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`IPR2018-00290
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`36.
`
`The ‘100 patent defines “sustained release” (i.e., SR) 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
`
`37.
`
`The ‘100 patent and the prior art relied upon in the Petition include
`
`figures illustrating 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 assist in
`
`understanding why the ‘100 patent claims are novel and non-obvious.
`
`38.
`
`The in vitro release of a drug from a formulation or dosage form under
`
`test conditions can be illustrated as a curve representing amount of drug dissolved
`
`as a function of time in various media. EX1001, 4:22-25 (Fig. 1), 9:47-49 (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 ‘100 patent, reproduced below.
`
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`39.
`
`This is different from the in vivo plasma concentration profile and its
`
`curve, which represent the concentration of drug in the bloodstream over time. See
`
`¶52, 53, 56, 57, 83, 126, infra.
`
`C.
`
`Pharmacokinetics, Pharmacodynamics, and the Unpredictability
`of In Vivo from In Vitro and Vice Versa
`40. Commonly, the goal of delivering a drug orally 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.
`
`Success at one stage is not a predictor and does not correlate with success at
`
`another. Success with one drug formulation does not predict success with a
`
`different drug formulation. Understanding the failures of science in attempting to
`
`correlate in vitro and in vivo information and data is helpful in understanding why
`
`the ‘100 patent claims are novel and non-obvious. This involves a basic
`
`understanding of pharmacokinetics and pharmacodynamics.
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`41.
`
`The steps between the administration of a drug and the emergence of a
`
`drug response by the body can be broken down into: (1) pharmacokinetics (“PK”),
`
`which encompasses the administration of a dose, distribution to the bloodstream,
`
`the elimination of drug from the body, and the achievement of drug concentrations
`
`in the bloodstream, and (2) pharmacodynamics, which includes the response to the
`
`drug at its action site including the onset, magnitude, and duration of the biological
`
`response. EX2022, 1; EX2023, 4-5; EX2034, 24.
`
`Pharmacokinetics
`a.
`Pharmacokinetics is the study of the driving forces and rates at which
`
`42.
`
`drugs enter the body, distribute throughout the body, and leave the body, i.e., the
`
`processes of drug absorption, distribution, and elimination (metabolism and
`
`excretion) (“ADME”). EX2010, 5; EX2022, 1; EX2023, 4.
`
`43. When drugs are administered orally, a portion of the dose may be
`
`unable to reach the systemic circulation due to incomplete release, interaction with
`
`excipients in the formulation and other components of the gastrointestinal fluids,
`
`inability of a portion of the dose to pass across the GI membrane, metabolism in
`
`the intestinal membrane, and first-pass metabolism in the liver. After absorption
`
`the drug is subject to elimination via the liver and/or kidneys. EX2022, 7-8;
`
`EX2024, 9-11; EX2029, 3.
`
`44. Drug absorption is a complex and unpredictable process.
`
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`IPR2018-00290
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`45.
`
`In the case of orally administered drugs, some of the dose can be lost
`
`at several points during absorption, including destruction in the gastrointestinal
`
`fluid,
`
`interaction with
`
`the formulation excipients,
`
`interaction with other
`
`components of the gastrointestinal fluid, poor membrane penetration, efflux and/or
`
`metabolism in the enterocyte (intestinal membrane cell), and hepatic first-pass
`
`metabolism. Id. Some pharmacokinetic principles that are useful in understanding
`
`the ‘100 patent PK claims follow.
`
`46.
`
`“Absorption rate constant” (“Ka”) is a parameter describing how
`
`much of given drug is absorbed from its application site per unit of time according
`
`to first-order kinetics. EX2024, 8, 18; EX2034, 23; EX2045, 6; EX2048, 3-4. This
`
`depends on the drug and on the dosage form. EX2010, 18; EX2022, 7; EX2025, 3;
`
`EX2026, 5; EX2029, 3; EX2048, 4.
`
`47.
`
`The fraction of the administered dose of the drug that reaches the
`
`systemic circulation is the drug’s “bioavailability factor” (“F”). It is the extent of
`
`absorption of a drug into the systemic circulation. EX2010, 18; EX2022, 7;
`
`EX2023, 20; EX2024, 11; EX2029, 3. This depends on the drug itself and on the
`
`dosage form. Id.; EX2025, 3.
`
`48. Collectively, the absorption rate constant and the bioavailability factor
`
`control a drug’s bioavailability, which is the rate and extent of absorption of a drug
`
`from a particular dosage form. Bioavailability of a given drug may vary from one
`
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`IPR2018-00290
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`dosage form to another. EX2010, 66; EX2026, 3, 5 (method of release affects
`
`bioavailability); EX2013, 4; EX2024, 10; EX2025, 3 (“dosage form can influence
`
`drug absorption”); EX2029, 3. Bioavailability cannot be determined from release
`
`or dissolution profiles. EX2035, 19; EX2043, 1-2, 4, 7, 9.
`
`49.
`
`“Bioequivalence” is a “comparison of bioavailabilities of different
`
`formulations, drug products, or batches of the same drug product.” EX2010, 16;
`
`EX2023, 20-21; EX2024, 10, 35; EX2028, 1.
`
`50.
`
` “Clearance” represents the combined ability of the organs of
`
`elimination (liver and kidney) to remove or eliminate drug in the plasma. EX2026,
`
`6; EX2022, 1-4; EX2024, 16-17. Clearance cannot be determined from release or
`
`dissolution profiles. EX2022, 1, 4; EX1027, 5-16, 20; EX2043, 4.
`
`51.
`
`The “plasma concentration” of a drug is the amount of drug present in
`
`its soluble form per unit of plasma volume. EX1027, 14; EX2023, 47. It rises and
`
`falls upon administration, release, absorption, drug distribution into a peripheral
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`compartment, and clearance of a drug. EX2022, 1; EX2043, 2-3. Plasma
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`concentration cannot be determined from release or dissolution profiles alone.
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`EX1024, 25; EX2035, 19; EX2043, 1-2, 4, 9.
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`52.
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`Plasma concentration can be plotted as a function of time. For
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`example, two plasma concentration curves are illustrated in ‘100 patent Figure 9
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`reproduced below (one curve from shaded circles and one curve from unshaded
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`16
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`diamonds).
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`IPR2018-00290
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`53.
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`The area under the curve (“AUC”) for a plasma concentration curve is
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`an expression of the total amount of drug in circulation (its total exposure to the
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`bloodstream). It is a function of the drug’s dose, the fraction of the dose absorbed
`
`and a drug’s elimination characteristics. EX1001, 12:41-49; EX2015, 7-8; EX2022,
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`4; EX2023, 6-7, 26; see also ¶¶58-62, infra. AUC cannot be determined from
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`release or dissolution profiles in vitro.
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`54.
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`The maximum concentration (“Cmax”) is the maximum plasma
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`concentration observed after oral administration. EX1001, 12:50-55. Cmax is
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`dependent on the drug, dose, extent of absorption, rate of absorption, rate of drug
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`elimination, and dosage form. EX1001, 12:41-58; EX2015, 7; EX2023, 6-7, 26,
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`39; EX2010, 5-6; EX2030, 5. Cmax cannot be determined from release or
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`dissolution profiles alone. EX2035, 19; EX2043, 1-2, 4, 7, 9.
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`55.
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`“Tmax” is the amount of time necessary to reach Cmax after oral
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`administration. EX1001, 12:56-58. Tmax depends on multiple facts, as does Cmax.
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`Id.; EX2015, 7; EX2023, 26. Tmax, like Cmax, cannot be determined from release
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`or dissolution profiles alone, either.
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`56. A release profile is different than a plasma concentration profile and
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`its curve. ¶¶52, 53, supra; ¶¶57, 83, 126, infra. Various dosage forms may exist
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`for a particular drug, and their release profiles and plasma concentration profiles
`
`may vary.
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`57.
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`The extent of absorption for two different dosage forms or
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`formulations of the same drug can be assessed by conducting a study to compare
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`their plasma concentration profiles. EX2028, 1-2; EX2024, 35.
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`58. When a drug is administered intravenously, the AUC and plasma
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`concentrations at any point in time are usually proportional to dose. Id., 4.
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`Intravenous proportionality for one drug does not extend to another delivery route.
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`When a drug is administered by any route other than intravenously, drug
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`dissolution and drug absorption have to occur to allow the drug to enter the
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`systemic circulation. See ¶¶26-28, 40, supra. This depends upon the drug and the
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`actual formulation and will, in turn, control the bioavailability metrics AUC,
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`Cmax, and Tmax.
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`59. Absorption parameters are highly dependent not only on the drug but
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`also on the specific dosage form in which the drug is formulated (e.g., structure,
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`mechanism of action and composition).
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`60.
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`The proportionality of AUC and Cmax with dose is also referred to as
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`linearity. Linearity between dose and AUC and plasma concentrations (AUC and
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`Cmax) occurs if the pharmacokinetic parameters of a given drug in a given dosage
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`form remain constant over different dose ranges. EX2024, 4; EX2023, 26.
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`61. However, linearity is not always the case and depends on the drug, the
`
`formulation, and the dosage form. EX2022, 7; EX2025, 3. Linearity is not per se
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`applicable to different drugs, different dosage forms or formulations of even the
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`same drug. EX2023, 26; EX2043, 4; EX2049, 3. Tmax also can vary when the
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`release profile of the dosage form varies, such as where a delayed release shifts
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`Tmax. No single parameter is responsible for linearity of a dosage form. This
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`becomes even more complex when several release mechanisms are used in a single
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`dosage form.
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`62.
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`Linearity or proportionality between dose and AUC and Cmax can
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`only be reasonably predicted for the same drug in the same dosage form at
`
`different doses of that drug, based on known data about that drug and dosage form,
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`including the same salt form for the drug and the same structure for the dosage
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`form. Additionally, owing the differences in the rate of absorption, two different
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`dosage forms would not be expected to display equivalent, linear, or proportional
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`results, just by delivering the same amount (dose) of drug or by proportionally
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`adjusting the dose. EX2022, 7; EX2024, 10 (“there is no assurance of the
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`bioequivalence of two dosage forms of the same drug simply because the amount
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`of drug absorbed each time is equivalent”); EX2038, 4; EX2043 4; EX2049, 3.
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`63.
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`In vitro models that can accurately predict drug absorption in vivo
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`have proven to be difficult. Problems include in vitro performance requirements,
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`the delivery rate from different dosage forms, and the complicated and changing in
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`vivo conditions. EX2038, 15. The difficulties with modeling have been the subject
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`of comment by numerous scientists. See, e.g., EX2038, 5 (testing and results
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`“[p]redictive of in vivo performance” was still a “Desired Future State”); id., 8
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`(“meaningful in vitro test methods that accurately reflect and predict oral
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`bioperformance would revolutionize oral formulation development”); id., 15
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`(problems include defining in vitro performance requirements, different dosage
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`form delivery rates, and changeable in vivo conditions); id., 19 ( “[s]o compendial
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`dissolution testing in 900 ml with a paddle (or rotating basket) doesn't really
`
`capture it.”); EX2041, Abstract (for SR products, “[t]here are enormous
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`difficulties” with dissolution testing); EX2042, 2 (oral administration “is not as
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`simple as it seems.” “The extent and rate of absorption ... depends on different
`
`factors that are either related with the drug itself, the formulation, or the patient. ...
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`reliable predictions ... are extremely difficult and often deficient.”); EX2056, 19
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`(“However, the complex interrelationships among drug properties and processes in
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`the gastrointestinal tract make the prediction of oral drug absorption a difficult
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`task.”)
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`64. Different formulations affect absorption differently “and thereby
`
`cause differences in the onset, extent, and duration of pharmacologic effect.”
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`EX2043, 2.
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`65. Drug absorption modeling has also suffered from many deficiencies
`
`and is largely unreliable. Most models of drug absorption are deficient in that they
`
`require broad assumptions and ignore many in vivo realities. For example, a survey
`
`of several different models explained their various problems. EX2056, 20
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`(Problems with Pseudoequilibrium Models); id., 23 (Problems with Mass Balance
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`Approaches); id., 28 (Problems with Dynamic Models); id., 35 (Many approaches
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`are based on fictional homogeneity that is “in fact contrary to the evidence….”); id.
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`35, 64-65 (Problems with heterogeneous analysis); id., 53-54 (problems with
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`Absorption Models Based on Structure).
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`66.
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`In-vitro (i.e., release/dissolution profile) - in-vivo (i.e., plasma
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`concentration) correlation (“IVIVC”) is largely unpredictable. EX2034, 4. In vivo
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`pharmacokinetics and pharmacodynamics generally cannot be determined from in
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`vitro dissolution or release testing alone and vice versa. See, e.g., EX1027, 16;
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`EX2023, 12; EX2034, 4 (“Unpredictable and poor in-vitro/in-vivo correlations
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`....”); EX1024, 25 (“current in vitro tests do not adequately predict in vivo
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`performances.”); EX2040 (estimating in vivo PK results from in vitro dissolution
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`testing is “empirical art or mystery,”); EX2043, 2 (“In vitro tests ... cannot be
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`presumed to predict in vivo drug availability,” must be compared “for every
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`formulation type”); EX2031, 7 (lack of IVIVC correlation).
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`67. Although correlations may be observed after experimentation,
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`correlations cannot be predicted in advance. EX2038, 4 (“Demonstration of in vitro
`
`in vivo correlations (IVIVC) is necessary.”); id., 11 (correlations cannot be
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`presumed. They are observed only after “proven efficacy”); id, 5 (testing and
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`results predicting in vivo are a “Desired Future State”); id., 8.
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`68.
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`Simply extending the release of a drug from a dosage form does not
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`mean similar in vivo performance. EX2041, 9. Predicting “expected bioavailability
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`characteristics for an ER product from dissolution profile characteristics is a long
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`sought after goal.” EX2039, 4.
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`69. Accordingly, various formulations and dosage forms may exist for a
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`