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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`DR. REDDY’S LABORATORIES INC.,
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`Petitioner v.
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`POZEN INC. and HORIZON PHARMA USA, INC.,
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`Patent Owners
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`U.S. Patent No. 9,220,698
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`Inter Partes Review No. Unassigned
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`DECLARATION OF RICHARD BERGSTROM, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 9,220,698
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`DRL EXHIBIT 1003
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`TABLE OF CONTENTS
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`Page
`I.
`Introduction .................................................................................................... 1
`II. Qualifications and Background ...................................................................... 1
`A.
`Education and Experience ................................................................... 1
`B.
`Bases for Opinions ............................................................................... 4
`C.
`Retention and Compensation ............................................................... 5
`III. Legal Standards .............................................................................................. 5
`IV. Definition of a Person of Ordinary Skill in the Art (POSA) .......................... 7
`V.
`Summary of Opinions .................................................................................... 7
`VI. Background on Pharmacokinetics and Pharmacodynamics .......................... 8
`VII. U.S. Patent No. 9,220,698 [Ex. 1001].......................................................... 17
`A.
`The ’698 Patent Specification ............................................................ 18
`B.
`The Challenged Claims .......................................................................... 28
`VIII. Claim Construction ...................................................................................... 31
`A.
`Legal Standard ................................................................................... 31
`B.
`The Term “Target” Means “With The Goal of Obtaining” ............... 31
`IX. The Prior Art ................................................................................................ 37
`A.
`Prior Art References Disclosed A Combined Dosage Form
`With Naproxen and Esomeprazole .................................................... 37
`(a) U.S. Patent No. 8,557,285 (“’285 Patent”) [Ex. 1005] ........... 37
`(b) U.S. Patent No. 6,926,907 (“’907 Patent”) [Ex. 1004] ........... 40
`(c) Goldstein [Ex. 1011] ............................................................... 41
`(d) Hochberg [Ex. 1012] ............................................................... 42
`(e) Hassan-Alin [Ex. 1016] ........................................................... 44
`Prior art references disclosed the target pharmacokinetics of
`naproxen ............................................................................................. 46
`(a) EC-Naprosyn label [Ex. 1009] ................................................ 47
`(b) Khosravan [Ex. 1017] ............................................................. 48
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`B.
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`2.
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`C.
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`Jung [Ex. 1018] ....................................................................... 48
`(c)
`(d) Davies [Ex. 1019] .................................................................... 49
`Prior Art References Disclosed The Target Pharmacokinetics
`of, and Pharmacodynamic Response To, Esomeprazole ................... 50
`(a) Howden 2005 [Ex. 1006] ........................................................ 50
`(b) Zegerid label [Ex. 1010] .......................................................... 51
`D.
`Esomeprazole is a Component of Omeprazole .................................. 53
`X. All Claims of the ’698 Patent Are Unpatentable ......................................... 54
`A. The ’285 Patent Anticipated the Claims of the ’698 Patent ................ 54
`(a) The ’285 Patent anticipated independent claim 1 ................... 54
`1.
`The ’285 patent taught a combined dosage form of
`naproxen and esomeprazole and its twice daily
`administration. ............................................................... 56
`The PK/PD elements are inherent in the twice-
`daily administration of the dosage forms disclosed
`in the ’285 patent. .......................................................... 57
`(b) Dependent claim 2 was anticipated ......................................... 60
`(c) Dependent claims 3 and 4 were anticipated ............................ 60
`(d) Dependent claims 5-7 were anticipated ................................... 61
`B. Ground 2: U.S. Patent No. 8,557,285 Rendered Obvious the
`Claims of the ’698 Patent .................................................................. 63
`(a) The pharmacokinetic and pharmacodynamic properties of
`the claimed unit dose form would have been obvious ............ 63
`(b) Dependent claim 2 would have been obvious ......................... 65
`(c) Dependent claims 3 and 4 would have been obvious .............. 65
`(d) Dependent claims 5-7 would have been obvious .................... 67
`C. Ground 3: U.S. Patent No. 8,557,285, in View of Howden 2005
`and the EC-Naprosyn Label, Rendered Obvious the Claims of
`the ’698 Patent .................................................................................... 68
`(a)
`Independent claim 1 would have been obvious ....................... 69
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`1.
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`2.
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`The prior art provided motivation to target (i.e.,
`have the goal of obtaining) the PK and PD
`elements. ........................................................................ 69
`The prior art provided a reasonable expectation of
`success in setting the PK and PD elements as targets.
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`(b) Dependent claim 2 would have been obvious .......................... 83
`(c) Dependent claims 3-4 would have been obvious ..................... 83
`(d) Dependent claims 5-7 would have been obvious ..................... 85
`There Are No Unexpected Results Arising From The Claimed
`Method ................................................................................................ 86
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`D.
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`I, Richard Bergstrom, Ph.D., do hereby declare:
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`I.
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`Introduction
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`1. My name is Richard Bergstrom. I have been retained by Dr. Reddy’s
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`Laboratories Inc. (“DRL”) in the matter set forth in the caption above. I understand
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`that DRL is petitioning for inter partes review (“IPR”) of claims 1-7 of U.S. Patent
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`No. 9,220,698 to Ault et al. (“the ’698 patent”) [Ex. 1001]. I submit this expert
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`declaration in support of DRL’s IPR petition for the ’698 patent.
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`II. Qualifications and Background
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`A.
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`2.
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`Education and Experience
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`I am an expert in pharmacokinetics, which is frequently abbreviated
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`as “PK.” Pharmacokinetics is the branch of pharmacology that deals with the
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`movement of a drug within the body of a living patient through the mechanisms
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`of absorption, distribution, metabolism, and excretion. I am also an expert in
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`pharmacodynamics, which is the study of a drug’s pharmacological effect on the
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`body. My background and qualifications are set forth in my curriculum vitae,
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`which is attached to this declaration as Exhibit A and includes a complete list of
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`my publications over the past ten years.
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`3.
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`In brief, I received a Bachelor of Science degree in Pharmacy from
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`the University of Pittsburgh in 1973, and a Master of Science degree from Butler
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`University in 1977. I also received a Doctor of Philosophy degree in
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`Pharmaceutical Chemistry at The University of Michigan in 1980.
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`4. At the University of Michigan, I studied under the mentorship of
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`Professor John G. Wagner, who is considered to be one of the pioneers in the
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`discipline of pharmacokinetics. Professor Wagner is the author of many seminal
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`manuscripts and two of the first published pharmacokinetics textbooks.
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`Professor Wagner’s textbooks discuss foundational pharmacokinetic concepts
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`and are still in broad usage. I am familiar with these textbooks and the concepts
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`they discuss, and also follow and am generally familiar with the pharmacokinetic
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`and pharmacodynamic literature.
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`5.
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`I am a Fellow of the American Association of Pharmaceutical
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`Scientists and I have served in a variety of voluntary and elected leadership
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`positions in that association including President (2000). I am also a member of
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`the Editorial Board for the American Associations of Pharmaceutical Scientists
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`Journal. I have also served on other editorial boards, serve as a reviewer for a
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`variety of pharmaceutical journals, and participate in a number of other
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`professional associations.
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`6.
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`I currently hold academic appointments as an Adjunct Professor of
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`Medicine at The Indiana University School of Medicine, Department of
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`Medicine, Division of Clinical Pharmacology, in Indianapolis, Indiana. I am also
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`an Adjunct Professor of Pharmaceutical Sciences, at Butler University College
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`of Pharmacy and Health Sciences in Indianapolis, Indiana. In addition, I serve
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`as
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`an
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`independent
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`expert
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`and
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`consultant
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`in
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`pharmacokinetics,
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`pharmacodynamics, and toxicokinetics for a variety of clients in the
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`pharmaceutical industry. I have held these positions since 2009, and they build
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`upon my 30 plus year career as a Research Scientist and Pharmacokineticist at
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`Eli Lilly and Company (“Lilly”) in Indianapolis, Indiana.
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`7.
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`I became a Senior Research Scientist at Lilly upon the completion
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`of my Ph.D. in 1980. I worked at the Lilly Laboratory for Clinical Research for
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`more than 20 years and worked at the Lilly Corporate Center for more than six
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`years. Throughout my career at Lilly, I continually used and expanded my
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`expertise in clinical research and pharmacokinetics. I also contributed to the
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`development of many of Lilly’s most medically and commercially successful
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`drugs including, among others, Oraflex®, Axid®, Humulin®, Strattera®, Prozac®,
`Prozac Weekly®, Zyprexa® , Zyprexa IntraMuscular®, Zyprexa Zydis®, Zyprexa
`Relprevv®, Symbyax®, and Cymbalta®.
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`8. Many of the projects that I was responsible for at Lilly included the
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`design and evaluation of pharmaceutical dosage forms and formulations,
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`including intramuscular dosage forms. My role in these projects was to use my
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`pharmacokinetic expertise to assist in the design of the dosage forms and
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`formulations, and to use my clinical skills to design, execute, and analyze animal
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`and human PK studies to assess the in vivo performance of dosage forms and
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`formulations.
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`9. The design of a human PK study requires expertise in the impact of
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`various factors on the disposition of a drug in the body, including, but not limited
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`to, gender, race, age, and genetics. These factors are known to influence how a
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`drug is processed in the body through absorption, distribution, metabolism, and
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`excretion. In addition, the design of a PK study requires a detailed understanding
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`of the physiochemical properties of the drug being evaluated and the potential
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`impact of these properties on the in vivo disposition of the drug. I am qualified
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`by my training and research experience to assess all of these properties and to
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`design, implement and analyze a PK study of a drug. I am also qualified to assess
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`the pharmacokinetic properties of drugs and dosage forms.
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`10. Within the past four years, I have testified by deposition in the
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`matters of Galderma Labs. Inc. v. Amneal Pharms., LLC, No. 1:l 1-cv-
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`01106-LPS (D. Del.), Forest Labs, Inc. v. Teva Pharms. USA, Inc., No. l:14-
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`cv-121-LPS (D. Del.), and Shire UC, et al. v. Abhai, LLC, No. 1:15-cv-13909
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`(D. Mass.).
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`B.
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`11.
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`Bases for Opinions
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`In forming my opinions set forth in this declaration, I have considered
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`and relied upon my education, background, and decades of experience in the field of
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`pharmaceutical sciences, including pharmaceutics and formulation science,
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`biopharmaceutics, pharmacokinetics, and pharmacodynamics. I have also relied on
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`the materials listed in Attachment B.
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`C. Retention and Compensation
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`12.
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`I am being compensated for my consulting work on this case at my
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`usual rate of $350.00 per hour plus expenses. My compensation in this proceeding
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`is not dependent on its outcome.
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`III. Legal Standards
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`13. Counsel has informed me that certain legal principles should guide me
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`in my analysis. Counsel has informed me that DRL carries the burden of proving
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`unpatentability by a preponderance of the evidence, which means DRL must show
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`that unpatentability is more likely than not.
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`14. Counsel has informed me that the question of whether the claims of a
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`patent are anticipated by, or obvious in view of, the prior art is to be considered from
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`the perspective of the person of ordinary skill in the art (“POSA”). Counsel has
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`further informed me that the answer to this question is ascertained as of the time the
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`invention was made.
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`15. Counsel has informed me that performing an obviousness analysis
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`involves ascertaining, as of the time the invention was made, the scope and content
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`of the prior art, the level of skill of the POSA, the differences between the claimed
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`invention and the scope and content of the prior art, and whether there are additional
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`factors present that may argue against a conclusion of obviousness (i.e., “secondary
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`considerations”), such as unexpected results attributable to the invention, or whether
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`the invention met a long-felt but unmet need.
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`16. Counsel has informed me that an invention may be found obvious:
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`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified,
`predictable solutions, a person of ordinary skill has good
`reason to pursue the known options within his or her
`technical grasp. If this leads to the anticipated success, it
`is likely the product not of innovation but of ordinary skill
`and common sense. In that instance the fact that a
`combination was obvious to try might show that it was
`obvious under § 103.
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`17. Counsel has informed me that a prior art reference anticipates a claimed
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`invention if the prior art reference disclosed each of the claimed elements of the
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`invention. A prior art reference not expressly disclosing a claim element may still
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`anticipate the claimed invention if the missing element is necessarily present, or
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`inherent, in the single anticipating reference. The missing element, or characteristic,
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`is inherent in the anticipating reference if the characteristic is a natural result flowing
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`from the reference’s explicit disclosure.
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`18. Counsel has informed me that if a patent claims a composition in terms
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`of a function, property, or characteristic, and the composition itself is in the prior art,
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`then the claim may be anticipated or obvious in view of the prior art reference
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`disclosing the composition.
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`IV. Definition of a Person of Ordinary Skill in the Art (POSA)
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`19. The field of art involves the knowledge of a medical doctor and that of
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`a pharmacologist or pharmacokineticist with experience in dosage form design and
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`evaluation. Thus, the hypothetical person of ordinary skill in the art is a collaboration
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`between a pharmacologist or pharmacokineticist having a Ph.D. degree or equivalent
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`training, or a M.S. degree with at least 2 years of some experience in dosage form
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`design and in in vitro and in vivo evaluation of dosage form performance, and a
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`medical doctor having at least 2 years of practical experience treating patients in the
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`gastroenterology field.
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`20.
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`I am offering my analysis from the perspective of the pharmacologist
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`or pharmacokineticist described above.
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`V.
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`Summary of Opinions
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`21. First, a POSA would have understood
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`that
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`the
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`targeted
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`pharmacokinetic (PK) and pharmacodynamic (PD) values recited in claims 1 and 2
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`of the ’698 patent are the natural result of administering the pharmaceutical
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`composition disclosed and claimed in U.S. Patent No. 8,557,285 (“’285 patent”). A
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`POSA would have also understood that the targeted PK and PD values recited in
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`claims 1 and 2 of the ’698 patent are a function, property, or characteristic of the
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`pharmaceutical composition disclosed and claimed in the ’285 patent.
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`22.
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`Second, it would have been routine for a POSA to make and test the
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`pharmaceutical composition disclosed and claimed in the ’285 patent as containing
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`500 mg naproxen and 20 mg esomeprazole. A POSA would have measured and
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`obtained the PK and PD values resulting from administration of the composition
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`described and claimed in the ’285 patent by routine testing and recording methods.
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`23. Third, a POSA would have been motivated to target the claimed PK
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`and PD values recited in the claims of the ’698 patent because these values were
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`known to be in the therapeutically effective ranges for naproxen and a proton pump
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`inhibitor, such as esomeprazole. Further, a POSA would have had a reasonable
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`expectation of success in targeting the claimed PK and PD values because a skilled
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`artisan would routinely target PK and PD values associated with marketed drugs
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`known to be effective.
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`24. Fourth, all elements recited in the ’698 patent’s dependent claims were
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`disclosed in the ’285 patent, as well as other prior art.
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`VI. Background on Pharmacokinetics and Pharmacodynamics
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`25.
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`“Pharmacokinetics” (PK) describes the body processes associated with
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`drug movement into (absorption or input), within (distribution or translocation) and
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`out of (metabolism and excretion) the body. These processes are often referred to by
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`the mnemonic ADME, which stands for Absorption, Distribution, Metabolism and
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`Excretion. Ex. 1021 at 5. While pharmacology is often described as studying the
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`“effect of the drug on the body,” PK is often described as the opposite: studying the
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`“effect of the body on the drug.” The two areas of study are, however, inextricably
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`connected.
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`26.
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`“Pharmacodynamics” (PD) describes how the concentration of a drug
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`at its site of action is related to the magnitude of the clinical effect observed.
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`Pharmacodynamics studies the relationship between a drug’s biochemical and
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`physiological effects and its mechanism of action. Ex. 1021 at 9.
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`27. While the science of pharmacology tends to be qualitative, the science
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`of pharmacodynamics is quantitative, describing the course of a pharmacological or
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`clinical effect over time. The PD properties of a drug are often studied in
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`combination with its PK properties. These two properties are then used to develop
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`PK/PD models of the drug, in both individuals and populations of patients. See
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`generally Ex. 1022. One of the most basic skills for a clinical pharmacologist or
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`pharmacokineticist is the ability to test a drug and gather the PK/PD data that
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`describe the drug’s behavior.
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`28. The diagram below depicts the relationship between pharmacokinetics
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`and pharmacodynamics:
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`Ex. 1022 at 6.
`29. As shown, PK/PD events overlap. The driving
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`Figure A
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`force
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`for
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`pharmacodynamic (i.e., clinical or toxic) events following drug dosing is generally
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`the concentration of drug in the blood (or plasma). In other words, the PD effects of
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`a drug are driven by its concentration in the plasma, and the time course of the PD
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`effects is driven or controlled by the PK properties of the drug and its dosage form.
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`Ex. 1021 at 5-8. Because of this, it is worthwhile to be able to describe the plasma
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`concentration-time profile of a drug after administering it to a patient. A stylized
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`single-dose plasma concentration-time profile resulting from oral dosing is depicted
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`below.
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`Figure B
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`See, e.g., Ex. 1022 at 21 (displaying exemplary curve with identified parameters).
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`30. To develop a single-dose plasma concentration-time profile, the clinical
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`pharmacologist or pharmacokineticist will, after administering a drug (e.g.,
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`administering orally), take frequent blood samples for a time sufficient to
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`characterize the entire profile. The blood samples, or a fluid derived from blood (e.g.,
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`plasma or serum), are treated and submitted to an analytical procedure from which
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`one can obtain a quantitative value for the concentration of the drug (and/or
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`metabolites of that drug) in the blood sample. The resulting concentration-time
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`profile can be plotted and analyzed, by using either a computer-based method to
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`obtain a mathematical model that best describes the data, or a model-independent
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`method. Either way, one obtains estimates of the values of the PK parameters for the
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`drug.
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`31. Following a single oral dose of a drug, the plasma concentration-time
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`profile can be used to estimate the Cmax (maximum plasma drug concentration
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`achieved), the Tmax (time after dosing corresponding to the Cmax), the t½ (half-life of
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`the drug in the body), and the AUC (extent of absorption or total exposure to the
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`drug, as measured by the total area under the plasma concentration vs time curve)
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`from time zero to time infinity. The AUC is a function of the amount of drug that
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`gets absorbed into the systemic circulation. The figure above is that of a
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`characteristic plasma concentration-time curve for an immediate-release dosage
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`form, i.e., one designed not to delay release and subsequent absorption.
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`32. Often, a POSA will want to depict graphically the PK profile of a
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`dosage form established in a study of multiple subjects. Placing the profile for
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`each subject on a single graph may, however, be cumbersome and confusing. It is
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`therefore common for a POSA to prepare an average plasma concentration-time
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`profile by plotting the average plasma concentrations over all subjects at each sample
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`time. Such a graph provides a useful indication of the PK behavior of the dosage
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`form across multiple subjects. A graph of this type is similar to the one included in
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`¶ 29, but derives its data from a population (as described), rather than an individual.
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`33. The drug’s dosage form and its formulation affect the shape of the
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`plasma concentration-time curve. In other words, immediate-release solid drug
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`dosage forms will result in a relatively high Cmax that occurs a short time after dosing
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`(i.e., small Tmax). In contrast, a “delayed-release” solid drug dosage form will have
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`a Tmax typically occurring later than that of an immediate-release dosage form.
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`Delayed release often is accomplished by coating a solid dosage form with an enteric
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`(or other polymer) layer, which is designed not to dissolve and release the drug until
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`the dosage form reaches the relatively higher pH of the small intestine. For an
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`enteric-coated dosage form, the delay in absorption can be quite prolonged,
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`governed by the nature and characteristics of the enteric coating, the time needed for
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`gastric emptying to occur, and the presence of food in the stomach.
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`34. Some single unit dosage forms, like Vimovo®, provide “pulsatile”
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`release; i.e., multiple drug releases occurring at different times after ingestion, for
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`either the same drug or different drugs. This design, sometimes referred to as “repeat
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`action,” was well known in the art. A repeat action is commonly achieved by having
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`an inner core of one drug (the second, or “repeat” dose) covered by an enteric coating
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`that delays release. An exemplary repeat-action dosage form, comprising delayed-
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`release naproxen and immediate-release esomeprazole, is shown below.
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`EXHIBIT 1003 – DECLARATION OF RICHARD BERGSTROM, PH.D.
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`Naproxen
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`Enteric Coating
`Esomeprazole
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`Figure C
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`35. The initial dose (or the other drug dose) that covers the enteric coating
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`provides the immediate release. An illustration of a plasma concentration-time
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`profile for a unit dose, repeat-action tablet is below.
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`Figure D
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`36. The solid line represents the total drug plasma concentration for a repeat
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`action or pulsatile dose form. Thus, the drug concentration first rises from immediate
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`release of drug A1 from the outer coating of the tablet. Total drug concentration then
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`declines until release of drug A2 (second pulse of A) or B (first pulse of new drug—
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`as with the dosage form shown in Figure C above) from the enteric-coated inner
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`core. The dashed line concentration shown as A2 or B is added to the A1
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`concentration curve to produce the total drug concentration-time solid line. Note that
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`for a pulsatile dosage form, one would see the A1 drug concentration line continue
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`to decrease according to the descending dashed line; and some time later,
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`concentrations from the other drug, B, will rise and decline (second dashed line),
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`with plasma concentrations for drug B being delayed relative to plasma
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`concentrations for drug A.
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`37. Many times, it is useful to characterize the pharmacokinetics of a drug
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`and its dosage form after multiple oral dosing. With multiple dosing, a drug
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`accumulates in the body until a maximum plasma concentration is achieved, such
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`that the concentration-time profile repeats after every dosing interval. When this
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`occurs, commonly after about 4 or 5 half-lives, a so-called “steady state” has been
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`obtained. This is a fluctuating steady state in which the drug concentrations repeat
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`but rise and fall periodically. A true steady state involves constant drug
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`concentrations with time, occurring when the rate of drug entry into the body equals
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`the rate of elimination of drug from the body. A stylized plasma concentration-time
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`profile, showing the rise from initial dosing to a fluctuating steady state, is depicted
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`below. Cmax, Tmax, and AUC(0-t) footnote1 are added as illustrated.
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`Ex. 1022 at 43.
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`Figure E
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`Cmax
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`AUC(t)
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`Tmax
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`38. The concentration-time profile can be analyzed once steady state has
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`been achieved. Both Cmax and Tmax will have the same meaning as for single dosing,
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`but the total area under the curve (AUC) is measured for a defined interval (often
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`the dosing interval τ (“tau”) (AUCτ)). Two other parameters that may be calculated
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`at steady state include the minimum plasma concentration, Cmin, often occurring just
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`before the next dose, and the average steady state plasma concentration, Cave. The
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`latter value is not the average of Cmax and Cmin, but rather is calculated as a time-
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`1 “AUC(0-t)” refers to the area under the curve from time zero to an arbitrary time, t.
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`averaged concentration, AUCτ/τ, the units of which are concentration. For
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`example, if the dosage interval is 24 hours, Cave will refer to the area under the curve
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`for the 24-hour dosing period, divided by 24, i.e., AUC24/24.
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`39. During a dosing interval at steady state, one can characterize different
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`dosage forms of a given drug by the PK parameters. For example, an immediate-
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`release product may have a rapidly-achieved Cmax and a low Cmin, depending upon
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`the dosing interval (the longer the interval, the lower the Cmin; the shorter the interval,
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`the greater the Cmin).
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`VII. U.S. Patent No. 9,220,698 [Ex. 1001]
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`40. U.S. Patent No. 9,220,698 (“’698 patent”) issued on December 29,
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`2015, and is entitled “Method for Delivering A Pharmaceutical Composition to a
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`Patient in Need Thereof.” See Ex. 1001 at [54]. The ’698 patent issued from U.S.
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`Patent Application No. 12/553,107, filed on September 3, 2009, which claims
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`priority to U.S. Provisional Patent Application No. 61/095,584, filed on September
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`9, 2008. Id. at [21], [22], [60].
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`41. The ’698 patent names as joint inventors Brian Ault, Mark Sostek,
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`Everardus Orlemans, and John Plachetka. See id. at [75]. The ’698 patent is assigned
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`on its face to Pozen Inc. and Horizon Pharma USA, Inc. Id. at [73].
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`42. The ’698 patent contains seven claims, of which claim 1 is the only
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`independent claim. Claims 2–7 depend from, and further limit, the subject matter
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`recited in claim 1. Id. at 52:25-53:29.
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`43. As issued, the ’698 patent contains several errors in at least its claims.
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`The U.S. Patent and Trademark Office (“USPTO”) issued a Certificate of Correction
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`for the ’698 patent, addressing some of those errors, on April 19, 2016. The USPTO
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`issued a second Certificate of Correction on July 12, 2016. Throughout this
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`declaration, I address the claims as corrected.
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`A.
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`The ’698 Patent Specification
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`44. The ’698 patent relates to methods for treating a patient having
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`osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, with a unit dose form
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`containing 500 mg of enteric-coated naproxen and 20 mg of immediate-release
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`esomeprazole to target a range of PK and PD values for naproxen and esomeprazole.
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`Ex. 1001 at 52:25-67. The ’698 patent refers to an exemplary dosage form, having
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`500 mg naproxen and 20 mg esomeprazole, as “PN400/E20,” Ex. 1001 at 26:44-45,
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`or “PN400,” Ex. 1001 at 46:43-44. The ’698 patent describes the results of treating
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`a patient population with PN400/E20, and the claims recite the reported PK/PD
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`values. See, e.g., Ex. 1001 at cols. 35-49, Tbls. 6, 8, 11, 13, 16-17; 52:25-67 (claim
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`1).
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`45. The ’698 patent describes and claimed PK parameters for the dosage
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`forms that were well-known to a POSA, including “Cmax,” “Tmax,” and “AUC,” each
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`of which is described and explained above. See, e.g., Ex. 1001 at 52:25-67 (claim
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`1). The ’698 patent also reports these PK parameters as the average (mean) or
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`median values plus or minus a variation. Id. The ’698 patent also describes and
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`claims the variation in these parameters as coefficients of variation (e.g., claiming
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`±20% variation), which reflects the variability inherent in biological and analytical
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`processes both within a patient, across multiple measurements, and between patients
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`in a population. Id. The percentage coefficient of variation (%CV) is calculated as
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`the standard deviation (SD) divided by the mean or average value, multiplied by 100.
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`Ex. 1001 at 5:55-56.
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`46. The ’698 patent acknowledges that NSAIDs were known to increase
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`the risk of gastrointestinal injury, such as ulcers, when used long-term. Ex. 1001 at
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`1:19-24. A POSA would have known, and the ’698 patent states, that stomach acid
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`was “[a] major factor contributing to the development of gastrointestinal lesions” in
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`these circumstances. Id. at 1:24-25. The ’698 patent also states that strategies were
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`known “to reduce the gastrointestinal risk associated with taking NSAIDs by
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`administering agents that inhibit stomach acid secretion, such as, for example, proton
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`pump inhibitors with the NSAID.” Id. at 1:27-30.
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`47. The ’698 patent specifically identifies U.S. Patent No. 6,926,907 (“’907
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`patent”) [Ex. 1004], as directed to a drug dosage form