UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`POZEN, INC.
`Patent Owner
`
`___________
`
`Inter Partes Review No.: UNASSIGNED
`
`___________
`
`Declaration of Umesh V. Banakar, Ph.D., in Support of Petition
`for Inter Partes Review of Claims 1-19 of 8,858,996
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Lupin Exh. 1002
`
`

`
`Table of Contents
`
`I.(cid:3)
`
`II.(cid:3)
`
`Introduction ......................................................................................................................... 1(cid:3)
`
`Qualifications ...................................................................................................................... 2(cid:3)
`
`III.(cid:3)
`
`Legal Standards ................................................................................................................... 7(cid:3)
`
`A.(cid:3)
`
`B.(cid:3)
`
`C.(cid:3)
`
`Anticipation............................................................................................................. 7(cid:3)
`
`Obviousness ............................................................................................................ 8(cid:3)
`
`Priority and Prior Art .............................................................................................. 9(cid:3)
`
`Background Of A Person of Ordinary Skill In The Art To The ’996
`D.(cid:3)
`Patent 10(cid:3)
`
`E.(cid:3)
`
`Claim Construction ............................................................................................... 12(cid:3)
`
`Basis and Summary of Opinions ....................................................................................... 12(cid:3)
`
`State of the Technology of the ’996 Patent as of June 1, 2001 ......................................... 13(cid:3)
`
`Claims 1-19 are Anticipated by the ’255 Publication ....................................................... 17(cid:3)
`
`IV.(cid:3)
`
`V.(cid:3)
`
`VI.(cid:3)
`
`VII.(cid:3) Claims 1-19 Would Have Been Obvious Over the ’556 Alone; in View of
`Chandramouli; or in View of the ’225 Patent ............................................................................... 22(cid:3)
`
`All Of The Limitations Of Independent Claims 1 and 12 Of The
`A.(cid:3)
`’996 Patent Are Disclosed In The ’556 Patent .................................................................. 23(cid:3)
`
`The Further Limitations of Dependent Claims 2-9 and 13-15 of the
`B.(cid:3)
`’996 Patent are Disclosed in the ’556 Patent .................................................................... 25(cid:3)
`
`All the Limitations of Dependent Method Claims 10-11 and 16-19
`C.(cid:3)
`of the ’996 Patent are Disclosed in the ’556 Patent .......................................................... 27(cid:3)
`
`Chandramouli Further Motivates Tablet Design to Release
`D.(cid:3)
`Esomeprazole Prior to Naproxen ...................................................................................... 27(cid:3)
`
`A POSA Would Have A Reasonable Expectation of Success That
`E.(cid:3)
`Non-Enteric Esomeprazole Would Be Therapeutically Effective .................................... 28(cid:3)
`
`The ’225 Patent Discloses Combination NSAIDs and Acid
`F.(cid:3)
`Inhibitor Formulations ...................................................................................................... 31(cid:3)
`
`Pilbrant and Other Prior Art Cited by Patentee Does Not Show that
`G.(cid:3)
`a POSA Would Avoid Using Non-Enteric Coated Esomeprazole ................................... 32(cid:3)
`
`

`
`VIII.(cid:3) Claims 1-19 of the ’996 Patent are Obvious in View of the ’118 Patent, the
`’225 Patent, and the ’192 Patent ................................................................................................... 36(cid:3)
`
`Claims 1-19 are Obvious in View Of the ’118, ’225, and ’192
`A.(cid:3)
`Patents 36(cid:3)
`
`Claims 1-19 of the ’996 Patent are Obvious in View of the ’225 Patent,
`IX.(cid:3)
`Chandramouli, and WO’185 ......................................................................................................... 38(cid:3)
`
`There Are No Secondary Consideration Factors That Change My Opinion
`X.(cid:3)
`That The Claims Would Have Been Obvious ............................................................................... 40(cid:3)
`
`XI.(cid:3)
`
`Conclusion ........................................................................................................................ 41(cid:3)
`
`

`
`Exhibit
`No.
`1001
`1006
`1007
`1008
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`1014
`1015
`1017
`
`1019
`1020
`1021
`
`1022
`
`1023
`
`1024
`
`Exhibits Referenced In This Declaration
`
`Description
`
`U.S. Patent No. 8,858,996
`Publication No. 2003/0069255 (“the ’255 publication”)
`U.S. Patent No. 6,544,556 (“the ’ 556 patent”)
`U.S. Patent No. 5,877,192 (“the ’192 patent”)
`Chandramouli et al., Prevention and management of NSAID-Induced
`Gastropathy, Journal of Pharmaceutical Pain and Symptom Control,
`8(4):27-40, 2000
`Pilbrant et al., Development of an Oral Formulation of Omeprazole,
`Scand. J. Gastroenterol., 20(Suppl. 108):113-120 (1985)(“Pilbrant”)
`Howden et al., Effects of Single and Repeated Doses of Omeprazole in
`Gastric Acid and Pepsin Secretion in Man, Gut, Vol. 25, 707-710
`(1984) (“Howden”)
`Preliminary Patent Owner Response to Petition for Inter Partes Review
`of U.S. Patent No. 8,557,285 submitted by Pozen Inc.
`U.S. Patent No. 5,698,225 (“the ’225 patent”)
`U.S. Patent No. 5,204,118 (“the ’118 patent”)
`WO/2000/026185 (“WO’185”)
`July 3, 2014 Citizen Petition Denial from FDA to Horizon Pharma
`(“Horizon Citizen Petition”)
`Curriculum Vitae of Umesh V. Banakar
`Pozen Website – John R. Plachetka educational background
`Naprosyn, Physicians’ Desk Reference, Medical Economics Company,
`2631-32 (2000)
`Acid Suppression: Optimizing Therapy for Gastroduodenal Ulcer
`Healing, Gastroesophageal Reflux Disease, and Stress-Related Erosive
`Syndrome, Wolfe, et al., Gastroenterology, 118:S9-S31 (2000)
`(“Wolfe”)
`Prichard et al., “Omeprazole: A Study of Its Inhibition of Gastric pH
`and Oral Pharmacokinetics After Morning or Evening Dosage,”
`Gastroenterol., 88:64-69 (1985) (“Prichard”)
`Clissold, et al. Omeprazole- A Preliminary Review of its
`Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic
`Potential in Peptic Ulcer Disease and Zollinger-Ellison Syndrome,
`Drugs 32: 15-47 (1986) (“Clissold”)
`
`-i-
`
`

`
`1025
`
`1026
`
`1027
`1028
`
`1029
`1030
`1031
`
`1032
`1033
`
`1034
`1035
`
`Tolman et al., “The Effects of Oral Doses of Lansoprazole and
`Omeprazole on Gastric pH,” J. Clin. Gastroenterol, 24(2):65-70 (1997)
`(“Tolman”)
`Prilosec, Physicians’ Desk Reference, Medical Economics Company,
`617-621 (2000)
`Claim Chart with ’225 Publication Disclosures
`Claim Chart with ’556 Patent, Chandramouli, and ’225 patent
`disclosures
`Nexium Label (2001)
`U.S. Patent No. 6,331,316 (“the ’316 patent”)
`Petition for Inter Partes Review of U.S. Patent No. 8,557,285 and
`Mandatory Notices Under 37 C.F.R. § 42.8 submitted by Dr. Reddy’s
`Laboratories, Inc.
`Fassihi, SA Pharm. J., July 1990, 259-265 (“Fassihi”)
`Gupta, et al., Ch. 6, Oral Controlled-Release Delivery, Treatise on
`Controlled Drug Delivery, A Kydonieus, Ed., Marcel Dekker, Inc., NY,
`NY: 1992; 256-274. (“Gupta”)
`Claim Chart with ’118, ’225, and ’192 Patent disclosures
`Claim Chart with’225 Patent, Chandramouli, and WO’185 disclosures
`
`-ii-
`
`

`
`I, Umesh V. Banakar, Ph.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I understand Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively,
`
`“Petitioners”) are filing in the U.S. Patent And Trademark Office (“USPTO”) a
`
`petition seeking inter partes review (“IPR”) of the patentability of certain claims
`
`of U.S. Patent No. 8,858,996 (“the ’996 patent”). (Exh. 1001.) The ’996 patent,
`
`entitled “Pharmaceutical Compositions for
`
`the Coordinated Delivery of
`
`NSAIDS,” issued on October 14, 2014. The inventor listed on the face of the
`
`patent is John R. Plachetka. It is my understanding that the ’996 patent is
`
`currently assigned to Pozen Inc. (“patentee”).
`
`2.
`
`I have been retained by Petitioners to provide certain scientific
`
`analysis and opinions relating to the validity of claims of the ’996 patent. My
`
`declaration includes a detailed discussion of my qualifications, the background of
`
`the technology related to the ’996 patent, and prior art references that disclose,
`
`either alone or in combination, the limitations and features of claims 1-19 of the
`
`’996 patent.
`
`3.
`
`I am being compensated for my time in connection with this
`
`proceeding at my standard consulting rate of $750.00 per hour and $950.00 per
`
`hour for my time during deposition and trial testimony, which is independent of
`
`the outcome of this proceeding.
`
`-1-
`
`

`
`II. QUALIFICATIONS
`
`4.
`
`As detailed in my current Curriculum Vitae attached as Exh. 1019, I
`
`am an independent consultant with over 35 years of experience and training with
`
`formulation
`
`technology
`
`including modified-release pharmaceutical dosage
`
`formulations, dissolution
`
`testing of modified-release
`
`formulations, and
`
`bioavailability assessment of such formulations.
`
`5.
`
`I am experienced in several fields within pharmaceutical formulation
`
`pertinent to the technology of the ’996 patent, including:
`
`a. Dosage Form Design (cid:16) the study of how to design drug product dosage
`forms in order to meet the goals for the product, including pertinent stability,
`handling characteristics, and administration.
`
`b. Drug Product Development and Formulation (cid:16) the study of how those of
`ordinary skill in the art prepare compositions for particular active
`pharmaceutical ingredients so that they can be made and sold for
`commercial products.
`
`c. Dissolution Assessment (cid:16) the process by which a solid drug substance enters
`a solvent (medium) to yield a solution.
`
`6.
`
`I received a Bachelor of Pharmacy degree in 1978 from Bombay
`
`University in Bombay, India. I received a Ph.D. in Pharmaceutical Technology,
`
`majoring in dosage form development, biopharmaceutics and pharmacokinetics,
`
`with a minor in pharmaceutical chemistry, in 1985 from Duquesne University in
`
`Pittsburgh, Pennsylvania. I performed post-graduate work at the Massachusetts
`
`-2-
`
`

`
`Institute of Technology in 1989, studying advances in drug formulation
`
`technology.
`
`7.
`
`Since the beginning of my education, I have worked in the
`
`pharmaceutical field. While obtaining my undergraduate degree at Bombay
`
`University, I interned at Pfizer, Ltd. Following graduation in 1978, I worked as a
`
`product chemist at Roussel Pharmaceuticals, Ltd. In 1980, I became a Lecturer in
`
`the Department of Pharmaceutics at J.N. Medical College in Belgaum, India.
`
`8.
`
`I came to the United States to pursue my Ph.D. and worked as
`
`Instructor-In-Charge of Pharmaceutics in the Department of Pharmaceutical
`
`Chemistry and Pharmaceutics at the School of Pharmacy at Duquesne University.
`
`After obtaining my Ph.D. in 1985, I taught for five years at Creighton University
`
`School of Pharmacy, as Assistant and
`
`then as Associate Professor of
`
`Pharmaceutics. While at Creighton, I developed courses addressing specialized
`
`dosage forms and formulations for pharmaceutical products.
`
`9.
`
`In 1990, I was recruited by the St. Louis College of Pharmacy, where
`
`I held positions of Section Head of Pharmaceutical Sciences, Director of
`
`Research, and Associate Professor of Pharmaceutics. In 1994, I was promoted to
`
`Professor of Pharmaceutics, less than ten years after obtaining my Ph.D. During
`
`my time there, I also developed courses addressing specialized dosage forms and
`
`formulations for pharmaceutical products. From 1997 to 1999, I served as
`
`-3-
`
`

`
`Professor of Pharmaceutics and Chairman of Pharmaceutical Sciences and the
`
`Graduate Program at Butler University’s College of Pharmacy and Health
`
`Sciences.
`
`10.
`
`I am now an independent consultant, specializing in assisting drug
`
`manufacturers around the world to develop new pharmaceutical products. Until
`
`recently, I was also an Adjunct Professor in the Department of Medicine at the
`
`University of Campinas in Brazil, where I developed and presented a Graduate
`
`Course for Masters and Doctoral programs entitled “Clinical Pharmacy Practice:
`
`Pharmacokinetics for the Practicing Healthcare Professional.” I also recently have
`
`been an adjunct Professor at Creighton University in the School of Pharmacy and
`
`Allied Health.
`
`11.
`
`I give advanced professional training programs worldwide in the areas
`
`of drug product design and evaluation, dissolution testing and solubility, and in
`
`vivo-in vitro correlation, among others to the pharmaceutical industrial and
`
`academic community.
`
`12.
`
`I currently work part-time as a consultant with the United States Food
`
`& Drug Administration
`
`(“FDA”),
`
`reviewing
`
`submissions,
`
`including
`
`Investigational New Drug Applications (“INDs”), New Drug Applications
`
`(“NDAs”), and Abbreviated New Drug Applications (“ANDAs”). I also review
`
`-4-
`
`

`
`grants and evaluate sites for compliance with Good Manufacturing Practices and
`
`Good Clinical Practices.
`
`13.
`
`I have authored more than one hundred publications, including
`
`numerous textbooks and manuals, in use by pharmaceutical scientists worldwide.
`
`As a specialist in formulations and pharmaceutical dosage forms, I have written
`
`many articles and book chapters on this topic, including, for example, IN SEARCH
`
`OF AN IDEAL ORAL SUSTAINED RELEASE DOSAGE FORM, Interphex-USA ‘91,
`
`WS07, New York, (1991); FUNDAMENTALS OF DRUG PRODUCT DEVELOPMENT
`
`WITH SPECIAL EMPHASIS ON THE DEVELOPMENT AND EVALUATION OF GENERIC
`
`PHARMACEUTICALS, Novartis Enterprises Pvt. Ltd., Mumbai, India (1999);
`
`“Beyond Traditional Non-conventional Drug Delivery Systems,” Chapter in
`
`DRUG DELIVERY SYSTEMS, PHARMACOKINETICS AND PHARMACODYNAMICS, ICB,
`
`Warsaw, Poland (1998); and “Materials Used in Controlled Release Technology –
`
`A Primer,” Ch. 8 in ADVANCES IN CONTROLLED DELIVERY OF DRUGS, Kohudic,
`
`MA, Fd., Technomic Publishing Co., Inc., Lancaster, PA, pp. 132-154 (1994).
`
`14.
`
`I have also served on the Editorial Boards of a variety of publications
`
`related to this field, including acting as Founding Editor-in-Chief of the
`
`INTERNATIONAL JOURNAL OF PHARMACEUTICAL ADVANCES; Editor-at-Large in the
`
`area of Pharmaceutical Technology, for Marcel Dekker, Inc., New York, New
`
`York (1990); member of the editorial board for the JOURNAL OF BIOMATERIAL
`
`-5-
`
`

`
`APPLICATIONS, Lancaster, Pennsylvania; BRAZILIAN JOURNAL OF BIOLOGICAL &
`
`MEDICAL
`
`SCIENCES,
`
`PHARMACOKINETIC/PHARMACODYNAMIC
`
`&
`
`BIOPHARMACEUTICS SECTION, Brazil; Acta Pharmaceutica, Ljubljnana, Republic
`
`of Slovenia; and INTERNATIONAL JOURNAL OF PHARMACEUTICAL EXCIPIENTS,
`
`Mumbai, India. I have also been invited to give presentations on the
`
`pharmaceutical arts all over the world.
`
`15.
`
`I have had the opportunity to serve in the public sector on both a
`
`national and international level. I currently am an advisor to the National
`
`Institutes of Health, NIAID, NINDS and SBIR/STTR programs. I have advised
`
`the United Nations International Executive Service Corps in Hungary and India
`
`and currently am an advisor to the United Nations Transfer of Knowledge
`
`Through Expatriate Nationals program and to the World Health Organization. In
`
`May 2014, the Society for Pharmaceutical Dissolution Science (SPDS) awarded
`
`me the Recognition Award for Outstanding Contributions to Pharmaceutical
`
`Dissolution Science.
`
`16.
`
`I have developed and formulated various types of pharmaceutical
`
`formulations (solids, liquid suspensions, specialized drug delivery systems such as
`
`topical and transdermal dosage forms) of numerous NSAIDS including naproxen.
`
`Similarly, I have developed and formulated pharmaceutical formulations of PPIs
`
`such as benzimidazoles - omeprazole, pantoprazole, lansoprazole, among others,
`
`-6-
`
`

`
`as solid dosage forms including rapidly disintegrating solid (non-enteric coated)
`
`dosage forms, enteric coated solid dosage forms, among others. Additionally, I
`
`have developed and formulated Fixed Dose Combination (FDC) pharmaceutical
`
`formulations containing two or more active substances, including FDC of a PPI
`
`and a NSAID. The development of such FDCs of a PPI and NSAID formulations
`
`included those that did not contain an enteric coating agent and neither were
`
`enteric coated dosage forms.
`
`III. LEGAL STANDARDS
`
`17.
`
`I am not a patent attorney, nor have I independently researched the
`
`law of patent validity. Attorneys for the Petitioners have explained certain legal
`
`standards to me that I have relied on in forming my opinions set forth in my
`
`declaration.
`
`A.
`
`Anticipation
`
`18.
`
`I understand a patent claim is invalid as anticipated when a single
`
`prior art reference discloses each and every element of that claim, either expressly
`
`or inherently, so as to enable one of ordinary skill in the art to make and use the
`
`claimed invention without anything more than routine experimentation in light of
`
`the general knowledge available in the art. I also understand material not
`
`expressly recited in a single prior art document may still be considered for
`
`purposes of anticipation if that material is incorporated by reference. I have been
`
`-7-
`
`

`
`further informed that the first step is to determine the meaning of the terms in the
`
`claim, and the second step is to compare the claim to the prior art reference.
`
`B.
`
`Obviousness
`
`19.
`
`I understand that a patent claim is invalid for obviousness if the
`
`differences between the subject matter of the claim and the prior art are such that
`
`the subject matter as a whole would have been obvious at the time the invention
`
`was made to a person having ordinary skill in the art. I also understand that
`
`certain factors are relevant to determining if a claim is obvious: (1) the scope and
`
`content of the prior art; (2) the level of ordinary skill in the art; (3) the difference
`
`between the prior art and the claims at issue; and (4) objective evidence of
`
`secondary considerations, such as long-felt need, commercial success, and
`
`unexpected results. I have also been informed that there must be a nexus (a
`
`connection) between the evidence that is the basis for the secondary factor and the
`
`scope of the invention claimed in the patent.
`
`20.
`
`I have been informed by counsel that obviousness may be based on a
`
`single prior art reference or on a combination of references and what those
`
`references would teach or disclose to a person of skill in the art. I have also been
`
`informed that, for the purposes, of an obviousness analysis, the person of skill in
`
`the art is presumed to be familiar with all relevant prior art. It is my
`
`understanding that if obviousness is based on a combination of references, there
`
`-8-
`
`

`
`should be some reason why a person of skill would have made such a
`
`combination. For example, a prior art reference itself may provide a disclosure
`
`that would motivate a person of skill to combine references with a reasonable
`
`expectation of success. I have further been informed that motivation to combine
`
`references may come from any source, including common knowledge or
`
`understanding of those skilled in the art, the prior art as a whole, any need or
`
`problem in the field, and the inferences, judgments, and ordinary creativity of a
`
`person of skill in the field.
`
`C.
`
`Priority and Prior Art
`
`21.
`
`I understand a “priority date” is the earliest effective filing date to
`
`which a patent claim may assert priority. I understand an application is entitled to
`
`the benefit of the earlier application’s priority date only if the earlier application
`
`fully discloses and enables the alleged invention claimed in the newer patent
`
`application. I also understand an application may not claim priority to an alleged
`
`parent application where its claims are broader than the scope of the disclosure in
`
`the alleged parent application. I further understand an application that cannot
`
`claim priority to an alleged parent application may be invalidated as anticipated or
`
`obvious on the basis of the earlier application if the respective invalidity
`
`requirements are met.
`
`-9-
`
`

`
`22.
`
`I have been informed the law provides certain categories of
`
`information (known as prior art) that may be used to anticipate or render obvious
`
`patent claims. I understand the ’996 patent claims priority to a related application
`
`that published as the ’255 publication on April 10, 2003. I have been informed
`
`the remaining references I discuss qualify as prior art because they were publicly
`
`available as of June 1, 2001, which is the earliest alleged priority date of the ’996
`
`patent, as shown on the front of the patent as the date of Provisional Application
`
`No. 60/294,588. Although I understand the priority date of the ’996 patent is
`
`disputed, I understand U.S. Patent No. 6,544,556 is prior art under at least 35
`
`U.S.C. § 102(e) because it is based on an application filed before June 1, 2001.
`
`D.
`
`Background Of A Person of Ordinary Skill In The Art To The
`’996 Patent
`
`23.
`
`I understand assessment of the validity of the claims of the ’996 patent
`
`must be undertaken from the perspective of what would have been known and
`
`understood by a person of ordinary skill in the art (“a POSA”) as of the time the
`
`invention was made, which I have been informed is the earliest priority date of the
`
`’996 patent. I have been asked to provide my opinion as to the background of a
`
`POSA to the ’996 patent and have been informed that a POSA is a hypothetical
`
`person having the knowledge, experience and skill of an “ordinary” worker in the
`
`“art” pertinent to the subject matter of the patent. In determining the level of skill
`
`of the POSA, I have also been informed that the following factors could be
`
`-10-
`
`

`
`applicable in the analysis to determine the level of a POSA: (1) the educational
`
`level of the inventor; (2) type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; (5)
`
`sophistication of the technology; and (6) educational level of active workers in the
`
`field.
`
`24.
`
`I understand that the listed inventor on the ’996 patent, John R.
`
`Plachetka, has a bachelor’s degree in pharmacy and a doctor of pharmacy degree
`
`(Pharm.D.). (Exh. 1020.)
`
`25. The ’996 patent is generally directed to pharmaceutical formulations
`
`and methods of treatment using such formulations. The type of problems
`
`encountered and the solutions to those problems involve identification and testing
`
`of different formulations using different active pharmaceutical ingredients and
`
`excipients. A POSA addressing problems of this nature would typically have a
`
`degree in the pharmaceutical sciences field or related field with experience in
`
`formulating drugs. Likewise, active workers in this field typically have the same
`
`background.
`
`26. Based on my evaluation of the ’996 patent, its file history, the factors
`
`above, and my over 35 years of experience working in the field of formulating
`
`pharmaceutical compositions, it is my opinion that a POSA would include a
`
`pharmaceutical scientist having a Ph.D. degree in the field of pharmaceutical
`
`-11-
`
`

`
`sciences or equivalent training or degree and at least two years of experience with
`
`pharmaceutical formulations.
`
`E.
`
`Claim Construction
`
`27.
`
`I am informed that, in connection with an Inter Partes Review, the
`
`USPTO assigns the broadest possible construction for the terms used in the patent
`
`claims. For purposes of my opinions in my declaration, I will apply plain and
`
`ordinary meaning to each term in light of the specification, which is consistent
`
`with how a POSA would understand those terms in the ’996 patent.
`
`IV. BASIS AND SUMMARY OF OPINIONS
`
`28.
`
`In preparing my opinions as set forth in this declaration, I have
`
`reviewed the ’996 patent and its prosecution history. I have also reviewed the
`
`documents cited herein and listed in the Exhibit List, above, in light of the general
`
`knowledge in the art from the view point of a person of skill in that art as of June
`
`2001.
`
`29. The opinions in this declaration are based on my more than 35 years
`
`of academic and clinical experience, training, research, and teaching in the fields
`
`of pharmaceutical formulation. As described herein, it is my opinion that claims
`
`1-19 of U.S. Patent No. 8,858,996 would have been anticipated by the prior art
`
`and obvious to a person of ordinary skill in the art as of June 2001.
`
`-12-
`
`

`
`V.
`
`STATE OF THE TECHNOLOGY OF THE ’996 PATENT AS OF
`JUNE 1, 2001
`
`30. The ’996 patent is entitled “Pharmaceutical Compositions For The
`
`Coordinated Delivery Of NSAIDs” and generally relates to pharmaceutical
`
`formulations and the use of those formulations to treat patients for pain or
`
`inflammation. The patent specification describes the formulations as containing a
`
`non-steroidal anti-inflammatory drug (NSAID) and an acid inhibitor. The claims
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`specifically require naproxen as the NSAID and esomeprazole as the acid
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`inhibitor. As detailed below, naproxen and esomeprazole were both well-known
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`and described in the prior art.
`
`31. NSAIDs are a class of drugs that have analgesic and anti-
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`inflammatory effects, and one of the best known examples of an NSAID is
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`aspirin. The ’996 patent acknowledges that NSAIDs, including naproxen, “are
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`widely accepted as effective agents for controlling pain.” Exh. 1001, 1:35-36.
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`However, it was also well known prior to June of 2001 that NSAIDs can cause
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`gastric injury. (See, e.g., Exh. 1001, 1:36-38; Exh. 1009 at 31.) The specific
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`NSAID naproxen was likewise known to cause gastric injury. (See, e.g., Exh.
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`1009 at 31; Exh. 1021 at 2631-32.)
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`32. As of June 2001, various acid inhibiting compounds were known to
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`treat and prevent NSAID-associated gastric injury. Commonly known acid
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`inhibiting compounds included the proton pump inhibitors (PPIs), prostaglandins,
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`and histamine H2 blockers. PPIs are used to treat or prevent gastrointestinal
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`injuries because they irreversibly bind to an enzyme called hydrogen-potassium
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`ATPase pump found on parietal cells in the duodenal region, the area that includes
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`the gastric region (the stomach) and the early intestinal region. (Exh. 1011, 709;
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`Exh. 1022 S9-31.) Upon binding to this proton pump enzyme, the PPI inhibits
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`secretion of hydrogen ions by the parietal cells. This mechanism decreases acidity
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`of the gastric environment and increases the pH of the stomach. (Exh. 1011, 709.)
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`33. An immediate increase in gastric pH occurs shortly after release of the
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`PPI. However, the full therapeutic effect of increased pH from PPIs is reached
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`after a steady-state gastric pH is achieved by repeated administration of the PPI.
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`(Id.) While PPIs are acid labile, meaning that they degrade in acidic
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`environments, repeated administration of PPIs results in a self-propagating effect.
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`(See, e.g., Exh. 1011, 709; Exh. 1023, 64; Exh. 1024, 32; and Exh. 1025, 69.) As
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`pH in the stomach rises due to initial doses of the PPI, gastric juices become less
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`acidic, and further administration of the PPI results in increasing effectiveness
`
`until reaching maximum effect. Steady state is achieved typically within a few
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`days of repeated administration. (Exh. 1011, 709.)
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`34. The first PPI approved and marketed in the United States was
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`omeprazole, which was approved in 1989 and sold as Prilosec®. (Exh. 1026.)
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`Esomeprazole is the S-enantiomer of the racemate omeprazole. (Exh. 1008, 1:50-
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`55.) The pure enantiomer esomeprazole was commonly recognized as having
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`substantially similar therapeutic effect to the racemic mixture omeprazole at
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`similar dosages. (Id. at 2:4-12.) Esomeprazole additionally was understood to
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`have less interindividual variability. (Id. at 2:29-36.) Both omeprazole and
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`esomeprazole were understood to be safe and effective, with little concern for side
`
`effects at dosages greater than the FDA-approved amounts. (See, e.g., Exh. 1026,
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`621; Exh. 1029, 23.) Non-enteric dosage forms of PPIs were known prior to
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`2001. See, e.g., Santarus, Inc. v. Par Pharmaceutical, 694 F.3d 1344 (Fed. Cir.
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`2012) (holding prior art
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`taught solid dosage forms of omeprazole for
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`administration without enteric coating)
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`35. Proton pump inhibitors function by inhibiting H2 receptors in the
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`parietal cells. (Exh. 1024, 20.) Parietal cells are located in the duodenum, which
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`is located immediately after the stomach within the GI tract. (See Figure 1.) A
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`POSA would know that a PPI such as esomeprazole should be available by the
`
`time it reaches the duodenal region in order to be therapeutically effective. (See
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`Exh. 1024, 20.) NSAIDs, on the other hand, are absorbed later in the GI tract
`
`because they have a slower absorption rate, as reflected in the time to reach
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`maximum concentration in the blood (Tmax) of 2-4 hours. (Ex. 1021, 2631.) Thus,
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`a POSA would have understood that esomeprazole should be released early in the
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`GI tract to reduce the acidity (inhibit proton pumps) while naproxen may be
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`released simultaneously, or preferably later than the release of esomeprazole, in
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`order to reduce the risk of NSAID-associated gastroduodenal injury.
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`Figure 1. Gastroduodenal Tract Anatomy
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`36. The ’996 patent describes a single dosage form with the NSAID in an
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`inner core of the formulation and the acid inhibitor in an outer layer. (Exh. 1001,
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`4:27-45.) The patent further describes a dosage form where the NSAID in the
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`inner core is coated and does not dissolve unless the surrounding medium is at a
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`pH of 3.5 or higher. The acid inhibitor is outside of the core and is released
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`before the NSAID. (Id.) As of June 2001, a POSA would have been able to
`
`prepare such a formulation using well known procedures. In fact, the ’996 patent
`
`acknowledges that the claimed dosage forms “can be made in accordance with
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`methods that are standard in the art” and cites a 1980 edition of a well-known
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`textbook in the pharmaceutical field, Remington’s Pharmaceutical Sciences. (Id.,
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`8:24-27.) Moreover, the patent discloses examples of the procedures to make the
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`dosage forms, and those examples use standard formulation procedures and
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`typical excipients that were well known in the art.
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`VI. CLAIMS 1-19 ARE ANTICIPATED BY THE ’255 PUBLICATION
`
`37. The ’255 publication discloses a combination tablet comprising an
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`acid inhibitor and an NSAID. (Exh. 1006, [0001].) It discloses that naproxen is a
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`preferable acid inhibitor, and lists esomeprazole as an optional acid inhibitor. (Id.,
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`claims 5, 29, 42.) A claim chart attached as Exhibit 1027 shows the relevant
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`disclosures from the ’225 patent that anticipates each and every limitation in
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`claims 1-19 of the ’996 patent.
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`38. A POSA would have understood the specification, examples, and
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`claims of the ’255 publication to teach only embodiments in which the NSAID is
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`entirely prevented from release by an enteric coating until pH is above 3.5. The
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`’255 publication repeatedly states the alleged invention provides for “coordinated
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`release”, meaning sequential release of the acid inhibitor prior to the NSAID and
`
`uses this feature to distinguish the alleged invention from the prior art. (See, e.g.,
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`Id., [0020], [0005].)
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`Recognizing the potential benefits of PPIs for the prevention of
`NSAID-induced gastroduodenal damage, others have disclosed
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`strategies for combining the two active agents for therapeutic
`purposes. However, these suggestions do not provide for coordinated
`drug release or for reducing intragastric acid levels to a non-toxic
`level prior to the release of NSAID (U.S. Pat. Nos. 5,204,118;
`5,417,980; 5,466,436; and 5,037,815). In certain cases, suggested
`means of delivery would expose the gastrointestinal tract to NSAIDs
`prior to onset of PPI activity (U.S. Pat. No. 6,365,184).
`
`(Id., [0005] (emphasis added).) Further, each example in the specification is
`
`directed to formulations or methods in which naproxen is completely enteric
`
`coated and “delayed” from release until after the pH has risen. (See, e.g., id.,
`
`[0053] (“The function of the enteric coat is to delay the release of naproxen until
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`the dosage form reach an environment where the pH is above about 4. The coating
`
`does not dissolve in the harshly acidic pH of the unprotected stomach.” (emphasis
`