UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`COALITION FOR AFFORDABLE DRUGS VII LLC
`Petitioner
`
`v.
`
`POZEN INC.
`Patent Owner
`______________
`
`Case No. IPR2015-01718
`Patent No. 8,945,621
`______________
`
`
`
`DECLARATION OF DAVID A. JOHNSON, M.D.
`
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
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`Table of Contents
`
`
`Page
`
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`INTRODUCTION AND SUMMARY OF QUALIFICATIONS...................................... 1
`
`MATERIALS CONSIDERED .......................................................................................... 6
`
`UNDERSTANDING OF THIS PROCEEDING ............................................................. 10
`
`UNDERSTANDING OF RELEVANT LEGAL PRINCIPLES ...................................... 11
`
`TECHNICAL BACKGROUND ...................................................................................... 13
`
`THE ’621 PATENT ......................................................................................................... 18
`
`VII. PETITIONER’S OBVIOUSNESS CHALLENGES ARE UNSUPPORTED ................ 22
`
`A.
`
`B.
`
`C.
`
`Plachetka .............................................................................................................. 25
`
`Graham ................................................................................................................. 26
`
`Goldstein .............................................................................................................. 28
`
`
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`I, David A. Johnson, M.D., hereby declare and state as follows:
`
`I.
`
`INTRODUCTION AND SUMMARY OF QUALIFICATIONS
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert opinion witness on behalf of Patent
`
`Owners Pozen Inc. and Horizon Pharma Inc. for the above-captioned inter partes
`
`review (“IPR”). I am being compensated for my time in connection with this IPR
`
`at my standard consulting rate, which is $600 per hour.
`
`3.
`
`I have no financial interest in, or affiliation with, the Petitioner or the
`
`Patent Owners. My compensation is not dependent upon the outcome of, or my
`
`testimony in, the present inter partes review or any litigation proceedings.
`
`4. My background, qualifications, and experience relevant to the issues
`
`in this proceeding are summarized below. A full description of my background and
`
`qualifications is set forth in my curriculum vitae, attached hereto.
`
`5.
`
`I am the Chief of Gastroenterology and Professor of Medicine at the
`
`Eastern Virginia Medical School in Norfolk, Virginia. I have held the title of
`
`Professor of Medicine since 1994, and Chief of Gastroenterology since 2000.
`
`6.
`
`I received a B.A. from University of Virginia in 1976, graduating
`
`magna cum laude. I graduated from the Medical College of Virginia in 1980, and
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`completed my medical internship in 1981 at the Naval Hospital in Portsmouth,
`
`Virginia. From 1981 to 1982, I was a Medical Officer on the USS Sylvania and
`
`was awarded a naval commendation medal. I completed my internal medicine
`
`residency in 1984 at the Naval Regional Medical Center in Portsmouth, Virginia.
`
`In 1986, I completed a fellowship in gastroenterology at the National Naval
`
`Medical Center in Bethesda, Maryland.
`
`7.
`
`Since 1984, I have been practicing gastroenterology, a subspecialty of
`
`medicine that is focused on the digestive system. As a practicing physician, I see
`
`patients virtually every day I am at work in my practice. In addition to my
`
`academic responsibilities discussed below, my focus is on clinical gastroenterology
`
`and I am engaged in patient care daily. I treat all aspects of adult patient disease
`
`states from primary GI disease to symptoms or complications of other diseases that
`
`have GI consequences. Since 1978, I have treated patients suffering from GI
`
`injury as a result of NSDAID use.
`
`8.
`
`As Chief of Gastroenterology and Professor of Medicine at the
`
`Eastern Virginia Medical School,
`
`I am
`
`involved
`
`in
`
`teaching clinical
`
`gastroenterology to medical students and residents for a variety of programs. I also
`
`regularly teach a number of continuing medical education (CME) courses to a
`
`broad array of physicians, including primary care and gastroenterologists.
`
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`9.
`
`I am also extremely active in clinical research. As with my teaching
`
`responsibilities, my research is focused on clinical gastroenterology. In particular,
`
`my research interests have included gastroesophageal reflux disease and the use of
`
`proton pump inhibitors in the treatment of gastrointestinal disorders.
`
`10.
`
`I am the past President of the American College of Gastroenterology
`
`(“ACG”). While President of the ACG, I formed the consensus groups with the
`
`American College of Cardiology and American Heart Association and from 2007-
`
`2011, I worked as a coauthor on three consensus documents on NSAID and
`
`antiplatelet issues for cardiology and gastroenterology.
`
`11.
`
`I have authored more than over 600 abstracts, chapters, and articles in
`
`peer-reviewed journals and books related to my work in internal medicine and
`
`gastroenterology. I have most recently edited the book The Human Microbiome in
`
`Health and Disease- Potential Translational Opportunities for Intervention.
`
`Additionally, I co-edited Dyspepsia, published by the American College of
`
`Physicians and Horizons on Gastroesophageal Reflux Disease, published by the
`
`Cleveland Clinic.
`
`12.
`
`I am past co-editor of Reviews in Gastroenterological Disorders, as
`
`well as Journal Medicine and section editor for the American Journal of
`
`Gastroenterology. I am
`
`the past co-editor of
`
`the American College of
`
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`Gastroenterology GI Universe and current editor for GI section editor for
`
`Medscape Gastroenterology, Medscape GI Viewpoints, and Medscape GI
`
`Consultant Corner, as well as the esophageal section editor for Journal Watch
`
`Gastroenterology (New England Journal of Medicine).
`
`13.
`
`I serve on numerous editorial boards and reviews for 21 medical
`
`journals including all of the GI journals. I am member/reviewer of the National
`
`Institutes of Health study section for esophageal/gastric diseases and have provided
`
`consultant testimony to the FDA.
`
`14.
`
`I have also been extensively involved initiating national consensus
`
`work groups and three related GI – Cardiology national society collaborative
`
`efforts regarding NSAID/antiplatelet upper GI mucosal complications and injury,
`
`which were jointly published by the American Heart Association, the American
`
`College of Cardiology and the American College of Gastroenterology.
`
`15.
`
`I have served in numerous leadership positions and advisory roles in
`
`professional organizations related to gastroenterology, for example, the American
`
`College of Gastroenterology, Centers for Medicare and Medicaid and National
`
`Quality Forum. I currently serve on the American Board of Internal Medicine
`
`Gastroenterology Certification Board, which develops the board certification and
`
`recertification exams for all licensed gastroenterologists. I have served as the
`
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`Gastroenterology Technical Advisory chair for the National Quality Forum (NQF)
`
`and as well is steering committee member quality outcomes NQF task force and
`
`participated in all GI related task force activities from 2005-2011) and chaired 3 of
`
`the 4 task force meetings. Additionally, I have served as a technical advisor to
`
`Center for Medicare/Medicaid (CMS) from 1995 to 1997.
`
`16. My work in the field of gastroenterology has been recognized and
`
`acknowledged by my peers. Most recently in 2016, I received the Distinguished
`
`Educator Award from the American Gastroenterologic Association. In 2015, I
`
`received the William D Carey MD American College of Gastroenterology
`
`Governor’s Award for life time contributions to gastroenterology as well as the
`
`Berk Award for Scientific Achievement. Additionally, in 2012, I was awarded the
`
`American College of Gastroenterology Berk/Fise Clinical Achievement Award.
`
`The award, given annually, recognizes a single individual for “distinguished
`
`contributions to clinical gastroenterology over a significant period of time.” In
`
`2013, I was advanced to “Master” status by the American College of
`
`Gastroenterology. I have also been honored as “Master of Gastroenterology” and
`
`“Presidential Award” by the Virginia GI Society.
`
`17.
`
`In May 2012, I was acknowledged as the invited lecturer at the
`
`National Institutes of Health as a “Great Teacher,” which is awarded annually to
`
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`two non-NIH physicians and streamed to 2,200 sites around the world with a target
`
`audience of 50,000-100,000 viewers. In 2013, I received the Dean’s Outstanding
`
`Faculty Award at Eastern VA Medical School and in 2000, I was honored as
`
`Outstanding Internal Medicine Faculty at the Eastern Virginia Medical School.
`
`18.
`
`I have extensive experience designing and conducting clinical trials
`
`and analyzing results from those trials for a broad array of diseases in the GI space
`
`including esophageal reflux disease, inflammatory bowel disease, and cancer
`
`detection and prevention.
`
`II. MATERIALS CONSIDERED
`19.
`In formulating my opinions, I have relied on my thirty years of
`
`experience as a physician specializing in gastroenterology. In addition to my
`
`expertise, I have specifically considered the ’621 patent, the Coalition for
`
`Affordable Drugs VII LLC’s (“Petitioner”) petition for inter partes review of the
`
`’621 patent (the “Petition”) and associated exhibits. I have also considered the
`
`declaration of Dr. Leon Shargel (the “Shargel Decl.”), the transcript of the May 25,
`
`2016 deposition of Dr. Shargel (the “Shargel Dep. Tr.”), and Patent Owner’s
`
`Preliminary Response.
`
`20.
`
`I have also considered the materials listed in the table below.
`
`
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`
`
`2007
`
`2008
`
`2009
`
`Exhibit No. Exhibit Description
`2005
`Angiolillo, D., et al., “Impact of Concomitant Low-Dose Aspirin on
`the Safety and Tolerability of Naproxen and Esomeprazole
`Magnesium Delayed-Release Tablets in Patients Requiring Chronic
`Nonsteroidal Anti-Inflammatory Drug Therapy: an Analysis from 5
`Phase III Studies,” J Thromb Thrombolysis, Vol. 38, pp. 11-23 (2014;
`first published 12/25/2013) doi: 10.1007/s11239-013-1035-4
`Goldstein, J.L., et al., “PN400 Significantly Reduces the Incidence of
`Gastric Ulcers Compared With Enteric-Coated Naproxen in Patients
`Requiring Chronic NSAID Therapy Regardless of Low-Dose Aspirin
`Use: Results from Two Prospective, Randomized Controlled Trials,”
`Arthritis Rheum, 60 Suppl. 10:842 (2009)
`Gabriel, S.E., et al., “Risk for Serious Gastrointestinal Complications
`Related to Use of Nonsteroidal Anti-inflammatory Drugs,” Annals of
`Internal Medicine, Vol. 115, No. 10, pp. 787-796 (1991)
`Cryer, B. and Feldman, M., “Effects of Nonsteroidal Anti-
`inflammatory Drugs on Endogenous Gastrointestinal Prostaglandins
`and Therapeutic Strategies for Prevention and Treatment of
`Nonsteroidal Anti-inflammatory Drug-Induced Damage,” Archives of
`Internal Medicine, Vol. 152, No. 6, pp. 1145-1155 (1992)
`Fries, J.F., et al., “Nonsteroidal Anti-inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models,” The American
`Journal of Medicine, Vol. 91, pp. 213-222 (1991)
`Sørensen, H.T., et al., “Risk of Upper Gastrointestinal Bleeding
`Associated With Use of Low-Dose Aspirin,” The American Journal of
`Gastroenterology, Vol. 95, No. 9, pp. 2218-2224 (2000)
`Tamura, A., et al., “Prevalence and independent factors for
`gastroduodenal ulcers/erosions in asymptomatic patients taking low-
`dose aspirin and gastroprotective agents: the OITA-GF study,” The
`Quarterly Journal of Medicine, Vol. 104, pp. 133-139 (2010)
`Derry, S. and Loke, Y.K., “Risk of gastrointestinal haemorrhage with
`long term use of aspirin: meta-analysis,” British Medical Journal,
`Vol. 321, pp. 1183-1187 (2000)
`Rodriguez, L.A.G., et al., “Association between aspirin and upper
`gastrointestinal complications: Systematic review of epidemiologic
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`
`
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`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`2021
`2023
`
`2024
`
`2025
`
`2026
`
`
`
`
`
`studies,” British Journal of Clinical Pharmacology, Vol. 52, pp. 563-
`571 (2001)
`Bellary, S.V., et al., “Upper Gastrointestinal Lesions in Elderly
`Patients Presenting for Endoscopy: Relevance of NSAID Usage,” The
`American Journal of Gastroenterology, Vol. 86, No. 8, pp. 961-964
`(1991)
`Weil, J., et al., “Prophylactic aspirin and risk of peptic ulcer
`bleeding,” British Medical Journal, Vol. 310, pp. 827-830 (1995)
`Goldstein, J.L., et al., “Effects of Concomitant Aspirin (81 mg qd) On
`Incidence of Gastric and/Or Duodenal Ulcers in Healthy Subjects
`Taking Celecoxib Or Naproxen: A Randomized, Placebo-Controlled
`Trial,” Gastroenterology, Vol. 130 (suppl. 2), pp. A-81-A-82 (2006)
`Rahme, E., et al., “Gastrointestinal Effects of Rofecoxib and
`Celecoxib Versus NSAIDs Among Patients on Low Dose Aspirin,”
`Gastroenterology, 126 (suppl. 2), pp. A-1-A-2 (2004)
`Silverstein, F.E., et al., “Gastrointestinal Toxicity With Celecoxib vs
`Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and
`Rheumatoid Arthritis,” The Journal of the American Medical
`Association, Vol. 284, No. 10, pp. 1247-1255 (2000)
`Deposition Transcript of Leon Shargel
`Declaration of Robert W. Makuch, Ph.D.
`Lee M., et al, “Dose effects of aspirin on gastric prostaglandins and
`stomach mucosal injury,” Ann Intern Med, Vol. 120, No. 3, pp. 184-
`189 (1994)
`Serrano P., et al., “Risk of upper gastrointestinal bleeding in patients
`taking low-dose aspirin for the prevention of cardiovascular diseases,”
`Aliment Pharmacol Ther, Vol. 16, pp. 1945-1953 (2002)
`doi:10.1046/j.0269-2813.2002.01355.x
`Chan, F.K., “Anti-platelet therapy and managing ulcer risk,” J
`Gastroenterol Hepatol, Vol. 27, pp. 195-199 (2012)
`Goldstein, J.L., et al, “The impact of low-dose aspirin on endoscopic
`gastric and duodenal ulcer rates in users of a non-selective non-
`steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective
`inhibitor,” Aliment Pharmacol Ther, Vol. 23, pp. 1489-1498 (2006)
`doi:10.1111/j.1365-2036.2006.02912.x
`
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`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`
`
`
`
`Goldstein, J.L., et al, “Clinical trial incidence of NSAID-associated
`endoscopic gastric ulcers in patients treated with PN 400 (naproxen
`plus esomeprazole magnesium) vs. enteric-coated naproxen alone,”
`Aliment Pharmacol Ther, Vol. 32, pp. 401-413(2010)
`doi:10.1111/j.1365-2036.2010.04378.x
`Sostres C. and Gargallo C.J., “Gastrointestinal lesions and
`complications of low-dose aspirin in the gastrointestinal tract,” Best
`Pract Res Clin Gastroenterol., Vol. 26, pp. 141-151 (2012) doi:
`10.1016/j.bpg.2012.01.016
`Wolfe, M., et al, “Gastrointenstinal Toxicity of Nonsteroidal
`Antiinflammatory Drugs,” The New England Journal of Medicine,
`Vol. 340, No. 24, pp. 1888-1899 (1999)
`Flower, R., “The Development of COX2 Inhibitors,” Nature Reviews
`Drug Discovery, Vol. 2, pp. 179-191 (2003)
`Public Health Advisory - FDA Announces Important Changes and
`Additional Warnings for COX-2 Selective and Non-Selective Non-
`Steroidal Anti-Inflammatory Drugs (NSAIDs) (April 7, 2005),
`downloaded from
`http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInforma
`tionforPatientsandProviders/ucm150314.htm on March 23, 2015
`Whitlock , C., et al, “Bleeding Risks With Aspirin Use for Primary
`Prevention in Adults: A Systematic Review for the U.S. Preventive
`Services Task Force,” Annals of Internal Medicine, Vol. 164, No. 12,
`pp. 826-837 (2016)
`Bombardier, E., et al, “Comparison of Upper Gastrointestinal Toxicity
`of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,”
`The New England Journal of Medicine, Vol. 343, No. 21, pp. 1520-
`1528 (2000)
`
`III. UNDERSTANDING OF THIS PROCEEDING
`21.
`I understand that this is an IPR proceeding conducted before the
`
`Patent Trial and Appeal Board (“Board”) of the U.S. Patent and Trademark Office
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`(“PTO”) to determine if claims 1-16 of the ’621 patent should be cancelled as
`
`unpatentable.
`
`22.
`
`I understand that Petitioner filed its Petition on August 12, 2015
`
`asserting that claims 1-16 of the ‘621 patent are invalid as obvious over
`
`combinations of references. Pet. at 4-5. I further understand that the Petition was
`
`accompanied by a declaration of Dr. Leon Shargel.
`
`23.
`
`I understand that on November 23, 2015 Patent Owner submitted a
`
`Preliminary Response in opposition to the Petition.
`
`24.
`
`I understand that on February 22, 2016, the Board decided to institute
`
`an IPR and found that the Petition satisfied the threshold standard for institution by
`
`showing a “reasonable likelihood that Petitioner would prevail in establishing the
`
`unpatentability” of the challenged claims. Further, I understand that the Board has
`
`not made any final determination that claims 1-16 are obvious.
`
`IV. UNDERSTANDING OF RELEVANT LEGAL PRINCIPLES
`25.
`I understand that the ’621 patent must be considered from the
`
`viewpoint of a person of ordinary skill in the relevant art (“POSA”) as of June 25,
`
`2009. A POSA is a hypothetical person who is presumed to be aware of all
`
`pertinent art. It is my opinion that a POSA would have the following
`
`qualifications: (1) an M.D. or equivalent degree; and (2) gastroenterology
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`experience or experience in treating patients at risk for developing gastric ulcer. In
`
`addition, it is my opinion that a POSA may consult with others who have
`
`experience in biostatistics and the evaluation of clinical trial results.
`
`26. Further, I have been advised of the following legal principles, and
`
`have applied those principles to my analysis and conclusions as set forth in this
`
`declaration.
`
`27.
`
`It has been explained to me that that an invention may be unpatentable
`
`“if the differences between the subject matter sought to be patented 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 to which said
`
`subject matter pertains.” 35. U.S.C. § 103. As I understand it, obviousness is a
`
`question of law that is based on the following factors: (i) the scope and content of
`
`the prior art, (ii) the claims at issue, (iii) the level of ordinary skill in the art, and
`
`(iv) objective evidence of secondary considerations. Routine experimentation does
`
`not render an otherwise obvious claim valid. .Obviousness only calls for a
`
`reasonable expectation of success, not a guarantee.
`
`28.
`
`I further understand that the Petitioner, in order to establish
`
`obviousness based on a combination of references, must provide sufficient
`
`rationale as to why, at the time of invention, a POSA would have been motivated
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`to combine the teachings of those references to come up with the claimed subject
`
`matter. The Petitioner must also establish that a POSA would have had a
`
`reasonable expectation of success in combining said references. I further
`
`understand that a POSA cannot rely on hindsight to provide a motivation to select
`
`and combine prior art references.
`
`29.
`
`I also understand that obviousness cannot be shown where the art in
`
`any material respect “teaches away” from the claimed invention.
`
`V. TECHNICAL BACKGROUND
`30. Non-steroidal anti-inflammatory drugs (“NSAIDs”) are valuable
`
`agents in the treatment of arthritis and other musculoskeletal disorders, and as
`
`analgesics in a wide variety of clinical scenarios. NSAIDs are one of the most
`
`widely used classes of drugs, but their use has been associated with mucosal injury
`
`to the upper gastrointestinal (“GI”) tract, including the development of peptic ulcer
`
`disease and its complications, most notably upper gastrointestinal hemorrhage and
`
`perforation. (Ex. 2009 at p. 1148.)
`
`31. These adverse gastrointestinal outcomes have resulted in significant
`
`morbidity and mortality. In a large meta-analysis published in 1991, the overall
`
`relative risk for these complications in patients taking NSAIDs was approximately
`
`2.4. (Ex. 2008 at p. 790.) However, this relative risk was reported to be increased
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`among patients who fell into various high-risk categories including: age greater
`
`than 60 years, a previous history of ulcer complications, previous ulcer history,
`
`multiple NSAID use
`
`(including aspirin), concomitant corticosteroid and
`
`anticoagulant use, and the presence of Helicobacter pylori infection, which is a
`
`recognized independent pathogenic risk for development of gastroduodenal ulcer
`
`disease. (Ex. 2015 at p. 962-964.)
`
`32. Although the cells of the GI tract have specialized defense
`
`mechanisms to protect against injury—including synthesis of prostaglandins that
`
`regulate the secretion of mucus and mucosal bicarbonate and inhibit gastric acid
`
`secretion—minor mucosal injury occurs regularly. (Ex. 2029 at p. 1891.) The
`
`majority of mucosal injury does not lead to clinically significant disruption of the
`
`function of the upper GI tract. There are circumstances, however, such as the
`
`administration of NSAIDS such as naproxen or aspirin, which result in an impaired
`
`mucosal defense system, rendering the upper GI tract more susceptible to injury.
`
`(Ex. 2029 at p. 1891.) For example, doses of aspirin as low as 30 mg have been
`
`found to be sufficient to suppress prostaglandin synthesis in the gastric mucosa.
`
`(Ex. 2023 at p. 187.)
`
`33. By the late 1990s, scientists recognized that that much of the mucosal
`
`injury caused by NSAIDs resulted from their inhibition of prostaglandin synthesis.
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`The synthesis of prostaglandins
`
`is catalyzed,
`
`in part, by
`
`the enzymes
`
`cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). In a normal, healthy
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`individual, COX-1 is constitutively expressed in the gastrointestinal tract and
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`functions as a housekeeping enzyme to maintain the normal lining of the GI tract.
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`In a normal, healthy individual, COX-2 is not typically present, but is induced as
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`part of the inflammatory response. NSAIDS inhibit the production of the COX-1
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`enzyme, resulting in a decrease in prostaglandins involved in maintaining a
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`normal, healthy GI tract. NSAIDS also inhibit COX-2 production, resulting in
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`their therapeutic usefulness, reducing symptoms of inflammation.
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`34.
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`In the late 1990s, there was tremendous interest in novel ways to
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`decrease NSAID-related upper GI injury and related consequences. Scientists
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`developed selective COX-2 inhibitors to avoid the GI complications of traditional
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`NSAIDS. (Ex. 2029 at p. 1895; Ex. 2030 at p. 179.) These agents included
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`rofecoxib, celecoxib, and valdecoxib. (Ex. 2030 at p. 179.) The COX-2 inhibitors
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`were shown to be safer than conventional NSAIDs as it relates to GI
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`complications, including ulcers. (Ex. 2026 at 1489.) The post-approval
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`recognition of the risk of significant cardiovascular complications, in particular for
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`rofecoxib however, led to the eventual withdrawal from the market of all but
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`celocoxib. (Ex. 2031).
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`35. Over the past twenty years, NSAID use, including aspirin has
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`emerged as one of the most prominent causes of peptic ulcer bleeding in developed
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`countries. (Ex. 2025 at p. 195.) In 2011, aspirin use was associated with a 2- to 4-
`
`fold increased risk of upper GI bleeding and ulcers. (Ex. 2012 at p 135.) Low-
`
`dose aspirin (“LDA”) use has been associated with a wide range of adverse side
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`effects in the upper GI tract, which range from troublesome symptoms without
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`mucosal lesions to more serious toxicity, including ulcers, GI bleeding, perforation
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`and even death. Upper GI symptoms in LDA users are common but often careless
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`or misinterpreted and they are not always related to the presence of mucosal injury.
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`The real clinical problem occurs when the ulcer results in a GI complication,
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`mostly bleeding. The estimated average excess risk of symptomatic or complicated
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`ulcer related to LDA use is five cases per 1000 aspirin users per year. (Ex. 2028 at
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`p. 148.) Even today, in 2016, it is reported that concomitant NSAID and LDA use
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`increased the risk of gastric bleeding over LDA use alone. (Ex. 2032 at p. 828.)
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`36. Given the fact that a large percentage of the population takes LDA for
`
`its cardiovascular protective properties, the notable increased risk of GI
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`complications is therefore clinically significant.
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`37. Furthermore, the combination of an NSAID, such as naproxen, with
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`low-dose aspirin, increases the risk of gastric ulcer. This is a significant issue as
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`concomitant use of low-dose aspirin for cardiovascular prophylaxis is common
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`among NSAID users (found to be approximately 20–25% in clinical trials). (Ex.
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`2027 at p. 408; Ex. 2019 at p. 1250). In a 2006 study, Goldstein et al compared
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`patients who were given low-dose aspirin (LDA) plus either naproxen, celocoxib,
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`or placebo. The patients receiving low-dose aspirin plus naproxen had the highest
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`incidence of gastric and duodenal ulcers (27%), compared to patients receiving
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`low-dose aspirin plus celocoxib (19%) or low-dose aspirin plus placebo (8%).
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`38. Similarly, in 2004, Rahme et al assessed the development of upper GI
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`bleeding and perforation related to use of LDA, non-selective NSAIDs and coxibs.
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`Patients taking coxibs alone had significantly fewer GI complications than those
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`using non-selective NSAIDs, but when low-dose aspirin was added to coxibs, the
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`rate of complications increased and approached that of the non-selective NSAIDs.
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`(Ex. 2018 at p. A-139.)
`
`39. Thus, prior to June 25, 2009, a POSA would have expected that a
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`patient treated with an NSAID and LDA would have a higher rate of GI injury,
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`including ulcers. (Ex. 2024 at p. 1950.)
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`40. The ’621 patent, however, unexpectedly demonstrates the opposite:
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`the administration on of a unit dose form of immediate-release acid inhibitor
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`(esomeprazole magnesium) and delayed-release NSAID (naproxen) is more
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`effective at reducing the incidence of the NSAID-associated ulcers in patients
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`taking LDA than in patients not taking LDA. Thus, rather than increasing the risk
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`of occurrence of an NSAID-associated gastric ulcer, the concomitant usage of
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`LDA with a unit dose form of immediate-release esomeprazole and delayed-
`
`release naproxen, surprisingly, reduces that risk.
`
`VI. THE ’621 PATENT
`41.
`I understand that the ’621 patent describes methods of reducing the
`
`incidence of gastric ulcers associated with use of NSAIDs in patients who are also
`
`taking low-dose aspirin. The claimed methods require that the patient receive a unit
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`dosage form that is comprised of 20 mg of esomeprazole and 500 mg of naproxen
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`and that provides for coordinated release of the esomeprazole and the naproxen.
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`Significantly, the claimed methods also require that the dosage form is more
`
`effective at reducing the incidence of NSAID-associated ulcers in patients taking
`
`LDA than in patients not taking LDA.
`
`42.
`
`I understand that Vimovo® is a pharmaceutical dosage form
`
`according to the ’621 patent that was designed to reduce the risk of upper GI injury
`
`due to NSAID use. Vimovo® consists of a combination of a delayed-release,
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`enteric-coated NSAID core (naproxen) surrounded by an immediate-release acid
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`inhibitor (esomeprazole magnesium). The acid inhibitor is released before the
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`NSAID which allows the acid inhibitor’s gastroprotective effects to take hold
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`before naproxen is released. This coordinated release of these two compounds
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`reduces the potential for gastric damage.
`
`43.
`
`It is my understanding that the ’621 patent is one of the patents listed
`
`in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations
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`(the “Orange Book”) as covering the pharmaceutical product VIMOVO®.
`
`44. The ’621 patent contains 16 claims. Claims 1, 8, 15, and 16 are
`
`independent claims
`
`45.
`
`Independent claim 1 is illustrative, and is copied below:
`
`1. A method of reducing the incidence of NSAID-associated
`gastric ulcers in patients taking low dose aspirin who are at risk of
`developing such ulcers, wherein the method comprises administering
`to said patient in need thereof a pharmaceutical composition in unit
`dose form comprising:
`(a) 20 mg of esomeprazole, or pharmaceutically acceptable salt
`thereof, in a form and route sufficient to raise the gastric pH
`of said patient to at least 3.5 upon the administration of one
`or more of said unit dosage forms, and
`(b) 500 mg of naproxen, or pharmaceutically acceptable salt
`thereof;
`wherein said unit dose form provides for coordinated release of
`the esomeprazole and the naproxen,
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`least a portion of said esomeprazole, or
`wherein at
`pharmaceutically acceptable salt thereof, is released independent of
`the pH of the surrounding medium,
`wherein the unit dosage form releases less than 10% of the
`naproxen or a pharmaceutically acceptable salt thereof after 2 hours
`when tested using the USP Paddle Method in 1000 ml of 0.1N HCl at
`75 rpm at 37º C.+/-0.5º C.,
`wherein said pharmaceutical composition in unit dose form
`reduces the incidence of NSAID-associated ulcers in said patient
`and wherein administration of the unit dose form is more
`effective at reducing the incidence of the NSAID-associated
`ulcers in patients taking LDA than in patients not taking LDA
`who are administered the unit dose form.
`(Ex. 1001 at 26:61–27:20) (emphasis added).
`
`46. Example 1 supports the surprising and unexpected results that the
`
`claimed unit dosage form is more effective at reducing the incidence of NSAID-
`
`associated ulcers in patients taking LDA than in patients not taking LDA. This
`
`example describes the results of two large, randomized clinical trials which were
`
`conducted to evaluate the incidence of gastric ulcers following the administration
`
`of either a dosage form consisting of 20 mg of immediate-release esomeprazole
`
`and 500 mg of enteric-coated naproxen (PN400), or 500 mg of enteric-coated
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`naproxen alone, in subjects at risk of developing NSAID-associated ulcers. (Id. at
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`12:37-46.) The study participants were stratified by LDA use and received either
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`PN400 or naproxen twice daily. (Id. at 12:49-54, 12:63-67; 13:2-3.) The primary
`
`endpoint of the studies was the incidence of gastric u