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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`HORIZON PHARMA USA, INC. and NUVO PHARMACEUTICALS
`(IRELAND) DESIGNATED ACTIVITY COMPANY
`Patent Owners
`______________
`
`Case No. IPR2018-00272
`Patent No. 9,393,208
`______________
`
`DECLARATION OF DAVID A. JOHNSON, M.D. IN SUPPORT OF
`PATENT OWNER RESPONSE TO PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,393,208
`
`
`
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`
`
`I.
`II.
`
`III.
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`Table of Contents
`
`EDUCATIONAL BACKGROUND AND QUALIFICATIONS ...................................... 1 
`BACKGROUND ............................................................................................................... 6 
`A.
`Legal Standards ...................................................................................................... 6 
`B.
`Scientific Background ............................................................................................ 9 
`1.
`NSAID Use and Gastrointestinal Injury .................................................... 9 
`2.
`Physiology of the Gastrointestinal Tract .................................................. 11 
`3.
`State of the Art of Treatment for GI Injury in 2007 ................................ 15 
`OPINIONS ....................................................................................................................... 23 
`A.
`The Person of Ordinary Skill in the Art ............................................................... 23 
`B.
`The ’285 Patent Is Not Prior Art to Claims 1-7 of the ’208 Patent ..................... 24 
`C.
`The ’285 Patent Does Not Inherently Anticipate Claims 1-7 of the ’208
`Patent.................................................................................................................... 26 
`The ’285 Patent Does Not Render Obvious Claims 1-7 of the ’208 Patent ........ 28 
`The ’285 Patent in view of the EC-Naprosyn® Label and Howden 2005
`Do Not Render Obvious Claims 1-7 of the ’208 Patent ...................................... 30 
`Secondary Indicia of Non-obviousness ............................................................... 31 
`1.
`Long-felt but unresolved need ................................................................. 31 
`2.
`Compliance issues related to multi-pill therapy ....................................... 33 
`3.
`Surprising and unexpected results ........................................................... 34 
`4.
`Skepticism by experts .............................................................................. 37 
`
`D.
`E.
`
`F.
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`
`
`
`
`i
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`I, Dr. David A. Johnson, M.D. declare as follows:
`
`
`1.
`
`I have been retained by Counsel for Horizon Medicines LLC, Horizon
`
`Pharma, Inc., Horizon Pharma USA, Inc., and Nuvo Pharmaceuticals (Ireland)
`
`Designated Activity Company (collectively “Patent Owner”) in the matter set forth
`
`in the caption above. I understand that the Patent Trial and Appeal Board
`
`(“PTAB”) has instituted Mylan Pharmaceuticals Inc.’s (“Mylan’s”) petition for
`
`inter partes review (“IPR”) of claims 1-7 of U.S. Patent No. 9,393,208 (“the ’208
`
`patent”). I submit this expert declaration in support of Patent Owner’s Response to
`
`Mylan’s petition.
`
`I.
`
`EDUCATIONAL BACKGROUND AND QUALIFICATIONS
`1.
`I am the Chief of Gastroenterology and Professor of Medicine at the
`
`Eastern Virginia Medical School in Norfolk, Virginia.
`
`2.
`
`I earned a B.A. from University of Virginia in 1976, and an M.D.
`
`from the Medical College of Virginia in 1980.
`
`3.
`
`I completed my residency in internal medicine at the Naval
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`Regional Medical Center in Portsmouth, Virginia in 1984, and I completed a
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`fellowship in gastroenterology at the National Naval Medical Center in Bethesda,
`
`Maryland in 1986.
`
`4.
`
`I have been practicing gastroenterology, a branch of medicine that is
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`focused on the digestive system, as a specialist since 1984. As a practicing
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`1
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`physician, I see patients nearly every day. In addition to my academic
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`responsibilities discussed below, my focus is on clinical gastroenterology and I am
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`engaged in patient care daily.
`
`5.
`
`In addition to being a practicing physician, I have been a Professor of
`
`Medicine at the Eastern Virginia Medical School in Norfolk, Virginia since 1994
`
`and Chief of Gastroenterology there since 2000. As such, I am involved in
`
`teaching medical curricula for a variety of programs and am extremely active in
`
`clinical research. Both my teaching and research are focused on gastroenterology.
`
`6.
`
`In particular, my research interests have included gastroesophageal
`
`reflux disease and the use of proton pump inhibitors (PPIs) in the treatment of
`
`gastrointestinal disorders. I have published more than 600 articles, reviews,
`
`abstracts and book chapters pertinent to gastrointestinal disorders, and I have
`
`also served as an editor and reviewer for a number of journals related to
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`medicine and, in particular, gastroenterology.
`
`7. My primary current research interests are esophageal reflux disease,
`
`the gut microbiome in health and disease, effects of sleep fragmentation on GI
`
`health/disease, colonoscopy quality metrics and colon cancer screening.
`
`8.
`
`I serve on numerous editorial boards and reviews for 21 medical
`
`journals, including all of the GI journals. I was a member/reviewer of the National
`
`
`
`
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`2
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`Institutes of Health study section for esophageal/gastric diseases and have provided
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`consultant testimony to the FDA.
`
`9.
`
`I am the past co-editor of Reviews in Gastroenterological Disorders,
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`as well as Journal Medicine and section editor for the American Journal of
`
`Gastroenterology. I am the founding co-editor of the American College of
`
`Gastroenterology GI Universe, and currently continue as the GI section editor for
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`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).
`
`10.
`
`I recently edited the book Gut Microbiome: New Understanding and
`
`Potential Translational Applications for Disease Management, published in
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`December 2015. Additionally, I co-edited the American College of Physicians
`
`(ACP) book Dyspepsia, edited the 2005 and 2010 GI Clinics of North America
`
`series on Obesity Issues for Gastroenterologists, and edited the 2012 American
`
`College of Physicians module on colorectal cancer (“CRC”) screening.
`
`11.
`
`I have also been extensively involved in collaborative efforts
`
`regarding NSAID/antiplatelet upper GI mucosal complications and injury as
`
`published in three expert consensus documents with the American Heart
`
`
`
`
`
`3
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`Association, the American College of Cardiology, and the American College of
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`Gastroenterology.
`
`12.
`
`I have served in countless leadership positions and advisory roles in
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`professional organizations related to gastroenterology, for example, the American
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`College of Gastroenterology, Centers for Medicare and Medicaid and National
`
`Quality Forum. From 2011-2017, I served on the American Board of Internal
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`Medicine Gastroenterology Certification Board, which develops the board
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`certification and recertification exams for licensed gastroenterologists.
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`13.
`
`I am the past President of the American College of Gastroenterology
`
`(ACG). While President of the ACG, I formed the consensus groups with the
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`American College of Cardiology and American Heart Association and from 2007-
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`2011, I worked as a coauthor on three published consensus documents on NSAID
`
`and antiplatelet issues for cardiology and gastroenterology.
`
`14.
`
`I served as Medicare Advisor for technical issues for endoscopy from
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`1994 to 1996. Additionally, I co-founded the National Medicare Carrier Advisory
`
`Committee and co-chaired that committee for 10 years. Since 2000, I have served
`
`on both the GI Multi-Society CRC Screening Task Force and ACG guidelines
`
`committee for CRC screening and have co-authored these screening guidelines and
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`other ongoing publications from 2000 to the present. Additionally, I was a
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`4
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`member of the Center for Disease Control (CDC) Task Force for quality
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`colonoscopy.
`
`15.
`
`I have also received a number of awards and other professional
`
`recognition. In 2012, I was awarded the ACG Berk/Fise Clinical Achievement
`
`Award. The award, given annually, recognizes a single
`
`individual for
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`“distinguished contributions to clinical gastroenterology over a significant period
`
`of time.” In 2013, I was advanced to “Master” status by the ACG. I have also
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`been honored as “Master of Gastroenterology” and “Presidential Award” by the
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`Virginia GI Society. In May 2012, I was acknowledged as the invited lecturer at
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`the National Institutes of Health as a “Great Teacher,” one of two non-NIH
`
`employed MDs invited per year. In 2013, I received the Dean’s Outstanding
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`Faculty Award at Eastern Virginia Medical School, and in 2000, I was honored as
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`Outstanding Internal Medicine Faculty at the Eastern Virginia Medical School. In
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`2015, I received the ACG Governor’s William D. Carey Award for Lifetime
`
`Contribution and Service in field of gastroenterology. In 2016, I received the
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`American Gastroenterology Association (AGA) Distinguished Educator Award. In
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`2018, I was honored as Master of the American College of Physicians.
`
`16. Additional details about my education and professional experience
`
`may be found in my curriculum vitae, which is attached as Exhibit A.
`
`
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`
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`5
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`17. A list of cases in which I have testified as an expert at trial or by
`
`deposition in the last four years is attached as Exhibit B.
`
`18.
`
`I am being paid $600 per hour for my time spent in study and
`
`testimony in this matter.
`
`19.
`
`I reserve the right to prepare exhibits to summarize or support the
`
`opinions set forth below.
`
`II. BACKGROUND
`A. Legal Standards
`20.
`I have been informed of the legal principles related to the opinions in
`
`my expert declaration. My understanding of the legal principles I used in forming
`
`my opinions is set forth below.
`
`21.
`
`I understand that a patent is entitled to the earliest priority date by
`
`which the invention disclosed therein was conceived of and reduced to practice. I
`
`have been informed that “conception” occurs when the idea of the invention is
`
`formed in the mind of the inventor. I have been further informed that there are two
`
`types of reduction to practice: (1) constructive reduction to practice, which occurs
`
`upon the filing of a patent application of the claimed invention, and (2) actual
`
`reduction to practice, which occurs upon proof that the claimed invention works
`
`for its intended purpose. Here, I understand that conception and actual reduction to
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`
`
`
`
`6
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`practice were achieved by June 25, 2007, when the clinical study disclosing the
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`claimed invention of the ’208 patent was completed.
`
`22.
`
`I understand that the claims of an issued patent are presumed to be
`
`valid. I have been informed that party seeking to prove that the claims of an issued
`
`patent are not patentable in an inter partes review must do so with a preponderance
`
`of the evidence. I further understand that this burden remains on the party
`
`challenging the patent.
`
`23.
`
`I understand that a patent can be found invalid as anticipated under 35
`
`U.S.C. § 102 only if each and every aspect of the subject matter claimed was
`
`disclosed in a single prior art reference at the time of invention.
`
`24.
`
`I understand that a patent can be found invalid under 35 U.S.C. § 103
`
`only if the subject matter claimed would have been obvious to a person of ordinary
`
`skill in the art at the time of the invention. It is also my understanding that in
`
`assessing the obviousness of the claimed subject matter one should evaluate
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`obviousness over the prior art from the perspective of one of ordinary skill in the
`
`art (and not from the perspective of either a layman or a genius in that art). It is
`
`also my understanding that in assessing the obviousness of a claimed subject
`
`matter, one must evaluate obviousness over the prior art, not in hindsight, but with
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`foresight at the time the invention was conceived.
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`7
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`25.
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`It is my further understanding that the question of obviousness is to be
`
`determined based on:
`
`•
`
`•
`
`The scope and content of the prior art;
`
`The difference or differences between the subject matter of the claim
`
`and the prior art;
`
`•
`
`The level of ordinary skill in the art at the time of the invention of the
`
`subject matter of the claim; and
`
`•
`
`Any relevant objective factors (the “objective indicia,” “secondary
`
`indicia,” or Graham Factors) indicating non-obviousness, including evidence
`
`of any of the following:
`
`a.
`
`b.
`
`c.
`
`d.
`
`A long-felt, but unresolved need for the invention;
`
`Unexpected results achieved by the alleged invention;
`
`Copying of the alleged inventions by others in the field;
`
`Expression of surprise by experts and those skilled in the art at the
`
`subject matter of the claim; and
`
`e. Whether the patentee proceeded contrary to accepted wisdom of the
`
`prior art.
`
`26.
`
`I understand that objective factors can often be the most probative
`
`evidence in determining whether claimed subject matter was non-obvious.
`
`
`
`
`
`8
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`27.
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`I also understand that multiple prior art references can be combined to
`
`show that a claim is obvious. However, I understand that most inventions rely on
`
`building blocks already long known in the field of the invention. I understand that
`
`most, if not all, inventions require a combination of known elements. The mere
`
`existence and knowledge of elements in the prior art does not by itself render a
`
`combination of those elements obvious; some reason for combining the elements
`
`must exist. I also understand that it can be important, for a claim of obviousness of
`
`a combination of elements, to identify a reason that would have prompted a person
`
`of skill in the art at the time of the invention to combine the elements as claimed in
`
`the patent.
`
`B.
`
`Scientific Background
`1.
`NSAID Use and Gastrointestinal Injury
`28. 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, and in 1999 it was reported that more than 70 million
`
`prescriptions and 30 billion over-the-counter tablets were sold annually in the
`
`United States.1 Unfortunately, their use has been associated with mucosal injury to
`
`
`1 Ex. 2042 (M.M. Wolfe et al., Gastrointestinal toxicity of nonsteroidal
`
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`9
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`the upper gastrointestinal (GI) tract, including the development of peptic ulcer
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`disease and its complications, most notably upper gastrointestinal hemorrhage, and
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`perforation.2
`
`29. These adverse gastrointestinal outcomes have resulted in significant
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`morbidity and mortality. It has been reported that as many as 25% of chronic
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`NSAID users will develop ulcer disease,3 and 2–4% will have major complications
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`of bleeding or perforation of the stomach or intestine.4 In the late 1990s, it was
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`recognized that these GI events resulted in more than 100,000 hospital admissions
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`annually in the United States and between 7,000 and 10,000 deaths, especially
`
`among those who have been designated as being in a high risk category.5
`
`
`antiinflammatory drugs, N. Engl. J. Med., 340(24):1888-99 (1999)).
`2 Ex. 2013 (B. Cryer & M. Feldman, Effects of nonsteroidal anti-inflammatory
`drugs on endogenous gastrointestinal prostaglandins and therapeutic strategies
`for prevention and treatment of nonsteroidal anti-inflammatory drug-induced
`damage, Arch. Intern. Med., 152:1145–55 (1992)).
`3 Ex. 2043 (L. Laine, Nonsteroidal anti-inflammatory drug gastropathy,
`Gastrointest. Endosc. Clin. North Am., 6(3):489–504 (1996)).
`4 Ex. 2044 (F.E. Silverstein et al., Gastrointestinal toxicity with celecoxib vs.
`nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis:
`the CLASS study: A randomized controlled trial, JAMA, 284(10):1247–55 (2000));
`Ex. 2045 (C. Bombardier et al., Comparison of upper gastrointestinal toxicity of
`rofecoxib and naproxen in patients with rheumatoid arthritis, N. Engl. J. Med.,
`343(21):1520–28 (2000)).
`5 Ex. 2046 (G. Singh, Gastrointestinal complications of prescription and over-the-
`counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database,
`Am. J. Ther., 7:115–21 (2000)); Exhibit 2042 (Wolfe 1999) at 1888.
`
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`10
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`30. According to prospective data from the Arthritis, Rheumatism, and
`
`Aging Medical Information System (ARAMIS), 13 of every 1000 patients with
`
`rheumatoid arthritis who take NSAIDs for one year have a serious gastrointestinal
`
`complication. The risk in patients with osteoarthritis is somewhat lower, but still
`
`significant (7.3 per 1000 patients per year).6
`
`2.
`Physiology of the Gastrointestinal Tract
`31. The gastrointestinal tract is an organ system functioning in digestion
`
`and elimination made up of a series of connected organs from the mouth to the
`
`anus. The upper GI tract includes mouth, esophagus, stomach, and duodenum (the
`
`first part of the small intestine) and the lower GI tract is made up of the rest of the
`
`small intestine (approximately 18-20 feet), and the entire large intestine. This is
`
`shown in the figure below.7
`
`
`6 Ex. 2042 (Wolfe 1999) at 1888.
`7 Ex. 2047 (NIH, National Institute of Diabetes and Digestive and Kidney
`Diseases, Bleeding in the Digestive Tract, available at
`http://www.niddk.nih.gov/health-information/health-topics/digestive-
`diseases/bleeding-in-the-digestive-tract/Pages/facts.aspx (last accessed March 23,
`2015)).
`
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`32. The lining of the GI tract forms a complex barrier between the body
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`and the luminal environment. This lining is also known as the gastric epithelium.
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`As shown in the graphic below, Figure 3, the gastric epithelium is made up of three
`
`discrete layers—preepithelial, epithelial, and subepithelial—each with unique
`
`defense mechanisms to safeguard against gastric mucosal injury.
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`12
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`33. The first lines of defense against mucosal injury are the pre-epithelial
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`mechanisms, consisting of a mucus layer containing mucus, bicarbonate, and
`
`surface active phospholipids. This mucus later primarily acts as a physiochemical
`
`barrier to noxious agents in the lumen, including gastric acid. The second line of
`
`defense is made up of the surface epithelial cells. These specialized cells secret
`
`mucus and bicarbonate, and can migrate into the site of injury to restore damaged
`
`areas in a process known as restitution. Additionally, these cells are packed tightly
`
`together to limit the diffusion of gastric acid (hydrogen ions) into the GI tissue.
`
`The third line of defense is the vascular system of the gastric sub-mucosal layer.
`
`The mucosal blood flow removes acid and toxic metabolic by-products, while
`
`bringing oxygen and micronutrients to the epithelial cells.
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`13
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`34. Despite these defense mechanisms against noxious agents in the
`
`lumen, minor mucosal injury occurs regularly. Mucosal defense is a dynamic
`
`process, and 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, which can lead to an impaired mucosal
`
`defense, rendering the upper GI mucosa more susceptible to injury.
`
`35. Erosions of the mucosa may lead to ulceration when the various
`
`components of mucosal defense are insufficient to restrict injury caused by gastric
`
`acid to the mucosal epithelial cells. An ulcer is a lesion larger and deeper than an
`
`erosion, and one that penetrates to the level of the submucosa. As shown in the
`
`figure below, ulcers can form in esophagus, stomach, or small intestine.
`
`
`
`14
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`36. Gastric and duodenal ulcers may lead to gastroduodenal hemorrhage,
`
`perforation, and even death. Other serious, less common, GI injuries resulting
`
`from NSAID use include small-bowel ulceration, colonic strictures, diverticular
`
`disease, exacerbated inflammatory bowel disease, and pill esophagitis.
`
`3.
`State of the Art of Treatment for GI Injury in 2007
`In 1999, Wolfe et al. described two approaches to prevent mucosal
`
`37.
`
`injury associated with NSAID use: (1) concomitant therapy with sucralfate,
`
`prostaglandins, H2-receptor antagonists, or proton pump inhibitors (PPIs); and (2)
`
`the development of “safer” NSAIDS including the development of COX-2
`
`inhibitors and nitric oxide-containing NSAIDs.8 These approaches were still
`
`standard in the art as of 2007. In his review of the state of the art, Wolfe did not
`
`suggest or describe the creation of a single formulation combining an NSAID and a
`
`gastric injury-preventing component.
`
`a.
`
`Concomitant therapy with sucralfate, prostaglandins,
`or H2-receptor antagonists
`38. Sucralfate is a mucosal protective agent that produces a cytoprotective
`
`barrier at the side of gastric injury, preventing further injury. It was approved by
`
`FDA in 1993 and marketed as Carafate®. Although clinical studies showed that
`
`sucralfate has demonstrated no significant benefit in preventing gastric ulcers in
`
`8 Ex. 2042 (Wolfe 1999) at 1893-96.
`
`
`
`
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`15
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`patients also receiving NSAID therapy, doctors continued to prescribe sucralfate in
`
`2007.9
`
`39. Synthetic prostaglandin analogues, such as misoprostol, are used to
`
`replace depleted endogenous prostaglandins. Misprostol, marketed as Cytotec®,
`
`was approved in 1988 for reducing the risk of NSAID-induced gastric ulcers in
`
`patients at high risk of complications for gastric ulcer. Misoprostol is potentially
`
`abortifacient, and should not be used by pregnant women, or women of
`
`childbearing age who may become pregnant.
`
` And despite misoprostol’s
`
`effectiveness in preventing gastroduodenal ulcers, patients taking misoprostol
`
`report frequent significant side effects including diarrhea, abdominal pain, nausea,
`
`and dyspepsia.
`
` In 2007, concomitant
`
`treatment with misoprostol was
`
`recommended as prophylactic therapy with NSAID usage to prevent mucosal
`
`injury.10
`
`40. Histamine H2-receptor antagonists bind to and block histamine H2-
`
`receptors on parietal cells (specialized gastrointestinal epithelial cells that secrete
`
`gastric acid), inhibiting acid secretion. This class of drugs is fast acting, but has a
`
`relatively short duration of action. Cimetidine (Tagamet®) was the first H2-
`
`9 See, e.g., Ex. 2048 (K.S. Jain, et al., Recent advances in proton pump inhibitors
`and management of acid-peptic disorders, Bioorganic & Medicinal Chemistry
`15:1181-1205 at 1187 (2007) (referring to the use of sucralfate)).
`10 Ex. 2042 (Wolfe 1999) at 1894, 1896.
`
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`receptor antagonist to receive FDA approval and was introduced to the market in
`
`the late 1970s. Ranitidine (Zantac®) was approved by FDA in 1981, and by 1988
`
`was the biggest selling prescription drug in the U.S. Famotidine (Pepcid ®) was
`
`approved in 1986 and nizatidine (Axid®) was approved in 1988. H2-receptor
`
`antagonists have been shown to reduce the risk of NSAID-related gastric ulcers
`
`and a 1997 study reported that patients with rheumatoid arthritis or osteoarthritis
`
`with known NSAID-related ulcers who were treated with high-dose famotidine
`
`therapy had a significant reduction in the cumulative incidence of ulcer recurrence
`
`compared with placebo.11 As of 2007, H2-receptor antagonists were still prescribed
`
`by doctors for the treatment and prevention of gastric injury.12
`
`b.
`Concomitant therapy with PPIs
`41. The first proton pump inhibitor (PPI), omeprazole, was developed by
`
`scientists at what is now AstraZeneca. Omeprazole was approved by the FDA in
`
`1989 and sold as Prilosec®. Lansoprazole was developed by Takeda and was first
`
`sold in the US in 1995, marketed as Prevacid®. Eisai created rabeprazole, which
`
`received FDA approval in 1999 and was sold under the brand name Aciphex®.
`
`Pantoprazole was developed by Altana and marketed under the brand name
`
`11 Ex. 2049 (N. Hudson et al., Famotidine for healing and maintenance in
`nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration,
`Gastroenterology, 112:1817-22 (1997)).
`12 See, e.g., Ex. 2048 (Jain 2007) (referring to the use of H2 receptor antagonists).
`
`
`
`
`
`17
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`Protonix®, beginning in 2000. All of these PPIs were approved as enteric coated
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`formulations.
`
`42. The enteric coating of these PPIs served to prevent the release of the
`
`PPI into the stomach until a certain pH was reached. For example, in 2005, Dr.
`
`Metz wrote, “[p]roton pump inhibitors are inactivated by gastric acid and thus must
`
`be given as enteric-coated granules in gelatin capsules or enteric-coated tablets.”13
`
`43. Scientific efforts by AstraZeneca, the developer of omeprazole and
`
`market leader of omeprazole-containing pharmaceuticals, looked at ways to
`
`improve efficacy for this class of therapy. This led to the approach of purifying
`
`one side of the racemic compound to enhance metabolic properties and thereby
`
`improve the acid reduction effect on disease treatment or prevention.14 This
`
`approach resulted in the development of esomeprazole, which was approved by
`
`FDA in 2001 as an enteric coated dosage form and sold under the brand name
`
`Nexium®.15 Esomeprazole is the S-enantiomer of omeprazole. Takeda, the other
`
`market leader in PPI drugs, also continued to improve the efficacy of its PPI,
`
`
`13 Ex. 2022 (Stollman & Metz, Pathophysiology and prophylaxis of stress ulcer in
`intensive care unit patients, Journal of Critical Care, 20:35-45, at 42 (2005)).
`14 A racemic compound is composed of equal amounts of both enantiomers of a
`chiral molecule. Enantiomers are mirror images of one another. Such molecules
`have the same molecular composition, but cannot be superimposed on one another.
`15 Ex. 2051 (L. Olbe et al., Reviews: Proton-pump inhibitor expedition: The case
`histories of omeprazole and esomeprazole, Nature 2:132-39 (2003)).
`
`
`
`
`
`18
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`lansoprazole, and developed dexlansoprazole (Dexilant®). Dexlansoprazole is the
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`R-enantiomer of lansoprazole, and was approved by FDA in 2009 as an enteric
`
`coated tablet.
`
`44. PPIs are absorbed into the systemic circulation of a patient and
`
`decrease the gastric acid secretion by parietal cells in the stomach. PPIs
`
`irreversibly bind to and inhibit the hydrogen-potassium ATPase pump on the
`
`luminal surface of the parietal cell membrane. This gastric proton pump is the
`
`final step in the secretion of hydrogen ions into the lumen. Irreversibly blocking
`
`the proton pump decreases the acidity of the gastric lumen.
`
`45. All approved PPI drugs are substituted benzimidazoles. Since initial
`
`development of the first PPI (omeprazole), this class of drugs has been known to
`
`be “acid labile,” meaning PPIs are susceptible to degradation in acidic
`
`environments such as in the lumen of the GI tract. As a result of their intolerance
`
`to acid, it was—and remains—widely accepted that PPIs must be administered
`
`with an enteric coating to protect the drug from gastric acid degradation.16 While
`
`
`16 Ex. 2021 (A. Norman & C.J. Hawkey, What you need to know when you
`prescribe a proton pump inhibitor, Frontline Gastroenterol. 2(4):199-205 (2011)
`(“PPIs are easily protonated and therefore unstable at acid pH. In gastric juice, this
`would result in inactivation before absorption. This is why PPIs are enteric
`coated.”)).
`
`
`
`
`
`19
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`this enteric coating protects acid-labile PPIs from acid degradation, it also reduces
`
`the PPI’s rate of absorption into the systemic circulation.
`
`46. FDA approved enteric coated PPIs generally take 4 to 5 days of daily
`
`use to reach maximal acid inhibition.17 In contrast, H2-receptor antagonists
`
`suppress gastric acid production more quickly, but are limited by the development
`
`of tachphylaxis (decrease in response; drug no longer provides the intended
`
`response).18 PPIs are thus less effective in the short term (on demand) than H2-
`
`receptor antagonists. PPIs also have a higher incidence of side effects than H2-
`
`receptor antagonists.19
`
`47.
`
`In 2007, it was well known that different PPIs behave differently in
`
`the clinical setting, due in part to their different pharmacokinetic properties.20
`
`Additionally,
`
`there were no clinical studies comparing
`
`the efficacy of
`
`esomeprazole to that if other PPIs, except for in the narrow indication of erosive
`
`
`17 Ex. 2052 (C.W. Howden, Clinical pharmacology of omeprazole, Clin.
`Pharmacokinet 20(1):38-49 (1991)).
`18 Ex. 2053 (J.Q. Huang & R.H. Hunt, Pharmacological and pharmacodynamic
`essentials of H2-receptor antagonists and proton pump inhibitors for the practising
`physician, Best Prac. & Res. Clin. Gastroenterol. 15(3):355-70 (2001)).
`19 Ex. 2054 (H. Koop, Review article: metabolic consequences of long-term
`inhibition of acid secretion by omeprazole, Aliment. Pharmacol. Ther. 6:399–406
`(1992)).
`20 Ex. 2048 (Jain 2007) at Table 3 (listing the different pharmacological properties
`of the different PPIs, including esomeprazole).
`
`
`
`
`
`20
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`oesophagitis.21 Without such comparative clinical data, and with the knowledge
`
`that PPIs have distinct pharmacokinetic behaviors, a person of ordinary skill in
`
`2007 would not have been motivated to substitute esomeprazole for another PPI.
`
`48. Before the development of Vimovo®—and even to this day—every
`
`PPI on the market is either enteric coated or administered with a buffer.
`
`49.
`
`In 2007, esomeprazole was available in doses of 20 mg and 40 mg,
`
`but clinicians rarely—if ever—prescribed the 20 mg dose of esomeprazole,
`
`because the 40 mg dose was widely regarded as being more effective at
`
`suppressing acid production.22 Further, esomeprazole was only ever administered
`
`once a day, as b.i.d. dosing was not yet common for esomeprazole. For example,
`
`the 2007 Nexium label recommends a dosing schedule for enteric-coated
`
`esomeprazole magnesium of only once daily for all but one indication.23
`
`c.
`Development of “safer” NSAIDs
`50. Despite the scientific evidence that concomitant administration of
`
`medications such as proton pump inhibitors and prostaglandins (misoprostol) was
`
`21 See, e.g., Ex. 2055 (Donnellan C., Preston C., Moayyedi P., Sharma N., Medical
`treatments for the maintenance therapy of reflux oesophagitis and endoscopic
`negative reflux disease (Rev