UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner
`
`V.
`
`POZEN INC. and HORIZON PHARMA USA, INC.
`Patent Owners
`
`Case No. IPR2017-01995
`Patent No. 9,220.698
`
`DECLARATION OF DAVID A. JOHNSON, M.D. IN SUPPORT OF
`PATENT OWNER RESPONSE TO PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,220,698
`
`Page 1 of 128
`
`exhibit
`
`/
`
`DATE;
`Penny Wile, RPR. RWR, CRR
`
`Patent Owner Ex. 2026
`Mylan v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 1
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner
`
`V.
`
`POZEN INC. and HORIZON PHARMA USA, INC.
`Patent Owners
`
`Case No. IPR2017-01995
`Patent No. 9,220.698
`
`DECLARATION OF DAVID A. JOHNSON, M.D. IN SUPPORT OF
`PATENT OWNER RESPONSE TO PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,220,698
`
`Page 1 of 128
`
`exhibit
`
`/
`
`DATE;
`Penny Wile, RPR. RWR, CRR
`
`Patent Owner Ex. 2026
`Mylan v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 1
`
`
`
`responsibilities discussed below, my focus is on clinical gastroenterology and 1 am
`
`engaged in patient care daily.
`
`5.
`
`Tn addition to being a practicing physician, J 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, 1 am involved in
`
`teaching medical curricula for a variety of programs and am extremely active in
`•' - if •
`^
`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 (PPls) in the treatment of
`
`gastrointestinal disorders. I have published more than 600 articles, reviews,
`
`abstracts and book chapters pertinent to gastrointestinal disorders, and 1 have
`
`also served as an editor and reviewer for a number of journals related to
`
`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.
`>
`I serve on numerous editorial boards and reviews for 21 medical
`
`8.
`
`journals, including all of the GI journals. 1 was^a member/reviewer of the National
`
`2
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`
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`Institutes of Health study section for esophageal/gastric diseases and have provided
`
`consultant testimony to the FDA.
`
`9.
`
`1 am the 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 founding co-editor of the American College of
`
`Gastroenterology GI Universe, and currently continue as the 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).
`
`10.
`
`I recently edited the book Gut Microhiome: New Understanding and
`
`Potential Translational Applications for Disease Management, published in
`
`December 2015. Additionally, 1 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
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`
`
`Association, the American College of Cardiology, and the American College of
`
`Gastroenterology.
`
`12.
`
`I have served in countless 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. From 2011^2017, 1 served on the American Board of Internal
`
`Medicine Gastroenterology Certification Board, which develops the board
`
`certification and recertification exams for licensed gastroenterologists.
`
`13.
`
`lam 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 published consensus documents on NSAID
`
`and antiplatelet issues for cardiology and gastroenterology.
`
`14.
`
`I served as Medicare Advisor for technical issues for endoscopy from
`
`I
`
`1994 to 1996. Additionally, I co-founded the National Medicare Carrier Advisory
`
`Comrnittee 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 Itave co-authored these screening guidelines and
`
`other ongoing publications from 2000 to the present. Additionally, I was a
`
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`
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`member of the Center for Disease Control (CDC) Task Force for quality
`
`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
`
`“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
`
`been honored as “Master of Gastroenterology” and “Presidential Award” by the
`
`Virginia GI Society. In May 2012, I was acknowledged as the invited lecturer at
`
`the National Institutes of Health as a “Great Teacher,” one of two non-NlH
`
`employed MDs invited per year. In 2013, I received the Dean’s Outstanding
`
`Faculty Award at Eastern Virginia Medical School, and in 2000,1 was honored as
`
`Outstanding Internal Medicine Faculty at the Eastern Virginia Medical School. In
`
`2015, I received the ACG Governor’s William D. Carey Award for Lifetime
`
`Contribution and Service in field of gastroenterology. In 2016, 1 received the
`
`American Gastroenterology Association (AGA) Distinguished Educator Award.
`
`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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`17. A list of cases in which T have testified as an expert at trial or by
`
`deposition in the last four years is attached as Exhibit B.
`
`f
`
`18.
`
`1 am being paid S600 per hour for my lime spent in study and
`
`testimony in this matter.
`
`'
`
`'
`
`.
`
`'
`
`19.
`
`r reserve the right to prepare exhibits to summarize or support the
`
`opinions set forth below.
`
`TI. 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. 1 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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`
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`practice were achieved by June 25, 2007, when the clinical study disclosing the
`
`claimed invention of the '698 patent was completed.
`
`22.
`
`1 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 prepor?derance
`
`of the evidence. ' 1 further understand that this burden remains on the party
`
`challenging the patent.
`
`23.
`
`1
`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
`
`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
`
`foresight at the time the invention was conceived.
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`25.
`
`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.
`
`c
`
`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 ail 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.
`
`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. 1 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 (NSAlDs) are valuable agents
`
`in the treatment of arthritis and other musculoskeletal disorders, and as analgesics
`
`in a wide variety of clinical scenarios. NSATDs 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.' Unfortunately, their use has been associated with mucosal injury to
`
`' Ex. 2042 (M.M. Wolfe et al.. Gastrointestinal toxicity of nonsteroidal
`
`9
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`
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`the upper gastrointestinal (GI) tract, including the development of peptic ulcer
`
`disease and its complications, most notably upper gastrointestinal hemorrhage, and
`
`perforation.“
`
`A
`
`29. These adverse gastrointestinal outcomes have resulted in significant
`
`morbidity and mortality. It has been repoited that as many as 25% of chronic
`
`NSAID users will develop ulcer disease,-' and 2-4% will have major complications
`
`of bleeding of perforation of the stomach or intestine.^ In the late 1990s, it was
`
`recognized that these GI events resulted in more than 100,000 hospital admissions
`
`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 categoi^.-
`
`antiinflammatory drugs, N. Engl. J. Med., 340(24): 1 888-99 (1999)).
`^ Ex. 2013 (B. Ciyer & M. Feldman, Effects of nonsteroidal anti~inJ1animatory
`drugs on endogenous gastrointestinal prostaglandins and therapeutic strategies
`for prevention and treatment of nonsteroidal anti-inflammatory drug-induced
`damage, Arch. Intern. Med., 152:1 145—55 (1992)).
`Ex. 2043 (L. Laine, Nonsteroidal anti-inflammatory drug gastropathy,
`Gastrointest. Endosc. Clin. North Am., 6(3):489-504 (1996)).
`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)).
`^ Ex. 2046 (G. Singh, Gastrointestinal complications of prescription and over-the-
`counter jionsteroidal anti-inflammatory drugs: a view from the ARAMIS database,
`Am. J. Then, 7:115-21 (2000)); Exhibk 2042 (Wolfe 1999) at 1888.
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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 NSAlDs 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).^
`
`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.^
`
`Ex. 2042 (Wolfe 1999) at 1 888.
`’ 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)).
`
`11
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`
`
`Mouth
`
`Duodenum,
`
`^
`
`Stomach
`
`Large
`intestine
`
`Small _
`intestine
`Rectum
`
`“ Anus
`
`32. The lining of the GI tract forms a complex barrier between the body
`
`and the luminal environment This lining is also known as the gastric epithelium.
`
`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.
`
`12
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`
`
`hunen
`
`1
`
`mucus
`I 1
`ephbdhim
`1 I
`
`GI tissue
`
`Pre^ithelial mechanisms
`• Mucus
`■ Bicarbonate
`•
`Surface active phospholipids
`
`Epithelial mechanisms
`• Growth factors, prostaglandins
`• Cell proliferation
`• Cellular resistance
`• Restitution
`
`Sub-ephbelial mechanisms
`■ blood circulation
`• leukocytes
`
`33. The first lines of defense against mucosal injury are the pre-epithelial
`
`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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`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.
`
`Esophagus
`
`Esophagsal'"
`ulcsr
`
`1’
`
`Stomael)
`
`^^Oastrtc ulcar
`
`Small
`intestlns*
`
`Duodenal ulcer
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`36. Gastric and duodenal ulcers may lead to gastroduodenal hemorrhage,
`
`perforation, and even death. Other serious, less common, G1 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 Gl Injury in 2007
`
`37.
`
`In 1999, Wolfe et al. described two approaches to prevent mucosal
`
`injury associated with NSAID use: (1) concomitant therapy with sucralfate,
`
`prostaglandins, Hi-receptor antagonists, or proton pump inhibitors (PPls): and (2)
`
`the development^of “safer’ NSAIDS including the development of COX-2
`
`inhibitors and nitric oxide-containing NSAlDs.^ 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 Hi-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
`
`Ex. 2042 (Wolfe 1999) at 1893-96.
`
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`patients also receiving NSAID therapy, doctors continued to prescribe sucralfate in
`
`2007.^
`
`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 NSAlD-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 misoprostoks
`
`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.'"
`
`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-
`
`See, e.g., Ex. 2048 (K.S. Jain, el al., Recent advances in proton pump inhibitors
`and management of acid-peptic disorders, Bioorganic & Medicinal Chemistr)'
`15:1 181-1205 at 1187 (2007) (referring to the use of sucralfate)).
`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 NSATD-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." As of 2007, H2-receptor antagonists were still prescribed
`
`by doctors for the treatment and prevention of gastric injury.
`
`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 ereated 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
`
`'' Ex. 2049 (N. Hudson et al., Famotidine for healing and maintenance in
`nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration,
`Gastroenterology, 112:1817-22 (1997)).
`See, e.g., Ex. 2048 (Jain 2007) (referring to the use of H2 receptor antagonists).
`
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`
`
`Protonix®, beginning in 2000. All of these PPls were approved as enteric coated
`
`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, “[pjroton pump inhibitors are inactivated by gastric acid and thus must
`
`be given as enteric-coated granules in gelatin capsules or enteric-coated tablets.'’'^
`
`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.''^ 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®.'^ Esomeprazole is the S-enantiomer of.omeprazole. Takeda, the other
`
`market leader in PPl drugs, also continued to improve the efficacy of its PPI,
`
`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)).
`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.
`Ex. 2051 (L. Olbe et al., Reviews: Proton-pump inhibitor expedition: The case
`histories of omeprazole and esomeprazole. Nature 2:132-39 (2003)).
`
`Page 20 of.128
`
`Patent Owner Ex. 2026
`Mylan v. Pozen
`, IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 18
`
`
`
`lansoprazole, and developed dexlansoprazole (Dexilant®). Dexlansoprazole is the
`
`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 PPl drugs are substituted benzimidazoles. Since initial
`
`development of the first PPl (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.’^ While
`
`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.”)).
`
`Page 21 of 128
`
`Patent Owner Ex. 2026
`Mylan v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 19
`
`
`
`this enteric coating protects acid-labile PPIs from acid degradation, it also reduces
`
`the PPJ’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.*' 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).'** PPIs are thus less effective in the short term (on demand) than H:-
`
`receptor antagonists. PPIs also have a higher incidence of side effects than H2-
`
`receptor antagonists.
`
`47.
`
`In 2007, it was well known that different PPIs behave differently in
`
`the clinical setting, due in part to their different pharmacokinetic properties.^"
`
`Additionally, there were no clinical studies comparing the efficacy of
`
`esomeprazole to that if other PPIs, except for in the narrow indication of erosive
`
`Ex. 2052 (C.W. Howden, Clinical pharmacology of omeprazole, Clin.
`Pharmacokinet 20(l):38-49 (1991)).
`'** 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)).
`Ex. 2054 (H. Koop, Review article: metabolic consequences of long-term
`inhibition of acid secretion by omeprazole. Aliment. Pharmacol. Ther. 6:399^06
`(1992)).
`Ex. 2048 (Jain 2007) at Table 3 (listing the different pharmacological properties
`of the different PPIs, including esomeprazole).
`
`-N
`
`20
`
`Page 22 of 128
`
`Patent Owner Ex. 2026
`Wlylan v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 20
`
`
`
`oesophagitis." Without such comparative clinical data, and with the knowledge
`
`that PPls have distinct pharmacokinetic behaviors, a person of ordinary skill in
`
`2007 would not have been motivated to substitute esomeprazole for another PPL
`
`48. Before the development of Vimovo®—and even to this day—every
`
`PPl 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.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.
`
`c. Development of‘‘safer” NSAIDs
`
`50. Despite the scientific evidence that concomitant administration of
`
`medications such as proton pump inhibitors and prostaglandins (misoprostol) was
`
`See, e.g., Ex. 2055 (Donnellan C., Preston C., Moayyedi P., SharmaN., Medical
`treatments for the maintenance therapy of reflux oesophagitis and endoscopic
`negative reflux disease (Review), The Cochrane Library, Issue 4, at 14 (2004)
`(“There is also a lack of data comparing equivalent doses of PPls”)).
`See, e.g., Ex. 2056 (David A. Johnson, Review of esomeprazole in the treatment
`of acid disorders. Expert Opin. Pharmacother. 4(2);253-264 (2003)).
`Ex. 2057 at 22 (MYL-EN000523782-818 at MYL-EN000523802-03
`(recommending once daily dosing schedules)).
`
`21
`
`Page 23 of 128
`
`Patent Owner Ex. 2026
`Myian v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 21
`
`
`
`helpful, it was well recognized that the ulcer related condition persisted in many
`
`palients'who requires NSAID therapy. Optimizing safety in these individuals, who
`
`often must take NSAID therapy for extended periods of time, was, and remains,
`
`critical.-*’
`
`51. Scientific research in the late 1990s to early 2000s turned to focus on
`
`“safer” NSATDs.-^ The search for a less gastrotoxic NSAID led to the
`'1
`development of the COX-2 inhibitors.-^ COX-2 inhibitors were developed by
`
`major pharmaceutical companies, including Merck (rofecoxib), Pfizer (celecoxib),
`
`and Novartis (valdecoxib). While these agents were shown to be safer than
`
`conventional NSAlDs as it relates to GI complications of ulcers,-^ post-release
`
`recognition of the cardiovascular complication risks led to the withdrawal from the
`
`market of all but celcoxib.-*^ The withdrawal of these COX-2 inhibitors intensified
`
`the unmet need to develop safer drugs to treat GI injury in 2007.
`
`Ex. 2058 (S. H. Roth, NSAID gastropathy: A neM- understanding, Arch. Intern.
`Med. 156:1623-28(1996)).
`Ex. 2059 (W. Bensen & A. Zizzo, Newer, safer nonsteroidal anti-inflammatory
`drugs. Rational NSAID selection for arthritis. Can. Earn. Physician 44:101-02,
`105-07(1998)).
`Ex. 2060 (R.J. Flower, Reviews: The development of COX2 inhibitors. Nature
`2:179-91 (2003)).
`Ex. 2061 (Wolfe et al., Gastroprotective therapy and risk of gastrointestinal
`ulcers: risk reduction by COX-2 therapy, J. Rheumatol. 29(3):467-73 (2002)).
`Ex. 2062 (FDA Public Health Advisory, April 7, 2005, available at
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsa
`
`22
`
`Page 24 of 128
`
`Patent Owner Ex. 2026
`Mylan v. Pozen
`IPR2017-01995
`
`MYLAN PHARMS. INC. EXHIBIT 1086 PAGE 22
`
`
`
`52.
`
`In the 1990s, scientists discovered that nitric oxide stimulates the
`
`cyclooxygenase enzymes and may act synergistically with prostaglandins to
`
`protect the gastric mucosa. Nitric oxide-containing NSATD compounds were
`
`found to retain the desired anti-inflammatory and fever-reducing properties of
`
`traditional NSAIDs without causing gastric mucosal injury.In 2007, this was
`
`(and continues to be) a promising avenue of research for the design and
`
`development of novel therapeutic agents.
`
`III. OPINIONS
`
`A. The Person of Ordinary Skill in the Art
`
`53.
`
`I understand that Dr. Mayersohn defined the hypothetical person of
`
`ordinary skill in the art as a collaboration between a pharmacologist or
`
`pharmacokineticist having a Ph.D. degree or equivalent training, or a M.S. degree
`
`with at least 2 years of some experience in dosage form design and in in vitro and
`
`in vivo evaluation of dosage form performance, and a medical doctor having at
`
`least 2 years of practical experience treating patients in the gastroenterology field.
`
`T understand that th
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