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
`______________
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`
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`DECLARATION OF ROBERT W. MAKUCH, PH.D.
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`IN SUPPORT OF PATENT OWNER’S RESPONSE
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`Ex. 2021
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`Table of Contents
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`Page
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`
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`I.
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`II.
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`III.
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`IV.
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`V.
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`VI.
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`INTRODUCTION AND SUMMARY OF QUALIFICATIONS...................................... 2
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`MATERIALS CONSIDERED .......................................................................................... 5
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`UNDERSTANDING OF THIS PROCEEDING ............................................................... 5
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`UNDERSTANDING OF RELEVANT LEGAL PRINCIPLES ........................................ 6
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`UNDERSTANDING OF THE TECHNICAL BACKGROUND...................................... 7
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`THE ’621 PATENT ........................................................................................................... 8
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`VII. PETITIONER’S OBVIOUSNESS CHALLENGES ......................................................... 9
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`VIII. THE PRIOR ART DOES NOT RENDER CLAIMS 1-16 OF THE ’621 PATENT
`OBVIOUS ........................................................................................................................ 11
`A.
`GRAHAM ............................................................................................................ 11
`B.
`GOLDSTEIN ....................................................................................................... 16
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`I, Robert W. Makuch, Ph.D., hereby declare and state as follows:
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`I.
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`INTRODUCTION AND SUMMARY OF QUALIFICATIONS
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`1.
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`2.
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`I am over the age of eighteen and otherwise competent to make this declaration.
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`I have been retained as an expert opinion witness on behalf of Patent Owners
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`Pozen Inc. and Horizon Pharma Inc. for the above-captioned inter partes review (“IPR”). I am
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`being compensated for my time in connection with this IPR at my standard consulting rate,
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`which is $625 per hour.
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`3.
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`I have no financial interest in, or affiliation with, the Petitioner or the Patent
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`Owners. My compensation is not dependent upon the outcome of, or my testimony in, the
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`present inter partes review or any litigation proceedings.
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`4.
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`My background, qualifications, and experience relevant to the issues in this
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`proceeding are summarized below. A full description of my background and qualifications is set
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`forth in my curriculum vitae, attached hereto..
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`5.
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`I am a tenured Full Professor in the Department of Biostatistics at the Yale
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`University School of Medicine. I am also currently Director of the Regulatory Affairs Track
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`Yale University School of Medicine.
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`6.
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`I possess nearly 38 years of experience in a variety of areas including but not
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`limited to identification, evaluation, and interpretation of clinical endpoints and other clinical
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`events. My research has focused primarily on the design, conduct, analysis, and interpretation of
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`clinical and pre-clinical data obtained from pre-clinical experiments, clinical trials, and
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`epidemiologic studies.
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`7.
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`My activities include, but are not limited to, serving as: 1) Special Government
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`Employee (SGE) to the U.S. Food and Drug Administration (FDA); 2) consultant/advisor to
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`numerous government and pharmaceutical-sponsored clinical and pre-clinical studies; and 3)
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`author or co-author of over 200 peer-reviewed publications in the medical and regulatory affairs
`
`literature.
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`8.
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`I received my M. Phil. and Ph.D. from Yale University in 1976 and 1977,
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`respectively.
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`9.
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`I received my M.A. degree from University of Washington in 1974 and my B.A.
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`degree from University of Connecticut in 1972.
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`10.
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`In 1977 I became an investigator and was subsequently promoted to Senior
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`Investigator at the National Cancer Institute. In 1983 I was again promoted to Section Head of
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`the biostatistics and data management section. I held that position until 1986. Many of my
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`activities in these roles involved the design, conduct, analysis, and interpretation of clinical trials
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`and pre-clinical studies.
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`11.
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`In 1986, I joined the faculty of Yale University in the Division of Biostatistics as
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`an Associate Professor. I was tenured in 1990 and promoted to Full Professor in 1995 which I
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`continue to hold today.
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`12.
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`From 1996-2003, I was the Acting Division Head, and then the Division Head, for
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`the Division of Biostatistics, Yale University School of Medicine.
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`13.
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`I am also Director of the Regulatory Affairs Program and Chairman of the
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`Regulatory Affairs Advisory Board at Yale University. I am Director of the Certificate Program
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`in Regulatory Affairs for Senior Delegations of the Chinese Food and Drug Administration
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`(CFDA), and an Invited Member of the Dean’s Advisory Board at the University of Connecticut
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`for the College of Liberal Arts and Sciences.
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`14.
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`I currently teach two courses at the graduate level at Yale: Fundamentals of
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`Clinical Trials and Introduction to Regulatory Affairs.
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`15.
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`I am an author or co-author on over 200 peer-reviewed publications, most of
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`which relate to the design, conduct, analysis, and interpretation of clinical and pre-clinical
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`studies, and have given numerous presentations on these topics at national and international
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`meetings, universities, and government locations.
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`16.
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`I was nominated and appointed to serve as a Special Government Employee
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`(SGE) to the FDA from 2002 to 2007. In this capacity, I performed a number of activities at the
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`request of the FDA including serving on Advisory Committees and providing expert advice to
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`the FDA on a variety of topics.
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`17.
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`Honors and awards I have received for teaching and research include the
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`Connecticut Public Health Association Award for AIDS Research (1987). This award was given
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`for my above-mentioned activities, and led to my selection to serve on The Stewart B. McKinney
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`Foundation Advisory Board, a Foundation in honor of Congressman Stewart B. McKinney of
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`Connecticut. I was also nominated and received the honor of becoming a Fellow of the
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`American Statistical Association (ASA) (2003), a superlative honor that, under the Association
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`by-laws, may be bestowed on no more than one-third of one percent of the total ASA
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`membership (roughly 18,000 members currently). I was nominated and became a Fellow of
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`Silliman College at Yale University. A complete list of my memberships on numerous academic,
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`professional, and scholarly societies is found in my curriculum vitae.
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`II. MATERIALS CONSIDERED
`18.
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`In formulating my opinions, I have relied on my thirty-eight years of experience
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`in biostatistics, clinical trials, epidemiology, and regulatory affairs. In addition to my expertise, I
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`have specifically considered the ’621 patent, the Coalition for Affordable Drugs VII LLC’s
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`(“Petitioner”) petition for inter partes review of the ’621 patent (the “Petition”) and associated
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`exhibits. I have also considered the declaration of Dr. Leon Shargel (the “Shargel Decl.”), the
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`transcript of the May 25, 2016 deposition of Dr. Shargel (the “Shargel Dep. Tr.”), and Patent
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`Owner’s Preliminary Response.
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`III. UNDERSTANDING OF THIS PROCEEDING
`19.
`I understand that this is an inter partes review (IPR) proceeding conducted before
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`the Patent Trial and Appeal Board (“Board”) of the U.S. Patent and Trademark Office (“PTO”)
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`to determine if claims 1-16 of the ’621 patent should be cancelled as unpatentable.
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`20.
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`I understand that Petitioner filed its Petition on August 12, 2015 asserting that
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`claims 1-16 of the ‘621 patent are invalid as obvious over combinations of references. Pet. at 4-5.
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`I further understand that the Petition was accompanied by a declaration of Dr. Leon Shargel.
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`21.
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`I understand that on November 23, 2015 Patent Owner submitted a Preliminary
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`Response in opposition to the Petition.
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`22.
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`I understand that on February 22, 2016, the Board decided to institute an IPR and
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`found that the Petition satisfied the threshold standard for institution by showing a “reasonable
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`likelihood that Petitioner would prevail in establishing the unpatentability” of the challenged
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`claims. Further, I understand that the Board has not made any final determination that claims 1-
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`16 are obvious.
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`IV. UNDERSTANDING OF RELEVANT LEGAL PRINCIPLES
`23.
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`I understand that the ’621 patent must be considered from the viewpoint of a
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`person of ordinary skill in the relevant art (“POSA”) as of June 25, 2009. A POSA is a
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`hypothetical person who is presumed to be aware of all pertinent art.
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`24.
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`Further, I have been advised of the following legal principles, and have applied
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`those principles to my analysis and conclusions as set forth in this declaration.
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`25.
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`It has been explained to me that that an invention may be unpatentable “if the
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`differences between the subject matter sought to be patented and the prior art are such that the
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`subject matter as a whole would have been obvious at the time the invention was made to a
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`person having ordinary skill in the art to which said subject matter pertains.” 35. U.S.C. § 103.
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`As I understand it, obviousness is a question of law that is based on the following factors: (i) the
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`scope and content of the prior art, (ii) the claims at issue, (iii) the level of ordinary skill in the art,
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`and (iv) objective evidence of secondary considerations. Routine experimentation does not
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`render an otherwise obvious claim valid. .Obviousness only calls for a reasonable expectation of
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`success, not a guarantee.
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`26.
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`I further understand that the Petitioner, in order to establish obviousness based on
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`a combination of references, must provide sufficient rationale as to why, at the time of invention,
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`a POSA would have been motivated to combine the teachings of those references to come up
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`with the claimed subject matter. The Petitioner must also establish that a POSA would have had
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`a reasonable expectation of success in combining said references. I further understand that a
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`POSA cannot rely on hindsight to provide a motivation to select and combine prior art
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`references.
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`27.
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`I also understand that obviousness cannot be shown where the art in any material
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`respect “teaches away” from the claimed invention.
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`V. UNDERSTANDING OF THE TECHNICAL BACKGROUND
`28.
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`It has been explained to me that non-steroidal anti-inflammatory drugs
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`(“NSAIDs”) are a class of drugs used to treat pain and inflammation associated with arthritis and
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`other musculoskeletal disorders. NSAIDS include drugs such as naproxen and aspirin. While
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`these drugs are widely used, their use has been associated with injury to the upper
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`gastrointestinal (“GI”) tract. I understand that prior to the inventions claimed in the ‘621 patent,
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`it was widely believed that a patient had an increased risk of upper GI injury, such as ulcer or
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`bleeding, when taking multiple NSAIDs, including the combination of naproxen and low-dose
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`aspirin (“LDA”).
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`29.
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`It has further been explained to me that the commercial embodiment of the ’621
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`patent, the pharmaceutical drug product, VIMOVO®, was designed to reduce the risk of upper
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`GI injury due to NSAID use. As I understand it, VIMOVO® consists of a combination of a
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`delayed-release, 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 NSAID which
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`allows the acid inhibitor’s gastroprotective effects to take hold before naproxen is released. This
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`coordinated release of these two compounds reduces the potential for gastric damage.
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`30.
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`As stated above, I understand that before the invention claimed in the ‘621 patent,
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`it was accepted that a patient’s concomitant use of an NSAID and LDA increased the risk of
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`gastrointestinal injury. I further understand, however, the ’621 patent unexpectedly demonstrates
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`the opposite: the administration on of a unit dose form of immediate-release esomeprazole and
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`delayed-release naproxen is more effective at reducing the incidence of the NSAID-associated
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`ulcers in patients taking LDA than in patients not taking LDA. Thus, rather than increasing the
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`risk of occurrence of an NSAID-associated gastric ulcer, the concomitant usage of LDA with a
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`unit dose form of immediate-release esomeprazole and delayed-release naproxen, surprisingly,
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`reduces that risk.
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`VI. THE ’621 PATENT
`31.
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`I understand that the ’621 patent describes methods of reducing the incidence of
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`gastric ulcers associated with use of NSAIDs in patients who are also taking low-dose aspirin.
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`The claimed methods require that the patient receive a unit dosage form that is comprised of 20
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`mg of esomeprazole and 500 mg of naproxen and that provides for coordinated release of the
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`esomeprazole and the naproxen. Significantly, the claimed methods also require that the dosage
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`form is more effective at reducing the incidence of NSAID-associated ulcers in patients taking
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`LDA than in patients not taking LDA.
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`32.
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`It is my understanding that the ’621 patent is one of the patents listed in the
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`FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”)
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`as covering the pharmaceutical product VIMOVO®.
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`33.
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`The ’621 patent contains 16 claims. Claims 1, 8, 15, and 16 are independent
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`claims
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`34.
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`Independent claim 1 is illustrative, and is copied below:
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`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:
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`(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,
`wherein at
`least a portion of said esomeprazole, or
`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).
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`VII. PETITIONER’S OBVIOUSNESS CHALLENGES
`35.
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`I understand that the Petitioner has raised two separate obviousness challenges to
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`the ’621 patent.
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`36.
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`In Ground 1, the Petitioner asserts that claims 1-16 are obvious over the
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`combination of U.S. Patent 6,926,907 (“Plachetka”) (Ex. 1004.); “Ulcer Prevention in Long-term
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`Users of Nonsteroidal Anti-inflammatory Drugs,” by David Y. Graham, et al., published in the
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`Archives of Internal Medicine, Vol. 162 on January 28, 2002. (“Graham”) (Ex. 1005); and
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`“Ulcer Recurrence in High-Risk Patients Receiving Nonsteroidal Anti-Inflammatory Drugs Plus
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`Low-Dose Aspirin: Results of a Post Hoc Subanalysis,” by Jay L. Goldstein, et al., published in
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`Clinical Therapeutics, Vol. 26, No. 10, on October 2004. (“Goldstein”) (Ex. 1006).
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`37.
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`In Ground II, the Petitioner asserts that claims 1-16 are obvious over Plachetka
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`alone.
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`38. My analysis and opinions are focused on Ground I, more specifically, the
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`combination of the Graham and Goldstein references.
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`39.
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`The Petitioner alleges that “Graham and Goldstein show that the combination of
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`lansoprazole and an NSAID was more effective at reducing gastric ulcers in patients also taking
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`low-dose aspirin (LDA) than in patients not also taking LDA.” (Pet. at 7.) Further, Petitioner
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`asserts that “the results disclosed by Graham and Goldstein would indicate that the compositions
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`disclosed in Plachetka could be used for treating patients on an LDA regimen to achieve the
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`predictable result of lower gastric ulcer incidence.” (Pet. at 12.)
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`40.
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`I understand, however, that the Board disagreed with Petitioner and concluded:
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`Petitioner has not established that Plachetka, Graham, and Goldstein
`teach or suggest that “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,” as required by each of independent
`claims 1, 8, 15, and 16 (emphasis added).
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`(Decision at 14).
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`41.
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`The Board further stated that the Petitioner and the Petitioner’s declarant, Dr.
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`Shargel, failed to identify a basis for the conclusion that a POSA would have understood that a
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`combination of lansoprazole (another acid inhibitor) and naproxen was more effective at
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`reducing the incidence of the NSAID-associated ulcers in patients taking LDA than in patients
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`not taking LDA. (Decision at 15.)
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`42.
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`As described more fully below, I agree with the Board’s conclusion on this point.
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`It is my opinion that a POSA, after reviewing Plachetka, Graham, and Goldstein, would not be
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`able to draw any conclusions about whether the administration of the claimed unit dose form is
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`more effective in reducing the incidence of NSAID-associated ulcers in patients taking LDA
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`than in patients not taking LDA.
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`VIII. THE PRIOR ART DOES NOT RENDER CLAIMS 1-16 OF THE ’621
`PATENT OBVIOUS
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`43. While my analysis below focuses on the Graham and Goldstein references, I
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`understand that Plachetka recognizes that NSAID administration can lead to upper GI injury, and
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`suggests that a POSA would have understood the risk of GI injury to patients taking both LDA
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`and an NSAID. (Ex. 1004 at 1:23-25; 2:35-40.) In my review of Plachetka, however, I saw no
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`mention of an unexpected reduction in the incidence of NSAID-associated upper GI injury in
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`patients taking the claimed unit dosage form.
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`A. GRAHAM
`44.
`
`Graham reports the results of a clinical trial comparing the efficacy of misoprostol
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`(a synthetic prostaglandin that acts as a cytoprotective agent) and lansoprazole (a proton pump
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`inhibitor that suppresses gastric acid production) in gastric ulcer prevention in long-term users of
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`NSAIDs.
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`45.
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`Graham enrolled 537 patients who were long-term NSAID users with a history of
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`endoscopically-documented gastric ulcer and were negative for H. pylori. (Ex. 1005 at 2.) The
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`patients were randomized to one of four treatment groups: placebo, misoprostol, lansoprazole
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`(15mg), and lansoprazole (30 mg). (Id.) Graham notes that patients were permitted to take “low
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`dose aspirin for cardiovascular protection.” (Id.) Graham makes no other mention of aspirin use
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`in the paper, except in passing with regards to ‘balance.’ He never used this factor as a variable
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`in any analysis.
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`46.
`
`It is significant that Graham does not describe how low dose aspirin use was
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`actually tracked or usage even verified. It is unknown exactly how patients were asked about
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`low-dose aspirin use or how frequently they were asked about low-dose aspirin use. For
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`example, it is unclear whether patients were on low-dose aspirin for the duration of the study, or
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`if patients stopped (or started) low-dose aspirin after starting the trial. Because the paper is silent
`
`on this fact, it is not possible to know when or how the clinical trial participants were provided or
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`took low-dose aspirin. It is also not possible to know the actual dosage of low-dose aspirin that
`
`the study participants actually took. Because of the lack of even the most elementary data on
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`low-dose aspirin use, Graham did not use this factor in any analyses. It is reasonable to conclude
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`that aspirin data were very limited, and that pill count data were never obtained to ensure that
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`patients actually took the low-dose aspirin.
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`47.
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`It is also noteworthy that low dose aspirin use is not listed in Table 2 as a
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`characteristic of the intent-to-treat population. We do not know if there is LDA balance or not
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`between the groups, although such data confirmation would be necessary to exclude
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`‘confounding’ when interpreting the trial’s data. A ‘confounding variable’ is a variable that has
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`an effect on the outcome. For example, in a hypothetical study looking at the relationship
`
`between physical activity and obesity levels, potential confounding variables would be age and
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`gender. If a confounding variable is distributed unequally among the groups being compared
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`(i.e., one treatment arm has a significantly higher number of elderly participants), this may
`
`introduce bias or suggest an alternative explanation to an observed correlation. Thus, in clinical
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`study design, it is imperative to identify all possible confounding variables at the outset. In my
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`experience, if a specific patient characteristic could possibly make a difference in the outcome, it
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`would be reported across treatment arms. This is not apparent in the Graham study. As shown
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`in Table 2, Graham reports the patient characteristics that were balanced across treatment arms—
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`but did not include any information regarding low-dose aspirin use. Because no data are
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`available to evaluate whether low-dose aspirin use was evenly balanced between treatment
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`groups at baseline, no scientifically valid conclusions about aspirin users can be drawn from this
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`paper.
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`48.
`
`I have reproduced Tables 1 and 2 below. From Table 2, it appears that the
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`treatment groups were well balanced at baseline (the “enrolled” patients) for the characteristics
`
`that Graham identified at the outset (including smoking, alcohol use, previous treatment, etc.).
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`Table 1 demonstrates, however, that the patients who withdrew from the trial were not evenly
`
`distributed across the four treatment groups. A higher percentage of patients withdrew from the
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`placebo and most notably, in the misoprostol arms. Even the authors noted this, reporting that
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`early withdrawals were significantly higher in the misoprostol group. (Ex. 1005 at 3.)
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`49. My experience in this disease area, reflected in my publications and in the general
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`area of clinical trials methodology, would indicate that differential early patient dropouts
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`between groups represent a major problem with the study, even putting the issues relating to
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`LDA usage aside. Usually, these patient dropouts are a special group precisely because they
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`dropped out early, and as a consequence, they are not similar to the remaining randomized
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`patients in the study. These different rates of patient withdrawals result in treatment groups that
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`are no longer comparable as a consequence of the randomization process. The reason that the
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`intent-to-treat population, defined as all subjects randomized, is the primary pre-specifed
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`population is that it carries the most weight of evidence. This is because the randomization
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`process distributes patients randomly among the four groups, which insures that there is no bias
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`among the groups at baseline. Bias is a form of systematic error introduced into a clinical trial
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`by selecting one outcome over others. Because the removal of randomized patients can
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`introduce bias, it is my opinion that any comparison of the resulting treatment groups is suspect
`
`because the imbalances could explain the results as opposed to the treatment group.
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`50.
`
`Graham does not report any comparative treatment data stratified by LDA use. In
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`other words, he does not compare treatment groups within LDA users and LDA non-users
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`separately. Given these significant analytical limitations of the study, a POSA could not have
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`relied on the Graham study to draw any conclusion about the interaction between NSAIDs,
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`proton pump inhibitors, and LDA usage. Further, a POSA could reach a false conclusion by
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`relying on the Graham study. For example, the non-compliance rate led to significant issues in
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`the interpretation of the results. Graham points out that, despite “the statistical advantage of
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`misoprostol over proton pump inhibitors for the prevention of ulcer relapse in long-term users of
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`NSAIDS, there is little, if any, practical advantage”. This is a speculation on the part of Graham,
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`and not supported by the data and its analysis as he himself admits.
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`51.
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`I’ve reviewed the declaration of Petitioner’s expert, Leon Shargel, Ph.D. He
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`made no attempt to review or assess the methodology of the Graham study, which is a
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`fundamental starting point in evaluating scientific publications.
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`B. GOLDSTEIN
`52.
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`The Goldstein publication represents a post-hoc subanalysis using the same data
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`reported in the Graham paper. Thus, Petitioners did not rely on two independent studies for
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`confirmatory purposes. Instead, they relied on one study with two populations, with the
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`Goldstein paper based on a very small subset of the entire intent-to-treat population in the
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`Graham paper. This reduces the weight of any conclusions drawn from this paper.
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`53.
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`Drawing from the group of 535 enrolled patients, Goldstein reports on just 70
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`patients (13%) who reported concomitant LDA usage at the beginning of the Graham study. As
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`described above, there is no indication how these patients were identified, how low-dose aspirin
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`usage was tracked or verified, or how or whether dosage was estimated.
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`54.
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`Goldstein concludes that for patients taking NSAIDs with LDA usage,
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`administration of misoprostol or lansoprazole reduced the risk of gastric ulcer compared to
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`placebo. Goldstein, however, does not describe any comparison between patients taking NSAID,
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`lansoprazole without LDA usage with patients taking NSAID, lansoprazole, but no LDA. Even
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`ignoring all of the shortcomings described below, Goldstein could not address the question now
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`being asked.
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`55.
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`Goldstein reports the following baseline demographics:
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`56.
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`It is noteworthy that the size of the four treatment groups ranged from 7 to 25.
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`These sample sizes are far too small to draw any meaningful conclusions. Prospectively
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`randomized clinical trials typically have hundreds of patients in each treatment arm. The reasons
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`for this are many, and include: 1) being able to make precise statements about the Type 1 error
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`(i.e., the false positive rate) and the Type 2 error (i.e., the false negative rate), and 2) being able
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`to obtain results that are ‘robust’ (i.e., a few changes in the outcome event will not have a
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`material effect on the outcome and interpretation of the study). For example, if there was only
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`one more male in the lansoprazole group, (i.e., 6 men and 1 woman, rather than the 5 men and 2
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`women reported in Table 2) then the proportion of males would increase from 71.4% to 85.7%.
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`This treatment group would have 23-36% more males than the other treatment groups, a marked
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`imbalance that would have a significant detriment on any scientifically valid comparison of these
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`groups. Thus, a small change to the very small sample sizes reported in Goldstein would have a
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`significant impact on the apparent results. As a result, one would be unable to differentiate
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`whether any observed between-group differences were due to treatment group as compared to
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`differences in gender.
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`57.
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`In designing a study, there is the ‘effect size’ that represents the ‘true difference’
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`of interest to detect. One also has the Type 1 error (i.e., the false positive rate, defined as the
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`probability of seeing a difference between groups although there is in truth no difference) and the
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`Type 2 error rate (i.e., the false negative rate, defined as the probability of seeing no difference
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`between groups although one truly exists). Type 1 error rates are usually set at 0.05 (1 in 20
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`chance of getting a falsely positive result), and Type 2 error rates are usually set at 0.20 or 0.10.
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`Taking the n = 7 for the lansoprazole group and n = 22 for the placebo group, detection of
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`between-group treatment differences of 10% would have a Type 1, false positive error rate
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`exceeding 85% (with a Type 2 error rate of 20%). And for a Type 1 error rate of 5%, the Type 2
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`error rate (false negative rate) exceeds 90%. The conclusion is that the exceedingly small sample
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`sizes in Goldstein provide totally unreliable results and no scientifically valid conclusions can be
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`drawn. The probability of reaching a false positive conclusion is in excess of 90% in my
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`example, an unacceptably high level. The error rates fall far outside the norms of accepted
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`clinical trial design and scientifically meaningful results. Typically, Type 1 error rates of 5% or
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`less, and Type 2 error rates of 20% or less, are required.
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`58.
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`The Type 2 error rate is the probability of saying that a treatment difference does
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`not exist, when the truth is that a difference exists between the groups. Such errors can arise for a
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`number of reasons, including biologic heterogeneity and the small sample sizes compared to all
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`people who are possible users. For example, we use aspirin when we have a headache. The
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`dosage is 2 full dose aspirin pills. But not everyone gets headache relief from taking two aspirin.
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`Some people need only one, some need two, some need three, and others may not get any
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`headache relief. So if a trial was done with a population drawn that never benefited form aspirin,
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`or had to take three pills for relief, then the trial would show no difference between the aspirin
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`users and non-users because the trial population by chance had mostly non-responders to aspirin.
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`But this would be a false negative result because we know that aspirin works most of the time, in
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`most people. It was only the biological heterogeneity of the particular population selected that
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`led to the negative trial outcome.
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`59.
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`For the reasons discussed above, the sample sizes confirm the presence of a
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`differential dropout rate, indicative of a corresponding imbalance among the groups with respect
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`to LDA usage. Until an analysis is performed to show this is not true, the correct presumption is
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`that an imbalance exists due to the substantial differences in sample size between treatment
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`grou