UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`GENERICO, LLC, and
`FLATLINE CAPITAL, LLC,
`Petitioners,
`
`v.
`
`DR. FALK PHARMA GmbH,
`Patent Owner.
`
`Case IPR2016-00297
`Patent No. 8,865,866
`
`
`
`DECLARATION OF ALAN VICTOR SAFDI, M.D., F.A.C.G.
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`TABLE OF CONTENTS
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`C.
`
`Background and Qualifications ....................................................................... 4
`I.
`Information Considered ................................................................................... 7
`II.
`III. Legal Principles ............................................................................................... 8
`IV. Summary of Opinions ...................................................................................... 9
`V.
`The ’688 Patent ................................................................................................ 9
`VI. The Person of Ordinary Skill in the Art ........................................................12
`VII. Claim Construction ........................................................................................14
`A.
`Paragraph [c]: “remission is defined as a DAI score of 0
`or 1” .....................................................................................................14
`VIII. Scientific Background and State of the Art ...................................................18
`B.
`Use of mesalamine to treat and maintain the remission of
`ulcerative colitis ..................................................................................18
`Oral mesalamine formulations commercially available to
`treat ulcerative colitis as of October 2008 ...........................................19
`Asacol® ......................................................................................19
`1.
`Pentasa® .....................................................................................20
`2.
`Lialda® .......................................................................................21
`3.
`Salofalk® Tablets .......................................................................21
`4.
`Salofalk® Granu-Stix® ...............................................................22
`5.
`D. Art as of October 2008 directed a person of ordinary skill
`towards the higher approved doses of commercially
`available oral mesalamine formulations to maintain
`remission of ulcerative colitis, and, in some studies,
`above and beyond those higher approved doses .................................23
`Despite compliance issues with commercially available
`mesalamine formulations as of October 2008 and a need
`for a simplified dosing regimen, no mesalamine
`formulation was approved for a once daily dose for
`maintenance of remission of ulcerative colitis ....................................27
`IX. CITED REFERENCES .................................................................................30
`A.
`Sept. 2007 Press Release .....................................................................30
`
`E.
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`X.
`
`Endonurse ............................................................................................31
`B.
`Davis-1985 ..........................................................................................31
`C.
`D. Marakhouski ........................................................................................32
`E.
`Brunner ................................................................................................32
`The Sept. 2007 Press Release, Endonurse, and Davis-1985, in
`View of Marakhouski or Brunner Do Not Render Claims 1 and
`16 of the ’688 Patent Obvious .......................................................................33
`A.
`Preamble and paragraphs [a] and [b]: “A method of
`maintaining the remission of ulcerative colitis in a
`subject comprising administering to the subject a
`granulated mesalamine formulation comprising four
`capsules each comprising 0.375 g of granulated
`mesalamine once per day in the morning” ..........................................34
`Paragraph [a]: “without food” .............................................................37
`Paragraph [c]: “remission is defined as a DAI score of 0
`or 1” .....................................................................................................44
`XI. Secondary Considerations of Nonobviousness .............................................47
`A.
`The unexpected result that granulated mesalamine could
`be administered without food ..............................................................47
`Long felt but unmet need for a low, once-daily dose of
`granulated mesalamine for the maintenance of remission
`of ulcerative colitis ..............................................................................51
`
`B.
`C.
`
`B.
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`I, Alan Victor Safdi, M.D., F.A.C.G., under penalty of perjury, declare as
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`follows:
`
`1.
`
`I have been retained by Womble Carlyle Sandridge & Rice LLP on
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`behalf of Dr. Falk Pharma GmbH (“Dr. Falk Pharma” or “Patent Owner”) in
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`connection with this action as an expert in the field of gastroenterology and more
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`particularly in the treatment of ulcerative colitis.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`2.
`
`I am a gastroenterologist practicing with the Ohio Gastroenterology
`
`and Liver Institute. I have practiced gastroenterology since July 1983 and have
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`over thirty-three years of experience in the field, with clinical expertise in
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`inflammatory bowel disease (“IBD”), including ulcerative colitis. I care for on
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`average over 30 patients a month with ulcerative colitis (both active and in
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`remission).
`
`3.
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`For the past twenty-eight years, I have served as the President for the
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`Ohio Gastroenterology and Liver Institute, and I am the President of Consultants
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`for Clinical Research, a position I have held since 1990. I am also Co-Chairman of
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`the Section of Inflammatory Bowel Disease for the Ohio GI and Liver Institute.
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`4.
`
`5.
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`I am board certified in gastroenterology.
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`I received my degree from Northwestern University in 1974, where I
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`was a member of the Phi Beta Kappa honor society, and I received my medical
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`degree from the University of Cincinnati College of Medicine in 1978, where I was
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`a member of the Alpha Omega Alpha Honor Medical Society and received honors
`
`in my Medical, Pediatric, and Surgical Clerkships.
`
`6.
`
`Following medical school, I completed my internship in Medicine and
`
`residency in Internal Medicine at University of California, San Diego in 1979 and
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`1981, respectively. I then completed a fellowship in gastroenterology at the
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`University of Cincinnati in 1983. During my fellowship, I obtained substantial
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`training in the diagnosis and treatment of IBD, including upper endoscopy,
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`colonoscopy, endoscopic biopsy, and sigmoidoscopy.
`
`7.
`
`I am a Fellow in the American College of Gastroenterology and a
`
`Diplomate of the American Board of Internal Medicine as well as a Diplomate of
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`the American Board of Gastroenterology.
`
`8.
`
`I am currently on the staff of Mercy West Hospital, Norwood
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`Endoscopy Center, Tri-State Endoscopy Center, and The Christ Hospital.
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`9.
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`In addition to my position as a clinician, I serve as Medical Director
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`of Tri-State Endoscopy Center (since 2005) and President of GCGA Physicians
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`(Ohio Gastroenterology and Liver Institute) (since 1988). I have also served as
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`President of Ohio Gastroenterology Society (2012-2014), Chairman of the Section
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`of Gastroenterology at Deaconess Hospital (1986-2011), and Chairman of the
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`Cincinnati Crohn’s & Colitis Medical Advisory Committee (2007-2010).
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`10.
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`I am a member of various professional societies, including the
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`American Society of Internal Medicine, the American Society for Gastrointestinal
`
`Endoscopy, Ohio Gastroenterology Society, Ohio State Medical Association,
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`Digestive Disease National Coalition, and The American Gastroenterology
`
`Association.
`
`11.
`
`I have also actively conducted research in my field of practice,
`
`participating as a principal investigator in approximately 132 clinical research
`
`projects and as a sub-investigator in approximately 439 clinical research projects,
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`including a number of studies regarding the treatment of IBD and the use of
`
`mesalamine in the treatment of ulcerative colitis.
`
`12. During my professional career, I have published extensively as the
`
`principal investigator or sub-investigator on research topics related to
`
`gastroenterology, IBD, Crohn’s disease, and ulcerative colitis. My research articles
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`have appeared in peer-reviewed journals such as the American Journal of Medicine
`
`and the American Journal of Gastroenterology.
`
`13.
`
`In addition, I have presented my research at the American College of
`
`Gastroenterology and Digestive Disease Week meetings, have been an invited
`
`lecturer at numerous university group practices and medical organizations, and
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`have served on the committee for investigator initiated studies on IBD.
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`14.
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`I have performed studies on a variety of mesalamine drugs including
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`Apriso®. I have performed studies involving dissolution of pH-dependent
`
`mesalamine in the form of Asacol®. I have been involved with Salix
`
`Pharmaceuticals, Inc. (“Salix”) as well as a number of other pharmaceutical
`
`companies as a consultant, researcher, and speaker bureau representative. I have
`
`also been involved in investigator-initiated studies with Salix and other
`
`pharmaceutical companies.
`
`15.
`
`I have maintained my well-regarded position in the field of
`
`gastroenterology, in part, by staying as up to date as possible on the medical
`
`advances in my field. In addition to attending various annual meetings of clinicians
`
`and researchers, I also routinely read peer-reviewed journals such as the American
`
`Journal of Gastroenterology, New England Journal of Medicine, Inflammatory
`
`Bowel Diseases, and Gut. I also read internet updates from a variety of sources
`
`almost daily.
`
`16. My curriculum vitae is attached as Exhibit A.
`
`17. On the basis of my education and experience described above, I
`
`believe I am qualified to give the opinion set out herein.
`
`II.
`
`INFORMATION CONSIDERED
`
`18. The opinions expressed in this declaration are based on my review of
`
`U.S. Patent No. 8,865,688 (“the ’688 patent”), the Petition for Inter Partes Review
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`of U.S. Patent No. 8,865,688 under 35 U.S.C. §§ 311 et seq. and 37 C.F.R.
`
`§ 42.100 et seq. (“Petition”) by Petitioners GeneriCo, LLC and Flat Line Capital,
`
`LLC (“Petitioners”) and Exhibits to the Petition, including the declaration of
`
`George A. Digenis, Ph.D. (Ex. 1002). I have also reviewed the transcript of Dr.
`
`Digenis’s cross-examination (Ex. 2032) and the Decision Institution of Inter Partes
`
`Review 37 C.F.R. § 42.08 (“Board Decision”). In arriving at my opinions, I have
`
`relied on my education and professional experience, information in various
`
`resource materials and scientific literature discussed herein, and my general
`
`knowledge of the art in the relevant time frame. As discussed below, I disagree
`
`with Dr. Digenis’s conclusions that claims 1 and 16 of the ’688 patent are invalid
`
`based on obviousness.
`
`III. LEGAL PRINCIPLES
`
`19.
`
`I have been informed by counsel that an obviousness analysis involves
`
`a review of the scope and content of the prior art, the differences between the prior
`
`art and the claimed subject matter, the level of ordinary skill in the art, and
`
`objective indicia of non-obviousness, such as whether the claimed invention
`
`satisfies a recognized but unmet need or whether the claimed invention provides
`
`unexpected benefits. I understand that for an invention to be regarded as obvious, a
`
`person of ordinary skill in the art must have had a reason to modify the prior art or
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`to combine one or more prior art references in a manner that would result in the
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`claimed subject matter with a reasonable expectation of success.
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`IV. SUMMARY OF OPINIONS
`
`20.
`
`I understand that the Board has granted the Petition to institute an
`
`inter partes review of the ’688 patent (Ex. 1001) on the following ground: Claims
`
`1 and 16 under 35 U.S.C. § 103 as obvious over the Sept. 2007 Press Release (Ex.
`
`1012), Endonurse (Ex. 1014), and Davis-1985 (Ex. 1009) in view of Marakhouski
`
`(Ex. 1024) or Brunner (Ex. 1025).
`
`21. Based on my study of the ’688 patent and the additional materials
`
`referenced herein, and my own knowledge and experience, it is my opinion that the
`
`subject matter claimed in claims 1 and 16 of the ’688 patent would not have been
`
`obvious to a person of ordinary skill in art over the cited prior art.
`
`V. THE ’688 PATENT
`
`22. The ’688 patent is entitled, “Compositions and Methods for Treatment
`
`of Bowel Diseases with Granulated Mesalamine.” I understand Dr. Falk Pharma is
`
`the owner by assignment of the ’688 patent. I further understand that Salix was the
`
`original assignee and current exclusive licensee of the ’688 patent.
`
`23.
`
`I understand that the ’688 patent has a priority date of October 3,
`
`2008. I further understand that the date of the invention could be as early as May
`
`21, 2004 or as late as October 11, 2007.
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`24.
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`In general, the ’688 patent is directed to a method of maintaining
`
`remission of ulcerative colitis by administering a 1.5 g dose of a granulated
`
`mesalamine formulation once daily in the morning without food. (See, e.g., Ex.
`
`1001, ’688 patent at claims.)
`
`25. The specification of the ’688 patent describes two Phase III clinical
`
`studies in which subjects in remission from ulcerative colitis were randomized to
`
`receive either a 1.5 g granulated mesalamine formulation or placebo once daily in
`
`the morning for six months. (Id. at 17:1-35 (Example 5, Table 2).) In both studies,
`
`the proportion of subjects who remained relapse-free at six months was greater for
`
`the granulated mesalamine formulation than for placebo, where relapse-free was
`
`defined as rectal bleeding subscale score of 0 and a mucosal subscale score of 0 or
`
`1 using the DAI. (Id.; see also id. at Figures 1–3; 6:43–7:25 (summarizing results
`
`of phase III studies discussed in Examples); 16:1–25 (Example 2); 25:14–33:64
`
`(Examples 8–11, Tables 10–14).)
`
`26. The ’688 patent also describes pharmacokinetic studies comparing
`
`absorption of mesalamine granules: (1) administered once and twice daily; and (2)
`
`administered under fed and fasted conditions. (Id. at 7:26–31; id. at 14:58–15:5
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`(Example 1—evaluation of effect of a high fat meal intake on absorption of
`
`mesalamine granules); id. at 16:47–67 (Example 4—effect of food on absorption
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`and disposition of granulated mesalamine formulations); id. at 17:38–21:15
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`(Example 6—comparison of once daily (QD) to twice daily (BID) administration).)
`
`27. Claim 1 of the ’688 patent is reproduced below and broken into
`
`paragraphs with bracketed lettering for ease of reference (as was done in the Board
`
`Decision at 4):
`
`1.
`
`A method of maintaining the remission of ulcerative colitis in a
`
`subject comprising
`
`
`
`[a] administering to the subject a granulated mesalamine
`
`formulation comprising four capsules each comprising 0.375 g of
`
`granulated mesalamine once per day in the morning, without food,
`
`wherein:
`
`
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`[b] said method maintains remission of ulcerative colitis in a
`
`subject for a period of at least 6 months of treatment;
`
`
`
`
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`[c] remission is defined as a DAI score of 0 or 1;
`
`[d] the granulated mesalamine formulation is not administered
`
`with antacids; and
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`
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`[e] wherein 85% to 90% of the mesalamine reaches the terminal
`
`ileum and colon.
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`(Ex. 1001, ’688 patent at 34:10-22 (claim 1).) Claim 16 is nearly identical to claim
`
`1 except that claim 16 recites an additional step, “advising the subject that
`
`granulated mesalamine should not be taken with antacids.” (Compare id., with id.
`
`at 35:4-17 (claim 16).)
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`VI. THE PERSON OF ORDINARY SKILL IN THE ART
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`28. Dr. Digenis opines that the person of ordinary skill in the art “would
`
`typically hold an advanced degree in the chemical or pharmaceutical fields (such
`
`as chemistry, polymer chemistry, pharmaceutics or pharmacokinetics), or a
`
`bachelor’s degree combined with several years of experience in these fields, or
`
`alternatively, an M.D. with several years specializing in the treatment of
`
`gastrointestinal disorders.” (Ex. 1002, Digenis Declaration at ¶ 14.)
`
`29.
`
`I disagree with Dr. Digenis’s opinion to the extent that that the person
`
`of ordinary skill in the art can solely be a person who “typically holds an advanced
`
`degree in the chemical or pharmaceutical fields or a bachelor’s degree combined
`
`with several years of experience in these fields.” I have reviewed the ’688 patent
`
`which, as described above, is a method of treatment patent claiming a method of
`
`maintaining remission of ulcerative colitis for at least 6 months by administering a
`
`1.5 g dose of a granulated mesalamine formulation once daily in the morning
`
`without food. The ’688 patent is not directed to novel mesalamine formulations
`
`and thus is not directed to a formulator. Rather, the ’688 patent is directed to
`
`clinicians with experience treating ulcerative colitis.
`
`30. More specifically, in my opinion, based on the disclosures in the ’688
`
`patent, the person(s) of ordinary skill to whom the ’688 patent is directed would be
`
`a physician with a medical degree with experience diagnosing, treating, and/or
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`prescribing medication to treat patients suffering from ulcerative colitis, and
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`similar diseases and conditions. If the physician does not have experience with
`
`interpreting or understanding pharmacokinetics, the person(s) of ordinary skill may
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`also include individuals who have an advanced degree in pharmacy or
`
`pharmaceutics with practical experience associated with ulcerative colitis.
`
`31.
`
`I am and have been a person of ordinary skill in the art as of the
`
`priority date of the ’688 patent under both Dr. Digenis’s definition and my
`
`definition of the person of ordinary skill in the art. However, based on my review
`
`of Dr. Digenis’s curriculum vitae and his deposition transcript, Dr. Digenis is not a
`
`person of ordinary skill in the art under my definition at least because he is not a
`
`medical doctor, did not go to medical school, does not have a medical degree, has
`
`not been trained to diagnose or treat ulcerative colitis or other diseases, is not
`
`licensed to treat patients, is not licensed to prescribe medicine, and does not have
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`any experience diagnosing, treating, and/or prescribing medication to patients who
`
`suffer from ulcerative colitis or other gastroenterological conditions (Ex. 2032,
`
`Digenis Tr. at 20:6-21:14.) Instead, Dr. Digenis admitted that his expertise is as a
`
`medicinal chemist, and he has spent his entire career in academics. (Id. at 19:22-
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`24; 20:3-5.)
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`VII. CLAIM CONSTRUCTION
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`
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`A.
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`Paragraph [c]: “remission is defined as a DAI score of 0 or 1”
`
`32. Based on my review of the ’688 patent, the ’688 patent prosecution
`
`history, and my education, knowledge, and experience as practicing
`
`gastroenterologist, the term “remission is defined as a DAI score of 0 or 1” as used
`
`in claims 1 and 16 of the ’688 patent means “remission is defined as a rectal
`
`bleeding subscore of 0 and a mucosal appearance subscore of less than 2 using
`
`the DAI.”
`
`33. As described above, the specification describes, in part, the results of
`
`two independent, randomized, double-blind, placebo-controlled trials conducted in
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`562 adult subjects in remission from ulcerative colitis. (See, e.g., Ex. 1001, ’688
`
`patent at 6:43-60; 17:1-38.) The patients were randomized to receive 1.5 g
`
`mesalamine in capsules, or a placebo, once daily for six months. (Id. at 6:57-58;
`
`17:13-15.) The primary efficacy endpoint was the proportion of patients who
`
`remained relapse-free (i.e., maintained remission) after 6 months of treatment. (Id.
`
`at 6:58-60; 17:18-21.) The results in both studies demonstrated that the proportion
`
`of subjects who remained relapse-free at six months was greater for the granulated
`
`mesalamine formulation than for placebo. (Id. at 17:21-23.)
`
`34. As described in the specification (see, e.g., id. at 25:32-35; 26:21-24
`
`and 51-53; 28:3-8; 33:27-31), ulcerative colitis disease activity was assessed in
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`these clinical trials using a modified Sutherland Disease Activity Index (“DAI”),
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`which is a “sum of a four subscores based on stool frequency, rectal bleeding,
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`mucosal appearance on endoscopy, and physician’s rating of disease activity. Each
`
`subscore can range from 0 to 3, for a total possible DAI score of 12.” (Id. at 17:7-
`
`12.)
`
`35. The specification further describes the DAI parameters used in the
`
`clinical trials to define “remission” (i.e., “relapse-free”) and, alternatively,
`
`“relapse.” Specifically, the “Detailed Description” of the invention states, “patients
`
`with documented UC remission (revised Sutherland Disease Activity Index
`
`[DAI] subscores: rectal bleeding 0; mucosal appearance < 2) were randomized
`
`2:1 to receive 1.5 g granulated mesalamine in capsules, or a placebo, once daily for
`
`6 months.” (Id. at 6:53-58 (emphasis added).) Thus, patients who entered the trials
`
`were in remission if they had a rectal bleeding subscore of 0 and a mucosal
`
`appearance subscore of less than 2.
`
`36. The “Detailed Description” of the invention further states that “[t]he
`
`primary efficacy endpoint was the proportion of patients who remained relapse
`
`free after 6 months of treatment (relapse defined as a rectal bleeding subscore ≥
`
`1 and a mucosal appearance subscore ≥ 2 per DAI; UC flare or UC symptoms
`
`leading to withdrawal; or initiated medication used to treat UC).” (Id. at 6:53-60
`
`(emphasis added).) Likewise, Example 5 of the ’688 patent states:
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`Relapse, as used herein, included, for example, a rectal bleeding
`subscale score of 1 or more and a mucosal appearance subscale
`score of 2 or more using the DAI. The analysis of the intent-to-treat
`
`population was a comparison of the proportions of subjects who
`remained relapse-free at the end of six months of treatment. In both
`studies, the proportion of subjects who remained relapse-free at six
`
`months was greater for granulated mesalamine formulation than for
`
`placebo.
`
`(Id. at 17:15-23 (emphasis added); see also id. at 26:56-58 (Example 9); 28:60-62
`
`(Example 10) (similarly defining relapse).)
`
`37. Numerous Examples in the ’688 patent further describe the clinical
`
`trials assessing maintenance of remission over a 6 month treatment period and
`
`similarly define remission. (See id. at 25:32-35 (Example 8); 26:21-24 & 51-53
`
`(Example 9); 28:3-8 (Example 10); 33:27-31 (Example 11).)
`
`38. Thus, the specification defines relapse in terms of the two objective
`
`DAI subscores—a rectal bleeding subscale score of 1 or more and mucosal
`
`appearance subscale score of 2 or more. A person of ordinary skill in the art would
`
`understand that relapse is the opposite of remission (i.e., relapse free) such that
`
`remission would require a rectal bleeding subscale score of 0 (because relapse
`
`required a subscale score of 1 or more) and a mucosal appearance subscale score of
`
`less than 2 (because relapse required a subscale score of 2 or more). As described
`
`above, this is consistent with how remission was defined in the patients with
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`documented ulcerative colitis in remission that entered the trials. The use of
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`objective criteria, as opposed to subjective (e.g., stool frequency and physician
`
`assessment), is also consistent with my clinical practice, and, in my experience, the
`
`practice of others in my field. As a treating physician, my focus is on objective
`
`components as opposed to patient memory or physician impressions that are
`
`subject to ambiguity. Further, only an experienced endoscopist would be able to
`
`interpret a mucosal scoring index adequately. A person that has never participated
`
`in the care of patients with ulcerative colitis would not be qualified to interpret
`
`mucosal scoring.
`
`39. Thus, in my opinion, the term “remission is defined as a DAI score of
`
`0 or 1” in claims 1 and 16 of the ’688 patent means “remission is defined as a
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`rectal bleeding subscore of 0 and a mucosal appearance subscore of less than 2
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`using the DAI.”
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`40. Further, in my opinion, it would be improper to read “remission is
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`defined as a DAI score of 0 or 1” in claims 1 and 16 and assume that it means a
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`DAI score of 0 or 1 based on the sum of all four DAI subscores. A person of
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`ordinary skill in the art would understand that the definition of remission can vary
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`among clinical trials and thus would look to the specification for information of
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`how remission was defined in each clinical trial. The specification consistently
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`describes that remission in the two clinical trials assessing efficacy was defined as
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`limited to a rectal bleeding subscore of 0 and a mucosal appearance subscore of
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`less than 2. Thus, a person of ordinary skill in the art would understand that
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`remission as claimed was limited in the same respect.
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`VIII. SCIENTIFIC BACKGROUND AND STATE OF THE ART
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`B. Use of mesalamine to treat and maintain the remission of
`ulcerative colitis
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`41. Ulcerative colitis is a chronic gastrointestinal disorder wherein the
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`inner lining of the colon becomes inflamed. Mesalamine (i.e., 5-aminosalicylic
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`acid, 5-ASA, or mesalazine) is an anti-inflammatory drug used to treat
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`inflammatory bowel diseases, including ulcerative colitis. Mesalamine is also a
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`locally-acting or topically active drug, which means that it must make physical
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`contact with the inflamed intestinal mucosa to reduce inflammation. “Unprotected”
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`mesalamine is quickly absorbed into the bloodstream in the upper gastrointestinal
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`tract, including the stomach and the small intestine. Once absorbed, mesalamine is
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`metabolized into a non-therapeutic metabolite—N-acetyl-5-aminosalicylic acid, or
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`N-ac-5-ASA. Controlling the release of mesalamine is necessary to maximize the
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`delivery of mesalamine to the targeted regions of the gastrointestinal tract while
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`minimizing systemic absorption of mesalamine in the upper intestinal tract.
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`Absorption of mesalamine in the upper intestinal tract lowers the amount of
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`mesalamine being delivered to the inflamed areas of the colon, thereby reducing
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`therapeutic efficiency.
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`C. Oral mesalamine formulations commercially available to treat
`ulcerative colitis as of October 2008
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`42.
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`In October 2008, there were numerous oral mesalamine formulations
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`commercially available within and outside of the United States. For example,
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`Asacol® (delayed-release mesalamine tablets); Pentasa® (controlled-release
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`mesalamine capsules) and Lialda® (delayed and extended release mesalamine
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`tablets) were available in the United States, while Salofalk® Tablets (delayed-
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`release mesalamine tablets) and Salofalk® Granu-Stix® (delayed and extended
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`release mesalamine pellets) were available outside the United States.1
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`1.
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`Asacol®
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`43. Asacol® was a delayed-release mesalamine formulation that was
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`approved by the FDA in January 1992. Asacol® was administered orally in the
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`form of a tablet. (Ex. 2001, 2009 Asacol PDR at 2579.) Asacol® delayed-release
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`1 In my opinion, a person of ordinary skill in the art would have considered
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`Salofalk® Granu-Stix® and Lialda® to be the closest to Salix’s granulated
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`formulation because, like Salix’s formulation, they were both delayed and
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`extended release mesalamine formulations. However, Salofalk® Granu-Stix® had to
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`be administered three times a day which in my opinion corresponds to
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`administration with food, and Lialda, though once daily, was indicated to be
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`administered with a meal for the induction of remission.
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`tablets were coated with a pH-dependent polymer, Eudragit® S, which was
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`intended to dissolve at pH 7 or greater. (Id.) As of October 2008, Asacol® was
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`indicated for the treatment of mildly to moderately active ulcerative colitis and for
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`the maintenance of remission of ulcerative colitis. (Id.) For the treatment of mildly
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`to moderate active ulcerative colitis, the recommended adult dosage was two 400
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`mg tablets taken three times a day for a total daily dose of 2.4 g for a duration of
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`six weeks. (Id. at 2580.) For the maintenance of remission of ulcerative colitis, the
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`recommended dosage in adults was 1.6 g daily in divided doses (two 400 mg
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`tablets twice daily). (Id.)
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`2.
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`Pentasa®
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`44. Pentasa® is a controlled release mesalamine formulation that was
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`approved by the FDA in May 1993. Pentasa® is administered orally in the form of
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`a capsule, and each capsule contains numerous controlled-release beads. (Ex. 2004,
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`2009 Pentasa PDR at 3030-31.) As of October 2008, Pentasa® was indicated for
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`the induction of remission and for the treatment of patients with mild to moderately
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`active ulcerative colitis. (Id. at 3030.) The recommended dosage was 4 g of
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`mesalamine daily, taken in four separate doses of 1 g each (either four 250 mg
`
`capsules four times a day or two 500 mg capsules four times a day). (Id. at 3031)
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`3.
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`Lialda®
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`45. Lialda® is a delayed and extended release mesalamine formulation
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`that was approved by the FDA in January 2007. Lialda® is an orally-administered
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`tablet that is coated with a pH dependent polymer that breaks down at about pH 7.
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`(Ex. 2044, 2009 Lialda PDR at 3029.) Each Lialda® tablet contains 1.2 g of
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`mesalamine in an enteric coated tablet form. (Id.) As of October 2008, Lialda® was
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`indicated for the induction of remission of active, mild to moderate ulcerative
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`colitis. (Id.) The dosing for the Lialda® induction indication was two to four 1.2 g
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`tablets, once per day, with a meal, for a total mesalamine intake of 2.4 to 4.8 g per
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`day. (Id. at 3030.)
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`4.
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`Salofalk® Tablets
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`46. Salofalk® Tablets were first commercialized in Germany in 1984 by
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`Dr. Falk Pharma. Salofalk® Tablets were not and are not commercially available in
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`the United States. Salofalk® Tablets were a delayed-release mesalamine
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`formulation administered orally. (Ex. 2008, Falk Brochure at 39, 51.) As of
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`October 2008, Salofalk® Tablets were indicated for the treatment of acute
`
`ulcerative colitis and for the recurrence prophylaxis (i.e., maintenance of remission
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`of ulcerative colitis). (Id. at 51.) In the case of an acute attack, the practice manual
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`instructed that two 250 mg tablets to two 500 mg tablets should be taken three
`
`times a day for a total daily dose of 1.5 to 3 g. (Id.) For the maintenance of
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`remission of ulcerative colitis, the recommended dosage was 1.5 g daily in divided
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`doses (two 250 mg tablets three times a day or one 500 mg tablet three times a
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`day). (Id.) Tablets were taken one hour before meals with pl