1
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TORRENTAPOTEX, INC. and MYLAN
`PHARMACEUTICALS LTDINC., Petitioner
`
`_
`
`Petiti
`oners
`v.
`
`NOVARTIS AG AND MITSUBISHI PHARMA CORPORATION,
`
`Patent
`OwnerOw
`ners
`
`Inter Partes Review No.: 2014-00784To
`Be Assigned
`
`U.S. Patent No.
`8,324,283
`
`DECLARATION OF JOHN S. KENTARTHUR KIBBE, PH.D
`
`Exhibit
`
`TORRENT – 1004
`
`Petition for Inter Partes Review
`
`Of U.S. Patent 8,324,283
`
`iiiB
`
`Torrent et al. v. Novartis
`IPR2014-00784/IPR2015-00518
`Novartis 2058
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`2
`
` I, John S. KentArthur Kibbe, Ph.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am a consultant on pharmaceutical development issues with more than
`
`I am a Professor of Pharmaceutical Sciences at the Nesbitt School of Pharmacy,
`1.
`Wilkes University. I am also the past Chair of the Department of Pharmaceutical Sciences in
`the School of Pharmacy.
`
`25 years of experience in all phases of new product and formulation development.
`
`I earned a B.S.Bachelor of Science degree in Pharmacy from Columbia University
`2.
`in 1966, a Master of Science degree in Pharmacy from the University of WisconsinFlorida in
`19651968, and amy Ph.D. in PharmacyPharmaceutics from the University of WisconsinFlorida in
`1969.
`
`From 1969 to 1989, I worked at Syntex within the Institute of Pharmaceutical Sciences
`3.
`(“Syntex”) (now Roche Bioscience) in various areas of pharmaceutical development and
`formulation. From 1969 to 1977, I served as a staff researcher in Syntex’s Dosage Design
`Department. From 1977 to 1979, I was a senior staff researcher in the Veterinary Pharmaceutical
`Development Department. From 1979 to 1981, I was the head of the Pharmaceutical
`Development Department (Systemic and Veterinary). From 1981 to 1984, I served as the head of
`the Human Pharmaceutical Development Department (Systemic). I was appointed director of
`Syntex’s pharmaceutical development in 1984. In my capacity as director of pharmaceutical
`development, I was responsible for the successful design and formulation of human
`pharmaceutical products, including numerous solid dosage forms suitable for oral administration.
`
`4.
`
`Following my position at Syntex, I became Vice President of
`
`1973. My areas of concentration at that time were pharmaceutics, pharmacokinetics and
`biopharmaceutics. My dissertation was on the stability of solid dosage forms.
`
`I joined the faculty of the Department of Pharmaceutical Sciences at Wilkes
`3.
`University as its Chair in 1994. In that capacity, I oversaw the construction of the laboratory and
`research space in the then-new School of Pharmacy. In 2013
`
`I stepped down as department chair but continue to teach undergraduate and professional courses
`in pharmaceutics (dosage form design and manufacture) and pharmacokinetics. I was chair of the
`faculty for the University from 2007 to 2010. I am also a member of the Pharmacy School’s
`curriculum committee and assessment committee.
`
`I have held a variety of positions in academia, industry and the government over
` 4.
`the course of my career. My work has been largely concentrated in the fields of pharmaceutical
`formulation development, pharmacokinetics, pharmaceutical testing, and drug regulatory and
`approval processes.
`
`Pharmaceutical Sciences at Allergan, Inc., a position that I held from 1990 to 2002.
`
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` While at Allergan, I supervised the research and development of new pharmaceutical products,
`establishing new preformulation techniques to enhance the company’s formulation
`development. I also oversaw the areas of pharmaceutical analysis, quality assurance, and
`clinical manufacturing throughout the formulation process.
`
`From 20021972 to 20041984, I worked as a pharmaceutical development
`5.
`consultant on formulation development and manufacturing issues for a number of small and large
`pharmaceutical companies.was an Assistant/Associate Professor of Pharmaceutics at the School
`of Pharmacy of the University of Mississippi. While at the University of Mississippi, I taught
`undergraduate and graduate level courses in the areas of formulation design and development,
`pharmacokinetics, and the physical chemistry of heterogeneous systems; conducted research in
`those areas, among others; and served as a thesis advisor to Ph.D. candidates.
`
`From 2004 to 2008, I served as the Vice President of Pharmaceutical Sciences in the
`6.
`area of technical operations at Theravance, Inc. At Theravance, I oversaw the pharmaceutical
`product development program primarily involving the development and manufacturing of a
`lyophilized injectable dosage form, Vibativ®, and supervised pharmaceutical development teams
`to ensure the plan for future development and drug formulation included the appropriate science,
`e.g., QbD, Quality by Design.
`
`From 2008 through the present, I have been serving as a consultant for
`7.
`pharmaceutical companies primarily in the areas of pharmaceutical and formulation
`development, and as an expert witness.
`
`I am the named inventor or co-inventor of 18 pharmaceutical patents, some of
`8.
`which are directed to formulations of solid oral dosages.
`
`I served as the Chief of Pharmaceutical Development Services for the National
`6.
`Institutes of Health (NIH) in 1984-1985. In that position, I directed a staff of 15 scientists,
`developed delivery systems for Phase I clinical trials and supported the internal NIH clinical
`research program.
`
`As the Senior Director of Professional and Scientific Affairs for the American
`7.
`Pharmaceutical Association from 1987-1992, my responsibilities included the development of
`policy statements on relevant scientific issues; the representation of the Association before
`Congress and the Food and Drug Administration (FDA); the development and management of
`symposia on scientific issues; the management of various professional staff; and the
`
` management of the Journal of Pharmaceutical Science. While with the American
`Pharmaceutical Association, I served as the Chair of a special panel appointed by the
`Commissioner of the FDA to investigate the generic drug approval process. The work of this
`special panel produced a report entitled “Fairness in the Generic Drug Approval Process,”
`sometimes referred to as “The Kibbe Report.”
`
`My experience also extends to the pharmaceutical industry. I was the Director of
`8.
`Client Services for BioResearch Laboratories, Ltd. from 1985-1987, where I negotiated the
`protocol design and contracts for hundreds of Phase I studies and bioequivalency studies. I was
`also the Director of Marketing for Pharmakon Research International, Inc. from 1992-1994,
`where I negotiated the protocol design and contracts for numerous preclinical trials.
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`4
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`I have authored and co-authored more than 30 articles on drug design and the
`9.
`development of drug delivery systems including solid oral dosage formulations, which have
`been published in peer-reviewed journals includingam a Fellow of the Academy of
`Pharmaceutical Research and Science, and have served on various editorial boards. I presently
`serve on the Editorial Review Panel of the Journal of the American Chemical Society, Drug
`Development and Industrial Pharmacy, and as a Reviewer for the Journal of Pharmaceutical
`SciencesScience and the Journal of the American Pharmacists Association.
`
`I was the Chair of the FDA Pharmaceutical Sciences Advisory Committee (2002
`10.
`to 2004) and its subcommittee on current good manufacturing practice (cGMP) and process
`analytical technology (PAT). I continued as a member of this Advisory Committee until 2006. I
`have also served as a scientific
`
` consultant to the Subcommittee on Oversight and Investigations of the Committee on Energy
`and Commerce of the United States House of Representatives. I have also served as a member of
`the FDA’s Generic Drug Advisory Committee.
`
`I have authored or co-authored numerous papers in refereed journals, have written
`11.
`a number of essays and articles published in the professional press, and have made a number of
`presentations before national and international professional societies.
`
`I co-authored the “Generic Drugs and Generic Equivalency” chapter in the
`12.
`Encyclopedia of Pharmaceutical Technology (1st Ed. 1993) and authored that chapter in the two
`subsequent editions of the Encyclopedia of Pharmaceutical Technology. As an invited guest
`speaker, I have lectured on the generic drug approval process.
`
`1013. I am currently a member of the American Associationserved as the Editor-in-Chief
`of the Handbook of Pharmaceutical Scientists, and was formerly Committee Chairman of the
`organization from 1988 to 1989. I have also been a member of multiple organizations related to
`pharmaceutical development and drug design, including the Controlled Release Society and
`APhA Academy of Pharmaceutical Sciences. I was a member ofExcipients (3rd Ed. 2000) and
`authored a number of the monographs contained therein. This is a standard reference text widely
`used by pharmaceutical formulators. I have served on the Steering Committee for PhRMA,the
`Handbook of Pharmaceutical Development Subsection, fromExcipients since its second edition
`published in 1994 and continue to do so to this date. I have also authored a chapter entitled
`“Theory of Dissolution” in the book, Dissolution Theory, Technology & Methods, edited by
`Anthony Palmieri III.
`
`1987 to 1989 and from 2000 to 2002. I was also elected Chairman of the Northern
`
`During the course of my career, I have received several awards and honors,
` 14.
`including recognition for my contributions to the training of pharmacy students. I have had the
`privilege of instructing students in pharmaceutical formulation for over 25 years.
`
`California Pharmaceutical Discussion Group from 1977 to 1978.
`
`1115. A more detailed account of my work experience, professional services, patents,
`publications, and other qualifications is listed in my Curriculum Vitae, which is attached hereto
`as Appendix A.
`
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`5
`
`1216. I have been retained by counsel for Petitioner Torrent PharmaceuticalsPetitioners
`Apotex, Inc. andLtdMylan Pharmaceuticals Inc. to provide an expert declaration in this
`action.
`
`13.
`
`As set forth in more detail below, the patent at issue here, U.S. Patent No.
`
`8,324,283, relates generally to the formulation of a solid oral dosage containing an
`
` active pharmaceutical compound and at least one excipient. Similar to the patent at
`issue, my previous research and industry experience focused on the design and formulation of
`pharmaceutical dosages suitable for oral administration including, for example, Aleve®.17.
`The opinions and conclusions I express in this declaration are based on my
`education, my extensive experience in this field, and my review of the materials related to this
`matter.
`
`1418. I am being compensated at my customary consulting rate for my time spent on this
`matter, and I am also being reimbursed for reasonable expenses incurred with respect to this
`matter. My compensation is not contingent on the conclusions I reach herein or on the specifics of
`my testimony. I have no financial stake in the outcome of this proceeding.
`
`II. MATERIALS REVIEWED
`
`1519. In forming my opinions, I have reviewed, among other thingsdocuments, U.S. Patent
`8,324,283 (“the ’283 patent”) and papers filed in the Patent Office in connection with
`prosecution of the ’283 patent, which I understand to constitute the prosecution history of the
`’283 patent. I have also reviewed the petition, the Board’s decision and related documents in
`IPR2014-00784 (the “Torrent IPR”). I note that I agree with the analysis and opinions set forth
`by the petitioner’s expert, Dr. Kent, in the declaration that was submitted in the Torrent IPR
`proceeding and share many of those same opinions below. Because my independent analysis of
`the claims and prior art led to the same conclusions as the expert in the Torrent IPR, I have
`incorporated many of his arguments and characterizations below as my own. A full list of
`materials I have considered can be found in Appendix B.
`
`III. LEGAL STANDARDS
`
`1620. In this section I describe my understanding of certain legal standards. I I have been
`informed of these legal standards by Petitioner’sPetitioners’ attorneys, who have
`
` supplied me with The Federal Circuit Bar Association’s Model Patent Jury Instructions. I am not
`an attorney, and I am relying only on instructions from Petitioner’sPetitioners’ attorneys for these
`legal standards. I have applied these understandings in my analysis as detailed below.
`
`I understand that in order to receive a patent an inventor must invent or discover a
`17.
`new and useful process, machine, manufacture, or composition of matter.
`
`I understand that patent protection may be granted for any new and useful process,
`18.
`machine, manufacture, or composition of matter, or any new and useful improvement thereof.
`
`19. With respect to the level of ordinary skill in the art at the relevant times applicable to
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`the ’283 patent, I understand that factors such as the education level of those working in the
`field, the sophistication of the technology, the types of problems encountered in the art, the
`prior art solutions to those problems, and the
`
`speed at which innovations are made may help establish the level of skill in the art.
`I understand that one with ordinary skill has the ability to understand the
`One21.
`technology and make modest adaptations or advances. A person of ordinary skill in the art is
`also a person of ordinary creativity, not an automaton.
`
`22.
`
`I agree with Dr. Kent that a person of ordinary skill in the art
`
`(“POSA”) at the time of the alleged invention of the ’283 patent would have been
`
`In my opinion, a person of ordinary skill in the art (“POSA”) at the time of the
`20.
`alleged invention would have been an individual with a high level of
`
` education and skill, including a Pharm.D. or a Ph.D. in pharmacy, chemical engineering,
`chemistry, or related discipline, and at least two years of formulation development work or
`research experience in the area of formulating oral dosage forms, which would include tablets
`and capsules, or an M.S. and at least five years additional commensurate experience. The
`individual would have a substantive understanding of other dosage forms such as topically
`administered products and injectable or parenteral products. A person of ordinary skill in the art
`would collaborate with others having expertise in, e.g., (i) methods
`
`of treating disease and administering medicines and (ii) analytical chemistry.
`
`2123. In determining the qualifications of a POSA I considered, among other
`factors, the field of the alleged invention and use thereof described in the
`
`’283 patent, and my experience with the educational level of practitioners in therelated
`fieldsof pharmacy, analytical chemistry, organic chemistry, or chemical engineering. In
`addition, my opinion is based upon my background, education, and personal experience
`devoted toin the fieldsfield of pharmaceutical development.
`
`2224. I consider myself to be an expert in the art of the ’283 patent at the time of the
`alleged inventions claimed therein.
`
`2325. I understand that the first step in comparing prior art to patent claims is to properly
`construe the claims to determine claim scope and meaning. I understand that in Inter Partes
`Reviewinter partes review proceedings the claim terms are presumed to take on
`
` their ordinary and customary meaning based on the broadest reasonable interpretation of
`the claim language.
`
` interpretation of the claim language that a POSA would apply to the claim terms, when those
`terms are read in light of the teachings in the specification.
`
`2426. I understand that a patent or other publication must first qualify as prior art
`before it can be used to invalidate a patent claim. I understand that documents and materials
`
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`that qualify as prior art can be used to render a claim unpatentable as anticipated under 35
`U.S.C. § 102 or as obvious under 35 U.S.C.
`
`§ 103.
`
`2527. I understand that the “priority date” of a patent is taken to be the date on which it is
`filed. I further understand that the “critical date” for a patent is one year prior to its effective
`filing date. It is my understanding that the critical date is significant because published
`information prior to the critical date is information that is published or otherwise publicly
`available more than one year before the priority date of a patent is prior art that can render a
`patent claim unpatentable regardless of the purported date of
`
` invention.
`
`2628. I understand that, once the claims of a patent have been properly construed, the
`second step in determining anticipation or obviousness of a patent claim requires a comparison
`of the properly construed claim language to the prior art on a limitation-by-limitation basis.
`
`2729. I understand that a prior art reference “anticipates” a claim, and thus renders the
`claim unpatentable, if all elements of the claim are disclosed in that prior art reference, either
`explicitly or inherently (i.e., necessarily present or implied).
`
`I understand that a claim is unpatenable under 35 U.S.C. § 102(b) of the Patent Act if
` 28.
`the invention was patented or published anywhere, or was in public use, on sale, or offered for
`sale in this country, more than one year prior to the filing date of the patent application. I
`understand that a U.S. or foreign patent qualifies as prior art under § 102(b) to a patent claim if
`the date of issuance of the patent is more than one year before the filing date of the patent claim.
`I further understand that a printed publication, such as an article published in a magazine or trade
`publication or a U.S. or foreign patent application, also qualifies as prior art under § 102(b) to a
`patent claim if the publication occurs more than one year before the filing date of the patent.
`
`29 30. I have been instructed by counsel on the law regarding obviousness, and
`understand that even if a patent is not anticipated, it will be unpatentable if the differences
`between the claimed subject matter and the prior art are such that the subject matter as a whole
`would have been obvious at the time the invention was made to a person of ordinary skill in the
`pertinent art.
`
`3031. I have been instructed by counsel that the “time of the inventionpriority date”
`for the purposes of the ’283 patent is April 8, 2003. I also have been instructed that the
`“critical date” is April 8, 2002. In my analyses, which is the earliest filing to which the ’283
`patent claims priority. In forming my opinions and conclusions below, I consider the
`ordinarily skilled artisan’s understanding as of April 8, 2003, but confirm that my opinions
`remain the same even if applying the April 8, 2002 date.
`
`I understand that a person of ordinary skill in the art provides a reference point from
` 31.
`which the prior art and claimed invention should be viewed. This reference point prevents one
`from using his or her own insight or hindsight in deciding whether a claim is obvious. Thus,
`“hindsight reconstruction” cannot be used to combine references together to reach a conclusion
`of obviousness.
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`I also understand that an obviousness determination includes the consideration
`32.
`of various factors such as, including (1) the scope and content of the prior art, (2) the
`differences between the prior art and the claims, (3) the level of
`
`ordinary skill in the pertinent art, and (4) the existence of secondary considerations of non-
`obviousnessnon-obviousness.
`
`I have been informed and understand that the obviousness analysis requires a
`33.
`comparison of the properly construed claim language to the prior art to determine whether the
`claimed subject matter as a whole would have been obvious. A claimed invention can be obvious
`when, for example, there is some teaching, suggestion, or motivation in the prior art that would
`have led one of ordinary skill
`
`to modify the prior art reference or to combine prior art reference teachings to
`
` arrive at the claimed invention. In other words, even if one reference does not show the whole of
`the invention, if it would have been obvious to a person of ordinary skill in the art at the relevant
`time to add the missing pieces to the invention (for example as a matter of standard engineering
`practice or application of a well-known principle in the field), then a single reference can render a
`claim invalid even if it does not show the whole invention. Moreover, a combination of two or
`more references can render a claim invalid as obvious whether or not there is an explicit
`suggestion in one of the references to combine the two references, if as a matter of engineering
`skill or practice in the field it would be known to do so.
`
`And as stated above, secondary considerations must be examined to determine
`34.
`whether a certain invention would have been obvious to one of ordinary skill in the art. I
`understand that secondary considerations of non-obviousness are part of the obviousness inquiry
`under § 103, and that some examples of secondary considerations include:
`
`(1)
`
`any long-felt and unmet need in the art that was satisfied by the invention
`of the patent;
`
`(2)
`
`any failure of others to achieve the results of the invention;
`
` (3)
`
`any commercial success or lack thereof of the products and
`
`(4)
`
` (5)
`
`(6)
`
`(7)
`
`(8)
`
`(9)
`
`processes covered by the invention;
`
`any deliberate copying of the invention by others in the field;
`
`any taking of licenses under the patent by others;
`
`any expression of disbelief or skepticism by those skilled in the art upon
`learning of the invention;
`
`any unexpected results achieved by the invention;
`
`any praise of the invention by others skilled in the art; and
`
`any lack of contemporaneous and independent invention by others.
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`9
`
`IV.
`
`SUMMARY OF OPINIONS
`
`It is my opinion that certain prior art references anticipate and/or render
`35.
`obvious the claims of the ’283 patent.
`
`U.S. Patent No. 6,277,888 (hereinafter “Sakai,” Ex. 1005) issued AugustIn
`36.
`particular, I agree with Dr. Kent that it would have been obvious
`
`21, 2001, more than one year before the August 8, 2003 filing date of the ’283 patent. Sakai
`discloses a solid pharmaceutical composition suitable for oral administration that meets each and
`every limitation of claims 1–4, 7, 8, 19, 22, and
`
`32 of the ’283 patent. Thus, it is my opinion that claims 1–4, 7, 8, 19, 22, and 32 of the ’283
`patent are unpatentable because they are anticipated by Sakai.
`
`It is also my opinion that it would have been obvious for a person of ordinary skill in the art
`37.
`to combine the teachings of U.S. Patent No.
`
`6,004,565 (hereinafter “Chiba”, Ex. 1006), issued on December 21, 1999, with the teachings of
`Pharmaceutics, The Science of Dosage Form Design (M.E. Aulton,
`
`1988, hereinafter “Aulton,” Ex. 1021) to arrive at the subject matter of claims 1-32 of the ’283
`patent, thus rendering the claims unpatentable. Chiba discloses formulating FTY720 in solid
`dosage forms suitable for oral administration. Aulton (and other prior art described in ¶¶ 10299-
`143140, below) describes the state of the art at the time of the invention with respect to
`formulating solid dosage forms with appropriate excipients, including mannitol and magnesium
`stearate.
`
`It is further my opinion that it would have been obvious for a person of ordinary skill in
`38.
`the art to combine the teachings of Chiba with Sakai and other prior art references showing the
`state of the art at the time of the invention to arrive at the subject matter of claims 1–32 of the
`’283 patent. Thus, for this reason also, I conclude that all claims of the ’283 patent are
`unpatentable because they would have been obvious to a person of ordinary skill in the art.
`
`V.
`
`U.S. PATENT NO. 8,324,283
`
`A.
`
`39.
`
`Claims 1–32 of the ’283 Patent
`
`The claims of the ’283 patent read as follows:
`
`1. A solid pharmaceutical composition suitable for oral
`administration, comprising:
`
`(a) a S1P receptor agonist which is selected from 2- amino-2-[2-(4-
`octylphenyl)ethyl]propane-1,3-diol, 2- amino-2-[4-(3-
`benzyloxyphenoxy)-2- chlorophenyl]propyl-1,3-propane-diol, 2-
`amino-2-[4- (3-benzyloxyphenylthio)-2-chlorophenyl]propyl-
`1,3- propane-diol, or 2-amino-2-[4-(3- benzyloxyphenylthio)-2-
`chlorophenyl]-2-ethyl-1,3- propane-diol, and its phosphates or a
`
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`10
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`pharmaceutically acceptable salt thereof; and
`
`(b) a sugar alcohol.
`
` 2. The composition of claim 1, wherein the salt is the hydrochloride.
`
`3. A composition according to claim 1, wherein the sugar alcohol is a non-
`hygroscopic sugar alcohol or a mixture thereof.
`
`4. A composition according to claim 1, wherein the sugar alcohol
`comprises mannitol.
`
`5. A composition according to claim 1, further comprising a lubricant.
`
`6. A composition according to claim 5, wherein the lubricant
`comprises magnesium stearate.
`
`7. A composition according to claim 1, comprising 0.01 to
`
`20% by weight of the S1P receptor agonist.
`
`8. A composition according to claim 7, comprising 0.5 to
`
`5% by weight of the S1P receptor agonist.
`
`9. A composition according to claim 1, comprising 75 to
`
`99.99% by weight of the sugar alcohol.
`
`10. A composition according to claim 9, comprising 90 to
`
`99.5% by weight of the sugar alcohol.
`
`11. A composition according to claim 5, comprising 0.01 to
`
`5% by weight of the lubricant.
`
` 12. A composition according to claim 11, comprising 1.5 to
`
`2.5% by weight of the lubricant.
`
`13. A composition according to claim 1, wherein the S1P
`
`receptor agonist is micronized.
`
`14. A composition according to claim 13, wherein the S1P receptor agonist
`is pre-screened with a 400 to 500 μm mesh screen.
`
`15. A composition according to claim 1, in the form of a tablet.
`
`16. A composition according to claim 1 in the form of a capsule.
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`
`17. A method of treating organ or tissue transplant rejection, graft versus host
`disease, an autoimmune disease, an inflammatory condition, viral
`myocarditis or a viral disease caused by viral myocarditis in a subject in
`need thereof, comprising administering to said subject a pharmaceutical
`composition according to claim 1.
`
`18. A method according to claim 17, wherein the disease or condition that is
`treated is multiple sclerosis.
`
`19. A solid pharmaceutical composition suitable for oral administration,
`comprising mannitol and 2-amino-2-[2- (4-octylphenyl)ethyl]propane-
`1,3-diol or a pharmaceutically acceptable salt thereof.
`
` 20. A composition according to claim 19, further comprising a lubricant.
`
`21. A composition according to claim 20, wherein the lubricant
`comprises magnesium stearate.
`
`22. A composition according to claim 19, wherein the compound 2-amino-2-
`[2-(4-octylphenyl)ethyl]propane-
`
`1,3-diol, or a pharmaceutically acceptable salt thereof, is present in an
`amount of 0.5 to 5% by weight, based on the total weight of the
`composition.
`
`23. A composition according to claim 19, wherein mannitol is present in an
`amount of 90 to 99.5% by weight, based on the total weight of the
`composition.
`
`24. A composition according to claim 19, wherein the lubricant is present
`in an amount of 1.5 to 2.5% by weight, based on the total weight of
`the composition.
`
`25. A composition according to claim 19, wherein said composition is in
`the form of a tablet.
`
`26. A composition according to claim 19, wherein said composition is in
`the form of a capsule.
`
`27. A composition according to claim 19, wherein the
`
`mannitol has a mean particle size of 100 to 300 μm.
`
`28. A composition according to claim 27, wherein the mannitol has a
`mean particle size of 150 to 250 μm.
`
` 29. A composition according to claim 19, wherein the
`mannitol has a bulk density of 0.4 to 0.6 g/mL.
`
`30. A composition according to claim 29, wherein the mannitol
`iiiB
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`has a bulk density of 0.45 to 0.55 g/mL.
`
`31. A composition according to claim 19, wherein the mannitol has
`a single point surface area of 1 m2/g to 7 m2/g.
`32. A pharmaceutical composition according to claim 1, wherein the
`S1P receptor agonist is 2-amino-2-[2-(4-
`octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically
`acceptable salt thereof.
`
`U.S. Patent. No. 8,324,283, Ex. 1001 at 000010-11.
`
`BA. The Specification of the ’283 Patent
`
`4037. The ’283 patent is directed to formulations comprised of “a solid pharmaceutical
`composition suitable for oral administration containing an S1P receptor agonist and a sugar
`alcohol,” and methods of treating an autoimmune disease, such as multiple sclerosis, by
`administering the composition. See Ex.
`
` 1001 at col. 1, ll. 33-35; col. 12, ll. 19-49. According to the patentees’283 patent, “[i]t has
`surprisingly been found that solid compositions comprising a sugar alcohol provide formulations
`which are particularly well suited to the oral administration of S1P receptor agonists.” Id. at col.
`1, ll. 36-39. The patentees’283 patent also statestates that these compositions “provide a
`convenient means of systemic administration of S1P receptor agonists, do not suffer from the
`disadvantages of liquid formulations . . . and have good physicochemical [ ] properties . . . as well
`as high stability.” Id. at col. 1; ll. 39-46.
`
`4138. The specification of the ’283 patent sets forth general formulas I, II, III, IVa, IVb,
`V, VI, VII, VIII, IX, X, XI, XII, and XIII that the patentees describeare described as “[e]xamples
`of appropriate S1P receptor agonists” for use in the claimed invention. Id. at col. 1, l. 51 – col. 8.
`l, 1. 4. The ’283 patent acknowledges that the chemical compounds of formulas I to XIII were
`previously disclosed. See, e.g., id. at col. 1, ll. 53-4.
`
`4239. The ’283 patent also acknowledges that a “particularly preferred S1P receptor
`agonist of formula I is FTY720, i.e., 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free
`form or in a pharmaceutically acceptable salt form . .
`
`. .” Id. at col. 8, ll. 23-26.
`
`4340. The ’283 patent discloses the chemical structure of the hydrochloride salt of
`FTY720 as follows:
`
`iiiB
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`Id. at col. 8, ll. 30-35.
`
`4441. The ’283 patent also discloses that the sugar alcohol in the claimed
`
` composition “may suitably be mannitol.” See id. at col. 9, ll. 53-54. Moreover,
`mannitol is provided as an example of a preferred excipient because the sugar alcohol is
`“preferably” non-hygroscopic. See id. at col. 9, ll. 55-56.
`
`4542. Regarding dosage forms, the specification of the ’283 patent states that the
`“composition may be in the form of a powder, granule or pallets or a unit dosage form, for
`example as a tablet or capsule.” Id. at col. 10, ll. 59-61. The specification of the ’283 patent
`also instructs that
`
`[t]he pharmaceutical composition of the present invention may
`be produced by standard processes, for instance by
`conventional mixing, granulating, sugar-
`
` coating, dissolving, or lyophilizing processes. Procedures which
`may be used are known in the art, e.g. those described in [citations
`omitted].
`
`Id. at col. 11l, ll. 11-15. In other words, the solid oral dosage formulations comprising the
`claimed compositions are conventional solid dosage forms and are prepared via conventional
`methods.
`
`4643. The ’283 patent includes 39 examples for formulating the claimed subject
`matter. See id. at col. 12, l12,1. 57 – col. 16, l1. 67. Twenty-eight of those examples recite solid
`pharmaceutical formulations containing the hydrochloride salt form of FTY720 as the active
`ingredient. All of the examples use mannitol as the chosen sugar alcohol.
`
` 4744. According to the ’283 patent, the pharmaceutical compositions of the alleged
`invention are useful for the treatment or prevention of conditions disclosed in other r