`
`Paper _____
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`STEADYMED LTD.,
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`
`Patent Owner.
`
`_______________
`
`Case IPR2016-00006
`Patent 8,497,393
`_______________
`
`DECLARATION OF ROBERT M. WILLIAMS, Ph.D., IN SUPPORT OF
`PATENT OWNER RESPONSE TO PETITION
`
`4851-2371-9220.1
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`P. 1
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`SteadyMed v. United Therapeutics
`IPR2016-00006
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`

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`IPR2016-00006
`patent 8,497,393
`
`
`
`
`TABLE OF CONTENTS
`
`I.(cid:3)
`
`QUALIFICATIONS AND BACKGROUND .............................................. 3(cid:3)
`A.(cid:3)
`Education and Experience ..................................................................... 3(cid:3)
`B.(cid:3) Materials Considered ........................................................................... 12(cid:3)
`LEGAL STANDARDS PROVIDED BY COUNSEL .............................. 12(cid:3)
`II.(cid:3)
`THE PERSON OF ORDINARY SKILL IN THE ART .......................... 12(cid:3)
`A.(cid:3)
`ANTICIPATION ......................................................................................... 14(cid:3)
`B.(cid:3)
`C.(cid:3) OBVIOUSNESS ........................................................................................... 14(cid:3)
`III.(cid:3) SUMMARY OF OPINIONS ....................................................................... 16(cid:3)
`IV.(cid:3) THE ’393 PATENT ..................................................................................... 16(cid:3)
`V.(cid:3) CLAIM CONSTRUCTION ........................................................................ 18(cid:3)
`VI.(cid:3) PHARES DOES NOT ANTICIPATE CLAIMS 1-5, 7-9, 11-14, OR
`16-20 OF THE ’393 PATENT .................................................................... 21(cid:3)
`THE PRODUCT DISCLOSED IN PHARES IS PHYSICALLY
`DIFFERENT THAN THE PRODUCTS DISCLOSED IN THE ’393
`PATENT CLAIMS ...................................................................................... 22(cid:3)
`PHARES DOES NOT DISCLOSE SEVERAL OTHER CLAIM
`LIMITATIONS ............................................................................................ 25(cid:3)
`VII.(cid:3) NONE OF THE CLAIMS OF THE ’393 PATENT ARE
`RENDERED OBVIOUS BY THE PRIOR ART ...................................... 27(cid:3)
`THE PRODUCT OF THE ’393 PATENT IS STRUCTURALLY
`DIFFERENT THAN THE PRODUCT OF THE PRIOR ART .............. 28(cid:3)
`CLAIMS 1-5, 7-9, 11-14, AND 16-20 ARE NOT RENDERED
`OBVIOUS BY THE COMBINATION OF MORIARTY AND
`PHARES ....................................................................................................... 34(cid:3)
`C.(cid:3) CLAIMS 6, 10, 15, 21, AND 22 ARE NOT RENDERED OBVIOUS
`BY THE COMBINATION OF MORIARTY, PHARES,
`KAWAKAMI, AND EGE ........................................................................... 36(cid:3)
`
`A.(cid:3)
`
`B.(cid:3)
`
`A.(cid:3)
`
`B.(cid:3)
`
`
`APPENDIX A…………………………………………………………………….42
`APPENDIX B…………………………………………………………………….47
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`IPR2016-00006
`patent 8,497,393
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`
`
`
`
`I have been retained by the law firm of Wilson Sonsini Goodrich & Rosati (“WSGR”) as
`
`an expert consultant to United Therapeutics Corporation (“UTC”) in connection with the above-
`
`identified matter to provide expert testimony concerning U.S. Patent No. 8,497,393 (“the ’393
`
`Patent”, Ex. 1001) by Batra et al., entitled “Process to prepare Treprostinil, the active ingredient
`
`in Remodulin,” issued on July 30, 2013. At the request of Counsel for UTC, I hereby submit this
`
`expert declaration.
`
`I.
`
`Qualifications and Background
`
`A.
`
`1.
`
`Education and Experience
`
`I am a tenured University Distinguished Professor of Chemistry at Colorado State
`
`University (CSU). I currently serve as the Director for the Colorado Center for Drug Discovery.
`
`I also served as co-Director (Experimental Therapeutics) for the Infectious Diseases Supercluster
`
`Initiative and also served as co-Director for the Cancer Supercluster Initiative at CSU. My
`
`curriculum vitae is attached hereto as Exhibit A (Ex. 2021).
`
`2.
`
`I received a B.A. in Chemistry from Syracuse University in 1975, and did
`
`laboratory research in the field of synthetic organic chemistry under the guidance of the recent
`
`Nobel Laureate Professor Ei-ichi Negishi. In 1979, I received both a Master’s degree and Ph.D.
`
`degree in Organic Chemistry from the Massachusetts Institute of Technology (MIT) under the
`
`direction of Professor William H. Rastetter. Upon graduating from MIT, I spent one year (1979-
`
`80) as a postdoctoral fellow at Harvard University in the laboratories of the Nobel Laureate, the
`
`late Professor Robert B. Woodward, whose laboratory was subsequently managed by Professor
`
`Yoshito Kishi.
`
`3.
`
`Subsequent to my fellowship at Harvard, I served as an Assistant Professor at
`
`Colorado State University from 1980–84. I was tenured and promoted early, to the rank of
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`Associate Professor in 1985, and in 1988, I was promoted to the rank of Full Professor. In 2002,
`
`
`
`I was named a University Distinguished Professor, which is my current position. University
`
`Distinguished Professor is the highest academic rank at Colorado State University, and there are
`
`a maximum of twelve University Distinguished Professors at any given time out of a faculty of
`
`1,200. This is a lifetime appointment until retirement, whereupon Emeritus status is granted. In
`
`addition to my positions at Colorado State University, I was a Visiting Professor of Chemistry at
`
`Harvard University from 1994–95, at which time I was sponsored by Professor Stuart L.
`
`Schreiber and taught a sophomore organic chemistry course for pre-medical students, Chem 17.
`
`I was also a Visiting Professor of Chemistry at the University of California at Berkeley in 1990
`
`and worked in the laboratory of Professor Peter G. Schultz.
`
`4.
`
`I have extensive experience in the field of synthetic organic chemistry and
`
`medicinal chemistry with an emphasis on biologically active compounds including anti-tumor
`
`agents, heterocycles, antibiotics, anti-fungal agents, anti-viral agents, immunomodulators, amino
`
`acids, peptides and alkaloids, among many other classes of biologically active organic substances.
`
`My organic chemistry research interests include the total synthesis of novel natural and synthetic
`
`products, heterocyclic chemistry, asymmetric synthesis, synthetic methodology, process
`
`chemistry, and reaction mechanisms. I have extensive experience in the synthesis, chemistry,
`
`conformational analysis, biochemical activity, and biological activity of a range of organic
`
`compounds.
`
`5.
`
`My research laboratory at Colorado State University has worked extensively on
`
`the chemistry and biology of numerous drugs over my career, including Quinocarcin
`
`(Quinocarmycin citrate), Tetrazomine, Bioxalomycin, Ecteinascidin 743 (Yondelis® or
`
`trabectidin), Renieramycin, Cribrostatin-4, Jorumycin, the Mitomycins, FR900482, FK973,
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`patent 8,497,393
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`FK317, FK228 (Romidepsin), Largazole, Stephacidins A and B, Avrainvillamide,
`
`
`
`Spirotryprostatins, TMC-95A/B, Rottlerin, and Antimycin, amongst many others.
`
`6.
`
`I have been the Principal Investigator on numerous research grants from Federal
`
`agencies, such as the National Institutes of Health (NIH) and the National Science Foundation
`
`(NSF) as well as from various Foundations, and corporations to synthesize biologically active
`
`compounds on both small laboratory scale as well as larger industrial scales.
`
`7.
`
`I held a funded research collaboration with the Infectious Diseases Research
`
`Institute (IDRI), in Seattle, Washington, to develop several novel adjuvants for the treatment and
`
`prevention of autoimmune diseases, infectious diseases and cancer (2010).
`
`8.
`
`From 1991-1993, I held a research grant from Symphony Pharmaceuticals,
`
`located in Philadelphia, Pennsylvania, to prepare anti-HIV drugs based on inhibition of the HIV
`
`protease. I supervised a graduate student who prepared several very potent peptide isosteres that
`
`exhibited in vitro activity against HIV.
`
`9.
`
`I have taught undergraduate and graduate courses in organic chemistry, organic
`
`synthesis, biosynthesis, biological chemistry, drug design, and the synthesis of natural products.
`
`I have also lectured at numerous professional conferences, universities, and in corporate R&D
`
`laboratories in those areas.
`
`10.
`
`I am a Scientific Founder, Acting President, and Chair of the Scientific Advisory
`
`Board of Cetya Therapeutics, a company that is developing several drugs, including drugs for the
`
`treatment of various cancers, multiple myeloma, autoimmune diseases, and hemoglobinopathies.
`
`I also direct all of the process scale synthesis optimization and drug formulation studies being
`
`conducted on Cetya’s HDAC inhibitors. This includes injectable formulations as well as oral
`
`formulations. Specifically, I directed and supervised post-doctoral researchers in my laboratory
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`patent 8,497,393
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`(on behalf of Cetya Therapeutics) to formulate the poorly water-soluble drug Largazole,
`
`
`
`including a myriad of synthetic analogs of Largazole prepared in my laboratory, as a
`
`polysorbate-80/ethanol co-solvent excipient system. This formulation has been used in animal
`
`studies for obtaining critical dose-escalation and pharmacokinetic data. I have also specifically
`
`directed and supervised the formulation of Largazole and related analogs in various PEG-based
`
`(polyethylene glycol) excipient systems. This work is currently being conducted in collaboration
`
`with oncologist Dr. Douglas Thamm of the Colorado State University Animal Cancer Center,
`
`pharmacologist Dr. Dan Gustafson of the Colorado State University Animal Cancer Center, Dr.
`
`Kimberly Stegmaier of the Dana-Farber Cancer Institute/Harvard Medical School and Dr. James
`
`E. Bradner of the Dana-Farber Cancer Institute/Harvard Medical School. The animal studies
`
`commenced in 2010, and the drug formulation studies are being conducted in my laboratory at
`
`Colorado State University under my direction.
`
`11.
`
`I was a Scientific Founder, Member of the Scientific Advisory Board, and
`
`Member of the Corporate Board of Directors for Xcyte Therapies, a company devoted to
`
`developing ex vivo T-cell therapies for treating cancer, autoimmune, and infectious diseases,
`
`including HIV. As a Scientific Founder and Member of the Board of Directors of Xcyte
`
`Therapies, I was deeply involved in writing the patents and developing formulation strategies for
`
`both topical and injectable drugs based on FK228 (Romidepsin).
`
`12.
`
`As a Scientific Founder and Acting Vice-President of Discovery Chemistry of
`
`HemaQuest Pharmaceuticals (Seattle, Washington), I have directed the pre-clinical and clinical
`
`synthesis, scale-up and formulation studies of several of the companies’ drugs. These include
`
`both water-soluble drugs and hydrophobic, poorly water-soluble drugs for therapeutic
`
`applications in both cancer and hemoglobinopathies. I directed both the medicinal chemistry
`
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`patent 8,497,393
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`efforts as well as the pre-process optimization work for potential industrial-scale syntheses of our
`
`
`
`lead drug candidates.
`
`13.
`
`In addition, I am a Scientific Founder and member of the Scientific Advisory
`
`Board of Sapientia Therapeutics, located in Philadelphia, Pennsylvania. I am the acting Director
`
`of the Medicinal Chemistry, Process Chemistry and Drug Formulation efforts of this company to
`
`develop novel small-molecule inhibitors of protein kinase C-delta for autoimmune diseases,
`
`cancer and scleroderma. My laboratory has synthesized the first lead compounds, which are
`
`protein kinase C-delta (PKC-(cid:507)) inhibitors and are water-insoluble substances. Under my
`
`direction we have engaged in early scale-up and route optimization for our leading drug
`
`candidates.
`
`14.
`
`As a chemist with expertise in structure-activity studies and synthesis of
`
`biologically active agents, I have been retained to consult for a number of pharmaceutical and
`
`biopharmaceutical companies for both drug discovery and process research applications over the
`
`past thirty years. I consulted for Ajinomoto Co., Japan from 2002-2014 in the general area of
`
`process chemistry in the manufacture of amino acids, their derivatives, pharmaceutical
`
`intermediates and peptide synthesis. I served as a consultant for Cubist Pharmaceutical
`
`Company (2000–03) in the general field of antibacterial agents. I consulted for NewBiotics, Inc.
`
`(2001–02) in the general fields of anti-infective agents and anti-cancer agents. I consulted for
`
`Hoffman-La Roche, Inc. (1989–92) in the field of cephalosporin-fluoroquinolone dual-action
`
`antibacterial agents, as well as on a project concerned with inhibitors of diaminopimelic acid
`
`(DAP) biosynthesis as potential antibacterial agents. I consulted for W.R. Grace (1985–90) in
`
`the area of specialty chemicals and pharmaceutical intermediates process manufacturing and
`
`process development. I was a Scientific Founder, Member of the Scientific Advisory Board,
`
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`patent 8,497,393
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`Consultant and sub-contractor for Microcide Pharmaceutical Co. (Microcide) in their drug
`
`
`
`discovery and early process research efforts. Microcide was a biopharmaceutical company
`
`devoted to developing antibacterial agents against a range of drug-resistant bacterial and fungal
`
`infectious diseases. In addition, I have consulted for EPIX Medical, G. D. Searle, Nutrasweet,
`
`and Boehringer-Ingelheim, among others. The consulting work I performed for Nutrasweet
`
`(1990-1991), was concerned with large-scale manufacturing process chemistry for Aspartame.
`
`15.
`
`I was a co-organizer of a special Symposium on process chemistry at The
`
`International Chemical Congress of Pacific Basin Societies, PacifiChem 2015 (December 15-18.
`
`Honolulu, Hawaii) entitled: “New Horizon of Process Chemistry by Scalable Reactions and
`
`Technology.”
`
`16.
`
`I have directed the research activities of more than sixty PhD students and eighty
`
`post-doctoral fellows; most of my former co-workers have gone on to successful careers in the
`
`pharmaceutical industry in both process research and medicinal chemistry.
`
`17.
`
`I have delivered numerous named and plenary lectures at Universities,
`
`corporations, and scientific societies on the synthesis, chemistry, biology, and mechanism of
`
`action of numerous classes of therapeutic agents, as detailed in my curriculum vitae attached
`
`hereto as Exhibit A.
`
`18.
`
`I have published more than 315 scientific research articles, authored numerous
`
`chapters in books, and have written a well-known textbook on the synthesis of optically active
`
`amino acids. I have particular expertise in the large-scale industrial synthesis of amino acids and
`
`their derivatives. I am also a named inventor on seventeen issued U.S. patents and published
`
`patent applications. My publications and patents are listed on my CV, provided in Exhibit 2021.
`
`4851-2371-9220.1
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`IPR2016-00006
`patent 8,497,393
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`
`
`
`19.
`
`I currently serve on the Editorial board for Chemistry & Biology. I have served as
`
`Editor for the Organic Chemistry Series published by Pergamon Press and Elsevier (1997-2012),
`
`and Mini Reviews in Organic Chemistry (Bentham Science). I have also served as an editor for
`
`several other journals in the past, including Tetrahedron: Asymmetry, Tetrahedron Publications,
`
`Amino Acids, and the Journal of the American Chemical Society.
`
`20.
`
`I am a member of the American Chemical Society, the Japan Antibiotics Research
`
`Association, the International Society of Heterocyclic Chemistry, and the American Association
`
`for the Advancement of Science. I am a Member of the University of Colorado Cancer Center,
`
`located in Aurora, Colorado. I have served as organizer or co-organizer of numerous scientific
`
`meetings and symposia, and served as the Vice President of the International Society of
`
`Heterocyclic Chemistry, Chairing the 2003 International Congress of Heterocyclic Chemistry.
`
`21.
`
`I serve on the Scientific Advisory Board of Arch Therapeutics, located in Boston,
`
`Massachusetts, that is developing self-assembling peptides for wound healing and surgical
`
`closure.
`
`22.
`
`I have also served on the Scientific Advisory Boards for a number of other
`
`companies. I currently serve on the External Advisory Committee for the Puerto Rico Alliance
`
`for the Advancement of Biomedical Research Excellence. I was a Scientific Founder, Director
`
`of Chemistry, and member of the Scientific Advisory Board for HemaQuest Pharmaceuticals. I
`
`was a Founding Scientist and Member of the Scientific Advisory Board of Microcide
`
`Pharmaceuticals from 1993 to 1998.
`
`23.
`
`I have expertise in drug formulation for injectable, topical and oral medications. I
`
`have directed research programs, both through my academic laboratory at Colorado State
`
`University as well as through my various consulting engagements and as a research director
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`and/or consultant for companies developing medicines for numerous therapeutic indications. I
`
`
`
`have consulted on many aspects of pharmaceutical drug discovery, development, formulation,
`
`and manufacturing. This includes basic discovery and optimization, early process research,
`
`large-scale manufacturing, and drug formulation.
`
`24.
`
`I have served as a consultant for a number of companies for both drug discovery
`
`and process research applications, including, for example, W.R. Grace Company (1985-1990,
`
`fine chemicals synthesis); Symphony Pharmaceuticals (1991-1993, anti-HIV drugs); G.D. Searle
`
`Co. (1988-1990, memory and learning enhancement agents based on NMDA receptor
`
`antagonists); Nutrasweet Co. (1990-1991, artificial sweeteners); EPIX Medical (1993-1997, MRI
`
`imaging and contrast agents); Hoffman-La Roche, Inc. (1989-1992, cephalosporin-
`
`fluoroquinolone dual-action antibacterial agents); Boehringer-Ingelheim Pharmaceuticals (1992-
`
`1993, antiviral agents); Cubist Pharmaceutical Company (2000-2003, macrocyclic peptide
`
`antibacterial agents); NewBiotics, Inc. (2001-2002, anti-infective agents and anti-cancer agents);
`
`Microcide Pharmaceutical Co. (1993-1998, analogs of macrocyclic anti-fungal agents related to
`
`echinocandin, cephalosporins, and quinolones); Xcyte Therapies (1996-2006, T-cell activation);
`
`Ajinomoto Co, Japan (2002-2014, amino acids, peptides, and other specialty chemicals);
`
`HemaQuest Pharmaceuticals (2006-2014, short chain fatty acids for treating
`
`hemoglobinopathies); Sapientia Therapeutics (2012-present, small-molecule inhibitors of protein
`
`kinase C-delta); Arch Therapeutics (2010-present, self-assembling peptides for wound healing);
`
`and most recently, Cetya Therapeutics (2012-present, histone deacetylase inhibitors as
`
`therapeutic agents for treating cancers, multiple myeloma, autoimmune diseases, and
`
`hemoglobinopathies).
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`IPR2016-00006
`patent 8,497,393
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`
`
`
`25.
`
`Under my direction, my laboratory developed the technology for the asymmetric
`
`synthesis of amino acids in 1985 that was commercialized by Aldrich Chemical Co. in 1988. My
`
`laboratory devised several large-scale (multi-kilogram) process routes for the manufacture of the
`
`so-called “Williams Lactone” that has been sold by Sigma-Aldrich Chemical Company since
`
`1988. Early manufacturing was conducted in China by several of my former co-workers at the
`
`Chengdu Institute of Organic Chemistry.
`
`26.
`
`I have been awarded numerous prizes and awards including the NIH Research
`
`Career Development Award (1984-89), the Eli Lilly Young Investigator Award (1986), the
`
`Merck, Sharp & Dohme Academic Development Award (1991), an award from the Japanese
`
`Society for the Promotion of Science Fellowship (1999), the Arthur C. Cope Scholar Award
`
`sponsored by The American Chemical Society (2002), the Multiple Myeloma Research
`
`Foundation Senior Award (2010), the ACS Ernest Guenther Award in the Chemistry of Natural
`
`Products sponsored by Givoudan and The American Chemical Society (2011), an award from the
`
`Japanese Society for the Promotion of Science Long-term Fellowship (2012-2013), and the
`
`Organic Synthesis Award from the local Rocky Mountain section of the American Chemical
`
`Society (2012).
`
`27.
`
`I have testified numerous times as an expert witness in process chemistry patent
`
`litigation in the following matters: Great Lakes Chemical versus Archimica SPA. Civil Action
`
`No. 99–728-JJF; Ranbaxy Laboratories versus Abbott Laboratories. Case No. 04 C 8078;
`
`Lundbeck versus Infosint. 06 Civ. 2869 (LAK); United Therapeutics Corp. versus Sandoz, Inc.
`
`C.A. Nos.: 12-1617 (PGS)(LHG) and 13-316 (PGS) (LHG); Gilead Sciences, Inc. and Emory
`
`University versus Cipla, Limited. Civil Action No.: 1:12-cv-06350-RJS; United Therapeutics
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`IPR2016-00006
`patent 8,497,393
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`Corp. versus Teva Pharmaceuticals, USA, Inc. C.A. No.: 3:14-cv-05498 (PGS)(LHG); United
`
`
`
`Therapeutics Corp. versus Sandoz, Inc. C.A. No.: 3:14-cv-05499 (PGS)(LHG).
`
`B.
`
`28.
`
`Materials Considered
`
`In forming my opinions in this report, I have relied upon my professional
`
`experience and personal knowledge. I have also reviewed a number of documents in this case
`
`including all documents cited by the SteadyMed and UTC as well as the materials I have cited in
`
`this declaration. In this report, I have provided representative citations to exemplary documents
`
`that I have relied upon in reaching my opinions. If I am provided additional information or
`
`documents in this proceeding, I may offer further opinions regarding the additional information.
`
`II.
`
`Legal Standards Provided By Counsel
`
`29.
`
`I have been informed by Counsel that, during an inter partes review (IPR), a
`
`petitioner must prove invalidity by a preponderance of the evidence. Accordingly, I understand
`
`that the burden is on a petitioner to prove invalidity, rather than a patent owner to prove validity.
`
`I have been informed by Counsel that because each claim defines a separate invention, the
`
`validity of each claim in a patent is addressed independently of the validity of the other claims in
`
`that patent.
`
`30.
`
`I have also been informed by Counsel that the claims of the ’393 patent are
`
`“product-by-process” claims. I have also been informed by Counsel that when evaluating the
`
`validity of a patent claim, the “product” of product-by-process claims must include structural
`
`and/or functional differences over the prior art, even if they are not explicitly claimed.
`
`A.
`
`31.
`
`The Person of Ordinary Skill in the Art
`
`I have been informed by Counsel that a patent is to be interpreted from the
`
`perspective of a hypothetical person referred to as the person of ordinary skill in the art (“POSA”)
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`to which the patent pertains. I am further informed that a determination of the level of ordinary
`
`
`
`skill is based on, among other things, the type of problems encountered in the art, prior art
`
`solutions to those problems, rapidity with which innovations are made, sophistication of the art,
`
`and the educational level of active workers in the field. I have been informed that in any
`
`particular case, every factor may not be present, and one or more factors may predominate. I
`
`understand the person of ordinary skill in the art is presumed to know all prior art that is
`
`reasonably relevant to the subject matter of the claimed invention.
`
`32.
`
`I understand from Counsel that the validity of a patent claim must be assessed
`
`from the perspective of a POSA at the time of the invention.
`
`33.
`
`Given the complexity of the chemistry involved in the ’393 patent, it is my
`
`opinion that a POSA with respect to the patent-in-suit would have had, at the time of the claimed
`
`invention, a doctorate degree in chemistry, pharmaceutics, pharmaceutical sciences, medicine, or
`
`a related discipline. Alternatively, the POSA may have had a lesser degree in one of those fields,
`
`with correspondingly more experience. To the extent necessary, a POSA may have collaborated
`
`with others of skill in the art, such that the individual and/or team collectively would have had
`
`experience in synthesizing and analyzing complex organic compounds. It is my understanding
`
`that a patent is to be interpreted from the perspective of a person of ordinary skill in the art at the
`
`time of the patent’s priority date.
`
`34.
`
`I understand that SteadyMed’s expert Dr. Winkler has opined that a POSA would
`
`have “a master’s degree or a Ph.D. in medicinal or organic chemistry, or a closely related field.
`
`Alternatively, a person of ordinary skill would include an individual with a bachelor’s degree
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`and at least five years of practical experience in medicinal or organic chemistry.” Ex. 1009 at ¶14.
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`4851-2371-9220.1
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`13
` P. 13
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`UT Ex. 2020
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`

`IPR2016-00006
`patent 8,497,393
`
`
`
`
`35.
`
`All of my opinions regarding validity contained in this report are expressed from
`
`the view of a POSA at the time of the priority date of the ’393 patent. These opinions apply
`
`equally whether my definition of a POSA or Dr. Winkler’s is applied.
`
`B.
`
`36.
`
`Anticipation
`
`I understand from Counsel that anticipation requires that each and every element
`
`of a claim is set forth in a single prior art reference, and that these elements are arranged or
`
`combined in that reference in the same way as recited by the claim. I further understand from
`
`Counsel that if there is any difference between the prior art reference and the claimed invention,
`
`there is no anticipation by that reference. Further, I understand that there is no anticipation if the
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`elements disclosed in a prior art reference must be combined with the knowledge of one skilled
`
`in the art to achieve the subject matter of the claim. I understand that for a prior art reference to
`
`be anticipatory, it must enable a POSA to make or practice the invention without undue
`
`experimentation.
`
`37.
`
`I also understand from Counsel that if the single prior art reference is missing a
`
`claimed feature, the reference may inherently anticipate if that missing feature is necessarily
`
`present in the single prior art reference.
`
`38.
`
`I also understand from Counsel that if there are structural or functional differences
`
`in the product of the product by process claims of the invention from the product of the prior art
`
`that arise from the process in which it was made, those differences may be evidence of no
`
`anticipation even if those differences are not explicitly claimed.
`
`C.
`
`39.
`
`Obviousness
`
`I understand from Counsel that obviousness requires that a POSA would have
`
`been able to arrive at the claimed invention by modifying a single prior art reference or by
`
`4851-2371-9220.1
`
`14
` P. 14
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`UT Ex. 2020
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`

`IPR2016-00006
`patent 8,497,393
`
`combining two or more prior art references. I also understand from Counsel that obviousness
`
`
`
`analysis must be conducted from the point of view of a POSA at the time of the invention, and
`
`that it is improper to employ hindsight or consider the inventors’ own path to the invention as
`
`proof of obviousness.
`
`40.
`
`Counsel has also informed me that obviousness requires that a POSA would have
`
`had a reasonable expectation of success in achieving the claimed invention.
`
`41.
`
`I understand from Counsel that four factual issues are relevant to obviousness
`
`analysis: the scope and content of the prior art; the level of ordinary skill in the field of the art at
`
`the time of the invention; the differences between the claimed invention and the prior art; and
`
`various objective indicia of non-obviousness.
`
`42.
`
`I understand from Counsel that, in addition to considering the prior art, certain
`
`objective indicia may also provide evidence that a claimed invention is not obvious. I am
`
`informed by Counsel that these objective indicia, which are also referred to as secondary
`
`considerations, may include factors such as commercial success, unexpected results, the
`
`resolution of long-felt but previously unmet needs, skepticism by others prior to achieving the
`
`invention, failure of others to achieve the invention, praise from others for the invention, and
`
`copying by others.
`
`43.
`
`I understand from Counsel that, like anticipation, if there are structural or
`
`functional differences in the product of the product by process claims of the invention from the
`
`product of the prior art that arise from the process in which it was made, those differences may
`
`be evidence of non-obviousness even if those differences are not explicitly claimed.
`
`4851-2371-9220.1
`
`15
` P. 15
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`UT Ex. 2020
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`

`IPR2016-00006
`patent 8,497,393
`
`III.
`
`Summary of Opinions
`
`
`
`44.
`
`It is my opinion that the term “product” as it is used in the claims of the ’393
`
`patent should be construed using UTC’s construction: “a substance resulting from a chemical
`
`reaction.”
`
`45.
`
`It is my opinion that the term “[a] product comprising a compound of formula
`
`I/IV or a pharmaceutically acceptable salt thereof” as it is used in the claims of the ’393 patent
`
`should be construed using UTC’s construction: “a substance resulting from a chemical reaction
`
`constituted primarily of formula I/IV or a pharmaceutically acceptable salt thereof.”
`
`46.
`
`It is also my opinion that none of the claims of the ’393 patent are anticipated by
`
`or rendered obvious by the prior art.
`
`47. My opinions and the bases for them are based on information that I know, that I
`
`have reviewed, and that I am currently aware exists. I reserve the right to supplement or amend
`
`my opinions in light of any additional evidence, testimony, or other information that may be
`
`provided to me after the date of this declaration. Additionally, I may use the cited materials to
`
`assist me in preparing demonstratives such as graphics and animations if I am asked to testify.
`
`IV.
`
`The ’393 Patent
`
`48.
`
`The ’393 patent is directed to an improved treprostinil product and improved
`
`process for making the product. I understand from Counsel that the priority date for the ’393
`
`patent is December 17, 2007.
`
`49.
`
`The synthesis of treprostinil is complex as several improvements resulting in
`
`improved products are disclosed in the ’393 patent itself. The structure of treprostinil has five
`
`chiral centers (stereogenic centers) resulting in 32 possible stereoisomers of treprostinil.
`
`4851-2371-9220.1
`
`16
` P. 16
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`UT Ex. 2020
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`

`IPR2016-00006
`patent 8,497,393
`
`
`
`
`50.
`
`The ’393 patent has two independent claims: Claims 1 and 9. Claim 1 requires “a
`
`product comprising a compound of formula I…or a pharmaceutically acceptable salt thereof,” in
`
`which formula I can be several structures including treprostinil. Claim 9 requires “[a] product
`
`comprising a compound having formula IV…or a pharmaceutically acceptable salt thereof,” in
`
`which is the structure of treprostinil. Both Claims 1 and 9 th