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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SAWAI USA, INC. and SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioners,
`
`v.
`
`ASTELLAS PHARMA INC.,
`Patent Owner
`
`Case No. IPR__
`Patent No. 6,346,532
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`
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`DECLARATION OF ROBERT M. WILLIAMS, PH.D.
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`SAWAI EX. 1002
`Page 1 of 77
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`QUALIFICATIONS ........................................................................................................... 1
`
`SCOPE OF WORK ........................................................................................................... 11
`
`OVERVIEW OF THE ‘532 PATENT .............................................................................. 11
`
`FILE HISTORY OF THE ‘532 PATENT ........................................................................ 16
`
`LEGAL STANDARDS .................................................................................................... 24
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`VI.
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`LEVEL OF ORDINARY SKILL IN THE ART AND RELEVANT TIME FRAME ..... 26
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`VII. CLAIM CONSTRUCTION .............................................................................................. 28
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`VIII. THE STATE OF THE PRIOR ART ................................................................................. 28
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`IX.
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`PRIOR ART REFERENCES DISCLOSED, TAUGHT, OR SUGGESTED EACH OF
`THE FEATURES OF CLAIMS 1, 3-6, 9-12, 15, AND 16 OF THE ‘532 PATENT ...... 34
`
`A. Brief Overview of Certain Prior Art References ................................................. 34
`
`X.
`
`EXEMPLARY COMBINATION OF PRIOR ART REFERENCES ............................... 43
`
`A.
`
`Independent Claims 1, 5 and 6, and Dependent Claims 3, 4, 9, 11, 12, 15, and 16
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`are Obvious over Merck US197, in view of Blin, and Thornber and/or Silverman. ................ 44
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`B.
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`Independent Claims 1, 5 and 6, and Dependent Claims 3, 4, 9, 11, 12, 15, and 16
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`are Obvious over Merck US197, in view of Blin, Merck US048, and Silverman and/or
`
`Thornber.
`
`56
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`C. Any Secondary Considerations will be Inadequate to Overcome the Obviousness
`
`of the Asserted Claims of the ’532 Patent. ............................................................................... 66
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`XI.
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`CONCLUDING STATEMENTS ..................................................................................... 67
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`
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`i
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`I, Robert M. Williams, declare as follows:
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`I.
`
`QUALIFICATIONS
`
`1.
`
`My name is Robert M. Williams. I am a tenured University Distinguished
`
`Professor of Chemistry at Colorado State University (CSU). I have been a member of the faculty
`
`of this university since 1980. I served as the Director for the Colorado Center for Drug
`
`Discovery from 2012-2016. I have served as co-Director (Experimental Therapeutics) for the
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`Infectious Diseases Supercluster Initiative and as co-Director (Experimental Therapeutics) for
`
`the Cancer Supercluster Initiative at CSU.
`
`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.
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`degree in Organic Chemistry from the Massachusetts Institute of Technology (MIT), under the
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`direction of Professor William H. Rastetter. Upon graduating from MIT, I spent one year (1979-
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`80) as a postdoctoral fellow at Harvard University in the laboratories of the Nobel Laureate, the
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`late Professor Robert B. Woodward, whose laboratory was subsequently managed by Professor
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`Yoshito Kishi following Professor Woodward’s untimely passing in July of 1979.
`
`3.
`
`Subsequent to my fellowship at Harvard, I served as an Assistant Professor at
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`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,
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`I was named a University Distinguished Professor, which is my current position. University
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`Distinguished Professor is the highest academic rank at Colorado State University, with a
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`maximum of fifteen University Distinguished Professors at any given time out of a faculty of
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`about 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
`
`
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`1
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`Chemistry at Harvard University from 1994–95, at which time I was sponsored by Professor
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`Stuart L. Schreiber. 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.
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`4.
`
`I have extensive experience in the field of synthetic organic chemistry and
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`medicinal chemistry with an emphasis on biologically active compounds including anti-tumor
`
`agents, heterocycles, antibiotics, anti-fungal agents, anti-viral agents, immunomodulators, amino
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`acids, peptides and alkaloids, among many other classes of biologically active organic
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`substances. My organic chemistry research interests include the total synthesis of novel natural
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`and synthetic products, heterocyclic chemistry, asymmetric synthesis, synthetic methodology,
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`and reaction mechanisms. I have extensive experience in the synthesis, chemistry, conformation
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`analysis, biochemical activity, and biological activity of a range of organic compounds.
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`5.
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`I have expertise in the synthesis, stereochemistry, reactivity and conformation of
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`phenethanolamines and beta-aminoalcohols generally. Several of my publications have dealt
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`specifically with the synthesis of beta-aminoalcohols including: J. Am. Chem. Soc., 1991, 113,
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`6976~6981; Tetrahedron Lett., 1994 35, 9371-74; J. Org. Chem., 1995, 60, 6791-97; Angew.
`
`Chem. Int. Ed. 2001, 40, 1463-65; Tetrahedron 2001, 57, 6505-09; Tetrahedron Lett. 2001, 42,
`
`4437-40; Org. Lett. 2001, 24, 4287-89; J. Org. Chem. 2002, 67, 6361-65; Angew. Chem. Int. Ed.
`
`2004, 43, 2930-33 Tetrahedron 2006, 62, 4549-62; Angew. Chem. Int. Ed. 2005, 44, 3879-81; J.
`
`Am. Chem. Soc. 2005, 127, 12684-90; Angew. Chem. Int. Ed. 2007, 46, 1517; J. Org. Chem.
`
`2008, 73, 9594-600; Org. Lett. 2006 8, 4051-54; and Chem. Biol., 1995, 2, 147-56.
`
`6.
`
`I have extensive experience in medicinal chemistry with a focus on the synthesis
`
`of nitrogen-containing compounds including aromatic amines and phenols, heterocyclic
`
`compounds, aromatic compounds generally and alkaloids and have published numerous papers
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`
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`on the preparation of amines, β-amino alcohols, substituted thiazoles, and related nitrogen-
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`containing compounds as reflected in my list of publications.
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`7.
`
`My research laboratory at Colorado State University has worked extensively on
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`the chemistry and biology of numerous heterocyclic drugs over my career, including
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`Bicyclomycin, Quinocarcin (Quinocarmycin citrate), Tetrazomine, Bioxalomycin, Ecteinascidin
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`743 (Yondelis® or trabectidin), Renieramycin, Cribrostatin-4, Jorumycin, the Mitomycins,
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`FR900482, FK973, FK317, FK228 (Romidepsin), Largazole, Stephacidins A and B,
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`Avrainvillamide, Spirotryprostatins, TMC-95A/B, Rottlerin and Antimycin amongst many
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`others. Amongst these natural compounds my laboratory has studied, many have nitrogen-
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`substituted and/or oxygen-substituted aromatic rings.
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`8.
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`I served as the Principal Investigator on a research grant from the National Cancer
`
`Institute entitled: “Multiple Myeloma and Cancer Therapies via Largazole Analogs” (September
`
`1, 2010 – June 30, 2015) wherein a sub-contract to Professor James E. Bradner’s laboratory at
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`Harvard Medical School supported biochemical, cell biology, and pre-clinical studies on
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`developing histone deacetylase inhibitors (HDACI’s) is for treating multiple myeloma as both
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`stand-alone and synergistic combination drug therapies.
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`9.
`
`I have an active and formal collaboration with Dr. Douglas H. Thamm, VMD and
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`Dr. Daniel Gustafson, VMD of the Colorado State University Animal Cancer Center on several
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`projects aimed at developing novel anti-cancer therapies for companion animals and humans.
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`This collaborative work has involved formulation of new anti-cancer drugs for potential clinical
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`use and formulations of drugs prepared in my laboratory have been used in animal studies
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`directed by Dr. Thamm.
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`10.
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`I held a special research grant from the Multiple Myeloma Research Foundation
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`from 2009-2011, the prestigious Multiple Myeloma Research Foundation Senior Award that
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`helped support our research program on developing a drug for multiple myeloma.
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`11.
`
`I held a funded research collaboration with the Infectious Diseases Research
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`Institute (IDRI), in Seattle, Washington, to develop several novel adjuvants for the treatment and
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`prevention of autoimmune diseases, infectious diseases and cancer (2010).
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`12.
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`From 1991-1993, I held a research grant from Symphony Pharmaceuticals,
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`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.
`
`13.
`
`I have taught undergraduate and graduate courses in organic chemistry, organic
`
`synthesis, biosynthesis, biological chemistry, drug design, and the synthesis of natural products.
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`I have also lectured at numerous professional conferences, universities, and in corporate R&D
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`laboratories in those areas.
`
`14.
`
`I am familiar with the β-adrenergic receptor agonist and antagonist family of
`
`compounds, including neurotransmitters, such as norepinephrine, cocaine, morphine-based
`
`alkaloids and many other classes of natural and non-natural agents. I teach graduate level
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`courses on the mechanism of action of drugs, the biosynthesis of primary and secondary
`
`metabolites and the synthesis of natural compounds and their derivatives in which I cover β-
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`adrenergic receptor agonist and antagonist families.
`
`15.
`
`I am a Scientific Founder, Acting President and Chair of the Scientific Advisory
`
`Board of Cetya Therapeutics, a company that is developing drugs including those for the
`
`treatment of various cancers, multiple myeloma, autoimmune diseases and hemoglobinopathies,
`
`and I am directing all of the early process chemistry, medicinal chemistry, and drug formulation
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`-4-
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`studies being conducted on Cetya’s HADC inhibitors. This includes injectable formulations as
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`well as oral and topical formulations. Specifically, I directed and supervised post-doctoral
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`researchers in my laboratory (on behalf of Cetya Therapeutics) to formulate the poorly water-
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`soluble drug Largazole, including a myriad of synthetic analogs of Largazole prepared in my
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`laboratory, as an injectable polysorbate-80/ethanol co-solvent excipient system. This formulation
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`has been used in animal studies for obtaining critical dose-escalation and pharmacokinetic data.
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`I have also specifically directed and supervised the formulation of Largazole and related analogs
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`in various PEG-based (polyethylene glycol) excipient systems. This work is currently being
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`conducted in collaboration with oncologist Dr. Douglas Thamm of the Colorado State University
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`Animal Cancer Center, pharmacologist Dr. Dan Gustafson of the Colorado State University
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`Animal Cancer Center, and Dr. James E. Bradner, formerly of the Dana-Farber Cancer Institute
`
`(now President of the Novartis Biomedical Research Institute). The animal studies commenced
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`in 2009, and the drug formulation studies are being conducted in my laboratory at Colorado State
`
`University under my direction.
`
`16.
`
`I was a Scientific Founder, Member of the Scientific Advisory Board, and
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`Member of the Corporate Board of Directors for Xcyte Therapies, a company devoted to
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`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
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`Therapies, I was deeply involved in writing the patents and developing formulation strategies for
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`both topical and injectable drugs based on FK228 (Romidepsin).
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`17.
`
`As a Scientific Founder and Acting Vice-President of Discovery Chemistry of
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`HemaQuest Pharmaceuticals (Seattle, Washington), I have directed the pre-clinical and clinical
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`formulation studies of several of the companies’ drugs. These included both water-soluble drugs
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`and hydrophobic, poorly water-soluble drugs for therapeutic applications in both cancer and
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`hemoglobinopathies. Oral formulations have been devised and tested on several families of
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`small-molecule drugs for the treatment of various hemoglobinopathies.
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`18.
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`In addition, I am a Scientific Founder and member of the Scientific Advisory
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`Board of Sapientia Therapeutics, located in Philadelphia, Pennsylvania (which just underwent a
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`reverse merger with BriaCell Therapeutics). I am the acting Director of the Medicinal
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`Chemistry, Process Chemistry and Drug Formulation efforts of this company to develop novel
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`small-molecule inhibitors of protein kinase C-delta for autoimmune diseases, cancer and
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`scleroderma. My laboratory has synthesized the first lead compounds, which are protein kinase
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`C-delta (PKC-δ) inhibitors and are water-insoluble substances. Under my direction we have
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`solubilized our lead drug candidate in both polysorbate-80/ethanol as well as PEG-based
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`excipient systems for animal studies which have recently commenced.
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`19.
`
`In connection with all of the above activities, I have read extensively on
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`pharmaceutical drug formulation, and have consulted on a number of occasions with
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`pharmaceutical and biopharmaceutical companies on various aspects of medicinal chemistry,
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`structure-activity relationships (SAR), pharmaceutical drug formulation and process chemistry .
`
`20.
`
`I am familiar with various classes of pharmaceutical drugs and cover material
`
`relevant to numerous structural families of drugs in my graduate courses on Medicinal Chemistry
`
`and Chemical Biology, which I have been teaching at Colorado State University for over thirty-
`
`five years. In my capacity as reviewer for proposals submitted to the National Institutes of
`
`Health, when I served as a member of the SBCB (Synthetic and Biological Chemistry) Study
`
`Section, as a co-Director of the CSU Cancer Supercluster, and as Director of the Colorado
`
`Center for Drug Discovery, I have reviewed and critiqued numerous research proposals dealing
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`
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`-6-
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`with various aspects of drug discovery and development including their preparation, mechanism
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`of action, metabolism and formulation. I read the chemical literature on medicinal chemistry
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`broadly and have been the recipient of numerous research grants from the National Institutes of
`
`Health over my career to conduct medicinal chemistry research on numerous structural families
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`of biomedically relevant drugs and drug candidates.
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`21. My laboratory at Colorado State University has synthesized numerous naturally
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`occurring and non-natural drugs and heterocycles including thiazole-containing natural products
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`and their analogs; most recently Largazole and analogs. I am very familiar with the literature
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`and chemistry relevant to the synthesis, stereochemistry, mode of action, and biochemistry of
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`nitrogen-containing compounds.
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`22.
`
`I have delivered numerous named and plenary lectures at Universities,
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`corporations, and scientific societies on the chemistry, biology and mechanism of action of
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`numerous classes of therapeutic agents, as detailed in my curriculum vitae.
`
`23.
`
`I have published more than 320 scientific research articles, authored numerous
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`chapters in books, and have written a well-known textbook on the synthesis of optically active
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`amino acids. I am also a named inventor on twenty-one issued U.S. Patents and published Patent
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`Applications.
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`24.
`
`I have served on the Editorial board for Chemistry & Biology, and served as
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`Editor for the Organic Chemistry Series published by Pergamon Press and Elsevier (1997-2012),
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`and Mini Reviews in Organic Chemistry (Bentham Science). I have served as an editor for
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`several other journals in the past, including Tetrahedron: Asymmetry, Tetrahedron Publications,
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`Amino Acids, and the Journal of the American Chemical Society.
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`25.
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`I am a member of the American Chemical Society, the Japan Antibiotics Research
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`Association, the International Society of Heterocyclic Chemistry and the American Association
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`for the Advancement of Science. I am a Member of the University of Colorado Cancer Center,
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`located in Aurora, Colorado. I have served as organizer or co-organizer of numerous scientific
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`meetings and symposia and served as the Vice President of the International Society of
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`Heterocyclic Chemistry, Chairing the 2003 International Congress of Heterocyclic Chemistry.
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`26.
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`I currently serve on the Scientific Advisory Board of Arch Therapeutics, located
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`in Boston, Massachusetts, that is developing self-assembling peptides for wound healing and
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`surgical closure. I am currently advising on and directing the medicinal chemistry efforts at
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`Arch.
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`27.
`
`I have also served on the Scientific Advisory Boards for a number of other
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`companies. I currently serve on the External Advisory Committee for the Puerto Rico Alliance
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`for the Advancement of Biomedical Research Excellence. I was a Scientific Founder, Director
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`of Chemistry, and member of the Scientific Advisory Board for HemaQuest Pharmaceuticals. I
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`was a Founding Scientist and Member of the Scientific Advisory Board of Microcide
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`Pharmaceuticals from 1993 to 1998. I also served on the Scientific Advisory Board and was a
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`member of the corporate Board of Directors of Xcyte Therapies from 1996-2006.
`
`28.
`
`I have expertise in drug formulation for injectable, topical and oral medications. I
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`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
`
`and/or consultant for companies developing medicines for numerous therapeutic indications. I
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`have consulted on many aspects of pharmaceutical drug discovery, development, formulation,
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`and manufacturing. This includes basic discovery and optimization, early process research,
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`large-scale manufacturing and drug formulation.
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`29.
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`I have served as a consultant for a number of companies for both drug discovery
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`and process research applications, including, for example, W.R. Grace Company (1985-1990,
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`fine chemicals synthesis; process manufacturing); Symphony Pharmaceuticals (1991-1993, anti-
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`HIV drugs); G.D. Searle Co. (1988-1990, memory and learning enhancement agents);
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`Nutrasweet Co. (1990-1991, artificial sweeteners; large-scale manufacturing of Aspartame);
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`EPIX Medical (1993-1997, MRI imaging and contrast agents); Hoffman-La Roche, Inc. (1989-
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`1992, cephalosporin-fluoroquinolone dual-action antibacterial agents); Boehringer-Ingelheim
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`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, antibiotics including anti-MRSA
`
`cephalosporins and quinolones; process development for the preparation of Microcide’s lead
`
`anti-MRSA cephalosporin); Xcyte Therapies (1996-2006, T-cell activation); Ajinomoto Co,
`
`Japan (2002-2013, process chemistry of unnatural amino acids, peptides, heterocycles, and other
`
`advanced pharmaceutical intermediates); HemaQuest Pharmaceuticals (2006-2014, small-
`
`molecule drugs 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, HIV, multiple myeloma,
`
`autoimmune diseases, and hemoglobinopathies).
`
`30.
`
`I have also testified at trial as an expert in process and medicinal chemistry.
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`Specifically, I testified at trial (before the Honorable Judge Farnan) on behalf of plaintiff Great
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`Lakes Chemical in the Great Lakes Chemical versus Archimica SPA, in Civil Action No. 99–
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`728-JJF concerning the manufacture of the anti-HIV drug Nelfinavir. I also testified at trial
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`(before the Honorable Judge Kaplan) on behalf of defendant/counter plaintiff Lunbeck in the
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`Lundbeck versus Infosint. 06 Civ. 2869 (LAK) concerning the manufacture of Citalopram and
`
`Escitalopram. I testified at trial as an expert in medicinal chemistry and process chemistry
`
`(before the Honorable Judge Sheridan) on behalf of plaintiff United Therapeutics in the United
`
`Therapeutics Corp. versus Sandoz, Inc. C.A. Nos.: 12-1617 (PGS)(LHG) and 13-316 (PGS)
`
`(LHG) concerning the prostacyclin analog Treprostinil.
`
`31.
`
`During my career as a Professor of Chemistry at Colorado State University, I have
`
`trained numerous scientists who have gone on to careers in the pharmaceutical industry in both
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`medicinal chemistry and process chemistry. In particular, several of my former co-workers have
`
`had very successful careers in pharmaceutical medicinal chemistry and process chemistry
`
`research which is evident from my CV.
`
`32.
`
`I have been awarded numerous prizes and awards including the NIH Research
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`Career Development Award (1984-89), the Eli Lilly Young Investigator Award (1986), the
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`Merck, Sharp & Dohme Academic Development Award (1991), The Japanese Society for the
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`Promotion of Science Fellowship Award (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), The Japanese Society for the
`
`Promotion of Science Long-term Fellowship Award (2012-2013), and the local Rocky Mountain
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`section of the American Chemical Society Organic Synthesis Award (2012).
`
`33.
`
`A summary of my education, experience, publications, awards and honors,
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`patents, publications, and presentations is provided in my CV, a copy of which is submitted
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`separately (Ex. 1003).
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`II.
`
`SCOPE OF WORK
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`34.
`
`I understand that a petition is being filed with the United States Patent and
`
`Trademark Office (“PTO”) for Inter Partes Review of U.S. Patent No. 6,346,532 (hereinafter,
`
`“the ’532 Patent,” Ex. 1001). I have been retained by Sawai USA, Inc. and Sawai Pharmaceutical
`
`Co., Ltd. as a technical expert to provide opinions regarding the ’532 Patent. I have reviewed the
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`’532 Patent and relevant sections of its prosecution history in the U.S. Patent and Trademark
`
`Office (Ex. 1015) as well as Astellas’ request for supplemental examination and the
`
`reexamination proceeding that followed (Ex. 1007). I have also reviewed and considered other
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`documents in arriving at my opinions, and cite them
`
`in this declaration. For convenience,
`
`documents cited in this declaration are listed in Appendix A.
`
`35.
`
`I am compensated at the rate of $650.00/hour for my work. No part of my
`
`compensation depends upon the outcome of this matter or the substance of my testimony. I have
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`no financial interest in the outcome of this matter.
`
`III.
`
`OVERVIEW OF THE ‘532 PATENT
`
`36.
`
`The ’532 Patent is titled “Amide Derivatives or Salts Thereof.” Ex. 1001. I have
`
`been advised that the ‘532 Patent originally issued on February 12, 2002. I also understand that
`
`Astellas filed a request for supplemental examination of the ‘532 Patent on November 21, 2013
`
`and that the PTO conducted an ex parte reexamination of the ‘532 Patent in light of Astellas’
`
`request. During reexamination, I understand that Astellas cancelled Claims 2, 7, 8 and amended
`
`other claims. I understand that the PTO issued an ex parte reexamination certificate for the ‘532
`
`Patent on February 24, 2015. I also understand that the ‘532 Patent claims priority to Japanese
`
`Application 9-285778, filed October 17, 1997.
`
`37.
`
`The ‘532 Patent is generally directed to phenylethanolamine compounds said to
`
`have selective stimulative action on the β3-adrenergic receptor (i.e. they are selective β3-
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`agonists), which purpotedly makes them useful as a diabetes remedy. See, e.g., Ex. 1001 at
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`Abstract. According to the ‘532 Patent, all of the thousands (if not, millions) of compounds
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`disclosed in the specification are “useful for the therapy of diabetes mellitus, having both an
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`insulin secretion promoting action and an insulin sensitivity potentiating action and further
`
`having anti-obesity and anti-hyperlipemia actions due to a selective stimulating action of β3-
`
`receptors ….” Id. at Col. 2:33-37.1
`
`38.
`
`Independent Claim 1 of the reexamined ‘532 Patent discloses a large genus of
`
`compounds, which are called “amide derivatives” by Applicants, having the general formula:
`
`
`
`Ex. 1001 at Col. 2:31-50. These compounds are essentially phenylehtanolamine derivatives
`
`(highlighted in red) with a variety of amide substituents X-B (highlighted in blue).
`
`39.
`
`There is a significant amount of structural variation between the different
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`molecules that are disclosed in Claim 1 as the compounds of the invention. Ex. 1001 at Col. 44;
`
`Claim 1. While there are at least hundreds of thousands of distinct compositions of matter
`
`encompassed by Claim 1, the ’532 Patent only discloses 113 actual examples with identified
`
`specific structures. Ex. 1001 at Cols. 16:5-28:67. Despite only having slightly more than one
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`hundred examples, a POSA would be able to envision multiple different structural variations
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`based on a written description of different possible substitutions in the large genus of Claim 1
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`1 The patentee is using the term “hyperlipemia,” which a POSA would understand to mean
`“hyperlipidemia.”
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`-12-
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`and also have a reasonable expectation about the activity of such structures. Of those 113
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`examples, 103 have the following core structure:
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`40.
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`Dependent Claims 3, 4, 9, and 15 define various subgenera of the compounds in
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`Claim 1. Below are Claims 1, 3, 4, 9 and 15 as they appear in the Ex Parte Reexamination
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`Certificate (Note: subject matter enclosed in heavy brackets [ ] appeared in the patent, but has
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`been deleted and is no longer part of the patent; matter printed in italics indicates additions made
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`to the patent):
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`41.
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`Independent Claim 5 is directed to a specific compound or salts thereof:
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`42.
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`The compound of Claim 5 is also known as (R)-2-(2-aminothiazol-4-yl)-4′-[2-(2-
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`hydroxy-2-phenylethyl)amino]ethyl]acetanilide or Mirabegron. For convenience, this compound
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`will be referred to as “Mirabegron.”
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`43. Mirabegron is one species within the large genus of Claim 1 and the subgenera of
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`Claims 3, 4, 9, and 15. Ex. 1001 at Col. 44-46; Reexam. Cert. at 1-2. Mirabegron is also one of
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`the nine compounds (excluding salts) encompassed by independent Claim 6. Ex. 1001 at Col.
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`
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`45:30-46:5.
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`44.
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`Dependent Claim 11 is directed to a composition comprising the compound of
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`Claim 5 or a salt thereof and a pharmaceutically acceptable carrier. Dependent Claim 12 is
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`directed to a composition comprising at least one compound of Claim 6 and a pharmaceutically
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`acceptable carrier. Dependent Claim 16 are directed to a composition comprising at least one
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`compound of Claims 1, 3, 4, and 15 and a pharmaceutically acceptable carrier. Claims 11, 12,
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`15 and 16 are reproduced below:
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`45.
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`In my opinion, and as explained in detail below, claims 1, 3-6, 9, 11, 12, 15, and
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`16 of the ’532 Patent would have been obvious to a person of ordinary skill in the art (“POSA”)
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`at the time of the earliest priority filing date of the ’532 Patent, i.e., prior to October 17, 1997.
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`IV.
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`FILE HISTORY OF THE ‘532 PATENT
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`46.
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`I have been advised that the ‘532 Patent originally issued from U.S. Application
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`No. 09/529,096 (“the ’096 Application”), which was filed with the PTO on April 7, 2000 as the
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`U.S. national phase application for PCT/JP98/04671, which was filed on October 15, 1998,
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`claiming priority to Japanese Application 9-285778, filed on October 17, 1997. I have reviewed
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`the file history of the ‘096 Application (Ex. 1015).
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`47.
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`The ’096 Application was filed with eight claims, of which Claims 1, 5, and 6
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`were independent. Ex. 1015 at PTO_00000163-66. On November 22, 2000, in response to a
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`October 27, 2000 Restriction Requirement (id. at PTO_00000634-38), Applicants provisionally
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`elected to prosecute Claims 1-8 drawn to compounds, compositions, and methods of use for
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`Formula I wherein Z is CH, with traverse (id. at PTO_00000639-41). Applicants also
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`provisionally elected, with traverse, the species of Examples 7, 12, and 41 (which is Mirabegron
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`dihydrochloride salt). Id. at PTO_00000641-42.
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`48.
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`On December 7, 2000, the Examiner rejected all of the claims of the ’096
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`Application. Ex. 1015 at PTO_00000643-53. Among other reasons, the Examiner rejected all of
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`the claims as anticipated by Japanese Application No. H10-218861 (Ex. 1007 at PTO_00001255-
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`98 (English translation); 1299-1318 (Japanese original), “JP ‘861”) and as obvious over DE
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`3743265 (“Schromm”) in view of a 1991 article by Konosu, Toshiyuki (“Konosu, Toshiyuki”)2
`
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`2 The full citation for Konosu, Toshiyuki is Konosu, T.; Tajima, Y.; Takeda, N; Miyaoki, T.;
`Kasahara, M.; Yasuda, H.; Oida, S., “Triazole Antifungals IV. Synthesis and Antifungal
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`-16-
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`based on the structural similarities between the compounds disclosed therein and the claimed
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`compounds and the motivation to combine these two references because of the therapeutic utility
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`of the similar compounds. Ex. 1015 at PTO_0000648-51.
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`49.
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`On May 4, 2001, Applicants responded by cancelling Claim 8, amending Claims
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`1, 3, and 5-7, and adding Claims 10-13. Ex. 1015 at PTO_00000655-61, 672-75. Regarding the
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`prior art rejections, Applicants argued that JP ‘861 is not prior art and therefore could not
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`anticipate. Id. at PTO_00000667-68. Applicants further argued that the claims were not obvious
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`because there was no motivation to combine broncholytic compounds (disclosed in Schromm)
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`with antifungal compounds (disclosed in Konosu, Toshiyuki). Id. at PTO_00000668-69. They
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`further argued that there was no reasonable expectation of success because the compounds in
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`Schromm were “so structurally different, and in a different field of endeavor” from those in
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`Toshiyuki. Id. at PTO_00000669.
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`50.
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`On June 19, 2001, the Examiner withdrew his previous rejections of anticipation
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`and obviousness. Ex. 1015 at PTO_00000821. However, the Examiner added a new rejection
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`for obviousness over U.S. Patent No. 5,223,614 (Ex. 1018, “Schromm US614”). Id. at
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`PTO_00000823-24. The Examiner stated that “Claim 1 in the instant application differ[s] from
`
`the [the ‘614 Patent] reference by reciting more limited subgenus, however it is obvious to a
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`chemist skilled in the art to select any species of the genus that will have reasonably similar
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`properties and equal or better pharmaceutical use.” Id. at PTO_00000823. I agree with this
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`proposition.
`
`
`Activities of 3-Acylamino-2-aryl-2-butanol Derivatives,” Chem. Pharm. Bull., 39/10, 2581-89
`(1991). Applicants referre