`___________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
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`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
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`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
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`U.S. Patent No. 9,284,342
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`___________
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`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
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`I.
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`II.
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`TABLE OF CONTENTS
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`QUALIFICATIONS ....................................................................................... 1
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`SCOPE OF WORK.......................................................................................... 7
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`III. OVERVIEW OF THE ‘342 PATENT ............................................................ 8
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`IV. FILE HISTORY OF THE ‘342 PATENT ....................................................... 9
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`V.
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`LEGAL STANDARDS ................................................................................. 12
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`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 14
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`VII. CLAIM CONSTRUCTION .......................................................................... 14
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`VIII. BACKGROUND KNOWLEDGE IN THE ART ......................................... 15
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`A. Nucleoside Analog Drugs Inhibited Viral Diseases ........................... 15
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`B.
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`C.
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`D.
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`E.
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`F.
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`G.
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`Some Nucleoside Drugs Were Poor Substrates for Phosphorylation . 19
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`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation ............................................................ 20
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`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome the
`Problem of Poor Phosphorylation ....................................................... 20
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`ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity .............. 22
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`ProTide Analogs of Compound 1D Were Active Against HCV ........ 23
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`Pharmaceutical Solids Could Exist in Multiple Forms ....................... 25
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`H. A Solid-State and Polymorph Screen Would Always Evaluate the
`Interactions of Water with a New Drug Candidate ............................. 27
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`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 29
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`A. WO 2008/121634 to Sophia (“Sophia ‘634”) ..................................... 29
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`B. WO 2005/003147 to Clark (“Clark”) .................................................. 31
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`C.
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`Sofia et. al., “Discovery of a b-D-2’-Deoxy-2’-a-fluoro-2’-b-C-
`methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of
`Hepatitis C Virus” J. Med. Chem., 2010, 53, 7202-7218 (“Sofia
`2010") .................................................................................................. 33
`
`D. Ma et. al., “Characterization of the Metabolic Activation of Hepatitis
`C Virus Nucleoside Inhibitor b-D-2’-Deoxy-2’-Fluoro-2’-C-
`methylcytidine (PSI-6130) and Identification of a Novel 5’-
`Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-29820
`(Ma) ..................................................................................................... 35
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`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘342 PATENT ........................................ 37
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`A. Claims 1-4 Were Obvious Over Sofia ‘634 and Sofia 2010 ............... 37
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`B.
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`C.
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`Claims 1-4 Were Obvious Over Sofia ‘634 and Ma ........................... 44
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`Claims 1-4 Were Obvious Over Clark ‘147 and Ma .......................... 50
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`XI. CONCLUSION .............................................................................................. 56
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`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 58
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`I, Joseph M. Fortunak, declare as follows:
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`I.
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`QUALIFICATIONS
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`1. My name is Joseph M. Fortunak. I am a Professor of Chemistry and
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`Pharmaceutical Sciences at Howard University, in Washington, D.C., where I
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`regularly teach courses in Organic Chemistry to undergraduate students. I also
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`teach courses in drug discovery, drug development, pharmaceutical chemistry,
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`pharmaceutical sciences, and green chemistry/chemical synthesis to PharmD and
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`PhD students in Chemistry and Pharmacy.
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`2.
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`I received my Bachelor of Science in Chemistry from Purdue
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`University in 1976, and my Doctorate in Philosophy in Organic Chemistry from
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`the University of Wisconsin-Madison in 1981. After earning my Ph.D., I was a
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`postdoctoral fellow and a research assistant professor at Cambridge University in
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`the United Kingdom from 1981-1983.
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`3. My career has spanned both the industrial and academic sectors,
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`including senior managerial and academic appointments.
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`4.
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`From 1983-1993, I worked at SmithKline Beecham Pharmaceutical
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`Corp., and served as Associate Senior Research Investigator, Senior Research
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`Investigator and Assistant Director. During that time, I was primarily responsible
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`for inventing processes to synthesize active pharmaceutical ingredients (“APIs”)
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`for investigational new drugs, including the drugs halofantrine, ropinerole,
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`topotecan and eprosartan, which the U.S. Food and Drug Administration (“FDA”)
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`has approved.
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`5.
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`From 1993-2000, I worked at DuPont Pharmaceutical Company
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`(“DuPont”), and served as Associate Director, Director, Senior Director and
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`Executive Director. During my tenure at DuPont, among other responsibilities, I
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`led the API development team for the major anti-HIV drug efavirenz, which is an
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`inhibitor of HIV-1 reverse transcriptase. I was also responsible for building a pre-
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`formulations group of experts in organic, solid-state chemistry (i.e. crystalline
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`forms, polymorphs, solvates, hydrates and amorphous forms), and for managing
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`the interface(s) between the API, Formulations, and Analytical groups at DuPont.
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`6.
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`From 1993-1999 I also served on the Scientific Advisory Board for
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`NaPro Biotherapeutics in Boulder, Colorado, working on a commercial semi-
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`synthesis of the anti-cancer drug paclitaxcel from renewable biomass.
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`7.
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`From 2000-2004, I worked at Abbott Laboratories as the Head of
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`Global Chemical Development. In that position I was responsible for managing
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`chemistry, engineering, and analytical development for all of Abbott's new drug
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`candidates. During that time, I built a Process Engineering Department with
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`expertise in separation sciences, solids engineering and process modeling. I also
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`was responsible for process validation for four New Drug Applications, including
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`XIENCE™ V drug-device combination (a coronary stent), and emtricitabine, an
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`anti-HIV drug that is a nucleoside reverse transcriptase inhibitor. My
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`responsibilities in this role included oversight for the API and physiochemical pre-
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`formulation activities for all new drug candidates, route discovery, polymorph
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`control, clinical supplies, analytical & process development and validation for
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`Abbott Labs and external customers. I was responsible for manufacturing several
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`small-volume, commercial products for Abbott Labs and external customers.
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`8.
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`I have, in the past, served as an industry representative to the FDA
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`/ICH Q7A Committee on guidelines for active pharmaceutical ingredients. I have
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`also served as Chair of the Regulatory and Compliance Section for the Midwest
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`Pharmaceutical Process Chemistry Consortium.
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`9. While employed as a scientist and manager in the innovator
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`pharmaceutical industry (1983-2004), I contributed to over 100 new chemical
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`entities that moved from discovery into development; approximately 15 of these
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`compounds were for the treatment of viral diseases. I also contributed to the
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`development and approval of twelve new drug applications (“NDAs”) approved
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`for marketing and a substantial number (approximately 20+) of generic products.
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`10.
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`I have consulted with a number of pharmaceutical companies on
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`issues relating to drug discovery, drug development, API and Finished
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`Pharmaceutical Product drug development and drug production
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`11. From 2004 to the present, as noted above, I have served as a Professor
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`of Chemistry and Pharmaceutical Sciences at Howard University in Washington,
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`DC. My research group of PhD/PharmD/MSc and undergraduate students develops
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`new science to decrease the cost of and increase access to quality-assured
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`medicines for low- and middle-income countries. We have contributed to new
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`chemistry and technologies that have improved production and reduced cost of
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`several drugs for HIV/AIDS, Malaria, TB, and opportunistic infections, including
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`the antiviral (HIV) drugs efavirenz, tenofovir disoproxil fumarate, darunavir,
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`dolutegravir, and atazanavir.
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`12.
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`In 2005, I helped found the Drug Access Technical Team of the
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`William J. Clinton Health Access Initiative where I contributed to increasing
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`global access to medications of assured quality at affordable prices, including
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`HIV/AIDS, malaria and tuberculosis medications.
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`13.
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`I presently work with organizations including the World Health
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`Organization, UNITAID, UNIDO, and the Medicines Patent Pool on novel
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`chemistry, formulations, and regulatory sciences for manufacturing, market
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`dynamics and regulation of quality-assured medicines for low- and middle-income
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`countries.
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`14. Since 2008 I have regularly taught a curriculum in drug discovery,
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`development, and manufacturing at the St. Luke Foundation/Kilimanjaro School of
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`Pharmacy (“KSP”) in Moshi, Tanzania, and the School of Pharmacy/Center for
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`Drug Discovery, Development, and Pharmaceutical Production (CDDDP) at the
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`University of Ibadan in Nigeria. This curriculum focuses on the science and
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`practice of drug discovery and development. My "students" include pharmaceutical
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`professionals, national drug regulators, and university professors. As part of the
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`curriculum, students learn how to formulate drugs, including dosage form design,
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`granulation, milling, drying, compression, coating, and process validation. This
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`teaching includes a focus on crystalline forms of pharmaceutical solids including
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`polymorphs, hydrates, solvates, and amorphous forms and their impact on APIs
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`and drug products. This curriculum has received numerous awards, including a
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`2013 US FDA Honor Award for excellence and innovation in teaching and drug
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`regulatory sciences.
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`15.
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`I also have served or currently serve as an adjunct professor at the
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`University of Alabama, Green Chemistry Manufacturing Institute, the Kilimanjaro
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`School of Pharmacy and the University of Ibadan in Nigeria. I am on the Scientific
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`Advisory Board of the Royal Society of Chemistry (UK) as an expert in Green
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`Chemistry.
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`16.
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`I have published over 75 peer-reviewed papers, book chapters, and
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`monographs. I have made hundreds of presentations in the areas of my expertise. I
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`am also an inventor on approximately 35 patents worldwide in the areas of
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`chemical synthesis, green chemistry, drug synthesis, and drug manufacturing. I
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`have managed approximately 800 professionals in the course of my career,
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`approximately 500 of whom are PhD-level scientists.
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`17. From 2006-2011, I was on the editorial board of the journal Current
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`Opinion in Drug Development. I am currently on the editorial boards of the Journal
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`of Tropical Pharmaceutical Research; I am also on the editorial board of the Royal
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`Society of Chemistry, Green Chemistry Journal.
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`18.
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`I have received several honors and awards for my research and
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`teaching work. Among many others, I have been awarded the Howard University
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`Faculty Senate Award for contributions to Africa and the African Diaspora, the
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`American Chemical Society “Astellas Foundation” Prize for Chemistry Impact on
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`Human Health, for, among other things, global access to anti-HIV drugs, the
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`African Union award for Corporate Social Responsibility, and a Corporate Award
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`from Abbott Labs for manufacturing improvements that reduced the rate of volatile
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`organic emissions (VOEs) over the island of Puerto Rico by over 60%.
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`19. My research has focused on the study of new synthetic chemistry and
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`methodology for the manufacture of essential medicines for the treatment of
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`HIV/AIDS, malaria and tuberculosis. I also currently work on new technologies for
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`Green Chemistry, safety and waste reduction. I am also heavily involved in
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`teaching drug development and industrial pharmacy in Low- and Middle-Income
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`Countries to enable local production of essential medicines according to
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`international standards of Current Good Manufacturing Practice (cGMP).
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`20. Further details concerning my education, employment history and
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`experience are set forth in my Curriculum Vitae which is submitted separately.
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`EX1003.
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`II.
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`SCOPE OF WORK
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`21.
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`I understand that a petition is being filed with the United States Patent
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`and Trademark Office for Inter Partes Review of U.S. Patent No. 9,284,342 (“the
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`’342 patent”; EX1001). I have been asked by the Petitioner to be a technical expert
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`to provide analysis and opinions regarding the ’342 patent. I have reviewed the
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`’342 patent and relevant sections of its prosecution history in the United States
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`Patent and Trademark Office. EX1004. I have also reviewed and considered
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`various other documents in arriving at my opinions, and cite them in this
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`declaration. For convenience, documents cited in this declaration are listed in the
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`Appendix below.
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`22.
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`I am the Pharmaceutical Scientist at Initiative for Medicines, Access
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`& Knowledge (I-MAK), Inc., Petitioner in this matter. I am not receiving any
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`additional compensation for my study and testimony in this matter, but I am being
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`reimbursed for reasonable and customary expenses. My position and compensation
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`are not contingent on the outcome of this matter or the specifics of my testimony.
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`23. This report sets forth the opinions that I have formed based on
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`information available as of the date below. If other material is introduced during
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`this matter that may fall within my area of expertise, I may have relevant and
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`important opinions regarding such material. I reserve the right to offer such
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`opinions if they may be relevant or important as such material is introduced. I
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`further reserve the right and intend to testify and offer additional opinions in
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`response to any opinions offered by Patent Owner or its witnesses.
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`III. OVERVIEW OF THE ‘342 PATENT
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`24. The ‘342 patent claims a crystalline compound represented by the
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`following formula:
`
`EX1001 at 89:42-58.
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`
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`
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`25.
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`In describing the claimed invention, the ‘342 patent states:
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`Disclosed herein are nucleoside phosphoramidates and their use as
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`agents for treating viral disease. These compounds are inhibitors of
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`RNA-dependent RNA viral replication and are useful as inhibitors of
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`HCV NS5B polymerase, as inhibitors of HCV replication and for
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`treatment of hepatitis C infection in mammals.
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`EX1001 at 1 (Abstract).
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`26. The '342 patent discloses that form 6 of the SP-4 compound is the
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`form with XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7. EX1001 at 76:9-42. The
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`'342 patent also discloses that there are at least two ways that the crystalline form 6
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`of SP-4 can be obtained from form 1 of the same compound: 1) suspension in water
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`(at 5-50 mg/mL) at ambient temperature for a few hours; and 2) grinding followed
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`by slow conversion to form 6 upon standing exposed to atmospheric humidity.
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`EX1001 at 73:10-50.
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`27. The following chart describes claims 1-4 of the ‘342 patent:
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`Claim(s)
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`Recite
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`1
`
`2
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`3, 4
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`Crystalline compound represented by the formula above having
`XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7.
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`Pharmaceutical composition having the crystalline compound of
`claim 1 and a pharmaceutically acceptable medium.
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`Method of treating a hepatitis C virus infection in a human by
`administering the compound of claim 1, alone or with another
`antiviral agent.
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`IV. FILE HISTORY OF THE ‘342 PATENT
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`28. U.S. Patent Application No. 13/925,078 (“the ‘078 application) was
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`filed on June 24, 2013, and issued as the ‘342 patent on March 15, 2016. The ‘078
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`application claimed priority as a continuation of U.S. Patent Application No.
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`13/076,552 (“the ‘552 application”) filed on Mar. 31, 2011, which claimed priority
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`as a continuation-in-part of U.S. Patent Application No. 12/783,680 (“the ‘680
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`application”) filed on May 20, 2010. The ‘078 application also claimed priority to
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`U.S. Provisional Applications Nos. 61/319,513 and 61/319,548, both of which
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`were filed on Mar. 31, 2010, and U.S. Provisional Application 61/179,923 filed on
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`May 20, 2009.
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`29. During prosecution of the ‘078 application, the Examiner made a
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`single substantive rejection of double patenting, which the Patent Owner overcame
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`by submitting a terminal disclaimer. EX1004 at 175. The Examiner then issued a
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`Notice of Allowance stating in part:
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`The claimed invention is seen to be novel and non-obvious over
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`the prior art. The prior art does not disclose a crystalline composition
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`of the claimed compound having the claimed XRPD peaks.
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`References to the claimed compound in the prior art (see for example
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`Sofia et al. WO2008/121634, reference included with PTO-1449) do
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`not disclose the specific crystal structure described in the claims, or a
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`method of preparing a crystalline form of the compound that would
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`have resulted in that particular crystal. Because of the unpredictability
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`of crystalline polymorphs, one of ordinary skill in the art would not
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`have been able to, based on the prior art disclosure, predict or make
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`this particular crystal form.
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`While the prior art reference US8916538 (cited in PTO-892)
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`discloses a crystalline 2'-C-methyluridine-N-alanyl phosphoramidite
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`having an x-ray powder diffraction pattern with peaks similar to those
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`described in the claims, the compound is a thiophosphate, and
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`additionally lacks the 2'-fluoro group of the claimed compound. One
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`of ordinary skill in the art would have had no motivation to modify
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`this compound by substituting these groups to produce the claimed
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`compound.
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`For these reasons the claims are seen to meet the requirements
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`of 35 USC 102 and 103.
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`EX1004 at 183-184.
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`30. As discussed below, the Examiner’s conclusion that the failure of the
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`prior art to expressly disclose a crystalline composition having the claimed XRPD
`
`peaks rendered the claims not obvious was incorrect. While that may be a basis to
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`conclude the specific crystal structure claimed in the ‘342 patent was novel, it is
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`not a basis to conclude it was also not obvious.
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`31. During prosecution the Examiner expressly discussed priority of the
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`‘078 application, finding:
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`The parent application 12/783680, and its provisional applications
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`61/319513, 61/319548, and 61 /179923, fail to provide support for the
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`claimed invention as they do not include a written description under
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`35 USC 112 of a crystalline compound having the claimed x-ray
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`diffraction peaks. Therefore the effective filing date of the present
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`application is the filing date of the parent application 13/076552, filed
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`March 31, 2011.
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`EX1004 at 169. Patent Owner never took issue with these findings.
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`V. LEGAL STANDARDS
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`32.
`
`I understand that prior art for the purpose of this declaration includes
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`references that were published at least before March 31, 2011.
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`33.
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`I understand that a claim is not patentable under 35 U.S.C. § 103, for
`
`obviousness, if the differences between it and the prior art are such that the subject
`
`matter as a whole would have been obvious to a person of ordinary skill in the art
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`(“POSA”) at the time of the invention. I further understand that a POSA may use
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`common sense and what was general knowledge in addressing a question of
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`obviousness.
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`34.
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`I further understand that in order to find a claim obvious there is no
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`rigid rule requiring the prior art to explicitly provide a teaching, suggestion or
`
`motivation to combine references to make the claimed invention. Accordingly,
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`simple substitution of known elements for another, or use of known techniques to
`
`improve a method in a similar way, such that the substitution or techniques are
`
`“obvious to try” to a POSA who would have had a reasonable expectation of
`
`success is one manner to form the basis of establishing obviousness. I understand
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`that multiple pieces of prior art, as well as the knowledge of a POSA, may be
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`combined to establish the obviousness of a claim and that the application,
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`combination, or substitution of elements or methods known in the prior art to yield
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`predictable results may establish a prima facie case of obviousness.
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`35.
`
`I also understand that the legal analysis as to whether a chemical
`
`compound would have been obvious over the prior art involves a two-part inquiry.
`
`First, one must determine whether a POSA would have selected a “lead
`
`compound” as a starting point for further development. I understand that a “lead
`
`compound” is a compound in the prior art that would be promising to modify by
`
`making improvements to achieve a compound with better properties (i.e. activity,
`
`toxicity, etc.). Second, I understand that one must then determine whether there
`
`was a reason or motivation to modify the lead compound to arrive at the claimed
`
`invention with a reasonable expectation of success. I understand that the reason or
`
`motivation may come from the prior art, common sense, or general knowledge of a
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`POSA.
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`36.
`
`I also understand that Patent Owner may present evidence of
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`“objective indicia of non-obviousness” to rebut a prima facie case of obviousness.
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`I understand that objective indicia of non-obviousness include unexpected results,
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`long-felt but unmet needs, skepticism of those in the art, subsequent praise and
`
`acceptance by those in the art, and commercial success. I understand that these
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`factors are only relevant, though, if the Patent Owner shows there is a “nexus” —
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`i.e., a connection — between the claimed invention and the specific objective
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`indicia of non-obviousness at issue. I understand Patent Owner may raise these
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`issues in response to this declaration and I reserve my right to respond thereto.
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`VI. PERSON OF ORDINARY SKILL IN THE ART
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`37.
`
`I understand that a POSA is a hypothetical person who is presumed to
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`have known the relevant art at the time of the invention and who has the capability
`
`of understanding the scientific and engineering principles applicable to the
`
`pertinent art. I also understand that a POSA is a person of ordinary creativity, not
`
`an automaton. Thus, a POSA would be able to reproduce the subject of a claimed
`
`invention in a patent, given the required resources, without undue experimentation.
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`38. Because the ‘342 patent pertains to nucleoside compounds, a POSA
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`would have either (1) a Ph.D. in chemistry or a closely related field with some
`
`experience in an academic or industrial laboratory focusing on drug discovery or
`
`development, and would also have some familiarity with antiviral drugs and their
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`design and mechanism of action, or (2) a Bachelor’s or Master’s degree in
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`chemistry or a closely related field with significant experience in an academic or
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`industrial laboratory focusing on drug discovery and/or development for the
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`treatment of viral diseases.
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`VII. CLAIM CONSTRUCTION
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`39.
`
`I have been advised that, in the present proceeding, the ‘342 patent
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`claims are to be given their broadest reasonable interpretation in view of the
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`specification. I also understand that, absent some reason to the contrary, claim
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`terms are typically given their ordinary and accustomed meaning as would be
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`understood by one of ordinary skill in the art. I have followed these principles in
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`my analysis throughout this declaration.
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`40. The ‘342 patent provides definitions for certain claim terms. In my
`
`opinion, these definitions are conventional. Thus, there is no reason to give any of
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`the terms of the claims of the ‘342 a meaning other than their ordinary and
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`accustomed meaning.
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`VIII. BACKGROUND KNOWLEDGE IN THE ART
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`41. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of March 31, 2011.
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` Nucleoside Analog Drugs Inhibited Viral Diseases
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`42. Nucleosides were well-known to be found as structural components in
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`deoxy-ribonucleic acids (DNA) or ribonucleic acids (RNA). Nucleosides are
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`glycosylamines composed of a five-carbon sugar linked to what is known as a
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`nitrogenous base. Adenine, cytosine, guanine, thymine, and uracil are naturally-
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`occurring nitrogenous bases. Naturally-occurring, five-carbon sugar rings include
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`ribose and deoxyribose. The following table shows structures for these nitrogenous
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`bases as well as the respective products of linking these bases to ribose and
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`deoxyribose sugar rings.
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`Nitrogenous Base
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`Ribose Derivative
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`Deoxyribose Derivative
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`Adenine
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`Guanine
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`Thymine
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`Uracil
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`Cytosine
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`Adenosine (A)
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`Deoxyadenosine (dA)
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`Guanosine (G)
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`Deoxyguanosine (dG)
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`5-Methyluridine (m5U)
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`Thymidine (dT)
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`Uridine (U)
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`Deoxyuridine (dU)
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`Cytidine (C)
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`Deoxycytidine (dC)
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`43.
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`It was also well known that analogs of naturally-occurring nucleosides
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`were attractive targets for drug discovery and that such analogs were routinely
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`used to treat diseases including viral infections and cancers. Examples of such
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`drugs included idoxuridine (antiviral) and gemcitabine for the treatment of cancer.
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`Additional examples of nucleoside drugs for the treatment of viral diseases
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`included azidothymidine (AZT), stavudine (d4T), and lamivudine (3TC) for the
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`treatment of viral infections and particularly HIV. Ribavirin is another nucleoside
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`analog used for the treatment of viral diseases including hepatitis C viral
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`infections.
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`44. Acyclic nucleoside analogs were also known for the treatment of viral
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`diseases. Such drugs included aciclovir, tenofovir disoproxil fumarate (TDF) and
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`tenofovir alafenamide fumarate (TAF) for the treatment of HIV and hepatitis B
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`viral infections. Both TDF and TAF are prodrugs of the nucleotide analog
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`tenofovir/PMPA. TAF is a ProTide™ phosphonamidate prodrug of PMPA. The
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`phosphorous diastereomers of TAF were known as of 2001 to possess
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`approximately a 10-fold difference in antiviral activity against HIV. Chapman,
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`“Practical synthesis, separation, and stereochemical assignment of the PMPA pro-
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`drug GS-7340” Nucleosides Nucleotides and Nucleic Acids, 2001, 20(4-7), 621-
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`628 (“Chapman”; EX1008). TDF and TAF are also used to treat hepatitis B viral
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`infections. Id.
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`45. Nucleosides, however, were also well-known to be therapeutically-
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`useful only after intracellular, enzymatic conversion into the corresponding 5'-
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`phosphorylated analogs; generally, these are the triphosphates. This conversion
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`into the triphosphates was known to happen in a stepwise fashion, with the first
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`step being conversion to the corresponding monophosphate. McGuigan et al.
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`“Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against
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`HIV and successfully by-pass thymidine kinase,” FEBS Letters, 1994, 351, 11-14
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`(“McGuigan 1994”; EX1009).
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`46. The mono-, di-, and triphosphate forms of the C2’-deoxy-C2’-
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`methyl(up)-C2’-fluoro(down) uridine nucleoside are shown below.
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`Compounds 1A, 1B and 1C are phosphorylated analogs of an SP-4 compound (the
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`compound of '342 claim 1), while compound 1D is un-phosphorylated.
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`47.
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`It was well-known that compound 1C was a preferred compound for
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`the treatment of human hepatitis C viral infections. Ma et al. “Characterization of
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`the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor -D-2'-Deoxy-
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`2-Fluro-2'-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-
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`Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-29820 (“Ma”;
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`EX1010). For instance, it was known that the triphosphate compound 1C had a
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`much longer intracellular half-life than its cytidine analog (38 hours vs. 4.7 hours)
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`resulting in a much longer duration of action. Id. at 1 and 8.
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`
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`Some Nucleoside Drugs Were Poor Substrates for
`Phosphorylation
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`48. A problem presented itself, however, in the identification of
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`compound 1C as a promising antiviral drug. Many nucleoside drugs – in particular,
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`thymidines and uridines – were also known to be poor substrates for conversion
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`into their monophosphate forms. EX1009 (McGuigan 1994) at 1-2 and Perrone P.,
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`"Application of the Phosphoramidate ProTide Approach to 4'-Azidouridine Sub-
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`micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside," Journal
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`of Medicinal Chemistry, 2007, 50(8), 1840-1843 (“Perrone”; EX1012) at 1.
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`49. This was also known to be more common for virally-infected cells,
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`which are often kinase-deficient. Such knowledge was very important because
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`drugs that would otherwise be very potent for disease treatment would be inactive
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`if they did not undergo this phosphorylation process inside an infected cell. Id.
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` Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation
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`50. Compound 1D had been disclosed in WO 2005/003147 to Clark
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`(“Clark ‘147”; EX1007) and in Clark, J., "Design, Synthesis, and Antiviral Activity
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`of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus
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`Replication," Journal of Medicinal Chemistry, 2005, 48(17), 5504-5508 (“Clark
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`2005”; EX1011). Clark 2005 indicated that compound 1D – the unmodified
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`nucleoside - had no activity in the HCV Replicon assay. EX1011 at 3.
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`51. Ma showed, however, that the triphosphate form of 1D (compound
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`1C) was a superior agent against hepatitis C virus, with excellent potency and a
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`long intracellular half-life. EX1010 at 1 and 8.
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`52. These publications established that - although compound 1C was an
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`excellent antiviral agent - compound 1D was inactive because it could not be
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`efficiently phosphorylated inside virally-infected cells to be converted to 1C.
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`
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`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome
`the Problem of Poor Phosphorylation
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`53. ProTide prodrugs of nucleosides were first described in the early
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`1990s. EX1009 (McGuigan 1994) at 2-3. These analogs were well-known to
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`provide advantages over unmodified nucleoside drugs in terms of physicochemical
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`properties, cellular absorption, improved half-life, and very importantly, in terms
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`of overcoming the problem of lack of biological activity due to poor intracellular
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`phosphorylation. The ProTide approach had been applied to activate nucleosides
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`through kinase bypass for hepatitis C antiviral compounds as in Perrone. EX1012
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`at 1. Thus, the ProTide approach was an obvious potential solution for overcoming
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`the problem of poor intracellular phosphorylation of compound 1D.
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`54. Prior publications had disclosed that nucleoside compounds that were
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`inefficiently phosphorylated inside a virally-infected cell could be converted into
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`very active prodrugs for the treatment of viral diseases and cancer. EX1009
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`(McGuigan 1994) at 2-4; EX1012 (Perrone) at 2.
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`55. Perrone, in particular, had shown that conversion into a ProTide
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`nucleoside analog completely overcame the lack of antiviral activity in the HCV
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`Replicon Assay for the compound AZU (1), resulting in a very potent compound
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`(2) against the hepatitis C virus. EX1012. Thus, it was known that an important
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`component of nucleoside drug discovery was th