UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00211
`U.S. Patent No. 9,393,256
`
`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`QUALIFICATIONS ........................................................................................ 1
`
`SCOPE OF WORK.......................................................................................... 7
`
`III. OVERVIEW OF THE ‘256 PATENT ............................................................ 8
`
`IV. FILE HISTORY OF THE ‘256 PATENT ....................................................... 9
`
`V.
`
`LEGAL STANDARDS ................................................................................. 10
`
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 11
`
`VII. CLAIM CONSTRUCTION .......................................................................... 12
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART ......................................... 13
`
`A. Nucleos(t)ide NS5B Polymerase Inhibitors PSI-7851 and PSI-7977
`(Compound 10 in ’256) for Treating HCV Were Known ................... 13
`
`B. Nucleos(t)ide NS5B Polymerase Inhibitors Were Combined With
`Other Antiviral Agents, Including NS5A Inhibitors, To Treat HCV . 15
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 20
`
`A.
`
`Legrand-Abravanel .............................................................................. 20
`
`B. Delaney ................................................................................................ 21
`
`C.
`
`Sofia ’634 ............................................................................................ 23
`
`D. Guo ...................................................................................................... 23
`
`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ’256 PATENT ........................................ 24
`
`A. Claims 1-4 Were Anticipated By And Obvious Over Legrand-
`Abravanel ............................................................................................ 24
`
`B.
`
`Claims 1-4 Were Anticipated By Delaney .......................................... 27
`
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`C.
`
`Claims 1-4 Were Obvious Over Sofia ‘634 and Guo ........................ 31
`
`XI. CONCLUSION .............................................................................................. 34
`
`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 36
`
`
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`I, Joseph M. Fortunak, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Joseph M. Fortunak. I am a Professor of Chemistry and
`
`Pharmaceutical Sciences at Howard University, in Washington, D.C., where I
`
`regularly teach courses in Organic Chemistry to undergraduate students. I also
`
`teach courses in drug discovery, drug development, pharmaceutical chemistry,
`
`pharmaceutical sciences, and green chemistry/chemical synthesis to PharmD and
`
`PhD students in Chemistry and Pharmacy.
`
`2.
`
`I received my Bachelor of Science in Chemistry from Purdue
`
`University in 1976, and my Doctorate in Philosophy in Organic Chemistry from
`
`the University of Wisconsin-Madison in 1981. After earning my Ph.D., I was a
`
`postdoctoral fellow and a research assistant professor at Cambridge University in
`
`the United Kingdom from 1981-1983.
`
`3. My career has spanned both the industrial and academic sectors,
`
`including senior managerial and academic appointments.
`
`4.
`
`From 1983-1993, I worked at SmithKline Beecham Pharmaceutical
`
`Corp., and served as Associate Senior Research Investigator, Senior Research
`
`Investigator and Assistant Director. During that time, I was primarily responsible
`
`for inventing processes to synthesize active pharmaceutical ingredients (“APIs”)
`
`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”)
`
`has approved.
`
`5.
`
`From 1993-2000, I worked at DuPont Pharmaceutical Company
`
`(“DuPont”), and served as Associate Director, Director, Senior Director and
`
`Executive Director. During my tenure at DuPont, among other responsibilities, I
`
`led the API development team for the major anti-HIV drug efavirenz, which is an
`
`inhibitor of HIV-1 reverse transcriptase. I was also responsible for building a pre-
`
`formulations group of experts in organic, solid-state chemistry (i.e. crystalline
`
`forms, polymorphs, solvates, hydrates and amorphous forms), and for managing
`
`the interface(s) between the API, Formulations, and Analytical groups at DuPont.
`
`6.
`
`From 1993-1999 I also served on the Scientific Advisory Board for
`
`NaPro Biotherapeutics in Boulder, Colorado, working on a commercial semi-
`
`synthesis of the anti-cancer drug paclitaxcel from renewable biomass.
`
`7.
`
`From 2000-2004, I worked at Abbott Laboratories as the Head of
`
`Global Chemical Development. In that position I was responsible for managing
`
`chemistry, engineering, and analytical development for all of Abbott's new drug
`
`candidates. During that time, I built a Process Engineering Department with
`
`expertise in separation sciences, solids engineering and process modeling. I also
`
`was responsible for process validation for four New Drug Applications, including
`
`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
`
`responsibilities in this role included oversight for the API and physiochemical pre-
`
`formulation activities for all new drug candidates, route discovery, polymorph
`
`control, clinical supplies, analytical & process development and validation for
`
`Abbott Labs and external customers. I was responsible for manufacturing several
`
`small-volume, commercial products for Abbott Labs and external customers.
`
`8.
`
`I have, in the past, served as an industry representative to the FDA
`
`/ICH Q7A Committee on guidelines for active pharmaceutical ingredients. I have
`
`also served as Chair of the Regulatory and Compliance Section for the Midwest
`
`Pharmaceutical Process Chemistry Consortium.
`
`9. While employed as a scientist and manager in the innovator
`
`pharmaceutical industry (1983-2004), I contributed to over 100 new chemical
`
`entities that moved from discovery into development; approximately 15 of these
`
`compounds were for the treatment of viral diseases. I also contributed to the
`
`development and approval of twelve new drug applications (“NDAs”) approved
`
`for marketing and a substantial number (approximately 20+) of generic products.
`
`10.
`
`I have consulted with a number of pharmaceutical companies on
`
`issues relating to drug discovery, drug development, API and Finished
`
`Pharmaceutical Product drug development and drug production
`
`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,
`
`DC. My research group of PhD/PharmD/MSc and undergraduate students develops
`
`new science to decrease the cost of and increase access to quality-assured
`
`medicines for low- and middle-income countries. We have contributed to new
`
`chemistry and technologies that have improved production and reduced cost of
`
`several drugs for HIV/AIDS, Malaria, TB, and opportunistic infections, including
`
`the antiviral (HIV) drugs efavirenz, tenofovir disoproxil fumarate, darunavir,
`
`dolutegravir, and atazanavir.
`
`12.
`
`In 2005, I helped found the Drug Access Technical Team of the
`
`William J. Clinton Health Access Initiative where I contributed to increasing
`
`global access to medications of assured quality at affordable prices, including
`
`HIV/AIDS, malaria and tuberculosis medications.
`
`13.
`
`I presently work with organizations including the World Health
`
`Organization, UNITAID, UNIDO, and the Medicines Patent Pool on novel
`
`chemistry, formulations, and regulatory sciences for manufacturing, market
`
`dynamics and regulation of quality-assured medicines for low- and middle-income
`
`countries.
`
`14. Since 2008 I have regularly taught a curriculum in drug discovery,
`
`development, and manufacturing at the St. Luke Foundation/Kilimanjaro School of
`
`Pharmacy (“KSP”) in Moshi, Tanzania, and the School of Pharmacy/Center for
`
`-4-
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`Drug Discovery, Development, and Pharmaceutical Production (CDDDP) at the
`
`University of Ibadan in Nigeria. This curriculum focuses on the science and
`
`practice of drug discovery and development. My "students" include pharmaceutical
`
`professionals, national drug regulators, and university professors. As part of the
`
`curriculum, students learn how to formulate drugs, including dosage form design,
`
`granulation, milling, drying, compression, coating, and process validation. This
`
`teaching includes a focus on crystalline forms of pharmaceutical solids including
`
`polymorphs, hydrates, solvates, and amorphous forms and their impact on APIs
`
`and drug products. This curriculum has received numerous awards, including a
`
`2013 US FDA Honor Award for excellence and innovation in teaching and drug
`
`regulatory sciences.
`
`15.
`
`I also have served or currently serve as an adjunct professor at the
`
`University of Alabama, Green Chemistry Manufacturing Institute, the Kilimanjaro
`
`School of Pharmacy and the University of Ibadan in Nigeria. I am on the Scientific
`
`Advisory Board of the Royal Society of Chemistry (UK) as an expert in Green
`
`Chemistry.
`
`16.
`
`I have published over 75 peer-reviewed papers, book chapters, and
`
`monographs. I have made hundreds of presentations in the areas of my expertise. I
`
`am also an inventor on approximately 35 patents worldwide in the areas of
`
`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,
`
`approximately 500 of whom are PhD-level scientists.
`
`17. From 2006-2011, I was on the editorial board of the journal Current
`
`Opinion in Drug Development. I am currently on the editorial boards of the Journal
`
`of Tropical Pharmaceutical Research; I am also on the editorial board of the Royal
`
`Society of Chemistry, Green Chemistry Journal.
`
`18.
`
`I have received several honors and awards for my research and
`
`teaching work. Among many others, I have been awarded the Howard University
`
`Faculty Senate Award for contributions to Africa and the African Diaspora, the
`
`American Chemical Society “Astellas Foundation” Prize for Chemistry Impact on
`
`Human Health, for, among other things, global access to anti-HIV drugs, the
`
`African Union award for Corporate Social Responsibility, and a Corporate Award
`
`from Abbott Labs for manufacturing improvements that reduced the rate of volatile
`
`organic emissions (VOEs) over the island of Puerto Rico by over 60%.
`
`19. My research has focused on the study of new synthetic chemistry and
`
`methodology for the manufacture of essential medicines for the treatment of
`
`HIV/AIDS, malaria and tuberculosis. I also currently work on new technologies for
`
`Green Chemistry, safety and waste reduction. I am also heavily involved in
`
`teaching drug development and industrial pharmacy in Low- and Middle-Income
`
`Countries to enable local production of essential medicines according to
`
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`international standards of Current Good Manufacturing Practice (cGMP).
`
`20. Further details concerning my education, employment history and
`
`experience are set forth in my Curriculum Vitae which is attached hereto.
`
`II.
`
`SCOPE OF WORK
`
`21.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 9,393,256 (“the
`
`’256 patent”; EX1001). I have been asked by the Petitioner to be a technical expert
`
`to provide analysis and opinions regarding the ‘256 patent. I have reviewed the
`
`’256 patent and its prosecution history in the United States Patent and Trademark
`
`Office. I have also reviewed and considered various other documents in arriving at
`
`my opinions, and cite them in this declaration. For convenience, documents cited
`
`in this declaration are listed in the Appendix below.
`
`22.
`
`I am the Pharmaceutical Scientist at Initiative for Medicines, Access
`
`& Knowledge (I-MAK), Inc., the Petitioner in this matter. I am not receiving any
`
`additional compensation for my study and testimony in this matter, but I am being
`
`reimbursed for reasonable and customary expenses. My position and compensation
`
`are not contingent on the outcome of this matter or the specifics of my testimony.
`
`23. This report sets forth the opinions that I have formed based on
`
`information available as of the date below. If other material is introduced during
`
`this matter that may fall within my area of expertise, I may have relevant and
`
`-7-
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`important opinions regarding such material. I reserve the right to offer such
`
`opinions if they may be relevant or important as such material is introduced. I
`
`further reserve the right and intend to testify and offer additional opinions in
`
`response to any opinions offered by Patent Owner or its witnesses.
`
`III. OVERVIEW OF THE ’256 PATENT
`
`24. The ’256 patent relates to compositions and therapeutic methods that
`
`are useful for treating hepatitis C virus (HCV) infection. Various compositions
`
`comprising two or more compounds are disclosed in ’256. Specifically the ’256
`
`patent claims a method of treating HCV by administering the following
`
`compounds to a human, either with or without ribavirin, but not including an
`
`interferon:
`
`
`
`Compound 10
`
`
`
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`
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`Compound 6
`
`EX1001 at 79 (139:12-26) and 95.
`
`25. The following chart describes the ’256 patent’s 4 claims:
`
`Claim(s)
`
`1, 2
`
`3, 4
`
`Recite
`
`A method of treating an HCV infection comprising administering orally
`to a human Compound 10 and Compound 6, wherein the method does
`not include administering interferon.
`
`The method of claim 1 wherein ribavirin either is or is not
`administered.
`
`
`IV. FILE HISTORY OF THE ’256 PATENT
`
`26. U.S. Patent Application No. 13/875,252 (“the ’252 application”), filed
`
`on May 1, 2013, issued as the ’256 patent on July 19, 2016. The ’252 application is
`
`a continuation of international application PCT/US2012/055621 filed on
`
`September 14, 2012, which claimed the benefit of two provisional applications,
`
`Provisional Application No. 61/535,885 filed on September 16, 2011, and
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`Provisional Application No. 61/561,753 filed on November, 18, 2011.
`
`27. During prosecution of the ’252 application, the Examiner allowed the
`
`currently granted claims without making any substantive prior-art based rejections.
`
`V. LEGAL STANDARDS
`
`28.
`
`I understand that prior art for the purpose of this declaration includes
`
`references that were published at least before September 16, 2011, or patents or
`
`published patent applications that were filed before September 16, 2011.
`
`29.
`
`I understand that a claim is not patentable under 35 U.S.C. § 102, for
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`30.
`
`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
`
`(“POSA”) at the time of the invention. I further understand that a POSA may use
`
`common sense and what was general knowledge in addressing a question of
`
`obviousness.
`
`31.
`
`I further understand that in order to find a claim obvious there is no
`
`rigid rule requiring the prior art to explicitly provide a teaching, suggestion or
`
`motivation to combine references to make the claimed invention. Accordingly,
`
`simple substitution of known elements for another, or use of known techniques to
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`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
`
`that multiple pieces of prior art, as well as the knowledge of a POSA, may be
`
`combined to establish the obviousness of a claim and that the application,
`
`combination, or substitution of elements or methods known in the prior art to yield
`
`predictable results may establish a prima facie case of obviousness.
`
`32.
`
`I also understand that Patent Owner may present evidence of
`
`“objective indicia of non-obviousness” to rebut a prima facie case of obviousness.
`
`I understand that objective indicia of non-obviousness include unexpected results,
`
`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
`
`factors are only relevant, though, if the Patent Owner shows there is a “nexus” —
`
`i.e., a connection — between the claimed invention and the specific objective
`
`indicia of non-obviousness at issue. I understand Patent Owner may raise these
`
`issues in response to this declaration and I reserve my right to respond thereto.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`33.
`
`I understand that a POSA is a hypothetical person who is presumed to
`
`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
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`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.
`
`34. Because the ’256 patent pertains to compounds (namely a
`
`nucleos(t)ide NS5B polymerase inhibitor and an NS5A inhibitor) useful for
`
`treating viral infections such as HCV, a POSA 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 design and mechanism of
`
`action, or (2) a Bachelor’s or Master’s degree in chemistry or a closely related field
`
`with significant experience in an academic or industrial laboratory focusing on
`
`drug discovery and/or development for the treatment of viral diseases.
`
`VII. CLAIM CONSTRUCTION
`
`35.
`
`I understand that, in the present proceeding, the ’256 patent claims are
`
`to be given their broadest reasonable interpretation in view of the specification. I
`
`also understand that, absent some reason to the contrary, claim terms are typically
`
`given their ordinary and accustomed meaning as would be understood by a POSA.
`
`36.
`
`I have followed these principles in my analysis throughout this
`
`declaration. The ’256 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. Thus, there is no reason to give any of the terms of
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`the claims of the ’256 a meaning other than their ordinary and accustomed
`
`meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`37. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of September 16, 2011.
`
`A. Nucleos(t)ide NS5B Polymerase Inhibitors PSI-7851 and PSI-7977
`(Compound 10 in ’256) for Treating HCV Were Known
`
`38. WO 2005/003147 to Clark (“Clark”; EX1002) taught modified
`
`fluorinated nucleoside analogs. More specifically, Clark taught (2’R)-2’-deoxy-2’-
`
`fluoro-2’-C-methyl nucleosides, their pharmaceutically acceptable salt forms and
`
`prodrugs. EX1002 at 18:3-17. Clark taught that these compounds could be used to
`
`treat Flaviviridae viruses, including HCV infections. EX1002 at 1 (Abstract).
`
`39.
`
`It was well known that, to interact with HCV NS5B polymerase, anti-
`
`viral nucleosides must generally first be converted into their triphosphate form.
`
`This was described, for example, in Ma et al. “Characterization of the Metabolic
`
`Activation of Hepatitis C Virus Nucleoside Inhibitor β-D-2'-Deoxy-2-Fluro-2'-C -
`
`Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-Triphosphate
`
`Species,” J. Biol. Chem., 2007, 282(41), 29812-29820 (“Ma”; EX1003), which
`
`recognized this general knowledge, saying, “[c]onversion to the active 5’-
`
`triphosphate form by cellular kinases is an important part of the mechanism of
`
`action for nucleoside analogs.” EX1003 at 2.
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`40. WO 2008/121634 to Sofia et al. (“Sofia ‘634”; EX1004) disclosed
`
`specific phosphoramidate prodrugs of nucleoside derivatives claimed in Clark,
`
`which are useful for the treatment of viral infections, including HCV. The
`
`phosphoramidate prodrugs disclosed
`
`in Sofia
`
`‘634 also
`
`included
`
`their
`
`stereoisomers, salts (acid or basic addition salts), hydrates, solvates or crystalline
`
`forms as represented by the following structure:
`
`
`
`EX1004 at 10.
`
`41. While Sofia ‘634 disclosed and claimed many compounds within the
`
`formula, it specifically disclosed Compound 10 as claimed in the ’256 patent. In
`
`particular, Sofia ’634 disclosed and claimed the molecule shown in Table IX-25 as
`
`compound IX-25-2. EX1004 at 255. This molecule was further disclosed as having
`
`been prepared and characterized, as example compound 25. EX1004 at 684.
`
`Compound 25 is further disclosed as one of 19 compounds for which antiviral
`
`testing results are revealed. EX1004 at 696. This compound is further disclosed in
`
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`claim 2, EX1004 at 703:48-50. This compound is also known as PSI-7851 and
`
`“(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-
`
`propionic acid isopropyl ester”, also known as PSI-7977 or GS-7977. Indeed, this
`
`is confirmed in the ’256 patent where U.S Patent No.7,964,580 (which corresponds
`
`to Sofia ’634) is incorporated by reference. EX1001 at 13 (8:42).
`
`B. Nucleos(t)ide NS5B Polymerase Inhibitors Were Combined With
`Other Antiviral Agents, Including NS5A Inhibitors, To Treat
`HCV
`
`42.
`
`It was widely known that monotherapy with a direct acting antiviral
`
`polymerase inhibitors such as a nucleos(t)ide NS5B polymerase inhibitor was
`
`limited because of resistance mutations of HCV to nucleos(t)ide analogs. Legrand-
`
`Abravanel et al. “New NS5B Polymerase Inhibitors for Hepatitis C, Expert
`
`Opinion on Investigational Drugs,” 2010, 19(8): 963-75 (“Legrand-Abravanel”;
`
`EX1005) at 7. Therefore, it was recognized in the field that combination therapy
`
`with small molecule inhibitors such as NS5A inhibitors without interferon was the
`
`optimal standard of care.). EX1005 at 9.
`
`43. Clark taught that its nucleoside NS5B polymerase inhibitors could be
`
`administered as a nucleotide prodrug in combination or in alternation with one or
`
`more other effective therapeutic agents i.e. another antiviral agent. For example,
`
`Clark taught:
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`In another embodiment for the treatment, inhibition, prevention
`
`and/or prophylaxis of any viral infection described herein, the active
`compound, derivative or salt can be administered in combination or
`alternation with another anitiviral agent. In general, in combination
`therapy, effective dosages of two or more agents are administered
`together, whereas during alternation therapy, an effective dosage of
`each agent is administered serially. The dosage will depend on
`absorption, inactivation and excretion rates of the drug as well as
`other factors known to those of skill in the art. It is to be noted that
`dosage values will also vary with the severity of the condition to be
`alleviated. It is to be further understood that for any particular subject,
`specific dosage regimens and schedules should be adjusted over time
`according to the individual need and the professional judgment of the
`person administering or supervising the administration of the
`compositions.
`
`It has been recognized that drug-resistant variants of
`flaviviruses, pestiviruses or HCV can emerge after prolonged
`treatment with an antiviral agent. Drug resistance most typically
`occurs by mutation of a gene that encodes for an enzyme used in viral
`replication. The efficacy of a drug against the viral infection can be
`prolonged, augmented or restored by administering the compound in
`combination or alternation with a second, and perhaps a third,
`antiviral compound that induces a different mutation from that caused
`by the principle drug. Alternatively, the pharmacokinetics,
`biodistribution or other parameter of the drug can be altered by such
`combination or alternation therapy. In general, combination therapy is
`typically preferred over alternation therapy because it induces
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`multiple simultaneous stresses on the virus.
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`For example, one skilled in the art will recognize that any
`antiviral drug or therapy can be used in combination or alternation
`with any nucleoside of the present invention. Any of the viral
`treatments described in the Background of the Invention can be used
`in combination or alternation with the compounds described in this
`specification. Nonlimiting examples of the types of antiviral agents or
`their prodrugs that can be used in combination with the compounds
`disclosed herein include: interferon, including interferon alpha 2a,
`interferon alpha 2b, a pegylated interferon, interferon beta, interferon
`gamma, interferon tau, and interferon omega, an interleukin, including
`interleukin 10 and interleukin 12, ribavirin; interferon alpha, or
`pegylated interferon alpha in combination with ribavirin or levovirin;
`levovirin; a protease inhibitor, including an NS3 inhibitor, a NS3-4A
`inhibitor; a helicase inhibitor; polymerase inhibitor including HCV
`RNA polymerase and NS5B polymerase inhibitor, gliotoxin; an IRES
`inhibitor; and antisense oligonucleotide, a thiazolidone derivative; a
`benzanilide, a ribozyme; another nucleoside, nucleoside prodrug or
`nucleoside derivative; a 1-amino-alkylcyclohexane; an antioxidant
`including vitamin E; squalene; amantadine; a bile acid; N-
`(phosphonoacetyl)-L-aspartic acid; a benzenedicarboxamide; a
`polyadenylic acid; a benzimidazoles; thymosin; a beta tubulin
`inhibitor; a prophylactic vaccine; an immune modulator, an IMPDH
`inhibitor, silybin-phosphatidylcholine phytosome; and
`mycophenolate.
`
`EX1002 at 62:7 – 63:26 (emphasis added).
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`44. Ma taught β-D-2’-deoxy-2’-fluoro-2’-C-methyluridine (RO2433, PSI-
`
`6026), a deaminated derivative of β-D-2’-deoxy-2’-fluoro-2’-C-methylcytidine
`
`(PSI-6130) and how antiviral agents targeting essential processes of HCV
`
`replication as part of optimized combination regimens could achieve increased
`
`clinical efficacy and potentially improved adverse event profiles as well as
`
`shortened treatment duration as compared to the current standard of care. EX1003
`
`at 1.
`
`45. Sofia et al, “β-D-2′-Deoxy-2′-C-methyluridine Phosphoramidates:
`
`Potent and Selective Inhibitors of HCV RNA Replication”, Poster #P-259,
`
`presented at the 14th International Symposium on Hepatitis C Virus and Related
`
`Viruses, Glasgow, Scotland, UK, Sep. 9-13, 2007. (“Sofia 2007”; EX1006) taught
`
`a prodrug of β-D-2’-deoxy-2’-fluoro-2’-C-methylcytidine (PSI-6130) for the
`
`treatment of chronic HCV and the need for direct acting antivirals for use in
`
`combination with the standard of care.
`
`46. Sofia ’634 taught that the nucleotide NS5B polymerase inhibitors
`
`disclosed and claimed therein, including PSI-7851 and PSI-7977 (Compound 10 in
`
`‘256) could be directed to a method of treatment in combination with another
`
`antiviral agent, wherein the administration is concurrent or alternative. Sofia ’634
`
`further suggested examples of “another antiviral agent” to include NS5A
`
`inhibitors. Sofia ’634 also provided:
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`It is contemplated that another antiviral agent includes, but is not limited to
`interferon-α, interferon-β, pegylated interferon-α, ribavirin, levovirin,
`viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-
`nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase
`inhibitor or a HCV fusion inhibitor. When the active compound or its
`derivative or salt are administered in combination with another antiviral
`agent the activity may be increased over the parent compound. When the
`treatment is combination therapy, such administration may be concurrent or
`sequential with respect to the nucleoside derivatives. “Concurrent
`administration” as used herein thus includes administration of the agents at
`the same time or different times. Administration of two or more agents at the
`same time can be achieved by a single formulation containing two or more
`active ingredients or by substantially simultaneous administration of two or
`more dosage forms with a single active agent.
`EX1004 at 668:24 – 669:8 (emphasis added).
`
`47. U.S. Pub. No. 2006/0276511 to Serrano-Wu et al. (“Serrano-Wu”;
`
`EX1007) taught some of the early NS5A inhibitor compounds designed to inhibit
`
`the function of HCV NS5A protein. Serrano-Wu suggested how the NS5A
`
`compounds disclosed therein could be used in combination therapy with other
`
`antiviral agents, including compounds that inhibit NS5B protein such as
`
`Compound 10 in ’256. EX1007 at 3 (¶0026).
`
`48. WO2006/100310 to Simmen et al. (“Simmen”; EX1008) taught the
`
`NS5A inhibitors disclosed therein could be co-administered in combination with
`
`small molecule antagonists such as NS5B polymerase antagonists to treat HCV
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`infections. EX1008 at 28:1-28.
`
`49. Pockros “New Direct-Acting Antivirals in the Development for
`
`Hepatitis C Virus Infection”, Therapeutic Advances in Gastroenterology, May
`
`2010, 3(3) 191-202 (“Pockros”; EX1009), taught that the compound BMS-790052
`
`(daclatasvir), a first-in-class potent HCV NS5A inhibitor, was additive/synergistic
`
`with protease and polymerase inhibitors (i.e. nucleos(t)ide NS5B polymerase
`
`inhibitors) in the replicon model and which may eventually be used in combination
`
`with protease and/or polymerase inhibitors. EX1009 at 8.
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART
`
`50. The following prior art references, alone or in combination with each
`
`other, teach or suggest the compounds and methods recited in claims 1-4 of the
`
`’256 patent. I understand these references, described in more detail below, may be
`
`applied in assessing the validity of the ‘256 patent.
`
`A. Legrand-Abravanel et al. New NS5B Polymerase Inhibitors for
`Hepatitis C, Expert Opinion on Investigational Drugs, 2010, 19(8):
`963-75 (“Legrand-Abravanel”; EX1005)
`
`51. Legrand-Abravanel was published online on July 15, 2010. See
`
`http://www.tandfonline.com/doi/full/10.1517/13543784.2010.500285. Therefore, I
`
`understand it is prior art to the ‘256 patent.
`
`52. Legrand-Abravanel taught that NS5B polymerase inhibitors will form
`
`an integral part of more effective anti-HCV therapy, in combination with interferon
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`or with other directly acting antiviral agents. EX1005 at 1.
`
`53. Legrand-Abravanel also highlighted that nucleos(t)ide inhibitors PS-
`
`7851 and PSI-7977 (Compound 10 in the ‘256 patent) had been selected for further
`
`clinical development. EX1005 at 4-5.
`
`54. However, due to the resistant mutations of HCV to nucleos(tide)
`
`analogues, Legrand-Abravanel taught that combination therapy with small
`
`molecule inhibitors and without IFN (interferon) was the