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
`
`___________
`
`U.S. Patent No. 8,334,270
`
`___________
`
`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`QUALIFICATIONS .....................................................................................1
`
`SCOPE OF WORK.......................................................................................7
`
`III. OVERVIEW OF THE ‘270 PATENT ..........................................................8
`
`IV.
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘270 PATENT.....................................................9
`
`LEGAL STANDARDS ................................................................................9
`
`PERSON OF ORDINARY SKILL IN THE ART.......................................12
`
`VII. CLAIM CONSTRUCTION........................................................................12
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART........................................13
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`The Use of Nucleoside Analogs As Antiviral Agents And Their
`Mechanism of Action Were Known..................................................13
`
`Anti-Viral Nucleosides Must Be Converted Into Their Triphosphates
`To Be Active, Monophosphorylation Was The Rate-Limiting Step In
`Such Conversion, and 5’-Phosphate Prodrugs Enabled Nucleosides To
`Overcome This Limitation ................................................................18
`
`The Means Were Available to Determine Which Nucleosides Were
`Kinase Dependent.............................................................................23
`
`Narrowing The Selection Of Options For The Phosphoramidate
`Prodrug.............................................................................................23
`
`Phosphoramidates Improved Nucleosides.........................................24
`
`The ‘270 Patent Acknowledges This Common Knowledge ..............25
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................27
`
`A.
`
`Sofia .................................................................................................28
`
`B. Ma ....................................................................................................29
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`C.
`
`D.
`
`E.
`
`Clark ‘147.........................................................................................30
`
`Clark 2005 ........................................................................................31
`
`Perrone .............................................................................................32
`
`F. McGuigan ‘327.................................................................................33
`
`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF CLAIMS 1, 2, 10-18 AND 20-25 OF THE ‘270
`PATENT.....................................................................................................34
`
`A.
`
`Claims 1, 2, 10-18, and 20-25 Were Anticipated By Sofia And
`Obvious Over Sofia and Perrone.......................................................35
`
`1.
`
`2.
`
`3.
`
`Claims 1, 2, 16-18 (compound)...............................................35
`
`Claims 10-12 and 20-22 (compositions comprising compound)44
`
`Claims 13-15 and 23-25 (methods of treating viral infections)45
`
`B.
`
`Claims 1, 2, 10-18 and 20-25 Were Obvious Over Ma and Perrone..46
`
`1.
`
`2.
`
`3.
`
`Claims 1, 2, 16-18 (compound)...............................................47
`
`Claims 10-12 and 20-22 (compositions comprising compound)55
`
`Claims 13-15 and 23-25 (methods of treating viral infections)56
`
`C.
`
`Claims 1, 2, 10-18 and 20-25 Were Obvious Over Clark ‘147, Clark
`2005 and Perrone ..............................................................................57
`
`1.
`
`2.
`
`3.
`
`Claims 1, 2, 16-18 (compound)...............................................58
`
`Claims 10-12 and 20-22 (compositions comprising compound)72
`
`Claims 13-15 and 23-25 (methods of treating viral infections)73
`
`D.
`
`Claims 1, 2, 10-18, 20-25 Were Obvious Over Clark ‘147, Clark 2005
`and McGuigan ‘327 ..........................................................................74
`
`1.
`
`Claims 1, 2, 16-18 (compound)...............................................74
`
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`2.
`
`3.
`
`Claims 10-12 and 20-22 (compositions comprising compound)86
`
`Claims 13-15 and 23-25 (methods of treating viral infections)86
`
`XI. CONCLUSION ..........................................................................................87
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................89
`
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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
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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 submitted separately.
`
`EX1003.
`
`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. 8,334,270 (“the
`
`‘270 patent”; EX1001). I have been asked by the Petitioner to be a technical expert
`
`to provide analysis and opinions regarding the ‘270 patent. I have reviewed the
`
`‘270 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 and identified in the list of exhibits in
`
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`the Appendix. If other material is introduced during this matter that may fall within
`
`my area of expertise, I may have relevant and 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 ‘270 PATENT
`
`24.
`
`The ‘270 patent relates to phosphoramidate prodrugs of nucleoside
`
`derivatives of the following general formula:
`
`EX1001 at 4:47 - 7:17. In defining the structure’s various components, the ‘270
`
`patent states that
`
`the Base is “a naturally occurring or modified purine or
`
`pyrimidine base.” EX1001 at 6:12-14. The ‘270 patent further provides a long list
`
`of substituents for each of R1, R2, R3a, R3b, R4, R5, R6, X and Y. EX1001 at 4:66 –
`
`6:11.
`
`25.
`
`The following chart describes claims 1, 2, 10-18 and 20-25 of the ‘270
`
`-8-
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`patent:
`
`Claim(s)
`
`Recite
`
`1, 2, 16,
`17, 18
`
`Specific compounds (including the individual diastereomers) within the
`general formula.
`
`10 - 12,
`20 - 22
`
`13 - 15,
`23 - 25
`
`Pharmaceutical compositions having the compound of claim 1 or 16,
`including to treat hepatitis C virus infection
`
`Methods of treating a subject infected by hepatitis C virus by
`administering an effective amount of the compound of claim 1 or 16,
`including co-administering another antiviral agent.
`
`IV. FILE HISTORY OF THE ‘270 PATENT
`
`26. U.S. Patent Application No. 13/099,671 (“the ‘671 application”), filed
`
`on May 3, 2011, issued as the ‘270 patent on December 18, 2012. The ‘270 patent
`
`claims the benefit of U.S. Patent Application No. 12/053,015 (“the ‘015
`
`application”), filed on March 21, 2008, and two provisional applications,
`
`Provisional Application No. 60/909,315 filed on March 30, 2007 (“the ‘315
`
`provisional application”), and Provisional Application No. 60/982,309 filed on
`
`October 24, 2007 (“the ‘309 provisional application”).
`
`27. During prosecution of the ‘671 application, the Examiner allowed the
`
`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 March 30, 2007, and may also
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`include references that were published before at least before October 24, 2007, if
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`the ‘315 provisional application does not contain sufficient support for the claims
`
`of the ‘270 patent.
`
`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
`
`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
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`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 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
`
`POSA.
`
`33.
`
`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” —
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`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
`
`34.
`
`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
`
`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.
`
`35. Because the ‘270 patent pertains to nucleoside compounds, 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
`
`36.
`
`I understand that, in the present proceeding, the ‘270 patent claims are
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`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.
`
`37.
`
`I have followed these principles in my analysis throughout this
`
`declaration. The ‘270 patent provides definitions for certain claim terms, but these
`
`definitions are conventional. Thus, there is no reason to give any of the terms of
`
`the claims of the ‘270 a meaning other than their ordinary and accustomed
`
`meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`38. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of either March 30, 2007, or October 24, 2007.
`
`A.
`
`The Use of Nucleoside Analogs As Antiviral Agents And Their
`Mechanism of Action Were Known
`
`39.
`
`It was generally known to persons skilled in the art that viruses
`
`replicate their genetic materials in their host cell through one of two mechanisms.
`
`RNA viruses and reverse-transcribing (RT) viruses rely on their special DNA/RNA
`
`polymerase to synthesize viral DNA/RNA chains in the host cell, while DNA
`
`viruses use host-cell DNA polymerases to synthesize their viral DNA chains.
`
`40.
`
`The basic building blocks that DNA/RNA polymerases recognize and
`
`use to synthesize viral DNA/RNA are 5’-triphosphate nucleosides (NTP, where
`
`N=A, U/T, G, C). Nucleoside (N), after entering the cell, is converted into its 5’-
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`monophosphate (NMP) by the intracellular host or viral nucleoside kinase. NMP is
`
`then further converted into the 5’-triphosphate form (NTP), and finally NTP is
`
`recognized by host or viral RNA/DNA polymerases and added to the tail of the
`
`viral DNA/RNA chain being synthesized. The below figure exemplifies the known
`
`mechanism for phosphorylation of nucleosides for incorporation into RNA.
`
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`41.
`
`The incorporation of modified nucleosides, however, into lengthening
`
`RNA chains can result in viral inhibition, when the modified nucleoside will
`
`inhibit further incorporation of subsequent nucleoside units. This inhibition is
`
`known as “chain termination.” Based on this mechanism, people in the art have
`
`long used nucleoside analogs (N’) that are recognizable by viral DNA/RNA
`
`polymerases or viral nucleoside kinases to subsequently inhibit the chain extension
`
`of viral DNA/RNA.
`
`42.
`
`Specifically, such nucleoside analogs (N’) are recognized by host or
`
`viral nucleoside kinases and converted sequentially into their 5’-triphosphate
`
`(NTP), which is then recognized by a corresponding host or viral DNA/RNA
`
`polymerase in the cell so as to compete with natural 5’-triphosphate nucleosides
`
`(NTP) and finally added to the tail of the viral DNA/RNA chain being synthesized.
`
`The extension of the viral DNA/RNA chain is terminated because of the difference
`
`between the analog and natural nucleosides, which results in suppression of viral
`
`replication.
`
`43.
`
`Several references recognized this general knowledge. First, Wagner
`
`et al. “Pronucleotides: Toward the In Vivo Delivery of Antiviral and Anticancer
`
`Nucleotides” Medical Research Reviews, 2000, 20(6), 417-451 (“Wagner”;
`
`EX1010), described the use of nucleoside analogs for inhibition of various viruses.
`
`Second, WO 2005/003147 to Clark (“Clark ‘147”; EX1006) described research
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`and results about use of various nucleoside analogs for treatment of Flaviviridae
`
`infections from 1994 to 2004. EX1006 at 12:11 – 13:4.
`
`44.
`
`The first commercially available antiviral nucleoside was the anti-
`
`herpes virus uridine analog Iododeoxuridine, which was synthesized in the 1950s.
`
`Prusoff et al. “Synthesis and biological activities of iododeoxyuridine, an analog of
`
`thymidine” Biochim Biophys Acta., 1959, 32(1), 295-6 (“Prusoff”; EX1011).
`
`45.
`
`Since then many nucleoside analogs have been discovered and used as
`
`inhibitors of viral enzymes involved in viral DNA/RNA synthesis, including those
`
`listed in the table below.
`
`Anti-viral nucleoside
`analog
`
`9-β-D-
`arabinofuranosyladeni
`ne (Vidarabine)
`
`Acycloguanosine
`(ACV, Aciclovir)
`
`Target for inhibition
`
`DNA polymerase of
`multiple viruses
`
`herpes simplex virus
`thymidine kinase;
`varicella herpes zoster
`virus thymidine kinase
`
`Analogous
`to
`
`Publication
`time
`
`adenosine
`
`1964
`
`guanosine
`
`1970s
`
`Ribavirin
`
`Hepatitis C virus (HCV)
`RNA polymerase
`
`guanosine
`/adenosine
`
`1972
`
`2′,3′-dideoxy-3′-
`thiacytidine (3TC,
`Lamivudine)
`
`Hepatitis B virus (HBV)
`reverse transcriptase;
`HIV reverse transcriptase
`
`cytidine
`
`1980s
`
`Stavudine (d4T)
`
`HIV reverse transcriptase
`
`thymidine
`
`1980s
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`Azidothymidine
`(AZT, Zidovudine)
`
`HTLV-III/LAV reverse
`transcriptase
`
`thymidine
`
`1985
`
`2′,3′-dideoxyinosine
`(ddI, Didanosine)
`
`2′,3′-dideoxycytidine
`(ddC, Zalcitabine)
`
`dideoxy uridine (ddU)
`5’-phosphates
`
`HIV reverse transcriptase
`
`thymidine
`
`HIV reverse transcriptase
`
`adenosine
`
`1986
`
`1988
`
`HIV reverse transcriptase
`
`cytidine
`
`1988
`
`HIV reverse transcriptase
`
`uridine
`
`1994
`
`Emtricitabine (FTC)
`
`HIV reverse transcriptase
`
`cytidine
`
`1996
`
`Abacavir (ABC)
`
`HIV reverse transcriptase
`
`guanosine
`
`Before 1998
`
`DHPG (Ganciclovir)
`
`Cytomegalovirus
`guanosine kinase
`
`guanosine
`
`1998
`
`Entecavir (ETV)
`
`HBV reverse transcriptase
`
`guanosine
`
`1990s
`
`(2’R)-2’-dO-2’-F-2’-
`C-methyluridine 5’-
`phosphate
`
`HCV RNA polymerase
`
`uridine
`
`2005
`
`Telbivudine
`
`HBV reverse transcriptase
`
`thymidine
`
`2005
`
`4’-azido-uridine 5’-
`phosphoramidate
`
`HCV RNA polymerase
`
`uridine
`
`Feb 2007
`
`46.
`
`Thus, as of March 2007, it was generally known that nucleoside
`
`analogs suppress viral replication by incorporation into viral DNA/RNA chains.
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`B.
`
`Anti-Viral Nucleosides Must Be Converted Into Their
`Triphosphates To Be Active, Monophosphorylation Was The
`Rate-Limiting Step In Such Conversion, and 5’-Phosphate
`Prodrugs Enabled Nucleosides To Overcome This Limitation
`
`47.
`
`It was well known that, to interact with HCV NS5B polymerase, anti-
`
`viral nucleosides must 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 -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”; EX1005), 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.” EX1005 at 2.
`
`48.
`
`Perrone et al. “Application of the Phosphoramidate ProTide Approach
`
`to 4’-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on
`
`an Inactive Nucleoside” J. Med. Chem. 2007, 50(8), 1840-1849 (“Perrone”;
`
`EX1008) also recognized this general knowledge, saying, “[a]ll antiviral agents
`
`acting via a nucleoside analogue mode of action need to be phosphorylated, most
`
`of them to their corresponding 5'-triphosphates.” EX1008 at 1.
`
`49.
`
`It was also well known that, for incorporation of a nucleoside analog
`
`into the viral DNA/RNA chain, kinase-mediated 5’-monophosphorylation of the
`
`nucleoside analog (N’→N’MP) is generally the rate-limiting step in the course of
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`its triphosphorylation. Several references recognized this general knowledge.
`
`50.
`
`First, Perrone recognized that, “the first phosphorylation step to
`
`produce the 5’-monophosphate has often been found to be the rate-limiting step in
`
`the pathway to intracellular nucleotide triphosphate formation.” EX1008 at 1 (“The
`
`first phosphorylation step to produce the 5'-monophosphate has often been found to
`
`be the rate-limiting step in the pathway to intracellular nucleotide triphosphate
`
`formation”). Second, Wagner recited that ddNs’ activation is hindered at the first
`
`phosphorylation step. EX1010 at 2. Third, McGuigan, et al. “Application of
`
`Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of
`
`Carbocyclic Adenosine Derivatives” J. Med. Chem., 2006, 49, 7215-7726
`
`(“McGuigan 2006”; EX1012), recognized that, “in most cases the first
`
`phosphorylation to the 5’-monophosphate is the rate-limiting step.” EX1012 at 1.
`
`51.
`
`Perrone (EX1008), Wagner (EX1010), and McGuigan 2006 (EX1012)
`
`also evinced the general knowledge that, although 5’-triphosphates of some
`
`nucleoside analogs (NTP) are potent viral inhibitors, these nucleoside analogs (N’)
`
`themselves showed little or no activity in inhibition assays, generally because of
`
`the host cell’s lack of corresponding kinase activity which renders the 5’-
`
`monophosphorylation of these analogs extremely slow.
`
`52.
`
`Several other references recognized this general knowledge. First,
`
`McGuigan et al. “Certain phosphoramidate derivatives of dideoxy uridine (ddU)
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`are active against HIV and successfully by-pass thymidine kinase” FEBS Letters,
`
`1994, 351, 11-14 (“McGuigan 1994”; EX1013), recognized that nucleoside
`
`analogs have limitations because they depend on kinase-mediated activation to
`
`generate the bioactive (tri)phosphate forms. EX1013 at 1. McGuigan 1994 also
`
`recognized that dideoxythymidine and 3’-O-methylthymidine are nucleoside
`
`analogs which are inactive against HIV, while their triphosphates are exceptionally
`
`potent inhibitors of HIV reverse transcriptase, and the inactivity of these
`
`nucleoside analogs is attributed to poor phosphorylation by host cells. Id.
`
`53. McGuigan 2006 also recognized that poor phosphorylation can be a
`
`major cause of poor activity, with several examples now known where nucleoside
`
`analogs are inactive but the corresponding triphosphates are inhibitors at their
`
`enzyme target. EX1012 at 1.
`
`54.
`
`To address this widely known issue, it was contemplated in the art to
`
`use the 5’-phosphate of nucleoside analogs as a prodrug to “bypass” the kinase-
`
`mediated monophosphorylation so that it can be quickly converted into the active
`
`triphosphate form. Since 1990 or earlier, stable 5’-phosphate-based prodrugs of
`
`nucleoside analogs have been designed and employed to improve the intracellular
`
`delivery and activation of the nucleoside analogs, and such prodrugs could readily
`
`be hydrolyzed into 5’-mo