`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00123
`U.S. Patent No. 8,735,372
`
`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 ‘372 PATENT ..........................................................8
`
`IV.
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘372 PATENT .....................................................9
`
`LEGAL STANDARDS ................................................................................9
`
`PERSON OF ORDINARY SKILL IN THE ART.......................................11
`
`VII. CLAIM CONSTRUCTION........................................................................12
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART........................................12
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`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 – in Particular
`Phosphoramidates - Enabled Nucleosides To Overcome This
`Limitation .........................................................................................17
`
`The Means Were Available To Determine Which Nucleosides Were
`Kinase Dependent.............................................................................24
`
`Narrowing The Selections For The Phosphoramidate Prodrug..........24
`
`Phosphoramidates Improved Nucleosides.........................................30
`
`The ‘372 Patent Acknowledges This Common Knowledge ..............31
`
`Nucleoside NS5B Inhibitors Were Combined With Other Antiviral
`Agents, Including NS5A Inhibitors, To Treat HCV ..........................33
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................37
`
`A.
`
`Sofia .................................................................................................37
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`B.
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`C.
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`Congiatu ...........................................................................................39
`
`Serrano-Wu.......................................................................................40
`
`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘372 PATENT.......................................40
`
`XI. CONCLUSION ..........................................................................................51
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................52
`
`ii
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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”)
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`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,
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`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
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`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. 8,735,372 (“the
`
`‘372 patent”; EX1001). I have been asked by the Petitioner to be a technical expert
`
`to provide analysis and opinions regarding the ‘372 patent. I have reviewed the
`
`‘372 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
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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
`
`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 ‘372 PATENT
`
`24.
`
`The ‘372 patent relates to phosphoramidate prodrugs of nucleoside
`
`derivatives for the treatment of viral infections of the following general formula:
`
`EX1001 at 5:4 – 7:45. In defining the structure’s various components, the ‘372
`
`patent states that
`
`the Base is “a naturally occurring or modified purine or
`
`pyrimidine base.” EX1001 at 6:36 – 7:10. The ‘372 patent further provides a long
`
`list of substituents for each of R1, R2, R3a, R3b, R4, R5, R6, X and Y. EX1001 at 5:15
`
`– 6:37.
`
`25.
`
`The following chart describes the ‘372 patent’s 2 claims:
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`Claim(s)
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`1, 2
`
`Recite
`
`Methods of treating hepatitis C virus by administering an NS5a
`inhibitor and a compound within the general formula.
`
`IV. FILE HISTORY OF THE ‘580 PATENT
`
`26. U.S. Patent Application No. 14/057,675 (“the ‘675 application”), filed
`
`on October 18, 2013, issued as the ‘372 patent on May 27, 2014. The ‘675
`
`application claimed the benefit of U.S. Patent Application No. 13/609,614 (“the
`
`‘614 application”), filed on September 11, 2012, U.S. Patent Application No.
`
`13/099,671 (“the ‘671 application”), filed on May 3, 2011, 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 ‘675 application, the Examiner allowed the
`
`claims without making any substantive prior-art based rejections.
`
`V.
`
`LEGAL STANDARDS
`
`28.
`
`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
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`common sense and what was general knowledge in addressing a question of
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`obviousness.
`
`29.
`
`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
`
`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.
`
`30.
`
`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
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`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.
`
`31.
`
`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
`
`32.
`
`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.
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`33. Because the ‘372 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
`
`34.
`
`I understand that, in the present proceeding, the ‘372 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.
`
`35.
`
`I have followed these principles in my analysis throughout this
`
`declaration. The ‘372 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 ‘372 a meaning other than their ordinary and accustomed
`
`meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`36. Below I describe some of the relevant aspects of what was generally
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`known in the art as of March 30, 2007, and March 21, 2008.
`
`A.
`
`The Use of Nucleoside Analogs As Antiviral Agents And Their
`Mechanism of Action Were Known
`
`37.
`
`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
`
`polymerases to synthesize viral DNA/RNA chains in the host cell, while DNA
`
`viruses use host-cell DNA polymerases to synthesize their viral DNA chains.
`
`38.
`
`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’-
`
`monophosphate (NMP) by intracellular host or viral nucleoside kinases. 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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`39.
`
`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
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`polymerases or viral nucleoside kinases to inhibit viral DNA/RNA replication.
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`40.
`
`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) for incorporation into 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.
`
`41.
`
`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”;
`
`EX1003), described the use of nucleoside analogs for inhibition of various viruses.
`
`Second, WO 2005/003147 to Clark (“Clark ‘147”; EX1004) described research
`
`and results about use of various nucleoside analogs for treatment of Flaviviridae
`
`infections from 1994 to 2004. EX1004 at 12:11 – 13:4.
`
`42.
`
`The first commercially available antiviral nucleoside was the anti-
`
`herpes virus uridine analog Idoxuridine. Prusoff, WH, "Synthesis and biological
`
`activities of iododeoxyuridine, an analog of thymidine," Biochim Biophys Acta.
`
`32(1):295-6 (1959) (“Prusoff”; EX1005).
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`43.
`
`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
`
`Azidothymidine
`(AZT, Zidovudine)
`
`HTLV-III/LAV reverse
`transcriptase
`
`thymidine
`
`1985
`
`2′,3′-dideoxyinosine
`(ddI, Didanosine)
`
`2′,3′-dideoxycytidine
`(ddC, Zalcitabine)
`
`HIV reverse transcriptase
`
`thymidine
`
`HIV reverse transcriptase
`
`adenosine
`
`1986
`
`1988
`
`HIV reverse transcriptase
`
`cytidine
`
`1988
`
`-16-
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`I-MAK 1002
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`
`
`dideoxy uridine (ddU)
`5’-phosphates
`
`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
`
`44.
`
`Thus, it was generally known that nucleoside analogs suppress viral
`
`replication, particularly by incorporation into viral DNA/RNA chains.
`
`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 – in Particular Phosphoramidates - Enabled
`Nucleosides To Overcome This Limitation
`
`45.
`
`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 -D-2'-Deoxy-2-Fluro-2'-C -
`
`Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-Triphosphate
`
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`
`
`Species,” J. Biol. Chem., 2007, 282(41), 29812-29820 (“Ma”; EX1006), 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.” EX1006 at 2.
`
`46.
`
`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”; EX1007) 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.” EX1007 at
`
`1.
`
`47.
`
`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’→NMP) is generally the rate-limiting step in the course of
`
`its trisphosphorylation. Several references recognized this general knowledge.
`
`48.
`
`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.” EX1007 at 1.
`
`Second, Wagner recited that ddNs’ activation is hindered at the first
`
`phosphorylation step. EX1003 at 2. Third, McGuigan, et al. “Application of
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`Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of
`
`Carbocyclic Adenosine Derivatives,” J. Med. Chem., 2006, 49, 7215-7726
`
`(“McGuigan 2006”; EX1008), recognized that, “in most cases the first
`
`phosphorylation to the 5’-monophosphate is the rate-limiting step.” EX1008 at 1.
`
`49.
`
`Perrone (EX1007), Wagner (EX1003), and McGuigan 2006 (EX1008)
`
`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.
`
`50.
`
`Several other references recognized this general knowledge. First,
`
`McGuigan et al. “Certain phosphoramidate derivatives of dideoxy uridine (ddU)
`
`are active against HIV and successfully by-pass thymidine kinase” FEBS Letters,
`
`1994, 351, 11-14 (“McGuigan 1994”; EX1009), recognized that nucleoside
`
`analogs have limitations because they depend on kinase-mediated activation to
`
`generate the bioactive (tri)phosphate forms. EX1009 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.
`
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`51. McGuigan 2006 also recognized that poor phosphorylation can be a
`
`major cause of poor activity, with several examples known where nucleoside
`
`analogs are inactive, but the corresponding triphosphates are inhibitors at their
`
`enzyme target. EX1008 at 1.
`
`52.
`
`To address this widely known issue, it was contemplated in the art to
`
`use the 5’-phosphate of nucleoside analogs as prodrugs to “bypass” the kinase-
`
`mediated monophosphorylation step of generating 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’-monophosphates of the nucleoside analogs (NMP) by enzymes
`
`inside the cell. EX1009 (McGuigan 1994). The 5’-monophosphate is then rapidly
`
`converted into the triphosphate form to be fully activated. Such a technique has
`
`been called “Pronucleotide” or simply “ProTide”.
`
`53.
`
`First, Wagner, recognized that various prodrug or “pronucleotide”
`
`approaches have been devised and investigated, with the general goal of promoting
`
`passive diffusion through cell membranes and increasing the bioavailability of
`
`nucleosides or phosphorylated nucleosides. EX1003 at 3 and 8. This approach of
`
`derivatization had been applied using various protecting groups for the phosphate
`
`moiety. Id.
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`54.
`
`Second, Cahard et al. “Aryloxy phosphoramidate triesters as pro-
`
`tides,” 2004, 4(4), 371-81 (“Cahard”; EX1010) recognized that aryloxy
`
`phosphoramidate triesters are an effective pro-tide motif for the intracellular
`
`delivery of (otherwise) charged antiviral nucleoside monophosphates and that the
`
`phenyl alanyl phosphoramidate approach was successful on a range of nucleosides
`
`by many research groups. EX1010 at 1, 4.
`
`55.
`
`Third, Perrone recognized that unmodified nucleoside
`
`monophosphates are unstable in biological media and also show poor membrane
`
`permeation because of the associated negative charges at physiological pH.
`
`EX1007 at 1. Perrone also recognized that the known aryloxy phosphoramidate
`
`ProTide approach allows bypass of the initial kinase dependence by intracellular
`
`delivery of the mono-phosphorylated nucleoside analog as a membrane-permeable
`
`ProTide form. Id. The technology greatly increased the lipophilicity of the
`
`nucleoside monophosphate analog with a consequent increase of membrane
`
`permeation and intracellular availability. Id.
`
`56.
`
`The “ProTide” technology was known to show great success in the
`
`intracellular delivery and activation of many nucleoside analogs. A large number
`
`of thus-modified nucleosides showed a boost in the inhibition activity on virus
`
`replication by tens, hundreds, or even thousands of times, in comparison with the
`
`parent nucleoside analogs.
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`57. McGuigan 1994 recognized that the aryloxy phosphoramidate (3c) of
`
`a ddU increases its potency by approximately 50 times. EX1009 at 3 (Fig. 1).
`
`58. Cahard recognized that the aryloxy phosphoramidate prodrug (21) for
`
`d4A boosts the activity of the parent nucleoside analog d4A by 1000 – 4000 fold
`
`and the aryloxy phosphoramidate prodrug (22) for ddA boosts the activity of the
`
`parent nucleoside analog ddA by >100 fold. EX1010 at 2-3 (Fig. 1).
`
`59. McGuigan 2006 recognized that the ProTide approach was highly
`
`successful when applied to L-Cd4A with potenc