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. 9,284,342
`
`___________
`
`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
`
`IPR2018-00126
`
`Page 1 of 62
`
`I-MAK 1002
`
`
`___________
`
`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. 9,284,342
`
`___________
`
`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
`
`IPR2018-00126
`
`Page 1 of 62
`
`I-MAK 1002
`
`
`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS ....................................................................................... 1
`
`SCOPE OF WORK.......................................................................................... 7
`
`III. OVERVIEW OF THE ‘342 PATENT ............................................................ 8
`
`IV. FILE HISTORY OF THE ‘342 PATENT ....................................................... 9
`
`V.
`
`LEGAL STANDARDS ................................................................................. 12
`
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 14
`
`VII. CLAIM CONSTRUCTION .......................................................................... 14
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART ......................................... 15
`
`
`
`
`
`A. Nucleoside Analog Drugs Inhibited Viral Diseases ........................... 15
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`Some Nucleoside Drugs Were Poor Substrates for Phosphorylation . 19
`
`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation ............................................................ 20
`
`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome the
`Problem of Poor Phosphorylation ....................................................... 20
`
`ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity .............. 22
`
`ProTide Analogs of Compound 1D Were Active Against HCV ........ 23
`
`Pharmaceutical Solids Could Exist in Multiple Forms ....................... 25
`
`H. A Solid-State and Polymorph Screen Would Always Evaluate the
`Interactions of Water with a New Drug Candidate ............................. 27
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 29
`
`A. WO 2008/121634 to Sophia (“Sophia ‘634”) ..................................... 29
`
`i
`
`IPR2018-00126
`
`Page 2 of 62
`
`I-MAK 1002
`
`
`
`
`
`B. WO 2005/003147 to Clark (“Clark”) .................................................. 31
`
`C.
`
`Sofia et. al., “Discovery of a b-D-2’-Deoxy-2’-a-fluoro-2’-b-C-
`methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of
`Hepatitis C Virus” J. Med. Chem., 2010, 53, 7202-7218 (“Sofia
`2010") .................................................................................................. 33
`
`D. Ma et. al., “Characterization of the Metabolic Activation of Hepatitis
`C Virus Nucleoside Inhibitor b-D-2’-Deoxy-2’-Fluoro-2’-C-
`methylcytidine (PSI-6130) and Identification of a Novel 5’-
`Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-29820
`(Ma) ..................................................................................................... 35
`
`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘342 PATENT ........................................ 37
`
`A. Claims 1-4 Were Obvious Over Sofia ‘634 and Sofia 2010 ............... 37
`
`B.
`
`C.
`
`Claims 1-4 Were Obvious Over Sofia ‘634 and Ma ........................... 44
`
`Claims 1-4 Were Obvious Over Clark ‘147 and Ma .......................... 50
`
`XI. CONCLUSION .............................................................................................. 56
`
`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 58
`
`ii
`
`IPR2018-00126
`
`Page 3 of 62
`
`I-MAK 1002
`
`
`
`
`
`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,
`
`1
`
`IPR2018-00126
`
`Page 4 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`2
`
`IPR2018-00126
`
`Page 5 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`3
`
`IPR2018-00126
`
`Page 6 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`IPR2018-00126
`
`Page 7 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`5
`
`IPR2018-00126
`
`Page 8 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`6
`
`IPR2018-00126
`
`Page 9 of 62
`
`I-MAK 1002
`
`
`
`
`
`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. 9,284,342 (“the
`
`’342 patent”; EX1001). I have been asked by the Petitioner to be a technical expert
`
`to provide analysis and opinions regarding the ’342 patent. I have reviewed the
`
`’342 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. EX1004. 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., 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
`
`7
`
`IPR2018-00126
`
`Page 10 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`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 ‘342 PATENT
`
`24. The ‘342 patent claims a crystalline compound represented by the
`
`following formula:
`
`EX1001 at 89:42-58.
`
`
`
`
`
`25.
`
`In describing the claimed invention, the ‘342 patent states:
`
`Disclosed herein are nucleoside phosphoramidates and their use as
`
`agents for treating viral disease. These compounds are inhibitors of
`
`8
`
`IPR2018-00126
`
`Page 11 of 62
`
`I-MAK 1002
`
`
`
`
`
`RNA-dependent RNA viral replication and are useful as inhibitors of
`
`HCV NS5B polymerase, as inhibitors of HCV replication and for
`
`treatment of hepatitis C infection in mammals.
`
`EX1001 at 1 (Abstract).
`
`26. The '342 patent discloses that form 6 of the SP-4 compound is the
`
`form with XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7. EX1001 at 76:9-42. The
`
`'342 patent also discloses that there are at least two ways that the crystalline form 6
`
`of SP-4 can be obtained from form 1 of the same compound: 1) suspension in water
`
`(at 5-50 mg/mL) at ambient temperature for a few hours; and 2) grinding followed
`
`by slow conversion to form 6 upon standing exposed to atmospheric humidity.
`
`EX1001 at 73:10-50.
`
`27. The following chart describes claims 1-4 of the ‘342 patent:
`
`Claim(s)
`
`Recite
`
`1
`
`2
`
`3, 4
`
`Crystalline compound represented by the formula above having
`XRPD 2Ɵ-reflections (o) at about: 6.1 and 12.7.
`
`Pharmaceutical composition having the crystalline compound of
`claim 1 and a pharmaceutically acceptable medium.
`
`Method of treating a hepatitis C virus infection in a human by
`administering the compound of claim 1, alone or with another
`antiviral agent.
`
`
`IV. FILE HISTORY OF THE ‘342 PATENT
`
`28. U.S. Patent Application No. 13/925,078 (“the ‘078 application) was
`
`9
`
`IPR2018-00126
`
`Page 12 of 62
`
`I-MAK 1002
`
`
`
`
`
`filed on June 24, 2013, and issued as the ‘342 patent on March 15, 2016. The ‘078
`
`application claimed priority as a continuation of U.S. Patent Application No.
`
`13/076,552 (“the ‘552 application”) filed on Mar. 31, 2011, which claimed priority
`
`as a continuation-in-part of U.S. Patent Application No. 12/783,680 (“the ‘680
`
`application”) filed on May 20, 2010. The ‘078 application also claimed priority to
`
`U.S. Provisional Applications Nos. 61/319,513 and 61/319,548, both of which
`
`were filed on Mar. 31, 2010, and U.S. Provisional Application 61/179,923 filed on
`
`May 20, 2009.
`
`29. During prosecution of the ‘078 application, the Examiner made a
`
`single substantive rejection of double patenting, which the Patent Owner overcame
`
`by submitting a terminal disclaimer. EX1004 at 175. The Examiner then issued a
`
`Notice of Allowance stating in part:
`
`The claimed invention is seen to be novel and non-obvious over
`
`the prior art. The prior art does not disclose a crystalline composition
`
`of the claimed compound having the claimed XRPD peaks.
`
`References to the claimed compound in the prior art (see for example
`
`Sofia et al. WO2008/121634, reference included with PTO-1449) do
`
`not disclose the specific crystal structure described in the claims, or a
`
`method of preparing a crystalline form of the compound that would
`
`have resulted in that particular crystal. Because of the unpredictability
`
`of crystalline polymorphs, one of ordinary skill in the art would not
`
`have been able to, based on the prior art disclosure, predict or make
`
`this particular crystal form.
`
`10
`
`IPR2018-00126
`
`Page 13 of 62
`
`I-MAK 1002
`
`
`
`
`
`While the prior art reference US8916538 (cited in PTO-892)
`
`discloses a crystalline 2'-C-methyluridine-N-alanyl phosphoramidite
`
`having an x-ray powder diffraction pattern with peaks similar to those
`
`described in the claims, the compound is a thiophosphate, and
`
`additionally lacks the 2'-fluoro group of the claimed compound. One
`
`of ordinary skill in the art would have had no motivation to modify
`
`this compound by substituting these groups to produce the claimed
`
`compound.
`
`For these reasons the claims are seen to meet the requirements
`
`of 35 USC 102 and 103.
`
`EX1004 at 183-184.
`
`30. As discussed below, the Examiner’s conclusion that the failure of the
`
`prior art to expressly disclose a crystalline composition having the claimed XRPD
`
`peaks rendered the claims not obvious was incorrect. While that may be a basis to
`
`conclude the specific crystal structure claimed in the ‘342 patent was novel, it is
`
`not a basis to conclude it was also not obvious.
`
`31. During prosecution the Examiner expressly discussed priority of the
`
`‘078 application, finding:
`
`The parent application 12/783680, and its provisional applications
`
`61/319513, 61/319548, and 61 /179923, fail to provide support for the
`
`claimed invention as they do not include a written description under
`
`35 USC 112 of a crystalline compound having the claimed x-ray
`
`diffraction peaks. Therefore the effective filing date of the present
`
`application is the filing date of the parent application 13/076552, filed
`
`11
`
`IPR2018-00126
`
`Page 14 of 62
`
`I-MAK 1002
`
`
`
`
`
`March 31, 2011.
`
`EX1004 at 169. Patent Owner never took issue with these findings.
`
`V. LEGAL STANDARDS
`
`32.
`
`I understand that prior art for the purpose of this declaration includes
`
`references that were published at least before March 31, 2011.
`
`33.
`
`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.
`
`34.
`
`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,
`
`12
`
`IPR2018-00126
`
`Page 15 of 62
`
`I-MAK 1002
`
`
`
`
`
`combination, or substitution of elements or methods known in the prior art to yield
`
`predictable results may establish a prima facie case of obviousness.
`
`35.
`
`I also understand that the legal analysis as to whether a chemical
`
`compound would have been obvious over the prior art involves a two-part inquiry.
`
`First, one must determine whether a POSA would have selected a “lead
`
`compound” as a starting point for further development. I understand that a “lead
`
`compound” is a compound in the prior art that would be promising to modify by
`
`making improvements to achieve a compound with better properties (i.e. activity,
`
`toxicity, etc.). Second, I understand that one must then determine whether there
`
`was a reason or motivation to modify the lead compound to arrive at the claimed
`
`invention with a reasonable expectation of success. I understand that the reason or
`
`motivation may come from the prior art, common sense, or general knowledge of a
`
`POSA.
`
`36.
`
`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
`
`13
`
`IPR2018-00126
`
`Page 16 of 62
`
`I-MAK 1002
`
`
`
`
`
`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
`
`37.
`
`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.
`
`38. Because the ‘342 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
`
`39.
`
`I have been advised that, in the present proceeding, the ‘342 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`14
`
`IPR2018-00126
`
`Page 17 of 62
`
`I-MAK 1002
`
`
`
`
`
`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 one of ordinary skill in the art. I have followed these principles in
`
`my analysis throughout this declaration.
`
`40. The ‘342 patent provides definitions for certain claim terms. In my
`
`opinion, these definitions are conventional. Thus, there is no reason to give any of
`
`the terms of the claims of the ‘342 a meaning other than their ordinary and
`
`accustomed meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
`
`41. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of March 31, 2011.
`
` Nucleoside Analog Drugs Inhibited Viral Diseases
`
`42. Nucleosides were well-known to be found as structural components in
`
`deoxy-ribonucleic acids (DNA) or ribonucleic acids (RNA). Nucleosides are
`
`glycosylamines composed of a five-carbon sugar linked to what is known as a
`
`nitrogenous base. Adenine, cytosine, guanine, thymine, and uracil are naturally-
`
`occurring nitrogenous bases. Naturally-occurring, five-carbon sugar rings include
`
`ribose and deoxyribose. The following table shows structures for these nitrogenous
`
`bases as well as the respective products of linking these bases to ribose and
`
`deoxyribose sugar rings.
`
`15
`
`IPR2018-00126
`
`Page 18 of 62
`
`I-MAK 1002
`
`
`
`
`
`
`
`Nitrogenous Base
`
`Ribose Derivative
`
`Deoxyribose Derivative
`
`
`Adenine
`
`Guanine
`
`Thymine
`
`
`
`Uracil
`
`
`
`
`
`
`Cytosine
`
`
`
`
`Adenosine (A)
`
`
`Deoxyadenosine (dA)
`
`Guanosine (G)
`
`
`
`
`Deoxyguanosine (dG)
`
`
`5-Methyluridine (m5U)
`
`
`Thymidine (dT)
`
`
`
`Uridine (U)
`
`
`Deoxyuridine (dU)
`
`
`Cytidine (C)
`
`
`Deoxycytidine (dC)
`
`16
`
`IPR2018-00126
`
`Page 19 of 62
`
`I-MAK 1002
`
`
`
`
`
`
`
`43.
`
`It was also well known that analogs of naturally-occurring nucleosides
`
`were attractive targets for drug discovery and that such analogs were routinely
`
`used to treat diseases including viral infections and cancers. Examples of such
`
`drugs included idoxuridine (antiviral) and gemcitabine for the treatment of cancer.
`
`Additional examples of nucleoside drugs for the treatment of viral diseases
`
`included azidothymidine (AZT), stavudine (d4T), and lamivudine (3TC) for the
`
`treatment of viral infections and particularly HIV. Ribavirin is another nucleoside
`
`analog used for the treatment of viral diseases including hepatitis C viral
`
`infections.
`
`44. Acyclic nucleoside analogs were also known for the treatment of viral
`
`diseases. Such drugs included aciclovir, tenofovir disoproxil fumarate (TDF) and
`
`tenofovir alafenamide fumarate (TAF) for the treatment of HIV and hepatitis B
`
`viral infections. Both TDF and TAF are prodrugs of the nucleotide analog
`
`tenofovir/PMPA. TAF is a ProTide™ phosphonamidate prodrug of PMPA. The
`
`phosphorous diastereomers of TAF were known as of 2001 to possess
`
`approximately a 10-fold difference in antiviral activity against HIV. Chapman,
`
`“Practical synthesis, separation, and stereochemical assignment of the PMPA pro-
`
`drug GS-7340” Nucleosides Nucleotides and Nucleic Acids, 2001, 20(4-7), 621-
`
`628 (“Chapman”; EX1008). TDF and TAF are also used to treat hepatitis B viral
`
`infections. Id.
`
`17
`
`IPR2018-00126
`
`Page 20 of 62
`
`I-MAK 1002
`
`
`
`
`
`45. Nucleosides, however, were also well-known to be therapeutically-
`
`useful only after intracellular, enzymatic conversion into the corresponding 5'-
`
`phosphorylated analogs; generally, these are the triphosphates. This conversion
`
`into the triphosphates was known to happen in a stepwise fashion, with the first
`
`step being conversion to the corresponding monophosphate. 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).
`
`46. The mono-, di-, and triphosphate forms of the C2’-deoxy-C2’-
`
`methyl(up)-C2’-fluoro(down) uridine nucleoside are shown below.
`
`
`
`18
`
`IPR2018-00126
`
`Page 21 of 62
`
`I-MAK 1002
`
`
`
`
`
`Compounds 1A, 1B and 1C are phosphorylated analogs of an SP-4 compound (the
`
`compound of '342 claim 1), while compound 1D is un-phosphorylated.
`
`47.
`
`It was well-known that compound 1C was a preferred compound for
`
`the treatment of human hepatitis C viral infections. 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”;
`
`EX1010). For instance, it was known that the triphosphate compound 1C had a
`
`much longer intracellular half-life than its cytidine analog (38 hours vs. 4.7 hours)
`
`resulting in a much longer duration of action. Id. at 1 and 8.
`
`
`
`Some Nucleoside Drugs Were Poor Substrates for
`Phosphorylation
`
`48. A problem presented itself, however, in the identification of
`
`compound 1C as a promising antiviral drug. Many nucleoside drugs – in particular,
`
`thymidines and uridines – were also known to be poor substrates for conversion
`
`into their monophosphate forms. EX1009 (McGuigan 1994) at 1-2 and Perrone P.,
`
`"Application of the Phosphoramidate ProTide Approach to 4'-Azidouridine Sub-
`
`micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside," Journal
`
`of Medicinal Chemistry, 2007, 50(8), 1840-1843 (“Perrone”; EX1012) at 1.
`
`49. This was also known to be more common for virally-infected cells,
`
`which are often kinase-deficient. Such knowledge was very important because
`
`19
`
`IPR2018-00126
`
`Page 22 of 62
`
`I-MAK 1002
`
`
`
`
`
`drugs that would otherwise be very potent for disease treatment would be inactive
`
`if they did not undergo this phosphorylation process inside an infected cell. Id.
`
` Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation
`
`50. Compound 1D had been disclosed in WO 2005/003147 to Clark
`
`(“Clark ‘147”; EX1007) and in Clark, J., "Design, Synthesis, and Antiviral Activity
`
`of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus
`
`Replication," Journal of Medicinal Chemistry, 2005, 48(17), 5504-5508 (“Clark
`
`2005”; EX1011). Clark 2005 indicated that compound 1D – the unmodified
`
`nucleoside - had no activity in the HCV Replicon assay. EX1011 at 3.
`
`51. Ma showed, however, that the triphosphate form of 1D (compound
`
`1C) was a superior agent against hepatitis C virus, with excellent potency and a
`
`long intracellular half-life. EX1010 at 1 and 8.
`
`52. These publications established that - although compound 1C was an
`
`excellent antiviral agent - compound 1D was inactive because it could not be
`
`efficiently phosphorylated inside virally-infected cells to be converted to 1C.
`
`
`
`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome
`the Problem of Poor Phosphorylation
`
`53. ProTide prodrugs of nucleosides were first described in the early
`
`1990s. EX1009 (McGuigan 1994) at 2-3. These analogs were well-known to
`
`provide advantages over unmodified nucleoside drugs in terms of physicochemical
`
`20
`
`IPR2018-00126
`
`Page 23 of 62
`
`I-MAK 1002
`
`
`
`
`
`properties, cellular absorption, improved half-life, and very importantly, in terms
`
`of overcoming the problem of lack of biological activity due to poor intracellular
`
`phosphorylation. The ProTide approach had been applied to activate nucleosides
`
`through kinase bypass for hepatitis C antiviral compounds as in Perrone. EX1012
`
`at 1. Thus, the ProTide approach was an obvious potential solution for overcoming
`
`the problem of poor intracellular phosphorylation of compound 1D.
`
`54. Prior publications had disclosed that nucleoside compounds that were
`
`inefficiently phosphorylated inside a virally-infected cell could be converted into
`
`very active prodrugs for the treatment of viral diseases and cancer. EX1009
`
`(McGuigan 1994) at 2-4; EX1012 (Perrone) at 2.
`
`55. Perrone, in particular, had shown that conversion into a ProTide
`
`nucleoside analog completely overcame the lack of antiviral activity in the HCV
`
`Replicon Assay for the compound AZU (1), resulting in a very potent compound
`
`(2) against the hepatitis C virus. EX1012. Thus, it was known that an important
`
`component of nucleoside drug discovery was th
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
