`___________
`
`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. 8,633,309
`
`___________
`
`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 ‘309 PATENT ..........................................................8
`
`IV.
`
`V.
`
`VI.
`
`FILE HISTORY OF THE ‘309 PATENT .....................................................9
`
`LEGAL STANDARDS ..............................................................................13
`
`PERSON OF ORDINARY SKILL IN THE ART.......................................15
`
`VII. CLAIM CONSTRUCTION........................................................................16
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART........................................16
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Nucleoside Analog Drugs Inhibited Viral Diseases...........................16
`
`Some Nucleoside Drugs Were Poor Substrates for Phosphorylation .21
`
`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation ..........................................................21
`
`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome the
`Problem of Poor Phosphorylation .....................................................22
`
`ProTide Prodrugs Were Diastereomeric at Phosphorous and Such
`Diastereomers Could Possess Different Biological Activity..............23
`
`ProTide Analogs of Compound 1D Were Active Against HCV........24
`
`IX.
`
`SCOPE AND CONTENT OF THE PRIOR ART .......................................27
`
`A. WO 2008/121634 (“Sofia ‘634”) ......................................................27
`
`B.
`
`J. Med. Chem. 2006 (“Congiatu”).....................................................29
`
`C. WO 2005/003147 (“Clark ‘147”)......................................................30
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`X.
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`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE ‘309 PATENT.......................................31
`
`A.
`
`Claims 1-12 Were Anticipated by Sofia ‘634....................................32
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................32
`
`Claims 4-6 (pharmaceutical compositions) .............................39
`
`Claims 7-12 (methods of treating hepatitis C).........................39
`
`B.
`
`Claims 1-12 Were Obvious Over Sofia ‘634 and Congiatu...............40
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................40
`
`Claims 4-6 (pharmaceutical compositions) .............................49
`
`Claims 7-12 (methods of treating hepatitis C).........................50
`
`C.
`
`Claims 1-12 Were Obvious Over Clark ‘147 and Congiatu...............50
`
`1.
`
`2.
`
`3.
`
`Claims 1-3 (compounds).........................................................51
`
`Claims 4-6 (pharmaceutical compositions) .............................56
`
`Claims 7-12 (methods of treating hepatitis C).........................56
`
`XI. CONCLUSION ..........................................................................................57
`
`XII. APPENDIX – LIST OF EXHIBITS............................................................59
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`I, Joseph M. Fortunak, declare as follows:
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`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”)
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`for investigational new drugs, including the drugs halofantrine, ropinerole,
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`topotecan and eprosartan, which the U.S. Food and Drug Administration (“FDA”)
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`has approved.
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`5.
`
`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
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`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
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`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
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`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,
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`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 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).
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`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. 8,633,309 (“the
`
`’309 patent”; Ex. 1001). I have been asked by the Petitioner to be a technical
`
`expert to provide analysis and opinions regarding the ’309 patent. I have reviewed
`
`the ’309 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. 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 a Pharmaceutical Scientist at the 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
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`information available as of the date below. If other material is introduced during
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`this matter that may fall within my area of expertise, I may have relevant and
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`important opinions regarding such material. I reserve the right to offer such
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`opinions if they may be relevant or important as such material is introduced. I
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`further reserve the right and intend to testify and offer additional opinions in
`
`response to any opinions offered by Patent Owner or its witnesses.
`
`III. OVERVIEW OF THE ‘309 PATENT
`
`24.
`
`The ‘309 patent claims a compound of the following “formula 4”:
`
`EX1001 at 76:2-15. The designation “P* represents a chiral phosphorous atom
`
`wherein the compound is at least 97% of the SP stereoisomer represented by the
`
`formula SP-4, and not more than 3% of the RP stereoisomer.” EX1001 at 76:16-48.
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`25.
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`The patent’s dependent claims further recite higher levels of chiral
`
`purity at the phosphorous atom (98% and 99%), pharmaceutical compositions
`
`containing the SP-4 diastereomer, methods of treatment of hepatitis C viral
`
`infection using SP-4 and using SP-4 in combination with another antiviral agent.
`
`The following chart describes the ‘309 patent’s 12 claims:
`
`Claim(s)
`
`Recite
`
`1-3
`
`4-6
`
`7-12
`
`The compound of formula 4 in which the compound is at least 97%,
`98% or 99% of the SP stereoisomer.
`
`compositions of claims 1 through 3 and a
`Pharmaceutical
`“pharmaceutically acceptable medium.”
`
`Methods of treating hepatitis C viral infection by administering the
`compounds of claims 1, 2 and 3 with or without another antiviral
`agent.
`
`IV. FILE HISTORY OF THE ‘572 PATENT
`
`26. U.S. Patent Application No. 13/738,425 (“the ‘425 application”), filed
`
`on January 10, 2013, issued as the ‘309 patent on January 21, 2014. The ‘425
`
`application claimed priority as a divisional of U.S. Patent Application No.
`
`12/783,680 (“the ‘680 application”), filed on May 20, 2010. The ‘425 application
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`also claimed the benefit of Provisional Applications Nos. 61/319,513 (“the ‘513
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`provisional application”), filed on March 31, 2010, and 61/179,923 (“the ‘923
`
`provisional application”), filed on May 20, 2009.
`
`27. During prosecution of the ‘425 application, the Examiner rejected the
`
`pending claims for being obvious over a 2007 publication by Sofia and provided
`
`the following analysis:
`
`Sofia [2nd International Workshop on HCV-Resistance and
`New Compounds, October 31, 2007] teaches a phosphoramidate
`prodrug of formula:
`
`wherein R3 is isopropyl group (page 8), which is a mixture of Sp and
`Rp stereoisomers. The disclosed phosphoramidate prodrug is a potent
`therapeutic agents for treating HCV infection (pages 1-13).
`Sofia does not expressly teach wherein the Sp stereoisomer is at
`least 97%, 98% or 99% and Rp stereoisomer is not more than 3%, 2%,
`or 1 %. Sofia does not expressly teach that the compound is in a
`pharmaceutical composition form.
`It would have been obvious to one of ordinary skill in the art at
`the time the invention was made to separate the mixture of Sp and Rp
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`stereoisomers and formulate it into a pharmaceutical composition for
`treating HCV infection.
`One having ordinary skill in the art at the time the invention
`was made would have been motivated to separate the mixture of Sp
`and Rp stereoisomers and formulate it into a pharmaceutical
`composition for treating HCV infection because the disclosed
`phosphoramidate prodrug containing a mixture of Sp and Rp isomers
`is known to have potential therapeutic effect and usefulness in treating
`HCV infection, and separation the two isomers of a known therapeutic
`drug and identifying the therapeutic potency of each isomer are well
`known in the art. One of ordinary skill in the art would have
`reasonably expected the success because separating the isomers of the
`known therapeutic agents and identifying the potency of each isomer
`and formulate into a pharmaceutical composition is well within the
`ordinary and routine level of one skilled in the art.
`Thus, the claimed invention as a whole is prima facie obvious
`over Sofia.
`EX1004 at 12-13.
`
`28.
`
`Patent Owner responded by arguing that the Office failed to establish
`
`a prima facie case of obviousness because (i) the Sofia article taught away from
`
`selecting an isopropyl group for R3, (ii) neither the Sofia article nor any other cited
`
`reference supported the assertion that one skilled in the art would have been
`
`motivated to separate the RP and SP stereoisomers and obtain compounds of at least
`
`97%, 98% and 99% of the SP stereoisomer, and (iii) one skilled in the art could not
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`have predicted the anti-hepatitis C virus activity of either the SP or RP stereoisomer.
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`EX1004 at 21-34.
`
`29.
`
`Patent Owner also argued that non-obviousness of the claimed
`
`invention was supported by unexpected results, namely that the SP stereoisomer
`
`was more potent than the mixture of the two phosphorous-based stereoisomers and
`
`>20 times more potent than the corresponding RP stereoisomer. EX1004 at 24.
`
`30.
`
`The Examiner responded to Patent Owner’s arguments by
`
`withdrawing the rejection because of the argument relating to unexpected results,
`
`not the arguments relating to the prima facie case of obviousness. EX1004 at 39.
`
`31.
`
`Specifically, the Examiner said:
`
`Applicant's arguments, submitted May 21, 2013, with respect to the
`rejection of instant claims 82-93 under 35 USC 103(a) for being
`obvious over Sofia et al., have been fully considered and found to be
`persuasive to remove the rejection as Applicant has demonstrated that
`the enantiomer Sp-4 is unexpectedly more potent in inhibiting HCV
`replication than the Rp-4 enantiomer, thereby overcoming the prima
`facie case of obviousness.
`
`32.
`
`Similarly, in his Reasons for Allowance, the Examiner said:
`
`While it is known in the art to make phosphoramidate compounds
`such as the instantly claimed ones, for example as described in US
`patent 7964580 (of record in previous action) and furthermore to
`resolve chiral compounds into individual enantiomers, Applicant has
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`discovered that the Sp enantiomer of the claimed compound is
`unexpectedly more potent in inhibiting HCV replication as disclosed
`on p. 97 of the specification as originally filed. Therefore any prima
`facie case of obviousness is overcome by this finding of unexpected
`results. For these reasons the claims meet the requirements of 35 USC
`102 and 103.
`Id. at 56.
`
`33. Again, the Examiner noted that it was the issue of purported
`
`unexpected results that overcame the pending rejections, not Patent Owner’s
`
`arguments with respect to the prima facie case of obviousness.
`
`V.
`
`LEGAL STANDARDS
`
`34.
`
`I understand that prior art for the purpose of this declaration includes
`
`references that were published at least before May 20, 2009.
`
`35.
`
`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.
`
`36.
`
`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.
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`37.
`
`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.
`
`38.
`
`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
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`motivation may come from the prior art, common sense, or general knowledge of a
`
`POSA.
`
`39.
`
`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
`
`40.
`
`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.
`
`41. Because the ‘309 patent pertains to nucleoside compounds, a POSA
`
`would have either (1) a Ph.D. in chemistry or a closely related field with some
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`experience in an academic or industrial laboratory focusing on drug discovery or
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`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
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`chemistry or a closely related field with significant experience in an academic or
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`industrial laboratory focusing on drug discovery and/or development for the
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`treatment of viral diseases.
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`VII. CLAIM CONSTRUCTION
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`42.
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`I have been advised that, in the present proceeding, the ’309 patent
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`claims are to be given their broadest reasonable interpretation in view of the
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`specification. I also understand that, absent some reason to the contrary, claim
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`terms are typically given their ordinary and accustomed meaning as would be
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`understood by one of ordinary skill in the art. I have followed these principles in
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`my analysis throughout this declaration. The ’309 patent provides definitions for
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`certain claim terms. In my opinion, these definitions are conventional. Thus, there
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`is no reason to give any of the terms of the claims of the ‘309 a meaning other than
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`their ordinary and accustomed meaning.
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`VIII. BACKGROUND KNOWLEDGE IN THE ART
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`43. Below I describe some of the relevant aspects of what was generally
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`known in the art as of May 20, 2009.
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`A.
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`Nucleoside Analog Drugs Inhibited Viral Diseases
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`44. Nucleosides were well-known to be found as structural components in
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`deoxy-ribonucleic acids (DNA) or ribonucleic acids (RNA). Nucleosides are
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`glycosylamines composed of a five-carbon sugar linked to what is known as a
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`nitrogenous base. Adenine, cytosine, guanine, thymine, and uracil are naturally-
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`occurring nitrogenous bases. Naturally-occurring, five-carbon sugar rings include
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`ribose and deoxyribose. The following table shows structures for these nitrogenous
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`bases as well as the respective products of linking these bases to ribose and
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`deoxyribose sugar rings.
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`Nitrogenous Base
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`Ribose Derivative
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`Deoxyribose Derivative
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`Adenine
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`Guanine
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`Adenosine (A)
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`Deoxyadenosine (dA)
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`Guanosine (G)
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`Deoxyguanosine (dG)
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`Thymine
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`5-Methyluridine (m5U)
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`Thymidine (dT)
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`Uracil
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`Cytosine
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`Uridine (U)
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`Deoxyuridine (dU)
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`Cytidine (C)
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`Deoxycytidine (dC)
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`45.
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`It was also well known that analogs of naturally-occurring nucleosides
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`were attractive targets for drug discovery and that such analogs were routinely
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`used to treat diseases including viral infections and cancers. Examples of such
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`drugs included idoxuridine (antiviral) and gemcitabine for the treatment of cancer.
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`Additional examples of nucleoside drugs for the treatment of viral diseases
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`included azidothymidine (AZT), stavudine (d4T), and lamivudine (3TC) for the
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`treatment of viral infections and particularly HIV. Ribavirin is another nucleoside
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`analog used for the treatment of viral diseases including hepatitis C viral
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`infections.
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`46. Acyclic nucleoside analogs were also known for the treatment of viral
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`diseases. Such drugs included aciclovir, tenofovir disoproxil fumarate (TDF) and
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`tenofovir alafenamide fumarate (TAF) for the treatment of HIV and hepatitis B
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`viral infections. Both TDF and TAF are prodrugs of the nucleotide analog
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`tenofovir/PMPA. TAF is a ProTide™ phosphonamidate prodrug of PMPA. The
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`phosphorous diastereomers of TAF were known as of 2001 to possess
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`approximately a 10-fold difference in antiviral activity against HIV. TDF and TAF
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`are also used to treat hepatitis B viral infections. Chapman, “Practical synthesis,
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`separation, and stereochemical assignment of the PMPA pro-drug GS-7340”
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`Nucleosides Nucleotides and Nucleic Acids, 2001, 20(4-7), 621-628 (“Chapman”;
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`EX1008).
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`47. Nucleosides, however, were also well-known to be therapeutically-
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`useful only after intracellular, enzymatic conversion into the corresponding
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`triphosphate analogs. This conversion into the triphosphates was known to happen
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`in a stepwise fashion, with the first step being conversion to the corresponding
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`monophosphate. McGuigan et al. “Certain phosphoramidate derivatives of dideoxy
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`uridine (ddU) are active against HIV and successfully by-pass thymidine kinase”
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`FEBS Letters, 1994, 351, 11-14 (“McGuigan 1994”; EX1009).
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`48.
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`The mono-, di-, and triphosphate forms of the C2’-deoxy-C2’-
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`methyl(up)-C2’-fluoro(down) uridine nucleoside are shown below.
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`Compounds 1A, 1B and 1C are phosphorylated analogs of a SP-4 compound, while
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`compound 1D is un-phosphorylated.
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`49.
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`It was well-known that compound 1C was a preferred compound for
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`the treatment of human hepatitis C viral infections. Ma et al. “Characterization of
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`the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor -D-2'-Deoxy-
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`2-Fluro-2'-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-
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`Triphosphate Species” J. Biol. Chem., 2007, 282(41), 29812-29820 (“Ma”;
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`EX1010). For instance, it was known that the triphosphate compound 1C had a
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`much longer intracellular half-life that its cytidine analog (38 hours vs. 4.7 hours)
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`resulting in a much longer duration of action. Id. at 1 and 8.
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`B.
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`Some Nucleoside Drugs Were Poor Substrates for
`Phosphorylation
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`50. A problem presented itself, however, in the identification of
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`compound 1C as a promising antiviral drug. Many nucleoside drugs – in particular,
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`uridines – were also known to be poor substrates for conversion into their
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`monophosphate forms. EX1009 (McGuigan 1994) at 1-2. This was also known to
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`be more common for virally-infected cells, which are often kinase-deficient. Such
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`knowledge was very important because drugs that would otherwise be very potent
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`for disease treatment would be inactive if they did not undergo this
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`phosphorylation process inside an infected cell.
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`C.
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`Compound 1D Was a Superior Agent Against HCV, But a Poor
`Substrate for Phosphorylation
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`51. Compound 1D had been disclosed in WO 2005/003147 to Clark
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`(“Clark ‘147”; EX1007) and in Clark, J., "Design, Synthesis, and Antiviral Activity
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`of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus
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`Replication," Journal of Medicinal Chemistry, 2005, 48(17), 5504-5508 (“Clark
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`2005”; EX1011). Clark 2005 indicated that compound 1D – the unmodified
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`nucleoside - had no activity in the HCV Replicon assay. EX1011 at 3.
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`52. Ma showed, however, that the triphosphate form of 1D (compound
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`1C) was a superior agent against hepatitis C virus, with excellent potency and a
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`long intracellular half-life. EX1010 at 1 and 8.
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`53.
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`These publications established that - although compound 1C was an
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`excellent antiviral agent - compound 1D was inactive because it could not be
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`efficiently phosphorylated inside virally-infected cells to be converted to 1C.
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`D.
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`ProTide Prodrugs of Nucleosides Were Well-Known to Overcome
`the Problem of Poor Phosphorylation
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`54.
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`ProTide prodrugs of nucleosides were first described in the early
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`1990s. EX1009 (McGuigan 1994) at 2-3. These analogs were well-known to
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`provide advantages over base nucleoside drugs in terms of physicochemical
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`properties, cellular absorption, improved half-life, and very importantly, in terms
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`of overcoming the problem of lack of biological activity due to poor intracellular
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`phosphorylation. The ProTide approach had been applied to activate nucleosides
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`through kinase bypass for hepatitis C antiviral compounds as in Perrone P.,
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`"Application of the Phosphoramidate ProTide Approach to 4'-Azidouridine Sub-
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`micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside," Journal
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`of Medicinal Chemistry, 2007, 50(8), 1840-1843 (“Perrone”; EX1012 at 1). Thus,
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`the ProTide approach was an obvious potential solution for overcoming the
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`problem of poor intracellular phosphorylation of compound 1D.
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`55