`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`___________
`
`Case No. IPR2018-00390
`U.S. Patent No. 8,889,159
`
`
`
`
`
`
`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
`
`
`
`IPR2018-00390
`
`Page 1 of 97
`
`I-MAK 1014
`
`
`
`TABLE OF CONTENTS
`QUALIFICATIONS ........................................................................................ 1
`
`SCOPE OF WORK.......................................................................................... 6
`
`I.
`
`II.
`
`III. OVERVIEW OF THE ‘159 PATENT ............................................................ 8
`
`IV. FILE HISTORY OF THE ‘159 PATENT ..................................................... 10
`
`V.
`
`LEGAL STANDARDS ................................................................................. 11
`
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 13
`
`VII. CLAIM CONSTRUCTION .......................................................................... 14
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART ......................................... 14
`
`A. GS-7977 Was A Known And Promising Antiviral Agent for Treating
`HCV ..................................................................................................... 14
`
`B.
`
`C.
`
`D.
`
`Crystalline Forms of GS-7977 Were Known ...................................... 16
`
`Tablet and Capsule Formulations Comprising Pharmaceutical
`Excipients Were Known ...................................................................... 19
`
`Tablet And Capsule Formulations Comprising Crystalline GS-7977
`And Pharmaceutical Excipients Were Known .................................... 20
`
`E. GS-7977 Was Known to Be in Human Clinical Trials at a 400mg
`Daily Dose ........................................................................................... 23
`
`F. Method of Treating HCV Using A Tablet Or Capsule Comprising
`Crystalline GS-7977 And A Pharmaceutical Excipient Was Known . 24
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART ......................................... 25
`
`A. Ross ’645 ............................................................................................. 25
`
`B.
`
`Ross ’257 ............................................................................................. 28
`
`i
`
`IPR2018-00390
`
`Page 2 of 97
`
`I-MAK 1014
`
`
`
`X.
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF EACH CLAIM OF THE ‘159 PATENT ........ 31
`
`A. Claims 1-37 Were Anticipated By And Obvious Over Ross ’645 ..... 31
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 1 and 2 (composition comprising compound and
`excipient) ................................................................................... 32
`
`Claims 3-12 (pharmaceutical composition comprising at least
`one pharmaceutically acceptable excipient) ............................. 36
`
`Claims 13-15 (composition comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 40
`
`Claims 16-17 (unit dosage form comprising 400mg of
`crystalline GD-7977) ................................................................ 42
`
`Claims 18-27 (unit dosage form comprising at least one
`pharmaceutical excipient) ......................................................... 43
`
`Claims 28-29 (unit dosage form comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 45
`
`Claim 30 (unit dosage form comprising a capsule or tablet) .... 47
`
`Claims 31-32 (process for preparing a tablet composition
`comprising the unit dosage form where GS-7977 is 400mg) ... 47
`
`Claims 33-37 (method of treatment comprising administering
`the composition) ........................................................................ 48
`
`B.
`
`Claims 1-37 Were Anticipated By And Obvious Over Ross ’257 ..... 50
`
`1.
`
`2.
`
`3.
`
`Claims 1 and 2 (composition comprising compound and
`excipient) ................................................................................... 50
`
`Claims 3-12 (pharmaceutical composition comprising at least
`one pharmaceutically acceptable excipient) ............................. 54
`
`Claims 13-15 (composition comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 59
`
`ii
`
`IPR2018-00390
`
`Page 3 of 97
`
`I-MAK 1014
`
`
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 16-17 (unit dosage form comprising 400mg of
`crystalline GS-7977) ................................................................. 60
`
`Claims 18-27 (unit dosage form comprising at least one
`pharmaceutical excipient) ......................................................... 61
`
`Claims 28-29 (unit dosage form comprising at least one
`pharmaceutically acceptable excipient by specific weight)...... 64
`
`Claim 30 (unit dosage form comprising a capsule or tablet) .... 65
`
`Claims 31-32 (process for preparing a tablet composition
`comprising the unit dosage form where GS-7977 is 400mg) ... 66
`
`Claims 33-37 (method of treatment comprising administering
`the composition) ........................................................................ 67
`
`XI. CONCLUSION .............................................................................................. 68
`
`XII. APPENDIX-LIST OF EXHIBITS ................................................................ 70
`
`iii
`
`IPR2018-00390
`
`Page 4 of 97
`
`I-MAK 1014
`
`
`
`I. QUALIFICATIONS
`I am a Professor of Chemistry and Pharmaceutical Sciences at
`1.
`
`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. (GlaxoSmithKline), 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, topotecan and eprosartan, which the U.S. Food and Drug
`
`1
`
`IPR2018-00390
`
`Page 5 of 97
`
`I-MAK 1014
`
`
`
`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 and for managing
`
`the transitions between the API, Formulations, and Analytical groups at DuPont.
`
`6.
`
`From 1993-1999, in addition to my work at SmithKline Beecham and
`
`Dupont, 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 (“Abbott Labs”) as
`
`the Head of Global Chemical Development. 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 anti-HIV drug that is a nucleotide reverse transcriptase
`
`inhibitor. My responsibilities in this role included oversight for the API and
`
`physiochemical pre-formulation activities for all new drug candidates, route
`
`2
`
`IPR2018-00390
`
`Page 6 of 97
`
`I-MAK 1014
`
`
`
`discovery, polymorph control, clinical supplies, analytical & process development
`
`and validation for Abbott Labs and external customers. My organization also
`
`manufactured several small-volume, commercial products for Abbott Labs and
`
`external customers.
`
`8.
`
`From 2001-2004 I 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 2004-2017, as noted above, I have served as a Professor 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
`
`3
`
`IPR2018-00390
`
`Page 7 of 97
`
`I-MAK 1014
`
`
`
`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 have contributed to the
`
`organization’s successes in increasing global access to medications, including
`
`HIV/AIDS, malaria and tuberculosis medications.
`
`13.
`
`I presently work with organizations including the World Health
`
`Organization, UNITAID, UNIDO, the Bill and Melinda Gates Foundation, 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 (i.e., two to three times a year) 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 Drug Discovery, Development, and Pharmaceutical
`
`Production (CDDDP) at the University of Ibadan in Nigeria. These courses focus
`
`on the science and practice of drug discovery and development. At the KSP and
`
`4
`
`IPR2018-00390
`
`Page 8 of 97
`
`I-MAK 1014
`
`
`
`Ibadan formulation pilot plants I teach students how to formulate drugs, including
`
`dosage form design, granulation, milling, drying, compression, coating, and
`
`process validation. 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, the University of Ibadan in Nigeria, and 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 also made hundreds of public presentations in the areas of my
`
`expertise. I am also an inventor on 17 US patents in the areas of chemical
`
`synthesis, green chemistry, drug synthesis, and drug manufacturing.
`
`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 and the Journal Sustainability; from 2014-
`
`2017 I was 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
`
`5
`
`IPR2018-00390
`
`Page 9 of 97
`
`I-MAK 1014
`
`
`
`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 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 according to international standards of
`
`Current Good Manufacturing Practice (cGMP). More recently (over the last 2
`
`years), my research has been heavily directed towards drug discovery and
`
`enhanced drug delivery.
`
`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
`I understand that a petition is being filed with the United States Patent
`21.
`
`6
`
`IPR2018-00390
`
`Page 10 of 97
`
`I-MAK 1014
`
`
`
`and Trademark Office requesting an Inter Partes Review of U.S. Patent No.
`
`8,889,159 (“the ’159 patent,” Ex. 1001). I have been asked by the Petitioner as a
`
`technical expert to provide analysis and opinions regarding the ’159 patent. I have
`
`reviewed the ’159 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.
`
`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
`
`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.
`
`7
`
`IPR2018-00390
`
`Page 11 of 97
`
`I-MAK 1014
`
`
`
`III. OVERVIEW OF THE ‘159 PATENT
`24. The ’159 patent relates to a composition and unit dosage form for the
`
`treatment of hepatitis C virus (HCV) infection comprising GS-7977 and at least
`
`one pharmaceutically acceptable excipient. The ’159 patent also covers methods
`
`for making the composition and unit dosage form disclosed therein and a method
`
`of treatment comprising administering to (preferably) a human subject an effective
`
`amount of GS-7977 and an effective amount of ribavirin for a period of time. One
`
`aspect of the method of treatment covered in the ’159 patent is an interferon-free
`
`treatment regimen. EX1001 at 1:14-28.
`
`25. More specifically, the ’159 patent relates to a composition comprising
`
`a crystalline form of the compound GS-7977 (also known as PSI-7977), which has
`
`the following molecular structure:
`
`EX1001 at 46:37-52. The crystalline form covered by the ’159 patent has X-ray
`
`
`
`8
`
`IPR2018-00390
`
`Page 12 of 97
`
`I-MAK 1014
`
`
`
`powder diffraction (XRPD) 2θ-reflections at about 6.1 and 12.7 (°). EX1001 at
`
`46:56. The patent also discloses that the crystalline form of GS-7977 possesses a
`
`more complete set of 2θ-reflections at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0,
`
`18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3 (°). EX1001 at 46:57-60.
`
`26. The pharmaceutical composition claimed by the ’159 patent contains
`
`about 25%-35% by weight of crystalline GS-7977. EX1001 at 46:36-37. The
`
`pharmaceutical composition also contains at least one pharmaceutically acceptable
`
`excipient that is a diluent, disintegrant, glidant, or lubricant. EX1001 at 46:61-63.
`
`The patent further claims several choices of each type of excipient, and various
`
`amounts of each excipient contained in the pharmaceutical composition. EX1001
`
`at 46:64-48:61.
`
`27. The ’159 patent also discloses a unit dosage form containing about
`
`400 mg of crystalline GS-7977. EX1001 at 47:51-52.
`
`28. The following chart describes the ’159 patent’s 37 claims:
`
`Claim(s)
`
`Recite
`
`1-2
`
`3-12
`
`13-15
`
`16-17
`
`A pharmaceutical composition comprising about 25%-35% by weight
`of crystalline GS-7977 and at least one excipient.
`The composition of claim 1 where at least one pharmaceutical
`excipient comprises a diluent, a disintegrant, a glidant and a lubricant,
`including various excipient options for selection.
`The composition of claim 1 wherein the at least one excipient
`comprises various weight percentages for each excipient.
`A unit dosage form containing about 400 mg of crystalline GS-7977
`
`9
`
`IPR2018-00390
`
`Page 13 of 97
`
`I-MAK 1014
`
`
`
`and at least one excipient
`The composition of claim 17 where at least one pharmaceutical
`excipient comprises a diluent, a disintegrant, a glidant and a lubricant,
`including various excipient options for selection.
`The composition of claim 17 wherein the at least one excipient
`comprises a weight range for each excipient.
`The unit dosage form of claim 17 comprising a capsule or tablet.
`
`A process for preparing a tablet composition comprising the unit
`dosage form of claim 28.
`A method of treating HCV in a human by administering the
`composition of claim 1, including in combination with ribavirin as
`part of an interferon-free regimen.
`
`18-27
`
`28-29
`
`30
`
`31-32
`
`33-37
`
`
`
`IV. FILE HISTORY OF THE ‘159 PATENT
`29. U.S. Patent Application No. 13/686,664 (“the ’664 application”), filed
`
`on November 27, 2012, issued as the ’159 patent on November 18, 2014. The ’664
`
`application claimed priority as a continuation-in-part of application No.
`
`PCT/US2012/055621, filed on Sep. 14, 2012, and as a continuation-in-part of U.S.
`
`Patent Application No. 13/661,509 (“the ’509 application”), filed on Oct. 26, 2012.
`
`The ’664 application also claimed the benefit of Provisional Applications Nos.
`
`61/564,500 (“the ‘500 provisional application”), filed on Nov. 29, 2011, and
`
`61/707,459 (“the ‘459 provisional application”), filed on Sep. 28, 2012.
`
`30. During prosecution of the ’664 application, the Examiner made only
`
`one prior art based rejection of the pending claims, for being obvious over U.S.
`
`Patent Application Publication No. US 2010/0298257 to Ross (“Ross ’257”) in
`
`10
`
`IPR2018-00390
`
`Page 14 of 97
`
`I-MAK 1014
`
`
`
`view of US Patent Application Publication No. US 2011/0020272 to Schubert
`
`(“Schubert”) and World Health Organization, “Pharmaceutical excipients - an
`
`overview including considerations for paediatric dosing” (“WHO”). EX1002 at 85.
`
`31.
`
`In response to the Examiner's obviousness rejection, Patent Owner
`
`amended the claims to recite polymorphic Form 6 of GS-7977 specifically and
`
`argued, “the claims, as currently amended, render the outstanding rejection moot
`
`for at least the reason that none of the cited references teaches or suggests Form 6
`
`of GS-7977.” EX1002 at 108.
`
`32. The Examiner withdrew the rejection, “because the claimed
`
`polymorph appears to be free of art.” EX1002 at 114. In the Notice of
`
`Allowability, the Examiner stated:
`
`The prior art including the applied references does not disclose or
`suggest the claimed polymorph: the crystalline GS-7977 has XRPD 2θ
`-reflections (°) at about: 6.1 and 12.7 as recited in claim 8. For
`example, while the closest prior art of Ross (US publication
`application no. 2010/0298257) does teach crystalline GS-7977 has
`XRPD 2θ -reflections (°) at about: 5.0, 7.3, 9.4 and 18.1, it requires
`different polymorph.
`EX1002 at 141.
`V. LEGAL STANDARDS
`I understand that prior art for the purpose of this declaration includes
`33.
`
`references that were published at least before November 29, 2011.
`
`34.
`
`I understand that a claim is not patentable under 35 U.S.C. § 102, for
`
`11
`
`IPR2018-00390
`
`Page 15 of 97
`
`I-MAK 1014
`
`
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`35.
`
`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.
`
`36.
`
`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.
`
`37.
`
`I also understand that Patent Owner may present evidence of
`
`12
`
`IPR2018-00390
`
`Page 16 of 97
`
`I-MAK 1014
`
`
`
`“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
`I understand that a POSA is a hypothetical person who is presumed to
`38.
`
`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.
`
`39. As the ’159 patent pertains to a composition and unit dosage form of a
`
`crystalline form of the nucleos(t)ide compound GS-7977, which can be used to
`
`treat a subject infected with HCV, a POSA with respect to the ’159 patent would
`
`(1) have a Ph.D. in chemistry or a closely related field with some experience in an
`
`academic or industrial laboratory focusing on drug discovery and/or development,
`
`13
`
`IPR2018-00390
`
`Page 17 of 97
`
`I-MAK 1014
`
`
`
`including formulations, 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, including
`
`formulations, for the treatment of viral diseases.
`
`VII. CLAIM CONSTRUCTION
`I understand that, in the present proceeding, the ’159 patent claims are
`40.
`
`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.
`
`41.
`
`I have followed these principles in my analysis throughout this
`
`declaration. The ’159 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 ’159 a meaning other than their ordinary and accustomed
`
`meaning.
`
`VIII. BACKGROUND KNOWLEDGE IN THE ART
` Below I describe some of the relevant aspects of what was generally
`42.
`
`known in the art as of November 29, 2011.
`
`A. GS-7977 Was A Known and Promising Antiviral Agent for
`Treating HCV
`
`43. WO 2008/121634 to Sofia et al. (“Sofia ’634”; EX1003) disclosed
`
`14
`
`IPR2018-00390
`
`Page 18 of 97
`
`I-MAK 1014
`
`
`
`specific phosphoramidate prodrugs of nucleoside derivatives, which are useful for
`
`the treatment of viral infections, including HCV. The phosphoramidate prodrugs
`
`disclosed in Sofia ’634 also included their stereoisomers, salts (acid or basic
`
`addition salts), hydrates, solvates or crystalline forms as represented by the
`
`following structure:
`
`
`
`EX1003 at 699.
`44. While Sofia ‘634 disclosed and claimed many compounds within the
`
`formula, it specifically covered the compound (S)-2-{[(2R,3R,4R,5R)-5-(2,4-
`
`Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-
`
`furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester,
`
`also known as GS-7977 (or PSI-7977). EX1003 at 703:48-50. Indeed, the ’159
`
`confirms this. EX1001 at 8:3 (citing U.S Patent No.7,964,580, which corresponds
`
`to Sofia ’634).
`
`15
`
`IPR2018-00390
`
`Page 19 of 97
`
`I-MAK 1014
`
`
`
`B. Crystalline Forms of GS-7977 Were Known
`45. Multiple crystalline forms of GS-7977 were already known in the art.
`
`Sofia et al. “Discovery of β-D-2’ Deoxy-2’-α-fluoro-2’-β-C-methyluridine
`
`Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis Virus”, September
`
`16, 2010, 53, 7202-7218 (“Sofia 2010”; EX1004) disclosed a dichloromethane
`
`solvate crystalline form of GS-7977. EX1004 at 8.
`
`46. U.S Publication No. 2010/0298257 to Ross et al. (“Ross ’257”;
`
`EX1005), which is identified as prior art by the ’159 patent, EX1001 at 8:3-47,
`
`disclosed the following compounds Rp-4 and Sp-4, also known as GS-7977:
`
`
`
`
`
`16
`
`IPR2018-00390
`
`Page 20 of 97
`
`I-MAK 1014
`
`
`
`
`
`EX1005 at ¶¶0080-0109.
`
`47. Ross ’257 also taught solvates, hydrates, or mixed solvate-hydrate
`
`forms of Sp-4. Sp-4 was also disclosed to possibly exist as a mixed solvate-hydrate
`
`form with additional adsorbed water. EX1005 at ¶0081. The compound
`
`represented by Sp-4 was also disclosed as having solid state properties of being
`
`crystalline, crystal-like, or amorphous. EX1005 at ¶0092.
`
`48. Furthermore, Ross ’257 taught multiple crystalline forms of Sp-4.
`
`Specifically, Ross ’257 disclosed XRPD patterns and 2θ-reflection angles for six
`
`distinct crystalline forms of Sp-4. EX1005 at ¶¶0098-0106. Ross ’257 also taught a
`
`substantially pure crystalline Sp-4. This disclosure of the subtantially pure
`
`crystalline Sp-4 therefore teaches that a genus of crystalline forms of Sp-4 existed
`
`including any additional crystalline forms. EX1005 at ¶¶0107-0108.
`
`49.
`
`Indeed, selecting a single crystalline form of a compound possessing
`
`the preferred combination of optimal properties including (e.g., stability,
`
`17
`
`IPR2018-00390
`
`Page 21 of 97
`
`I-MAK 1014
`
`
`
`dissolution, and bioavailability) is a necessary and routine step in ensuring optimal
`
`drug performance.
`
`50. The ICH Q6A Guideline “Specifications: Test Procedures and
`
`Acceptance Criteria For New Drug Substances and New Drug Products: Chemical
`
`Substances” (“ICH”; EX1006) provides in Section 3.3.1 New Drug Substances:
`
`c) Polymorphic forms: Some new drug substances exist in different
`crystalline forms, which differ in their physical properties.
`Polymorphism may also include solvation or hydration products (also
`known as pseudopolymorphs) and amorphous forms. Differences in
`these forms could, in some cases, affect the quality or performance of
`the new drug products. In cases where differences exist which have
`been shown to affect drug product performance, bioavailability or
`stability, then the appropriate solid state should be specified.
`EX1006 at 12. ICH taught a set of three Decision Trees for guidance about the
`
`need to set acceptance criteria for polymorphism in drug substances and drug
`
`products: “Decision trees #4(1) through 4(3) provide additional guidance on when,
`
`and how, polymorphic forms should be monitored and controlled.” EX1006 at 13,
`
`28.
`
`51.
`
`It was also known that the selection of a single most-preferred solid-
`
`state form was a matter of concern for drug regulatory agencies. Routine
`
`approaches (including decision trees) to guide the evaluation and selection of an
`
`optimal crystalline form of a new drug substance for development are available in
`
`18
`
`IPR2018-00390
`
`Page 22 of 97
`
`I-MAK 1014
`
`
`
`many relevant publications, including Byrn et al., “Pharmaceutical Solids: A
`
`Strategic Approach to Regulatory Considerations,” Pharmaceutical Research,
`
`12(7), 1995, 945-954 (“Byrn”; EX1007).
`
`52. WO2011/123645 to Ross (“Ross ’645”; EX1008) also taught both
`
`GS-7977 compounds Rp-4 and Sp-4. EX1008 at 8:1-5. Ross ’645 specifically
`
`disclosed multiple crystalline forms of Sp-4. In particular, Ross ’645 disclosed the
`
`specific crystalline form of compound Sp-4 as claimed in the pharmaceutical
`
`composition of the ’159 patent. EX1008 at 20:16-18. Indeed, the ‘159 patent
`
`concedes this. EX1001 at 8:3 (citing US 2011/0251152, which relates to
`
`Ross’645).
`
`C. Tablet And Capsule Formulation Comprising Pharmaceutical
`Excipients Were Known
`
`53. Tablet formulations were well known and routine for use in the
`
`pharmaceutical industry for drug delivery. Several textbooks and guides existed
`
`setting out general principles of tablet design, excipient selection, and tablet
`
`manufacture, all of which are commonly practiced in the field. Examples of such
`
`principles are explained in, Lieberman, Lachman and Schwartz, “Pharmaceutical
`
`Dosage Forms: Tablets”, Volume 1, Chapter 3, 1989 by Marcel Dekker
`
`(“Lieberman”; EX1009), U.S Pharmacopeia 24 (NF19), “Pharmaceutical Dosage
`
`Forms”, General Information 1151-1161, 2117-2118, 2000 (“USP”; EX1010), and
`
`Remington, “The Science and Practice of Pharmacy”, 19th Edition, 1995
`
`19
`
`IPR2018-00390
`
`Page 23 of 97
`
`I-MAK 1014
`
`
`
`(“Remington”; EX1011).
`
`54. Both Ross ’257 and Ross ’645 incorporate Remington by reference in
`
`relation to describing suitable formulations and pharmaceutical carriers, diluents
`
`and excipients. EX1005 at ¶0119; EX1008 at 23:13-16.
`
`55. The ’159 patent itself states that its embodiments may be modified
`
`using the materials and methods taught by Remington. EX1001 at 17:54-58.
`
`56. Rowe et al., “Handbook of Pharmaceutical Excipients”, Fourth
`
`Edition, 2003 (“Rowe”; EX1012) provided a more thorough review of the
`
`excipients approved for use by the U.S Food and Drug Administration. Rowe
`
`taught a compendium of monographs for excipients used in pharmaceutical
`
`compositions. The monographs
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
