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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
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`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
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`
`
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`
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`DECLARATION OF JOSEPH M. FORTUNAK, Ph.D.
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`TABLE OF CONTENTS
`QUALIFICATIONS ........................................................................................ 1
`
`SCOPE OF WORK.......................................................................................... 6
`
`I.
`
`II.
`
`III. OVERVIEW OF THE ‘159 PATENT ............................................................ 8
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`IV. FILE HISTORY OF THE ‘159 PATENT ..................................................... 10
`
`V.
`
`LEGAL STANDARDS ................................................................................. 11
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`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 13
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`VII. CLAIM CONSTRUCTION .......................................................................... 14
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`VIII. BACKGROUND KNOWLEDGE IN THE ART ......................................... 14
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`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
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`A. Ross ’645 ............................................................................................. 25
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`B.
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`Ross ’257 ............................................................................................. 28
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`X.
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`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF EACH CLAIM OF THE ‘159 PATENT ........ 31
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`A. Claims 1-37 Were Anticipated By And Obvious Over Ross ’645 ..... 31
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`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
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`8.
`
`9.
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`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
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`4.
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`5.
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`6.
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`7.
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`8.
`
`9.
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`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
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`XI. CONCLUSION .............................................................................................. 68
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`XII. APPENDIX-LIST OF EXHIBITS ................................................................ 70
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`I. QUALIFICATIONS
`I am a Professor of Chemistry and Pharmaceutical Sciences at
`1.
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`Howard University, in Washington, D.C., where I regularly teach courses in
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`Organic Chemistry to undergraduate students. I also teach courses in drug
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`discovery, drug development, pharmaceutical chemistry, pharmaceutical sciences,
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`and green chemistry/chemical synthesis to PharmD and PhD students in Chemistry
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`and Pharmacy.
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`2.
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`I received my Bachelor of Science in Chemistry from Purdue
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`University in 1976, and my Doctorate in Philosophy in Organic Chemistry from
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`the University of Wisconsin-Madison in 1981. After earning my Ph.D., I was a
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`postdoctoral fellow and a research assistant professor at Cambridge University in
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`the United Kingdom from 1981-1983.
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`3. My career has spanned both the industrial and academic sectors,
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`including senior managerial and academic appointments.
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`4.
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`From 1983-1993, I worked at SmithKline Beecham Pharmaceutical
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`Corp. (GlaxoSmithKline), and served as Associate Senior Research Investigator,
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`Senior Research Investigator and Assistant Director. During that time, I was
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`primarily responsible for inventing processes to synthesize active pharmaceutical
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`ingredients (“APIs”) for investigational new drugs, including the drugs
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`halofantrine, ropinerole, topotecan and eprosartan, which the U.S. Food and Drug
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`Administration (“FDA”) has approved.
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`5.
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`From 1993-2000, I worked at DuPont Pharmaceutical Company
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`(“DuPont”), and served as Associate Director, Director, Senior Director and
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`Executive Director. During my tenure at DuPont, among other responsibilities, I
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`led the API development team for the major anti-HIV drug efavirenz, which is an
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`inhibitor of HIV-1 reverse transcriptase. I was also responsible for building a pre-
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`formulations group of experts in organic, solid-state chemistry and for managing
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`the transitions between the API, Formulations, and Analytical groups at DuPont.
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`6.
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`From 1993-1999, in addition to my work at SmithKline Beecham and
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`Dupont, I also served on the Scientific Advisory Board for NaPro Biotherapeutics
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`in Boulder, Colorado, working on a commercial semi-synthesis of the anti-cancer
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`drug paclitaxcel from renewable biomass.
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`7.
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`From 2000-2004, I worked at Abbott Laboratories (“Abbott Labs”) as
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`the Head of Global Chemical Development. During that time, I built a Process
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`Engineering Department with expertise in separation sciences, solids engineering
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`and process modeling. I also was responsible for process validation for four New
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`Drug Applications, including XIENCE™ V drug-device combination, a coronary
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`stent, and emtricitabine, an anti-HIV drug that is a nucleotide reverse transcriptase
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`inhibitor. My responsibilities in this role included oversight for the API and
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`physiochemical pre-formulation activities for all new drug candidates, route
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`discovery, polymorph control, clinical supplies, analytical & process development
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`and validation for Abbott Labs and external customers. My organization also
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`manufactured several small-volume, commercial products for Abbott Labs and
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`external customers.
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`8.
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`From 2001-2004 I also served as Chair of the Regulatory and
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`Compliance Section for the Midwest Pharmaceutical Process Chemistry
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`Consortium.
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`9. While employed as a scientist and manager in the innovator
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`pharmaceutical industry (1983-2004), I contributed to over 100 new chemical
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`entities that moved from discovery into development; approximately 15 of these
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`compounds were for the treatment of viral diseases. I also contributed to the
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`development and approval of twelve new drug applications (“NDAs”) approved
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`for marketing and a substantial number (approximately 20+) of generic products.
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`10.
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`I have consulted with a number of pharmaceutical companies on
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`issues relating to drug discovery, drug development, API and Finished
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`Pharmaceutical Product drug development and drug production
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`11. From 2004-2017, as noted above, I have served as a Professor of
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`Chemistry and Pharmaceutical Sciences at Howard University in Washington, DC.
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`My research group of PhD/PharmD/MSc and undergraduate students develops new
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`science to decrease the cost of and increase access to quality-assured medicines for
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`low- and middle-income countries. We have contributed to new chemistry and
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`technologies that have improved production and reduced cost of several drugs for
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`HIV/AIDS, Malaria, TB, and opportunistic infections, including the antiviral
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`(HIV) drugs efavirenz, tenofovir disoproxil fumarate, darunavir, dolutegravir, and
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`atazanavir.
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`12.
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`In 2005, I helped found the Drug Access Technical Team of the
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`William J. Clinton Health Access Initiative where I have contributed to the
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`organization’s successes in increasing global access to medications, including
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`HIV/AIDS, malaria and tuberculosis medications.
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`13.
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`I presently work with organizations including the World Health
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`Organization, UNITAID, UNIDO, the Bill and Melinda Gates Foundation, and the
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`Medicines Patent Pool on novel chemistry, formulations, and regulatory sciences
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`for manufacturing, market dynamics and regulation of quality-assured medicines
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`for low- and middle-income countries.
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`14. Since 2008 I have regularly taught (i.e., two to three times a year) a
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`curriculum in drug discovery, development, and manufacturing at the St. Luke
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`Foundation/Kilimanjaro School of Pharmacy (“KSP”) in Moshi, Tanzania, and the
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`School of Pharmacy/Center for Drug Discovery, Development, and Pharmaceutical
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`Production (CDDDP) at the University of Ibadan in Nigeria. These courses focus
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`on the science and practice of drug discovery and development. At the KSP and
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`Ibadan formulation pilot plants I teach students how to formulate drugs, including
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`dosage form design, granulation, milling, drying, compression, coating, and
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`process validation. This curriculum has received numerous awards, including a
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`2013 US FDA Honor Award for excellence and innovation in teaching and drug
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`regulatory sciences.
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`15.
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`I also have served or currently serve as an adjunct professor at the
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`University of Alabama, Green Chemistry Manufacturing Institute, the Kilimanjaro
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`School of Pharmacy, the University of Ibadan in Nigeria, and the Scientific
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`Advisory Board of the Royal Society of Chemistry (UK) as an expert in Green
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`Chemistry.
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`16.
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`I have published over 75 peer-reviewed papers, book chapters, and
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`monographs. I have also made hundreds of public presentations in the areas of my
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`expertise. I am also an inventor on 17 US patents in the areas of chemical
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`synthesis, green chemistry, drug synthesis, and drug manufacturing.
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`17. From 2006-2011, I was on the editorial board of the journal Current
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`Opinion in Drug Development. I am currently on the editorial boards of the Journal
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`of Tropical Pharmaceutical Research and the Journal Sustainability; from 2014-
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`2017 I was on the editorial board of the Royal Society of Chemistry, Green
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`Chemistry Journal.
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`18.
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`I have received several honors and awards for my research and
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`teaching work. Among many others, I have been awarded the Howard University
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`Faculty Senate Award for contributions to Africa and the African Diaspora, the
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`American Chemical Society “Astellas Foundation” Prize for Chemistry Impact on
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`Human Health, for, among other things, global access to anti-HIV drugs, the
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`African Union award for Corporate Social Responsibility, and a Corporate Award
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`from Abbott Labs for manufacturing improvements that reduced the rate of volatile
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`organic emissions (VOEs) over the island of Puerto Rico by 60%.
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`19. My research has focused on the study of new synthetic chemistry and
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`methodology for the manufacture of essential medicines for the treatment of
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`HIV/AIDS, malaria and tuberculosis. I also currently work on new technologies for
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`Green Chemistry, safety and waste reduction. I am also heavily involved in
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`teaching drug development and industrial pharmacy in Low- and Middle-Income
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`Countries to enable local production according to international standards of
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`Current Good Manufacturing Practice (cGMP). More recently (over the last 2
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`years), my research has been heavily directed towards drug discovery and
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`enhanced drug delivery.
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`20. Further details concerning my education, employment history and
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`experience are set forth in my Curriculum Vitae which is attached hereto.
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`II. SCOPE OF WORK
`I understand that a petition is being filed with the United States Patent
`21.
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`and Trademark Office requesting an Inter Partes Review of U.S. Patent No.
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`8,889,159 (“the ’159 patent,” Ex. 1001). I have been asked by the Petitioner as a
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`technical expert to provide analysis and opinions regarding the ’159 patent. I have
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`reviewed the ’159 patent and its prosecution history in the United States Patent and
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`Trademark Office. I have also reviewed and considered various other documents in
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`arriving at my opinions, and cite them in this declaration. For convenience,
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`documents cited in this declaration are listed in the Appendix.
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`22.
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`I am a Pharmaceutical Scientist at the Initiative for Medicines, Access
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`& Knowledge (I-MAK), INC., the Petitioner in this matter. I am not receiving any
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`additional compensation for my study and testimony in this matter, but I am being
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`reimbursed for reasonable and customary expenses. My position and compensation
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`are not contingent on the outcome of this matter or the specifics of my testimony.
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`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
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`response to any opinions offered by Patent Owner or its witnesses.
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`III. OVERVIEW OF THE ‘159 PATENT
`24. The ’159 patent relates to a composition and unit dosage form for the
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`treatment of hepatitis C virus (HCV) infection comprising GS-7977 and at least
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`one pharmaceutically acceptable excipient. The ’159 patent also covers methods
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`for making the composition and unit dosage form disclosed therein and a method
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`of treatment comprising administering to (preferably) a human subject an effective
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`amount of GS-7977 and an effective amount of ribavirin for a period of time. One
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`aspect of the method of treatment covered in the ’159 patent is an interferon-free
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`treatment regimen. EX1001 at 1:14-28.
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`25. More specifically, the ’159 patent relates to a composition comprising
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`a crystalline form of the compound GS-7977 (also known as PSI-7977), which has
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`the following molecular structure:
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`EX1001 at 46:37-52. The crystalline form covered by the ’159 patent has X-ray
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`powder diffraction (XRPD) 2θ-reflections at about 6.1 and 12.7 (°). EX1001 at
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`46:56. The patent also discloses that the crystalline form of GS-7977 possesses a
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`more complete set of 2θ-reflections at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0,
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`18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3 (°). EX1001 at 46:57-60.
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`26. The pharmaceutical composition claimed by the ’159 patent contains
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`about 25%-35% by weight of crystalline GS-7977. EX1001 at 46:36-37. The
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`pharmaceutical composition also contains at least one pharmaceutically acceptable
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`excipient that is a diluent, disintegrant, glidant, or lubricant. EX1001 at 46:61-63.
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`The patent further claims several choices of each type of excipient, and various
`
`amounts of each excipient contained in the pharmaceutical composition. EX1001
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`at 46:64-48:61.
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`27. The ’159 patent also discloses a unit dosage form containing about
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`400 mg of crystalline GS-7977. EX1001 at 47:51-52.
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`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
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`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
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`
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`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.
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`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.
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`61/564,500 (“the ‘500 provisional application”), filed on Nov. 29, 2011, and
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`61/707,459 (“the ‘459 provisional application”), filed on Sep. 28, 2012.
`
`30. During prosecution of the ’664 application, the Examiner made only
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`one prior art based rejection of the pending claims, for being obvious over U.S.
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`Patent Application Publication No. US 2010/0298257 to Ross (“Ross ’257”) in
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`view of US Patent Application Publication No. US 2011/0020272 to Schubert
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`(“Schubert”) and World Health Organization, “Pharmaceutical excipients - an
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`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
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`of GS-7977.” EX1002 at 108.
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`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
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`lack of novelty, if each and every element of the claim is described, either
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`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
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`rigid rule requiring the prior art to explicitly provide a teaching, suggestion or
`
`motivation to combine references to make the claimed invention. Accordingly,
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`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
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`“objective indicia of non-obviousness” to rebut a prima facie case of obviousness.
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`I understand that objective indicia of non-obviousness include unexpected results,
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`long-felt but unmet needs, skepticism of those in the art, subsequent praise and
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`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
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`academic or industrial laboratory focusing on drug discovery and/or development,
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`including formulations, and would also have some familiarity with antiviral drugs
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`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
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`given their ordinary and accustomed meaning as would be understood by a POSA.
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`41.
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`I have followed these principles in my analysis throughout this
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`declaration. The ’159 patent provides definitions for certain claim terms, but these
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`definitions are conventional. Thus, there is no reason to give any of the terms of
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`the claims of the ’159 a meaning other than their ordinary and accustomed
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`meaning.
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`VIII. BACKGROUND KNOWLEDGE IN THE ART
` Below I describe some of the relevant aspects of what was generally
`42.
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`known in the art as of November 29, 2011.
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`A. GS-7977 Was A Known and Promising Antiviral Agent for
`Treating HCV
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`43. WO 2008/121634 to Sofia et al. (“Sofia ’634”; EX1003) disclosed
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`specific phosphoramidate prodrugs of nucleoside derivatives, which are useful for
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`the treatment of viral infections, including HCV. The phosphoramidate prodrugs
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`disclosed in Sofia ’634 also included their stereoisomers, salts (acid or basic
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`addition salts), hydrates, solvates or crystalline forms as represented by the
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`following structure:
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`
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`EX1003 at 699.
`44. While Sofia ‘634 disclosed and claimed many compounds within the
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`formula, it specifically covered the compound (S)-2-{[(2R,3R,4R,5R)-5-(2,4-
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`Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-
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`furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester,
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`also known as GS-7977 (or PSI-7977). EX1003 at 703:48-50. Indeed, the ’159
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`confirms this. EX1001 at 8:3 (citing U.S Patent No.7,964,580, which corresponds
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`to Sofia ’634).
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`B. Crystalline Forms of GS-7977 Were Known
`45. Multiple crystalline forms of GS-7977 were already known in the art.
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`Sofia et al. “Discovery of β-D-2’ Deoxy-2’-α-fluoro-2’-β-C-methyluridine
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`Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis Virus”, September
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`16, 2010, 53, 7202-7218 (“Sofia 2010”; EX1004) disclosed a dichloromethane
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`solvate crystalline form of GS-7977. EX1004 at 8.
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`46. U.S Publication No. 2010/0298257 to Ross et al. (“Ross ’257”;
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`EX1005), which is identified as prior art by the ’159 patent, EX1001 at 8:3-47,
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`disclosed the following compounds Rp-4 and Sp-4, also known as GS-7977:
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`EX1005 at ¶¶0080-0109.
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`47. Ross ’257 also taught solvates, hydrates, or mixed solvate-hydrate
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`forms of Sp-4. Sp-4 was also disclosed to possibly exist as a mixed solvate-hydrate
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`form with additional adsorbed water. EX1005 at ¶0081. The compound
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`represented by Sp-4 was also disclosed as having solid state properties of being
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`crystalline, crystal-like, or amorphous. EX1005 at ¶0092.
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`48. Furthermore, Ross ’257 taught multiple crystalline forms of Sp-4.
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`Specifically, Ross ’257 disclosed XRPD patterns and 2θ-reflection angles for six
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`distinct crystalline forms of Sp-4. EX1005 at ¶¶0098-0106. Ross ’257 also taught a
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`substantially pure crystalline Sp-4. This disclosure of the subtantially pure
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`crystalline Sp-4 therefore teaches that a genus of crystalline forms of Sp-4 existed
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`including any additional crystalline forms. EX1005 at ¶¶0107-0108.
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`49.
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`Indeed, selecting a single crystalline form of a compound possessing
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`the preferred combination of optimal properties including (e.g., stability,
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`dissolution, and bioavailability) is a necessary and routine step in ensuring optimal
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`drug performance.
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`50. The ICH Q6A Guideline “Specifications: Test Procedures and
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`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
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`need to set acceptance criteria for polymorphism in drug substances and drug
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`products: “Decision trees #4(1) through 4(3) provide additional guidance on when,
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`and how, polymorphic forms should be monitored and controlled.” EX1006 at 13,
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`28.
`
`51.
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`It was also known that the selection of a single most-preferred solid-
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`state form was a matter of concern for drug regulatory agencies. Routine
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`approaches (including decision trees) to guide the evaluation and selection of an
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`optimal crystalline form of a new drug substance for development are available in
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`many relevant publications, including Byrn et al., “Pharmaceutical Solids: A
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`Strategic Approach to Regulatory Considerations,” Pharmaceutical Research,
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`12(7), 1995, 945-954 (“Byrn”; EX1007).
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`52. WO2011/123645 to Ross (“Ross ’645”; EX1008) also taught both
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`GS-7977 compounds Rp-4 and Sp-4. EX1008 at 8:1-5. Ross ’645 specifically
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`disclosed multiple crystalline forms of Sp-4. In particular, Ross ’645 disclosed the
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`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
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`concedes this. EX1001 at 8:3 (citing US 2011/0251152, which relates to
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`Ross’645).
`
`C. Tablet And Capsule Formulation Comprising Pharmaceutical
`Excipients Were Known
`
`53. Tablet formulations were well known and routine for use in the
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`pharmaceutical industry for drug delivery. Several textbooks and guides existed
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`setting out general principles of tablet design, excipient selection, and tablet
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`manufacture, all of which are commonly practiced in the field. Examples of such
`
`principles are explained in, Lieberman, Lachman and Schwartz, “Pharmaceutical
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`Dosage Forms: Tablets”, Volume 1, Chapter 3, 1989 by Marcel Dekker
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`(“Lieberman”; EX1009), U.S Pharmacopeia 24 (NF19), “Pharmaceutical Dosage
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`Forms”, General Information 1151-1161, 2117-2118, 2000 (“USP”; EX1010), and
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`Remington, “The Science and Practice of Pharmacy”, 19th Edition, 1995
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`(“Remington”; EX1011).
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`54. Both Ross ’257 and Ross ’645 incorporate Remington by reference in
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`relation to describing suitable formulations and pharmaceutical carriers, diluents
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`and excipients. EX1005 at ¶0119; EX1008 at 23:13-16.
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`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.
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`56. Rowe et al., “Handbook of Pharmaceutical Excipients”, Fourth
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`Edition, 2003 (“Rowe”; EX1012) provided a more thorough review of the
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`excipients approved for use by the U.S Food and Drug Administration. Rowe
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`taught a compendium of monographs for excipients used in pharmaceutical
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`compositions. The monographs