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
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`v.
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`GILEAD PHARMASSET LLC
`Patent Owner
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`Case IPR2018-00122
`Patent 8,334,270
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`PATENT OWNER GILEAD PHARMASSET LLC’S
`PRELIMINARY RESPONSE
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`Case IPR2018-00122
`Attorney Docket No: 36583-0020IP5
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`TABLE OF CONTENTS
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` I.
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`INTRODUCTION ............................................................................................... 1
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`II. THE SOFIA ’270 PATENT ................................................................................ 3
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`A. Hepatitis C and the previous treatments. .......................................................... 4
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`B. Many researchers tried to develop anti-HCV drugs but failed. ....................... 5
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`1. Changes to nucleoside structure can have significant and unpredictable
`impacts on activity and toxicity. .......................................................................... 6
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`2. Persons of ordinary skill in this field understood that the effectiveness
`of prodrugs was unpredictable and nucleoside-specific. ..................................... 9
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`C. Sofosbuvir was a “game-changing” treatment for HCV. ............................... 10
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`D. The Sofia ’270 patent claims .......................................................................... 11
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`III. ARGUMENT .................................................................................................. 11
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`A. I-MAK’s proposed combination of Clark ’147 and Clark 2005 is flawed. ... 16
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`1. I-MAK fails to show that a person of ordinary skill would select the
`genus of Clark ’147 claim 40 as a lead compound for modification. ............... 17
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`2. I-MAK fails to show that a person of ordinary skill would select the
`inactive uridine analog instead of the active cytidine analog. ........................... 23
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`B. I-MAK’s proposed combination of Clark ’147 and Clark 2005 with
`Perrone or McGuigan ’327 is flawed .................................................................... 26
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`1. I-MAK fails to show that a person of ordinary skill would modify the
`nucleoside of Clark ’147/Clark 2005 with the phosphoramidate prodrug of
`Perrone, or have a reasonable expectation of success of doing so. ................... 27
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`2. I-MAK fails to show that a person of ordinary skill would modify the
`nucleoside of Clark ’147/Clark 2005 with the isopropyl ester of McGuigan
`’327, or have a reasonable expectation of success of doing so. ........................ 30
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`Case IPR2018-00122
`Attorney Docket No: 36583-0020IP5
`C. Dr. Fortunak’s opinions are conclusory and insufficient to support
`institution .............................................................................................................. 35
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`IV. PRESERVATION OF RIGHTS UNDER OIL STATES ................................ 36
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`V. CONCLUSION .................................................................................................. 37
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`ii
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`Exhibit No.
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`GIL 2001
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`GIL 2002
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`GIL 2003
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`GIL 2004
`GIL 2005
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`GIL 2006
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`GIL 2007
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`GIL 2008
`GIL 2009
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`GIL 2010
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`GIL 2011
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`GIL 2012
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`GIL 2013
`GIL 2014
`GIL 2015
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`GIL 2016
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`GIL 2017
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`Case IPR2018-00122
`Attorney Docket No: 36583-0020IP5
`LIST OF EXHIBITS
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`Exhibit Description
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`Carroll et al. Nucleoside Analog Inhibitors of Hepatitis C
`Virus Replication. Infectious Disorders – Drug Targets, 2006
`Chung, M.D. et al. Curing Chronic Hepatitis C – The Arc of a
`Medical Triumph. The New England Journal of Medicine,
`2014.
`Tucker, Miriam E. FDA Approves ‘Game Changer’ Hepatitis
`C Drug Sofosbuvir. Medscape, 2013.
`HARVONI® label
`Norton, Amy. Hepatitis C Killing More Americans than HIV:
`Studies. Reuters, 2012.
`Secrist III et al. Clofarabine: From Design to Approval.
`Modified Nucleosides: in Biochemistry, Biotechnology and
`Medicine, 2008.
`America’s Overspend: How the Pharmaceutical Patent
`Problem is Fueling High Drug Prices. I-MAK, 2017.
`I-MAK: Our People
`Lawitz et al. Development of Sofosbuvir for the Treatment of
`Hepatitis C Virus Infection. Annals of the New York Academy
`of Sciences, 2014.
`Ninburg, Michael. Hepatitis C Deserves the Attention.
`Seattlepi.com, 2007.
`Pollack, Andrew. F.D.A. Approves Pill to Treat Hepatitis C.
`The New York Times, 2013.
`Rockoff, Jonathan D. FDA Approves Gilead’s Hepatitis C
`Drug. The Wall Street Journal, 2013.
`RESERVED
`RESERVED
`Sofia et al. Discovery of a β-D-2’-Deoxy-2’-β-C-
`methyluridine Nucleotide Prodrug (PSI-7977) for the
`Treatment of Hepatitis C Virus. Journal of Medicinal
`Chemistry Article, 2010.
`Thompson et al. Review Article: Investigational Agents for
`Chronic Hepatitis C. Alimentary Pharmacology &
`Therapeutics, 2009.
`Meier, C. Pro-Nucleotides – Recent Advances in the Design of
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`Case IPR2018-00122
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`Efficient Tools for the Delivery of Biologically Active
`Nucleoside Monophosphates. Synlett, 1997
`Pierra et al. Synthesis and Pharmacokinetics of Valopicitabine
`(NM283), an Efficient Prodrug of the Potent Anti-HCV Agent
`2’-C-Methylcytidine. J. Med. Chem., 2006
`Krise et al. Prodrugs of Phosphates, Phosphonates, and
`Phosphinates. Advanced Drug Delivery Review, 1996.
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`GIL 2018
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`GIL 2019
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`Case IPR2018-00122
`Attorney Docket No: 36583-0020IP5
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`I.
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`INTRODUCTION
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`U.S. 8,334,270 (“the Sofia ’270 patent”) covers sofosbuvir, the active
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`ingredient that forms the backbone of Gilead’s revolutionary Hepatitis C virus
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`(“HCV”) therapies, SOLVADI®, HARVONI®, EPCLUSA®, and VOSEVI®.
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`HCV is a global health crisis. In the United States alone, more than three million
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`people have been infected with the virus. EX. 2009 (Lawitz et al.), p. 1. Left
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`untreated, HCV leads to liver disease and is a primary cause of liver cancer. EX.
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`2002 (Chung), p. 1. Before sofosbuvir, the standard of care HCV treatment had
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`debilitating, often permanent, side effects and low success rates. As a result, many
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`patients opted to live with the disease rather than attempt treatment. The invention
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`of sofosbuvir changed all of that.
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`On December 6, 2013, after expedited review, the FDA approved
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`sofosbuvir. Sofosbuvir’s approval was hailed throughout the scientific and popular
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`press, including the front pages of the New York Times and Wall Street Journal,
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`and was recognized as a “game changer.” EX. 2003 (Tucker); EX. 2011 (Pollack);
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`EX. 2012 (Rockoff).
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`I-MAK, in its petition, tries to minimize the significance of this game-
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`changing accomplishment. I-MAK attacks the Sofia ’270 patent on two grounds,
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`both of which rely on a proposed combination of Clark ’147 (EX.1006) and Clark
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`2005 (1007) as the primary reference. I-MAK then proposes to modify the
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`Case IPR2018-00122
`Attorney Docket No: 36583-0020IP5
`compound resulting from this proposed combination with either Perrone (EX.
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`1008) or McGuigan ’327 (EX. 1009). However, I-MAK fails to perform a proper
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`lead compound analysis as part of its challenge. In particular, I-MAK provides no
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`evidence to establish that the genus resulting from its proposed Clark ’147/Clark
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`2005 combination is an appropriate starting point or that it is sufficiently narrow to
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`define a lead compound.
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`I-MAK’s proposed combinations with either Perrone or McGuigan ’327
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`ignore important structural differences between the molecules it seeks to
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`combine—differences that a person of ordinary skill would not ignore. Instead, I-
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`MAK would have the Board believe that the “general knowledge in the art” made
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`the discovery of sofosbuvir routine and rendered its ability to treat HCV expected.
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`But I-MAK presents no evidence to support its theory. Instead, I-MAK relies on
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`the musing of its biased expert, Dr. Joseph Fortunak.
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`Dr. Fortunak is not an independent expert at all. Rather, he is an I-MAK
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`employee whose real objective is to eliminate pharmaceutical patents. See EX.
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`1002 ¶ 22; EX. 2007 (I-MAK); EX. 2008 (I-MAK “Our People”). Dr. Fortunak
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`fails to offer a reasoned scientific explanation, backed by objective facts, for any of
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`his opinions. Instead, he offers only vague, conclusory statements regarding what
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`he believes was known and what he believes a person of ordinary skill would have
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`done. It is telling that despite all of this “general knowledge” and the recognized
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`need for a better HCV treatment, no one met this need until the invention of
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`sofosbuvir.
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`Only in hindsight, with the Sofia ’270 patent as a guide, could a person of
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`ordinary skill have chosen the specific claimed molecules and predicted that they
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`would be effective against HCV. And there, in a nutshell, is I-MAK’s problem: its
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`attack on the Sofia ’270 patent is nothing more than hindsight. I-MAK’s petition
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`should be denied.
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`II. THE SOFIA ’270 PATENT
`The Sofia ’270 patent covers certain nucleoside phosphoramidate prodrugs,
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`including sofosbuvir, and their use in treating HCV. Sofosbuvir has the chemical
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`name (S)-isopropyl 2-(((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-
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`1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-
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`yl)methoxy(phenoxy)phosphorylamino)propanoate. It has the following chemical
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`formula:
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`As shown in the formula, sofosbuvir has a uracil base bonded to a modified
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`deoxyribose sugar at the 1’ position. The sugar is further substituted at the 2’
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`position with a methyl group in the “up” configuration and a fluoro group in the
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`“down” configuration. The stereochemistry at the phosphorus atom is the “S”
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`configuration (“Sp”) and the stereochemistry of the methyl group results in the “L”
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`configuration of the alanine group of the phosphoramidate prodrug portion.
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`To appreciate the significance of this life-changing invention, it is necessary
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`to understand the state of the art at the time sofosbuvir was invented, including the
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`bleak prospects for patients infected with HCV and the many failures to develop
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`anti-HCV drugs that were both effective and non-toxic.
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`A. Hepatitis C and the previous treatments.
` Hepatitis C virus is a disease that targets the liver. In 2000, former U.S.
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`Surgeon General, C. Everett Koop, in describing the threat HCV posed, said “We
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`stand at the precipice of a grave threat to our public health ... it affects people from
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`all walks of life, in every state, in every country. And unless we do something
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`about it soon, it will kill more people than AIDS.” EX. 2010 (Ninburg). His
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`statement proved prescient. By 2007, HCV was causing more deaths than HIV and
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`AIDS. EX. 2005 (Norton). Over 170 million people worldwide suffer from HCV.
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`See, e.g., EX. 2002 (Chung), p. 1; EX. 2009 (Lawitz), p. 1.
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`Because of the incredibly rapid rate at which HCV replicates in the body, as
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`well as the large number of mutations that form during replication, developing an
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`effective HCV therapy has been daunting. Before sofosbuvir, the treatments for
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`HCV were typically a combination of antiviral medicines, taken for prolonged
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`periods—up to 48 weeks—that caused side effects so severe that many patients
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`were not healthy enough to take the treatment at all and others chose to live with
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`the life-threatening disease rather than endure treatment. See EX. 2009 (Lawitz),
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`p. 2. One of the prior medicines used, interferon, is particularly debilitating,
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`requiring weekly injections and causing side effects that run the gamut from
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`cardiac abnormalities, persistent flu-like symptoms, and mental illnesses such as
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`depression and anxiety. See id.
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`B. Many researchers tried to develop anti-HCV drugs but failed.
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`In the late 1990s and early 2000s, because the medical need was so great and
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`the financial upside so large, institutions big and small, including universities,
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`hospitals, and corporations, from across the globe searched for effective treatments
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`for HCV. Because no single approach held the answer, thousands of different
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`paths were taken. Some pursued nucleoside analogs. In the course of their
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`research, the inventors and other scientists in this field discovered that changes to
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`the structure of a nucleoside, or a prodrug used with a nucleoside, could have
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`unpredictable and often negative impacts on the activity and toxicity of that
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`nucleoside. This understanding was reflected in the published literature at the time
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`of the claimed invention.
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`1.
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`Changes to nucleoside structure can have significant and
`unpredictable impacts on activity and toxicity.
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`Persons of skill in the art recognized that changes in nucleoside structure can
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`have a significant impact on biological activity. For example, the authors of a
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`leading textbook in the field stated that they “have become strong proponents of
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`the view that small changes, at least in nucleotides, can have a significant effect on
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`the clinical and toxicological profile of a drug—as supported by the only structural
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`difference between clofarabine and cladribine being the replacement of a hydrogen
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`atom at the 2’ position with a fluorine atom. Nonetheless, this small difference is
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`sufficient to endow clofarabine with biochemical and clinical activities which
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`differ widely from those of cladribine.” EX. 2006 (Secrist), p. 14.
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`Other contemporaneous publications support this conclusion. For example,
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`in 2005 Pharmasset scientists published an article describing the design, synthesis,
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`and antiviral activity of certain 2’-deoxy-2’-fluoro-2’-C-methyl nucleosides. EX.
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`1007. Among the nucleoside analogs tested were 2’-deoxy-2’-fluoro-2’-C-
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`methylcytidine (compound 1) and a compound with the same nucleoside sugar ring
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`but a uracil base instead of a cytosine base (compound 9):
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`Id. at Fig. 1, Fig. 3.
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`Table 2 of the article describes the activity of 2’-deoxy-2’-fluoro-2’-C-
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`methylcytidine (compound 1) and 2’-deoxy-2’-fluoro-2’-C-methyluridine
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`(compound 9). Id., p. 3, Table 2. The data showed that while 2’-deoxy-2’-fluoro-
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`2’-C-methylcytidine exhibited strong activity in the HCV replicon assay, the
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`uridine analog “demonstrated no activity or cytotoxicity in any assay.”
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`Id.
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`Scientists outside of Pharmasset also recognized that certain structural
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`changes could have significant effects on nucleoside activity and toxicity. For
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`example, in 2006 Carroll et al. studied the effects of varying nucleoside
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`substituents and concluded that their results “indicate that a very narrow range of
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`substituents gives rise to potent inhibition, particularly in the replicon assay, owing
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`in large part to the multiple structural requirements for efficient uptake of the
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`nucleoside into the cell, conversion to the 5’-triphosphate, and the absence of
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`unwanted metabolic conversion to inactive analogs, that are necessary in order to
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`inhibit viral RNA replication in the cellular environment.” EX. 2001 (Carroll), p.
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`3.
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`As shown, persons of skill at the time of the invention claimed in the Sofia
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`’270 patent appreciated that certain changes to the nucleoside structure could have
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`significant and unpredictable impact on biological activity and toxicity.
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`2.
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`Persons of ordinary skill in this field understood that the
`effectiveness of prodrugs was unpredictable and nucleoside-
`specific.
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`The unpredictability of nucleoside analogs extends to prodrugs of such
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` 
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`analogs. In particular, scientists at the time of the claimed invention understood
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`that the effectiveness of a prodrug, or lack thereof, was nucleoside-specific. For
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`example, Perrone, an article relied on by Petitioner (EX. 1008), described the anti-
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`HCV effects of various phosphoramidate prodrugs for a certain nucleoside
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`analogue (4’-azidouridine). The Perrone authors noted that “quite distinct”
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`structure-activity relationships were found for the particular 4’-azidouridine
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`nucleoside analogs studied compared to nucleosides previously studied, thus
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`emphasizing that the effectiveness of a prodrug was nucleoside-specific. Id.
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`Similarly, a 1997 publication by Meier reported that an arylphosphoramidate
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`prodrug approach that had been previously found effective in delivering certain
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`nucleosides (EX. 2017 (Meier), p. 5) was not effective for the anti-HIV drugs AZT
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`and 3TC, which involved different nucleosides (id., p. 6). The article also reported
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`that an amino acid phosphoramidate prodrug approach that had been previously
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`applied to AZT “could not be transferred to the antitumor-active nucleoside 5-
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`FdU.” Id. Meier also noted that “the enormous disparity in anti-HIV activity that
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`is evident for a large number of dideoxynucleoside analogues belies their apparent
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`structural similarity.” Id., p. 1.
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`These conclusions are consistent with the understanding of scientists in this
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`field that there is no one size fits all approach to nucleoside prodrug development.
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`Indeed, a review article on prodrugs noted that “although we have been successful
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`at identifying numerous phosphate and phosphonate functional group-containing
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`drugs as antiviral and anticancer agents, as well as for other uses, our ability to
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`orally deliver these drugs and to target them to desired sites has led to limited
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`success.” EX. 2019 (Krise 1996), abstract.
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`Sofosbuvir was a “game-changing” treatment for HCV.
`C.
`On December 6, 2013, after expedited review, the FDA approved sofosbuvir
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`as Gilead’s Sovaldi®, a once-daily oral nucleotide analogue for the treatment of
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`chronic HCV infection. See EX. 2009 (Lawitz), p. 10. For the first time, many
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`patients could now be cured of HCV without interferon, while others only needed
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`to take interferon for 12 weeks. See id. Just ten months later, Gilead took
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`sofosbuvir to still another level when the FDA approved Harvoni®, which
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`combines sofosbuvir with another drug to cure 95% of the patients who take it in
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`as little as 8 weeks without subjecting the patients to interferon. See id.; see also
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`EX. 2004 at §2.2 (HARVONI Prescribing Information). It was thus possible to
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`cure patients after a short period of time with almost no side effects. Sofosbuvir
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`truly was a “game-changing” invention, and indeed is the only nucleoside ever
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`approved for the treatment of HCV.
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`The Sofia ’270 patent claims
`D.
`The Sofia ’270 patent contains 25 claims. I-MAK challenges only claims 1,
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`2, 10-18, and 20-25. Claims 1 and 16 are independent. They cover particular
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`nucleoside phosphoramidate prodrugs, including sofosbuvir, which have a uracil
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`base bonded to a sugar substituted at the 2’ position with a methyl group in the
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`“up” configuration and a fluoro in the “down” configuration.
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`Claims 1 and 2 specifically covers sofosbuvir, among other recited
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`nucleoside phosphoramidate prodrugs. Claims 16-18 cover the same chemical
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`structure as sofosbuvir with the exception that they cover the Sp stereoisomer, the
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`Rp stereoisomer, and mixtures of the two, rather than just the Sp stereoisomer.
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`Claims 2 and 10-15 depend on claim 1 while claims 17, 18 and 20-25
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`depend on claim 16. Claims 10-12 and 20-21 cover pharmaceutical compositions.
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`Claims 14-15 and claims 22-25 cover methods of treating viruses, including HCV.
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`III. ARGUMENT
`I-MAK alleges that claims 1, 2, 10-18 and 20-25 of the Sofia ’270 patent are
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`obvious over Clark ’147 (EX. 1006) in combination with Clark 2005 (EX. 1007)
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`and either Perrone (EX. 1008)1 or McGuigan ’327 (EX. 1009). However, I-
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`MAK’s petition fails to satisfy the legal requirements for obviousness.
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`Determining whether claims to a chemical compound would have been
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`obvious over prior art compounds generally requires a two-part analysis. Otsuka
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`Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291-93 (Fed. Cir. 2012); Incyte Corp.
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`v. Concert Pharmaceuticals, Inc., IPR2017-01256, Paper No. 9, p. 14 (PTAB Oct.
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`19, 2017). In the first step, the party challenging validity must establish that “a
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`chemist of ordinary skill would have selected the asserted prior art compounds as
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`lead compounds, or starting points for further development efforts.” Otsuka, 678
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`F.3d at 1291. A lead compound is “a compound in the prior art that would be most
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`promising to modify in order to improve upon its … activity and obtain a
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`compound with better activity.” Id. In other words, “a lead compound is a ‘natural
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`choice for further development efforts.’” Id., citing Altana Pharma AG v. Teva
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`Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009).  In this regard, a
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`compound included in a long list of compounds, without more, does not meet the
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`standard for a lead compound. Id. at 1295 (rejecting a proposed lead compound
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`                                                            
`1 Gilead does not concede that Perrone is prior art. Nevertheless, for purposes of
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`deciding whether to grant I-MAK’s petition, it is not necessary to reach this issue
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`because I-MAK’s petition is deficient regardless of whether Perrone is prior art.
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`where the compound was listed as one of hundreds of compounds that might be
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`useful).
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`The PTAB’s decision in Apotex Inc. v. Merck Sharp & Dohme Corp.,
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`IPR2015-00419, Paper No. 14 (PTAB June 25, 2015) illustrates the first step of the
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`analysis. The claims at issue covered tachykinin receptor antagonists useful in
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`treating inflammatory diseases, pain or migraine, asthma, and emesis that were
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`prodrugs of a parent compound. Id., p. 2. In its obviousness challenge, the
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`petitioner relied on a reference (“Dorn ’699”) to teach the structure of the parent
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`compound. Id., p. 7. The petitioner argued that Dorn disclosed both a specific
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`compound having the structure of the claimed parent (“compound 96”) and a genus
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`having a “narrowed range of preferred substituents” that encompassed compound
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`96. Id., p. 8.
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`The PTAB rejected the petitioner’s argument and denied the petition. First,
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`the PTAB disagreed that Dorn ’699 disclosed a “narrowed range” of substituents
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`for the genus:
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`[T]he scope of R2 and R3 each includes possibly hundreds of preferred
`substituents—hardly the “narrowed range” suggested by Petitioner.
`Petitioner also does not explain why one skilled in the art would have
`chosen hydrogen independently for each position, let alone
`simultaneously for both R2 and R3 to arrive at compound 96.
`Similarly, Petitioner does not adequately explain why a skilled artisan
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`would have chosen any of the preferred substituents for each of R1, R4
`(which further includes R6, R7, R8, and Z), and R5 according to
`compound 96, not to mention all of them at the same time. Thus, we
`reject Petitioner’s contention that the substituents for compound 96
`“were preferred.”
`Id., pp. 10-11.
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`The PTAB also rejected the petitioner’s selection of compound 96 as a lead
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`compound because it was included in “a laundry list of 600 other specific
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`compounds by their chemical names as specific compounds within the scope of its
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`invention.” Id., p. 11. The Dorn ’699 reference included no data on any of the
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`listed compounds. The PTAB thus concluded that the petitioner “failed to explain
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`why, at the time of the ’336 patent invention, a skilled artisan would have chosen
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`compound 96 of Dorn ’699 to further develop its prodrug, which is the subject
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`matter of the challenged claims.” Id., p. 12.
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`In the second step of the obviousness analysis, the party challenging validity
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`must demonstrate that a person of ordinary skill would have been motivated to
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`modify the lead compound to make the claimed compound with a reasonable
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`expectation of success. Id. at 1292. In assessing the motivation to modify, it is
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`improper to disregard structural and functional differences between the lead
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`compound and compounds described in a secondary reference. Mylan Labs. Ltd. v.
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`Aventis Pharma S.A., IPR2016-00627, Paper No. 10, pp. 12-17 (PTAB Aug. 23,
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`2016). In Mylan, the petitioner alleged unpatentability based on a combination of
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`two references: Kant and Klein. Id., pp. 6-8. The petitioner used Kant’s
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`compound 20 as the lead compound and argued a POSA would have substituted
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`compound 20’s C-7 hydroxyl group with the methoxy groups shown in Klein’s
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`compounds to arrive at the claimed compound. Id., pp. 10-11. Unlike Kant’s
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`compound 20 and the claimed compound, however, Klein’s compounds had an
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`acetyl group at C-10 and a hydroxyl group at C-9. Id., p. 9. The Board rejected
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`petitioner’s argument on the ground that it ignored important structural differences
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`between the compounds:
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`[W]e are not persuaded a POSA would have disregarded the improved
`aqueous solubility and stability provided by a C-9 hydroxyl, a key
`teaching in Klein, when considering possible modifications to Kant
`Compound 20 …. We reach the same conclusion with respect to
`Klein’s C-10 acetyl.
`Id., p. 16.
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`A reasonable expectation of success requires more than simply trying a
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`multitude of choices and hoping for success. See In re Stepan Co., 868 F.3d 1342,
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`1347 (Fed. Cir. 2017) (vacating Board’s determination of obviousness where it
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`failed to explain why it would have been routine optimization to arrive at the
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`claimed invention). A mere invitation to experiment is insufficient. See Leo
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`Pharm. Prods. v. Rea, 726 F.3d 1346, 1357 (Fed. Cir. 2013) (“And, even if it was
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`obvious to experiment with these options, ‘there is nothing to indicate that a skilled
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`artisan would have had a reasonable expectation that such an experiment would
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`succeed in being therapeutically effective.’”), quoting In re Cyclobenzaprine
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`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1070 (Fed.
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`Cir. 2012).
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`Underlying the lead compound analysis is a proscription against the use of
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`hindsight:
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`[T]he attribution of a compound as a lead compound after the fact
`must avoid hindsight bias; it must look at the state of the art at the
`time the invention was made to find a motivation to select and then
`modify a lead compound to arrive at the claimed invention.
`Otsuka, 678 F.3d at 1291-92.
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`Here, I-MAK’s obviousness analysis is based entirely on hindsight. I-MAK
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`presents no evidence to establish that the genus disclosed in Clark ’147 would be
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`an appropriate lead compound. I-MAK, with the aid of Dr. Fortunak, simply re-
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`assembles the structure of sofosbuvir guided by what the Sofia ’270 patent taught.
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`This is a textbook case of hindsight, made all the more egregious because it is
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`being applied to patent claims directed to a life-saving drug that cures HCV.
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`A.
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`I-MAK’s proposed combination of Clark ’147 and Clark 2005 is
`flawed.
`
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`Both grounds of I-MAK’s petition rely on the combination of Clark ’147
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`plus Clark 2005 to supply the nucleoside portion of the claimed compounds.
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`Case IPR2018-00122
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`Petition, pp. 28-58. In particular, I-MAK alleges that a person of ordinary skill
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`would select claim 40 of Clark ’147, which discloses a genus of compounds, as a
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`starting point to develop an anti-HCV nucleoside drug. Id., pp. 28-36. I-MAK,
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`however, provides no evidence for this allegation, nor does I-MAK provide any
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`evidence to support its argument that a person of ordinary skill would select the
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`specific chemical substituents present in the claimed compounds from the many
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`possible options presented in claim 40. I-MAK also presents no evidence to
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`explain why a person of ordinary skill, when presented with the data in Clark 2005
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`showing that the cytidine analog was active in the HCV replicon assay but the
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`uridine analog was inactive, would nonetheless pursue the inactive uridine analog.
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`These failures are fatal to both proposed grounds, and thus to I-MAK’s petition.
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`1.
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`I-MAK fails to show that a person of ordinary skill would
`select the genus of Clark ’147 claim 40 as a lead compound
`for modification.
`
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`I-MAK fails to provide any rationale whatsoever for why a person of
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`ordinary skill would select Clark ’147’s genus as a lead compound from among the
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`many possible candidates for treating HCV that had been published by various
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`companies at the time of the invention. See, e.g., EX. 2016 (Thompson et al.), p. 3
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`Table 1. Instead, I-MAK’s argument starts with the Sofia ’270 patent claims, and
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`Case IPR2018-00122
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`proceeds to undertake a hindsight analysis of Clark ’147 using the Sofia ’270
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`patent as a guide. See Petition, pp. 28-36.
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`Dr. Fortunak’s declaration is of no help because Dr. Fortunak likewise
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`provides no reason or evidence for why a person of ordinary skill would select
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`Clark ’147 as a starting point from among the many other available possible anti-
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`HCV compounds being considered at the time of the invention. See EX. 1002 ¶¶
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`158-174. Instead, Dr. Fortunak merely parrots the arguments in the petition. Id.
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`I-MAK’s reliance on the genus set forth in Clark ’147’s claim 40 as a lead
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`compound is deficient as a matter of law for an additional reason. Sofosbuvir, as
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`recited in the Sofia ’270 patent claims, requires a nucleotide portion that is a 5’-
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`phosphate of the (2’R)-2’-deoxy-2’-fluoro-2’-C-methyl uridine analog. I-MAK’s
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`petition provides no evidence that a person of ordinary skill would select the
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`specific nucleoside portion of sofosbuvir from among the many possible options
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`encompassed within Clark ’147 claim 40. See Petition, pp. 30-36; EX. 1002 ¶¶
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`158-174. I-MAK’s argument regarding why a person of ordinary skill would
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`select this particular nucleoside is conclusory and, again, based on hindsight with
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`the Sofia ’270 patent in hand.
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`Clark ’147 claim 40 is a broad claim to a genus of nucleosides and
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`nucleotides. It recites structures for the sugar and base portions, and then lists
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`many possibilities for the various R groups in each. EX. 1006, pp. 137-138. In its
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`Case IPR2018-00122
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`petition, I-MAK uses ellipses and then crops claim 40 to make it appear as though
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`the list of possible substituents is much shorter. As the full text reveals, claim 40
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`recites many more possibilities for R1, R7, R3, and R4, and a number of possibilities
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`for R’, which I-MAK’s cropped claim omits. Claim 40 is shown below with
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`portions that I-MAK omitted highlighted:
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`40. Use of an antivirally effective amount of a (2’R)-2’-deoxy-2’-fluoro- 2’-
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`C-methyl nucleoside (β-D or β-L) of the formula:
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`wherein
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`Base is
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`
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`
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`R1 and R7 are independently H, phosphate, including monophosphate,
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`diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate,
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`including stabilized H-phosphonates, acyl, including optionally substituted phenyl
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`Case IPR2018-00122
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`and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or
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`its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl,
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`including methanesulfonyl and benzyl, wherein the phenyl group is optionally
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`substituted, a lipid, including a phospholipid, an L or D-amino acid, a
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`carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving
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`group which when administered in vivo is capable of providing a compound
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`wherein R1or R7 is independently H or phosphate; R1 and R7 can also be linked
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`with cyclic phosphate group;
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`R3 and R4 are independently H, halogen including F, Cl, Br, I, OH, OR', SH,
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`SR', NH2, NHR’, NR’2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl
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`of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-