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 IPR2018-00119
`Patent 7,964,580
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`PATENT OWNER GILEAD PHARMASSET LLC’S
`PRELIMINARY RESPONSE
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
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`TABLE OF CONTENTS
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`INTRODUCTION ................................................................................... 1 
`I.
`II. THE SOFIA ’580 PATENT .................................................................... 3 
`A. Hepatitis C and the previous treatments. ............................................ 4 
`B. Many researchers tried to develop anti-HCV drugs but failed. ........... 5 
`1. Changes to nucleoside structure can have significant and
`unpredictable impacts on activity and toxicity. .................................. 6 
`2. Persons of ordinary skill in this field understood that
`the effectiveness of prodrugs was unpredictable and nucleoside-
`specific. ............................................................................................... 9 
`C. Sofosbuvir was a “game-changing” treatment for HCV. .................. 11 
`D. The Sofia ’580 patent claims ............................................................ 12 
`III. ARGUMENT ..................................................................................... 13 
`A. The Sofia Abstract and Ma are not prior art. ................................... 13 
`1. I-MAK has done no analysis under 35 USC § 112. ..................... 15 
`2. Claims 1-14 are entitled to the March 30, 2007 filing date of
`the ’315 provisional application. ...................................................... 16 
`B. The Sofia Abstract does not anticipate claims 1-14. ....................... 20 
`C. Claims 1-14 are not obvious. ........................................................... 23 
`1. Claims 1-14 are patentable over the Sofia Abstract plus
`Perrone. ............................................................................................. 28 
`a. I-MAK fails to establish a motivation to combine the
`Sofia Abstract with Perrone. ..................................................... 29 
`b. I-MAK fails to establish a reasonable expectation of
`success. ...................................................................................... 31 
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`c. I-MAK fails to establish that a person of skill would have
`chosen the (phenyl)(isopropyl-L-alaninyl)phosphate group
`disclosed in Perrone. ................................................................. 33 
`2. Claims 1-14 are patentable over Ma plus Perrone. ....................... 34 
`a. Ma does not suggest experimenting with RO2433 but
`rather teaches developing PSI-6130. ........................................ 34 
`b. I-MAK fails to establish a motivation to combine Ma
`with Perrone. ........................................................................... 37 
`c. I-MAK fails to establish a reasonable expectation of
`success ....................................................................................... 39 
`D.  Dr. Fortunak’s opinions are conclusory and insufficient to support
`institution ............................................................................................... 40 
`IV.  PRESERVATION OF RIGHTS UNDER OIL STATES ...................... 41 
`V.  CONCLUSION ...................................................................................... 42 
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`ii
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`LIST OF EXHIBITS
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`Exhibit No.
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`Exhibit Description
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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
`GIL 2017
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`GIL 2018
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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.
`United States Provisional Application Serial No. 60/909,315
`United States Provisional Application Serial No. 60/982,309
`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.
`RESERVED
`Meier, C. Pro-Nucleotides – Recent Advances in the Design of
`Efficient Tools for the Delivery of Biologically Active
`Nucleoside Monophosphates. Synlett, 1997
`RESERVED
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`iii
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`GIL 2019
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`Krise et al. Prodrugs of Phosphates, Phosphonates, and
`Phosphinates. Advanced Drug Delivery Review, 1996.
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
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`I.
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`INTRODUCTION
`U.S. 7,964,580 (“the Sofia ’580 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 ’580 patent on several
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`grounds that rely on two primary references, the Sofia Abstract (EX. 1004) and Ma
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`(EX. 1005). But neither reference qualifies as prior art because the Sofia ’580
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`patent is entitled to the filing date of a provisional application that antedates both
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`the Sofia Abstract and Ma. I-MAK fails to perform a priority analysis to establish
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`that the Sofia ’580 claims are not entitled to the provisional filing date. I-MAK’s
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`failure, by itself, is sufficient reason to deny its petition.
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`Even assuming the Sofia Abstract and Ma are prior art, which they are not,
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`I-MAK’s petition remains deficient. I-MAK alleges that the Sofia Abstract
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`anticipates the claims even though the Sofia Abstract fails to disclose the specific
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`substituent groups on the sofosbuvir molecule that each claim of the Sofia ’580
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`patent requires.
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`I-MAK’s obviousness attacks are equally flawed. I-MAK alleges that the
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`claims are obvious over either the Sofia Abstract plus Perrone (EX. 1008) or Ma
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`plus Perrone. However, I-MAK ignores important structural differences between
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`the molecules described in these references—differences that a person of ordinary
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`skill would not have ignored. Instead, I-MAK would have the Board believe that
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`the “general knowledge in the art” made the discovery of sofosbuvir routine and
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`rendered its ability to treat HCV expected. But I-MAK presents no evidence to
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`support its theory. Instead, I-MAK relies on the musing of its biased expert, Dr.
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`Joseph Fortunak.
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`Dr. Fortunak is not an independent expert. 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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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`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 ’580 patent as a guide, could a person of
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`ordinary skill have chosen the specific molecular structure of sofosbuvir and
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`predicted that it would be effective against HCV. And there, in a nutshell, is I-
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`MAK’s problem: its attack on the Sofia ’580 patent is nothing more than
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`hindsight. I-MAK’s petition should be denied.
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`II. THE SOFIA ’580 PATENT
`The Sofia ’580 patent covers sofosbuvir and its use in treating HCV.
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`Sofosbuvir is a specific nucleoside phosphoramidate prodrug having 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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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
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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 in the “down”
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`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.
`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.
`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. 5506 Table 2. The data showed that while 2’-deoxy-2’-
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`fluoro-2’-C-methylcytidine exhibited strong activity in the HCV replicon assay,
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`the 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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`’580 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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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`Persons of ordinary skill in this field understood that the
`effectiveness of prodrugs was unpredictable and nucleoside-
`specific.
`The unpredictability of nucleoside analogs extends to prodrugs of such
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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). Perrone reported that the l-naphthyl analogue of an L-
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`alanine benzyl ester (compound 33) was the most active compound tested, and did
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`not report any detectable toxicity (CC50 >100).
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`EX. 1008, p. 4 Table 3. The Perrone authors also 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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`Consistent with the Perrone authors’ observation, when Pharmasset later
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`tested a l-naphthyl analog of a different nucleoside ̶ the nucleoside used in
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`sofosbuvir, “this substitution also led to substantial cytotoxicity and was therefore
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`not considered a viable substituent.” EX. 2015 (Sofia 2010), p. 4.
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`Id., Table 2.
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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 ’580 patent claims
`D.
`The Sofia ’580 patent contains 14 claims. Claims 1 and 8 are independent.
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`They read as follows:
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`1. (S)-2-{[2R, 3R, 4R, 5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-
`1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phenoxy-phosphorylamino}-propionic acid isopropyl ester or a
`stereoisomer thereof.
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`8. (S)-isopropyl 2-(((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-
`dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-
`methyltetrahydrofuran-2-
`yl)methoxy(phenoxy)phosphoryl)amino)propanoate.
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`Claim 8 specifically covers sofosbuvir. Claim 1 covers the same chemical
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`structure as claim 8 with the exception that it covers the Sp stereoisomer, the Rp
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`stereoisomer, and mixtures of the two, rather than just the Sp stereoisomer.
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`Claims 2-7 depend on claim 1 while claims 9-14 depend on claim 8. Claims
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`2-3 and 9-10 cover formulations that include sofosbuvir. Claims 4-5 and 11-12
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`cover methods of treating HCV with sofosbuvir. Claims 6 and 13 cover methods
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`of making sofosbuvir. Claims 7 and 14 are product by process claims that cover
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`sofosbuvir made according to the methods of claims 6 and 13.
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`III. ARGUMENT
`A. The Sofia Abstract and Ma are not prior art.
` I-MAK bears the burden of establishing that the Sofia Abstract and Ma are
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`prior art. See Merck Sharp & Dohme Corp., v. Wyeth LLC., IPR2017-01211,
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`Paper No. 9, at 11 (PTAB Oct. 20, 2017) (denying petition because Petitioner
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`failed to establish reference qualified as prior art). This burden includes
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`demonstrating that the challenged claims have an effective filing date that post-
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`dates the asserted reference. Id. at 3 (“[T]his case turns on whether Petitioner
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`establishes that claims 1-13 have an effective filing date that post-dates the applied
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`reference.”). Conclusory expert testimony is insufficient to satisfy this burden.
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`See id. at 11, 16 (denying petition where petitioner’s priority analysis relied on
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`conclusory statements from its expert rather than providing a thorough priority
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`analysis).
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`For a patent claim to gain the benefit of the filing date of a provisional
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`application, the disclosure of the provisional application must be assessed under 35
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`U.S.C. § 112. New Railhead Mfg., L.L.C. v. Vermeer Mfg. Co., 298 F.3d 1290,
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`1294 (Fed. Cir. 2002), see also Zenon Envtl., Inc, v, U.S. Filter Corp., 506 F. 3d
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`1370, 1378 (Fed. Cir. 2007). Accordingly, to challenge a patent’s priority claim
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`properly, the challenger must address the adequacy of the provisional application’s
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`specification under Section 112. Id.
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`Case IPR2018-00119
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`Here, the Sofia ’580 patent claims priority to two provisional applications:
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`(1) USSN 60/909,315 (“the ’315 provisional;” EX. 2013) filed March 30, 2007 and
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`(2) USSN 60/982,309 (“the ’309 provisional;” EX. 2014) filed October 24, 2007.
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`EX. 1001, p. 1.1 Both the Sofia Abstract and Ma published after March 30, 2007.2
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`Thus, if claims 1-14 are entitled to the filing date of the ’315 provisional, neither
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`the Sofia Abstract nor Ma qualifies as prior art.
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` I-MAK fails to carry its burden of demonstrating that the Sofia Abstract and
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`Ma are prior art. In its petition, I-MAK does not provide any evidence
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`demonstrating that claims 1-14 are not entitled to the March 30, 2007 filing date of
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`the ’315 provisional application. I-MAK’s failure to perform a proper priority
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`analysis is fatal. Moreover, I-MAK’s conclusory assertion regarding priority is
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`wrong.
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`Because I-MAK fails to demonstrate that either of the primary references on
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`which it relies qualifies as prior art, each of I-MAK’s proposed grounds fails and
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`the petition should be denied.
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`1 The priority claim is set forth in a certificate of correction.
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` 2
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` Specifically, Sofia published no earlier than September 9, 2007 and Ma
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`published October 12, 2007. See EX. 1004, p. 1; EX. 1005, p. 1.
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`I-MAK has done no analysis under 35 USC § 112.
`1.
`I-MAK has failed to perform any analysis, much less present evidence, that
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`the Sofia ’580 patent is not entitled to its earliest priority date. All I-MAK has
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`done, in cursory fashion at pp. 23 and 25 of its petition, is assert that the ’315
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`provisional application allegedly
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`[does] not include a description of the specific compounds claimed by
`the ‘580 patent. EX1002 at ¶73. While it discusses broad genera of
`compounds, it does not discuss the specific compounds and
`stereochemistry around the phosphorous atom claimed in the ‘580
`patent.
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`I-MAK cites only a single, two-sentence paragraph from Dr. Fortunak’s
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`declaration in support of this contention. But the entirety of that paragraph merely
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`repeats—verbatim and without any support—what is in the petition:
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`EX. 1002 ¶73.
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`In short, neither I-MAK nor its expert has presented a legitimate priority
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`analysis. In particular, Petitioner provides no written description or Wands
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`analysis at all regarding the sufficiency of the ’315 provisional application.
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`Rather, they present no more than an unsupported, conclusory statement that the
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`’315 provisional application does not describe the claimed compounds. Indeed, I-
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`MAK’s “priority analysis” is even more superficial than the analysis the Board
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`rejected in Merck. See Merck, IPR2017-01211 at 11, 16 (denying petition where
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`petitioner’s expert failed to perform a thorough Wands analysis as part of its
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`priority analysis). Accordingly, the Board should deny I-MAK’s petition on the
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`basis of I-MAK’s failure to demonstrate that claims 1-14 are not entitled to the
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`filing date of the ’315 provisional application.
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`2.
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`Claims 1-14 are entitled to the March 30, 2007 filing date of
`the ’315 provisional application.
`Even if the Board were to analyze the priority issue (and it need not to deny
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`institution), I-MAK’s assertion of lack of priority to the March 30, 2007
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`provisional filing is wrong. A review of the ’315 application, which I-MAK fails
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`to do, reveals that the ’315 provisional application discloses both the specific
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`compounds and the stereochemistry around the phosphorous atom for the
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`compounds claimed in the Sofia ’580 patent.
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`As described above, claim 1 of the Sofia ’580 patent covers stereoisomers of
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`a particular compound (and mixtures thereof). Stereoisomers are compounds
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`having the same molecular formula and bond sequence, but that differ in the three-
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`dimensional orientation of their atoms in space. Claim 8 covers a particular
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`stereoisomer (the Sp stereoisomer) otherwise known as sofosbuvir. The ’315
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`application describes stereoisomers covered by claim 1, including the specific
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`stereoisomer—sofosbuvir—that is also covered by claim 8.
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`For example, Structure IX-25-2 of the ’315 provisional application is the
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`compound set forth in claim 1 of the Sofia ’580 patent. EX. 2013 (’315 app.), pp.
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`187, 195. Depicted below is Structure IX from the ’315 provisional application,
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`which is a phosphoramidate compound with variable substituents at particular
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`points in the molecular structure. Id. p. 187. Also depicted below is a table
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`showing the specific substituents associated with Structure IX-25-2. Id., p. 195.
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`The specific compound represented by Structure IX-25-2 is the compound set forth
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`in claim 1 of the Sofia ’580 patent. Accordingly, and contrary to I-MAK’s
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`unsupported assertion, the ’315 provisional describes the specific compounds
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`claimed in the Sofia ’580 patent.
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
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`The ’315 provisional application also addresses stereochemistry, including
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`the stereochemistry around the phosphorous atom. For example, in describing the
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`structures disclosed in the specification, the ’315 provisional explains that, while
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`the depicted compounds and corresponding tables themselves (such as Table IX-25
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`above) do not explicitly show stereochemistry, the disclosed compounds embody
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`variations in stereochemical configuration of atoms. See EX. 2013 (’315 app.), pp.
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`63-64. The ’315 provisional explains that for the compounds depicted, “the
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`phosphoramidate substituent containing the substituents R3a and R3b are depicted
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`without reference to stereochemical structure” but that variations in
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`stereochemistry are contemplated. Id., p. 63. In particular, the ’315 provisional
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`explains that “[i]t is contemplated that the compounds recited below embody
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`compounds in which R3a projects towards the viewer while R3b projects away from
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`the viewer . . . [m]oreover, it is contemplated that the compounds recited below
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`also embody compounds in which R3a projects away from the viewer while R3b
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`projects towards the viewer.” Id., p. 63 (emphasis added). Accordingly, the ’315
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`application describes the stereoisomers set forth in claims 1 and 8 of the Sofia ’580
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`patent.
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`The ’315 provisional also specifically describes the stereochemistry around
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`the phosphorous atom. The ’315 provisional states:
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`The inventors recognize that the phosphorous atom of the
`phosphoramidate moiety is another source of chirality. Although the
`structures below do not specifically depict chirality at phosphorous,
`the inventors recognize that stereochemical configurations are
`possible such that in a staggered (or zig-zag) line structure the oxo-
`substituent projects towards the viewer while the OR1 substituent
`projects away from the viewer, and vice versa. Therefore, the
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`Case IPR2018-00119
`Attorney Docket No: 36583-0020IP2
`structures below include all possible stereochemical configurations
`possible for phosphorous.
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`Id., pp. 63-64. I-MAK’s unsupported assertion that the ’315 provisional does not
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`discuss “stereochemistry around the phosphorous atom” is simply wrong.
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`Moreover, the ’315 provisional describes not only the specific compounds
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`claimed in the Sofia ’580 patent, but also how to make representative
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`phosphoramidates. For example, Example 5 of the ’315 provisional describes a
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`synthetic method for preparing a representative phosphoramidate of the 2’-deoxy -
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`2’-fluoro-2’-C-methyluridine compound PSI-6206. Id., pp. 614-15.
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`In short, the ’315 application both describes the compounds claimed in the
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`Sofia ’580 patent and discloses a synthetic method for producing the types of
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`compounds claimed in the Sofia ’580 patent. I-MAK provides no objective
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`evidence that would support a conclusion that the Sofia ’580 patent is not entitled
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`to the priority date of the ’315 provisional.
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`B.
`The Sofia Abstract does not anticipate claims 1-14.
`The Sofia Abstract does not disclose the particular compounds claimed in
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`the Sofia ’580 patent. Accordingly, the Sofia Abstract does not anticipate the
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`claims of the Sofia ’580 patent even if the Board considers it as prior art (and it
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`should not).
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`Case IPR2018-00119
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`“A claim is anticipated only if each and every element as set forth in the
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`claim is found, either expressly or inherently described, in a single prior art
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`reference.” Verdegaal Bros. v. Union Oil Co. of California, 814, F.2d 628, 631
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`(Fed. Cir. 1987). Although in limited circumstances the disclosure of “a very
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`small genus” may constitute a disclosure of each species within that genus, “it is
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`well established that the disclosure of a genus in the prior art is not necessarily a
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`disclosure of every species that is a member of that genus.” Atofina v. Great Lakes
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`Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006); see also In re Petering, 301 F.2d
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`676, 682 (1962). Accordingly, “[t]here may be many species encompassed within
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`a genus that are not disclosed by a mere disclosure of the genus.” Atofina, 441
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`F.3d at 999; see also Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1083 (Fed.
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`Cir. 2008) (reference disclosing a genus did not anticipate a species where the
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`refer