UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`INITIATIVE FOR MEDICINES, ACCESS & KNOWLEDGE (I-MAK), INC.
`Petitioner
`
`v.
`
`GILEAD PHARMASSET LLC
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`Case IPR2018-00123
`Patent 8,735,372
`
`
`
`
`
`
`
`
`
`
`
`
`PATENT OWNER GILEAD PHARMASSET LLC’S
`PRELIMINARY RESPONSE
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ............................................................................................... 1
`
` I.
`II. THE SOFIA ’372 PATENT ................................................................................ 4
`
`A. Hepatitis C and the previous treatments. .......................................................... 5
`
`B. Researchers examined different mechanisms to inhibit HCV ......................... 6
`
`C. Many researchers tried to develop anti-HCV drugs but failed. ....................... 7
`
`1. Changes to nucleoside structure can have significant and unpredictable
`impacts on activity and toxicity. .......................................................................... 7
`
`2. Persons of ordinary skill in this field understood that the effectiveness
`of prodrugs was unpredictable and nucleoside-specific. ................................... 10
`
`D. Sofosbuvir was a “game-changing” treatment for HCV. ............................... 12
`
`E. The Sofia ’372 patent claims .......................................................................... 13
`
`III. ARGUMENT .................................................................................................. 13
`
`A. Claims 1-2 are not obvious. ............................................................................ 13
`
`I-MAK fails to establish a motivation to combine the Sofia with
`1.
`Congiatu. ............................................................................................................ 17
`
`2. I-MAK fails to establish a reasonable expectation of success. ................... 23
`
`3. I-MAK fails to establish a motivation to combine sofosbuvir with an
`NS5A inhibitor with a reasonable expectation of success. ............................... 25
`
`B. Dr. Fortunak’s opinions are conclusory and insufficient to support
`institution .............................................................................................................. 27
`
`IV. PRESERVATION OF RIGHTS UNDER OIL STATES ................................ 28
`
`V. CONCLUSION .................................................................................................. 28
`
`
`
`i
`
`

`

`Exhibit No.
`GIL 2001
`
`GIL 2002
`
`GIL 2003
`
`GIL 2004
`GIL 2005
`
`GIL 2006
`
`GIL 2007
`
`GIL 2008
`GIL 2009
`
`GIL 2010
`
`GIL 2011
`
`GIL 2012
`
`GIL 2013
`GIL 2014
`GIL 2015
`
`GIL 2016
`GIL 2017
`
`GIL 2018
`GIL 2019
`
`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`LIST OF EXHIBITS
`
`Exhibit Description
`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.
`RESERVED
`Meier, C. Pro-Nucleotides – Recent Advances in the Design of
`Efficient Tools for the Delivery of Biologically Active
`Nucleoside Monophosphates. Synlett, 1997
`RESERVED
`Krise et al. Prodrugs of Phosphates, Phosphonates, and
`
`ii
`
`

`

`GIL 2020
`
`GIL 2021
`
`GIL 2022
`
`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`Phosphinates. Advanced Drug Delivery Review, 1996.
`Romero-Lopez et al. Targets and Tools: Recent Advances in
`the Development of Anti-HCV Nucleic Acids. Infectious
`Disorders – Drug Targets, 2006.
`Wyles et al. Synergy of Small Molecular Inhibitors of
`Hepatitis C Virus Replication Directed at Multiple Viral
`Targets. Journal of Virology, 2007.
`O’Leary et al. Hepatitis C Virus Replication and Potential
`Targets for Direct-Acting Agents. Therapeutic Advances in
`Gastroenterology, 2010.
`
`iii
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`
`I.
`
`INTRODUCTION
`U.S. 8,735,372 (“the Sofia ’372 patent”) covers a method of treating
`
`Hepatitis C virus (“HCV”) by administering sofosbuvir in combination with an
`
`antiviral agent known as an “NS5A inhibitor.” This combination forms Gilead’s
`
`revolutionary HCV therapies HARVONI®, EPCLUSA®, and VOSEVI®.1 HCV
`
`is a global health crisis. In the United States alone, more than three million people
`
`have been infected with the virus. EX. 2009 (Lawitz et al.), p. 1. Left untreated,
`
`HCV leads to liver disease and is a primary cause of liver cancer. EX. 2002
`
`(Chung), p. 1. Before sofosbuvir, the standard of care HCV treatment had
`
`debilitating, often permanent, side effects and low success rates. As a result, many
`
`patients opted to live with the disease rather than attempt treatment. The invention
`
`of sofosbuvir, and its use in combination with an NS5A inhibitor, changed all of
`
`that.
`
`On December 6, 2013, after expedited review, the FDA approved
`
`sofosbuvir. Sofosbuvir’s approval was hailed throughout the scientific and popular
`
`press, including the front pages of the New York Times and Wall Street Journal,
`
`and was recognized as a “game changer.” EX. 2003 (Tucker); EX. 2011 (Pollack);
`
`EX. 2012 (Rockoff). FDA approved HARVONI®, which combined sofosbuvir
`
`                                                            
`1 Sofosbuvir alone forms Gilead’s HCV therapy sold under the name SOVALDI®.
`
`1
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`with an NS5A inhibitor, approximately ten months later. EX. 2009 (Lawitz), p. 10.
`
`The combination cures HCV patients in as little as 8 weeks—a stunning
`
`achievement. See id.; see also EX. 2004 at §2.2 (HARVONI® Prescribing
`
`Information).
`
`I-MAK, in its petition, tries to minimize the significance of this game-
`
`changing accomplishment. I-MAK attacks the Sofia ’372 patent on a single
`
`ground that relies on three references: the Sofia Abstract (EX. 1012), Congiatu
`
`(EX. 1011), and Serrano-Wu (EX. 1013). I-MAK proposes to combine the Sofia
`
`Abstract and Congiatu to come up with sofosbuvir, and then argues that it would
`
`have been obvious to combine sofosbuvir (a specific type of NS5B inhibitor) with
`
`an NS5A inhibitor because Serrano-Wu suggested generally that NS5A inhibitors
`
`could be used alone or in combination with other antiviral agents, including NS5B
`
`inhibitors.
`
`I-MAK’s obviousness attack is flawed. I-MAK’s proposed combination of
`
`the Sofia Abstract and Congiatu ignores important structural differences between
`
`the molecules described in these references—differences that a person of ordinary
`
`skill would not have ignored. I-MAK also presents no evidence to demonstrate
`
`why a person of ordinary skill would have been motivated to combine sofosbuvir
`
`(a specific NS5B inhibitor) with an NS5A inhibitor based upon Serrano-Wu’s
`
`general teachings.
`
`2
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`I-MAK attempts to paper over these deficiencies with vague references to
`
`the “general knowledge in the art.” I-MAK would have the Board believe that the
`
`discovery of sofosbuvir, and its combination with an NS5A inhibitor, was routine
`
`and the ability of the combination to treat HCV expected. But I-MAK presents no
`
`evidence to support its theory. Instead, I-MAK relies on the musing of its biased
`
`expert, Dr. Joseph Fortunak.
`
`Dr. Fortunak is not an independent expert. Rather, he is an I-MAK
`
`employee whose real objective is to eliminate pharmaceutical patents. See EX.
`
`1002 ¶22; EX. 2007 (I-MAK); EX. 2008 (I-MAK “Our People”). Dr. Fortunak
`
`fails to offer a reasoned scientific explanation, backed by objective facts, for any of
`
`his opinions. Instead, he offers only vague, conclusory statements regarding what
`
`he believes was known and what he believes a person of ordinary skill would have
`
`done. It is telling that despite all of this “general knowledge” and the recognized
`
`need for a better HCV treatment, no one met this need until the invention of
`
`sofosbuvir and its combination with an NS5A inhibitor.
`
`Only in hindsight, with the Sofia ’372 patent as a guide, could a person of
`
`ordinary skill have chosen the specific molecular structure of sofosbuvir, combined
`
`it with an NS5A inhibitor, and predicted that the combination would be effective
`
`against HCV. And there, in a nutshell, is I-MAK’s problem: its attack on the
`
`3
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`Sofia ’372 patent is nothing more than hindsight. I-MAK’s petition should be
`
`denied.
`
`II. THE SOFIA ’372 PATENT
`
`The Sofia ’372 patent covers a method of treating HCV by administering
`
`sofosbuvir in combination with an NS5A inhibitor. Sofosbuvir is a specific
`
`nucleoside phosphoramidate prodrug that falls in a class of antiviral agents called
`
`“NS5B inhibitors.” Sofosbuvir has the chemical name (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)phosphorylamino)propanoate,
`
`which corresponds to the following chemical formula:
`
`
`
`As shown in the formula, sofosbuvir has a uracil base bonded to a modified
`
`deoxyribose sugar at the 1’ position. The sugar is further substituted at the 2’
`
`position with a methyl group in the “up” configuration and a fluoro in the “down”
`
`4
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`configuration. The stereochemistry at the phosphorus atom is the “S”
`
`configuration (“Sp”) and the stereochemistry of the methyl group results in the “L”
`
`configuration of the alanine group of the phosphoramidate prodrug portion.
`
`To appreciate the significance of this life-changing invention, it is necessary
`
`to understand the state of the art at the time sofosbuvir was invented, including the
`
`bleak prospects for patients infected with HCV and the many failures to develop
`
`anti-HCV drugs that were both effective and non-toxic.
`
`A. Hepatitis C and the previous treatments.
`
`Hepatitis C virus is a disease that targets the liver. In 2000, former U.S.
`
`Surgeon General, C. Everett Koop, in describing the threat HCV posed, said “We
`
`stand at the precipice of a grave threat to our public health … it affects people from
`
`all walks of life, in every state, in every country. And unless we do something
`
`about it soon, it will kill more people than AIDS.” EX. 2010 (Ninburg). His
`
`statement proved prescient. By 2007, HCV was causing more deaths than HIV and
`
`AIDS. EX. 2005 (Norton). Over 170 million people worldwide suffer from HCV.
`
`See, e.g., EX. 2002 (Chung), p. 1; EX. 2009 (Lawitz), p. 1.
`
`Because of the incredibly rapid rate at which HCV replicates in the body, as
`
`well as the large number of mutations that form during replication, developing an
`
`effective HCV therapy has been daunting. Before sofosbuvir, the treatments for
`
`HCV were typically a combination of antiviral medicines, taken for prolonged
`
`5
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`periods—up to 48 weeks—that caused side effects so severe that many patients
`
`were not healthy enough to take the treatment at all and others chose to live with
`
`the life-threatening disease rather than endure treatment. See EX. 2009 (Lawitz),
`
`p. 2. One of the prior medicines used, interferon, is particularly debilitating,
`
`requiring weekly injections and causing side effects that run the gamut from
`
`cardiac abnormalities, persistent flu-like symptoms, and mental illnesses such as
`
`depression and anxiety. See id.
`
`B. Researchers examined different mechanisms to inhibit HCV
`
`At the time of the Sofia ’372 patent invention, researchers were evaluating
`
`many different approaches to inhibit HCV. By the mid 2000s, researchers had
`
`identified several protein products involved in HCV processing, including the NS2,
`
`NS3, and NS4A proteins. EX. 2020 (Romero-Lopez), p. 2. Other proteins had
`
`been identified as involved in HCV replication, including the NS4B, NS5A, and
`
`NS5B proteins. Id. Each of these proteins were studied as potential targets to
`
`develop anti-HCV drugs. Id., pp. 5-9; EX. 2021 (Wyles), pp. 2-3.
`
`From this research, various classes of compounds were developed and
`
`studied for anti-HCV activity. These included NS5A inhibitors, metalloprotease
`
`inhibitors, serine protease inhibitors, protease active-site mimics, polymerase
`
`inhibitors, helicase inhibitors, NS4B protein inhibitors, HCV entry inhibitors, HCV
`
`assembly inhibitors, HCV egress inhibitors, nucleoside analogs, non-nucleoside
`
`6
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`NS5B inhibitors, and IMPDH. EX. 1013, p. 3; EX. 2021 (Wyles), p. 2; EX. 2022
`
`(O’Leary), p. 3. While some researchers had reported that combinations of
`
`inhibitors with different viral targets may produce greater HCV viral load
`
`decreases, e.g. EX. 2021 (Wyles), pp. 2-3, there was no consensus regarding which
`
`combination of compounds would be effective to treat HCV.
`
`C. 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
`
`the financial upside so large, institutions big and small, including universities,
`
`hospitals, and corporations, from across the globe searched for effective treatments
`
`for HCV. Because no single approach held the answer, thousands of different
`
`paths were taken. Some pursued nucleoside analogs. In the course of their
`
`research, the inventors and other scientists in this field discovered that changes to
`
`the structure of a nucleoside, or a prodrug used with a nucleoside, could have
`
`unpredictable and often negative impacts on the activity and toxicity of that
`
`nucleoside. This understanding was reflected in the published literature at the time
`
`of the claimed invention.
`
`1.
`
`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
`
`have a significant impact on biological activity. For example, the authors of a
`
`7
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`leading textbook in the field stated that they “have become strong proponents of
`
`the view that small changes, at least in nucleotides, can have a significant effect on
`
`the clinical and toxicological profile of a drug—as supported by the only structural
`
`difference between clofarabine and cladribine being the replacement of a hydrogen
`
`atom at the 2’ position with a fluorine atom. Nonetheless, this small difference is
`
`sufficient to endow clofarabine with biochemical and clinical activities which
`
`differ widely from those of cladribine.” EX. 2006 (Secrist), p. 14.
`
`Other contemporaneous publications support this conclusion. For example,
`
`in 2005 Pharmasset scientists published an article describing the design, synthesis,
`
`and antiviral activity of certain 2’-deoxy-2’-fluoro-2’-C-methyl nucleosides. EX.
`
`1007. Among the nucleoside analogs tested were 2’-deoxy-2’-fluoro-2’-C-
`
`methylcytidine (compound 1) and a compound with the same nucleoside sugar ring
`
`but a uracil base instead of a cytosine base (compound 9):
`
`
`
`
`
`
`
`Id. at Fig. 1, Fig. 3.
`
`8
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`Table 2 of the article describes the activity of 2’-deoxy-2’-fluoro-2’-C-
`
`methylcytidine (compound 1) and 2’-deoxy-2’-fluoro-2’-C-methyluridine
`
`(compound 9). Id., p. 5506 Table 2. The data showed that while 2’-deoxy-2’-
`
`fluoro-2’-C-methylcytidine exhibited strong activity in the HCV replicon assay,
`
`the uridine analog “demonstrated no activity or cytotoxicity in any assay.”
`
`
`
`Id.
`
`Scientists outside of Pharmasset also recognized that certain structural
`
`changes could have significant effects on nucleoside activity and toxicity. For
`
`example, in 2006 Carroll et al. studied the effects of varying nucleoside
`
`substituents and concluded that their results “indicate that a very narrow range of
`
`substituents gives rise to potent inhibition, particularly in the replicon assay, owing
`
`in large part to the multiple structural requirements for efficient uptake of the
`
`nucleoside into the cell, conversion to the 5’-triphosphate, and the absence of
`
`unwanted metabolic conversion to inactive analogs, that are necessary in order to
`
`9
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`inhibit viral RNA replication in the cellular environment.” EX. 2001 (Carroll), p.
`
`3.
`
`As shown, persons of skill at the time of the invention claimed in the Sofia
`
`’372 patent appreciated that certain changes to the nucleoside structure could have
`
`significant and unpredictable impact on biological activity and toxicity.
`
`2.
`
`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
`
`analogs. In particular, scientists at the time of the claimed invention understood
`
`that the effectiveness of a prodrug, or lack thereof, was nucleoside-specific. For
`
`example, Perrone, an article that Petitioner cites (EX. 1007), described the anti-
`
`HCV effects of various phosphoramidate prodrugs for a certain nucleoside
`
`analogue (4’-azidouridine). Perrone reported that the l-naphthyl analogue of an L-
`
`alanine benzyl ester (compound 33) was the most active compound tested, and did
`
`not report any detectable toxicity (CC50 >100).
`
`
`
`10
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`EX. 1008, p. 4 Table 3. The Perrone authors also noted that “quite distinct”
`
`structure-activity relationships were found for the particular 4’-azidouridine
`
`nucleoside analogs studied compared to nucleosides previously studied, thus
`
`emphasizing that the effectiveness of a prodrug was nucleoside-specific. Id.
`
`Consistent with the Perrone authors’ observation, when Pharmasset later
`
`tested a l-naphthyl analog of a different nucleoside ̶ the nucleoside used in
`
`sofosbuvir, “this substitution also led to substantial cytotoxicity and was therefore
`
`not considered a viable substituent.” EX. 2015 (Sofia 2010), p. 4.
`
`
`
`Id., Table 2.
`
`Similarly, a 1997 publication by Meier reported that an arylphosphoramidate
`
`prodrug approach that had been previously found effective in delivering certain
`
`nucleosides (EX. 2017 (Meier), p. 5) was not effective for the anti-HIV drugs AZT
`
`and 3TC, which involved different nucleosides (id., p. 6). The article also reported
`
`11
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`that an amino acid phosphoramidate prodrug approach that had been previously
`
`applied to AZT “could not be transferred to the antitumor-active nucleoside 5-
`
`FdU.” Id. Meier also noted that “the enormous disparity in anti-HIV activity that
`
`is evident for a large number of dideoxynucleoside analogues belies their apparent
`
`structural similarity.” Id., p. 1.
`
`These conclusions are consistent with the understanding of scientists in this
`
`field that there is no one-size-fits-all approach to nucleoside prodrug development.
`
`Indeed, a review article on prodrugs noted that “although we have been successful
`
`at identifying numerous phosphate and phosphonate functional group-containing
`
`drugs as antiviral and anticancer agents, as well as for other uses, our ability to
`
`orally deliver these drugs and to target them to desired sites has led to limited
`
`success.” EX. 2019 (Krise 1996), abstract.
`
`D.
`
`Sofosbuvir was a “game-changing” treatment for HCV.
`
`On December 6, 2013, after expedited review, the FDA approved sofosbuvir
`
`as Gilead’s Sovaldi®, a once-daily oral nucleotide analogue for the treatment of
`
`chronic HCV infection. See EX. 2009 (Lawitz), p. 10. For the first time, many
`
`patients could now be cured of HCV without interferon, while others only needed
`
`to take interferon for 12 weeks. See id. Just ten months later, Gilead took
`
`sofosbuvir to still another level when the FDA approved Harvoni®, which
`
`combines sofosbuvir with an NS5A inhibitor to cure 95% of the patients who take
`
`12
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`it in as little as 8 weeks without subjecting the patients to interferon. See id.; see
`
`also EX. 2004 at §2.2 (HARVONI® Prescribing Information.) It was thus
`
`possible to cure patients after a short period of time with almost no side effects.
`
`Sofosbuvir truly was a “game-changing” invention, and indeed is the only
`
`nucleoside ever approved for the treatment of HCV.
`
`E.
`
`The Sofia ’372 patent claims
`
`The Sofia ’372 patent contains 2 claims. Claim 1 covers a method of
`
`treating a patient infected with HCV by administering effective amounts of an
`
`NS5A inhibitor and a compound selected from a limited genus that includes
`
`sofosbuvir. Claim 2 depends on claim 1 and specifically requires the compound to
`
`be sofosbuvir.
`
`III. ARGUMENT
`A. Claims 1-2 are not obvious.
`
`I-MAK contends that claims 1-2 would have been obvious over the Sofia
`
`Abstract (EX. 1012) in combination with Congiatu (EX. 1011) and Serrano-Wu
`
`(EX. 1013).2 I-MAK starts with the compound described in the Sofia Abstract and
`
`                                                            
`2 Gilead does not concede that either the Sofia Abstract or Serrano-Wu qualifies as
`
`prior art. Nevertheless, for purposes of deciding whether to grant I-MAK’s
`
`13
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`purports to modify it with Congiatu to come up with sofosbuvir. I-MAK then
`
`proposes to combine sofosbuvir (a specific type of NS5B inhibitor) with an NS5A
`
`inhibitor based on Serrano-Wu. I-MAK also makes vague, sweeping statements
`
`regarding the “general knowledge in the art” to support its challenge. However, I-
`
`MAK’s challenge is legally flawed.
`
`Determining whether claims covering a chemical compound would have
`
`been obvious over prior art compounds generally requires a two-part analysis.
`
`Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291-93 (Fed. Cir. 2012);
`
`Incyte Corp. v. Concert Pharmaceuticals, Inc., IPR2017-01256, Paper No. 9, p. 14
`
`(PTAB Oct. 19, 2017). In the first step, the party challenging validity must
`
`establish that “a chemist of ordinary skill would have selected the asserted prior art
`
`compounds as lead compounds, or starting points for further development efforts.”
`
`Otsuka, 678 F.3d at 1291. A lead compound is “a compound in the prior art that
`
`would be most promising to modify in order to improve upon its … activity and
`
`obtain a compound with better activity.” Id. In other words, “a lead compound is
`
`a ‘natural choice for further development efforts.’” Id., citing Altana Pharma AG
`
`v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009).
`                                                                                                                                                                                                
`petition, it is not necessary to reach this issue because I-MAK’s petition is
`
`deficient regardless of whether these references are prior art.
`
`  
`
`14
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`In the second step of the obviousness analysis, the party challenging validity
`
`must demonstrate that a person of ordinary skill would have been motivated to
`
`modify the lead compound to make the claimed compound with a reasonable
`
`expectation of success. Id. at 1292. In assessing the motivation to modify, it is
`
`improper to disregard structural and functional differences between the lead
`
`compound and compounds described in a secondary reference. Mylan Labs. Ltd. v.
`
`Aventis Pharma S.A., IPR2016-00627, Paper No. 10, pp. 12-17 (PTAB Aug. 23,
`
`2016).
`
`A reasonable expectation of success requires more than simply trying a
`
`multitude of choices and hoping for success. See In re Stepan Co., 868 F.3d 1342,
`
`1347 (Fed. Cir. 2017) (vacating Board’s determination of obviousness where it
`
`failed to explain why it would have been routine optimization to arrive at the
`
`claimed invention). A mere invitation to experiment is insufficient. See Leo
`
`Pharm. Prods. v. Rea, 726 F.3d 1346, 1357 (Fed. Cir. 2013) (“And, even if it was
`
`obvious to experiment with these options, ‘there is nothing to indicate that a skilled
`
`artisan would have had a reasonable expectation that such an experiment would
`
`succeed in being therapeutically effective.’”), quoting In re Cyclobenzaprine
`
`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1070 (Fed.
`
`Cir. 2012).
`
`15
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`Underlying the lead compound analysis is a proscription against the use of
`
`hindsight:
`
`[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.
`
`Here, I-MAK’s obviousness analysis is based entirely on hindsight.
`
`Regardless of whether the compound in the Sofia Abstract is an appropriate lead
`
`compound, I-MAK’s proposed modifications ignore important structural
`
`differences between the compounds disclosed in the Sofia Abstract and Congiatu,
`
`as well as the unpredictability in this field. In particular, I-MAK ignores the fact
`
`that prodrugs were nucleoside-specific. Persons of ordinary skill recognized that
`
`changes in nucleoside structure can have a huge impact on the properties of the
`
`final molecule, including whether the molecule is effective against HCV and
`
`whether it has toxic side effects. I-MAK also provides no evidence that a person
`
`of ordinary skill would have been motivated to combine sofosbuvir with an NS5A
`
`inhibitor or that the combination could effectively treat HCV.
`
`16
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`
`1.
`
`I-MAK fails to establish a motivation to combine the
`Sofia with Congiatu.
`
`
`
`
`The Sofia Abstract (EX. 1012) discloses a phosphoramidate compound said
`
`to be capable of inhibiting HCV replication. The compound has the following
`
`structure:
`
`
`
`As shown in the drawing, the compound has a specific nucleoside portion,
`
`which the Sofia Abstract labels “PSI-6206,” that includes (a) a natural uracil base
`
`and (b) a sugar substituted at the 2’ position with a methyl group in the “up”
`
`configuration and a fluoro in the “down” configuration. However, the Sofia
`
`Abstract discloses nothing about the identities of the R1, R2, or R3 subgroups in the
`
`prodrug portion. The Sofia Abstract puts no limits on what R1 or R2 or R3 could be
`
`and does not even suggest any examples of potential R groups.
`
`In contrast, claim 1 of the Sofia ’372 patent requires that each substituent be
`
`selected from Markush groups having a limited number of members. Importantly,
`
`17
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`for purposes of the present case, the only aryl group listed in claim 1 for R1 is a
`
`phenyl or substituted phenyl group:
`
`R1 is hydrogen, methyl ethyl, n-propyl, i-propyl, or a substituted or
`unsubstituted phenyl, where the substituent of the substituted phenyl
`is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a
`CH3-q-Xq, where X is F, Cl, Br, or I, and q is 1-3 ….
`
`
`Claim 2 is even more specific because it covers sofosbuvir itself, and thus
`
`requires R1 to be phenyl; R2 to be methyl; and R3 to be isopropyl.3
`
`Recognizing the limitations of the Sofia Abstract, I-MAK proposes to
`
`modify it using Congiatu. However, Congiatu is directed to the study of
`
`phosphoramidate derivatives of a particular nucleoside analog, brivudine
`
`(“BVdU”), an anticancer drug.4 See Ex. 1006 at 1. It focuses on “the synthesis
`
`                                                            
`3 In the Sofia ’372 claims, R3b corresponds to group R2 of the Sofia Abstract, and
`
`R4 corresponds to group R3 of the Sofia Abstract.
`
`4 Congiatu contains one sentence in its introduction that states that nucleoside
`
`analogs also represent an “effective tool” for the treatment of viral infections. EX.
`
`1011 at 1. However, the remainder of the paper is exclusively directed to
`
`anticancer compounds, without any further mention of treating viral infection.
`
`18
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`and biological evaluation of a new family of BVdU ProTides . . . with the new aryl
`
`group on the phosphate, naphthyl.” Id. An exemplary structure is shown below:
`
`
`There are multiple structural differences between these nucleoside
`
`phosphoramidates and the compounds recited in the Sofia Abstract and the Sofia
`
`’372 claims with respect to both the nucleoside and prodrug portions.
`
`First, the Congiatu compounds have a modified uracil base, containing a
`
`-CH=CH-Br group, whereas the compounds of the Sofia Abstract and the Sofia
`
`’372 patent claims require an unmodified uracil base.
`
`Second, the 2’-position of the sugar moiety in the Congiatu compounds
`
`contains hydrogen in both the up and down positions, while the 2’-position of the
`
`sugar moiety in the compounds of the Sofia Abstract and the Sofia ’372 patent
`
`claims require a methyl up and fluoro down.
`
`Third, the aryl group of the phosphoramidate moiety in the Congiatu
`
`molecules is naphthyl. In fact, Congiatu teaches that the naphthyl derivatives have
`
`19
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`superior potency compared to a previously studied phenyl derivative. See id. at 2.
`
`(“According to the data shown in Table 1, most of the naphthyl phosphoramidates
`
`synthesized appear to be significantly more active than [the phenyl-containing
`
`compound], which displays only a moderate activity in our in vitro evaluations.”).
`
`The Sofia Abstract is silent as to the identity of this moiety. However, the Sofia
`
`’372 patent claims exclude naphthyl groups at this position. The only aryl groups
`
`permitted are phenyl or substituted phenyl groups.
`
`I-MAK provides no evidence to demonstrate why a person of ordinary skill
`
`seeking to treat HCV would look to an anti-cancer drug in order to modify an anti-
`
`HCV drug. Moreover, even if the Sofia Abstract and Congiatu could somehow be
`
`combined, the resulting combination would not yield sofosbuvir (claim 2) or the
`
`class of compounds including sofosbuvir (claim 1). As noted above, both the Sofia
`
`Abstract and the claimed compounds have fundamental structural differences.
`
`Recognizing this conundrum, I-MAK and Dr. Fortunak offer vague
`
`statements about the “general knowledge it the art,” referring variously to a
`
`number of other references (Perrone (EX. 1007), Wagner (EX. 1003), McGuigan
`
`(EXs 1008 and 1009), and Cahard (EX. 1010)). See Petition, pp. 11-18. However,
`
`I-MAK never explains how any of these references supports an obviousness
`
`challenge that relies on the Sofia Abstract and Congiatu.
`
`20
`
`

`

`Case IPR2018-00123
`Attorney Docket No: 36583-0020IP6
`Instead, I-MAK selectively plucks substituents from this “general
`
`knowledge,” as allegedly shown in the cited references, ignores the myriad of
`
`differences between the compounds, and then re-assembles the claimed
`
`compounds. For example, I-MAK argues that options for R1, R2, and R3 of the
`
`So