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Idenix Pharmaceuticals LLC v. Gilead Sciences Inc.

United States Court of Appeals, Federal Circuit

October 30, 2019

IDENIX PHARMACEUTICALS LLC, UNIVERSITA DEGLI STUDI DI CAGLIARI, Plaintiffs-Appellants
v.
GILEAD SCIENCES INC., Defendant-Appellee

          Appeal from the United States District Court for the District of Delaware in No. 1:14-cv-00846-LPS, Chief Judge Leonard P. Stark.

          Gregory A. Castanias, Jones Day, Washington, DC, argued for plaintiffs-appellants. Also represented by Jennifer Loraine Swize; Lisa Lynn Furby, Chicago, IL; Calvin Griffith, Ryan Boyd McCrum, Cleveland, OH; Anthony Insogna, San Diego, CA; Jeffrey A. Lamken, Sarah Justine Newman, Michael Gregory Pattillo, Jr., MoloLamken LLP, Washington, DC.

          E. Joshua Rosenkranz, Orrick, Herrington & Sutcliffe LLP, New York, NY, argued for defendant-appellee. Also represented by Edmund Hirschfeld; Elizabeth Moulton, Menlo Park, CA; Brian Philip Goldman, San Francisco, CA; Eric Shumsky, Washington, DC; Frank Scherkenbach, Fish & Richardson, PC, Boston, MA; Craig E. Countryman, W. Chad Shear, Jonathan Elliot Singer, San Diego, CA.

          Before Prost, Chief Judge, Newman and Wallach, Circuit Judges.

          OPINION

          Prost. Chief Judge

         Idenix Pharmaceuticals LLC and Universita Degli Studi Di Cagliari (collectively, "Idenix") appeal from the decision of the U.S. District Court for the District of Delaware granting judgment as a matter of law ("JMOL") against Idenix and finding that U.S. Patent No. 7, 608, 597 is invalid for lack of enablement. Idenix Pharm. LLC v. Gilead Scis., Inc., 2018 WL 922125, at *25 (D. Del. Feb. 16, 2018) ("JMOL Opinion"). Gilead Sciences Inc., ("Gilead") argues that the patent is also invalid for failure to meet the written description requirement, and that the district court erred by failing to grant JMOL on that ground as well. We affirm as to non-enablement and hold that the patent is also invalid for lack of written description.

         I

         This appeal stems from Idenix's December 2013 patent infringement suit against Gilead, originally filed in the U.S. District Court for the District of Massachusetts and later transferred to the District of Delaware. J.A. 259-69. At the time of the suit, both Idenix and Gilead were researching and developing drugs for treatment of the hepatitis C virus ("HCV"). HCV is a leading cause of chronic liver disease, infecting hundreds of millions of people worldwide, and accounting for tens of thousands of deaths per year in the United States alone. Idenix alleged that the imminent Food and Drug Administration approval, and launch, of Gilead's HCV treatment drug sofosbuvir would infringe Idenix's U.S. Pat. No. 7, 608, 597 (the "'597 patent").

         Following years of litigation, Chief Judge Stark held a two-week jury trial in December 2016. Gilead stipulated to infringement under the district court's claim construction but argued that the '597 patent was invalid for failure to meet the written description and enablement requirements. The jury found for Idenix, upholding the validity of the patent and awarding damages. After trial, Gilead filed a renewed motion for JMOL with respect to written description and enablement. The district court denied the motion with respect to written description but granted JMOL on enablement, holding the '597 patent invalid.

         Idenix timely appealed. We have jurisdiction under 28 U.S.C. § 1295(a)(1).

         II

         We review the denial or grant of a motion for JMOL under regional circuit law. See Tr. of Boston Univ. v. Everlight Elecs. Co., 896 F.3d 1357, 1361 (Fed. Cir. 2018). Applying Third Circuit law, we "exercise plenary review over a district court's rulings on motions for JMOL, applying the same standard as the district court." Agrizap, Inc. v. Woodstream Corp., 520 F.3d 1337, 1341-42 (Fed. Cir. 2008) (citing Gagliardo v. Connaught Labs., Inc., 311 F.3d 565, 568 (3d Cir. 2002)). A grant of JMOL is appropriate "where a party has been fully heard on an issue during a jury trial and the court finds that a reasonable jury would not have had a legally sufficient evidentiary basis to find for the party on that issue." Id. at 1342; see Fed. R. Civ. P. 50(a).

         Enablement requires that "the specification teach those in the art to make and use the invention without undue experimentation." In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). A claim is not enabled when, "at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation." Wyeth & Cordis Corp. v. Abbott Labs., 720 F.3d 1380, 1384 (Fed. Cir. 2013). Whether a claim satisfies the enablement requirement is a question of law that we review de novo. Tr. of Boston Univ., 896 F.3d at 1361. However, "in the context of a jury trial, we review the factual underpinnings of enablement for substantial evidence." Id.

         III

         The '597 patent claims a method of treating HCV by administering nucleoside compounds having a specific chemical and stereochemical structure. The nucleosides claimed in the '597 patent contain a sugar ring having five carbon atoms, numbered 1' (one prime) to 5' (five prime), as well as a base. At each carbon, substituent atoms or groups of atoms can be added in either the "up" or "down" position. This structure is illustrated below, with a hydroxyl group (OH) shown attached at the 2'-down and 3'-down positions:

         (Image Omitted)

         Appellant's Br. 8. The parties' arguments focus on the presence of various possible substituents at the 2'-up and 2'-down positions.

         Idenix argues that the key to its invention, and to treatment of HCV, is the use of 2'-methyl-up nucleosides: nucleosides "having a methyl substitution ('CH3') at the 2' 'up' position of the molecule's sugar ring," illustrated below.

         (Image Omitted)

Appellant's Br. 7-8.

         Gilead argues that this characterization is overly broad, as the '597 patent provides no guidance in determining which of the billions of potential 2'-methyl-up nucleosides are effective in treating HCV. See Appellee's Br. 8. According to Gilead, the '597 patent primarily describes 2'-methyl-up nucleosides that have a hydroxyl group (OH) at the 2'-down position. But Gilead's accused product has fluorine (F), not OH, at the 2'-down position. Id. According to Gilead, the '597 patent cannot enable the full scope of effective 2'-methyl-up nucleosides at least because its accused embodiment, 2'-methyl-up 2'-fluoro- down, is not disclosed in or enabled by the specification.[1]

1. A method for the treatment of a hepatitis C virus infection, comprising administering an effective amount of a purine or pyrimidine β-D-2'-methyl-ribofuranosyl nucleoside or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

'597 patent claim 1. The district court construed the structural limitation "β-D-2'-methyl-ribofuranosyl nucleoside" to require "a methyl group in the 2' up position and non-hydrogen substituents at the 2' down and 3' down positions." Idenix Pharm., Inc. v. Gilead Scis., Inc., 2015 WL 9048010, at *6 (D. Del. Dec. 16, 2015) ("Claim Construction Order"). Thus, while the claim requires methyl at the 2'-up position, it allows nearly any imaginable substituent at the 2'-down position.[2]

         At Idenix's urging, the district court also construed the preamble, "[a] method for the treatment of a hepatitis C virus infection," as a narrowing functional limitation. Idenix Pharm. LLC v. Gilead Scis., Inc., 2016 WL 6802481, at *5 (D. Del. Nov. 16, 2016). In combination with the requirement to administer an "effective amount," this claim language "limit[s] the scope of the claims to the use of some set of compounds that are effective for treatment of HCV." Id. at *6.

         Neither party challenges the district court's claim constructions in this appeal. Claim 1, therefore, encompasses any β-D nucleoside meeting both the structural limitations (including a methyl group at 2'-up) and the functional limitations (efficacy in treating HCV). It is undisputed, however, that there are billions of potential 2'-methyl-up nucleosides. The key enablement question is whether a person of ordinary skill in the art would know, without undue experimentation, which 2'-methyl-up nucleosides would be effective for treating HCV. We conclude that they would not.[3] Taking into account the evidence presented at trial, a reasonable jury would not have had a legally sufficient basis to find otherwise.

         In analyzing undue experimentation, we consider the factors first enumerated in In re Wands. The uncontested jury instructions in this case formulate the Wands factors as follows:

(1) the quantity of experimentation necessary;
(2) how routine any necessary experimentation is in the relevant field;
(3) whether the patent discloses specific working examples of the claimed invention;
(4) the amount of guidance presented in the patent;
(5) the nature and predictability of the field;
(6) the level of ordinary skill; and
(7) the scope of the claimed invention.

J.A. 179; see Wands, 848 F.3d at 737. The parties agree that the level of ordinary skill in the art is high, but dispute the impact of the remaining factors. We discuss each in turn.

         A

         We agree with the district court that the quantity of experimentation required to determine which 2'-methyl-up nucleosides meet claim 1 is very high, which favors a finding of non-enablement. The evidence presented to the jury could not support any other finding. At trial, Gilead presented expert testimony that because the claim allows for nearly any substituent to be attached at any position (other than 2'-up), a person of ordinary skill in the art would understand that "billions and billions" of compounds literally meet the structural limitations of the claim. J.A. 37545.

         Idenix did not dispute that math, but argued to the jury that this approach was merely "theoretical," because a person of ordinary skill in the art ("POSA") would not attach substituents at random. See J.A. 37734. Instead, Idenix argued, a POSA would know to "take into account the patent as a whole" to focus on a "significantly smaller" set of candidate compounds. Id. The district court accepted this argument, but concluded that even taking into account the knowledge and approach of a POSA, the candidate compounds number "likely[] millions or at least many, many thousands." JMOL Opinion, at *12.

         On the evidence presented, a reasonable jury could only have concluded that at least "many, many thousands" of candidate compounds exist. Idenix's evidence, which supports at best an unspecified number "significantly smaller" than "billions," could not lead a reasonable jury to any other conclusion. As Gilead points out, even hundreds of millions is a "significantly smaller" number when the starting point is "billions and billions." Appellee's Br. 35-36. Idenix's counsel conceded that in its "best case," considering the knowledge of a POSA, the structural limitations still encompass "some number of thousands" of compounds. J.A. 40013.

         This conclusion is supported by the '597 patent itself, which discloses enormous quantities of 2'-methyl-up nucleosides that would need to be tested for efficacy against HCV. The specification contains 18 Formulas, each of which is represented by a diagram with variables at multiple positions. For example, Formula XVII, described as the "eleventh principal embodiment," provides:

         a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

         (Image Omitted)

wherein:
Base is a purine or pyrimidine base as defined herein;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, - C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), - O(lower acyl), -O(alkyl), -O(lower alkyl), - O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), - C(O)O(lower alkyl), -O(acyl), -O(lower acyl), - O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, -NH(lower alkyl), - NH(acyl), -N(lower alkyl)2, -N(acyl)2;
R10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R7 and R10 can come together to form a pi bond; and
X is O, S, SO2 or CH2.

'597 patent col. 12 ll. 20-67. The 2'-up position in this formula, represented as R6, includes a methyl group as one of two dozen possible substituents.[4] Even limiting this formula only to its 2'-methyl-up variations, however, the formula provides more than a dozen options at the R1 position, more than a dozen independent options at the 2'-down position, more than a dozen independent options at the 3'- down position, and multiple independent options for the base.

         As the district court meticulously calculated, this formula alone discloses more than 7, 000 unique configurations of 2'-methyl-up nucleosides. JMOL Opinion, at *12.[5] Other formulas in the specification provide equally large numbers of compounds. Idenix argues that a POSA would have focused on only a narrow subset of billions of possible candidates, but the jury was not free to adopt a number lower than the many, many thousands of configurations identified as "principal embodiment[s]" in the patent itself. See, e.g., '597 patent col. 12 ll. 20-22. Testing the compounds in the specification alone for efficacy against HCV requires enough experimentation for this factor to weigh in favor of non-enablement.

         Idenix relatedly argues that a POSA would understand the "focus" of the claim to be "the inhibition of the NS5B polymerase" to effectively cure HCV. Appellant's Br. 16. Therefore, Idenix argues, a POSA would know which candidates were likely to inhibit NS5B, and would test only those, resulting in a "predictable and manageable" group of candidate compounds. Id. This argument improperly attempts to narrow the claim to only those nucleosides that would inhibit the NS5B polymerase. But the district court's claim construction, not challenged in this appeal, made clear that "as a matter of law, NS5B activity is not a claim limitation." JMOL Opinion, at *26 (emphasis in original).

         Moreover, it would be improper to rely on a POSA's knowledge of NS5B to fill the gaps in the specification. "It is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement." Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). Idenix's attempt to treat NS5B as a claim limitation, based on the knowledge ...


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