  United States Court of Appeals
      for the Federal Circuit
                 ______________________

 IDENIX PHARMACEUTICALS LLC, UNIVERSITA
         DEGLI STUDI DI CAGLIARI,
             Plaintiffs-Appellants

                            v.

              GILEAD SCIENCES INC.,
                  Defendant-Appellee
                ______________________

                       2018-1691
                 ______________________

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

               Decided: October 30, 2019
                ______________________

   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
2       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




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 for the court filed by Chief Judge PROST.
    Dissenting opinion filed by Circuit Judge NEWMAN.
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
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          3



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).
4       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




    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:
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.           5



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.




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-
6       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




down, is not disclosed in or enabled by the specification. 1
    The only independent claim of the ’597 patent recites:
    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.




    1   We have previously held that an Idenix patent on
similar technology failed to enable 2'-methyl-up 2'-fluoro-
down nucleosides, albeit in a different procedural posture.
See Storer v. Clark, 860 F.3d 1340 (Fed. Cir. 2017).
    2   Neither party contends that the sole limitation on
2'-down, which excludes hydrogen substituents, is signifi-
cant in this appeal.
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.           7



    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


    3   The dissent, making an argument not advanced by
Idenix at trial or before us, reaches the opposite conclusion
only by disregarding the district court’s binding claim con-
struction, ignoring the resulting stipulation of infringe-
ment, and analyzing a case that is not the one presented to
us.
    Before the district court, Gilead proposed a narrow
claim construction that required “hydroxyl groups at the 2'
down and 3' down positions.” Claim Construction Order at
*6. Because Gilead’s accused product has fluorine at 2'-
down, rather than a hydroxyl group, this would have re-
sulted in non-infringement. However, the district court ex-
pressly rejected that proposal, instead adopting a broader
construction that allowed for any “non-hydrogen substitu-
ents,” including fluorine. Id. On the basis of that broad
construction, Gilead stipulated to infringement, and the
parties held a trial solely on invalidity. J.A. 6. Neither side
challenged the claim construction on appeal, and the issue
is not before us.
    The question before us is whether the ’597 patent ena-
bles the full scope of its claims under the district court’s
broad construction. The dissent declines to answer that
question, and instead applies its own “narrow” claim con-
struction, under which only hydroxyl groups are permitted
at the 2'-down position. Dissent at 3; id. at 7 (limiting
8       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




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



claim to where “R7 is OH”); id. at 12 (“narrow formula of
three OH groups and a CH3 group as pictured”). In es-
sence, the dissent adopts Gilead’s rejected claim construc-
tion. Indeed, the dissent admits that under its new claim
construction, Gilead’s accused product “is not within the
scope of the claims.” Dissent at 15.
    We agree with the dissent that, under a narrower con-
struction, the claims of the ’597 patent might well be ena-
bled, and the accused product would not infringe. But that
is not the case before us. We are tasked with deciding
whether the claims¸ as construed, are enabled. The dissent
appears to agree with us that they are not. Dissent at 12
(“the ’597 specification did not describe and enable prod-
ucts other than . . . the narrow formulas of three OH
groups”). But rather than answer that question, the dis-
sent has applied its newly invented claim construction to
find a hypothetical narrower claim valid but not infringed.
Respectfully, that is no way to conduct an appeal.
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.            9



    (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
10       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




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 nucle-
osides 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 multi-
ple positions. For example, Formula XVII, described as the
“eleventh principal embodiment,” provides:
     a compound of Formula XVII, or a pharmaceuti-
     cally acceptable salt or prodrug thereof:




     wherein:
     Base is a purine or pyrimidine base as defined
     herein;
     R1 and R2 are independently H; phosphate (includ-
     ing 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
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.            11



    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 al-
    kyl), 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, hy-
    droxy, 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, bro-
    mine 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 for-
mula, represented as R6, includes a methyl group as one of
two dozen possible substituents. 4 Even limiting this for-
mula only to its 2'-methyl-up variations, however, the for-
mula provides more than a dozen options at the R1 position,
more than a dozen independent options at the 2'-down po-
sition, more than a dozen independent options at the 3'-



    4  The term “alkyl” is defined in the ’597 patent to in-
clude methyl. ’597 patent col. 37 ll. 9–25.
12       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




down position, and multiple independent options for the
base.
    As the district court meticulously calculated, this for-
mula alone discloses more than 7,000 unique configura-
tions 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 com-
pounds 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.


     5   This figure is conservative, as the district court
noted. JMOL Opinion, at *12 (noting that “Formula XVII
on its own constitutes at least a minimum of approximately
7,000 unique configurations” (emphasis added)). The
number of candidates disclosed by this formula is likely
orders of magnitude higher. For example, the district
court’s calculation considered “alkyl” to be one possible
option at each position. But the specification defines
“alkyl” to include at least twenty distinct options that could
be substituted. ’597 patent col. 37 ll. 9–26. The terms
“purine or pyrimidine base” and “acyl” are similarly each
defined to include at least twenty independent options. See
id. at col. 37 l. 59–col. 38 l. 29; JMOL Opinion, at *12 n.11
(“The number of possible configurations increases
considerably (by an order of magnitude) when all the
compounds the patent defines as a purine or pyrimidine
base are taken into account.”).
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.        13



Therefore, Idenix argues, a POSA would know which can-
didates were likely to inhibit NS5B, and would test only
those, resulting in a “predictable and manageable” group of
candidate compounds. Id. This argument improperly at-
tempts 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 orig-
inal).
     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 of a POSA, would be an impermissible
end-run around the requirement to enable the full scope of
the claim. 6
    At oral argument here on appeal, Idenix presented an
additional theory for why little or no experimentation was
required. According to Idenix, “the jury could have con-
cluded that all 2'-methyl-up ribonucleosides were active
against the hepatitis C virus, so that the numbers don’t
matter. Screening [of each candidate for efficacy against
HCV] was irrelevant.” Oral Arg. at 6:07–6:18, No. 2018-
1691,         http://www.cafc.uscourts.gov/oral-argument-


    6   Idenix does not argue that the full scope of the
claim includes only compounds that inhibit the NS5B pol-
ymerase. Nor could it, as the ’597 patent describes treating
HCV in other ways. See ’597 patent col. 139 ll. 30–32
(“Compounds can exhibit anti-hepatitis C activity by inhib-
iting HCV polymerase, or by inhibiting other enzymes
needed in the replication cycle, or by other pathways.”).
14      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




recordings. We do not agree that the evidence presented
could have supported this conclusion. Indeed, Idenix’s own
evidence contradicts it.
     At trial, Idenix’s expert agreed that the field of modify-
ing nucleosides for anti-HCV activity was “in its infancy”
and “unpredictable.” J.A. 37736. Another of Idenix’s ex-
perts testified that screening was performed to “actually
cut down on the number of compounds, by removing all in-
active ones to a few interesting ones.” J.A. 37747. A third
Idenix expert testified that “you don’t know whether or not
a nucleoside will have activity against HCV until you make
it and test it.” J.A. 37411. And at oral argument on the
post-trial motions, Idenix’s counsel agreed that “not all 2'
methyl up ribonucleosides will be effective to treat HCV,”
and therefore screening was necessary. J.A. 40007; see also
id. (“But would one have to do some screening? Certainly.”)
In light of this evidence, and this concession, no reasonable
jury could have concluded that all 2'-methyl-up nucleosides
were effective against HCV or that no screening was
needed.
    Because the claims of the ’597 patent encompass at
least many, many thousands of 2'-methyl-up nucleosides
which need to be screened for HCV efficacy, the quantity of
experimentation needed is large and weighs in favor of
non-enablement.
                              B
     The district court concluded that a reasonable jury
could only find that many candidate nucleosides would
need to be synthesized before they could be screened, as not
all candidate nucleosides were available for purchase. We
agree.
    Idenix argues that “a significant number of nucleosides
were available off-the-shelf in libraries.” Appellant’s
Br. 40. However, in light of the billions of possible 2'-me-
thyl-up nucleosides, or even the many, many thousands of
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          15



nucleosides that meet the formulas provided in the patent,
no reasonable jury could conclude that “a significant num-
ber” of available nucleosides removes the need for synthe-
sis. Moreover, Idenix’s expert testified that synthesis was
often required even when starting with a compound pur-
chased from a library or database. See J.A. 37735 (“the
general approach is starting from an intact nucleoside that
you can buy . . . and then you start doing chemistry on this
intact nucleoside and modify the nucleoside structure in
the sugar part or even the base part”). In light of this evi-
dence, a reasonable jury could only have found that synthe-
sis was necessary. 7
     We do agree with Idenix, however, that a jury could
have found that the synthesis of an individual compound
was largely routine. Gilead argued that synthesis was dif-
ficult, presenting the jury with evidence of an Idenix scien-
tist who repeatedly tried and failed to synthesize 2'-methyl-
up 2'-fluoro-down, which is the nucleoside at issue in Gil-
ead’s accused product. See JMOL Opinion, at *16. Idenix
countered this with evidence of a scientist at a Gilead sub-
sidiary who produced a 2'-methyl-up 2'-fluoro-down com-
pound “in relatively short order.” See id. As a reviewing
court, “we are mindful that we ‘may not weigh the evidence,
determine the credibility of witnesses, or substitute [our]
version of facts for the jury’s version.’” Agrizap, 520 F.3d
at 1342 (quoting Lightning Lube, Inc. v. Witco Corp., 4 F.3d
1153, 1166 (3d Cir. 1993)). In light of this conflicting testi-
mony, a reasonable jury was entitled to conclude that a
POSA could synthesize this particular compound in rela-
tivity short order.



    7   Our analysis does not rely on the contested state-
ment in the district court’s opinion as to whether or not
Idenix’s expert expressly testified that “not all compounds
of interest were commercially available.” JMOL Opinion,
at *15.
16      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




   Because a jury could only have found that synthesis of
many 2'-methyl-up nucleosides was necessary, but could
have concluded that synthesis of an individual nucleoside
was largely routine, this factor weighs against a finding of
non-enablement.
                             C
    We analyze the presence of working examples and the
amount of guidance presented in the specification together.
Idenix argues that these factors weigh against non-enable-
ment because the specification “identifies the ‘key’ modifi-
cation (2'-methyl-up)” and contains “working examples of
active 2'-methyl-up ribonucleosides that were tested.” Ap-
pellant’s Br. 44. We disagree.
     Idenix contends that the ’597 patent provides meaning-
ful guidance as to which nucleosides meet the functional
limitations of the claim because it identifies the “key” mod-
ification of 2'-methyl-up. Appellant’s Br. 44. That is insuf-
ficient. An enabling disclosure must “be commensurate in
scope with the claim.” In re Hyatt, 708 F.2d 712, 714 (Fed.
Cir. 1983). Claim 1 requires more than just an identifica-
tion of 2'-methyl-up: it requires identification of which 2'-
methyl-up nucleosides will effectively treat HCV. Without
specific guidance on that point, the specification provides
“only a starting point, a direction for further research.”
ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 941 (Fed.
Cir. 2010). That guidance is absent from the ’597 specifi-
cation.
    Idenix argues that the ’597 patent provides this guid-
ance because a POSA would understand NS5B to be the
“target” enzyme or would understand that the modified nu-
cleoside must have “either the natural -OH (hydroxyl) or a
mimicking substitute at 2'-down.” Appellant’s Br. 38, 44.
But reliance on a POSA is insufficient to meet the enable-
ment requirement. A patent owner is “required to provide
an enabling disclosure in the specification; it cannot simply
rely on the knowledge of a person of ordinary skill to serve
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.        17



as a substitute for the missing information in the specifica-
tion.” ALZA, 603 F.3d at 941. Even if we credit Idenix’s
position that a POSA would look for compounds that would
“target” NS5B, the specification fails to provide an ena-
bling disclosure. It is not enough to identify a “target” to
be the subject of future testing. A specification that re-
quires a POSA to “engage in an iterative, trial-and-error
process to practice the claimed invention” does not provide
an enabling disclosure. Id.
     It is true that the specification contains some data
showing working examples of 2'-methyl-up nucleosides
with efficacy against HCV. See ’597 patent col. 139 l. 61–
col. 142 l. 57. As discussed, however, the specification
alone encompasses tens if not hundreds of thousands of
“preferred” 2'-methyl-up nucleosides that would need to be
tested for efficacy against HCV. In the face of that broad
disclosure, four examples on a single sugar are insufficient
to support enablement. Where, as here, working examples
are present but are “very narrow, despite the wide breadth
of the claims at issue,” this factor weighs against enable-
ment. Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362,
1374 (Fed. Cir. 1999); see Enzo Life Scis., Inc. v. Roche Mo-
lecular Sys., Inc., 928 F.3d 1340, 1348 (Fed. Cir. 2019)
(working example that was “insufficient to enable the
breadth of the claims here, especially in light of the unpre-
dictability of the art” did not support enablement).
    Because the ’597 patent fails to provide meaningful
guidance as to which 2'-methyl-up nucleosides are or are
not effective against HCV, and because the only working
examples provided are exceedingly narrow relative to the
claim scope, these two factors weigh in favor of non-enable-
ment.
                             D
    Based on the testimony presented at trial, a reasonable
jury could only have concluded that the use of modified nu-
cleosides to treat HCV was an unpredictable art. Gilead’s
18      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




experts testified at trial that the art was “highly unpredict-
able” because “in the nucleoside area . . . the smallest
change can have a dramatic effect not only on the activity
of that compound but on the toxicity of the compound. So
nothing is predictable.” J.A. 37547.
     Idenix’s experts also testified at trial that the field was
new and unpredictable. On cross-examination, Idenix’s ex-
pert admitted that at the time the ’597 patent was in-
vented, the field of “modified nucleosides activity for HCV”
was “in its infancy.” J.A. 37736. He also admitted that,
even as late as 2012, it was “unpredictable to make a com-
pound and determine whether or not it is active” against
HCV. J.A. 37736–37. Another of Idenix’s witnesses con-
firmed that “you don’t know whether or not a nucleoside
will have activity against HCV until you make it and test
it.” J.A. 37441.
    In light of both parties’ testimony that the art was un-
predictable, this factor could only weigh in favor of non-en-
ablement. See In re Fisher, 427 F.2d 833, 839 (CCPA 1970)
(“In cases involving unpredictable factors, such as most
chemical reactions and physiological activity, the scope of
enablement obviously varies inversely with the degree of
unpredictability of the factors involved.”).
                               E
     For largely the same reasons discussed with respect to
the quantity of experimentation factor, we conclude that
the scope of the claims could only support a finding of non-
enablement. On appeal, Idenix makes two arguments spe-
cifically directed to this factor. Neither is persuasive.
    First, Idenix argues that “[w]hen required to take all of
the claim limitations into account, Gilead’s witnesses de-
scribed the claims as embracing only a ‘small’ number of
compounds.” Appellant’s Br. 46. This analysis is back-
wards. Gilead’s expert testified that, in order for the ’597
patent to teach which 2'-methyl-up nucleosides effectively
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.         19



treat HCV, the patent would need to detail “how to get from
a large number [of candidate compounds] to a relatively
speaking small number [of effective compounds].” J.A.
37546–47. In other words, the ’597 patent leaves a POSA
searching for a needle in a haystack to determine which of
the “large number” of 2'-methyl-up nucleosides falls into
the “small” group of candidates that effectively treats HCV.
The size disparity between those two groups requires sig-
nificant experimentation, which weighs against enable-
ment, not for it. 8
    Second, Idenix argues that the claim is not broad be-
cause “evidence showed that the POSA, with common
sense, the claims, and the specification as guidance, would
focus on a narrow set of candidates.” Appellant’s Br. 46.
This factor, however, considers the scope of the claim as
written, not just the subset of the claim that a POSA might
practice. Idenix does not, and cannot, argue that the scope
of the claim is actually limited to this narrow set of candi-
dates. “[A]s a matter of law, NS5B activity is not a claim
limitation.” JMOL Opinion, at *26 (emphasis in original).
We therefore conclude that the breadth of the claims
weighs in favor of non-enablement.
                              F
     Weighing each of these factors, we conclude as a matter
of law that the ’597 patent is invalid for lack of enablement.
As described above, a reasonable jury could only have
found that at least many, many thousands of 2'-methyl-up
nucleosides meet the structural limitations of claim 1, not
all of which are effective to treat HCV. Due to the



    8    Although not necessary to our decision, we also
note that this “small number” argument is inconsistent
with Idenix’s claim at oral argument that the jury implic-
itly found that all 2'-methyl-up nucleosides are effective to
treat HCV. Oral Arg. at 6:07–18.
20      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




unpredictability of the art, and as admitted by Idenix, each
of these compounds would need to be screened in order to
know whether or not they are effective against HCV. More-
over, a significant number of candidate 2'-methyl-up nucle-
osides would need to be synthesized before they could be
screened, which increases at least the quantity of experi-
mentation required, even if the synthesis was routine. Alt-
hough the level of skill in the art is high, the ’597 patent
does not provide enough meaningful guidance or working
examples, across the full scope of the claim, to allow a
POSA to determine which 2'-methyl-up nucleosides would
or would not be effective against HCV without extensive
screening. The immense breadth of screening required to
determine which 2'-methyl-up nucleosides are effective
against HCV can only be described as undue experimenta-
tion.
    Our decision in Wyeth and Cordis Corp. v. Abbott La-
boratories compels this conclusion, and as the district court
correctly acknowledged, the similarities between that case
and this one are striking. In Wyeth, as here, we considered
a claim that encompassed “millions of compounds made by
varying the substituent groups,” while only a “significantly
smaller” subset of those compounds would have the
claimed “functional effects.” 720 F.3d at 1384. We then
credited the patent owner’s argument that, based on the
knowledge of a POSA, the number of candidate compounds
to be tested could be as little as “tens of thousands.” Id. at
1384–85. In both cases, scientific testimony confirmed that
practicing the full scope of the claims would require syn-
thesizing and screening tens of thousands of candidate
compounds for the claimed efficacy. Compare id. at 1385
(Wyeth scientist testifying “until you test [compounds], you
can’t really tell whether they work or not”), with J.A. 37441
(Idenix scientist testifying “you don’t know whether or not
a nucleoside will have activity against HCV until you make
it and test it”).
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.       21



     Notwithstanding the fact that screening an individual
compound for effectiveness was considered “routine,” we
concluded as a matter of law in Wyeth that the claim was
not enabled because there were “at least tens of thousands
of candidate compounds” and “it would be necessary to first
synthesize and then screen each candidate compound.” Id.
at 1385–86. As we explicitly stated: “The remaining ques-
tion is whether having to synthesize and screen each of at
least tens of thousands of candidate compounds constitutes
undue experimentation. We hold that it does.” Id. at 1385.
That principle controls here. A reasonable jury could only
have concluded that there were at least many, many thou-
sands of candidate compounds, many of which would re-
quire synthesis and each of which would require screening.
That constitutes undue experimentation.
     We are not persuaded by Idenix’s attempts to distin-
guish Wyeth based on the state of the arts of screening and
synthesis in 1992, when the Wyeth patent application was
filed, as compared to 2000, when Idenix’s first application
was filed. Our decision in Wyeth, and our decision here,
rests on the “limits on permissible experimentation,” not
on the relative time that the experimentation would take.
Id. at 1386. We found the patent in Wyeth not enabled even
while “putting the challenges of synthesis aside,” and ac-
cepting as true that screening was “routine[].” Id. at 1384,
1386. Where, as here, “practicing the full scope of the
claims would have required excessive experimentation,
even if routine,” the patent is invalid for lack of enable-
ment. Id. at 1384.
                            IV
    We separately address the district court’s denial of
JMOL on the issue of written description. The Patent Act
contains a written description requirement distinct from
the enablement requirement. 35 U.S.C. § 112; see Ariad
Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340 (Fed.
Cir. 2010) (en banc). To fulfill the written description
22      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




requirement, a patent owner “must ‘convey with reasona-
ble clarity to those skilled in the art that, as of the filing
date sought, he or she was in possession of the invention,’
and demonstrate that by disclosure in the specification of
the patent.” Carnegie Mellon Univ. v. Hoffmann-La Roche
Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (citation omitted)
(quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563–
64 (Fed. Cir. 1991)). That test “requires an objective in-
quiry into the four corners of the specification from the per-
spective of a person of ordinary skill in the art.” Ariad, 598
F.3d at 1351.
    The question in this case is whether the ’597 patent
demonstrates that the inventor was in possession of those
2'-methyl-up nucleosides that fall within the boundaries of
the claim (i.e., are effective against HCV), but are not en-
compassed by the explicit formulas or examples provided
in the specification. The parties focus in particular on
whether the specification demonstrates possession of the
2'-methyl-up 2'-fluoro-down nucleosides that are the basis
for Gilead’s accused product.
     There is no dispute that neither the ’597 patent nor any
of its predecessor applications discloses a 2'-methyl-up 2'-
fluoro-down nucleoside, including in any formulas or exam-
ples. See J.A. 37102–03 (admission of Idenix’s inventor).
Nor is there any dispute as to why. Idenix “only came up
with the methyl up fluoro down embodiment a year or so
after the application was filed.” See J.A. 25562 (admission
of Idenix’s counsel). Idenix argues instead that its claims
are directed to the entire genus of 2'-methyl-up compounds
for treating HCV, and are enabled by the disclosure of a
number of examples, without needing to disclose each spe-
cies of nucleoside. See Reply Br. 31–32.
    Idenix is correct that generally a genus can be suffi-
ciently disclosed by “either a representative number of spe-
cies falling within the scope of the genus or structural
features common to the members of the genus so that one
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          23



of skill in the art can visualize or recognize the members of
the genus.” Ariad, 598 F.3d at 1350 (internal quotation
marks omitted). We have alternatively described this in-
quiry as “looking for blaze marks which single out particu-
lar trees” in a forest, rather than simply “pointing to trees.”
See Fujikawa v. Wattanasin, 93 F.3d 1559, 1570 (Fed. Cir.
1996) (quoting In re Ruschig, 379 F.2d 990, 994–95 (CCPA
1967)).
     In this case, we hold that the ’597 patent is invalid for
lack of written description, as it fails to provide sufficient
blaze marks to direct a POSA to the specific subset of 2'-
methyl-up nucleosides that are effective in treating HCV.
The patent provides eighteen position-by-position formulas
describing “principal embodiments” of compounds that
may treat HCV. See generally ’597 patent col. 5 l. 29–
col. 13 l. 42. However, other than generic language regard-
ing “pharmaceutically acceptable salts and prodrugs
thereof” (a category not at issue here), the specification pro-
vides no indication that any nucleosides outside of those
disclosed in its formulas could be effective to treat HCV—
much less any indication as to which of those undisclosed
nucleosides would be effective. See id. at col. 15 l. 51–col.
16 l. 10. “A written description of an invention involving a
chemical genus, like a description of a chemical species, ‘re-
quires a precise definition, such as by structure, formula,
[or] chemical name’ of the claimed subject matter sufficient
to distinguish it from other materials.” Bos. Sci. Corp. v.
Johnson & Johnson, 647 F.3d 1353, 1363 (Fed. Cir. 2011)
(quoting Regents of the Univ. of Cal. v. Eli Lilly & Co.,
119 F.3d 1559, 1568 (Fed. Cir. 1997)). The ’597 patent pro-
vides adequate written description for the compounds
within its formulas. The specification, however, provides
no method of distinguishing effective from ineffective com-
pounds for the compounds reaching beyond the formulas
disclosed in the ’597 patent.
    Idenix argues that it provides “abundant traditional
blazemarks for the claims—working examples, formulas,
24       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




data, synthesis routes, and the target.” Reply Br. 32. Each
of these suffer from the same flaw. They provide lists or
examples of supposedly effective nucleosides, but do not ex-
plain what makes them effective, or why. As a result, a
POSA is deprived of any meaningful guidance into what
compounds beyond the examples and formulas, if any,
would provide the same result. In the absence of that guid-
ance, the listed examples and formulas cannot provide ad-
equate written description support for undisclosed
nucleosides that also happens to treat HCV. The written
description requirement specifically defends against such
attempts to “cover any compound later actually invented
and determined to fall within the claim’s functional bound-
aries.” See Ariad, 598 F.3d at 1353.
     We are mindful of Ariad’s caution that written descrip-
tion does not require “a nucleotide-by-nucleotide recitation
of the entire genus.” Id. at 1352. The purpose of that rule
is to allow relatively few representative examples or formu-
las to support a claim on a structurally similar genus. See
id. It does not extend to this case, where the specification
lists tens or hundreds of thousands of possible nucleosides,
substituent-by-substituent, with dozens of distinct stereo-
chemical structures, and yet the compound in question is
conspicuously absent.
     The absence of 2'-fluoro-down is indeed conspicuous.
Seven of the provided formulas permit 2'-methyl-up. See,
e.g., ’597 patent col. 6 ll. 5–20 (Formula II), col. 8 ll. 5–20
(Formula V), col. 10 ll. 5–47 (Formulas X and XI), col. 11
l. 42–col. 12 l. 17 (Formula XVI), col. 12 ll. 23–54 (Formula
XVII), col. 13 ll. 5–41 (Formula XVIII). All seven formulas
explicitly list fluorine as a possibility at other positions, in-
cluding 2'-up. See, e.g., id. at col. 10 ll. 42–47 (listing
“fluoro” at 2'-up). Yet not one of them includes fluorine at
2'-down, despite each listing more than a dozen possible
substituents at that position. This is true even though the
formulas include every other recited halogen at both posi-
tions. Compare ’597 patent col. 8 ll. 48–54 (listing “chloro,
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          25



bromo, fluoro, iodo” at 2'-up), with col. 8 ll. 55–61 (listing
“chlorine, bromine, iodine,” but not fluorine, at 2'-down).
    Further, to the extent Idenix argues that, although not
disclosed, a POSA would have known to include fluorine at
2'-down based on its similarities to other halogens, that is
insufficient for written description. “[A] description that
merely renders the invention obvious does not satisfy” the
written description requirement. Ariad, 598 F.3d at 1352.
    We therefore disagree with Idenix’s characterization
that “the specification plainly embraces the use of the [2'-
fluoro-down] embodiment.” Reply Br. 34. In light of the
conspicuous absence of that compound, a POSA would not
“visualize or recognize the members of the genus” as in-
cluding 2'-fluoro-down, and the specification could not
demonstrate to a POSA that the inventor had possession of
that embodiment at the time of filing. Ariad, 598 F.3d at
1350.
                              V
     For the foregoing reasons, we affirm the district court’s
grant of judgment as a matter of law that the ’597 patent
is invalid for lack of enablement. We reverse the district
court’s denial of judgment as a matter of law for failure to
meet the written description requirement and hold that the
’597 patent is invalid for lack of written description as well.
  AFFIRMED-IN-PART AND REVERSED-IN-PART
                            COSTS
    Costs to appellee.
   United States Court of Appeals
      for the Federal Circuit
                  ______________________

 IDENIX PHARMACEUTICALS LLC, UNIVERSITA
         DEGLI STUDI DI CAGLIARI,
             Plaintiffs-Appellants

                              v.

                GILEAD SCIENCES INC.,
                    Defendant-Appellee
                  ______________________

                        2018-1691
                  ______________________

    Appeal from the United States District Court for the
District of Delaware in No. 1:14-cv-00846-LPS, Chief Judge
Leonard P. Stark.
                 ______________________
NEWMAN, Circuit Judge, dissenting.
    I respectfully dissent. The court errs in holding that
the specific narrow claims of the ’597 patent are invalid.
The large number of unclaimed chemical variants in the
specification are not described, not synthesized, and not
tested for antiviral activity. It is incorrect to include these
variants in the claims and then to invalidate the claims be-
cause these variants are not described and not enabled.
    The panel majority, overturning the jury verdict, finds
the ’597 claims invalid on the grounds of non-enablement
and inadequate description. The majority finds that there
are “billions and billions” of possible nucleosides in the om-
nibus specification. On this reasoning, the majority finds
2       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




invalid the narrow claims of the ’597 patent. However, a
reasonable jury could have understood the claims as di-
rected to the nucleosides that are specifically described and
that are shown to have the claimed antiviral activity. A
reasonable jury could have credited the evidence that the
’597 claims are for these specific compounds, not the “bil-
lions and billions” of unsynthesized and unevaluated vari-
ants in the specification. It is not disputed that the specific
claimed compounds meet the requirements of 35 U.S.C.
§ 112. The jury verdict of validity must be viewed in light
of the evidence and argument before the jury.
    The majority’s holding that validity under section 112
is determined based on whether unclaimed subject matter
is described and enabled, provides a new path of uncer-
tainty and unreliability of the patent grant. I respectfully
dissent.
                              I
     I write in concern for the majority’s flawed theory of
section 112, whereby the court requires description and en-
ablement of the unclaimed and unsupported subject mat-
ter, in order to sustain validity of claims to the supported
subject matter. A reasonable jury could have applied the
jury instructions, in light of the patent document and the
testimony of witnesses, to understand that the claims are
for the subject matter that is produced and described and
evaluated for antiviral activity. On the correct claim con-
struction, a reasonable jury could have found the claimed
subject matter to be described and enabled.
    A reasonable jury could have understood that subject
matter that is unclaimed is irrelevant to validity under sec-
tion 112. With all respect to my colleagues, they err in
holding that because “billions and billions” of nucleosides
are within the specification but not characterized and not
evaluated, the claims to the products that are synthesized
and shown to have antiviral activity are invalid as “indefi-
nite.”
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.           3



    The jury could have found, as witnesses testified, that
the claims are directed to the nucleosides that are synthe-
sized as shown in the ’597 specification, and shown to have
antiviral efficacy. This is a narrow class of nucleosides, pic-
tured as set forth in the briefs and in the majority’s opinion:




Idenix Br. 8; Gilead Br. 8; Maj. Op. at 5.
    The ’597 specification is an omnibus disclosure of eight-
een broad “Formulas” of nucleosides—variants that are un-
tested, uncharacterized, and unclaimed. In contrast, only
the above molecule is included in the patent Figures that
report antiviral data. The specification describes Figures 2
and 3 as follows:
    FIG. 2 is a line graph of the pharmacokinetics
    (plasma concentrations) of β-D-2'-CH3-riboG ad-
    ministered to six Cynomolgus Monkeys over time
    after administration.
    FIGS. 3a and 3b are line graphs of the pharmaco-
    kinetics (plasma concentrations) of β-D-2'-CH3-
    riboG administered to Cynomolgus Monkeys either
    intravenously (3a) or orally (3b) over time after ad-
    ministration.
’597 patent, col. 15, ll. 31–38. Figure 1, captioned “Chemi-
cal Structure of Illustrative Nucleosides,” presents the
structures of eight nucleosides and two comparative com-
pounds. ’597 patent, col. 15, ll. 27–30 (“FIAU and Ribavi-
rin, which are used as comparative examples”). All eight
4       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




nucleosides have the three OH groups in the positions and
stereochemistry pictured above, and six of the eight struc-
tures in Figure 1 also have a methyl group in the 2'-up po-
sition as required by all the claims.
    The jury was told by Dr. Meier, an expert witness for
Idenix, that for all of the 2'-methyl-up nucleosides in Fig-
ure 1, “all of the compounds have hydroxide at the 2' down
position.” J.A. 37673 at 1859:25–1860:2. Dr. Secrist, an
expert witness for Gilead, testified that the first four com-
pounds in Figure 1 are β-D-2'-methyl-ribofuranosyl nucle-
osides, stating “[a]ll of them have a 2' up methyl and a 2'
down hydroxyl, yes, and they are ribonucleoside.”
J.A. 37638 at 1721:8–11.
    My colleagues err in ruling that the claims cover “bil-
lions” of variants. The ’597 specification recites a very
large number of substituents for nucleosides that are not
synthesized, not characterized, not evaluated, and not in-
cluded in the claims. Some of these variants have been
claimed in other patents and applications. 1 However, they
are not claimed in the ’597 patent. My colleagues err in
holding that because other substituents and modifications


    1   At least nine additional patents and applications
are reported to claim priority from this Provisional Appli-
cation No. 60/206,585, viz. Patent No. 6,914,054 (claiming
Formulas V, X, XI, XVI, XVII, and XVIII); Patent
No. 7,169,766 (claiming Formula XVII); Application
No. 10/602,142 (claiming Formulas X, XI, and XVII); Pa-
tent No. 7,157,441 (claiming Formulas II, X, XI, XVII); Pa-
tent No. 8,299,038 (claiming Formulas II and V);
Application No. 13/623,674 (claiming Formulas X, XI, XVI,
XVII, and XVIII); Patent No. 10,363,265 (claiming Formu-
las V and X); Application No. 13/953,687 (claiming Formula
XI); Application No. 16/440,659. See USPTO’s PAIR data-
base at http://portal.uspto.gov/pair/PublicPair, tab “Conti-
nuity Data.”
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          5



are mentioned in the specification, claims that do not in-
clude such variants are invalid on grounds of indefinite-
ness and lack of written description.
    The broadest claim of the ’597 patent is claim 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-ri-
    bofuranosyl nucleoside or a phosphate thereof, or a
    pharmaceutically acceptable salt or ester thereof.
’597 patent, col. 142, ll. 63–67. This nucleoside with pyrim-
idine base is pictured and labeled in the specification as
follows:




’597 patent, col. 142, ll. 43–55. The specification provides
pharmacologic data for the β-D-2'-methyl-ribofuranosyl nu-
cleosides of the claimed structure. The narrow scope exem-
plified in the specification cannot be reconciled with the
majority’s count of “billions and billions,” Maj. Op. at 9; or
“hundreds of millions,” id.; or even “many, many thou-
sands,” id. at 12, of nucleosides covered by the claims.
    The jury was instructed that the claims define a pa-
tent’s scope:
    The claims are important because it is the words of
    the claims that define what a patent covers. The
    claims are intended to define, in words, the
6       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




    boundaries of the invention that constitute the pa-
    tent owner’s property rights. The figures and text
    in the rest of the patent provide a description
    and/or examples of the invention and provide a con-
    text for the claims, but it is the claims that define
    the breadth of the patent’s coverage. Each of the
    asserted claims must be considered individually.
J.A. 169; J.A. 37800 at 2068:17–25 (instructing the jury).
    The panel majority discards this instruction, and re-
produces in the majority opinion portions of the specifica-
tion that relate to the other “Formulas” that are pictured
in the specification and directed to other nucleosides, some
of which are the subject of continuation patents and appli-
cations. See n.1, ante. For example, the majority presents
the specification structure designated Formula XVII,
which depicts, with “R” and “X” designations, a large num-
ber of substituents of the molecule:




Maj. Op. at 10–11 (citing ’597 patent, col. 12, ll. 20–67).
The majority states that the variants for Formula XVII are
“more than 7,000.” Id. at 12. However, a reasonable jury
could have understood, as witnesses for both sides testified,
that the only variants synthesized and evaluated in the
’597 patent have the structure where R1 is H, R9 is OH, R10
is H, R7 is OH, R6 is CH3, and X is oxygen.
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.            7



    The ’597 patent was the subject of expert testimony
throughout the two-week jury trial. The patent was given
to the jury; see J.A. 170 (“[R]efer to the copy of the ’597 pa-
tent that you have been given.”). Following is a sampling
of the expert testimony:
    •   Q. Is the difference between DNA and RNA at
        2' down, so OH in RNA, the H in DNA, is that
        important to a nucleoside chemist in 2000-
        2001? A. Oh, yes. It is a critical distinction, of
        course. J.A. 37543 at 1568:9–12.
    •   Q. Now, you have depicted the treatment with
        an OH down at 2'. Is that correct? A. Yes.
        Q. Why did you do that? A. Well, it’s – number
        one, you would expect, when you’re making
        something – this is in the 2001 time frame, you
        would expect modified nucleotides to have that
        OH down because you want to be accepted by
        the machinery that makes that RNA virus. So
        you want to have that 2- down. J.A. 37544 at
        1571:1–10.
    •   Q. [Discussing a 1998 publication concerning
        the enzymes] If you look at the end of the par-
        agraph, it concludes with the statement that
        “These results indicate that the HCV enzyme
        has a strict specificity for ribonucleoside 5' tri-
        phosphates and requires the 2' and 3'-OH
        groups.” . . . What does that mean with respect
        to this 2' position you and I have just been talk-
        ing about? A. Well, as I have always main-
        tained, the entire molecule, when you are
        making a drug, is absolutely critical. However,
        in the case of doing something for RNA, then
        having this 2' prime, for the reasons I talked
        about earlier, that’s what the enzymes use, is
        really important. J.A. 37545 at 1574:16–
        1575:2.
8       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




    •   Q. In the patent, did you see, after reading it,
        any data on any other nucleoside that had
        something different at 2' down than the OH
        known as hydroxyl? A. No. J.A. 37548 at
        1588:18–21.
    •   Q. What did these examples teach a skilled
        person to put at the 2' down position in a nucle-
        oside? A. Well, if you are thinking about effec-
        tive treatment of HCV, at best they teach that
        you would put an OH down at the 2' along with
        a methyl up at the 2 prime. J.A. 37548 at
        1588:22–1589:1.
    •   Q. And is that teaching, OH down at 2', is that
        consistent or inconsistent with the conven-
        tional wisdom of nucleoside chemists at the
        time? A. Well, speaking as a nucleoside chem-
        ist at the time, I would have expected and cer-
        tainly not been surprised by compounds
        identified that had 2' down hydroxyls. J.A.
        37548 at 1589:4–9.
    •   Q. We talked about this, but . . . is there any
        antiviral data to guide the person of skill
        amongst the possibilities covered by that
        2'-Beta-D-methyl-ribofuranosyl      nucleoside?
        A. No. We heard about it before but there is
        no antiviral data in this patent application.
        J.A. 37549–50 at 1593:20–1594:1.
    •   Q. And even considering that other data, does
        that cover a lot of compounds or only a few?
        A. Well, it only covers the four compounds and
        they all have the 2' down OH only at this criti-
        cal spot, 2' down. J.A. 37550 at 1594:2–5.
    •   Q. Let’s turn to the making of the compound.
        What kind of guidance does the patent provide
        and what kind of compounds are actually – or
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.         9



       the patent teaches you can actually make?
       A. Well, it gives, I’ll say, standard literature
       ways to make nucleosides that have 2' up me-
       thyl and a 2' or maybe even a 2' up alkyl and a
       2' down OH. J.A. 37550 at 1594:6–12.
   •   Q. [Displaying the ’597 patent] What are we
       looking at here, Dr. Secrist, at DDX-721, which
       excerpts the patent at column 48, lines 30 to
       page [sic] 49, line 5? A. This is one of two gen-
       eral schemes that are in the patent, and I won’t
       go through it other than to note that you take
       a starting material, that you go through a
       whole series of steps, and you end up with a nu-
       cleoside with a down OH. J.A. 37550 at
       1594:13–21.
   •   Q. And a 2'-methyl up? A. A 2'-methyl, or as
       you can sigh [sic] in ours, it could be another
       group up. J.A. 37550 at 1595:16–18.
   •   Q. What compound does the patent show being
       made in relation to the 2' position? A. Okay.
       It shows only compounds that have a 2' down
       hydroxyl group. J.A. 37550 at 1595:12–15.
   •   Q. Are there any other synthetic schemes, any
       other schemes in the patent that show some-
       thing different at 2' down? A. No, just OH.
       J.A. 37550 at 1595:19–22.
   •   Q. Does the patent show any of these com-
       pounds being made at R7 other than 2' OH
       down? A. No. J.A. 37551 at 1598:10–12.
   •   Q. So Dr. De Francesco, we were just talking
       about your 2003 paper. We were talking about
       the phrase . . . Beta-D 2' methyl ribofuranosyl
       guanosine, and I think where we left off was
       that you were confirming that that phrasing
       describes the structure . . . that’s a methyl up
10       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




        at the 2' position, OH or hydroxy down at the 2'
        and 3' position? A. Right. Correct. J.A. 37755
        at 2001:19–2002:3.
There’s much more, as the jury was informed concerning
the chemical structure, the specification, and the claims.
The verdict form was explicit as to the asserted claims and
the burden of proof:
     [1] Has Gilead proven by clear and convincing evi-
     dence that each of the asserted claims of the ’597
     patent is invalid because the specification of the
     ’597 patent does not enable the asserted claims?
     [2] Has Gilead proven by clear and convincing evi-
     dence that each of the asserted claims of the ’597
     patent is invalid because the specification of the
     ’597 patent does not contain an adequate written
     description of the asserted claims?
J.A. 143. The jury answered “No” to both questions. Id.
    The panel majority now discards the jury verdict, stat-
ing “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.” Maj. Op.
at 12 (alteration in original). However, the jury was not
free to adopt an incorrect view of the patent, for almost all
of the embodiments that the specification calls “principal
embodiments” are for Formulas for which no synthesis and
no evaluation data are provided in the ’597 specification.
    The panel majority makes no mention of the relation of
the ’597 claims to the Figures, the examples, and the data
in the specification, holding only that the claims are invalid
based on “billions and billions” of unclaimed nucleosides.
Gilead’s expert Dr. Secrist testified that the preferred
subembodiments of Formula XVII “ends up with a total of
five compounds”:
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.          11



   Q. To be fair, the patent does boil these formulas
   down a little bit down into something called pre-
   ferred embodiments. Is that true? A. Absolutely,
   it does.
   Q. Can you explain, it is a term we haven’t heard
   before, can you explain to the jury what your un-
   derstanding of a preferred embodiment is?
   A. Well, you take—I will do my best. If you have
   this many compounds that you are starting with, a
   preferred embodiment would narrow it down by
   some means, usually by looking at data, to this
   many, in a more preferred embodiment similarly
   by some means, usually data would get down to
   this number of compounds. So you would go from
   here to here with preferred embodiments, usually
   based on seeing the data for compounds that are in
   these embodiments. . . .
   Q. If we go to [the ’597 patent]. What are we look-
   ing at here, Dr. Secrist, from Column 32 of the pa-
   tent, lines 42 to 59? A. On the right is the same
   structures, Roman Numeral XVII that we have al-
   ready seen. Now we are looking at what’s up and
   what’s down at the 2' position. . . . I have suggested
   it is an important position. It is. What they show
   is a methyl up, you can see it, R6 is methyl in all
   cases and a hydroxyl down in all cases. This ends
   up with a total of five compounds.
J.A. 37554 at 1612:4–1613:7.
    A patent specification must “contain a written descrip-
tion of the invention, and of the manner and process of
making and using it, in such full, clear, concise, and exact
terms as to enable any person skilled in the art to which it
pertains . . . to make and use the same.” 35 U.S.C. § 112
para. 1. It was undisputed that the ’597 specification did
not describe and enable products other than those whose
synthesis and antiviral properties were shown in the
12      IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




specification, all of which had the narrow formula of three
OH groups and a CH3 group as pictured. A reasonable jury
could have so viewed the claims. “Courts are not free to
reweigh the evidence and set aside the jury verdict merely
because the jury could have drawn different inferences or
conclusions or because judges feel that other results are
more reasonable.” Tennant v. Peoria & P.U. Ry. Co., 321
U.S. 29, 35 (1944).
    Based on the evidence, a reasonable jury could have
found that the claims are directed to the subject matter
that was described and evaluated. “Our appellate role ends
when there is shown to be substantial evidence, on the rec-
ord as a whole, as could have been accepted by a reasonable
jury as probative of the issue.” Nat’l Presto Indus., Inc. v.
West Bend Co., 76 F.3d 1185, 1192 (Fed. Cir. 1996). My
colleagues err in holding that the ’597 claims are invalid
unless the billons or millions or thousands of variants are
synthesized and shown to have antiviral activity. The evi-
dence could reasonably support a jury finding that the
claims are of the scope that is described and enabled in con-
formity with section 112. From my colleagues’ contrary
ruling, I respectfully dissent.
                             II
     The basis of this litigation is Idenix’s complaint that
the ’597 patent is infringed by the Gilead product sofos-
buvir, which has a fluorine substituent in the 2'-down po-
sition, as follows:
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.            13



    The issue in litigation was whether this product in-
fringes the ’597 claims. Gilead presented extensive testi-
mony and argument on this question. For example, there
was testimony that this product could not be made by the
procedures in the ’597 specification. There was testimony
that an Idenix scientist had tried and failed to synthesize
this fluorine-containing molecule.       J.A. 37402–03 at
1178:2–1179:20. A witness testified that attaching fluorine
to a nucleoside is “very tricky,” for “it could lead to com-
pounds that explode.” J.A. 37279 at 836:12–837:1. There
was testimony that it was known that 2'-F nucleosides
were toxic. J.A. 37196 at 696:6–10, J.A. 37286 at 866:5–
14, J.A. 37327 at 1030:7–22. There was testimony about
stereochemical doubts that this molecule could be pro-
duced. J.A. 37314 at 976:22–977:13, J.A. 37319 at 998:6–
999:23.
     It is pointed out that fluorine is conspicuously omitted
from the list of halogen substituents at 2'-down in several
of the general “Formulas” in the ’597 specification. Gilead
Br. at 68–69 (citing ’597 patent, col. 10, ll. 42–55, col. 12,
ll. 5–12, col. 12, ll. 55–61). It is pointed out that Idenix lost
an interference contest on this specific molecule. Gilead
Br. at 1 (citing Storer v. Clark, 860 F.3d 1340 (Fed. Cir.
2017)).
    The panel majority states that this aspect was “not ad-
vanced by Idenix at trial or before us.” Maj. Op. at 7–8 n.3.
However, Gilead did advance this aspect at trial, and ar-
gues it on this appeal. At the trial Gilead presented evi-
dence with respect to the 2'-down fluorine substituent, as I
have outlined, and on appeal Gilead devotes a substantial
portion of its brief to the argument that its fluorinated com-
pound is not within the scope of correctly construed claims.
The issue was not waived, although the Supreme Court has
recognized that even issues that were waived may be con-
sidered on appeal. The Court has explained:
14       IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.




     Nor did prudence oblige the Court of Appeals to
     treat the unasserted argument . . . as having been
     waived. . . . [A] court may consider an issue “ante-
     cedent to . . . and ultimately dispositive of” the dis-
     pute before it, even an issue the parties fail to
     identify and brief. . . . [A] court “need not render
     judgment on the basis of a rule of law . . . simply
     because the parties agree upon it.”
U.S. Nat’l Bank of Or. v. Indep. Ins. Agents of Am., 508 U.S.
439, 447 (1993) (quoting Arcadia v. Ohio Power Co., 498
U.S. 73, 77 (1990) and United States v. Burke, 504 U.S. 229,
246 (1992) (Scalia, J., concurring in judgment)).
    The judicial responsibility and authority are to assure
that the correct law is applied. Contrary to my colleagues’
position, the Court admonishes that:
     Rules of practice and procedure are devised to pro-
     mote the ends of justice, not to defeat them. A rigid
     and undeviating judicially declared practice under
     which courts of review would invariably and under
     all circumstances decline to consider all questions
     which had not previously been specifically urged
     would be out of harmony with this policy. Orderly
     rules of procedure do not require sacrifice of the
     rules of fundamental justice.
Hormel v. Helvering, 312 U.S. 552, 557 (1941); see Single-
ton v. Wulff, 428 U.S. 106, 121 (1976) (“The matter of what
questions may be taken up and resolved for the first time
on appeal is one left primarily to the discretion of the courts
of appeals, to be exercised on the facts of individual
cases. We announce no general rule.”).
    The Federal Circuit has so recognized. See Wilson v.
Principi, 391 F.3d 1203, 1211 (Fed. Cir. 2004) (“The Court
stated that such instances should be based on ‘particular
circumstances which will prompt a reviewing or appellate
court, where injustice might otherwise result, to consider
IDENIX PHARMACEUTICALS LLC v. GILEAD SCIENCES INC.        15



questions of law which were neither pressed nor passed
upon . . . below.’ The matter is one left largely to the dis-
cretion of the court of appeals.” (quoting Hormel, 312 U.S.
at 557)). On appeal, our responsibility is to the law, and
just conduct of the appeal.
    There was substantial evidence that Gilead’s fluori-
nated product is not within the scope of the claims as they
reasonably could have been viewed by the jury. The jury
verdict of validity under section 112 is in accordance with
law and supported by substantial evidence. I would decide
this appeal on the ground that the claims, correctly con-
strued, are valid and not infringed. From my colleagues’
contrary rulings, I respectfully dissent.
