  United States Court of Appeals
      for the Federal Circuit
              __________________________

  ELI LILLY AND COMPANY AND TRUSTEES OF
          PRINCETON UNIVERSITY,
              Plaintiffs-Appellees,
                           v.
      TEVA PARENTERAL MEDICINES, INC.
        AND BARR LABORATORIES, INC.,
              Defendants-Appellants,
                          and
          APP PHARMACEUTICALS, LLC,
               Defendant-Appellant.
              __________________________

                   2011-1561, -1562
              __________________________

    Appeals from the United States District Court for the
District of Delaware in consolidated Case Nos. 08-CV-
0335, 08-CV-0384, 08-CV-0860, and 09-CV-0272, Chief
Judge Gregory M. Sleet.
               __________________________

  ELI LILLY AND COMPANY AND TRUSTEES OF
          PRINCETON UNIVERSITY,
              Plaintiffs-Appellees,
                           v.
          APP PHARMACEUTICALS, LLC,
               Defendant-Appellant.
ELI LILLY   v. APP PHARMA                              2


                  __________________________

                          2012-1037
                  __________________________

    Appeal from the United States District Court for the
District of Delaware in Case No. 11-CV-0628, Chief Judge
Gregory M. Sleet.
               ____________________________

                   Decided: August 24, 2012
                ____________________________

    ADAM L. PERLMAN, Williams & Connolly, LLP, of
Washington, DC, argued for plaintiff-appellee. With him
on the brief were BRUCE R. GENDERSON, KANNON K.
SHANMUGAM, DOV P. GROSSMAN, and DAVID M. KRINSKY.
Of counsel was ELLEN E. OBERWETTER.

    JOHN C. ENGLANDER, Goodwin Procter, LLP, of Bos-
ton, Massachusetts, argued for defendants-appellants.
With him on the brief were DARYL L. WIESEN and EMILY
L. RAPALINO. Of counsel on the brief were ERIC H. YECIES
and MICHAEL B. COTTLER.
              __________________________

   Before LOURIE, DYK, and WALLACH, Circuit Judges.
LOURIE, Circuit Judge.
    Appellants Teva Parenteral Medicines, Inc., Barr
Laboratories, Inc., and APP Pharmaceuticals, LLC appeal
from the judgment of the United States District Court for
the District of Delaware holding that U.S. Patent
5,344,932 (the “’932 patent”) is not invalid for obvious-
ness-type double patenting. See Eli Lilly & Co. v. Teva
Parenteral Meds. Inc., No. 08-335-GMS, 2011 U.S. Dist.
3                                    ELI LILLY   v. APP PHARMA


LEXIS 83124, 2011 WL 3236037 (D. Del. July 28, 2011).
We affirm.
                       BACKGROUND
    This patent infringement dispute concerns applica-
tions filed by several generic pharmaceutical manufactur-
ers seeking regulatory approval to market generic
formulations of the chemotherapy agent pemetrexed. To
begin, we outline the necessary background information
and procedural history, as set forth below.
                   A. Antifolate Drugs
    Folates, which include the B vitamin folic acid and its
derivatives, 1 play a critical role in nucleic acid synthesis
within human cells and, as such, are required for cell
growth and division. To that end, numerous cellular
enzymes recognize and process folates—some folate-
specific enzymes such as dihydrofolate reductase
(“DHFR”) and glycinamide ribonucleotide formyltrans-
ferase (“GARFT”) catalyze biochemical reactions impor-
tant for making both DNA and RNA, while others such as
thymidylate synthetase (“TS”) selectively affect DNA
production. 2


    1
         Although folic acid itself predominates in most
dietary supplements and fortified foods, the compound
naturally occurs in various other chemical forms includ-
ing folic acid salts and esters. For convenience, we refer
to folic acid and such related compounds collectively as
“folates.”
    2
         Purines and pyrimidines are key building blocks
in the production of both RNA and DNA. DHFR and
GARFT participate in global purine synthesis, so those
enzymes affect both DNA and RNA production. In con-
trast, TS serves only in the production of deoxythymidine
monophosphate, a pyrimidine nucleotide that is incorpo-
rated into DNA but not RNA.
ELI LILLY   v. APP PHARMA                                  4


    Given the key role of folates in DNA synthesis, and
thus in cellular replication, folate metabolism presents an
attractive target for cancer treatments because cancerous
cells characteristically exhibit rapid, unchecked division
and proliferation. Accordingly, researchers and physi-
cians have developed numerous compounds, known as
“antifolates,” intended to inhibit one or more of the folate-
specific enzymes necessary for DNA synthesis. Structur-
ally analogous to natural folates, antifolates induce initial
recognition by one or more of the folate-specific enzymes
yet contain important structural differences that prevent
the target enzyme from carrying out its normal function.
For example, the chemical structure of folic acid is repre-
sented below—highlighting key structural features in-
cluding the bicyclic core, bridge region, aryl position, and
glutamic acid domain—along with the closely related
structure of methotrexate, a well-known antifolate that
was first introduced around 1950.




                            Folic Acid
5                                    ELI LILLY   v. APP PHARMA




                      Methotrexate
    Methotrexate is used as a chemotherapy agent for
treating certain cancers, including leukemias, lympho-
mas, and osteosarcoma, among others. In addition to its
anticancer effects, however, methotrexate, like many
antifolates, exhibits significant toxicity due to deleterious
effects on non-cancerous, healthy cells. Such toxicity is
thought to arise at least in part because methotrexate
primarily inhibits DHFR and therefore substantially
impairs DNA and RNA synthesis. While DNA synthesis
is of principal importance for actively dividing cells (e.g.,
cancer cells), ongoing RNA synthesis is necessary for
essentially all living cells in the body. Methotrexate and
other antifolate drugs that inhibit both the DNA and RNA
synthesis pathways are thus prone to undesirable off-
target effects.
    In the 1980s, researchers sought to develop anti-
folates capable of inhibiting TS, which would selectively
impede DNA synthesis and presumably mitigate the
toxicity issues associated with methotrexate and other
then-existing antifolates. One such effort led by Prof.
Edward Taylor, a chemist at Princeton University,
yielded pemetrexed, the antifolate at the heart of this
appeal:
ELI LILLY   v. APP PHARMA                                 6




                            Pemetrexed
As with methotrexate, pemetrexed exhibits some struc-
tural similarity to folic acid. One key difference that
distinguishes pemetrexed from folic acid and meth-
otrexate is that pemetrexed contains a pyrrolo[2,3-
d]pyrimidine bicyclic core, characterized by a five-member
ring fused with a six-member ring, rather than the dual
six-member rings found in the pteridine cores of folic acid
and methotrexate. After synthesizing pemetrexed, the
Princeton group collaborated with researchers at Eli Lilly
to test the new compound for antifolate activity, and the
results soon revealed that pemetrexed acts as a potent
inhibitor of TS. Princeton and Eli Lilly (together, “Lilly”)
thereafter began exploring for related compounds with
similar activity as TS inhibitors and pursuing preclinical
and clinical studies to evaluate promising candidates for
therapeutic use.
    Among the many pemetrexed-related compounds that
were developed and tested, pemetrexed itself proved to be
the best therapeutic candidate and ultimately won FDA
approval in 2004 for use in treating mesothelioma and
then in 2008 for treatment of non-small cell lung cancer.
7                                   ELI LILLY   v. APP PHARMA


Lilly manufactures and distributes pemetrexed under the
brand name Alimta®.
                    B. Lilly’s Patents
    In conjunction with their antifolate research, the in-
ventors filed U.S. patent application 07/448,742 (the “’742
application”) on December 11, 1989. The ’742 application
disclosed and claimed pemetrexed as well as a broader
group of related antifolates containing pemetrexed’s
characteristic core structure.      The ’742 application,
though itself eventually abandoned, founded a family of
related applications that ultimately yielded the three
patents at issue in this appeal.
    The ’932 patent issued on September 6, 1994, from an
application filed on March 22, 1991, claiming priority
from the ’742 application through a series of continua-
tions. Claim 3 of the ’932 patent claims pemetrexed.
Claims 1, 2, and 7 are generic, Markush-style claims that
encompass pemetrexed as well as other structurally
related antifolates.
    U.S. Patent 5,028,608 (the “’608 patent”) issued on
July 2, 1991, from an application filed on May 24, 1990, as
a continuation-in-part of the ’742 application. The ’608
patent claims, inter alia, an antifolate (the “’608 Com-
pound”) that differs from pemetrexed only in its aryl
region—the ’608 Compound contains a five-member
thiophene ring in place of pemetrexed’s six-member
benzene ring. 3




    3
       The parties use the expressions “thienyl group”
and “phenyl group”; accordingly, we will also.
ELI LILLY   v. APP PHARMA                                8




                    The ’608 Compound
    U.S. Patent 5,248,775 (the “’775 patent”) issued on
September 28, 1993, from an application filed January 31,
1992, as a continuation-in-part of the application that led
to the ’932 patent. The ’775 patent discloses a family of
chemical intermediates that can be used to make a vari-
ety of antifolates, including pemetrexed, that contain a
pyrrolo[2,3-d]pyrimidine bicyclic core. Among others, the
’775 patent claims a compound (the “’775 Intermediate”)
that is used as an intermediate in one method for making
pemetrexed. The ’775 Intermediate differs from pe-
metrexed in having a carbon-carbon triple bond in its
bridge region and three protecting groups at substituent
positions in its core and glutamate domains. 4 In addition,

    4
        Protecting groups are selectively reversible
chemical modifications often used to prevent unwanted
side reactions during multistep organic syntheses. In
general, protecting groups are introduced at one or more
particularly reactive positions in a complex molecule to
stabilize or “protect” those parts of the molecule during
later chemical manipulation of other target sites. Once a
desired modification has been achieved elsewhere in the
molecule, the protecting groups can be removed to recon-
stitute a reactive substituent at each protected position.
The ’775 Intermediate contains a pivaloyl protecting
group (denoted “t-BuCO”) in its core region and two
methyl ester protecting groups (denoted “OMe”) in its
glutamate domain.
9                                     ELI LILLY   v. APP PHARMA


Examples 6 and 10 of the ’775 patent disclose reduction
and hydrolysis reactions, respectively, that could together
be used to derive pemetrexed from the ’775 Intermediate.
’775 patent col. 9, l. 59 – col. 10, l. 5; col. 12, ll. 51–66.




                 The ’775 Intermediate
    The ’932, ’608, and ’775 patents were assigned to the
Trustees of Princeton University and exclusively licensed
to Eli Lilly. The ’608 and ’775 patents have expired, but
the ’932 patent remains in effect until July 24, 2016, due
to a patent term extension of over four years to compen-
sate for delays in the regulatory approval of Alimta®. See
35 U.S.C. § 156. Lilly holds a further six months of
market exclusivity over pemetrexed pursuant to 21 U.S.C.
§ 355a.
               C. District Court Proceedings
     Teva Parenteral Medicines, Inc., Barr Laboratories,
Inc., and APP Pharmaceuticals, LLC (collectively, “Teva”)
filed abbreviated new drug applications (“ANDAs”) seek-
ing approval to manufacture and sell generic versions of
Alimta® before the expiration of the ’932 patent. Those
ANDAs each included a Paragraph IV certification assert-
ing that the ’932 patent was invalid, unenforceable, or
would not be infringed by the proposed generic products.
ELI LILLY   v. APP PHARMA                                  10


See 21 U.S.C. § 355(j)(2)(A)(vii)(IV). In response, Lilly
brought suit in the United States District Court for the
District of Delaware, alleging infringement of claims 1, 2,
3, and 7 of the ’932 patent pursuant to 35 U.S.C.
§ 271(e)(2)(A).
    During the proceedings, Teva conceded infringement
but maintained that the asserted claims of the ’932 patent
were invalid for obviousness-type double patenting over
two earlier-issued claims: (1) claim 3 of the ’608 patent,
which claims the ’608 Compound, and (2) claim 7 of the
’775 patent, which claims the ’775 Intermediate.
    Regarding the ’608 Compound, Teva presented evi-
dence that various antifolates known at the time of the
invention contained a phenyl group in the aryl position,
and Teva contended that it would have been obvious to
incorporate a phenyl group into the ’608 Compound
consistent with such “conventional wisdom” in the field.
As to the ’775 Intermediate, Teva argued that the as-
serted claims of the ’932 patent constitute a use for the
’775 Intermediate—i.e., synthesizing pemetrexed—that
had already been disclosed in the specification of the
earlier-issued ’775 patent, rendering such claims invalid
for obviousness-type double patenting. In addition, Teva
argued that even ignoring the specification of the ’775
patent, an ordinarily skilled chemist presented with the
’775 Intermediate immediately would have recognized
pemetrexed as an obvious potential end product.
    Following a bench trial, the district court rejected
Teva’s arguments and held that claims 1, 2, 3, and 7 of
the ’932 patent were not invalid for obviousness-type
double patenting over either the ’608 Compound or the
’775 Intermediate. Eli Lilly, 2011 WL 3236037, at *2–4.
Specifically, the district court rejected Teva’s “focus[] only
on the aryl region of the [’608 Compound] in isolation,”
11                                  ELI LILLY   v. APP PHARMA


finding persuasive other evidence indicating that one of
skill in the art would have pursued changes outside of the
aryl region to improve TS inhibition and would have
avoided introducing a phenyl group into the ’608 Com-
pound based on previous reports of toxicity with analo-
gous antifolate structures. Id. at *4. The district court
also declined to hold the asserted claims invalid over the
’775 Intermediate. The court held (1) that the ’932 patent
“does not claim the use of the [’775 Intermediate],” so the
teachings from the ’775 patent’s specification were inap-
plicable to its obviousness-type double patenting analysis,
and (2) that pemetrexed would not have been obvious
from the structure of the ’775 Intermediate because,
among many possible choices, a person of ordinary skill
would not have made the structural changes necessary to
derive pemetrexed. Id. at *2–3.
    Accordingly, the district court entered a final judg-
ment in Lilly’s favor and enjoined approval of Teva’s
proposed generic pemetrexed products until after the
expiration of Lilly’s exclusive rights on January 24, 2017.
Eli Lilly & Co. v. Teva Parenteral Meds. Inc., Nos. 08-335-
GMS, 08-384-GMS, 08-860-GMS, and 09-272-GMS (D.
Del. Aug. 22, 2011) (Am. Final J. Order), ECF No. 115.
Teva timely appealed, and we have jurisdiction under 28
U.S.C. § 1295(a)(1). 5

     5
         After trial, individual appellant APP Pharmaceu-
ticals supplemented its ANDA to add a further Paragraph
IV certification relating to a particular pemetrexed dosage
form. Appellees initiated a new infringement suit to
address APP’s supplemental ANDA filing, and the parties
agreed to be bound in that action by any judgment in the
antecedent litigation. Accordingly, following its August
22, 2011, judgment in favor of Lilly, the district court
entered a stipulated judgment against APP as to its
supplemental ANDA filing. Eli Lilly & Co. v. APP
Pharm., LLC, No. 11-628-GMS (D. Del. Oct. 17, 2011)
ELI LILLY   v. APP PHARMA                                 12


                            DISCUSSION
    The sole disputed issue in this appeal is whether the
asserted claims of the ’932 patent are invalid for obvious-
ness-type double patenting. The doctrine of obviousness-
type double patenting is intended to “prevent the exten-
sion of the term of a patent . . . by prohibiting the issu-
ance of the claims in a second patent not patentably
distinct from the claims of the first patent.” In re Longi,
759 F.2d 887, 892 (Fed. Cir. 1985). “A later patent claim
is not patentably distinct from an earlier claim if the later
claim is obvious over, or anticipated by, the earlier claim.”
Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 968 (Fed.
Cir. 2001). As with statutory obviousness under 35
U.S.C. § 103, obviousness-type double patenting is an
issue of law premised on underlying factual inquiries.
Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1290
(Fed. Cir. 2012). Accordingly, we consider the district
court’s ultimate conclusion on obviousness-type double
patenting without deference, but we review any predicate
findings of fact for clear error. Id.
                    A. The ’608 Compound
    We first address the ’608 Compound. Claim 3 of the
’608 patent recites the ’608 Compound, an antifolate that
is structurally related to pemetrexed but never advanced
to clinical use. As described, the ’608 patent issued in
July 1991, more than three years before the ’932 patent
issued with its claims covering pemetrexed. The question,
then, is whether the asserted claims of the ’932 patent are


(Stipulation and J. Order), ECF No. 10. We granted
APP’s unopposed motion to consolidate that action with
the related matters on appeal. Eli Lilly & Co. v. Teva
Parenteral Meds. Inc., Nos. 2011-1561, -1562, 2012-1037
(Fed. Cir. Nov. 29, 2011) (Order Consolidating Appeals).
13                                   ELI LILLY   v. APP PHARMA


patentably distinct from Lilly’s earlier-issued claim to the
’608 Compound.
    On appeal, Teva contends that the district court erred
by failing to invalidate the claims for obviousness-type
double patenting. Teva’s primary argument concerns the
appropriate legal standard for evaluating obviousness-
type double patenting. Relying on our decision in Amgen
Inc. v. Hoffmann-La Roche Ltd., 580 F.3d 1340 (Fed. Cir.
2009), Teva contends that the correct analysis involves
only the differences between the claims at issue, so that
any features held in common between the claims—in this
case, all but the aryl regions of the ’608 Compound and
pemetrexed—would be excluded from consideration. In
Amgen, we explained that once the differences between
claims are established, the obviousness-type double
patenting analysis entails determining “whether the
differences in subject matter between the claims render
the claims patentably distinct.” 580 F.3d at 1361. But
those differences cannot be considered in isolation—the
claims must be considered as a whole. Amgen expressly
noted that “[t]his part of the obviousness-type double
patenting analysis is analogous to an obviousness analy-
sis under 35 U.S.C. § 103.” Id. And just as § 103(a)
requires asking whether the claimed subject matter “as a
whole” would have been obvious to one of skill in the art,
so too must the subject matter of the ’932 claims be con-
sidered “as a whole” to determine whether the ’608 Com-
pound would have made those claims obvious for purposes
of obviousness-type double patenting. Gen. Foods Corp. v.
Studiengesellschaft Kohle mbH, 972 F.2d 1272, 1278 (Fed.
Cir. 1992) (“Claims must be read as a whole in analyzing
a claim of double patenting.”). Thus, the district court did
not err by examining whether one of ordinary skill in the
art would have been motivated to modify the ’608 Com-
ELI LILLY   v. APP PHARMA                                 14


pound to create pemetrexed, considering the compounds
as a whole.
    On the merits, Teva also disputes the district court’s
findings and conclusions in view of the evidence pre-
sented. Specifically, Teva contends (1) that placing a
phenyl group in the aryl position represented inescapable
“conventional wisdom” in the field based on antifolate
structures known at the time, (2) that the district court
erred in finding that one of skill in the art would have
considered a phenyl group undesirable within the struc-
tural context of the ’608 Compound, and (3) that the
district court erred by discounting its theory that princi-
ples of bioisosterism 6 would have suggested replacing the
’608 Compound’s thienyl with phenyl.
    Lilly defends the district court’s findings, arguing that
the evidence amply supported the court’s view that a
person of ordinary skill would not have had reason to
manipulate the ’608 Compound to produce pemetrexed.
Lilly contended, and the district court found, that a
chemist at the time seeking to develop TS inhibitors
would have looked specifically to data from that emerging
sub-discipline rather than attempting to emulate the
“conventional” antifolates highlighted by Teva. In fact,
according to Lilly, the contemporary experience and
understanding in the TS field not only would have failed
to suggest substituting a phenyl group into the ’608
Compound, but earlier reports of associated inefficacy and
toxicity would have actively dissuaded one from doing so.
Finally, Lilly maintains that bioisosterism provides no


    6
         Bioisosterism refers to a process that involves re-
placing one atom or functional group in a molecule with
another of similar chemical, physical, or electronic proper-
ties in hopes that the substitution will result in similar or
enhanced activity.
15                                  ELI LILLY   v. APP PHARMA


basis for predicting whether a substituted compound will
prove more or less effective than the original.
    Based on the evidence presented at trial, we discern
no error in the district court’s findings or its conclusion
that the asserted claims are patentably distinct from the
’608 Compound. In the chemical context, we have held
that an analysis of obviousness-type double patenting
“requires identifying some reason that would have led a
chemist to modify the earlier compound to make the later
compound with a reasonable expectation of success.”
Otsuka, 678 F.3d at 1297. Here, the district court consid-
ered the parties’ arguments and evidence, particularly
their conflicting expert testimony as to how an ordinarily
skilled chemist presented with the ’608 Compound would
have been motivated to proceed at the time. In its deci-
sion, the court credited Lilly’s evidence to find that “the
ways in which a person of ordinary skill in the art would
modify [the ’608 Compound] would not result in pe-
metrexed.” Eli Lilly, 2011 WL 3236037, at *4. We owe
that finding considerable deference on appeal, and we see
no clear error based on the record before us. Moreover, a
complicated compound such as the ’608 Compound pro-
vides many opportunities for modification, but the district
court did not find that substituting a phenyl group into
the aryl position was the one, among all the possibilities,
that would have been successfully pursued. Thus, absent
any motivation to derive pemetrexed from the ’608 Com-
pound or reason to expect success in doing so, the district
court correctly concluded that the asserted claims were
not invalid for obviousness-type double patenting over the
’608 Compound.
                B. The ’775 Intermediate
    As with the ’608 Compound, Lilly’s claim covering the
’775 Intermediate was issued before the ’932 patent. As
ELI LILLY   v. APP PHARMA                               16


an independent basis for holding the ’932 claims invalid
for obviousness-type double patenting, Teva similarly
contends that pemetrexed is not patentably distinct from
the ’775 Intermediate.
    Teva’s arguments regarding the ’775 Intermediate can
be summarized as follows. According to Teva, the ’775
Intermediate is used to make pemetrexed, and Lilly
disclosed that use in the ’775 patent. By later claiming
pemetrexed itself, Teva maintains, the ’932 patent appro-
priates a previously disclosed use for a previously pat-
ented compound, which renders the asserted ’932 claims
invalid for obviousness-type double patenting under a line
of our precedent including In re Byck, 48 F.2d 665 (CCPA
1931), and Sun Pharmaceutical Industries, Ltd. v. Eli
Lilly & Co., 611 F.3d 1381 (Fed. Cir. 2010). We conclude
that Teva’s reliance on Byck, Sun, and related cases is
unsound and that the district court did not err when it
upheld the asserted claims of the ’932 patent over the ’775
Intermediate.
    As a general rule, obviousness-type double patenting
determinations turn on a comparison between a pat-
entee’s earlier and later claims, with the earlier patent’s
written description considered only to the extent neces-
sary to construe its claims. E.g., In re Avery, 518 F.2d
1228, 1232 (CCPA 1975). This is so because the non-
claim portion of the earlier patent ordinarily does not
qualify as prior art against the patentee and because
obviousness-type double patenting is concerned with the
improper extension of exclusive rights—rights conferred
and defined by the claims. The focus of the obviousness-
type double patenting doctrine thus rests on preventing a
patentee from claiming an obvious variant of what it has
previously claimed, not what it has previously disclosed.
See generally Gen. Foods, 972 F.2d at 1280–82.
17                                    ELI LILLY   v. APP PHARMA


    The cases on which Teva relies represent a limited ex-
ception to this customary framework. In Byck, our prede-
cessor court considered obviousness-type double patenting
rejections against claims to an insulated coil made up of a
conductive winding material coated with an “infusible,
flexible, phenol-fatty oil composition.” 48 F.2d at 665.
The patent applicant, Byck, had earlier obtained a patent
claiming the same phenol-oil composition, and the prior
art disclosed similar coils coated with other insulating
compositions. Id. at 665–66. Moreover, Byck’s earlier
patent had discussed using his phenol-oil composition to
produce adherent insulating films on metal substrates.
Id. at 666. The court concluded that, in view of the prior
art and Byck’s earlier patent, the pending claims were
drawn not to a second, distinct invention “but only . . . an
obvious use of the composition there patented.” Id. The
court explained:
     It would shock one’s sense of justice if an inventor
     could receive a patent upon a composition of mat-
     ter, setting out at length in the specification the
     useful purposes of such composition, manufacture
     and sell it to the public, and then prevent the pub-
     lic from making any beneficial use of such product
     by securing patents upon each of the uses to
     which it may be adapted.
Id. Thus, even though Byck’s earlier patent was not prior
art, the court held that its disclosure of an intended use
for the previously claimed phenol-oil composition could be
used in the obviousness-type double patenting analysis to
reject a later claim directed to that use of the same com-
pound. Id. at 667.
    A trio of our more recent decisions applied the same
exception to allow limited consideration of teachings in an
earlier-issued patent’s specification. In Geneva Pharma-
ELI LILLY   v. APP PHARMA                                 18


ceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373
(Fed. Cir. 2003), the plaintiff had patented methods of
using clavulanic acid to mitigate antibiotic resistance
when treating bacterial infections. The plaintiff then
acquired a preexisting patent that claimed clavulanic acid
compositions and disclosed their utility for treating pa-
tients harboring antibiotic-resistant bacteria. Id. at 1377,
1385. In that case, we relied on Byck to hold the plain-
tiff’s method claims invalid for double patenting: “Our
predecessor court recognized that a claim to a method of
using a composition is not patentably distinct from an
earlier claim to the identical composition in a patent
disclosing the identical use.” Id. at 1385–86 (citing Byck,
48 F.2d at 666). Similarly, in Pfizer, Inc. v. Teva Pharma-
ceuticals USA, Inc., 518 F.3d 1353, 1363 (Fed. Cir. 2008),
we held claims to methods of administering a particular
anti-inflammatory drug invalid for obviousness-type
double patenting where the patentee’s earlier patent
claimed the drug itself and disclosed the same methods of
administering the drug. And in Sun, the patent holder
had developed an antiviral compound, gemcitabine, that
also proved useful for treating cancer. An initial patent
issued with composition claims covering gemcitabine as
well as method claims drawn to using the drug to treat
herpesvirus infections; also mentioned in the specifica-
tion, but not claimed, was gemcitabine’s potential anti-
cancer activity. Sun, 611 F.3d at 1383. As in Geneva and
Pfizer, we held the patentee’s subsequent claims to meth-
ods of using gemcitabine to treat cancer invalid for double
patenting, looking to the disclosure of anticancer utility in
the first patent’s specification. Id. at 1386–89.
    Byck, Geneva, Pfizer, and Sun thus “address the
situation in which an earlier patent claims a compound,
disclosing the utility of that compound in the specifica-
tion, and a later patent claims a method of using that
19                                   ELI LILLY   v. APP PHARMA


compound for a particular use described in the specifica-
tion of the earlier patent.” Sun, 611 F.3d at 1389. Fur-
thermore, in each of those cases, the claims held to be
patentably indistinct had in common the same compound
or composition—that is, each subsequently patented “use”
constituted a, or the, disclosed use for the previously
claimed substance.
     That is not the case before us. Rather than a compo-
sition and a previously disclosed use, the claims at issue
recite two separate and distinct chemical compounds: the
’775 Intermediate and pemetrexed, differing from each
other in four respects. That alone suffices to undermine
Teva’s argument regarding the ’775 Intermediate, for the
asserted claims of the ’932 patent do not recite a use of the
same compound, but a different compound altogether.
The cited cases therefore do not govern.
    Furthermore, even if one composition could somehow
be considered a “use” of another, the record makes clear
that, unlike in the cited cases, Lilly’s successive claims
are wholly independent of one another. For example,
pemetrexed and the ’775 Intermediate exhibit substantial
structural differences, and neither embodies or subsumes
the other. Moreover, pemetrexed can be made via any of
several synthetic techniques, many of which do not in-
volve the ’775 Intermediate. The ’775 Intermediate and
pemetrexed are thus separate and independent chemical
compounds; Lilly’s original claim to the ’775 Intermediate
offered no protection for pemetrexed, and its claims to
pemetrexed do not incorporate or require use of the ’775
Intermediate. The particular concerns motivating our
prior decisions are thus absent here. In sum, although
the specification of the ’775 patent discloses one method
for deriving pemetrexed using the ’775 Intermediate, we
agree with the district court’s conclusion that that disclo-
ELI LILLY   v. APP PHARMA                                20


sure does not render Lilly’s claims to pemetrexed invalid
for obviousness-type double patenting.
    As the district court recognized, the correct double
patenting analysis in this case turns on an evaluation of
what Lilly has claimed, not what it has disclosed. Putting
aside the teachings in the ’775 patent’s specification,
Teva’s double patenting contentions evaporate.          The
evidence of record characterizes the ’775 Intermediate as
a versatile compound from which a skilled chemist could
derive innumerable final products beyond just pe-
metrexed, and the district court found that there would
have been “no reason” to pursue pemetrexed among the
various other avenues that would have been considered
possible at the time. We see no error in the district
court’s findings or its conclusion on this point, and, al-
though not controlling, we further note that its analysis
comports with PTO guidelines on the patentability of
related products. See Manual of Patent Examining Pro-
cedure § 806.05(j) (8th ed., rev. 8, 2010) (“[A]n intermedi-
ate product and a final product can be shown to be
distinct inventions if the intermediate and final products
are mutually exclusive inventions (not overlapping in
scope) that are not obvious variants, and the intermediate
product as claimed is useful to make other than the final
product as claimed.”). In sum, the district court correctly
concluded that the asserted claims are not invalid for
obviousness-type double patenting over the ’775 Interme-
diate.
            C. Objective Indicia of Nonobviousness
     Finally, Lilly presented evidence at trial that pe-
metrexed exhibited unexpected clinical properties and
achieved considerable commercial success. But the dis-
trict court disregarded that evidence, holding that “secon-
dary considerations are not relevant to the analysis of
21                                  ELI LILLY   v. APP PHARMA


invalidity for obviousness-type double patenting.” Eli
Lilly, 2011 WL 3236037, at *1 n.1. For that proposition,
the district court relied on a footnote in Geneva, in which
we remarked only that inquiry into secondary considera-
tions is not required in every obviousness-type double
patenting analysis, not that such evidence is off-limits or
irrelevant. See Geneva, 349 F.3d at 1378 n.1. The district
court’s categorical repudiation of Lilly’s evidence was
therefore erroneous. When offered, such evidence should
be considered; a fact-finder “must withhold judgment on
an obviousness challenge until it has considered all rele-
vant evidence, including that relating to the objective
considerations.” In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litig., 676 F.3d 1063,
1079 (Fed. Cir. 2012). Given that the district court none-
theless rejected Teva’s double patenting arguments,
however, such error was, in this instance, harmless.
                       CONCLUSION
    In view of the foregoing, we hold that the asserted
claims of the ’932 patent are not invalid for obviousness-
type double patenting over claim 3 of the ’608 patent or
claim 7 of the ’775 patent. We have considered each of
Teva’s remaining arguments and find them unpersuasive.
Accordingly, the judgment of the district court is
                      AFFIRMED
