  United States Court of Appeals
      for the Federal Circuit
                ______________________

    ALLERGAN, INC., AND DUKE UNIVERSITY,
              Plaintiffs-Appellees,

                           v.

APOTEX INC., APOTEX CORP., SANDOZ, INC., AND
      HI-TECH PHARMACAL CO., INC.,
             Defendants-Appellants.
             ______________________

                2013-1245, -1246, -1247
                ______________________

   Appeals from the United States District Court for the
Middle District of North Carolina in Nos. 10-CV-0681, 11-
CV-0298, and 11-CV-0650, Judge Catherine C. Eagles.
                 ______________________

            -------------------------

    ALLERGAN, INC., AND DUKE UNIVERSITY,
              Plaintiffs-Appellees,

                           v.

 WATSON PHARMACEUTICALS, INC., now known
 as Actavis, Inc., WATSON LABORATORIES, INC.,
           AND WATSON PHARMA, INC.,
                Defendants-Appellants.
                ______________________

                       2013-1249
2                             ALLERGAN, INC.   v. APOTEX INC.



                 ______________________

   Appeal from the United States District Court for the
Middle District of North Carolina in No. 12-CV-0321,
Judge Catherine C. Eagles.
                ______________________

                 Decided: June 10, 2014
                 ______________________

    JONATHAN E. SINGER, Fish & Richardson P.C., of Min-
neapolis, Minnesota, argued for plaintiffs-appellees. With
him on the brief were DEANNA J. REICHEL; and JUANITA R.
BROOKS, of San Diego, California.         Of counsel was
JEFFREY T. THOMAS, Gibson, Dunn & Crutcher, LLP, of
Irvine, California.

    DEANNE M. MAZZOCHI, Rakoczy Molino Mazzochi
Siwik LLP, of Chicago, Illinois, argued for defendants-
appellants Apotex Inc., et al. With her on the brief were
WILLIAM A. RAKOCZY, PAUL J. MOLINO, and ANDREW M.
ALUL, for Apotex Inc., et al; MEREDITH MARTIN ADDY,
THOMAS FILARSKI, and BRANDON C. HELMS, Steptoe &
Johnson LLP, of Chicago, Illinois, for Sandoz Inc.; STEVEN
ROTH, Hi-Tech Pharmacal Co., Inc., of Amityville, New
York, and THOMAS J. VETTER, Lucas & Mercanti, LLP, of
New York, New York, for Hi-Tech Pharmacal Co., Inc.;
and GARY E. HOOD, ROBYN H. AST and MARK T. DEMING,
Polsinelli PC, of Chicago, Illinois for Watson Pharmaceu-
ticals, Inc., et al. Of counsel were LUKE T. SHANNON and
HARVEN V. DESHIELD, Locke Lord LLP, of Chicago, Illi-
nois, for Apotex Inc., et al.
                    ______________________
ALLERGAN, INC.   v. APOTEX INC.                          3



  Before PROST, ∗ Chief Judge, REYNA and CHEN, Circuit
                         Judges.
Opinion for the court filed by Chief Judge PROST. Opinion
     dissenting in part filed by Circuit Judge CHEN.
PROST, Chief Judge.
     Apotex Inc., Apotex Corp., Sandoz, Inc., Hit-Tech
Pharmacal Co., Inc., Actavis, Inc., Watson Laboratories,
Inc., and Watson Pharma, Inc. (collectively “appellants”)
appeal from a final judgment of the U.S. District Court for
the Middle District of North Carolina finding that appel-
lants had infringed claims of U.S. Patent Nos. 7,388,029
(“’029 patent”) and 7,351,404 (“’404 patent”) and had
failed to establish they were invalid. For the reasons
stated below, we reverse the district court’s findings with
respect to the validity of each patent.
                         BACKGROUND
    Plaintiff-appellee Allergan, Inc. (“Allergan”) has U.S.
Food and Drug Administration (FDA) approval to sell
Latisse®, a 0.03% bimatoprost ophthalmic solution, as a
topical solution to treat hypotrichosis (i.e., hair loss or
reduction) of the eyelashes by stimulating hair growth.
    Bimatoprost is a synthetic prostaglandin F-2-alpha
(“PGF”) analog. Prostaglandins are naturally occurring
molecules that bind to receptors on the surface of cells.
When prostaglandins bind to a cell’s receptors, they
generate signals that change the way that the cell func-
tions, for example, by controlling cell growth. Because of
the ability of prostaglandins to control cell properties,
they are significant targets for pharmaceutical research
in a variety of areas. PGF is a particular type of prosta-
glandin that binds with the FP receptor.


   ∗
       Sharon Prost assumed the position of Chief Judge
on May 31, 2014.
4                             ALLERGAN, INC.   v. APOTEX INC.



     The chemical structure of naturally occurring PGF is
illustrated below:




    The structure includes a “cyclopentane ring” of carbon
atoms, which is illustrated above as the pentagonal
structure at the left of the diagram. Two chains of atoms
are attached to the ring. The top chain is called the
“alpha chain,” and the chain below it is called the “omega
chain.”
    By the mid-1980s, it was established that naturally
occurring PGF could alleviate intraocular pressure (IOP),
which is associated with the eye disease glaucoma. To
develop an effective treatment and minimize side effects,
scientists worked on synthesizing and testing more selec-
tive derivatives and analogs of PGF. A particular kind of
PGF analog, 17-phenyl PGF analogs, proved to be particu-
larly useful in the treatment of glaucoma. Bimatoprost is
one such synthetic 17-phenyl PGF analog, which emerged
in the course of research by Allergan scientists. In 2001,
Allergan received FDA approval to sell Lumigan®, a
0.03% bimatoprost ophthalmic solution—identical to
Latisse®—as an eyedrop to treat glaucoma, which it
continues to market.
    Hair loss treatment was another area in which certain
PGF analogs proved useful. In the 1990s, Dr. Murray
Johnstone performed studies on latanoprost, another kind
of 17-phenyl analog. Latanoprost optical solution also
received FDA approval for use in glaucoma treatment,
and it continues to be marketed as Xalatan®. Dr. John-
stone observed that in the course of treating glaucoma
patients with latanoprost eyedrops, a substantial fraction
ALLERGAN, INC.   v. APOTEX INC.                           5



of them grew much longer and denser eyelash hair. Dr.
Johnstone filed a patent application on the use of latano-
prost and other 17-phenyl PGF analogs to promote hair
growth in February 1997.
    The work that led to the ’029 patent, the first of the
two patents asserted by appellees in this case, was con-
ducted by researchers at Proctor & Gamble led by Dr.
Mitchell DeLong. Dr. DeLong and his team studied the
effects of a wide range of prostaglandin compounds in
mice. In the course of their studies they observed that
administration of PGF compounds that were selective for
the FP receptor resulted in growth of longer and thicker
hair. On March 21, 2000, Dr. DeLong and others filed a
provisional patent application on the topical application of
compounds that bind the FP receptors to treat hair loss.
The ’029 patent claims priority to this provisional applica-
tion. During prosecution, in 2003, the parent application
of the ’029 patent was assigned to Duke University, and
the patent issued on June 17, 2008.
    The second patent asserted by appellees in this suit is
the ’404 patent, which is assigned to Allergan. The ’404
patent arises from observations made during the clinical
trials for Lumigan®. As had been observed for latano-
prost, glaucoma patients treated with bimatoprost
eyedrops spontaneously grew longer and thicker eyelash
hair. See ’404 patent col. 11 ll. 5-62. The ’404 patent
covers the treatment of eyelash hair loss through topical
application of bimatoprost, and it claims priority to a
provisional application filed on February 4, 2002.
    Allergan and Duke University (collectively “appel-
lees”) sued each of the appellants under 35 U.S.C.
§ 271(e)(2)(A) after they submitted Abbreviated New Drug
Applications (ANDAs) to the FDA seeking to market a
generic version of Allergan’s Latisse® product. Appellees
asserted claims 1, 8, 14, 18, and 20 of the ’029 patent and
claim 14 of the ’404 patent. After a bench trial in the
6                              ALLERGAN, INC.   v. APOTEX INC.



consolidated Hatch-Waxman action, the district court
held, inter alia, that the asserted claims of the ’029 and
’404 patents are not invalid for anticipation, obviousness,
insufficient written description, or lack of enablement,
and, moreover, that appellants infringed. Allergan, Inc. v.
Apotex, Inc., Nos. 1:10-CV-681, 1:11-CV-298, 1:11-CV-650,
2013 WL 286251, at *1 (M.D.N.C. Jan. 24, 2013). The
district court subsequently enjoined appellants, along
with any persons or entities who are in privity with
appellants or to whom appellants transfer the ANDA,
from commercial manufacture, use, offer to sell and/or
sale of the proposed products until the latest of the expi-
ration dates of the ’029 and ’404 patents. Allergan, Inc. v.
Apotex, Inc., No. 1:10-CV-681 Permanent Inj. and Final J.
2-3, ECF No. 231.
    This appeal followed, in which appellees raise issues
of claim construction for the ’029 patent, as well as the
invalidity of the asserted claims of the ’029 and ’404
patents.      We have jurisdiction under 28 U.S.C.
§ 1295(a)(1).
                       DISCUSSION
                 I. CLAIM CONSTRUCTION
    Claim construction is an issue of law that we review
de novo. Lighting Ballast Control LLC v. Philips Elecs. N.
Am. Corp., 744 F.3d. 1272, 1276-77, (Fed. Cir.) (en banc);
Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1454-55
(Fed. Cir. 1998) (en banc). In construing a claim term, we
look at the term’s plain and ordinary meaning as under-
stood by a person of ordinary skill in the art. Phillips v.
AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005) (en
banc). There is an exception to this general rule when a
patentee sets out a definition and acts as her own lexicog-
rapher. Thorner v. Sony Computer Entm’t Am., LLC, 669
F.3d 1362, 1365 (Fed. Cir. 2012).
ALLERGAN, INC.   v. APOTEX INC.                               7



    Appellants raise a single claim construction issue on
appeal concerning the ’029 patent. The ’029 patent’s
asserted claims are directed towards a method of “treat-
ing hair loss.” Appellants challenge the district court’s
construction of this term as “‘arresting hair loss, reversing
hair loss, or both and promoting hair growth’ meaning
that the invention may arrest hair loss, reverse hair loss,
or promote hair growth in the alternative.” All parties, as
well as the district court, agreed that the specification
provides an express definition for the term: “‘Treating
hair loss’ includes arresting hair loss or reversing hair
loss, or both, and promoting hair growth.” ’029 patent col.
3 ll. 29-30. Appellants argue, however, that use of the
conjunctive “and” in the inventor’s own lexicography
expressly provides that the method for treating hair loss
must both arrest or reverse hair loss, as well as also
promote hair growth. Appellants argue that under their
proposed construction, a generic version of Latisse®
would not infringe because Latisse® treats hair loss by
lengthening, thickening, and darkening existing healthy
hair—which appellants argue means only the promotion
of hair growth.
     The district court agreed with the appellees that the
use of the word “includes” in the definition of “treating
hair loss” plainly means that the patentee intended to
define treating hair loss to include the possibility of one or
all of arresting hair loss, reversing hair loss, or promoting
hair growth. Appellees argue that this comports with the
plain meaning of “treating hair loss,” which would be
understood in the art as including treatments that exclu-
sively promote hair growth. Most compellingly, even if
there may be some ambiguity in how the patentee defined
the term, numerous examples in the patent describe the
use of claimed compositions to “induce hair growth,”
“darken and thicken eyelashes,” “promote hair growth,”
and “promote eyelash growth.” See, e.g., ’029 patent at
cols. 58 ll. 17-19, 59 ll. 43-44, 59 ll. 61-62, 60 ll. 31-32, 60
8                             ALLERGAN, INC.   v. APOTEX INC.



ll. 11-12. There is nothing in either the specification or
the claims suggesting that the patentee would have
excluded these examples from the scope of claimed meth-
ods.
    Reading the patentee’s own lexicography in light of
the whole specification, we conclude that a method of
“treating hair loss” may include a method of promoting
hair growth without also arresting or reversing hair loss.
Accordingly, we affirm the district court’s construction.
                      II. INVALIDITY
                      A. ’029 Patent
                     1. Anticipation
    A patent is invalid for anticipation under 35 U.S.C.
§ 102 1 if a single prior art reference discloses each and
every limitation of the claimed invention. Schering Corp.
v. Geneva Pharm., 339 F.3d 1373, 1377 (Fed. Cir. 2003).
A single prior art reference may anticipate without dis-
closing a feature of the claimed invention if such feature
is necessarily present, or inherent, in that reference. Id.
Anticipation is a question of fact that we review for clear
error. Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1346
(Fed. Cir. 1999).
    The presumption of a patent’s validity under 35
U.S.C. § 282 can be rebutted by clear and convincing
evidence. Microsoft Corp. v. i4i Ltd. P’ship, 131 S.Ct.
2238, 2245-46 (2011). The standard of proof does not “rise
and fall with the facts of each case.” Id. at 2250. In
particular, “[w]hether a reference was previously consid-


    1   The America Invents Act (“AIA”), Pub. L. No. 112–
29, took effect on September 16, 2012. Because the appli-
cations for the patents at issue in this case were filed
before that date, we refer to the pre-AIA versions of
§§ 102 and 103.
ALLERGAN, INC.   v. APOTEX INC.                          9



ered by the PTO, the burden of proof is the same: clear
and convincing evidence of invalidity.” Sciele Pharma Inc.
v. Lupin Ltd., 684 F.3d 1253, 1259-61 (Fed. Cir. 2012).
    With respect to the ’029 patent, appellants raise two
allegedly anticipatory references: (i) the published patent
application arising from Dr. Johnstone’s aforementioned
research on promoting hair growth using latanoprost and
related compounds, and (ii) Allergan’s earlier patent on
the use of bimatoprost and related compounds to treat
glaucoma. We discuss each reference in turn.
              a. Johnstone PCT Application
    Dr. Johnstone’s research led to the filing of Interna-
tional Patent Application No. PCT/US98/02289 (“John-
stone”) on February 3, 1998. In particular, Johnstone
discloses methods for stimulating hair growth using a
broad genus of prostaglandin analogs that, among other
properties, have an alpha chain with the following struc-
ture (see Johnstone at 16 ll. 16-22):




    The cited art of the ’029 patent includes U.S. Patent
No. 6,262,105 to Johnstone, which shares its disclosure
with the Johnstone PCT application. The Johnstone PCT
application was also raised during the prosecution of
the ’029 patent. Following issue of the initial notice of
allowance, the patentee filed an amendment to add a
proviso to independent claims with the aim of expressly
excluding the compounds disclosed in Johnstone. J.A.
4130-37. The examiner accepted the amendment and
issued a notice of allowance for the patent with the claims
amended to include the provisos.
    Appellants argue that Johnstone anticipates never-
theless. As illustrated above, Johnstone expressly dis-
closes PGF structures in which the alpha chain includes a
10                            ALLERGAN, INC.   v. APOTEX INC.



double (also known as “unsaturated”) bond at the C5-C6
position, shown as a doubled line in the above diagram.
The provisos within the ’029 claim expressly exclude such
a structure. Appellants contend that even so, Johnstone
goes on to also disclose compounds with a single (also
known as “saturated”) bond at the C5-C6 position: “The
chain could preferably be a C6-C10 chain which can be
saturated or unsaturated, having one or more double
bonds, and allenes, or a triple bond.” Johnstone at 12 ll.
22-24 (emphasis added). As a result of this additional
disclosure, in appellants’ view, Johnstone also teaches a
single, or saturated, bond at the C5-C6 position, which
would not be excluded by the provisos and consequently
reads on the independent claims of the ’029 patent.
    Johnstone, however, contains no other disclosure of a
structure with a single, saturated, bond at that location.
All of the examples of Johnstone are drawn to composi-
tions in which the C5-C6 bond is a double bond. The
district court moreover agreed with appellees and found
that in the context of the state of the art, a person of
ordinary skill would not read Johnstone as disclosing a
single bond structure. The district court accepted appel-
lees’ evidence that a PGF analog with such a structure
would not have been thought to have a therapeutic effect
because it would not selectively bind to the FP receptor.
Allergan, 2013 WL 286251, at *5. The district court
further supported its determination by citing to the ’029
patent’s notice of allowance, in which the examiner indi-
cated Johnstone “lacks motivation to modify the prosta-
glandins taught therein in order to obtain the presently
claimed prostaglandins.” Id.; J.A. 5559-65 at 5564. The
district court found, therefore, that the disclosure on
which appellants rely does not “clearly and unequivocally
disclose” the use of compounds with the saturated bond.
Allergan, 2013 WL 286251, at *6 (citing Net MoneyIN,
Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir.
2008)).
ALLERGAN, INC.   v. APOTEX INC.                          11



    We are persuaded that in light of the very limited dis-
closure, the court did not commit clear error. Appellants
are correct that where a disclosure was written to provide
an optional ingredient, structure, or step, we have held
that the optional component still anticipates. See Upsher-
Smith Labs., Inc. v. Pamlab, L.L.C., 412 F.3d 1319, 1320-
21 (Fed. Cir. 2005) (“[A] prior art composition that ‘op-
tionally includes’ an ingredient anticipates a claim for the
same composition that expressly excludes that ingredi-
ent.”); Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
246 F.3d 1368, 1379 (Fed. Cir. 2001) (“[A]nticipation does
not require actual performance of suggestions in the
disclosure.”). Indeed, even if the reference discloses the
option within the context of a reference that “disparages”
or “teaches away,” we do not consider those issues in the
context of an anticipation analysis. Upsher-Smith, 412
F.3d at 1323.
    The court was not clearly erroneous, however, in its
determination that in this case, the disclosure was too
sparse and ambiguous for a person of ordinary skill to
comprehend Johnstone’s disclosure as anticipating
the ’029 patent. Net MoneyIN, 545 F.3d at 1371. Accord-
ingly, we affirm.
                        b. ’819 Patent
    U.S. Patent No. 5,688,819 (“’819 patent”) emerged
from research by Allergan scientists on selective PGF
analogs that could effectively treat glaucoma. The ’819
patent discloses the use of a set of selective PGF analogs,
including bimatoprost, which is specifically identified by
its chemical structure. ’819 patent col. 7 ll. 44-46.
The ’819 patent does not refer to hair growth or treating
hair loss, nor does it disclose topical application of any
compounds. Appellants argue, however, that because (i)
the ’819 patent’s disclosure teaches the application of
eyedrops containing compounds within the scope of the
asserted ’029 patent claims, in particular bimatoprost,
12                             ALLERGAN, INC.   v. APOTEX INC.



and (ii) the application of eyedrops containing bimato-
prost results in the growth of eyelashes, the disclosed
method inherently anticipates the ’029 patent.
    At issue is whether promoting hair growth through
topical application of bimatoprost on the skin is necessari-
ly present or inherent in the method of applying eyedrops
containing bimatoprost. 2 Schering, 339 F.3d at 1377.
There is no dispute that the application of eyedrops
containing bimatoprost can result in the promotion of
eyelash hair. Allergan’s own description of the conception
of the ’404 patent was that scientists first observed that
after monkeys were treated with bimatoprost in their
eyes, some of them showed enhanced eyelash growth.
Appellees’ Br. 13 (citing J.A. 396-98, 5617-29, 5624).
Similar results were found in clinical trials, during which
some patients who used bimatoprost eyedrops reported
eyelash growth. Id. at 15 (citing J.A. 525-33, 5855-71).
    The ’404 patent, moreover, includes as its enabling
example the administration of bimatoprost by eyedrop in
a study of patients. ’404 patent col. 10 l. 38-col. 12 l. 3.
As such, the specification recites a direct link between
eyedrop administration and the claims directed to topical
application: “the course of treatment with eye drops”
results in excess fluid gathering in the lid area, which in
turn once wiped gets to “the adjacent skin of the lid area.”
Id. at col. 10 ll. 51-56. Appellants argue that if the ’819
patent discloses a method of eyedrop administration of



     2  Not all asserted claims of the ’029 patent are lim-
ited to topical application, and irrespective of the answer
to this more narrow question, those claims may be inher-
ently anticipated by the ’819 patent’s disclosure of system-
ic administration. Appellants do not raise this issue, and
in any event, appellees assert claim 14, which is so lim-
ited.
ALLERGAN, INC.   v. APOTEX INC.                              13



bimatoprost that is sufficient to enable the claims of
the ’404 patent, then that method must also inherently
anticipate.
     The district court rejected appellants’ arguments.
The district court found that appellees’ expert witness,
Dr. Noecker, had persuasively testified that a “properly
applied drop” would not transfer to the skin. Allergan,
2013 WL 286251, at *6. The district court additionally
found that Lumigan® clinical trials only showed that a
fraction of patients experience eyelash growth. Id. The
district court found that because a bimatoprost eyedrop
only may contact skin, the ’819 patent does not inherently
anticipate as inherency “may not be established by proba-
bilities or possibilities.” Id. (citing Bettcher Indus., Inc. v.
Bunzl USA, Inc., 661 F.3d 629, 639 (Fed. Cir. 2011).
    Appellants argue that the district court erroneously
required certainty as a prerequisite for inherent anticipa-
tion. In their view, the district court should not have
relied on the finding that only some patients who received
eyedrops experienced eyelash growth.
    Appellants are correct that inherent anticipation can
be found based on a trace amount. For example, we have
held that a chemical process that produces only “trace”
amounts of a compound inherently anticipates that com-
pound. SmithKline Beecham Corp. v. Apotex Corp., 403
F.3d 1331, 1344 (Fed. Cir. 2005). All that needs to be
shown is that the outcome of the process be a “natural
result flowing from the operation as taught in the prior
art.” Id. (citing In re Oelrich, 666 F.2d 578, 581 (CCPA
1981)). We have also held that a product would be inher-
ently anticipated where it was a natural result of the
prior art process, even when it would be possible to pre-
vent the formation of the product through “extraordinary
measures.” Atlas Powder, 190 F.3d at 1349.
    We review the district court’s findings of fact on in-
herent anticipation for clear error. In this case, the
14                             ALLERGAN, INC.   v. APOTEX INC.



district court found that it was at least possible to admin-
ister eyedrops in a way as to reduce the flow of liquid to
the eye to close to zero. Cf. Glaxo Inc. v. Novopharm Ltd.,
52 F.3d 1043, 1047 (Fed. Cir. 1995). The district court
also found no express teaching in the ’819 patent that
described how fluid from the eyedrop could transfer to the
skin. MEHL/Biophile Int’l Corp. v. Milgraum, 192 F.3d
1362, 1365 (Fed. Cir. 1999). We cannot say either of these
findings, nor the conclusion that the prior art does not
necessarily include the claimed limitations, is clearly
erroneous. Accordingly, we are not persuaded that the
district court committed clear error in finding that
the ’819 patent does not inherently anticipate the claims
of the ’029 patent, and we affirm. 3
                     2. Obviousness
     Appellants alternatively allege that the aforemen-
tioned references render obvious the asserted claims of
the ’029 patent. A patent is invalid for obviousness “if the
differences between the subject matter sought to be
patented and the prior art are such that the subject
matter as a whole would have been obvious at the time
the invention was made to a person having ordinary skill
in the art to which said subject matter pertains.” 35
U.S.C. § 103(a). Obviousness is a legal conclusion based
on underlying facts. Graham v. John Deere Co., 383 U.S.
1, 17 (1966).




     3  Appellants raise the same arguments regarding
inherent anticipation of the asserted claim of the ’404
patent, which similarly claims the topical application of
bimatoprost specifically as a method of promoting eyelash
growth. We affirm the district court’s finding of no inher-
ent anticipation of the ’404 patent on the same grounds as
explained for the ’029 patent.
ALLERGAN, INC.   v. APOTEX INC.                              15



      On appeal from a bench trial, we review the underly-
ing findings of fact for clear error, and we review de novo
the court’s ultimate legal conclusion of whether the
claimed invention would have been obvious.                 Novo
Nordisk A/S v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346,
1354 (Fed. Cir. 2013). Underlying factual inquiries in-
clude (i) the scope and content of the prior art; (ii) the
differences between the prior art and the claims at issue;
(iii) the level of ordinary skill in the field of the invention;
and (iv) relevant secondary considerations including
commercial success, long-felt but unsolved needs, failure
of others, and unexpected results. KSR Int’l Co. v. Tele-
flex, Inc., 550 U.S. 398, 406 (2007); Graham, 383 U.S. at
17-18.
    The district court held that the ’029 patent was non-
obvious, based principally on its finding that there was no
motivation to combine Johnstone and the ’819 patent due
to “pharmacological differences” between the compounds
that each reference discloses. Allergan, 2013 WL 286251,
at *9. Specifically, the ’819 patent discloses a list of
thirteen chemical compositions for 17-phenyl PGF ana-
logs, which were like those disclosed in Johnstone in that
they contain a C5-C6 double bond and have demonstrably
high pharmaceutical activity in treating intraocular
pressure with minimal side effects. ’819 patent col. 3 ll. 9-
18, col. 7 ll. 19-57. However, the ’819 patent’s compounds
contain a C1-amide group whereas Johnstone generally
discloses compounds with esters or carboxylic acids at the
C1 location. The district court was persuaded by Aller-
gan’s expert that it was understood at the time of the
invention of the ’029 patent that because of this C1-amide
group, bimatoprost and the other 17-phenyl PGF analog
compositions disclosed in the ’819 patent were thought to
bind to a receptor other than the FP receptor.
   As a result, even though the ’819 patent compounds
were like the Johnstone compounds in that they were 17-
phenyl PGF analogs that had proved effective in treating
16                             ALLERGAN, INC.   v. APOTEX INC.



glaucoma, the district court agreed that a person of ordi-
nary skill would not have been motivated to use any C1-
amide compounds to treat hair loss. The district court
found that such “pharmacological differences are especial-
ly significant in the hair growth field,” as “hair growth is
and was unpredictable and mysterious,” pointing to data
that showed that certain glaucoma drugs based on pros-
taglandin analogs only result in low levels of eyelash
growth. Allergan, 2013 WL 286251, at *10. The district
court determined that secondary considerations addition-
ally weighed in favor of non-obviousness, based on its
finding that the invention of the ’029 patent was an
unexpected result (for the same reasons that it found a
lack of reasonable expectation of success), as well as the
commercial success of Latisse® and the paucity of compet-
ing hair growth treatments.
    The district court reached its conclusion of nonobvi-
ousness by looking only at properties of the C1-amide
group and, particularly, bimatoprost. In doing so, the
district court erred by failing to take into account the full
scope of the ’029 patent claims. 4 “[T]he person of ordinary



     4   The record before us does not demonstrate that
the appellants’ obviousness arguments regarding the ’029
patent were limited to the obviousness of bimatoprost.
Rather, it appears the district court failed to account for
the full scope of the ’029 patent claims despite appellants’
raising such an assertion in its pre- trial brief, post-trial
brief, and proposed findings of fact. See Letter from
Appellants, Ex. A (Excerpt of Defendants’ Amended
Proposed Findings of Fact and Conclusions of Law) 6-7,
11-12, ECF No. 94 (contending that the asserted claims of
the ’029 patent are obvious over Johnstone alone in view
of the knowledge of those of ordinary skill in the art); see
also Allergan, Inc. v. Apotex, Inc., No. 1:10-CV-681 Defs.’
Opening Post-Trial Br. 47-48, ECF No. 190 (arguing that
ALLERGAN, INC.   v. APOTEX INC.                         17



skill need only have a reasonable expectation of success of
developing the claimed invention.” Allergan, Inc. v.
Sandoz Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013) (em-
phasis added). The ’029 patent is not limited to com-
pounds with a C1-amide group, such as bimatoprost or
the broader class of compounds described in the ’819
patent. The scope of the independent claims of the ’029
patent encompasses thousands of permutations of PGF
analogs, including structures with all kinds of functional
groups at the C1 location, such as carboxylic acids, alkyl
carboxylates, and hydroxyls. 5     Given the breadth of
the ’029 patent’s claimed invention, appellants did not
have the exacting burden of showing a reasonable expec-
tation of success in using the narrow class of PGF analogs
with C1-amide groups to treat hair loss, let alone a rea-
sonable expectation of success in using bimatoprost in
particular. Appellants instead had the burden of showing
that any compounds within the broad genus claimed by
the ’029 patent, including those that did not have C1-
amide groups, were obvious at the time of the invention.
    The district court’s reasoning was especially problem-
atic because the feature of bimatoprost that it relied on



plaintiffs did not show a nexus to unexpected results and
other secondary considerations within the scope of
the ’029 claims).
   5    For example, claim 1 of ’029 patent, which de-
scribes the functional group at the C1 location as “R1,”
recites that it claims structures “wherein R1 is selected
from the group consisting of C(O)OH, C(O)NHOH,
C(O)OR3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4,
tetrazole, a cationic salt moiety, a pharmaceutically
acceptable amine or ester comprising 2 to 13 carbon
atoms, and a biometabolizable amine or ester comprising
2 to 13 atoms.”
18                             ALLERGAN, INC.   v. APOTEX INC.



was that it and the other PGF analogs with a C1-amide
group disclosed in the ’819 patent bind to a variant of the
FP receptor. 6 Neither the district court nor appellees
explain the nexus between this finding and the broad
scope of ’029 patent’s claimed invention. The ’029 patent’s
claimed invention is not unique to PGF analogs that bind
the variant FP receptor. The ’029 patent also claims
compounds that do bind the garden-variety FP receptor,
such as C1-esters and C1-carboxylic acids. Indeed, almost
every disclosed exemplar in the ’029 patent describes one
of the latter compounds. The district court’s improperly
limited analysis meant that it did not answer the question
prerequisite to its conclusion. The district court needed to
have found that other embodiments falling within the
claim will behave in the “same manner” as compounds
with C1-amide groups, in order to establish that evidence
of unexpected results “is commensurate with the scope of
the claims.” 7 In re Huai-Hung Kao, 639 F.3d 1057, 1068
(Fed. Cir. 2011). The district court failed, however, to
make a finding on how the C1-amide compounds’ property
of binding to the variant FP receptor necessarily applied
to the reasonable expectation of success for the full
scope ’029 patent’s claimed invention, which included the


     6  Appellees take the position, which appellants dis-
pute, that bimatoprost interacts with a splice variant of
the FP receptor, i.e., a form of the FP receptor in which
the sub-units of the structure receptor have been rear-
ranged. See Appellees’ Br. 19, n.2.
     7  This is in contrast with circumstances such as
those in Genetics Institute, LLC v. Novartis Vaccines &
Diagnostics, Inc., 655 F.3d 1291, 1308-09 (Fed. Cir. 2011).
There, the court noted that unexpected results applied
across the full scope of a claimed protein structure, since
any exceptions were limited to minor variations within
only “10%” of the claimed structure.
ALLERGAN, INC.   v. APOTEX INC.                          19



utility of compounds that bound the normal FP receptor
to treat hair loss.
    The district court compounded its error by taking an
overly cramped view of what the prior art teaches. The
person of ordinary skill reading Johnstone would have
found it replete with references to the advantages of using
17-phenyl PGF compounds generally, including those
with carboxylic acids, esters, and other related groups at
the C1 location—all covered by the ’029 patent’s claims.
We do agree with the district court that Johnstone does
not “clearly and unequivocally disclose” compounds that
also include a C5-C6 saturated bond to the extent that it
would anticipate the ’029 patent, as explained above in
section II.A.1.a. This does not diminish, however, the fact
that Johnstone does suggest the possibility of using a PGF
analog structure that would include such a bond, merely
without adequate explanation within the reference itself.
See Johnstone at 12 ll. 22-24. A motivation to combine
may be implicit in the prior art—silence does not imply
teaching away. Syntex (U.S.A.) LLC v. Apotex, Inc., 407
F.3d 1371, 1380 (Fed. Cir. 2005); Alza Corp. v. Mylan
Labs., Inc., 464 F.3d 1286, 1291 (Fed. Cir. 2006) (rejecting
the necessity of an express disclosure of motivation where
it “may be found implicitly in the prior art”). Johnstone’s
mere disclosure of alternative preferences does not teach
a person of ordinary skill away from the broad swath of
compounds within the scope of the ’029 patent. In re
Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004).
     Johnstone does not even teach away from compounds
that bind variant forms of the FP receptor. On the con-
trary, Johnstone even provides an alternative preference
for the PGF analogs that were known to have different FP
receptor binding properties—the vasodilatory compounds
taught in the parent of the ’819 patent, U.S. Patent No.
20                             ALLERGAN, INC.   v. APOTEX INC.



5,352,708. Johnstone at 17 ll. 13-15. 8 The conclusion of
Johnstone’s detailed description makes this clear. What
Johnstone unequivocally teaches is that “[p]rostaglandin
derivatives that exhibit high pharmacological activity and
no or only very small side effects, such as [latanoprost]
and its carboxylic acid esters, are also presently particu-
larly preferred, especially in use in large areas of the skin
and the scalp.” Id. at 22 ll. 21-23 (emphasis added).
Johnstone discloses a preference for PGF analogs that
had already been identified and were known in the art to
have selective pharmacological activity, irrespective of
whether such activity was due to binding to the FP recep-
tor or a variant, as well as whether there was a saturated
or unsaturated bond at the C5-C6 location. The dissent
inappositely emphasizes the complexity of changing a
bond at this location, implying that the ’029 patent repre-
sents compounds that are newly isolated or synthesized
over those of Johnstone. Dissenting Op. at 5-6. However,
following Johnstone, there was nothing left for a chemist



     8   To be sure, we agree with appellees (and the dis-
sent, which addresses this issue at length, see Dissenting
Op. at 7-8) that appellants fail to show that this is a
sufficiently clear reference to the ’819 patent itself, since
the list of compounds expressly disclosed as being vasodi-
latory in the ’708 patent exclude the 17-phenyl PGF
analogs that the ’819 patent discloses, such as bimato-
prost. Rather, the point is that the analogs disclosed in
the ’708 patent and its progeny, including the ’819 patent,
had different chemical structures and properties—
including, for example, the binding of variant FP recep-
tors. This is especially salient because the district court’s
conclusion relied so heavily on its finding that—even in
light of Johnstone’s disclosure—the utility of a compound
that binds a variant FP receptor was an unexpected
result.
ALLERGAN, INC.   v. APOTEX INC.                          21



to do. As discussed above, Johnstone taught squarely
towards a new utility for a finite set of already identified
and isolated compounds with properties that had already
been characterized—for example, as disclosed in the ’708
and ’819 patents.
    The district court also did not find any express teach-
ing away in the art as a whole. The district court did find
that the prior art included PGF analogs other than those
disclosed in Johnstone that had identical physiological
effects, as evinced by the ’819 patent’s disclosure of thir-
teen such compounds, including bimatoprost, that could
be used in reducing intraocular pressure and thereby
treating glaucoma. However, the district court concluded
that in the context of hair growth as a generally “unpre-
dictable and mysterious” art, any difference in the chemi-
cal activity of a PGF analog, even one with a structure
very similar to one claimed by the ’029 patent, would be
sufficient to teach away.
    But, it does not matter whether hair growth is gener-
ally an unpredictable endeavor—the question is more
narrowly whether the success of using selective PGF
analogs to treat hair loss would be reasonably unpredict-
able. The district court and the dissent commit the same
error of examining the state of the art before the time of
the invention. See Dissenting Op. at 9. Once Johnstone
was published, the general characteristics of the hair
growth art ceased to be relevant. Johnstone taught that
PGF analogs could be used to grow hair. Indeed, John-
stone even more specifically taught that PGF analogs that
were effective glaucoma drugs could grow hair. There-
fore, the correct question, at the time of the ’029 patent’s
invention, was whether there was anything “unpredicta-
ble and mysterious” about a PGF analog that could treat
glaucoma growing hair.
   On this point, the district court chiefly cited the fail-
ure of certain therapeutic PGF analogs to grow hair—
22                             ALLERGAN, INC.   v. APOTEX INC.



remarkably, even though eyelash growth was a known
potential side effect of one of the two cited examples. 9
Even so, “[o]bviousness does not require absolute predict-
ability of success.” In re O’Farrell, 853 F.2d 894, 903
(Fed. Cir. 1988). What does matter is whether the prior
art gives direction as to what parameters are critical and
which of many possible choices may be successful. Id.;
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1366 (Fed. Cir.
2007). Johnstone did not make a general exhortation
covering thousands of possibilities—its teaching focused
on specific classes of compositions of PGF analogs with
specifically described structures and properties that
guided persons of ordinary skill in the art to compounds
with similar structures that would fall within the scope of
the ’029 patent’s claims. See Altana Pharma AG v. Teva
Pharm. USA, Inc., 566 F.3d 999, 1007 (Fed. Cir. 2009)
(“Obviousness based on structural similarity may be
proven by the identification of some motivation that
would have led one of ordinary skill in the art to select
and modify a known compound in a particular way to
achieve the claimed compound.”). While success in em-
ploying the disclosed compounds to treat hair loss may
not have been guaranteed, Johnstone’s teaching provided
sufficient guidance as to what parameters would lead to a
reasonable expectation of success.
    The district court’s findings on secondary considera-
tions suffer from the same infirmity of lacking a nexus
with the scope of the ’029 patent’s claimed invention. It is
the established rule that “objective evidence of non-
obviousness must be commensurate in scope with the


     9  See Allergan, 2013 WL 286251, at *10 (“The label
for the glaucoma drug Rescula® includes a warning that
10-14% of patients had increased length of eyelashes, 7%
had decreased length of eyelashes, and 80% showed no
response whatsoever.”).
ALLERGAN, INC.   v. APOTEX INC.                           23



claims which the evidence is offered to support.” Applica-
tion of Tiffin, 448 F.2d 791, 792 (CCPA 1971); see also
MeadWestVaco Corp. v. Rexam Beauty & Closures, Inc.,
731 F.3d 1258, 1264-65 (Fed. Cir. 2013); In re Huai-Hung
Kao, 639 F.3d at 1068; In re Peterson, 315 F.3d 1325, 1331
(Fed. Cir. 2003); In re Hiniker Co., 150 F.3d 1362, 1369
(Fed. Cir. 1998). As discussed above, the district court’s
findings on unexpected results, which were closely inter-
twined with its analysis of motivation to combine and
reasonable expectation of success, were not commensurate
with the full scope of the patent’s claims.
    In sum, even if the district court did not commit clear
error in its findings of fact, failure to consider the appro-
priate scope of the ’029 patent’s claimed invention in
evaluating the reasonable expectation of success and
secondary considerations constitutes a legal error that we
review without deference.
    Taking an appropriate view of the scope of the ’029
patent’s claimed invention, the facts found by the district
court weigh towards the conclusion of obviousness. The
validity of the ’029 patent rests on the provisos that
exclude certain PGF analog structures from its claim
scope, which were designed to avoid anticipation by
Johnstone.     As discussed above, however, Johnstone
contains a plethora of teaching towards PGF analog
structures that are outside the scope of the provisos,
including an express suggestion to employ compositions
with saturated C5-C6 bonds, as well as teaching to PGF
analogs that are selective in having maximized therapeu-
tic effect with minimized side effects. The ’029 patent
claims many different kinds of PGF analog structures,
including PGF analogs with both unsaturated and satu-
rated C5-C6 bonds, as well as PGF analogs that both bind
the FP receptor and its variant. The district court’s
finding that bimatoprost and the ’819 patent’s other
disclosed compounds only bind the variant FP receptor is
not relevant to the ’029 patent’s actual claimed invention.
24                             ALLERGAN, INC.   v. APOTEX INC.



Accordingly, the district court made no finding that would
diminish the more probative facts supporting a person of
ordinary skill’s substantial reasonable expectation of
success and motivation to use PGF analogs with high
pharmacological activity and structures similar to those
disclosed in Johnstone to treat hair loss. Even if we were
to determine that the aforementioned flaws in the district
court’s analysis do not rise to the level of clear error, the
evidence of commercial success cannot on its own remedy
the district court’s other errors leading to its overall
conclusion of non-obviousness. 10
    We therefore reverse the district court’s finding that
the asserted claims of the ’029 patent are non-obvious.
                      B. ’404 Patent
                   1. Brandt References
    The ’404 patent emerged from the results of Allergan’s
clinical trials evaluating the safety and efficacy of bima-
toprost eyedrops for glaucoma treatment, which were
subsequently marketed as Lumigan®. Appellants identi-
fy four publications of clinical trials that they allege
disclose the ability of bimatoprost to promote eyelash hair
growth (collectively the “Brandt references”). Appellants
argue that, among other grounds for invalidity, the


     10 The district court made a further finding that La-
tisse® was the only drug approved by the FDA and mar-
keted for eyelash hair growth. It further noted that
latanoprost, the subject of the Johnstone PCT, has not
been approved. It is unclear from the district court’s
opinion whether this finding related to commercial suc-
cess or long-felt need. In any event, however, it is under-
cut by Allergan’s exclusive license of the patent that
issued from the Johnstone PCT. See Merck & Co., Inc. v.
Teva Pharm. USA, Inc., 395 F.3d 1364, 1376 (Fed. Cir.
2005).
ALLERGAN, INC.   v. APOTEX INC.                         25



Brandt references would render the ’404 patent obvious in
light of Johnstone. The Brandt references include the
following:
   a presentation given by Dr. James Brandt, a clini-
   cal investigator working on Lumigan®, to the
   American Academy of Ophthalmology Meeting on
   October 23, 2000, disclosing three month results
   from a bimatoprost eyedrop trial, which identifies
   the drug only by the name “Lumigan,” stating
   that more than 5% of patients experience eyelash
   growth;
   a press release issued by Allergan on October 23,
   2000, containing the same information as the Oc-
   tober 23, 2000 presentation;
   a publication by Drs. Sherwood and Brandt enti-
   tled “Six-Month Comparison of Bimatoprost Once-
   Daily and Twice-Daily with Timolol Twice-Daily
   in Patients with Elevated Intraocular Pressure” in
   Survey of Ophthalmology in May 2001 disclosing
   that in a six month glaucoma study, eyelash
   growth was reported in between 35 and 48% of pa-
   tients receiving bimatoprost, depending on dose;
   a publication by Drs. Brandt, VanDenburgh (a
   named inventor of the ’404 patent), Chen, and
   Whitcup in Ophthalmology in June 2001 disclos-
   ing that in a three month study, eyelash growth
   was reported in between 25.6% and 33.7% of pa-
   tients receiving bimatoprost, depending on dose.
    The first two Brandt references are indisputably prior
art under § 102(b), as they were published more than one
year before the priority date of the ’404 patent, February
4, 2002. These references do not, however, expressly refer
to bimatoprost. A person of ordinary skill hence would be
unaware that the results reported therein were associated
with bimatoprost. With respect to the more fulsome May
26                             ALLERGAN, INC.   v. APOTEX INC.



and June 2001 references, the district court found that
the ’404 patent was invented prior to their publication
date and, therefore, that the references were not prior art
under § 102(a). 11
                   a. Date of Invention
    The invention date is the date of conception. Invitro-
gen Corp. v. Clontech Labs., Inc., 429 F.3d 1052, 1063
(Fed. Cir. 2005). Conception is “the formation in the mind
of the inventor, of a definite and permanent idea of the
complete and operative invention, as it is hereafter to be
applied in practice.” Burroughs Wellcome Co. v. Barr
Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994). The issue
of the conception date of an invention is a legal conclusion
based on underlying factual findings. Taurus IP, LLC v.
DaimlerChrysler Corp., 726 F.3d 1306, 1322 (Fed. Cir.
2013). While defendants bear the burden of persuasion to
show that the Brandt references are prior art to the ’404
patent by clear and convincing evidence, the patentee
nevertheless must meet its burden of production to
demonstrate an earlier conception date. Mahurkar v.
C.R. Bard, Inc., 79 F.3d 1572, 1577 (Fed. Cir. 1996).
    In evaluating the patentee’s evidence of conception
date, courts “must give due regard to the trial court’s
opportunity to judge the witnesses’ credibility.” Fed. R.
Civ. P. 52(a)(6). The court’s inquiry is guided by the
principle that “[i]t is well established that when a party
seeks to prove conception via the oral testimony of a
putative inventor, the party must proffer evidence corrob-



     11  The district court opinion suggests that it found
that all four “Brandt references are not prior art under 35
U.S.C. § 102(a),” even though the first two references
were published more than one year before the priority
date of the ’404 patent. Allergan, 2013 WL 286251, at *7.
ALLERGAN, INC.   v. APOTEX INC.                         27



orating that testimony.” Shu-Hui Chen v. Bouchard, 347
F.3d 1299, 1309 (Fed. Cir. 2003). In particular, the “defi-
nite and permanent” idea required for conception “must
be supported by corroborating evidence.” Burroughs
Wellcome, 40 F.3d at 1230.
    The district court found that the conception date of
the ’404 patent was in mid-2000 based on the following
facts: (i) Dr. Woodward’s credible testimony that he
reached a “concrete conclusion” that topical application of
bimatoprost would grow hair in mid-2000, (ii) Dr. Van-
Denburgh’s credible testimony of meeting with patent
attorneys between late 2000 and early 2001 to discuss the
invention, and (iii) internal Allergan memoranda report-
ing eyelash growth in clinical trials, which were received
by Drs. Woodward and VanDenburgh in early 2000.
Allergan, 2013 WL 286251, at *7.
    The problem is that to the extent there is any docu-
mentary evidence, it does not relate to the claimed inven-
tion of the ’404 patent—the topical application of
bimatoprost for use to promote eyelash hair growth. The
Allergan memoranda refer only to eyelash growth result-
ing from the administration of eyedrops. The memoranda
reported the side effects of bimatoprost used in eyedrops
and did not disclose the claimed invention of topical
application for intended therapeutic effect. The only
evidence that corroborates Dr. Woodward’s testimony that
he conceived of topical application of bimatoprost in mid-
2000 is the oral testimony of his co-inventor, Dr. VanDen-
burgh. This is not one of the cases cited by appellees in
which corroborating evidence is found through multiple
written documents, such as a collection of engineering
notebooks. Spansion, Inc. v. Int’l Trade Comm’n, 629
F.3d 1331, 1356 (Fed. Cir. 2010); Univ. of Pittsburgh v.
Hedrick, 573 F.3d 1290, 1298 (Fed. Cir. 2009). Rather,
this is a case in which there is no corroborating document
that shows anything about the claimed invention. The
only corroboration of the claimed invention is the oral
28                             ALLERGAN, INC.   v. APOTEX INC.



testimony of an inventor, which we must treat with
skepticism due to the possibility of an inventor’s self-
interest in obtaining or maintaining an existing patent.
Shu-Hui Chen, 347 F.3d at 1309; Price v. Symsek, 988
F.3d 1187, 1994 (Fed. Cir. 1993).
    The district court, therefore, committed clear error in
finding corroboration of an earlier priority date in docu-
ments that collectively do not include any description of
the claimed invention of the ’404 patent. As the only
other potentially corroborating evidence of conception is
the oral testimony of a co-inventor, we reverse the district
court’s finding that the ’404 patent was conceived prior to
the date of publication of the May and June 2001 Brandt
references.
         b. Authorship of the Brandt References
    Appellees argue that even if the ’404 patent cannot
claim an earlier priority date, the later Brandt references
are still not § 102(a) art as they represent the work of the
inventors themselves. “[O]ne’s own work is not prior art
under § 102(a) even though it has been disclosed to the
public in a manner or form which otherwise would fall
under § 102(a).” In re Katz, 687 F.2d 450, 454 (CCPA
1982). Appellees claim that the Brandt references are the
product of the ’404 patent’s co-inventor Dr. VanDen-
burgh’s work in designing and directing the Lumigan®
clinical trials. Appellees rely predominately on Dr. Van-
Denburgh’s testimony regarding her role in the clinical
trials, in which she described her role supervising and
managing the work being done by various clinical study
locations, including writing internal memoranda and
reports. This, appellees contend, amounts to Dr. Brandt
and other authors of the Brandt references being a “pair
of hands” for the ’404 patent’s inventors, in particular Dr.
VanDenburgh. Mattor v. Coolegem, 530 F.2d 1391, 1395
(CCPA 1976).
ALLERGAN, INC.   v. APOTEX INC.                             29



    Appellants argue that, as an initial matter, appellees
did not timely raise this issue. To the extent that appel-
lees did argue this point, it appears to have been during
closing arguments and post-trial briefing. 12 However,
under Fourth Circuit law, appellees may have waived the
issue of the Brandt references’ authorship by not present-
ing it in pretrial briefing, even if appellees raised it later.
See McLean Contracting Co. v. Waterman Steamship
Corp., 277 F.3d 477, 480 (4th Cir. 2002) (“Failure to
identify a legal issue worthy of trial in the pretrial confer-
ence or pretrial order waives the party’s right to have that
issue tried.”).
    Even if appellees did not waive this issue, their belat-
ed arguments raised towards the end of trial are unavail-
ing. First and foremost, the question is not whether, as
appellees seem to argue, Dr. VanDenburgh or Dr. Brandt
was the first to recognize bimatoprost’s potential thera-
peutic value for eyelash hair growth. Appellants do not
argue that the Brandt references expressly teach bimato-
prost’s intentional use to grow hair—that is, they do not
argue inventorship. The relevant inquiry must be wheth-
er the Brandt references, which describe the methods,
detailed results, statistical analysis and discussion of
bimatoprost clinical trials, were solely Dr. VanDenburgh’s
work and hers alone. In re Katz, 687 F.2d at 455. On
this, appellees’ explanations strain reason.
   First, Dr. VanDenburgh’s testimony was at best
equivocal as to whether she alone directed clinical trials
and wrote internal reports. J.A. 508, 540-41. Second,
while she was at least a co-author of one Brandt reference


    12  Letter from Appellees, ECF No. 93 (attaching “ex-
cerpts from the closing argument transcript, Allergan and
Duke’s post-trial brief, and Allergan and Duke’s post-trial
findings of fact and conclusions of law” regarding this
issue).
30                             ALLERGAN, INC.   v. APOTEX INC.



in dispute, along with two other Allergan scientists, Dr.
VanDenburgh was not listed as a co-author at all in the
other one. Brandt’s May 2001 journal article includes one
co-author, Dr. Sherwood, also unaffiliated with Allergan.
The author line of the latter article describes it as being
written “for the Bimatoprost Study Group 1 or 2,” refer-
ring to a long list of study group members—a list in which
Dr. VanDenburgh’s name does not appear. J.A. 2413-14.
The fact that a reference does not list any co-inventors as
authors, or that it lists other authors, is certainly not
dispositive in itself. However, in this case, whether Dr.
VanDenburgh supervised the logistics of the clinical trial
on her own or not, appellees have not produced evidence
that shows she was responsible for directing the produc-
tion of either article’s content, which includes the design,
trial, and analysis of results. There is no evidence, there-
fore, that appellees’ explanation of the Brandt references
is in any way consistent with the content of the articles
and the nature of the publications. In re Katz, 687 F.2d at
455.
     Since appellees have produced no evidence—
unsurprising given their belated recourse to this argu-
ment—and provided no supported explanation demon-
strating that the Brandt references were in fact printed
publications authored by Dr. VanDenburgh for the pur-
poses of § 102(a), we see no reason to remand to make
further findings on this issue. The question of whether a
reference is a work of others for the purposes of § 102(a)
is, like that of inventorship, a question of law based on
underlying facts. Ethicon, Inc. v. U.S. Surgical Corp., 135
F.3d 1456, 1460 (Fed. Cir. 1998). Even if appellees had
not waived their arguments on this point, the evidence
appellees presented at trial could not support the legal
conclusion that the Brandt references represented Dr.
VanDenburgh’s own work. See Soverain Software LLC v.
Newegg Inc., 705 F.3d 1333, 1337 (Fed. Cir. 2013) amend-
ed on reh’g, 728 F.3d 1332 (Fed. Cir. 2013) and cert.
ALLERGAN, INC.   v. APOTEX INC.                          31



denied, 134 S. Ct. 910 (2014) (declining to remand for
further factual findings on obviousness where there was
no material factual dispute and the legal conclusion was
apparent). Accordingly, we hold that the Brandt refer-
ences are prior art to the ’404 patent.
                         2. Invalidity
    The district court’s findings on the obviousness of
the ’404 patent were limited to reiterating that the May
and June 2001 Brandt references were not prior art (as a
consequence of its finding on the mid-2000 invention date
of the ’404 patent) and that the ’404 patent was not obvi-
ous in light of Johnstone alone. Allergan, 2013 WL
286251, at *10. The district court did make findings
regarding inherent anticipation in light of the two earlier
Brandt references. Paralleling its reasoning on inherent
anticipation by the ’819 patent, as discussed above in
section III.A.1.b, the district court found that the disclo-
sure of 48.4% incidence of eyelash growth did not inher-
ently anticipate. Id. at *8. While we need not reach the
question of whether the district court’s inference repre-
sents clear error, we do note that the Brandt references
disclose a substantial rate of eyelash hair growth as a side
effect of using bimatoprost in eyedrops.
    Johnstone details at length how eyedrops containing
latanoprost (marketed as the glaucoma drug Xalatan®)
promote the eyelash hair growth through the mechanism
of fluid containing latanoprost making topical contact
with the eyelid. Johnstone at 22 ll. 28-35. Johnstone also
discloses the topical application of latanoprost to treat
hair loss. In light of the Brandt reference’s disclosure of
bimatoprost’s effect in growing eyelash hair, a person of
ordinary skill in the art would have had substantial
motivation to follow Johnstone and use topical application
of bimatoprost to grow eyelash hair.
   Likewise, the Brandt references provided a reasonable
expectation of success for the topical application of bima-
32                             ALLERGAN, INC.   v. APOTEX INC.



toprost. Clinical trials showed that nearly 50% of pa-
tients using bimatoprost in eyedrop form were experienc-
ing eyelash hair growth. Johnstone additionally taught
that fluid contacting the eyelid from eyedrops was the
likely mechanism of hair growth. Appellees’ only remain-
ing argument for nonobviousness in light of the Brandt
references is the secondary consideration of commercial
success, which is unavailing on its own.
    Given the overwhelming weight of evidence, remand
is unnecessary “as here, the content of the prior art, the
scope of the patent claim, and the level of ordinary skill in
the art are not in material dispute, and the obviousness of
the claim is apparent in light of these factors.” Soverain,
705 F.3d at 1337 (citing KSR, 550 U.S. at 427). Accord-
ingly, we reverse the district court’s finding that the ’404
patent is not invalid for reasons of obviousness.
                       CONCLUSION
    For the foregoing reasons, we reverse the district
court’s invalidity findings on the asserted claims of both
the ’029 and ’404 patents, and we vacate the court’s
injunction accordingly. 13
              REVERSED AND VACATED




     13 Because we reverse the court’s invalidity finding
on both asserted patents on the grounds of obviousness
and thus vacate the court’s injunction, we need not reach
appellants’ arguments regarding insufficient written
description for the asserted claims of the ’029 patent and
inadequate enablement of claim 14 of the ’404 patent, as
well as the question of whether the court abused its
discretion in granting a permanent injunction.
  United States Court of Appeals
      for the Federal Circuit
                ______________________

    ALLERGAN, INC., AND DUKE UNIVERSITY,
              Plaintiffs-Appellees,

                           v.

APOTEX INC., APOTEX CORP., SANDOZ, INC., AND
      HI-TECH PHARMACAL CO., INC.,
             Defendants-Appellants.
             ______________________

                2013-1245, -1246, -1247
                ______________________

   Appeals from the United States District Court for the
Middle District of North Carolina in Nos. 10-CV-0681, 11-
CV-0298, and 11-CV-0650, Judge Catherine C. Eagles.
                 ______________________

            -------------------------

    ALLERGAN, INC., AND DUKE UNIVERSITY,
              Plaintiffs-Appellees,

                           v.

 WATSON PHARMACEUTICALS, INC., now known
 as Actavis, Inc., WATSON LABORATORIES, INC.,
           AND WATSON PHARMA, INC.,
                Defendants-Appellants.
                ______________________

                       2013-1249
2                              ALLERGAN, INC.   v. APOTEX INC.



                 ______________________

   Appeals from the United States District Court for the
Middle District of North Carolina in No. 12-CV-0321,
Judge Catherine C. Eagles.
                ______________________

CHEN, Circuit Judge, dissenting-in-part.
    I join the majority opinion except for Part II.A.2,
which reverses the district court’s conclusion that Appel-
lants failed to meet their burden of proving that the prior
art rendered the ’029 patent obvious by Johnstone, either
alone or in combination with the ’819 patent. In my view,
Johnstone’s teachings are simply too vague and equivocal
to justify invalidating the patent. Therefore, I respectful-
ly dissent.
    To begin with, issued patents enjoy a presumption of
validity, which can only be rebutted by clear and convinc-
ing evidence. Microsoft Corp. v. i4i Ltd. P’ship, 131 S. Ct.
2238, 2245–46 (2011). A party challenging a patent’s
validity must do so with “evidence which produces in the
mind of the trier of fact an abiding conviction that the
truth of [the] factual contentions are highly probable.”
Buildex Inc. v. Kason Indus., Inc., 849 F.2d 1461, 1463
(Fed. Cir. 1988) (citing Colorado v. New Mexico, 467 U.S.
310, 316 (1984)). This is not a burden that is easily
satisfied.
    Moreover, the majority relies heavily on Johnstone
alone, but the Patent Office specifically considered that
reference during the prosecution of the ’029 patent and
came to the same conclusion that the fact-finder did
below: Johnstone does not render the claims obvious. As
a reviewing court, we should be particularly careful before
overturning the verdict under these circumstances. See
Tokai Corp. v. Easton Enterprises, Inc., 632 F.3d 1358,
1367 (Fed. Cir. 2011) (explaining that the burden of proof
ALLERGAN, INC.   v. APOTEX INC.                           3



to invalidate a patent claim is more difficult to meet when
the challenge is based on the same prior art considered by
the Patent Office during examination).
    The majority is correct that Johnstone contemplates a
large class of prostaglandins—the 17-phenyl PGF2 analog
compounds—citing latanoprost in particular, for treating
hair loss. But that reference does not teach or sufficiently
suggest using a prostaglandin with a saturated (i.e.,
single) C5-C6 bond on the alpha chain, as claimed in the
’029 patent. Instead, Johnstone serves up a menu of
seemingly unlimited possibilities. For example, when it
comes to the alpha chain, Johnstone states that the good
ones are those characterized by “the presence or lack of
various modifications of the alpha chain.” J.A. 2293.
Then, for the omega chain, Johnstone again states that
preferred prostaglandins are those characterized by the
“presence or lack of modifications to their omega chain.”
Id. Such a broad, generic disclosure would appear to
cover almost any conceivable prostaglandin. And among
a variety of other possible modifications for the chains,
Johnstone vaguely states that the alpha chain “could
preferably be a C6-C10 chain which can be either saturated
or unsaturated, having one or more double bonds, and
allenes or a triple bond.” J.A. 2293. This lone sentence
does not provide a sufficient blaze mark for using a satu-
rated C5-C6 bond. For the same reason that I agree with
the majority that Johnstone does not anticipate the
claimed compounds—it does not “clearly and unequivocal-
ly” disclose a compound with a saturated C5-C6 bond—I
would find that it does not suggest one either. The speci-
fication contains no other language or examples of satu-
rated alpha chains and certainly no references to
saturating the specific bond at issue. The dozens of
figures and summary of the invention only depict an
unsaturated (i.e., double) C5-C6 bond, and Johnstone’s
claims cover only compounds with this bond. The steady
and persistent message from the entirety of Johnstone’s
4                             ALLERGAN, INC.   v. APOTEX INC.



teachings is clear: when it comes to the C5-C6 bond, keep
it unsaturated.
    Also, as the majority recognizes, the patentee amend-
ed the claims during prosecution to add a proviso carving
out the Johnstone compounds, which resulted in a notice
of allowance. The notice of allowance even pointed out
that the amended claims were not obvious over John-
stone:
    The prior art teaches the use of prostaglandins for
    treating hair loss (see for example, WO 98/33497
    [Johnstone]). However, the prior art lacks motiva-
    tion to modify the prostaglandins taught therein
    in order to obtain the presently claimed prosta-
    glandins, and thus, does not teach or suggest the
    presently claimed invention.
J.A. 5564. In light of the particularly heavy burden to
show obviousness over a reference disclosed during prose-
cution and discussed by the examiner, Appellants have
not shown that Johnstone now somehow teaches or sug-
gests the very structural feature that the patentee
claimed to distinguish the Johnstone compounds.
    Nothing in the record compels a different result. Al-
lergan’s expert, Dr. MacDonald, testified that a person of
ordinary skill would not have saturated Johnstone’s C5-C6
double bond because “[i]t was considered to be a very
important parameter in binding to the FP receptor.” J.A.
1773. Prostaglandins bind to receptors on the surface of
cells, and that binding creates a signal to the cell to
change its properties or functions. At the time of inven-
tion, it was well-understood that identifying which recep-
tors a prostaglandin can bind to is key to designing a drug
that affects the cells. See J.A. 23 (“Studying receptors is
central to pharmacology—the science of drug therapeu-
tics—because knowing what receptors are associated with
a biological effect aids in designing a drug to [bind to]
those receptors and produce or inhibit that effect.”). And,
ALLERGAN, INC.   v. APOTEX INC.                            5



at that time, the state of the art suggested that saturating
the C5-C6 bond in Johnstone’s compounds would have
destroyed the critical binding property of the compounds.
Id. at 30 (“Before [the inventor of the ’029 patent] discov-
er[ed] that saturated prostaglandin F analogs could bind,
this double bond was thought vital for FP-receptor bind-
ing.”). The ’029 patent’s compounds have saturated C5-C6
bonds but do, in fact, bind to the FP-receptor (contrary to
popular belief at the time), which further suggests nonob-
viousness. See DePuy Spine, Inc. v. Medtronic Sofamor
Danek, Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009) (“An
inference of nonobviousness is especially strong where the
prior art’s teachings undermine the very reason being
proffered as to why a person of ordinary skill would have
combined the known elements.”). The majority finds no
clear error in the district court’s acceptance of this undis-
puted fact for purposes of anticipation. See Majority Op.
at 10. I would also find that the district court correctly
concluded that it would not have been obvious to a person
of ordinary skill at the time of invention to change the
unsaturated C5-C6 bond in Johnstone’s compounds to a
saturated bond. See DePuy, 567 F.3d at 1326 (suggesting
nonobviousness “if the prior art indicated that the inven-
tion would not have worked for its intended purpose or
otherwise taught away from the invention”); Eli Lilly &
Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1378
(Fed. Cir. 2006) (holding prior art supplied no motivation
to modify compound to include claimed structural features
because no reasonable expectation of success).
    This is not a situation in which there are a finite
number of identified, predictable solutions. See KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). Rather, the
single sentence in Johnstone actually proposes hundreds
of thousands, or even millions, of variations on the alpha
6                               ALLERGAN, INC.   v. APOTEX INC.



chain. 1 Cf. Eli Lilly, 471 F.3d at 1376 (prior art reference
that disclosed millions of compounds did not spell out “a
definite and limited class of compounds that enabled a
person of ordinary skill in the art to at once envisage each
member of this limited class”). The compound in John-
stone could have a saturated bond at any position on the
alpha chain, an unsaturated bond at any position, a triple
bond at any position, or even a combination of any of
these bonds. As a result, a person of ordinary skill in the
art was not faced with a “small or easily traversed” num-
ber of options based on Johnstone. See Bayer Schering
Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed.
Cir. 2009) (“[A]n invention would not have been obvious to
try when the inventor would have had to try all possibili-
ties in a field unreduced by direction of the prior art.”). In
this instance, covering everything effectively tells us
nothing. See Bayer, 575 F.3d at 1347 (“When what would
have been obvious to try would have been to vary all
parameters or try each of numerous possible choices until
one possibly arrived at a successful result, where the prior
art gave either no indication of which parameters were
critical or no direction as to which of many possible choic-
es is likely to be successful an invention would not have
been obvious.”) (internal quotations omitted).
    The majority further reasons that it would have been
obvious to select the claimed compounds because they,
like Johnstone’s compounds, also “exhibit high pharmaco-
logical activity and no or very small side effects.” Majori-
ty Op. at 20. But the fact that we now know that the



    1   To the extent that the majority maintains that
Johnstone does not cover thousands of possibilities,
Majority Op. at 22, I respectfully disagree. True, John-
stone reaches specific classes of compounds, but John-
stone’s suggested modifications, which the majority relies
on, cover many more variations.
ALLERGAN, INC.   v. APOTEX INC.                           7



claimed compounds contain highly desirable properties
should not compel us to conclude that this would have
been obvious at the time of invention, especially when
there is no expert testimony or other evidence in the
record supporting the notion that it would be obvious to
treat hair loss using any prostaglandin that exhibits “high
pharmacological activity.” See Sanofi-Synthelabo v. Apo-
tex, Inc., 550 F.3d 1075, 1088 (Fed. Cir. 2008) (“Only with
hindsight knowledge that the dextrorotatory enantiomer
has highly desirable properties, can Apotex argue that it
would have been obvious to select this particular race-
mate and undertake its arduous separation.”).
    I also depart from the majority’s combination of John-
stone with the ’819 patent. Following the Appellants’
argument, the majority links Johnstone’s methods of
treating hair loss and the ’819 patent’s methods of treat-
ing glaucoma by looking to the vasodilation properties
shared by the compounds in those references. Majority
Op. at 19–20. I find Johnstone’s discussion of vasodila-
tion too ambiguous to amount to a clear motivation to
combine.
     For example, Johnstone states that “PGF2 alpha ana-
logs can cause a vasodilation effect and through that
mechanism may provide enhanced perfusion to the region
of the hair bulb and thus stimulate increased trophic
activity in the hair follicles.” J.A. 2291–92 (emphasis
added). That Johnstone frames his vasodilation theory in
somewhat uncertain terms (“may”) is not surprising since
he later acknowledges that his representative prostaglan-
din derivative, latanoprost, “was specifically tailored to
eliminate . . . vasodilation.” Id. at 2290. Ultimately,
Johnstone surmises that there are “several possible
mechanisms that may individually or in concert explain
the altered growth pattern of hair follicles observed in the
current clinical study.” Id. at 2291. This level of uncer-
tainty in Johnstone cannot then establish motivation to
combine with the ’708 patent and then with ’819 patent.
8                              ALLERGAN, INC.   v. APOTEX INC.



Unlike the Brandt references, which suggested that
bimatoprost could be used to grow hair, the ’708 and ’819
patents have nothing to do with hair growth. These
patents concern treatment methods for glaucoma. Appel-
lants have not established by clear and convincing evi-
dence that a person of ordinary skill in the art would look
to these references for solutions in the hair growth field.
This is especially true when the correlation between
vasodilation and hair growth—the alleged link between
Johnstone and the ’819 patent—is so speculative. See
Star Scientific, Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d
1364, 1376 (Fed. Cir. 2011) (reference’s discussion of what
“might” or “may” or “seems” to lead to nitrite and TSNA
production does not suggest obviousness).
     Appellants further assert that one of ordinary skill in
the art would use the compounds disclosed in the ’819
patent with Johnstone’s method of stimulating hair
growth because Johnstone refers to the ’708 patent, which
is the parent of the ’819 patent.
    But Johnstone’s link to the ’819 patent via the ’708
patent is tenuous at best. Johnstone describes “preferred
derivatives” for hair growth as those compounds lacking a
phenyl ring structure in their omega chains, such as those
described in the ’708 patent. J.A. 2298. Any motivation
to combine Johnstone with the compounds of the ’819
patent via the ’708 patent is then confined to those com-
pounds lacking a phenyl ring structure. The ’819 patent,
however, teaches bimatoprost, which has a phenyl ring
structure in its omega chain. Thus, as the majority
concedes, “the list of compounds expressly disclosed [in
Johnstone] as being vasodilatory in the ’708 patent ex-
clude the 17-phenyl PGF analogs that the ’819 patent
discloses.” Majority Op. at 20 n.8. Consequently, John-
stone’s reference to the ’708 patent simply does not
amount to a motivation to combine Johnstone with the
’819 patent.
ALLERGAN, INC.   v. APOTEX INC.                            9



    It is undisputed that the field of hair growth is “un-
predictable and mysterious.” See J.A. 38. The majority
errs in minimizing this unpredictability. Majority Op. at
21 (“But, it does not matter whether hair growth is gener-
ally an unpredictable endeavor . . . .”). Our case law
makes plain: unpredictability is a factor. Eisai Co. Ltd. v.
Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir.
2008) (“To the extent an art is unpredictable, as the
chemical arts often are . . . potential solutions are less
likely to be genuinely predictable.”). In light of our case
law and the unpredictability of hair growth, Appellants
have not satisfied their burden of showing clear and
convincing evidence of obviousness.
    Accordingly, looking at the evidence of obviousness as
a whole, I would find that the district court did not clearly
err in holding the asserted claims of the ’029 patent
nonobvious. For these reasons, I respectfully dissent.
