Court Opinion

ID: 816174
Source: CourtListenerOpinion
Date Created: 2013-01-28 22:15:59.284078+00
Date Added: 2024-06-11T15:21:38.800883
License: Public Domain

NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
                ______________________

                  ALLERGAN, INC.,
                   Plaintiff-Appellee,

                           v.

         BARR LABORATORIES, INC.,
     TEVA PHARMACEUTICALS USA, INC.,
AND TEVA PHARMACEUTICAL INDUSTRIES LTD.,
            Defendants-Appellants,

                          AND

                    SANDOZ INC.,
                 Defendant-Appellant.
                ______________________

                   2012-1040, -1054
                ______________________

    Appeals from the United States District Court for the
District of Delaware in No. 09-CV-0333, Judge Sue L.
Robinson.
                ______________________

               Decided: January 28, 2013
                ______________________

   JONATHAN E. SINGER, Fish & Richardson, P.C., of
Minneapolis, Minnesota, argued for plaintiff-appellee.
2                                    ALLERGAN   v. BARR LABS

With him on the brief were DEANNA J. REICHEL; and
JUANITA R. BROOKS, of San Diego, California; and
DOUGLAS E. MCCANN, of Wilmington, Delaware. Of
counsel on the brief was JEFFREY T. THOMAS, Gibson,
Dunn & Crutcher LLP, of Irvine, California.

     MEREDITH MARTIN ADDY, Steptoe & Johnson, LLP, of
Chicago, Illinois, argued for defendants-appellants. With
her on the brief for Sandoz, Inc. were THOMAS J. FILARSKI
and BRANDON C. HELMS. On the brief for Barr Laborato-
ries, Inc., et al, were GEORGE C. LOMBARDI and BRADLEY
C. GRAVELINE, Winston & Strawn, LLP, of Chicago,
Illinois.
                   ______________________

    Before RADER, Chief Judge, BRYSON,  and WALLACH,
                     Circuit Judges.

WALLACH, Circuit Judge.
    Barr Laboratories, Inc., Teva Pharmaceuticals USA,
Inc., and Teva Pharmaceutical Industries Ltd. (collec-
tively, “Barr”), and Sandoz Inc. (“Sandoz”) appeal from
the decision of the United States District Court for the
District of Delaware, which held that Barr’s and Sandoz’s
proposed products (described in Abbreviated New Drug
Applications (“ANDA”) Nos. 91-194 and 200487, respec-
tively) infringed claim 10 of Allergan, Inc.’s (“Allergan”)
U.S. Patent No. 5,688,819 (“the ’819 patent”) and that the
asserted claim was not invalid. 1 Allergan, Inc. v. Barr

       
            Judge Bryson assumed senior status on Janu-
ary 7, 2013.
       1    Allergan also asserted claims 1-3 of its U.S.
Patent 6,403,649 (“the ’649 patent”), and the district court
likewise found the ’649 patent was not invalid and in-
fringed by Barr’s and Sandoz’s ANDAs. Allergan, 808 F.
 ALLERGAN   v. BARR LABS                                3

Labs., Inc., 808 F. Supp. 2d 715, 717 (D. Del. 2011).
Because the district court correctly construed the relevant
claim term and determined the asserted claim was not
obvious, we affirm.
                       BACKGROUND
    Allergan markets and sells Lumigan®, which was
approved by the Food and Drug Administration (“FDA”)
to reduce intraocular pressure (“IOP”) in people with
ocular hypertension or glaucoma. The active ingredient
in Lumigan® is bimatoprost. Allergan’s ’819 patent
claims bimatoprost and methods of using bimatoprost to
treat ocular hypertension or glaucoma.
              1. Background of the Invention
      In a healthy eye, proper IOP is maintained by
aqueous humor, which is fluid between the cornea and the
lens of the eye that transports nutrients like vitamins,
sugars, and amino acids to the cornea. Too much aqueous
humor disrupts IOP and poses a substantial risk factor
for developing glaucoma. PGF2α is a naturally-occurring
prostaglandin that is known to lower IOP by increasing
the outflow of aqueous humor from the eye. Prostagland-
ins are a class of naturally-occurring substances, all of
which share the following twenty-carbon basic structure:

Supp. 2d at 736. However, the ’649 patent expired on
September 21, 2012 and thus is not at issue in this ap-
peal.
4                                      ALLERGAN   v. BARR LABS

Allergan, 808 F. Supp. 2d at 719. The above carbon atoms
are numbered from 1 to 20, with 1 through 7 forming an α
(alpha) chain, 13 through 20 forming an ω (omega) chain,
and 8 through 12 forming a five-membered (cyclopentane)
ring. The C-1 position (highlighted by the box above)
features carboxylic acid, which is present in all naturally-
occurring prostaglandins.
     As noted, it was known prior to the invention at issue
that PGF2α lowered IOP. The prior art also revealed that
certain lipid-soluble esters of PGF2α lowered IOP, and
actually showed greater hypotensive effects than the
parent compound PGF2α. ’819 patent col. 2 ll. 9-38. Ac-
cording to the ’819 patent’s specification, however, pros-
taglandins like PGF2α and its isopropyl ester were
associated with negative side effects like “ocular surface
hyperemia” (red eye) and “foreign-body sensation.” Id. col.
2 ll. 41-46. The ’819 patent discloses that certain com-
pounds that replace the carboxylic acid group with a non-
acidic substituent can reduce these side effects while
retaining the desired IOP-lowering effect. Id. col. 3 ll. 9-
18. One such compound is bimatoprost (cyclopentane N-
ethyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-
pentenyl)-3, 5-dihydroxy, [1α,2β,3α,5α]). Id. col. 7 ll. 44-46.
       Bimatoprost is PGF2α, with an ethyl amide instead
of a carboxylic acid group at the C-1 position and a phenyl
 ALLERGAN   v. BARR LABS                               5

ring at C-17. 2 [J.A.10] Bimatoprost has the structure
depicted below:

Allergan, 808 F. Supp. 2d at 720. Bimatoprost lowers IOP
by increasing the flow of aqueous humor leaving the eye.
                     2. Patent-in-Suit
      The ’819 patent is related to and claims priority
from U.S. Patent No. 5,352,708 (“the ’708 patent”), filed
on September 21, 1992. The ’819 patent was issued on
November 18, 1997, and was extended for 698 days as a
result of the FDA’s regulatory review of Lumigan®.
Asserted claim 10 of the ’819 patent ultimately depends
from independent claim 5, which recites:
   5. A method of treating ocular hypertension or
   glaucoma which comprises applying to the eye an
   amount sufficient to treat ocular hypertension or
   glaucoma of the formula

      2   Bimatoprost is a prostamide and is also
known as 17-phenyl PGF2α C-1 ethylamide.
6                                    ALLERGAN   v. BARR LABS

    wherein . . . X is a radical selected from the group
    consisting of –OR4 and –N(R4)2 wherein R4 is se-
    lected from the group consisting o[f] hydrogen, a
    lower alkyl radical having from one to six carbon
    atoms,

    wherein R5 is a lower alkyl radical having from
    one to six carbon atoms . . . .
’819 patent col. 13 l. 49 – col. 14 l. 7 (emphasis added to
disputed claim term). Dependent claim 10 discloses five
compounds that may be used in the treatment of ocular
hypertension or glaucoma in which X is –N(R4)2. Id. col.
14 l. 55 – col. 15 l. 7. One of these compounds is bimato-
prost, listed as cyclopentane N-ethyl heptenamide-5-cis-2-
(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,      5-dihydroxy,
[1α,2β,3α,5α]. Id. col. 15 ll. 1-3.
          3. Barr’s and Sandoz’s Abbreviated New
                      Drug Applications
        On March 26, 2009, Barr filed an ANDA for a ge-
neric version of Lumigan®, listing Allergan’s ’819 patent
as one of the Orange Book-listed patents associated with
Lumigan®. 3 Barr’s ANDA contained a Paragraph IV
certification stating that Barr believed each relied-upon
Orange Book patent was “invalid or [would] not be in-

      3    The FDA lists all patents protecting FDA-
approved drugs in a publication titled the “Approved Drug
Products With Therapeutic Equivalence Evaluations,”
which is generally referred to as the “Orange Book.”
Caraco Pharm. Labs., Ltd. v. Forest Labs., Ltd., 527 F.3d
1278, 1282 (Fed. Cir. 2008) (citing 21 U.S.C. § 355(b)(1),
(c)(2)).
 ALLERGAN   v. BARR LABS                                 7

fringed by the manufacture, use, or sale of the new drug
for which the application [was] submitted.” 21 U.S.C. §
355(b)(2)(A)(iv). Sandoz likewise filed an ANDA for a
generic version of Lumigan®, also with an accompanying
Paragraph IV certification. Allergan filed patent in-
fringement suits against Barr and Sandoz; the suits were
consolidated into one action for a bench trial on patent
invalidity and infringement.
               4. District Court Proceedings
                  A. Claim Construction
       The only claim term disputed before the district
court was –N(R4)2 as used in claim 5, on which asserted
claim 10 depends. The parties disagree whether or not
–N(R4)2 requires identical R4 substituents. If it does,
bimatoprost’s use of nonidentical R4 substituents—
hydrogen (H) and an ethyl group (CH2CH3)—would fall
outside the protection of the ’819 patent. The district
court initially agreed with Barr and Sandoz that “the
plain and ordinary meaning” of –N(R4)2 suggested that
identical R4 substituents were required; however, it
ultimately found that Allergan had acted as its own
lexicographer by defining –N(R4)2 to permit nonidentical
R4 elements. Therefore, the district court held that, as
used in the ’819 patent, the –N(R4)2 limitation did not
require the R4 substituents to be identical. Allergan, Inc.,
808 F. Supp. 2d at 726-27. Given this claim construction,
the district court found that bimatoprost satisfied all
limitations of the asserted claims, and consequently found
Barr’s and Sandoz’s proposed uses of bimatoprost as set
forth in their ANDAs constituted infringement of the ’819
patent.
8                                     ALLERGAN   v. BARR LABS

                      B. Invalidity
        The district court found that asserted claim 10 of
the ’819 patent was not invalid, and rejected Barr and
Sandoz’s arguments based upon anticipation and obvi-
ousness.      The primary invalidity reference asserted
during trial was a patent to Johan Stjernschantz, pub-
lished as Patent Cooperation Treaty Application No. WO
90/02253 on March 22, 1990 and entitled “Prostaglandin
Derivatives for the Treatment of Glaucoma or Ocular
Hypertension” (“Stjernschantz”).      Barr and Sandoz’s
expert witness, Dr. Ashim Kumar Mitra, testified that
asserted claim 10 was obvious over Stjernschantz, wheth-
er alone or in combination with other prior art, including
unexamined Japanese Patent Application No. S49-69636
(“JP ’636”). 4 Barr and Sandoz also asserted post-trial that
all of the asserted claims were obvious over Stjernschantz
in combination with a chapter in the textbook “Prodrugs:
Topical and Ocular Drug Delivery” entitled “Improved
Ocular Drug Delivery with Prodrugs” (“Lee & Bund-
gaard”).
       Stjernschantz discloses IOP-reducing derivatives of
certain prostaglandins. Two such derivatives are dis-
closed compounds 2 and 9, which are both isopropyl esters
that convert into bimatoprost-free acid upon hydrolysis in
the eye. 5 A third disclosed derivative is compound 17,

      4     Other prior art discussed by Dr. Mitra at trial
included: U.S. Patent No. 4,599,353, and a chapter of a
1977 textbook (“Design of Biopharmaceutical Properties
through Prodrugs and Analogs”) entitled “Physical Model
Approach to the Design of Drugs with Improved Intestinal
Absorption.”
       5    Compound 9 differs from compound 2 only in
that it has a single bond between C-13 and C-14, whereas
compound 2 has a double bond in that position. Com-
 ALLERGAN   v. BARR LABS                                  9

bimatoprost-free acid or 17-phenyl PGF2α, which features
a carboxylic acid functional group at C-1. The structural
difference between bimatoprost and these Stjernschantz
derivatives is that bimatoprost features an ethyl amide
functional group at the C-1 position, whereas compounds
2 and 9 have an isopropyl ester at C-1, and compound 17
has carboxylic acid.
       However, these obviousness theories were under-
mined when “Mitra’s credibility was eviscerated on cross-
examination.” Allergan, 808 F. Supp. 2d at 733. Finding
“Mitra’s credibility flawed on a fundamental level,” the
district court accorded no weight to his testimony. Id. at
735. The court then declined to “review the prior art
references and weigh their import absent the guidance of
an expert.” Id. at 736 n.21. Furthermore, based on its
finding that Barr and Sandoz had improperly switched
obviousness theories after Dr. Mitra’s testimony was
discredited, the district court held Barr and Sandoz had
waived any obviousness theory that relied “primarily on
JP ’636, or that combine[d] Stjernschantz with Lee &
Bundgaard.” Id. at 735. Due to the lack of credible evi-
dence to support Barr’s and Sandoz’s obviousness theo-
ries, plus the waiver of post-trial obviousness theories, the
court held that Barr and Sandoz failed to prove obvious-
ness of the asserted claim by clear and convincing evi-
dence.
       Barr and Sandoz filed this timely appeal. This
court has jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

pound 9 became latanoprost, which is marketed as Xala-
tan®, a leading antiglaucoma treatment.
10                                   ALLERGAN   v. BARR LABS

                       DISCUSSION
     1. The District Court Correctly Held That –N(R4)2
      As Used in the ’819 Patent Includes Compounds
             With Non-Identical R4 Elements
       The district court determined that “the plain and
ordinary meaning of –N(R4)2 would support [Barr and
Sandoz’s] construction that the R4 elements are identical
functional groups,” but went on to find that Allergan had
acted as its own lexicographer in defining –N(R4)2 con-
trary to its ordinary meaning. Allergan, 808 F. Supp. 2d
at 725-26. Barr and Sandoz appeal the district court’s
construction of the –N(R4)2 term, arguing that the plain
and ordinary meaning of –N(R4)2 requires identical R4
elements, and that Allergan failed to make any express
statement departing from that plain and ordinary mean-
ing.
    Claim construction is a question of law subject to de
novo review. Cybor Corp. v. FAS Techs., Inc., 138 F.3d
1448, 1456 (Fed. Cir. 1998) (en banc). Claim terms are
generally given their “ordinary and customary meaning”
as they would be understood by a person of ordinary skill
in the art. Phillips v. AWH Corp., 415 F.3d 1303, 1312-13
(Fed. Cir. 2005) (en banc). “Importantly, the person of
ordinary skill in the art is deemed to read the claim term
not only in the context of the particular claim in which the
disputed term appears, but in the context of the entire
patent, including the specification.” Id. at 1313. Indeed,
“the context in which a term is used in the asserted claim
can be highly instructive,” as can other claims of the
patent in question. Id. at 1314. The inventor’s lexicogra-
phy governs when “the specification [ ] reveal[s] a special
definition given to a claim term by the patentee that
differs from the meaning it would otherwise possess.” Id.
at 1316.
 ALLERGAN   v. BARR LABS                                11

    In this case, a person of ordinary skill in the art
considering the entire ’819 patent would construe the
disputed –N(R4)2 term to encompass nonidentical R4
elements. The disputed claim term arises in independent
claim 5, in which –N(R4)2 is used to claim one of the
molecules that may be located at the C-1 position of the
compound. Claim 5 further recites that R4 must be se-
lected from a Markush group 6 “consisting of hydrogen, a
lower alkyl radical having from one to six carbon atoms,

wherein R5 is a lower alkyl radical having from one to six
carbon atoms.” ’819 patent col. 13 ll. 31-39. [J.A.49]
Asserted claim 10 ultimately depends from claim 5 and
expressly includes three compounds with nonidentical R4
elements, including bimatoprost. 7 Specifically, bimato-
prost has two different substituents at the R4 position,
both of which are claimed in the Markush group: hydro-
gen (H) and an ethyl group (CH2CH3). Id. col. 14 l. 60 -
col. 15 l. 7. Two other compounds listed in claim 10 also

      6      “A Markush group is a listing of specified al-
ternatives of a group in a patent claim, typically ex-
pressed in the form: a member selected from the group
consisting of A, B, and C.” Abbott Labs. v. Baxter Pharm.
Prods., Inc., 334 F.3d 1274, 1280 (Fed. Cir. 2003).
       7     Claim 9 ultimately depends from claim 5 and
claims –N(R4)2 as one of the molecules at the C-1 position.
’819 patent col. 14 ll. 56-57. Claim 10, in turn, depends
from claim 9. Id. col. 14 l. 58. Therefore, although Barr
and Sandoz stress that the –N(R4)2 term does not appear
in claim 10, the compounds in claim 10 plainly contain –
N(R4)2.
12                                     ALLERGAN   v. BARR LABS

feature differing R4 elements. 8 Id. col. 14 ll. 65-67; col. 15
ll. 4-6. Consistently, claim 18, depending from claim 11,
recites the same three compounds as having a –N(R4)2
molecule at the C-1 position. Id. col. 17 ll. 14-22. These
same three compounds, all with nonidentical R4 substitu-
ents of –N(R4)2, also appear in the specification’s list of
“novel compounds [that] may be used in the pharmaceuti-
cal compositions and the methods of treatment of the
present invention.” Id. col. 7 ll. 19-21, 41-49.
       Barr and Sandoz nevertheless focus on the district
court’s preliminary conclusion that the plain and ordinary
meaning of –N(R4)2 required identical R4 elements.
However, this preliminary conclusion was based on ex-
trinsic evidence, such as expert testimony that “[t]he (X)y
nomenclature” was “commonly used” to represent identi-
cal substituents, Allergan, 808 F. Supp. 2d at 725, which
failed to consider the –N(R4)2 term as it was used in the
’819 patent. Phillips, 415 F.3d at 1321 (“Properly viewed,
the ‘ordinary meaning’ of a claim term is its meaning to
the ordinary artisan after reading the entire patent.”)
(emphasis added). When the district court later consid-
ered the term in the context of the ’819 patent, it con-
cluded that Allergan “clearly manifest[ed]” in the claims
and specification that the –N(R4)2 term was meant to
encompass nonidentical R4 elements such as bimatoprost.
Allergan, 808 F. Supp. 2d at 726. Barr and Sandoz’s
argument regarding the plain meaning of –N(R4)2 is
unpersuasive; when properly construed in light of the

      8       These compounds are: cyclopentane N-
isopropyl       heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-
trans-pentenyl)-3, 5-dihydroxy, [1α,2β,3α,5α], and cyclopen-
tane N-methyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-
1-trans-pentenyl)-3, 5-dihydroxy, [1α,2β,3α,5α]. ’819 patent
col. 14 ll. 65-67; col. 15 ll. 4-6 (emphases added).
 ALLERGAN   v. BARR LABS                                13

entire patent, the –N(R4)2 term plainly encompasses
nonidentical R4 substituents.
      2. The District Court Correctly Held That the
        Asserted Claim Is Not Invalid As Obvious
       The district court held that Barr and Sandoz failed
to prove obviousness by clear and convincing evidence.
Barr and Sandoz appeal this determination. First, they
argue that the district court’s adverse credibility determi-
nation of Dr. Mitra did not excuse the court from its
obligation to independently review the submitted prior art
references. Additionally, they assert that their obvious-
ness theories are supported even when considering only
the testimony of Allergan’s experts and corroborating
evidence.
      “The ultimate judgment of obviousness is a legal
determination,” KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 427 (2007), which we review de novo, Procter &
Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 993
(Fed. Cir. 2009). Following a bench trial, underlying
findings of fact are reviewed for clear error. Alza Corp. v.
Mylan Labs., Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006). A
party seeking to invalidate a patent based on obviousness
must prove such obviousness by clear and convincing
evidence. Procter & Gamble Co., 566 F.3d at 993-94. A
patented invention is obvious when “a skilled artisan
would have been motivated to combine the teachings of
the prior art references to achieve the claimed invention,
and [ ] the skilled artisan would have had a reasonable
expectation in doing so.” Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1361 (Fed. Cir. 2007).
14                                   ALLERGAN   v. BARR LABS

     A. The District Court Did Not Err In Finding Expert
         Testimony Was Required To Show Invalidity
       The district court found that Dr. Mitra’s credibility
was “flawed on a fundamental level” and declined to
assign any weight to his opinions. Allergan, 808 F. Supp.
2d at 735. This was a fair assessment of the testimony of
Dr. Mitra, whose prevarication and inconsistency were
repeatedly demonstrated during Allergan’s cross exami-
nation. For instance: (1) Dr. Mitra incorrectly drew the
bimatoprost molecule and utilized slides that inaccurately
represented bimatoprost; (2) his previous testimony given
at another trial directly contradicted his stated opinion
that Stjernschantz persuasively showed the hypotensive
effect of prostaglandin analogues; and (3) his previously
published opinions that bimatoprost was more effective
than latanoprost and acted through a “novel prostamide
receptor” contradicted his trial testimony that bimato-
prost was just a “delivery vehicle” for bimatoprost-free
acid. Id. at 733-34.
       The district court declined to independently “review
the prior art references and weigh their import absent the
guidance of an expert.” Allergan, 808 F. Supp. 2d at 736
n.21. On appeal, Barr and Sandoz challenge this refusal
to consider their obviousness theories, contending that
discrediting Dr. Mitra “did not then permit the [district]
court to ignore all other evidence. . . .” BB.49.
      This court has noted that “‘expert testimony re-
garding matters beyond the comprehension of laypersons
is sometimes essential,’ particularly in cases involving
complex technology.” Wyers v. Master Lock Co., 616 F.3d
1231, 1240 n.5 (Fed. Cir. 2010) (quoting Centricut, LLC v.
Esab Group, Inc., 390 F.3d 1361, 1369-70 (Fed. Cir.
2004)). Obviousness is one area in which expert testi-
mony may be required. See Proveris Scientific Corp. v.
Innovasystems, Inc., 536 F.3d 1256, 1267 (Fed. Cir. 2008)
 ALLERGAN   v. BARR LABS                                  15

(holding the district court did not abuse its discretion “in
requiring [the party asserting invalidity] to present
expert testimony in order to establish invalidity” because
the technology was “sufficiently complex to fall beyond the
grasp of an ordinary layperson.”). In complex cases where
invalidity on the grounds of obviousness is asserted,
“expert testimony may be critical, for example, to estab-
lish the existence of certain features in the prior art or the
existence (or lack thereof) of a motivation to combine
references.” Wyers, 616 F.3d at 1240 n.5 (interior refer-
ences omitted).
     The district court appears to have found this case to
be “sufficiently complex to fall beyond [the] grasp of
ordinary layperson[s].” Allergan, 808 F. Supp. 2d at 736
n.21 (characterizing the holding of Proveris Scientific
Corp., 536 F.3d at 1367). Indeed, this is not a case where
“[t]he technology is simple,” Sundance, Inc. v. DeMonte
Fabricating Ltd., 550 F.3d 1356, 1365 (Fed. Cir. 2008), or
where the references are “easily understandable without
the need for expert explanatory testimony,” Union Car-
bide v. American Can Co., 724 F.2d 1567, 1573 (Fed. Cir.
1984). Additionally, this is emphatically not a case where
“[t]he factual inquiries underlying [the] determination of
obviousness are not in material dispute.” Sundance, Inc.,
550 F.3d at 1365; see, e.g., Allergan, Inc., 808 F. Supp. 2d
at 721 (explaining that “[b]imatoprost’s mechanism of
action is greatly debated in this case,” with Barr and
Sandoz arguing it functions as a “prodrug” with no inher-
ent biological activity, and Allergan arguing that it is not
a prodrug, but rather acts on a novel prostamide recep-
tor). Although in some cases, “the legal determination of
obviousness may include recourse to logic, judgment, and
common sense, in lieu of expert testimony,” Wyers, 616
F.3d at 1239, the district court did not err in finding that
common sense and logic were not sufficiently illuminating
16                                  ALLERGAN   v. BARR LABS

in this case to carry Barr and Sandoz’s burden of proving
obviousness.
     B. Allergan’s Expert’s Testimony Does Not Support
          Barr and Sandoz’s Obviousness Theories
       On appeal, Barr and Sandoz argue that their obvi-
ousness theories are supported by expert testimony: that
of Allergan’s expert, Dr. Timothy L. Macdonald, whose
testimony the district court found to be credible. 9 In
particular, they contend that Dr. Macdonald’s testimony
supports the three facts needed to show the asserted
claim is obvious in view of Stjernschantz and other refer-
ences: (1) Stjernschantz taught that bimatoprost-free acid
lowered IOP; (2) Stjernschantz’s compound 2 hydrolyzed
into bimatoprost-free acid when placed in the eye; and (3)
a skilled artisan would have known that substituting an
amide for the ester at the C-1 position would result in a
prodrug that hydrolyzed into bimatoprost-free acid in the
eye.
       Dr. Macdonald provided testimony consistent with
the first two propositions. See J.A.2086 (testifying that
Stjernschantz taught bimatoprost-free acid would have
the effect of lowering IOP); J.A.2062-63 (testifying that
Stjernschantz taught compound 2 would hydrolyze into
bimatoprost-free acid once in the body). However, his
testimony contradicts the third requirement. Dr. Mac-
donald instead asserted that one of skill in the art would
not have believed substituting an amide at the C-1 posi-
tion would create a prodrug that hydrolyzed into bimato-

       9    Barr and Sandoz also rely on other Allergan
witnesses to support their obviousness claim, but we have
carefully reviewed the record and find nothing in the
testimony of these additional witnesses that could over-
ride Dr. Macdonald’s expert opinion of non-obviousness or
establish clear and convincing evidence of obviousness.
 ALLERGAN   v. BARR LABS                                17

prost-free acid once in the eye. To the contrary, Dr.
Macdonald testified that an amide converts into carbox-
ylic acid at such a slow rate that “one doesn’t consider it
as a candidate [as a prodrug].” J.A.2065-66. He explained
that “a prodrug approach relies on efficient conversion of
the prodrug into the drug,” and the “500-year half life” of
an amide in water was “not an efficient conversion.”
J.A.2067; see also J.A.1996. Dr. Macdonald concluded
that the prior art did not teach or motivate one of skill in
the art to substitute an amide at the C-1 position to create
a glaucoma drug. Given Dr. Macdonald’s testimony to the
contrary, Barr and Sandoz can point to no credible expert
testimony showing that substituting an amide at the C-1
position would have been obvious to a skilled artisan at
the time of the invention. Because of this gap, we hold
that Barr and Sandoz have failed to show obviousness of
the ’819 patent by clear and convincing evidence. 10
                           CONCLUSION
       For the foregoing reasons, we affirm the district
court’s claim construction and determination of nonobvi-
ousness.
                       AFFIRMED

      10   We need not determine whether the district
court abused its discretion in finding that Barr and San-
doz waived their post-trial obviousness theories, because,
as determined above, the record contains insufficient
expert testimony to support any of Barr and Sandoz’s
obviousness theories.