Senju Pharmaceutical Co. v. Lupin Limited , 780 F.3d 1337 ( 2015 )

United States Court of Appeals
for the Federal Circuit
______________________
SENJU PHARMACEUTICAL CO., LTD.,
KYORIN PHARMACEUTICAL CO., LTD.,
ALLERGAN, INC.,
Plaintiffs-Appellants
v.
LUPIN LIMITED, LUPIN PHARMACEUTICALS,
INC.,
Defendants-Appellees
HI-TECH PHARMACAL CO., INC.,
Defendant-Appellee
______________________
2013-1630
______________________
Appeal from the United States District Court for the
District of Delaware in No. 11-CV-0271, 11-CV-0439, 11-
CV-0926, 11-CV-1059, Judge Sue L. Robinson.
______________________
Decided: March 20, 2015
______________________
MARK ANDREW PERRY, Gibson, Dunn & Crutcher LLP,
Washington, DC, argued for plaintiffs-appellants. Also
represented by JEFFREY T. THOMAS, Irvine, CA, LUCAS C.
TOWNSEND, Washington, DC; RICHARD D. KELLY, FRANK
JONAH WEST, STEPHEN G. BAXTER, Oblon, Spivak, McClel-
land, Maier & Neustadt, LLP, Alexandria, VA.
2 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
DEANNE M. MAZZOCHI, Rakoczy Molino Mazzochi
Siwik LLP, Chicago, IL, argued for defendants-appellees
Lupin Limited, Lupin Pharmaceuticals, Inc. Also repre-
sented by WILLIAM A. RAKOCZY, PAUL J. MOLINO, ANUJ
KUMAR WADHWA, JOHN POLIVICK, BRIAN PETER MURRAY.
JEFFREY T. CASTELLANO, Shaw Keller LLP, Wilming-
ton, DE, argued for defendant-appellee Hi-Tech Pharma-
cal Co., Inc. Also represented by KAREN E. KELLER;
STEVEN D. ROTH, Locke Lord, LLP, New York, NY.
______________________
Before NEWMAN, PLAGER, and MOORE, Circuit Judges.
Opinion for the court filed by Circuit Judge PLAGER.
Dissenting opinion filed by Circuit Judge NEWMAN.
PLAGER, Circuit Judge.
This is a patent case brought under the Hatch-
Waxman Act, Pub. L. No. 98-417, 98 Stat. 1585 (“the
Act”), on appeal from the United States District Court for
the District of Delaware. Pursuant to the Act, plaintiffs-
appellants Senju Pharmaceutical Co., Ltd., Kyorin Phar-
maceutical Co., Ltd., and Allergan, Inc. (collectively
“Senju”) sued defendants-appellees Lupin Limited and
Lupin Pharmaceuticals, Inc. (collectively “Lupin”) and Hi-
Tech Pharmacal Co., Inc. (“Hi-Tech”) for infringement of
asserted claims 6 and 12-16 of reexamined U.S. Patent
No. 6,333,045 (“the ’045 patent”). Defendants counter-
claimed seeking a declaratory judgment of non-
infringement and invalidity. The district court, Judge
Sue L. Robinson, adjudged the claims infringed but inva-
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 3
lid for obviousness. Plaintiffs appeal the invalidity judg-
ment. 1
I. INTRODUCTION
The invention at issue relates to gatifloxacin, an
aqueous liquid pharmaceutical eye drop composition, with
added disodium edetate (“EDTA”). Seven prior art pa-
tents are alleged as the basis for the obviousness deter-
mination, each containing some of the same chemistry as
the claimed invention. In addition, there are several prior
patent infringement suits involving the same chemistry
and the same ’045 patent; these suits are relevant, though
to some extent the issues and parties vary. Three of these
infringement suits, including this one, have all been tried
before and decided by the same district judge in the
District of Delaware.
The underlying issues in this case—constructive in-
fringement under Hatch-Waxman, countered by alleged
non-infringement and invalidity for obviousness—are
familiar patent issues. Yet, the combination of the chem-
istry and the prior litigation has produced here a complex
of arguments by both parties. We address below in detail
only those arguments that we believe have saliency with
regard to the outcome.
Regarding the prior law suits, the first began in
2007. Pursuant to the Hatch-Waxman Act, a manufac-
turer of generic drugs, Apotex Inc. and Apotex Corp.
(“Apotex”), filed an Abbreviated New Drug Application
(“ANDA”) with the Food and Drug Administration
(“FDA”), seeking to market generic versions of Allergan’s
1 Hi-Tech filed a brief in which it adopted by refer-
ence and joined most of Lupin’s brief. Hi-Tech’s addition-
al arguments in its brief relate to issues of intervening
rights, which in view of the outcome we need not address
in this opinion.
4 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
gatifloxacin product Zymar®. The patent on Zymar® was
listed in the FDA’s record of Approved Drug Products
With Therapeutic Equivalence, what is known as the
“Orange Book.”
In this first suit, the district court in 2010 ruled that
the asserted claims were infringed, but that claims 1-3
and 6-9 were invalid as obvious over the prior art. How-
ever, the court found that defendant Apotex failed to
demonstrate that claims 6 and 7 were invalid for lack of
enablement and failed to demonstrate inequitable con-
duct. Senju Pharm. Co. v. Apotex Inc., 717 F. Supp. 2d
404, 433 (D. Del. 2010) (“Apotex 1”).
Following a motion for a new trial, or, alternatively, to
amend judgment and findings regarding claim 7, the
court reopened the case to consider additional evidence
regarding claim 7. Thereafter, the court in 2011 found
claim 7 obvious by clear and convincing evidence. Senju
Pharm. Co. v. Apotex Inc., 836 F. Supp. 2d 196, 210-11 (D.
Del. 2011) (“Apotex 2”). On appeal of the judgment re-
garding claim 7, this court affirmed the judgment of
invalidity in a summary affirmance, Senju Pharm. Co. v.
Apotex Inc., 485 F. App’x 433 (Fed. Cir. 2012) (“Apotex I”);
the other parts of the district judge’s rulings were not
appealed.
Meanwhile, in February 2011, before final judgment
was entered in that litigation, the Senju plaintiffs peti-
tioned the Patent and Trademark Office (“PTO”) for ex-
parte re-examination of the ’045 patent. Plaintiffs sub-
mitted the prior art, the arguments relied upon by the
court and parties, and the court’s opinion. However,
plaintiffs did not notify either the defendants or the court
that they were seeking re-examination; it was not until
shortly before the re-examination was completed that the
trial court was informed.
On initial reexamination, the PTO agreed with the
district court that the original claims would have been
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 5
obvious in light of the cited prior art patents. Subse-
quently, in October 2011, the PTO issued a reexamination
certificate for the ’045 patent which cancelled claims 1-3
and 8-11, allowed amended claim 6, and added claims 12-
16.
Then plaintiff Senju filed another suit against Apotex,
alleging infringement of the reexamined claims and
seeking a declaratory judgment of infringement based on
the same ANDA filing at issue in the first litigation.
Apotex responded to the new action by seeking dismissal
on the grounds of res judicata, or claim preclusion (“claim”
here referring to the civil procedure concept, not the
patent law meaning).
Ultimately the district court sided with Apotex and
gave judgment against Senju on the grounds of claim
preclusion: “the reexamination of the patent-at-issue did
not create a new cause of action against the same previ-
ous defendants and accused product.” Senju Pharm. Co.
v. Apotex Inc., 891 F. Supp. 2d 656, 662 (D. Del. 2012)
(“Apotex 3”). On appeal, this judgment was upheld in an
extensive opinion by the Federal Circuit, Senju Pharm.
Co. v. Apotex Inc., 746 F.3d 1344 (Fed. Cir. 2014) (“Apotex
II”).
While all this was going on, Senju, in 2011, filed the
suit at issue here against the Lupin and Hi-Tech defend-
ants, asserting infringement under the Hatch-Waxman
Act of the ’045 patent. 2 As in the second suit against
Apotex, Senju specifically alleged infringement of the
reexamined claims 6 and 12-16, this time based on Lu-
2 Civ. No. 11-271, filed March 31, 2011, against Lu-
pin, was consolidated with Civ. Nos. 11-439, filed May 18,
2011, against Lupin, as well as 11-926, filed October 11,
2011, and 11-1059, filed October 31, 2011, against Hi-
Tech.
6 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
pin’s earlier-filed ANDA Nos. 202-653, 0.5 w/v% gatifloxa-
cin and 202-709, 0.3 w/v% gatifloxacin, as well as Hi-
Tech’s ANDA Nos. 203189, 0.5 w/v% gatifloxacin and
203190, 0.3 w/v% gatifloxacin. The Lupin and Hi-Tech
defendants had sought FDA approval to market and sell
generic copies of Senju’s FDA approved gatifloxacin
ophthalmic solution.
Lupin moved for judgment on the pleadings, alleging
that the narrower reexamined claims of the ’045 patent
were invalid for obviousness, and that plaintiffs should be
collaterally estopped from relitigating these claims based
on the court’s findings in Apotex 3. The district court
ruled that, although Lupin might later at trial succeed in
showing that the reexamined claims were invalid for
obviousness, Senju in the Apotex 1 & 2 litigations had not
fully litigated a claim with a limitation of 0.01 w/v%
EDTA and, therefore, collateral estoppel would not ap-
ply. 3 J.A. 7.
As noted earlier, the ’045 patent is directed to aque-
ous liquid pharmaceutical compositions comprising gat-
ifloxacin and EDTA, as well as various methods utilizing
these compositions. The ’045 patent’s original U.S. filing
date is April 21, 2000. The reexamined claims at issue
are:
6. A method for raising corneal permeability of an
aqueous pharmaceutical Gatifloxacin eye drop so-
lution comprising Gatifloxacin or its salt, having a
pH of from above 5 to about 6 containing from
about 0.3 to about 0.8 w/v% Gatifloxacin or its
salt, which comprises incorporating about 0.01
3 At the time of trial, the district court declined to
entertain Lupin’s renewed collateral estoppel argument.
J.A. 7.
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 7
w/v% disodium edetate into said Gatifloxacin eye
drop solution.
12. An aqueous liquid pharmaceutical eye drop
composition which comprises from about 0.3 to
about 0.8 w/v% Gatifloxacin or its salt, about
0.01 w/v% disodium edetate, and wherein the
aqueous liquid pharmaceutical composition has a
pH of from about 5 to about 6.
13. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising
about 0.3 w/v% Gatifloxacin or its salt.
14. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising
about 0.5 w/v% Gatifloxacin or its salt.
15. The aqueous liquid pharmaceutical eye drop
composition according to claim 12, comprising at
least one isotonic agent selected from the group
consisting of sodium chloride, potassium chloride,
glycerin, mannitol and glucose.
16. The aqueous liquid pharmaceutical eye drop
composition according to claim 14, wherein the at
least one isotonic agent is sodium chloride.
’045 patent Reexamination Certificate, 1:25-2:24; J.A.
2702.
The district court, having reserved the question of in-
fringement and the validity of the reexamined claims in
light of the prior art of record, proceeded to trial. The
court’s ultimate judgment was that the reexamined
claims were infringed, but were invalid for obviousness.
Thus, the question before us is in this appeal is whether
the district court erred when, in the current suit against
Lupin and Hi-Tech, it concluded that reexamined claims 6
and 12-16 of the ’045 patent were invalid for obviousness.
8 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
We have jurisdiction under 28 U.S.C. §§ 1292(c)(2) and
1295(a).
II. DISCUSSION
A. Standard of Review
Obviousness is a question of law that we review with-
out deference. Pozen Inc. v. Par Pharm., Inc., 696 F.3d
1151, 1160 (Fed. Cir. 2012). Following a bench trial, we
review underlying factual determinations for clear error.
Id.
An obviousness inquiry assesses “the differences be-
tween the subject matter sought to be patented and the
prior art” to ascertain whether “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)
(1994). “[A] patent composed of several elements is not
proved obvious merely by demonstrating that each of its
elements was, independently, known in the prior art.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Thus, a defendant asserting obviousness in view of a
combination of references has the burden to show by clear
and convincing evidence that a person of ordinary skill in
the relevant field had reason to combine the elements in
the manner claimed. Id. at 418-19. In addition to show-
ing a reason to combine the elements in the manner
claimed, a defendant must also demonstrate that a person
of ordinary skill would have a reasonable expectation of
success in combining the elements. PharmaStem Thera-
peutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed.
Cir. 2007).
B. Analysis
The Senju appellants make two main arguments re-
lating to obviousness: (1) the district court erred by find-
ing that the prior art taught using 0.01 w/v% EDTA in an
ophthalmic formulation would work to increase corneal
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 9
permeability; and (2) the district court erred by finding
appellants’ proffer of evidence of unexpected results
unavailing. We will consider each of these arguments in
turn.
1. Obviousness
Before addressing the substantive obviousness analy-
sis conducted by the district court, we address Senju’s
arguments regarding the methodology the district court
used in its analysis. First, appellants argue that the
district court improperly utilized its obviousness findings
from its decision in Apotex 1 as the basis from which to
begin its invalidity inquiries in this case, essentially
lessening appellees’ burden of proving by clear and con-
vincing evidence that the reexamined claims asserted in
the present case would have been obvious. Appellants
argue that the district court’s factual findings in Apotex 1
should have played no role in the invalidity inquiry in this
case because the currently asserted reexamined claims
contain new limitations and disclose only a narrow subset
of the original claimed invention, commensurate with
objective evidence of unexpected results.
Appellants argue that the district court relied upon
findings from Apotex 1 regarding EDTA concentrations
and pH range to conclude that the new limitations in the
reexamined claims do not distinguish the claimed inven-
tions from the prior art. They argue that the court ana-
lyzed the claims in piecemeal fashion, violating the
requirement in section 103 of the Patent Act that courts
analyze the obviousness of an invention “as a whole.” See
35 U.S.C. § 103(a).
Appellants argue that the district court by this meth-
od of analysis effectively applied a presumption of invalid-
ity to the reexamined claims, resulting in the district
court’s failure to evaluate the limitations holistically. In
effect, appellants argue, the district court used the prede-
cessor claims as prior art to the present claims even
10 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
though such methodology is erroneous as a matter of law.
Appellant Br. 63-64 (citing Interconnect Planning Corp. v.
Feil, 774 F.2d 1132, 1137 (Fed. Cir. 1985)).
Appellees respond that appellants’ pursuit of reex-
amined claims 6 and 12-16 was merely a failed attempt to
bypass the district court’s Apotex 1 invalidity judgment
and prior art teachings and that appellants cannot now
claim the district court’s methodology is the reason for
their failings. Appellees argue that the district court did
not err by declining to repeat the identical reasoning for
identical factual findings that appellants never appealed
in Apotex 1. Appellees note that appellants’ singular
focus at trial was the 0.01 w/v% EDTA for corneal perme-
ability and that appellants never raised the arguments
rejected in Apotex 1, or new arguments outside this issue.
Thus, appellees argue, the district court properly declined
to “find” anew facts appellants did not dispute at trial or
those already found and not appealed in Apotex 1 because
such facts are undisputed. Nevertheless, appellees point
out that the district court properly made new fact findings
specific to the reexamined claims as a whole, even beyond
the 0.01 w/v% EDTA issue appellants pursued at trial,
repeating a complete obviousness analysis for each claim
appellants asserted, and supporting all of its findings
with evidence of record from this case.
In support of their position that the district court used
the predecessor claims as prior art to the present claims
and failed to analyze the reexamined claims holistically,
appellants cite Interconnect Planning Corp., 774 F.2d
1132. In Interconnect, we held that the district court
improperly weighed the changes in the reissue claim
against the original claim and failed to consider the
differences between the prior art and the reissue claim as
a whole. Id. at 1137. This case is distinguishable from
the present case. Contrary to appellants’ characteriza-
tion, the district court in the present case did not hand-
pick limitations in the reexamined claims to analyze.
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 11
Instead, the district court focused on appellants’ own
arguments, which highlighted key claim limitations that
distinguished the reexamined claims from the prior art
generally.
We conclude that the district court properly consid-
ered as a whole all of the limitations in appellants’
amended and newly-added claims, including “using 0.3
w/v% to 0.8 w/v% gatifloxacin;” a “pH of above 5 to about
6;” and “using 0.01 w/v% EDTA,” including “to increase
corneal permeability” in the context of the prior art.
Specifically, the district court stepped through the disput-
ed claim limitations and pointed out where each is found
in the prior art, along with the reasoning for combining
the prior art to reach the disclosure in the asserted
claims. See, e.g., J.A. 25-34.
Moving on to the conclusion of obviousness by the dis-
trict court, we address first the obviousness of claims 12-
16, the composition claims, and then the obviousness of
claim 6, a method claim. The four prior art references
from the Apotex 1 & 2 cases, U.S. Patent Nos. 4,551,456
(“the ’456 patent”), 4,780,465 (“the ’465 patent”), and
4,980,470 (“the ’470 patent”), and Grass 1985 4, are again
at issue in this case.
The earliest of the prior art patents, the ’456 patent,
issued on November 5, 1985, teaches that then-known
quinolones are both “compatible with ocular tissue” and
useful in treating bacterial ocular infections through
topical administration. ’456 patent, 1:13-17. The ’456
patent also discloses an exemplary ophthalmic composi-
tion that comprises an aqueous solution of 0.3 w/v%
4 “Grass 1985” is Grass et al., Effects of Calcium
Chelating Agents on Corneal Permeability, 26 Investiga-
tive Ophthalmology & Visual Science 110 (1985). J.A.
2707-10.
12 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
norfloxacin and 0.01 w/v% EDTA, as well as the use of
EDTA as one of 8 conventional excipients. Id. at 2:5-10.
The ’465 patent, issued on October 25, 1988, discloses
aqueous compositions for the quinolone lomefloxacin, also
characterizing EDTA as a conventional excipient. ’465
patent, 2:31-46. The ’465 patent describes two exemplary
ophthalmic compositions, similar to the ophthalmic
composition disclosed by the ’456 patent, containing 0.3
w/v% lomefloxacin and 0.01 w/v% EDTA. Id. at 4:1-23.
The ’470 patent, issued on December 25, 1990, teaches
that gatifloxacin represents an improvement over the
prior art quinolones in that it exhibits a broader antibac-
terial activity, higher selective toxicity and safe oral and
parenteral administration. ’470 patent, 1:32-61. The ’470
patent also teaches that each of the disclosed quinolones
have “similar substituents,” id. at 1:41-43, and that
pharmaceutical formulations of gatifloxacin follow “the
routes well known” with respect to “oral[ ] and parenteral
[ ]” administration, including “liquids [and] eye drops.”
Id. at 7:21-26.
The Grass 1985 reference is directed to the study of
EDTA’s impact on the permeability of organic and inor-
ganic compounds with respect to the corneal epithelia.
J.A. 2707. Grass 1985 teaches that EDTA can reduce the
number of calcium ions through chelation, thus creating
small channels between corneal epithelial cells, which
allow polar molecules to penetrate through the cornea
into the aqueous humor of the eye. Grass 1985 specifical-
ly reports that the addition of 0.5 w/v% EDTA to separate
solutions of glycerol and cromolyn resulted in increased
corneal permeability in both solutions. A lower unspeci-
fied concentration of EDTA was also shown to function in
this manner, albeit to a lesser extent.
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 13
In addition to these four references, appellees also
raise the Grass 1988-I 5, Grass 1988-II 6, and Rojanasakul 7
references, mainly to address the additional claim limita-
tions in the narrower, reexamined claims. The Grass
1988-I and Grass 1988-II references build on the work in
Grass 1985 (collectively, “Grass references”), testing lower
concentrations of 0.1, 0.05, and 0.01 w/v% EDTA, finding
increased corneal permeability at these lower concentra-
tions. The Rojanasakul reference is directed to studying
the promoting mechanisms of various penetration en-
hancers, including EDTA, in the cornea, as well as to
developing methods for evaluating tissue damage and
viability. J.A. 2788. This reference builds further on the
teachings of the Grass references by testing EDTA con-
centrations as low as 0.00037 w/v% EDTA, and finding
that even these very low concentrations increased corneal
permeability to some degree. J.A. 2795-96.
Appellants also raise two additional references, the
Mitra reference and the Kompella reference, as evidence
of nonobviousness. The Mitra reference is a comprehen-
sive review of ophthalmic drug delivery systems. J.A.
2768-72. The Mitra reference specifically studies the
mechanisms of EDTA for corneal drug penetration exam-
5 “Grass 1988-I” is Grass et al., Mechanisms of Cor-
neal Drug Penetration 1: In Vivo and In Vitro Kinetics, 77
Journal of Pharm. Sciences 3 (1988). J.A. 2773-84.
6 “Grass 1988-II” is Grass et al., Mechanisms of
Corneal Drug Penetration II: Ultrastructural Analysis of
Potential Pathways for Drug Movement, 77 Journal of
Pharm. Sciences, 15 (1988). J.A. 2800-08.
7 “Rojanasakul” is Rojanasakul et al., Mechanisms
of action of some penetration Enhancers in the Cornea:
Laser Scanning Confocal Microscopic and Electrophysiol-
ogy Studies, 66 Int’l Journal of Pharm., 131 (1990). J.A.
2787-98.
14 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
ining the concentrations at which increases in permeabil-
ity of the cornea occur. J.A. 2772. The Kompella refer-
ence is a peer-reviewed abstract that reinforces the
teachings of Mitra, studying the impact of EDTA on
corneal permeability. J.A. 2810-11.
First, appellants argue that the seven prior art refer-
ences relied upon by the district court predate the claimed
invention by at least eight years, which, “is itself evidence
of nonobviousness.” Appellant Br. 25 (citing Panduit
Corp. v. Dennison Mfg. Co., 810 F.2d 1561, 1577 (Fed. Cir.
1987)). Second, appellants argue that the district court
misconstrued the teachings of the prior art. Specifically,
with respect to claims 12-16, appellants argue that a
skilled artisan would not have been motivated to cherry-
pick individual limitations from the ’456, ’465, and ’470
patents and combine them to achieve the compositions of
claims 12-16. Appellants argue that the district court
erred in selectively excerpting teachings from these three
prior art references to reverse-engineer the claimed
invention. In its analysis, appellants argue, the district
court failed to consider whether an ordinary practitioner
would have had a reason to make the multiple selections,
combinations, and modifications needed under its analy-
sis to arrive at the claimed compositions.
Appellants also argue that the district court improper-
ly declined to consider evidence on corneal permeability
with reference to the composition claims. Appellants
point out that corneal permeability is relevant to these
claims because the claimed compositions embody the
method of reexamined claim 6 and the purpose of the
composition and the functions of its limitations cannot be
divorced from the obviousness inquiry. Appellant Reply
Br. 19 (citing Leo Pharmaceutical Products, Ltd. v. Rea,
726 F.3d 1346, 1353, 1356 (Fed. Cir. 2013)). Because,
according to appellants, no prior art disclosed 0.01 w/v%
EDTA as preferred for the purpose of raising corneal
permeability, appellants argue that they did more than
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 15
merely seek to patent a combination of known ingredients
to achieve established functions.
Appellants argue that the district court improperly
found claims 12-16 obvious without finding that the ’456,
’465, and ’470 patents actually teach any gatifloxacin
formulations for ocular administration. Appellants argue
that the district court improperly surmised that the ’456
patent teaches that quinolones are useful in treating
bacterial infections, the ’465 patent teaches that EDTA is
a conventional excipient for use with the quinolone lomef-
loxacin, and the ’470 patent teaches that gatifloxacin
formulations can be used in known routes of oral and
parenteral administration, including liquid eye drops.
Based on these conclusions, appellants argue that the
district court then improperly relied on the fact that
gatifloxacin is a member of the quinolone family of com-
pounds to combine the ’456 and ’470 patents and arrive at
the idea of an ophthalmic gatifloxacin solution, pulling
teachings of gatifloxacin concentrations and pH from the
’456 and ’465 patents and 0.01 w/v% EDTA from the ’456
patent to arrive at the specific ranges recited in the
claims. Essentially, appellants argue that the district
court selectively excerpted teachings from each of the
three prior art patents to improperly reverse-engineer the
claimed invention. Appellants point out that this is
improper hindsight bias because the ’456, ’465, and ’470
patents themselves do not disclose anything about corneal
permeability of gatifloxacin solutions and, therefore,
provide no reason to arrive at the claimed compositions.
Appellants argue that the district court failed to identify
any reasons for a skilled artisan to combine the prior art
to achieve the claimed invention, finding only that a
skilled artisan would have been motivated to use gatiflox-
acin and EDTA together and that the claimed pH and
EDTA concentration limitations are found in the prior art.
16 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
Appellees respond that, with respect to claims 12-16,
not only did appellants waive the issue of the years be-
tween the publication of the prior art and the filing date
of the ’045 patent application being “itself evidence of
nonobviousness” by raising this issue for the first time on
appeal, but also that the Panduit case appellants cite in
support of their position is not comparable to the current
case. Appellees point out that in the Panduit case, there
were no prior art references at issue that disclosed or
suggested all of the claimed structural limitations, while
in this case several prior art references do just that.
Appellee Br. 38 (citing Panduit, 810 F.2d at 1577).
With respect to appellants’ main obviousness argu-
ments, appellees point out that because the composition
claims do not contain the corneal permeability limitation
found in method claim 6, the corneal permeability teach-
ing away arguments are irrelevant to claims 12-16.
Appellees argue that the only composition element appel-
lants deemed missing from the ’456 and ’465 quinolone
ophthalmic formulation patents was an express mention
of gatifloxacin for improving corneal permeability of any
drug. Appellees argue, however, that when combined
with the ’470 patent, this limitation of the claims is
obvious. Additionally, appellees argue there was suffi-
cient reason to combine the claims in these three patents
to render the asserted claims obvious.
Appellees characterize the ’456 patent as teaching us-
ing norfloxacin and structurally related antibodies in
topical ocular formulations, while the ’465 patent taught
preparing stable ophthalmic fluoroquinolone composi-
tions, with both patents containing ingredient ranges
encompassing those claimed. Both the ’456 and ’465
patents also taught topical ocular formulations containing
various features encompassed by the composition claims,
such as 0.01 w/v% EDTA and 5.2 pH. Because the art
viewed gatifloxacin as an improved fluoroquinolone,
appellees argue that one of ordinary skill in the art would
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 17
have had reason to combine the ’470 patent’s gatifloxacin
disclosure to improve the ’456 and ’465 patents’ formula-
tions.
Appellees also argue that these disclosures combined
with appellants failure to dispute that the art viewed
gatifloxacin as an improved fluoroquinolone, provides the
reason why one of ordinary skill would want to improve
the ’456 and ’465 patents by incorporating the ’470 pa-
tent’s gatifloxacin. Appellees point out that the ’470
patent’s gatifloxacin eye drop teaching is directed to the
same drug class as the ’456 and ’465 patents and provides
evidence that gatifloxacin should work in the ’456 patent’s
formulation.
With respect to claims 12-16, we conclude that the
district court properly held these claims obvious. Appel-
lants’ argument relating to the eight year gap between
the prior art and the filing of the ’045 patent application
is unconvincing and not properly raised. Appellants only
show of support for this issue being raised prior to this
appeal is a single citation to the district court opinion in
which appellants argue, in a footnote, that the district
court “acknowledged the vintage of the prior art,” citing to
portions of the district court opinion that merely recite the
years in which the prior art was published. Appellant Br.
19 n.4 (citing J.A. 10-14). This is insufficient discussion
to consider this argument raised at the district court, and
this argument is, therefore, waived. See Sage Prods., Inc.
v. Devon Indus., Inc., 126 F.3d 1420, 1426 (Fed. Cir. 1997)
(finding that “[w]ith few notable exceptions . . . appellate
courts do not consider a party’s new theories, lodged first
on appeal”).
For the purpose of claims 12-16, the main focus of ap-
pellants’ appeal brief was on the inclusion of the corneal
permeability limitation in the analysis of the validity of
these claims. We conclude that the district court properly
found that corneal permeability is not relevant in the
18 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
discussion of composition claims 12-16 because these
claims do not contain the corneal permeability limitation
found in method claim 6, discussed below. J.A. 24 n.25.
We do not find persuasive appellants’ argument that
it is necessary to consider corneal permeability when
analyzing claims 12-16 because the claimed compositions
embody the method of reexamined claim 6. The Leo
Pharmaceutical Products, Ltd. v. Rea, 726 F.3d 1346,
1349-50 (Fed. Cir. 2013), case appellants cite in support of
their argument examines a composition claim that in-
cludes as a limitation the function of the composition. In
composition claims 12-16 of the ’045 patent, there is no
limitation denoting the function of the composition and
we decline to import this limitation into the claims. See
Phillips v. AWH Corp., 415 F.3d 1303, 1323 (Fed. Cir.
2005) (stating that we have repeatedly warned against
confining the claims to particular embodiments in the
written description).
Further, there were several other factors in Leo
Pharmaceutical that led the court to conclude that the
claims were nonobvious, including a lack of reasons for
one of ordinary skill in the art to combine the asserted
prior art references. Leo Pharm., 126 F.3d at 1354. In
the present case, there were sufficient reasons to improve
upon the ’456 and ’465 patents by utilizing gatifloxacin, as
disclosed in the ’470 patent, and described fully below.
All three of these patents relate to quinolones and their
derivatives for use as antibacterial agents, and we con-
clude that the district court properly determined that
combining them would have been obvious to one of ordi-
nary skill in the art.
The ’045 and ’456 patents disclose ophthalmic quino-
lone compositions in topical ocular formulations, which
gave reasons to one of ordinary skill in the art to combine
with the gatifloxacin disclosure of the ’470 patent because
gatifloxacin was recognized in the art as an improved
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 19
fluoroquinolone. Appellants never disputed that the art
viewed gatifloxacin as an improved fluoroquinolone.
Thus, it would have been obvious to improve the ’456 and
’465 patent formulations by incorporating the ’470 pa-
tent’s gatifloxacin.
Many of appellants’ arguments on the lack of reasons
to combine the teachings of these three patents rely on
the fact that they do not disclose anything about corneal
permeability of gatifloxacin solutions. As discussed
above, this is not a limitation of claims 12-16 and, there-
fore, is not relevant to the obviousness determination.
Lastly, the use of gatifloxacin with EDTA would have
been obvious to a person of ordinary skill in the art.
EDTA is listed among eight “conventional ingredients” in
the ’456 patent and a similar group of excipients. ’456
patent, 2:1-16; ’456 patent, 2:36-49. Further, the use of
0.3 to 0.8 w/v% of gatifloxacin is outlined in the prior art,
such as in the ’456 patent, 1:37-43 (“from about 0.03 to
3%”), and in the ’465 patent, 2:22-25 (“preferably about
0.3% to 5% w/v”). As the district court pointed out the use
of 0.01 w/v% EDTA was also known from the ’456 patent,
which discloses an exemplary formulation of 0.3% quino-
lone solution that incorporates 0.01 w/v% EDTA, and
teaches using “from about 0.03 to 3% and especially 0.15%
to 0.6% of medicament although higher or lower dosages
can be employed.” ’456 patent at 1:37-40, 4:1-23.
Based on the foregoing, we conclude that the district
court properly held that claims 12-16 were invalid as
obvious.
Next, we analyze whether method claim 6 would have
been obvious. In general, appellants argue that the
district court improperly found that all of the features of
claim 6 of the ’045 patent are disclosed in the prior art,
and that appellees failed to prove invalidity of claim 6 by
clear and convincing evidence. Specifically, appellants
argue that nothing in the prior art reasonably suggested
20 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
that the claimed limitations of 0.01 w/v% EDTA at pH 5-6
would have any effect in improving gatifloxacin’s corneal
permeability in vivo. In fact, appellants argue, the prior
art expressly taught that these claimed limitations would
have no effect on corneal permeability.
Appellants argue that several prior art references
which teach away from the claimed invention, including
the Mitra and Kompella references, are notably absent
from the district court’s invalidity analysis. Appellants
argue that the district court’s boilerplate language stating
that it had “considered the documentary evidence and
testimony” is insufficient to discharge the challenger’s
burden of proving obviousness. Appellant Reply Br. 3
(citing In re Cyclobenzaprine Hydrochloride Extended-
Release Capsule Patent Litig., 676 F.3d 1063, 1075, 1077
(Fed. Cir. 2012)). Appellants argue that, by addressing
only those references that, in the view of the district
court, pointed towards obviousness, the district court
failed to weigh all of the evidence on both sides of the
question of invalidity.
Appellants argue that the prior art taught the use of
high EDTA concentrations to increase corneal permeabil-
ity, not the use of low EDTA concentrations, such as those
disclosed in the ’045 patent. For example, appellants
argue that in the Kompella reference, researchers used
EDTA at a concentration of 0.5 w/v%, fifty times that of
the ’045 patent, to increase corneal permeability of sever-
al beta-blockers, while also teaching that increasing pH to
8.4—well above the claimed pH range of 5-6—improved
corneal permeability. Appellants further argue that the
Mitra reference expressly discouraged seeking to improve
corneal permeability using the claimed EDTA concentra-
tion in vivo, reporting that such concentrations are “de-
void of any effects” in in vitro experiments. Thus,
appellants argue, both Mitra and Kompella suggest a line
of development pointing towards higher EDTA concentra-
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 21
tions and higher pH levels to increase corneal permeabil-
ity—and thus away from the claimed invention.
Appellants also argue that the Grass references do not
render claim 6 obvious. Specifically, appellants argue
that Grass 1985 did not study the corneal permeability of
gatifloxacin or any quinolone, nor did it employ concen-
trations and conditions resembling those specified in the
reexamined claims. Further, appellants argue that Grass
1988-I explicitly reported that 0.01 w/v% EDTA has “0”
effect on corneal permeability in vitro, reporting the
results for 0.01 w/v% EDTA statistically indistinguishable
from zero. Appellants argue that the district court im-
properly focused on the Grass 1988-I raw data to find
increased permeability even though the percentage
change was reported as zero.
Appellants further argue that the district court’s reli-
ance on the Rojanasakul reference was misplaced. Appel-
lants point out that Rojanasakul did not measure the
passage of any molecule through the corneal membrane,
rather, Rojanasakul measured changes in the electrical
resistance of corneal tissue, using electrical resistance as
a general proxy for membrane permeability of ions.
According to appellants, appellees did not deny that
Rojanasakul did not measure the corneal permeability of
any molecule, relying only on attorney argument to sup-
port its position that a person of ordinary skill in the art
would have expected electrical resistance to correlate with
the corneal transport of gatifloxacin based on Rojanasa-
kul. Further, appellants argue that the district court
misconstrued Rojanasakul, which uses “permeability” to
refer not only to the permeability of the corneal mem-
brane comprising the surface of the eye, but also to per-
meability of the plasma membrane surrounding
individual cells. Thus, the increase in permeability
disclosed in Rojanasakul is not applicable to the asserted
claims.
22 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
Appellants argue that because none of the ’456, ’465,
and ’470 patents even mention corneal permeability,
these prior art patents would not have provided a reason
for a skilled artisan to seek improved corneal permeabil-
ity using low EDTA concentrations. Appellants argue
that if it was as simple as incorporating gatifloxacin into
existing formulations, as appellees contend, this invention
would have likely been achieved within months as op-
posed to the eight years that passed before anyone con-
ceived the claimed compositions. Appellants argue that
the inclusion of EDTA among the possible excipients
mentioned in the ’456 and ’465 patents does not render its
eventual use in raising corneal permeability of gatifloxa-
cin unpatentable, because the asserted claims, at a mini-
mum, present a new way of using an existing drug.
Lastly, appellants argue that the prior art taught the
use of higher pH, not lower pH, to improve corneal per-
meability. Appellants argue that the prior art uniformly
taught using pH levels higher than the claimed range of
5-6, citing Grass 1985 (pH 7.4), Grass 1988-I (pH 7.4-7.6),
Grass 1988-II (pH 7.4), Kompella (pH 8.4), and Rojanasa-
kul (pH 7.4). Appellants point out that the only evidence
appellees have of a change in permeability is a decrease in
permeability when lowering the pH, not an increase in
permeability with a decrease in pH as claimed in the
patent. Thus, appellants argue that the evidence con-
firms the surprising nature of the inventors’ discovery
that 0.01 % w/v% EDTA formulations significantly in-
crease gatifloxacin concentrations in the aqueous humor,
even at relatively low pH levels.
Appellees respond that appellants’ experts offered no
opinions defending the non-obviousness of the claim
elements relating to pH, gatifloxacin percentages, use of
isotonic agents, or the combination thereof in an oph-
thalmic formulation. Instead, appellees argue, appellants’
expert opined solely upon the question of whether one of
ordinary skill would expect 0.01 w/v% EDTA to work to
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 23
increase corneal permeability. Thus the district court
correctly found that all of the features of the asserted
claims of the ’045 patent are disclosed in the prior art.
Appellees argue that the district court was not obli-
gated to cite the Kompella and Mitra references in its
opinion. Appellee Br. 45 (citing MySpace, Inc. v.
GraphOn Corp., 672 F.3d 1250, 1263-64 (Fed. Cir. 2012);
Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315
F.3d 1335, 1343 (Fed. Cir. 2003)). Appellees point out
that the district court explained that it considered the
documentary evidence and testimony, along with the
parties’ post-trial briefing, which discussed both of these
references. Thus, appellees argue, the references were
presumptively considered.
Further, appellees argue that neither the Kompella or
Mitra references teach away from the claimed invention.
According to appellees, the Kompella reference says
nothing derogatory about 0.01 w/v% EDTA or lower pH
ranges, never even testing or commenting on 0.01 w/v%
EDTA formulations. Appellees also argue that the Mitra
reference nowhere discourages investigation or dissuades
the development of 0.01 w/v% EDTA formulations for
polar drugs, such as gatifloxacin, which has an ability to
readily ionize and contains several polar moieties. J.A.
10. In fact, appellees argue, appellants mischaracterize
the disclosure in Mitra that 0.2 and 5 mM EDTA doses
are devoid of any effects, omitting the important fact that
the numbers for these tests were with a different com-
pound, even without EDTA, that had no transport across
the membranes. Appellees argue that Mitra supports
Grass’s teachings that a range of EDTA levels increased
corneal permeability, recognizing that an EDTA drug
combination deserves some consideration in improving
the bioavailability of poorly penetrating drugs. Appellee
Br. 16 (citing J.A. 2772).
24 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
Appellees add that Grass 1985 taught the broad effect
of EDTA’s corneal permeability-increasing properties,
recognizing that since “chelating agents are added rou-
tinely to ophthalmic medications for stability purposes,”
the results of the Grass tests would have a “direct bearing
upon ophthalmic solutions currently in use” even though
such solutions used EDTA amounts “at lower concentra-
tions.” Appellee Br. 10-11 (citing J.A. 2707, 2709-10).
Appellees also argue that appellants mischaracterize the
Grass 1988-I and Grass 1988-II references as establishing
a 0.01 w/v% threshold where EDTA’s effect on corneal
permeability was zero. Instead, as Lupin’s expert ex-
plained, it is appellees position that the art showed the
skilled person that “EDTA works at exceedingly low
concentrations” and did not “magically start” at a specific
number. Appellee Br. 12-13 (citing J.A. 1695). Appellees
further point out that there is no support for appellants’
argument that the “0” assigned to the 0.01 w/v% EDTA
numbers in Table XIII of Grass 1988-I means that the
measured result is unreliable. Instead, appellees argue,
this “0” simply signifies that the data did not reach statis-
tical significance, even though one of ordinary skill read-
ing Grass 1988-I observed raw data confirming an actual
measured increase of corneal permeability, even at 0.01
w/v% EDTA levels.
As characterized by appellees, Senju’s arguments with
respect to Rojanasakul include a variety of uncited attor-
ney characterizations about the reference’s teachings that
no trial witness offered. Appellees point to Rojanasakul’s
teaching that changes in electrical resistance and capaci-
tance correlate well with changes in the aqueous intercel-
lular space and membrane surface integrity, respectively,
to support the relevance of Rojanasakul’s finding that
electrical resistance changed after being exposed to EDTA
levels as low as 0.00037 w/v%. Because appellants admit
that intercellular space is the space between cells through
which gatifloxacin travels, appellees argue that a person
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 25
of ordinary skill in the art could reasonably conclude that
even very low EDTA levels would impact the cellular
junctions, thereby promoting transport of gatifloxacin.
With respect to claim 6, we conclude that the district
court properly held this claim invalid as obvious in light
of the ’456, ’465, and ’470 patents, along with the Grass
1985, Grass 1988-I, Grass 1988-II, and Rojanasakul
references. 8 We find that the district court applied correct
legal standards, accepting that the ’045 patent was enti-
tled to a presumption of validity; that appellees had to
establish the underlying factual proofs of obviousness by
clear and convincing evidence; and that the court properly
considered all of the relevant evidence. See Sciele Phar-
ma Inc. v. Lupin Ltd., 684 F.3d 1253, 1260 (Fed. Cir.
2012) (“Whether a reference was previously considered by
the PTO, the burden is the same: clear and convincing
evidence of invalidity.”).
Though the district court did not specifically cite to
Kompella and Mitra in its opinion, this is not fatal be-
cause neither the Mitra nor the Kompella reference
actually teach away from utilizing a lower EDTA concen-
tration at the claimed pH level. While both references
find success at higher EDTA concentrations, they do not
provide any indication that lower EDTA concentrations
would not also work. See J.A. 2811, 2772. Because the
district court was not required to directly address these
references and the references do not provide evidence of
teaching away from the ’045 patent disclosure, the district
court did not commit clear error in its analysis. See
8 With regard to appellants’ “size-dependent” theo-
ry, it was untimely because appellants provided no evi-
dence that they alleged gatifloxacin’s size precluded
movement through EDTA-created intercellular spaces.
The district court properly excluded this argument as
untimely and we decline to address it further.
26 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
MySpace, Inc., 672 F.3d at 1263 (finding that “[w]here the
record adequately supports the judgment, the district
court does not have an obligation to recite every detail of
its reasoning”) (citing Lexion Med., LLC v. Northgate
Techs., Inc., 641 F.3d 1352, 1359 (Fed. Cir. 2011)).
Appellants focus on the use of 0.01 w/v% EDTA to in-
crease corneal permeability as the distinguishing feature
of claim 6. However, this feature does not sufficiently
distinguish claim 6 from the prior art. The asserted
references demonstrate that one of ordinary skill in the
art would have known that using 0.01 w/v% EDTA would
result in an increase in corneal permeability. Specifically,
we look to Grass 1985, which suggests that EDTA concen-
trations lower than 0.5 w/v% would be effective in view of
the increased corneal permeability of the 0.5 w/v% EDTA
formulation to which calcium was added. J.A. 2710. This
disclosure in Grass 1985 would lead one of ordinary skill
to apply this teaching in conjunction with the pre-existing
quinolone formulations, which incorporated between 0.05
and 0.1 w/v% EDTA, in arriving at a gatifloxacin formula-
tion characterized by increased corneal permeability. See,
e.g., J.A. 2712-13.
Contrary to appellants’ arguments that the prior art
teaches that the use of 0.01 w/v% EDTA fails to increase
corneal permeability of either of the polar compounds
tested, the prior art actually teaches that adding EDTA to
any polar compound will increase corneal permeability
dose-dependently. For example, after experimenting with
higher concentrations, Grass 1988-I tested 0.1, 0.05, and
0.01 w/v% EDTA, finding that each concentration raised
corneal permeability, even though not all of the increases
were statistically significant. J.A. 2780. Appellants
improperly focus on the percentage change in permeabil-
ity over the control, which was zero for both methanol and
glycerol, to conclude that the data showed no increase in
corneal permeability. In reality, though the percent
changes were not statistically significant, appellees set
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 27
forth expert testimony that a person of ordinary skill
would have recognized from the data that 0.01 w/v%
EDTA would increase corneal permeability. J.A. 1695.
This testimony is consistent with other prior art, such as
Rojanasakul, which confirmed a dose dependent relation-
ship between EDTA concentration and corneal permeabil-
ity, testing concentrations of EDTA as low as 0.00037
w/v%. J.A. 2795-96. Thus, the prior art suggests that the
use of concentrations as low as 0.01 w/v% EDTA would be
effective to increase corneal permeability.
At bottom, the district court’s analysis rests largely on
a determination that Lupin’s experts were more credible
than Senju’s experts. J.A. 30-31. Based on this determi-
nation, the district court found that Grass 1988-I, along
with the other cited references, taught that 0.01 w/v%
EDTA would be effective to increase corneal permeability.
J.A. 31. On the evidence before us, that determination by
the district court falls well within the wide discretion the
court has to weigh expert credibility. Ordinarily, and
absent compelling reason otherwise, an appellate court
defers to such credibility determinations. See Celsis In
Vitro, Inc. v. CellzDirect, Inc., 664 F.3d 922, 929 (Fed. Cir.
2012).
2. Unexpected Results
Appellants argue that the district court engaged in an
improper post hoc analysis of appellants’ evidence of
unexpected results, concluding that the claims were
obvious before fully considering evidence of unexpected
results and without making any finding of the results a
skilled artisan would have expected. Appellants point out
that a complete administrative record—including the
Senju studies and the Grass 1985 and Grass 1988-I
references—was before the PTO at the reexamination and
that the examiners’ decision to grant the amended and
new claims “‘carries with it a presumption that [each]
Examiner did his duty and knew what claims he was
28 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
allowing.’” Appellant Br. 53 (citing Al-Site Corp. v. VSI
Int’l, Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999) (quoting
Intervet Am., Inc. v. Kee-Vet Labs., Inc., 887 F.2d 1050,
1054 (Fed. Cir. 1989))). Thus, appellants argue, the
district court erred in failing to give weight to the PTO’s
factual findings on validity and unexpected results.
Appellants argue that two pre-litigation studies con-
ducted by Senju in 2006 (the “’901 study” and the “’904
study”) measured and compared corneal concentrations of
gatifloxacin after administering the compound in solu-
tions with and without EDTA, demonstrating the ex-
pected and surprising benefits of the claimed invention.
Appellants expound that these studies provide undisputed
results demonstrating that the addition of 0.01% w/v%
EDTA results in a 27-40% increase in gatifloxacin in the
aqueous humor. The Grass 1988-I reference, appellants
argue, reported a zero percent change in permeability of
glycerol upon addition of 0.01 w/v% EDTA in vitro, and
the Grass 1988-II article taught that concentrations of
EDTA about 0.01 w/v% were needed in vitro to show an
effect on corneal permeability of glycerol. Appellants
point out that even if Grass 1998-I was interpreted as
teaching some miniscule increase in corneal permeability
of gatifloxacin with 0.01 w/v% EDTA, the sheer magni-
tude of improvement observed in Senju’s ’901 and ’904
studies would have been unexpected and surprising.
Appellants further argue that appellees presented no
evidence that anyone in 1998 would have expected a low
concentration of EDTA to produce a significant increase in
gatifloxacin’s corneal permeability. In fact, appellants
argue, the remainder of the prior art references, including
Grass 1985, Mitra, and Rojanasakul, reinforce the sur-
prising results of Senju’s ’901 and ’904 studies, as none of
these references suggest that the claimed EDTA concen-
tration would result in an increase in aqueous humor
concentrations of glycerol and cromolyn. Additionally, the
prior art uniformly taught using pH levels higher than
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 29
the claimed range of 5-6, confirming the surprising nature
of the inventor’s discovery that 0.01 w/v% EDTA formula-
tions significantly increase gatifloxacin concentrations in
the aqueous humor even at relatively low pH levels.
Appellees respond that the district court properly
found the claims obvious only after considering appel-
lants’ unexpected results evidence and finding it unper-
suasive. Despite Senju setting forth a persuasive case
before the Examiner at the USPTO, their theories col-
lapsed before the district court. Appellees point out
testimony from appellants’ expert who testified that the
’901 study did not show the gatifloxacin-0.01 w/v% EDTA
solution produced corneal permeability benefits that were
statistically significant compared to a non-EDTA solution.
Appellees argue that the district court heard testimony
from both experts, weighed their credibility, and reviewed
Grass 1988-I as a whole before finding more credible
Lupin’s expert’s opinions that the skilled person would
not interpret Grass 1988-I as teaching “no increase”
occurred at 0.01 w/v% EDTA.
Appellees also argue that the raw data reported in
Grass 1988-I shows that numerically, the corneal perme-
ability levels did increase compared to control even with
the 0.01 w/v% EDTA formulations. Appellees point out
that the 27 and 40% permeability increase numbers in the
raw data appellants rely on for evidence of unexpected
success occurred in studies where all of the numbers
(including control values) widely varied, with large,
unexplained error bars. Appellees argue that if a mere
pH adjustment of one unit can produce a 30% difference
in corneal permeability, and pH adjustments are routine-
ly done, appellants’ 27-40% change in corneal permeabil-
ity with 0.01 w/v% EDTA has a magnitude achievable by
other formulation tweaks and routine practice. Further,
appellees argue, the district court properly found that
achieving changes on this order of magnitude reflected
the “product of routine optimization.” J.A. 33-34.
30 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
Appellees argue that the district court properly found
the unexpected results evidence unpersuasive because the
results of the ’901 and ’904 studies were not statistically
significant and merely reported numerical increases that
were unsurprising in light of Grass 1988-I. Appellees
point out that Dr. Grass only acknowledged that the
Senju ’901 study reports a single time point that the study
claimed was statistically significant, but that Lupin’s
statistician demonstrated this time point was statistically
insignificant under a correct analysis. Appellees argue
that Senju’s studies achieved nothing better than Grass
1988-I in which 0.01 w/v% EDTA solutions were tested as
single doses and showed concentration and time depend-
ence where the 30 minutes’ permeability numbers quad-
rupled or more than the 20 minute permeability numbers.
We conclude that the district court properly consid-
ered evidence of unexpected results, J.A. 32-34, and did
not err in finding that, based on the record and testimony
offered, the increase in corneal permeability shown by
plaintiffs using a 0.01 w/v% EDTA is not unexpected or
surprising, but is a product of routine optimization that
would have been obvious to one of skill in the art. J.A. 33-
34. These determinations, much like many of the obvi-
ousness determinations, were based on credibility judg-
ments on which, on the evidence before us, we defer to the
district court. See Celsis In Vitro, 664 F.3d at 929.
We further conclude that the district court properly
applied a presumption of validity, considering both the
evidence of obviousness and the evidence of unexpected
results, to find that appellees set forth clear and convinc-
ing evidence of invalidity in this case. See Sciele Pharma
Inc., 684 F.3d at 1260. We agree that it was not clear
error for the district court to conclude that the unexpected
results evidence that Senju relied upon during reexami-
nation, J.A. 2692, did not withstand scrutiny by Lupin’s
experts and the district court. Ultimately, the district
court properly concluded that the theories presented
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 31
during reexamination proved too weak when challenged
in a judicial forum to rise to the level of unexpected re-
sults sufficient to rebut a strong case of obviousness. See
Proctor & Gamble Co. v. Teva Pharms. USA, Inc., 566
F.3d 989, 994 (Fed. Cir. 2009).
We have considered and find unpersuasive the re-
mainder of appellants’ arguments. Concluding that the
district court did not err in its judgment that the reex-
amined claims at issue are invalid for obviousness, we
need not reach the issues of infringement and estoppel.
III. CONCLUSION
The judgment of the district court is affirmed.
AFFIRMED
United States Court of Appeals
for the Federal Circuit
______________________
SENJU PHARMACEUTICAL CO., LTD.,
KYORIN PHARMACEUTICAL CO., LTD.,
ALLERGAN, INC.,
Plaintiffs-Appellants
v.
LUPIN LIMITED, LUPIN PHARMACEUTICALS,
INC.,
Defendants-Appellee
HI-TECH PHARMACAL CO., INC.,
Defendant-Appellee.
______________________
2013-1630
______________________
Appeals from the United States District Court for the
District of Delaware in Nos. 11-CV-0271, 11-CV-0439, 11-
CV-0926, 11-CV-1059, Judge Sue L. Robinson.
______________________
NEWMAN, Circuit Judge, dissenting.
In prior litigation, the district court held Senju’s pa-
tent claims invalid on the ground of obviousness. Before
that decision reached finality, Senju requested PTO
reexamination, presenting new claims of significantly
narrowed scope. The PTO reexamined Senju’s U.S.
Patent No. 6,333,045 (“the ’045 patent”), and held the
narrowed claims patentable. In this subsequent litiga-
2 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
tion, the district court gave no deference to the PTO’s
review of the restricted claim scope or the unexpected
results at that scope, and held the narrowed claims inva-
lid on the same grounds it previously applied to the
original claims. 1
My colleagues on this panel repeat that flawed analy-
sis: they do not consider the scope of the reexamined
claims, the unexpected results at that scope, and the
teaching-away of the prior art. I respectfully dissent, for
these claims have not been shown to be invalid.
DISCUSSION
The Senju inventors discovered that a composition
containing the antibiotic gatifloxacin enhances corneal
permeability when combined with very low amounts of
ethylenediaminetetracetic acid (EDTA) at a specific pH.
This is the appellants’ Zymar® product, whose commercial
and medicinal success is the impetus for this Hatch-
Waxman Act challenge to Senju’s patent.
The prior art is crowded. It contains much data on
quinolones, the family of which gatifloxacin is a member.
The prior art also shows the use of chelating agents, such
as EDTA, as excipients that enhance stability of ophthal-
mic medications. However, no combination of prior art
references shows or suggests the use of very low concen-
trations of EDTA to enhance the corneal permeability of
antibiotic formulations of gatifloxacin, or of any other
quinolone.
In this crowded field, the specific combination and
concentration here claimed is not shown, and the pub-
lished scientific data lead away from the claimed subject
1 Senju Pharm. Co., Ltd. v. Lupin Ltd., Civ. No. 11-
271-SLR, 2013 WL 4101820 (D. Del. Aug. 9, 2013) (“Dist.
Ct. Op.”).
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 3
matter. These inventors discovered that, when using
EDTA at a concentration of 0.01 w/v%, the formulation is
not only effective as an antibiotic, but, contrary to the
prior art, increases the corneal permeability of gatifloxa-
cin.
I focus specifically on reexamined claim 6:
6. A method for raising corneal permeability of an
aqueous pharmaceutical Gatifloxacin eye drop so-
lution comprising Gatifloxacin or its salt, having a
pH of from above 5 to about 6 containing from
about 0.3 to about 0.8 w/v% Gatifloxacin or its
salt, which comprises incorporating about 0.01
w/v% disodium edetate into [eye drops containing
Gatifloxacin or its salt] said Gatifloxacin eye drop
solution.
’045 patent, col. 1 l. 25–col. 2 l. 5.
During reexamination, the PTO examiner found that
no reference or combination of references teaches or
suggests the improved corneal permeability obtained
using EDTA at the low concentration of 0.01 w/v%. The
prior art experimental data show either no effect at 0.01
w/v% or enhanced permeability at concentrations above
0.01 w/v%.
No reference shows improved corneal permeability at
such low concentrations of EDTA; all indications are that
the EDTA concentration should be above 0.01 w/v%. The
Senju discovery contradicts the observations reported in
the prior art. Nonetheless, the panel majority holds that
it was obvious that superior results would be obtained by
reducing the concentration.
The Grass et al. Scientific Articles
Of primary import to the district court’s opinion are
three publications by Dr. George M. Grass, et al. The
panel majority states that these publications render the
4 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
claimed combination obvious. To the contrary, these
publications teach away from the direction taken by the
Senju inventors.
Grass et al., Mechanisms of Corneal Drug Pene-
tration I: In Vivo and In Vitro Kinetics, 77 J. Pharm.
Sci. 3 (1988) (“Grass 1988-I”):
The panel majority states that the Grass 1988-I refer-
ence shows that the three concentrations of EDTA tested
(0.1, 0.05 and 0.01 w/v%) are effective at enhancing cor-
neal permeability. That is incorrect. Grass 1988-I shows
that EDTA at a concentration of 0.01 w/v% produced a
zero percent increase in corneal permeability, measured
for both methanol and glycerol. Grass 1988-I also states
that the in vitro experiments were performed at exposures
(3 hours) significantly longer than most topical applica-
tions would provide, yet the reported data are that EDTA
at 0.01 w/v% was totally ineffective.
Grass 1988-I discusses the work of other investiga-
tors, and reports no corneal penetration of mannitol using
EDTA at concentrations of 0.2 and 5 mM. Grass 1988-I
concludes that corneal permeability increases with in-
creased concentration of EDTA. This leads directly away
from any suggestion or expectation of improved permea-
bility of gatifloxacin formulations with concentrations of
EDTA as low as 0.01 w/v%.
The appellees concede that Grass 1988-I shows no
statistically significant increase in corneal permeability at
the low concentration of 0.01 w/v%: “the data did not
reach statistical significance.” Appellee Br. at 13. Yet,
the panel majority affirms the district court’s unsupported
finding that the “prior art suggests the use of concentra-
tions as low as 0.01 w/v% EDTA would be effective to
increase corneal permeability.” Dist. Ct. Op. at *11. This
finding is contrary to the record. The most that Grass
1988-I can be deemed to “suggest” is that the EDTA
concentration should be higher than 0.01 w/v%.
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 5
The two other cited Grass publications reinforce the
“teaching away” of the prior art:
Grass et al., Effects of Calcium Chelating Agents
on Corneal Permeability, 26 Investigative Ophthal-
mology & Visual Sci. 110 (1985) (“Grass 1985”):
Grass 1985 describes the effects of the chelating
agents EDTA and Cromolyn on corneal permeability of
glycerol and progesterone in rabbit eyes. Grass 1985
reports that EDTA at concentrations of 0.5 w/v% in-
creased glycerol concentration in the aqueous humour,
and concludes that the addition of chelators at high
concentrations or by frequent application may increase
the permeability of the corneal epithelium. This reference
shows enhanced effects at higher concentrations, not the
low concentration in claim 6.
Grass et al., Mechanisms of Corneal Drug Pene-
tration II: Ultrastructural Analysis of Potential
Pathways for Drug Movement, 77 J. Pharm. Sci. 15
(1988) (“Grass 1988-II”):
Grass 1988-II describes electron microscope studies of
rabbit eyes exposed to EDTA and glycerol, specifically
analyzing corneal epithelial cell junctions after treatment
with EDTA and glycerol. Grass 1988-II reports that the
effects of EDTA depend on concentration and exposure
time, and that at concentrations of 0.01 w/v% EDTA, the
epithelial tissue showed no visible expansion of the inter-
cellular spaces, which is described as correlating with
corneal permeability. The authors interpret these results
as showing that “in vitro concentrations of EDTA above
0.01% caused increased permeability of the cornea to
glycerol.” Grass 1988-II at 22.
Collectively, the Grass references show or suggest
that EDTA must be used at concentrations higher than
0.01 w/v% to effectively increase corneal permeability.
6 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
OPTHALMIC DRUG DELIVERY SYSTEMS, (Ashim K.
Mitra ed., Marcell Dekker, Inc., 1993) (“Mitra”):
The Mitra book summarizes the research and
knowledge in this field, and states that experiments using
low concentrations of EDTA were “devoid of any effects
(62), suggesting a concentration dependence.” Mitra at
188. Mitra states that EDTA-drug combinations “deserve
investigation,” but that “[i]t seems likely that the high
concentration of divalent cations in the tear film would
prevent EDTA from enhancing permeability.” Id. Mitra
adds that while improving drug transport across the
cornea found some success, “it is in the modification of the
drug that has generated greater interest.” Id.
The panel majority rejects the argument that Mitra
teaches away from Senju’s discovery, stating that Mitra
does not “provide any indication that lower EDTA concen-
trations would not also work.” Maj. Op. at 25. That is not
the law of “teaching away.” A reference need not foresee a
later-discovered invention and warn against it, to teach
away from the discovery. Spectralytics, Inc. v. Cordis
Corp., 649 F.3d 1336, 1343 (Fed. Cir. 2011).
A reference teaches away when it leads to a path di-
vergent from that taken by the patentee. Pozen, Inc. v.
Par Pharm., Inc., 696 F.3d 1151, 1165 (Fed. Cir. 2012).
Mitra explicitly sets forth two separate paths for investi-
gation – high concentrations of EDTA and drug modifica-
tion – both of which diverge from the path in claim 6. The
entire body of prior art leads in the direction opposite to
reducing the EDTA concentration, for the body of prior art
points toward higher, not lower, concentrations of EDTA
to enhance corneal permeability.
Other References
Three other references relied on by the district court
(U.S. Patent Nos. 4,551,456; 4,780,465; and 4,980,470)
make no mention of improving corneal permeability.
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 7
Those references describe gatifloxacin as an antibiotic and
EDTA as a traditional excipient, i.e., as an inactive drug
ingredient; they contain no teaching or suggestion related
to corneal permeability.
The Legal Conclusion of Obviousness
Obviousness is a matter of foresight, not hindsight. A
determination of obviousness requires some reason or
suggestion, in the prior art or in common sense, that the
claimed subject matter is likely to be effective for its
intended purpose. KSR Int’l Corp. v. Teleflex Inc., 550
U.S. 398, 420–22 (2007). Here, the prior art taught away
from the claimed combination when it indicated that
higher concentrations of EDTA are needed to enhance
corneal permeability.
The panel majority relies on the unsupported opinion
of Lupin’s expert witness, and gives that unsupported
opinion greater weight than the experimental data. Such
reliance is discredited. See Daubert v. Merrell Dow
Pharm., Inc., 509 U.S. 579, 589 (1993) (“Proposed testi-
mony must be supported by appropriate validation – i.e.,
‘good grounds,’ based on what is known. In short, the
requirement that an expert’s testimony pertain to ‘scien-
tific knowledge’ establishes a standard of evidentiary
reliability.”).
Contrary to the theory of Lupin’s expert, the extensive
Grass data show no statistically significant enhancement
of corneal permeability in the experiments using EDTA at
low concentrations, or for other chelating agents at low
concentrations. The prior art did not test the specific
combination of gatifloxacin and 0.01 w/v% of EDTA and
did not discover the subject matter that is here claimed.
Notwithstanding the published contrary data, the
panel majority calls upon judicial hindsight and finds that
persons skilled in the field of the invention would have
recognized that 0.01 w/v% EDTA would increase corneal
8 SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED
permeability of gatifloxacin formulations. However, the
scientists conducting the Grass studies interpreted their
data to “suggest that under conditions of sufficient calci-
um chelation, either by high enough concentrations of one
or more chelators or frequent application at short inter-
vals, preservatives may indeed enter anterior segment
tissue.” Gras 1988-I at 11. Grass suggested “high enough
concentrations,” not very low concentrations.
The published contemporaneous statements of scien-
tists interpreting their experiments warrant more weight
than unsupported opinions appearing for the first time in
litigation. Grass did not test the composition here pa-
tented, and reported to be a product now of medical
choice.
Senju’s pre-litigation experiments further support the
conclusion that one skilled in the art would not have
expected to enhance corneal permeability using the meth-
od of claim 6. The district court acknowledged that the
claimed levels of EDTA were shown in Senju’s experi-
ments to produce a significant increase in the concentra-
tion of gatifloxacin in the aqueous humour. Nevertheless,
the court faulted Senju’s expert because he did not use
statistical analysis to show that the effects were unex-
pected. Statistical analysis can indeed be helpful at
times, but the perspective of those skilled in the art
cannot be ignored. With the exception of Lupin’s expert
witnesses, those skilled in the art interpreted Senju’s
experiments as demonstrating unexpected results.
CONCLUSION
The scientific references, the experimental record, and
the commercial success all support the conclusion that the
subject matter of claim 6 would not have been obvious to a
person of ordinary skill at the time of the invention. The
PTO on reexamination correctly applied the law of obvi-
ousness. Invalidity of reexamined claim 6 was not proved
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 9
by clear and convincing evidence. From my colleagues’
contrary ruling, I respectfully dissent.