Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-13-01630/USCOURTS-ca13-13-01630-0/pdf.json

Parties Involved:
Allergan, Inc.
Appellant
Hi-Tech Pharmacal Co., Inc.
Appellee
Kyorin Pharmaceutical Co., Ltd.
Appellant
Lupin Limited
Appellee
Lupin Pharmaceuticals, Inc.
Appellee
Senju Pharmaceutical Co., Ltd.
Appellant

Document Text:

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, McClelland, Maier & Neustadt, LLP, Alexandria, VA.

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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 represented by WILLIAM A. RAKOCZY, PAUL J. MOLINO, ANUJ 

KUMAR WADHWA, JOHN POLIVICK, BRIAN PETER MURRAY. 

JEFFREY T. CASTELLANO, Shaw Keller LLP, Wilmington, DE, argued for defendant-appellee Hi-Tech Pharmacal 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 HatchWaxman 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, plaintiffsappellants Senju Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Allergan, Inc. (collectively 

“Senju”) sued defendants-appellees Lupin Limited and 

Lupin Pharmaceuticals, Inc. (collectively “Lupin”) and HiTech 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 counterclaimed seeking a declaratory judgment of noninfringement and invalidity. The district court, Judge 

Sue L. Robinson, adjudged the claims infringed but invaCase: 13-1630 Document: 73-2 Page: 2 Filed: 03/20/2015
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 3

lid for obviousness. Plaintiffs appeal the invalidity judgment.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 patents are alleged as the basis for the obviousness determination, 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 infringement under Hatch-Waxman, countered by alleged 

non-infringement and invalidity for obviousness—are 

familiar patent issues. Yet, the combination of the chemistry 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 manufacturer 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 reference and joined most of Lupin’s brief. Hi-Tech’s additional arguments in its brief relate to issues of intervening 

rights, which in view of the outcome we need not address 

in this opinion.

 

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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. However, 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 conduct. 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 regarding 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 petitioned the Patent and Trademark Office (“PTO”) for exparte re-examination of the ’045 patent. Plaintiffs submitted 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 

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obvious in light of the cited prior art patents. Subsequently, 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 previous 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 defendants, 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 Lu2 Civ. No. 11-271, filed March 31, 2011, against Lupin, 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 HiTech.

 

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pin’s earlier-filed ANDA Nos. 202-653, 0.5 w/v% gatifloxacin and 202-709, 0.3 w/v% gatifloxacin, as well as HiTech’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 apply.3 J.A. 7. 

As noted earlier, the ’045 patent is directed to aqueous liquid pharmaceutical compositions comprising gatifloxacin 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 solution 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.

 

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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 infringement 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. 

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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 without 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 between 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 showing 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 Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. 

Cir. 2007).

B. Analysis

The Senju appellants make two main arguments relating to obviousness: (1) the district court erred by finding that the prior art taught using 0.01 w/v% EDTA in an 

ophthalmic formulation would work to increase corneal

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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 analysis 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 convincing 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 inventions from the prior art. They argue that the court analyzed 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 method of analysis effectively applied a presumption of invalidity 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 predecessor claims as prior art to the present claims even 

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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 reexamined 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 permeability 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’ characterization, the district court in the present case did not handpick limitations in the reexamined claims to analyze. 

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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 considered 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 disputed 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 district 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 19854, 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 composition 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 Investigative Ophthalmology & Visual Science 110 (1985). J.A. 

2707-10.

 

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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 antibacterial 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 inorganic 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 specifically 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 unspecified concentration of EDTA was also shown to function in 

this manner, albeit to a lesser extent.

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In addition to these four references, appellees also 

raise the Grass 1988-I5, Grass 1988-II6, and Rojanasakul7

references, mainly to address the additional claim limitations 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 concentrations. The Rojanasakul reference is directed to studying 

the promoting mechanisms of various penetration enhancers, 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 concentrations 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 comprehensive review of ophthalmic drug delivery systems. J.A. 

2768-72. The Mitra reference specifically studies the 

mechanisms of EDTA for corneal drug penetration exam5 “Grass 1988-I” is Grass et al., Mechanisms of Corneal 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 Electrophysiology Studies, 66 Int’l Journal of Pharm., 131 (1990). J.A. 

2787-98.

 

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ining the concentrations at which increases in permeability of the cornea occur. J.A. 2772. The Kompella reference 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 references 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 cherrypick 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 analysis to arrive at the claimed compositions.

Appellants also argue that the district court improperly 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

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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 lomefloxacin, 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 compounds 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 gatifloxacin and EDTA together and that the claimed pH and 

EDTA concentration limitations are found in the prior art.

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Appellees respond that, with respect to claims 12-16, 

not only did appellants waive the issue of the years between 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 arguments, appellees point out that because the composition 

claims do not contain the corneal permeability limitation 

found in method claim 6, the corneal permeability teaching away arguments are irrelevant to claims 12-16. 

Appellees argue that the only composition element appellants 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 sufficient reason to combine the claims in these three patents 

to render the asserted claims obvious.

Appellees characterize the ’456 patent as teaching using norfloxacin and structurally related antibodies in 

topical ocular formulations, while the ’465 patent taught 

preparing stable ophthalmic fluoroquinolone compositions, 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 

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have had reason to combine the ’470 patent’s gatifloxacin 

disclosure to improve the ’456 and ’465 patents’ formulations.

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 patent’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. Appellants’ 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 appellants’ 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 

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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 includes 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 conclude that the district court properly determined that

combining them would have been obvious to one of ordinary skill in the art. 

The ’045 and ’456 patents disclose ophthalmic quinolone 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 

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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 patent’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, therefore, 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% quinolone 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 

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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 ExtendedRelease 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 permeability, 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 several 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 concentration in vivo, reporting that such concentrations are “devoid of any effects” in in vitro experiments. Thus, 

appellants argue, both Mitra and Kompella suggest a line 

of development pointing towards higher EDTA concentraCase: 13-1630 Document: 73-2 Page: 20 Filed: 03/20/2015
SENJU PHARMACEUTICAL CO. v. LUPIN LIMITED 21

tions and higher pH levels to increase corneal permeability—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 concentrations 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 improperly 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 reliance on the Rojanasakul reference was misplaced. Appellants 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 support 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 Rojanasakul. Further, appellants argue that the district court 

misconstrued Rojanasakul, which uses “permeability” to 

refer not only to the permeability of the corneal membrane comprising the surface of the eye, but also to permeability of the plasma membrane surrounding 

individual cells. Thus, the increase in permeability 

disclosed in Rojanasakul is not applicable to the asserted 

claims.

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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 permeability 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 opposed to the eight years that passed before anyone conceived 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 gatifloxacin unpatentable, because the asserted claims, at a minimum, 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 permeability. 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 Rojanasakul (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 confirms the surprising nature of the inventors’ discovery 

that 0.01 % w/v% EDTA formulations significantly increase 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 ophthalmic 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 

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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 obligated 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 compound, 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).

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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 routinely 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 concentrations.” 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 explained, 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 statistical significance, even though one of ordinary skill reading 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 attorney characterizations about the reference’s teachings that 

no trial witness offered. Appellees point to Rojanasakul’s

teaching that changes in electrical resistance and capacitance correlate well with changes in the aqueous intercellular 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 

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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 entitled 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 Pharma 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 because neither the Mitra nor the Kompella reference 

actually teach away from utilizing a lower EDTA concentration 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” theory, it was untimely because appellants provided no evidence 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.

 

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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 increase 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 concentrations 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 formulation 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 permeability 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 

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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 relationship between EDTA concentration and corneal permeability, 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 determination, 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 

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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 conducted by Senju in 2006 (the “’901 study” and the “’904 

study”) measured and compared corneal concentrations of 

gatifloxacin after administering the compound in solutions with and without EDTA, demonstrating the expected 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 magnitude 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 surprising results of Senju’s ’901 and ’904 studies, as none of 

these references suggest that the claimed EDTA concentration would result in an increase in aqueous humor 

concentrations of glycerol and cromolyn. Additionally, the 

prior art uniformly taught using pH levels higher than 

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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 formulations 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 appellants’ unexpected results evidence and finding it unpersuasive. Despite Senju setting forth a persuasive case 

before the Examiner at the USPTO, their theories collapsed 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 permeability 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 routinely done, appellants’ 27-40% change in corneal permeability 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.

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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 dependence where the 30 minutes’ permeability numbers quadrupled or more than the 20 minute permeability numbers.

We conclude that the district court properly considered 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 obviousness determinations, were based on credibility judgments 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 convincing 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 reexamination, 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 

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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 results 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 remainder of appellants’ arguments. Concluding that the 

district court did not err in its judgment that the reexamined 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

Case: 13-1630 Document: 73-2 Page: 31 Filed: 03/20/2015
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-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 patent 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 litigaCase: 13-1630 Document: 73-2 Page: 32 Filed: 03/20/2015
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 invalid on the same grounds it previously applied to the 

original claims.1

My colleagues on this panel repeat that flawed analysis: 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 HatchWaxman 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 ophthalmic medications. However, no combination of prior art 

references shows or suggests the use of very low concentrations 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 published 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.”). 

 

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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 gatifloxacin. 

I focus specifically on reexamined claim 6:

6. A method for raising corneal permeability of an 

aqueous pharmaceutical Gatifloxacin eye drop solution 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 

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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 Penetration 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 reference shows that the three concentrations of EDTA tested 

(0.1, 0.05 and 0.01 w/v%) are effective at enhancing corneal 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 applications 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 investigators, 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 increased concentration of EDTA. This leads directly away 

from any suggestion or expectation of improved permeability 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 concentrations 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%. 

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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 Ophthalmology & 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% increased 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 Penetration 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 intercellular 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.

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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 concentrations 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 divergent 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 investigation – high concentrations of EDTA and drug modification – 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. 

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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 testimony 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 ‘scientific 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

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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 calcium chelation, either by high enough concentrations of one 

or more chelators or frequent application at short intervals, 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 scientists interpreting their experiments warrant more weight 

than unsupported opinions appearing for the first time in

litigation. Grass did not test the composition here patented, 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 method of claim 6. The district court acknowledged that the 

claimed levels of EDTA were shown in Senju’s experiments to produce a significant increase in the concentration 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 unexpected. 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 obviousness. Invalidity of reexamined claim 6 was not proved

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by clear and convincing evidence. From my colleagues’ 

contrary ruling, I respectfully dissent. 

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