Eisai Co. Ltd. v. Dr. Reddy's Laboratories, Ltd.

United States Court of Appeals for the Federal Circuit
2007-1397, -1398

EISAI CO. LTD. and EISAI, INC.,

Plaintiffs-Appellees,

v.

DR. REDDY’S LABORATORIES, LTD.
and DR. REDDY’S LABORATORIES, INC.,

Defendants-Appellants,

and

TEVA PHARMACEUTICALS USA, INC.,

Defendant-Appellant.

Joseph M. O’Malley, Jr., Paul, Hastings, Janofsky & Walker, LLP, of New York, New
York, argued for plaintiffs-appellees. With him on the brief were Bruce M. Wexler, David M.
Conca, Gary G. Ji, and Quinn E. Clancy.

Maurice N. Ross, Budd Larner, P.C., of Short Hills, New Jersey, argued for
defendants-appellants Dr. Reddy’s Laboratories, Ltd., and Dr. Reddy’s Laboratories, Inc.
With him on the brief were Andrew J. Miller, Louis H. Weinstein, Ellen T. Lowenthal, and
Dmitry V. Sheluho.

Henry C. Dinger, Goodwin Procter LLP, of Boston, Massachusetts, argued for
defendant-appellant Teva Pharmaceuticals USA, Inc. With him on the brief were Elaine H.
Blais, and David M. Hashmall, Frederick H. Rein, and Emily L. Rapalino, of New York, New
York.

Appealed from: United States District Court for the Southern District of New York

Judge Gerard E. Lynch
 United States Court of Appeals for the Federal Circuit

2007-1397, -1398

EISAI CO. LTD. and EISAI, INC.,

Plaintiffs-Appellees,

v.

DR. REDDY’S LABORATORIES, LTD.
and DR. REDDY’S LABORATORIES, INC.,

Defendants-Appellants,

and

TEVA PHARMACEUTICALS USA, INC.,

Defendant-Appellant.

Appeals from the United States District Court for the Southern District of New York in
case No. 03-CV-9053 and 03-CV-9223, Judge Gerard E. Lynch.
___________________________

DECIDED: July 21, 2008
___________________________

Before RADER, LINN, and PROST, Circuit Judges.

RADER, Circuit Judge.

On summary judgment, the United States District Court for the Southern District

of New York found in favor of plaintiffs Eisai Co., Ltd. and Eisai, Inc. (collectively Eisai)

with respect to the validity and enforceability of U.S. Patent No. 5,045,552 (’552 patent).

Eisai Co. v. Teva Pharms. USA, Inc., No. 03 Civ. 9223 (S.D.N.Y. Oct. 5, 2006) (SJ

Validity Order); Eisai Co. v. Dr. Reddy’s Labs., Ltd., No. 03 Civ. 9053 (S.D.N.Y. Oct. 5,
2006) (SJ Enforceability Order). After a bench trial, the district court found that Dr.

Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc. (collectively Dr. Reddy’s)

and Teva Pharmaceuticals USA, Inc. (Teva) had failed to prove the remaining

allegations of inequitable conduct, and that Eisai had established that Dr. Reddy’s and

Teva infringed Eisai’s ’552 patent. Eisai Co. v. Dr. Reddy’s Labs, Ltd., No. 03 Civ. 9053

(S.D.N.Y. May 11, 2006) (Trial Order). Because the district court correctly determined

that the ’552 patent is non-obvious over the proffered prior art and that Eisai’s alleged

acts during prosecution did not rise to the level of inequitable conduct, this court affirms.

I

The ’552 patent claims rabeprazole and its salts. Rabeprazole is part of a class

of drugs known as proton pump inhibitors, which suppress gastric acid production by

inhibiting action of the enzyme H+K+ATPase. The distinctions between rabeprazole and

its salts are not relevant for this appeal. Therefore this court refers to rabeprazole and

its salts collectively as “rabeprazole.” Rabeprazole’s sodium salt is the active ingredient

in Aciphex, a pharmaceutical approved in 1991 by the FDA for the treatment of

duodenal ulcers, heartburn, and associated disorders. Aciphex has been a commercial

success, garnering over $1 billion in worldwide yearly sales.

Dr. Reddy’s and Teva each filed Abbreviated New Drug Applications (ANDAs)

under the Hatch-Waxman Act, 21 U.S.C. § 355 and 35 U.S.C. § 271(e), seeking to

manufacture a generic version of Aciphex before the expiration of the ’552 patent.

Because filing an ANDA is an artificial, but legally cognizable, act of patent infringement,

see Glaxo Group Ltd. v. Apotex, Inc., 376 F.3d 1339, 1344 (2004), Eisai filed suit

against Dr. Reddy’s and Teva. Eisai also sued Mylan Laboratories Inc. and Mylan

2007-1397, -1398 2
Pharmaceuticals Inc. (collectively Mylan), another ANDA filer, but that proceeding was

stayed pending the outcome of these actions. Mylan agreed to be bound by the final

judgments and any appeals in these cases. Eisai Co., Ltd. v. Mylan Labs., Inc., No. 04

Civ. 656 (S.D.N.Y. Nov. 3, 2004). Both Dr. Reddy’s and Teva conceded infringement of

claims 1-6 of the ’552 patent, but asserted that the ’552 patent is unenforceable for

inequitable conduct. Trial Order at 6-7. Dr. Reddy’s stipulated to the validity of all six of

the ’552 patent’s claims, id. at 6, but Teva argued before the district court and maintains

on appeal that the ’552 patent is invalid for obviousness. Both Dr. Reddy’s and Teva

appeal the trial court’s judgments of enforceability. Neither Dr. Reddy’s nor Teva

appeals the trial court’s judgment of infringement. This court has jurisdiction under 28

U.S.C. § 1295(a)(1).

II

This court reviews a grant of summary judgment without deference. Dayco

Prods., Inc. v. Total Containment, Inc., 329 F.3d 1358, 1362 (Fed. Cir. 2003).

Obviousness under 35 U.S.C. § 103(a) is ultimately a legal question, based on

underlying factual determinations. See Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d

1476, 1479 (Fed. Cir. 1997). The factual determinations underpinning the legal

conclusion of obviousness include 1) the scope and content of the prior art, 2) the level

of ordinary skill in the art, 3) the differences between the claimed invention and the prior

art, and 4) evidence of secondary factors, also known as objective indicia of non-

obviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). Thus, in reviewing

a district court’s summary judgment of non-obviousness, this court reviews the record

for genuine issues of material fact without deference, bearing in mind the movant’s

2007-1397, -1398 3
burden to prove invalidity by clear and convincing evidence. See Monarch Knitting

Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877, 881 (Fed. Cir. 1998).

Where, as here, the patent at issue claims a chemical compound, the analysis of

the third Graham factor (the differences between the claimed invention and the prior art)

often turns on the structural similarities and differences between the claimed compound

and the prior art compounds. See Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471

F.3d 1369, 1377 (Fed. Cir. 2006) (noting that, for a chemical compound, a prima facie

case of obviousness requires “structural similarity between claimed and prior art subject

matter . . . where the prior art gives reason or motivation to make the claimed

compositions” (quoting In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc))).

Obviousness based on structural similarity thus can be proved by identification of some

motivation that would have led one of ordinary skill in the art to select and then modify a

known compound (i.e. a lead compound) in a particular way to achieve the claimed

compound. See Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1356

(Fed. Cir. 2007). In keeping with the flexible nature of the obviousness inquiry, KSR

Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1739 (2007), the requisite motivation can

come from any number of sources and need not necessarily be explicit in the art. See

Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed. Cir.

2007). Rather “it is sufficient to show that the claimed and prior art compounds possess

a ‘sufficiently close relationship . . . to create an expectation,’ in light of the totality of the

prior art, that the new compound will have ‘similar properties’ to the old.” Id. (quoting

Dillon, 919 F.2d at 692).

2007-1397, -1398 4
 Teva asserts that a combination of three prior art references renders the ’552

patent obvious: 1) European Patent No. 174,726 (owned by Takeda), claiming

lansoprazole (EP ’726); 2) United States Patent No. 4,255,431 (to Junggren), claiming

omeprazole (’431 patent); and 3) an article by Brändström, et al., entitled “Structure

Activity Relationships of Substituted Benzimidazoles” (Brändström). EP ’726 teaches,

inter alia, the ulcer treatment compound lansoprazole. Lansoprazole differs structurally

from rabeprazole at the 4-position on the pyridine ring, as indicated in the diagram

below. Lansoprazole has a trifluoroethoxy (OCH2CF3) substituent, whereas rabeprazole

has a methoxypropoxy (OCH2CH2CH2OCH3) substituent.

Appellant Teva’s Br. at 28. Otherwise, the two compounds are identical. See SJ

Validity Order at 7. Both rabeprazole and lansoprazole are “asymmetrically substituted”

with respect to the 4-position on the pyridine ring because the substituent at the 3-

position (a methyl group in both compounds) is not the same as the substituent at the 5-

position (a hydrogen in both compounds).

The ’431 patent discloses a broad class of gastric acid inhibiting compounds,

including omeprazole, the first commercial proton pump inhibitor, sold as Prilosec.

Although sharing the same basic structure, omeprazole is structurally farther afield from

rabeprazole than is lansoprazole. For instance, omeprazole’s pyridine ring is

symmetrically substituted and has a methoxy (OCH3) group at the 4-position.

2007-1397, -1398 5
 Finally, Brändström describes a class of anti-ulcerative compounds having a

benzimidazole-sulfinylmethyl-pyridine core (the Brändström core structure):

Brändström Core Structure

Rabeprazole, lansoprazole, and omeprazole are all Brändström core structure

compounds. Taking the evidence in the light most favorable to Teva, this court

assumes that as per EP ’726, lansoprazole is twenty times superior to omeprazole for

anti-ulcer action, as measured by an indomethacin-induced gastric lesion assay in rats.

This court also assumes that lansoprazole has certain traits, including lipophilicity (the

ability of a compound to cross lipid membranes) and low molecular weight, that would

have made it desirable to a skilled artisan.

Under these assumptions, one of skill in this art may have considered it a

candidate for a lead compound in the search for anti-ulcer compounds. To the contrary,

the district court emphasized the differences between anti-ulcer action and gastric acid

inhibition. The trial court specifically noted that Teva’s expert testified with respect to

the EP ’726 data that “[t]he level of acid secretion . . . from these [anti-ulcer] data . . .

cannot be determined.” SJ Validity Order at 13. In this context, this court consults the

counsel of KSR that “any need or problem known in the field of endeavor at the time of

2007-1397, -1398 6
invention and addressed by the patent can provide a reason for combining the elements

in the manner claimed.” 127 S. Ct. at 1742. Thus lansoprazole’s candidacy as a

starting point to develop new anti-ulcer compounds versus new gastric acid inhibitors

does not resolve the lead compound analysis, at least not in the absence of any

contrary indications. Cf. Takeda, 492 F.3d at 1359 (negative side effects could

dissuade one of skill from using a particular compound as a starting point).

Nonetheless, as the district court noted, the EP ’726 reference teaches at best

that the fluorinated substituent of lansoprazole provides “a special path to achieving

lipophilicity.” SJ Validity Order at 10 (emphasis in original). And Teva’s expert identified

a separate reference teaching that fluorine-substituted groups increase lipophilicity. Id.

The record, however, shows no discernible reason for a skilled artisan to begin with

lansoprazole only to drop the very feature, the fluorinated substituent, that gave this

advantageous property. Indeed, Teva’s pharmacology expert, Dr. John Forte, declined

to opine on lansoprazole’s relevance to an examiner assessing the patentability of

rabeprazole. J. A. at 14894. And Dr. Reddy’s pharmacology expert, Dr. Simmy Bank,

testified in deposition that “I thought [lansoprazole] had nothing to do with this trial.”

J. A. at 14756.

This court notes that the district court did not rigidly limit Teva’s obviousness

arguments by forcing Teva to select a single lead compound. Rather Teva alone

selected lansoprazole as the anchor for its obviousness theory, not the district court. In

KSR, the Supreme Court noted that an invention may have been obvious “[w]hen there

[was] . . . a design need or market pressure to solve a problem and there [were] . . . a

finite number of identified, predictable solutions.” 127 S. Ct. at 1742 (tense changes

2007-1397, -1398 7
supplied to clarify, as the Court stated and as per 35 U.S.C. § 103, that the obviousness

inquiry must rely on evidence available “at the time” of the invention, see Takeda, 492

F.3d at 1356 n.2). The Supreme Court’s analysis in KSR thus relies on several

assumptions about the prior art landscape. First, KSR assumes a starting reference

point or points in the art, prior to the time of invention, from which a skilled artisan might

identify a problem and pursue potential solutions. Second, KSR presupposes that the

record up to the time of invention would give some reasons, available within the

knowledge of one of skill in the art, to make particular modifications to achieve the

claimed compound. See Takeda, 492 F.3d at 1357 (“Thus, in cases involving new

chemical compounds, it remains necessary to identify some reason that would have led

a chemist to modify a known compound in a particular manner to establish prima facie

obviousness of a new claimed compound.”). Third, the Supreme Court’s analysis in

KSR presumes that the record before the time of invention would supply some reasons

for narrowing the prior art universe to a “finite number of identified, predictable

solutions,” 127 S. Ct. at 1742. In Ortho-McNeil Pharmaceutical, Inc. v. Mylan

Laboratories, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008), this court further explained

that this “easily traversed, small and finite number of alternatives . . . might support an

inference of obviousness.” To the extent an art is unpredictable, as the chemical arts

often are, KSR’s focus on these “identified, predictable solutions” may present a difficult

hurdle because potential solutions are less likely to be genuinely predictable.

In other words, post-KSR, a prima facie case of obviousness for a chemical

compound still, in general, begins with the reasoned identification of a lead compound.

Teva cannot create a genuine issue of material fact on obviousness through the

2007-1397, -1398 8
unsupported assertion that compounds other than lansoprazole might have served as

lead compounds. Further, the record contains no reasons a skilled artisan would have

considered modification of lansoprazole by removing the lipophilicity-conferring

fluorinated substituent as an identifiable, predictable solution. In sum, the district court

properly concluded that the record did not support a case of obviousness of the ’552

patent as a matter of law.

III

As with other summary judgment issues, this court reviews a district court’s

summary judgment on inequitable conduct without deference. Innogenetics, N.V. v.

Abbott Labs., 512 F.3d 1363, 1378 (Fed. Cir. 2008). In contrast, where a judgment

regarding inequitable conduct follows a bench trial, this court reviews the district court’s

findings of materiality and intent for clear error and its ultimate conclusion for an abuse

of discretion. ACCO Brands, Inc. v. ABA Locks Mfrs. Co., 501 F.3d 1307, 1315 (Fed.

Cir. 2007).

Inequitable conduct in prosecuting a patent application before the United States

Patent & Trademark Office may take the form of an affirmative misrepresentation of

material fact, a failure to disclose material information, or the submission of false

material information, but in every case this false or misleading material communication

or failure to communicate must be coupled with an intent to deceive. Innogenetics, 512

F.3d at 1378 (citations omitted). Materiality, defined as “what a reasonable examiner

would have considered important in deciding whether to allow a patent application,” and

intent are both questions of fact, and require proof by clear and convincing evidence.

Id. To satisfy the “intent” prong for unenforceability, “the involved conduct, viewed in

2007-1397, -1398 9
light of all the evidence, including evidence indicative of good faith, must indicate

sufficient culpability to require a finding of intent to deceive.” Kingsdown Med.

Consultants, Ltd. v. Hollister Inc., 863 F.2d 867, 876 (Fed. Cir. 1988) (en banc) (citing

Norton v. Curtiss, 433 F.2d 779 (CCPA 1970)). Gross negligence is not sufficient. Id.

This is a high bar.

On appeal, Teva and Dr. Reddy’s allege that Eisai misled the Patent Office in five

ways: 1) failing to disclose Eisai’s own co-pending ’013 application, which claimed the

“ethyl homolog” of rabeprazole (compound SHKA 661); 2) withholding rejections from

the ’013 application’s prosecution that also would have been applicable to the ’552

patent’s prosecution; 3) failing to disclose the prior art “Byk Gulden patent” (WO

8602646); 4) submitting a misleading declaration (the Fujisaki Declaration) to the

examiner of the ’552 patent; and 5) concealing lansoprazole from the examiner. The

district court rejected the fifth assertion on summary judgment, SJ Enforceability Order

at 58, and the other four after a bench trial, Trial Order.

Teva and Dr. Reddy’s first and second allegations rely on Eisai’s failure to

disclose the fact of, and rejections contained in, Eisai’s patent application claiming the

“ethyl homolog” of rabeprazole. Known to Eisai’s scientists as compound SHKA 661,

the ethyl homolog differs from rabeprazole as its name suggests. SHKA 661 has one

fewer methylene unit at the 4-position of the pyridine ring, giving SHKA 661 an ethoxy

group rather than a propoxy group at this position. The district court correctly pointed

out that calling SHKA 661 the “ethyl homolog” of rabeprazole in this case could carry a

misleading implication with respect to inequitable conduct. The record supplies no

evidence to suggest that Eisai’s scientists ever referred to SHKA 661 by this name, or

2007-1397, -1398 10
thought of SHKA 661 and rabeprazole “primarily in relation to each other.” Trial Order

at 17 n.7. Rather, the district court found credible the testimony that Eisai scientists

considered SHKA 661 separately patentable, even though Eisai ultimately did not

pursue that course. Id. at 22-23; 42-43. Furthermore, even if a provisional

obviousness-type double-patenting rejection might have issued in the prosecution of the

’552 patent due to the co-pending SHKA 661 application, the district court found the

materiality of this potential situation low, because applicants routinely overcome this

type of rejection, id. at 44, by amending claims or filing a terminal disclaimer.

Nonetheless, the district court did not hold that the fact of the copendency of these two

applications to be totally immaterial, accurately noting that applicants should be

encouraged to disclose closely related applications. Id. at 47.

While disclosure of the co-pending SHKA 661 application to the Patent Office

during the prosecution of the ’552 patent would have been prudent, Eisai’s failure to do

so is by no means fatal, for two reasons. First, the district court had ample evidence

from which to conclude that the materiality of the SHKA 611 application was low, as

outlined above. Second, the record is devoid of any real suggestion of intent to deceive

the Patent Office, much less the clear and convincing evidence required to support a

finding of inequitable conduct.

As for the rejections of the ’013 application that would have been relevant to the

prosecution of the ’552 patent, the district court did not reach materiality because it

discerned insufficient proof of intent to deceive. The district court found the

documentary evidence (faxed exchange between Eisai employees Mr. Shuhei

Miyazawa, one of the inventors of the ’552 patent, and Mr. Mitsuo Taniguchi, Eisai’s

2007-1397, -1398 11
patent agent, regarding Mr. Miyazawa’s presentation to a pharmaceutical trade industry

group) to supply no compelling evidence of intent, based on testimony from both parties

to the fax. Witness credibility determinations lie squarely within the district court’s

discretion. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1171 (Fed. Cir. 2006).

The district court was ultimately undisturbed by the Taniguchi/Miyazawa communication

based on its evaluation of the witness testimony presented, and this court sees no

abuse of discretion. These facts certainly do not rise to the level of “culpability” this

court required in Kingsdown, 863 F.2d at 876, to establish intent to deceive, or even

gross negligence.

Finally, the district court found that Teva’s theory that Eisai deliberately hid the

ball from the Patent Office by separately filing the ’552 and ’013 prosecutions to be

“implausibly risky,” given that such similar applications would usually be assigned to the

same examiner in the same art unit. Trial Order at 53. The district court thus had

ample bases from which to conclude that Eisai’s failure to disclose its co-pending ’013

application along with the rejections issued in its prosecution, while not completely

forthcoming, did not rise to the level of inequitable conduct.

With respect to the Byk Gulden patent, Teva and Dr. Reddy’s argue that Eisai’s

failure to disclose this reference to the Patent Office during prosecution of the ’552

patent was material because a reasonable examiner would have used it to issue a new

and stronger prima facie obviousness rejection on the basis of Byk Gulden’s disclosure

of asymmetrically-substituted compounds having a methoxyethoxy at the 4-position of

the pyridine ring. But the district court found Byk Gulden’s teachings cumulative with

references already disclosed to the Patent Office (Junggren or Junggren combined with

2007-1397, -1398 12
Beecham). As per 37 C.F.R. § 1.56, cumulative evidence is definitionally not material

evidence. See Monsanto Co. v. Bayer Bioscience N.V., 514 F.3d 1229, 1237 (Fed. Cir.

2008). Here, the Junggren reference specifically disclosed asymmetrically substituted

compounds, including a compound having a 4-position methoxyethoxy substituent.

Thus the Byk Gulden reference offered nothing new to the record already before the

Patent Office. And even Teva’s expert conceded Byk Gulden would not have provided

the examiner with anything new. Id. at 57. Thus the district court was well within its

discretion in concluding that the Byk Gulden patent was not material to the prosecution

of the ’552 patent. Even if Byk Gulden had been material, the lack of clear and

convincing evidence of intent to deceive would nonetheless have imposed an

insurmountable bar to finding inequitable conduct, for the reasons given by the district

court.

As for the Fujisaki Declaration, Eisai submitted it during prosecution to overcome

an obviousness rejection. Because this reference shows rabeprazole’s

pharmacological properties, the trial court found it highly material. Id. at 59. Teva and

Dr. Reddy’s argue that the data presented in the Fujisaki Declaration were misleading.

They contend that the comparison with two non-prior art compounds without a

comparison of the ethyl homolog of rabeprazole, SHKA 661, sent the examiner on a

dead-end side trip. The district court properly characterized this argument as

“contorted.” Id. The Fujisaki Declaration indisputably showed a comparison between

rabeprazole and the prior art compound called out by the examiner, demonstrating

rabeprazole’s superiority. Further, as discussed above, the materiality of SHKA 661

and the patent application claiming it was low. The data from the Fujisaki Declaration

2007-1397, -1398 13
were relevant to prosecution, but Eisai had no obligation to include additional,

unnecessary data such as a comparison to SHKA 661. Thus the district court did not

abuse its discretion in concluding that Eisai did not commit inequitable conduct in failing

to include additional data in the Fujisaki Declaration to the examiner. Even here, where

the submission to the Patent Office itself was highly material to prosecution, the lack of

deceptive intent rendered stillborn yet another allegation of inequitable conduct.

Finally, Teva and Dr. Reddy’s assert that that Eisai deceptively declined to inform

the examiner of a patent application for lansoprazole, a prior art proton pump inhibitor

(and the active ingredient in Prevacid). The district court disposed of this argument on

summary judgment. The district court found that Teva and Dr. Reddy’s had presented

neither direct evidence of deceptive intent nor any evidence to support an inference of

materiality. SJ Enforceability Order at 58. The strongest evidence of some problem

was the passing comment of one Eisai “insider” that the similarity of lansoprazole and

rabeprazole “bothers me.” Id. at 59. But this vague, subjective statement is not

sufficient by any means to establish materiality, let alone intent. Moreover, given

lansoprazole’s fluorinated substituent and its resultant impotence to render the ’552

patent invalid, the district court properly rejected this strained theory of inequitable

conduct on summary judgment.

IV

In a series of thoughtful, thorough opinions, the district court carefully explained

its reasoning with respect to both obviousness and inequitable conduct. Because the

district court properly concluded that Teva and Dr. Reddy’s failed to prove that the ’552

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patent was invalid for obviousness or unenforceable for inequitable conduct, this court

affirms the district court’s judgment.

AFFIRMED

COSTS

Each party shall bear its own costs.

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