Aventis Pharma Deutschland GmbH v. Lupin, Ltd.

United States Court of Appeals for the Federal Circuit
2006-1530, -1555

AVENTIS PHARMA DEUTSCHLAND GMBH,

Plaintiff-Cross Appellant,

and

KING PHARMACEUTICALS, INC.,

Plaintiff-Cross Appellant,

v.

LUPIN, LTD.
and LUPIN PHARMACEUTICALS, INC.,

Defendants-Appellants.

Joel Katcoff, Kaye Scholer LLP, of New York, New York, argued for plaintiff-cross
appellant Aventis Pharma Deutschland GmbH. With him on the brief were Benjamin C.
Hsing, Sapna Walter Palla, and Tatiana N. Alyonycheva.

F. Dominic Cerrito, Jones Day, of New York, New York, argued for plaintiff-cross
appellant King Pharmaceuticals, Inc. With him on the brief were Daniel L. Malone, Eric
Stops, and Jonathan A. Muenkel.

Deanne M. Mazzochi, Rakoczy Molino Mazzochi Siwik LLP, of Chicago, Illinois,
argued for defendants-appellants. With her on the brief were William A. Rakoczy, Paul J.
Molino, and Alice L. Riechers.

Appealed from: United States District Court for the Eastern District of Virginia

Judge Robert G. Doumar
 United States Court of Appeals for the Federal Circuit
2006-1530, -1555

AVENTIS PHARMA DEUTSCHLAND GMBH,

Plaintiff-Cross Appellant,

and

KING PHARMACEUTICALS, INC.,

Plaintiff-Cross Appellant,

v.

LUPIN, LTD. and LUPIN PHARMACEUTICALS, INC.,

Defendants-Appellants.

__________________________

DECIDED: September 11, 2007
__________________________

Before MAYER and LINN, Circuit Judges, and ROBERTSON, District Judge. *

LINN, Circuit Judge.

This is a patent infringement action concerning the pharmaceutical compound

ramipril, which is marketed by King Pharmaceuticals, Inc. (“King”) as a blood pressure

medication under the name Altace®. Lupin Ltd. and Lupin Pharmaceuticals, Inc.

(collectively, “Lupin”) appeal from a final judgment of infringement entered by the United

States District Court for the Eastern District of Virginia in favor of King and Aventis

Pharma Deutschland GmbH (“Aventis”). Aventis Pharma Deutschland GmbH v. Lupin

Ltd., No. 2:05-CV-421 (E.D. Va. July 18, 2006). The district court concluded at

*
Hon. James Robertson, District Judge, United States District Court for the
District of Columbia, sitting by designation.
summary judgment that Lupin’s filing of an Abbreviated New Drug Application (ANDA)

for a generic version of ramipril infringed Aventis’s U.S. Patent. No. 5,061,722 (“the ’722

patent”) under the doctrine of equivalents, and concluded after a bench trial that the

asserted claims of the ’722 patent were not invalid. 1 Lupin appeals from these

decisions. Aventis cross-appeals from the district court’s decision to dismiss its claim of

willful infringement. For the reasons that follow, we conclude that the subject matter of

the asserted claims of the ’722 patent would have been obvious. Accordingly, we

reverse. The cross-appeal and the remaining issues raised by the parties are deemed

moot and are not addressed.

I. BACKGROUND

A. The Claimed Technology

The patent at issue in this appeal is directed to the pharmaceutical compound

ramipril in a formulation “substantially free of other isomers.” Ramipril, like many

complex organic molecules, is one of a family of stereoisomers. As the district court

explained in greater detail in its opinion regarding validity, Aventis Pharma Deutschland

GmbH v. King Pharms., Inc., No. 2:05-CV-421 (E.D. Va. July 17, 2006) (“Invalidity

Opinion”), an isomer of a compound is a separate compound in which each molecule

contains the same constituent atoms as the first compound, but with those atoms

arranged differently. A stereoisomer is an isomer in which the same atoms are bonded

to the same other atoms, but where the configuration of those atoms in three

dimensions differs. The following structural formula represents ramipril:

1
Aventis is the owner of the ’722 patent, and King is its exclusive licensee.
Both parties are plaintiff-cross appellants. For convenience, and because Aventis and
King have adopted each other’s arguments on appeal pursuant to Fed. R. App. P. 28(i),
we refer to them collectively as “Aventis.”

2006-1530, -1555 2
Each of the five carbon atoms marked with an asterisk can be spatially oriented in two

different ways. 2 For example, the dashed triangle leading from the leftmost marked

carbon to a hydrogen (“H”) atom indicates that the hydrogen atom lies below the planes

of the two five-sided rings of which the carbon atom is a part. The hydrogen atom may

also lie above the planes of the rings, resulting in a structure that is a stereoisomer of

ramipril. Because there are five carbon atoms that may take either of two orientations—

or five “stereocenters,” as such atoms are known—ramipril is one of 25, or 32,

stereoisomers. There are a number of different ways of naming these stereoisomers;

one comparatively simple system, used by both parties and by the district court,

involves labeling each stereocenter with an “R” or an “S” depending on its configuration.

Using this system, all five stereocenters in ramipril are in the “S” configuration, so it is

known as an “SSSSS” or “5(S)” stereoisomer. Other stereoisomers would include

RRRRR, SSSSR, RRSSS, etc.

Some of the prior art references also use the terms “enantiomer” and

“diastereomer.” Enantiomers are stereoisomers that are mirror images of each other,

like left and right hands. Diastereomers are stereoisomers that are not enantiomers.

2
As is customary in chemical diagrams, carbon atoms may be indicated by
an intersection of two line segments; in such cases, hydrogen atoms that are bonded to
the carbons may be omitted from the diagram for simplicity and should be inferred.

2006-1530, -1555 3
 The asserted claims of the ’722 patent read as follows:

1. A compound of the formula

or a physiologically acceptable salt thereof, wherein R2 is hydrogen,
methyl, ethyl, or benzyl, and wherein hydrogen atoms on the ring carbon
atoms in the 1- and 5-positions are in the cis-configuration relative to one
another, the carboxyl group on the ring carbon atom in the 3-position is in
the endo position relative to the bicyclic ring system, and the chirality
centers in the chain and on the ring carbon atom in the 3-position all have
the S-configuration, said compound or salt being substantially free of other
isomers.

2. A compound or salt as in claim 1 which is N-(1-S-carboethoxy-3-phenyl-
propyl)-S-alanyl-cis,endo-2-azabicyclo-[3.3.0]-octane-3-S-carboxylic acid
or a salt thereof.

4. A hypotensive composition for reducing blood pressure comprising a
hypotensively effective amount of a compound or salt as in claim 1 and a
pharmaceutically acceptable excipient therefor.

5. A method for reducing blood pressure in a patient which comprises
administering to said patient a hypotensively effective amount of a
compound or salt as in claim 1.

Claim 1, the only independent claim, covers a small genus of compounds, each of

which has a different functional group at location R2. The language of the claim,

“wherein hydrogen atoms on the ring carbon atoms in the 1- and 5-positions are in the

cis-configuration relative to one another, the carboxyl group on the ring carbon atom in

the 3-position is in the endo position relative to the bicyclic ring system, and the chirality

centers in the chain and on the ring carbon atom in the 3-position all have the S-

configuration,” limits claim 1 (and thus all the other claims) to the 5(S) stereoisomer.

2006-1530, -1555 4
When the R2 functional group is ethyl, the compound of claim 1 is ramipril. This is the

compound claimed specifically by claim 2.

B. The Development of Ramipril

Ramipril is one of a family of drugs known as “Angiotensin-Converting Enzyme

inhibitors,” or “ACE inhibitors.” ACE inhibitors inhibit a biochemical pathway that

constricts blood vessels and therefore are useful for treating high blood pressure. The

earliest ACE inhibitors, dating back to the late 1960s, were based on the venom of the

Brazilian Viper, which was known to reduce blood pressure. The active compound

isolated from viper venom, known as BPP5a, has six stereocenters, all of which are in

the S configuration. Synthetic ACE inhibitors have been developed by making structural

modifications to this venom and to successive generations of ACE inhibitors. For

example, captopril, the first synthetic ACE inhibitor, consists of part of the BPP5a

molecule with a sulfur atom at the end. Captopril retains two stereocenters from BPP5a,

both of which remain in the S configuration.

Ramipril’s immediate predecessor is an ACE inhibitor known as enalapril that

was introduced by Merck in 1980. Enalapril has three stereocenters. In a published

article, Merck scientists explained that the all-S (SSS) stereoisomer of enalapril was

found to have 700 times the potency of the SSR stereoisomer. A.A. Patchett et al., A

New Class of Angiotensin-Converting Enzyme Inhibitors, 288 Nature 280 (Nov. 20,

1980), available at J.A. 15475. The Merck article taught how to separate the all-S

isomer using standard chromatography techniques.

Both Aventis and its competitor Schering sought to create new ACE inhibitors

based on enalapril. Soon after enalapril’s introduction, Dr. Elizabeth Smith, a chemist at

2006-1530, -1555 5
Schering, conceived of the structure of ramipril and recorded it in her laboratory

notebooks. Ramipril has the same overall structure as enalapril, with one distinction:

where ramipril has two linked five-sided carbon rings (a “5,5 fused ring system”),

depicted, in the chemical diagrams above, on the left side of the molecule, enalapril has

only a single ring. The addition of the second ring gives rise to two more stereocenters

than are present in enalapril; thus, ramipril has the same three stereocenters as

enalapril, plus two new ones that span the fused ring system and are therefore known

as “bridgehead” carbons, for a total of five as discussed above.

Based on the work of Dr. Smith, Schering filed U.S. Patent Application No.

06/199,886 (“the ’886 application”) on October 23, 1980. Thereafter, the U.S. Patent

and Trademark Office (“PTO”) granted Schering Patent No. 4,587,258 (“the ’258

patent,” issued May 6, 1986) and No. 5,348,944 (“the ’944 patent,” issued Sept. 20,

1994), both claiming priority from the ’886 application via a series of continuations and

continuations-in-part. The ’886 application, the ’258 patent, and the ’944 patent

disclose the structure of ramipril but do not describe how its stereocenters should be

configured.

Example 20 of the ’886 application discloses a method for making ramipril and is

contained in the published specification of the ’944 patent. ’944 patent, col. 15, ll. 1–15.

The title of Example 20 encompasses only eight of the 32 stereoisomers of ramipril, but

there is some suggestion in the record that, in fact, Example 20 would have produced

only four stereoisomers in practice. Invalidity Opinion at 22–23. The district court

described one of the experts testifying on the topic as “somewhat credible” and did not

make any explicit findings as to which stereoisomers Example 20 would create. Id. at

2006-1530, -1555 6
23. For purposes of this appeal, it is sufficient to observe that it is uncontested that

Example 20 yields a mixture of several, but not all, stereoisomers of ramipril, one of

which is the 5(S) form. It appears likely that in some of these stereoisomers, the

“bridgehead” carbons are in the R configuration.

In February 1981, Dr. Smith synthesized a mixture of 5(S)-configuration ramipril

and its SSSSR stereoisomer, which mixture came to be known as SCH 31925. To

make SCH 31925, Smith followed the process disclosed in Example 20, with one

“tweak”: she used a catalytic hydrogenation step instead of the mercuric acetate

oxidation step taught by Example 20. The record is unclear as to why Smith used that

step, but there has been no showing that Smith was attempting to select particular

stereoisomers. However, the district court found, and Aventis does not dispute on

appeal, that SCH 31925—the product of the process as modified by Smith—contains

exactly two isomers, the 5(S) and SSSSR forms, and was successfully produced by Dr.

Smith. In both the 5(S) and SSSSR forms, the two “bridgehead” carbons are in the S

configuration. In light of the teachings of Example 20, Dr. Smith’s written laboratory

notebooks, and the test results that Dr. Smith obtained within weeks of SCH 31925’s

synthesis, we see no clear error in the district court’s findings that Dr. Smith had

conceived of the various stereoisomers and appreciated which of them SCH 31925

contained. See id. at 22–23, 68–69. Moreover, in vivo testing completed by the end of

March 1981 confirmed the mixture’s therapeutic activity as well as its stereochemistry.

We agree with the district court that Dr. Smith did not separate the 5(S) and SSSSR

isomers, and there is no evidence that she conceived of a purified formulation

containing only 5(S) ramipril. Id. at 69.

2006-1530, -1555 7
 In October 1981, Dr. Volker Teetz, an Aventis chemist, also synthesized ramipril.

Id. at 23. On November 5, 1981, Aventis filed a German precursor to the application

that would become the ’722 patent-in-suit. On November 3, 1982, Aventis filed the first

in a chain of U.S. patent applications that led to the ’722 patent. In all these

applications, Aventis claimed the benefit of the German application. There is no dispute

that Aventis is entitled to the November 5, 1981 priority date.

On May 6, 1986, Schering’s ’258 patent issued. Shortly thereafter, Schering

granted Aventis a royalty-bearing license under the ’258 patent. Around the same time,

the PTO declared Interference No. 101,833 between the ’258 patent and a pending

continuation application belonging to Aventis. The interference settled. Schering

agreed to reduce Aventis’s royalty payment and to disclaim some of its patent claims.

In exchange, Aventis conceded priority as to the primary subject matter of the ’258

patent—the structure, production, and therapeutic use of ramipril, without specification

of particular stereoisomers. Aventis retained the right to prosecute its application as to

the 5(S) stereoisomer of ramipril in formulations “substantially free of other isomers,”

which it contended (and still contends) represents a separately patentable invention.

The dispute about patent rights having been resolved between Schering and

Aventis, Aventis proceeded to seek FDA approval of ramipril (apparently in a

substantially pure 5(S) form). On January 28, 1991, the FDA granted approval, and

Aventis began to sell ramipril under the name Altace®. Acting as Schering’s agent,

Aventis sought and obtained an extension of the ’258 patent’s term on the basis of the

period of regulatory review by the FDA.

On October 29, 1991, the ’722 patent issued.

2006-1530, -1555 8
 C. Procedural History

The ’258 patent expired on January 27, 2005. On March 18, 2005, Lupin filed an

ANDA seeking approval for a generic version of ramipril. In response, pursuant to 35

U.S.C. § 271(e)(2)(A), Aventis sued Lupin for infringement, including willful

infringement, of the ’722 patent in the United States District Court for the Eastern

District of Virginia.

The district court granted Lupin’s Rule 12(c) motion for judgment on the

pleadings as to Aventis’s claim for willful infringement and dismissed that claim, leaving

only counts alleging non-willful infringement. Aventis Pharma Deutschland GmbH v.

King Pharms., Inc., No. 2:05-CV-421 (E.D. Va. Jan. 18, 2006). After construing the

claims, see Aventis Pharma Deutschland GmbH v. King Pharms., Inc., No. 2:05-CV-421

(E.D. Va. May 11, 2006), the district court considered the issue of infringement pursuant

to motions filed by both sides for summary judgment. The district court declined to

grant summary judgment to either party as to literal infringement, finding disputed

issues of material fact as to whether Lupin’s formulation of ramipril was “substantially

free of other isomers.” Aventis Pharma Deutschland GmbH v. King Pharms., Inc., No.

2:05-CV-421, slip op. at 11–16 (E.D. Va. June 5, 2006). However, the district court

granted summary judgment of infringement under the doctrine of equivalents, subject to

a subsequent ruling as to the ’722 patent’s validity. Id.

The district court then held a bench trial on validity. During the trial, the district

court orally granted Aventis’s motion for judgment as a matter of law that the ’722 patent

was not unenforceable for inequitable conduct. On July 17, 2006, the district court

issued its opinion on validity, concluding that the ’722 patent was neither anticipated nor

2006-1530, -1555 9
obvious. Invalidity Opinion at 87. Although the district court “reache[d] this decision

reluctantly” and observed that “[i]f the standard . . . had been by a preponderance of the

evidence rather than by clear and convincing evidence, the Court might have

determined this case in Lupin’s favor,” id. at 1–2, the court concluded that the prior art

did not teach ramipril “substantially free of other isomers,” nor would a person of

ordinary skill in the art “have necessarily been motivated to isolate Ramipril in the 5(S)

configuration substantially free of other isomers,” id. at 75.

Lupin appeals. Aventis cross-appeals, asserting error in the district court’s

finding that the filing of an ANDA cannot give rise to willful infringement. We have

jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

II. DISCUSSION

A. The Relevant Prior Art

The record contains a litany of potential prior art references, only some of which

are summarized in Part I.B above, and the prosecution histories of both the ’722 patent

and Schering’s ramipril patents are complex. Accordingly, and because Aventis

challenges the prior art status of a number of the references that Lupin cites, we begin

by identifying and describing the references on which our decision depends and

explaining why we consider them to be prior art.

Least controversial are the various references regarding BPP5a, captopril, and

enalapril. It is uncontested that these references were publicly disclosed or published

well before the development of ramipril and that both Schering’s and Aventis’s efforts

towards developing ramipril were based on this body of earlier knowledge. Notably, all

of the stereocenters in the most therapeutically active stereoisomers of these prior art

2006-1530, -1555 10
compounds are in the S configuration, and this fact was taught by, among other

references, Merck’s enalapril article in Nature.

Unlike these earlier references, however, Aventis challenges the prior art status

of the ’944 patent. 3 The ’944 patent, it observes, is a continuation-in-part of Schering’s

U.S. Patent Application No. 06/258,484 (“the ’484 application”), itself a continuation-in-

part of the ’886 application. Because Schering had abandoned the ’484 application

before the ’944 patent’s filing date, Aventis argues, 35 U.S.C. § 120 bars the ’944 patent

from benefiting from the earlier ’886 filing date. Lupin responds that the PTO cured this

defect by reviving the ’484 application nunc pro tunc. We need not and do not decide

Aventis’s challenge on this ground, however, because Aventis presents it for the first

time on appeal. In the district court, the ’944 patent was relied upon as prior art and its

status went unchallenged. Accordingly, the issue is waived. See Sage Prods., Inc. v.

Devon Indus., Inc., 126 F.3d 1420, 1426 (Fed. Cir. 1997). We thus consider the ’944

patent entitled to the ’886 filing date and treat it as prior art to the ’722 patent. The ’944

patent discloses Example 20 and also contains the following teaching: “When

diastereomeric products result from the synthetic procedures, the diastereomeric

products can be separated by conventional chromatographic or fractional crystallization

methods.” ’944 patent, col. 10, ll. 28–31.

Finally, we rely, as did the district court, on Dr. Smith’s synthesis of SCH 31925,

which qualifies as prior art under 35 U.S.C. § 102(g) as of a date no later than the end

of March 1981, several months before Aventis’s own synthesis of ramipril. See E.I. du

3
Aventis also challenges the prior art status of the ’258 patent on the
ground that it is a continuation-in-part containing previously undisclosed new matter.
We need not resolve this issue because we do not rely on the ’258 patent.

2006-1530, -1555 11
Pont de Nemours & Co. v. Phillips Petroleum Co., 849 F.2d 1430, 1436–37 (Fed. Cir.

1988) (discussing use of § 102(g) prior art in § 103 obviousness determinations).

Section 102(g) affords prior art status to an “invention [that] was made in this country by

another inventor who had not abandoned, suppressed, or concealed it.” 35 U.S.C.

§ 102(g). Aventis argues that Dr. Smith “abandoned, suppressed, or concealed” SCH

31925, but we see no error in the district court’s implicit rejection of this argument. A

very similar method to the one Dr. Smith used had already been disclosed in the ’886

patent application, the exact method was subsequently disclosed in the ’258 patent, and

the composition was developed in the course of extensive ongoing research and

development and concurrent ongoing patent prosecution. There has been no showing

either that Smith “intentionally suppress[ed] or conceal[ed] h[er] invention” or that an

“inference of suppression or concealment can be drawn based on an unreasonable

delay in making the invention publicly known.” Flex-Rest, LLC v. Steelcase, Inc., 455

F.3d 1351, 1358 (Fed. Cir. 2006). Accordingly, SCH 31925—a mixture of 5(S) ramipril

with its SSSSR stereoisomer—is part of the prior art.

B. Obviousness of Claims 1 and 2

We turn to the question of obviousness. “Obviousness is a question of law,

reviewed de novo, based upon underlying factual questions which are reviewed for

clear error following a bench trial.” Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1289

(Fed. Cir. 2006). The key question is whether the 5(S) stereoisomer of ramipril, in a

form substantially free of other isomers, 4 would have been obvious over the prior art

4
We note that the parties dispute the claim construction of “substantially
free of other isomers.” We need not address this question directly, however, because
their dispute centers on how much of another isomer a composition might contain while

2006-1530, -1555 12
listed above to one of ordinary skill in the art at the time of the ’722 patent’s priority date.

See 35 U.S.C. § 103(a). Such a composition is precisely the subject matter of claim 2

of the ’722 patent, but the question is dispositive of the obviousness of claim 1 as well,

because claim 1 is to a broader genus containing the same subject matter. See, e.g.,

Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 971 (Fed. Cir. 2001) (noting that a

“genus claim limitation is anticipated by, and therefore not patentably distinct from, [a]

species claim”).

The district court held that Lupin failed to meet its burden of proof by clear and

convincing evidence that a person of ordinary skill in the art would have been motivated

to purify 5(S) ramipril into a composition substantially free of other isomers. Invalidity

Opinion at 74–75. The district court saw this as a close case based principally on the

absence of a clear and convincing showing of motivation. Since the date of that

decision, however, the Supreme Court decided KSR International Co. v. Teleflex Inc.,

127 S. Ct. 1727 (2007), which counsels against applying the “teaching, suggestion, or

motivation” (“TSM”) test as a “rigid and mandatory formula[].” See KSR, 127 S. Ct. at

1741. It remains necessary to show “‘some articulated reasoning with some rational

underpinning to support the legal conclusion of obviousness,’” but such reasoning “need

not seek out precise teachings directed to the specific subject matter of the challenged

claim.” See id. (quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)). Requiring an

explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active

still remaining “substantially free of other isomers.” Whatever the answer to this
question might be, it is undisputed that SCH 31925 and the other mixtures of ramipril
isomers in the prior art are mixtures that are not substantially free of isomers other than
the 5(S) form, whereas the claimed composition of 5(S) ramipril is ipso facto
“substantially free” enough.

2006-1530, -1555 13
ingredient is precisely the sort of rigid application of the TSM test that was criticized in

KSR.

In the chemical arts, we have long held that “structural similarity between claimed

and prior art subject matter, proved by combining references or otherwise, where the

prior art gives reason or motivation to make the claimed compositions, creates a prima

facie case of obviousness.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., No.

06-1329, slip op. at 9 (Fed. Cir. June 28, 2007) (quoting In re Dillon, 919 F.2d 688, 692

(Fed. Cir. 1990) (en banc)); see also In re Papesch, 315 F.2d 381 (C.C.P.A. 1963). The

“reason or motivation” need not be an explicit teaching that the claimed compound will

have a particular utility; 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.

Dillon, 919 F.2d at 692; see also In re Wilder, 563 F.2d 457, 460 (C.C.P.A. 1977)

(“[O]ne who claims a compound, per se, which is structurally similar to a prior art

compound must rebut the presumed expectation that the structurally similar compounds

have similar properties.”). Once such a prima facie case is established, it falls to the

applicant or patentee to rebut it, for example with a showing that the claimed compound

has unexpected properties. Dillon, 919 F.2d at 692.

The analysis is similar where, as here, a claimed composition is a purified form of

a mixture that existed in the prior art. Such a purified compound is not always prima

facie obvious over the mixture; for example, it may not be known that the purified

compound is present in or an active ingredient of the mixture, or the state of the art may

be such that discovering how to perform the purification is an invention of patentable

2006-1530, -1555 14
weight in itself. However, if it is known that some desirable property of a mixture

derives in whole or in part from a particular one of its components, or if the prior art

would provide a person of ordinary skill in the art with reason to believe that this is so,

the purified compound is prima facie obvious over the mixture even without an explicit

teaching that the ingredient should be concentrated or purified. See In re May, 574

F.2d 1082, 1090–94 (C.C.P.A. 1978) (holding isolated stereoisomer nonobvious over

racemic mixture of stereoisomers, after conceded prima facie showing of obviousness,

because isolated stereoisomer was unexpectedly nonaddictive); In re Adamson, 275

F.2d 952, 954–55 (C.C.P.A. 1960) (holding isolated stereoisomer obvious over racemic

mixture of stereoisomers, given insufficient showing of any unexpected result); see also

In re Merz, 97 F.2d 599, 601 (C.C.P.A. 1938) (holding, prior to the enactment of § 103,

that an applicant “is not entitled to a patent on [an] article which after being produced

has a greater degree of purity than the product produced by former methods” unless the

purification results in “properties and characteristics which were different in kind from

those of the known product rather than in degree”). Ordinarily, one expects a

concentrated or purified ingredient to retain the same properties it exhibited in a mixture,

and for those properties to be amplified when the ingredient is concentrated or purified;

isolation of interesting compounds is a mainstay of the chemist’s art. If it is known how

to perform such an isolation, doing so “is likely the product not of innovation but of

ordinary skill and common sense.” KSR, 127 S. Ct. at 1742.

The record suggests that when Dr. Smith synthesized SCH 31925, she

understood that the 5(S) form of ramipril was the mixture’s therapeutically active

ingredient. Even if she did not, however, the prior art provides a sufficient reason to

2006-1530, -1555 15
look to the 5(S) configuration. The SCH 31925 composition contained only the 5(S) and

SSSSR stereoisomers of ramipril. Importantly, these forms differ by the configuration of

only one carbon atom, and that atom is not one of the “bridgehead” carbons. Rather,

that carbon atom is in the part of the ramipril molecule that is common to the enalapril

molecule. In enalapril, as in captopril and BPP5a before it, all of the stereocenters are in

the S configuration; the Merck article taught that the SSS configuration of enalapril is

700 times as potent as the SSR form. The close structural analogy between 5(S) and

SSSSR ramipril and SSS and SSR enalapril would have led a person of ordinary skill to

expect 5(S) and SSSSR ramipril to differ similarly in potency. Moreover, the ’944 patent

specifically taught that stereoisomers of ramipril “can be separated by conventional

chromatographic or fractional crystallization methods.” ’944 patent, col. 10, ll. 28–31.

Aventis’s protestations notwithstanding, there is no evidence that separating 5(S) and

SSSSR ramipril was outside the capability of an ordinarily skilled artisan.

Aventis attempts to rebut this prima facie case of obviousness by arguing that

purified 5(S) ramipril exhibited unexpected results in the form of increased potency. In

support, Aventis points to the district court’s finding that 5(S) ramipril is 18 times as

potent as the next most potent isomer, the RRSSS form. Invalidity Opinion at 44.

Aventis is correct that, on the basis of the record, the RRSSS and 5(S) forms might

have been expected to have comparable potencies; both of them have only S-

configured stereocenters in the part of the ramipril molecule that is common to enalapril,

as the R stereocenters in the RRSSS form are the “bridgehead” carbons. This,

however, is the wrong comparison. The prior art supporting prima facie obviousness

included the SCH 31925 mixture, and so Aventis must show that 5(S) ramipril had

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unexpected results not over all of its stereoisomers, but over that mixture, which did not

contain the RRSSS form. And the potency of pure 5(S) ramipril is precisely what one

would expect, as compared to a mixture containing other, inert or near-inert

stereoisomers. All evidence suggests, and the district court found, that potency varies

with the absolute amount of the 5(S) isomer in a mixture. Invalidity Opinion at 37. That

is, a 30 milligram dose of a mixture that is 1/3 5(S) ramipril has the same effectiveness

as a 10 milligram dose of pure 5(S) ramipril. Id. Aventis has thus failed to show

unexpected results that would tend to rebut a prima facie case of obviousness. See

Pfizer v. Apotex, 480 F.3d 1348, 1368–69 (Fed. Cir. 2007) (holding obvious a patent

claim to amlodipine besylate over prior art disclosing the small genus of

pharmaceutically acceptable amlodipine salts, where there was an insufficient showing

that the properties of amlodipine besylate, purportedly superior for the purpose of mass-

manufacturing tablets, were unexpectedly superior to other obvious-to-try salts); cf.

Forest Labs., Inc. v. Ivax Pharms., Inc., No. 07-1059, slip op. at 10–11 (Fed. Cir. Sept.

5, 2007) (holding that prima facie obviousness of a claim to a particular stereoisomer

over a racemic mixture was rebutted where the particular stereoisomer showed

unexpected benefits and evidence indicated that the isomers would have been difficult

for a person of ordinary skill in the art to separate).

In sum, we hold that claims 1 and 2 of the ’722 patent, which cover the 5(S)

stereoisomer of ramipril in a composition substantially free of other isomers, are invalid

under 35 U.S.C. § 103 over the SCH 31925 mixture, the ’944 patent, and the enalapril

references in the prior art.

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 C. Obviousness of Claims 4 and 5

Two asserted claims of the ’722 patent remain for discussion. Claim 4 addresses

a “hypotensive composition” of the compound in claim 1 “comprising a hypotensively

effective amount” of the compound “and a pharmaceutically acceptable excipient

therefor.” Claim 5 addresses a “method for reducing blood pressure” by administering

the compound of claim 1. The parties argue this case by discussing the invalidity of the

’722 patent as a whole, but “we must evaluate obviousness on a claim-by-claim basis.”

DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356,

1372 (2006). However, the parties do not challenge the district court’s observation that

“all the claims rise or fall with the validity of claim 1,” Invalidity Opinion at 17, and with

good reason. The added limitations of claims 4 and 5 appear almost verbatim in

virtually all the prior art patents, including the ’944 patent and its parent ’886 application.

E.g., ’944 patent, claims 3–4, col. 36, ll. 43–52. The prior art thus reveals that it was

well understood by ordinarily skilled artisans that ACE inhibitors were to be used in the

manner these claims describe. Accordingly, we hold that claims 4 and 5 of the ’722

patent are also invalid as obvious.

III. CONCLUSION

Having concluded that all asserted claims of the ’722 patent are invalid as

obvious, we need not reach Lupin’s remaining arguments in favor of reversal. Likewise,

Aventis’s cross-appeal is moot. Because Lupin is entitled to entry of judgment in its

favor, the judgment of the district court is

REVERSED.

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