United States Court of Appeals 

for the Federal Circuit ______________________ 

SPECTRUM PHARMACEUTICALS, INC., 

UNIVERSITY OF STRATHCLYDE,

Plaintiffs-Appellants

v.

SANDOZ INC.,

Defendant-Appellee

______________________ 

2015-1407

______________________ 

Appeal from the United States District Court for the 

District of Nevada in No. 2:12-cv-00111-GMN-NJK, Judge 

Gloria M. Navarro.

______________________ 

Decided: October 2, 2015

______________________ 

MARK HARRY IZRAELEWICZ, Marshall, Gerstein & Borun LLP, Chicago, IL ̧ argued for plaintiffs-appellants. 

Also represented by AMANDA ANTONS, KEVIN M. FLOWERS,

THOMAS IRVING ROSS. 

DEANNE MAYNARD, Morrison & Foerster LLP, Washington, DC, argued for defendant-appellee. Also represented by BRIAN ROBERT MATSUI. 

______________________ 

Before LOURIE, WALLACH, and HUGHES, Circuit Judges. 
2 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

LOURIE, Circuit Judge. 

Spectrum Pharmaceuticals, Inc. (“Spectrum”) appeals 

from the decisions of the United States District Court for 

the District of Nevada holding claims 1–2 of U.S. Patent 

6,500,829 (“the ’829 patent”) invalid as obvious, and 

finding claims 5–9 of the ’829 patent not infringed by the 

submission of an Abbreviated New Drug Application 

(“ANDA”) by Sandoz Inc. (“Sandoz”). Spectrum Pharm., 

Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2015 WL 794674 

(D. Nev. Feb. 25, 2015) (“Trial Order”); Spectrum Pharm., 

Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2014 WL 7368845

(D. Nev. Dec. 29, 2014) (“Summary Judgment Order”). 

Because the district court did not err in concluding that 

claims 1–2 are invalid, and additionally did not clearly err 

in finding claims 5–9 not infringed by Sandoz’s ANDA 

product, we affirm.

BACKGROUND

Leucovorin is a compound used to ameliorate the toxic

effects of methotrexate, a chemotherapy treatment 

(“methotrexate rescue”); to treat folate deficiency; and to 

enhance the efficacy of a 5-fluorouracil cancer treatment 

(“5-FU combination therapy”). Due to an asymmetric C6 

carbon, leucovorin may exist as a 50/50 mixture of two

diastereoisomers, the (6S) and (6R) isomers. The (6S)

diastereoisomer is also known as levoleucovorin or 

l-leucovorin, and is the isomer with the desired biological 

activity.

The ’829 patent is directed to pharmaceutical compositions of substantially pure levoleucovorin. Claim 1 of 

the ’829 patent reads as follows:

1. A pharmaceutical composition for therapeutic 

use which consists essentially of a therapeutically 

effective amount sufficient for the treatment of 

human beings for methotrexate rescue or folate deficiency, of a pharmaceutically acceptable com-
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 3

pound which is a (6S) diastereoisomer selected 

from the group consisting of (6S) leucovorin (5-

formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin; wherein the compound consists of a mixture 

of (6S) and (6R) diastereoisomers and consists of 

at least 92% by weight of the (6S) diastereoisomer, 

the balance of said compound consisting of the 

(6R) diastereoisomer; in combination with a 

pharmaceutically acceptable carrier.

’829 patent col. 9 ll. 55–67 (emphases added). The written 

description states that “a typical daily dose” of the 

(6S) isomer for methotrexate rescue would be “up to 

150 mg[,] e.g.[,] in the range from 25 to 150 mg,” and that 

“a typical daily dose [for treating folate deficiency] for an 

adult human is generally in the range from 2 to 25 mg.” 

Id. col. 5 ll. 15–19, 21–24. Claim 2 depends from claim 1, 

with the additional limitation that the composition “consists of greater than 95% by weight of the (6S) diastereoisomer.” Id. col. 10 ll. 1–3 (emphasis added). 

Claim 5 of the ’829 patent reads as follows:

5. A pharmaceutical composition for therapeutic 

use for the treatment of human beings comprising:

a pharmaceutically acceptable composition 

which is a (6S) diastereoisomer selected 

from the group consisting of (6S) leucovorin (5-formyl-(6S)-tetrahydrofolic acid) 

and pharmaceutically acceptable salts and 

esters of (6S) leucovorin, wherein the 

composition consists of a mixture of (6S) 

and (6R) diastereoisomers and consists of 

at least about 92% by weight of the (6S) 

diastereoisomer, the balance of said composition consisting of the (6R) diastereoisomer; and
4 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

a pharmaceutically acceptable carrier; and

said composition being of a quantity at 

least sufficient to provide multiple doses of 

said mixture of (6S) and (6R) diastereoisomers in an amount of 2000 mg per dose. 

Id. col. 10 ll. 10–24 (emphases added). Claims 6–9 depend 

from claim 5 and contain additional limitations not at 

issue in this appeal.

During prosecution of the application that became the

’829 patent, the examiner rejected the application’s claims 

as anticipated by or obvious over an article disclosing an 

enzymatic synthesis technique by which 0.91 grams of lleucovorin had been synthesized. J.A. 4872–77 (office 

action detailing rejection over Lilias Rees et al., Asymmetric Reduction of Dihydrofolate Using Dihydrofolate Reductase and Chiral Boron-Containing Compounds, 42 

Tetrahedron 117–136 (1986) (“Rees”)). The applicants 

responded by adding new claims, including what later 

issued as claims 5–9, and by emphasizing the specific

claim limitations relating to quantities of the specified 

mixture, which were allegedly not disclosed by the prior 

art. J.A. 4901–05. After a final office action rejecting the 

claims, the applicants appealed to the U.S. Patent and 

Trademark Office’s Board of Patent Appeals and Interferences (“the Board”), again emphasizing that the quantity

limitations could not be met by Rees. J.A. 4971, 4993–98. 

The patent eventually issued with the University of 

Strathclyde listed as the assignee.

Spectrum, as the exclusive licensee of the ’829 patent, 

holds the approved New Drug Application for a levoleucovorin formulation, and accordingly listed the patent as 

claiming the drug product in the U.S. Food and Drug 

Administration (“FDA”) publication, Approved Drug 

Products with Therapeutic Equivalence Evaluations

(commonly known as the “Orange Book”). Spectrum’s 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 5

product, Fusilev®, is indicated for the three uses described earlier. 

Sandoz submitted an ANDA in October 2011, seeking 

approval from the FDA for a drug product that will be 

imported in the form of single-use vials with 175 mg or 

250 mg of levoleucovorin, indicated for methotrexate 

rescue at doses of 7.5–75 mg per dose (“the ANDA product”). Its ANDA contained a certification that the ’829

patent was invalid or would not be infringed by the ANDA 

product. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV).

After receiving notice of that certification, Spectrum 

filed a timely patent infringement suit in January 2012, 

alleging that Sandoz’s ANDA submission infringed the 

’829 patent under 35 U.S.C. § 271(e)(2). The asserted 

claims were directed to pharmaceutical compositions 

comprising a mixture of (6S) and (6R) isomers, with at 

least 92% or 95% of the (6S) isomer. The patent discloses, 

but does not claim, a process for purifying the (6S) isomer 

from a 50/50 mixture using a chiral auxiliary group.

The district court construed the term “said composition being of a quantity at least sufficient to provide 

multiple doses of said mixture of (6S) and (6R) diastereoisomers in an amount of 2000 mg per dose” as having its 

plain and ordinary meaning. Spectrum Pharm., Inc. v. 

Sandoz Inc., No. 2:12-cv-00111, 2013 WL 6865692, at 

*18–20 (D. Nev. Dec. 31, 2013) (emphases added). The 

court elaborated that the plain meaning required the 

composition to contain “enough of the (6S)/(6R) mixture to 

provide two or more doses of, at minimum, 2000 mg per 

dose.” Id.

After construing the claims, the district court granted

Sandoz’s motion for summary judgment of noninfringement of claims 5–9. Summary Judgment Order at *1. 

Comparing the product described in Sandoz’s ANDA to 

the claims of the ’829 patent, the court found that because 

the individual vials will contain only up to 250 mg of 
6 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

levoleucovorin, the approved product would not satisfy the 

claim limitation of at least two doses of 2000 mg. Id. at 

*5. The court also rejected Spectrum’s argument that an 

aggregation of Sandoz’s approved product—that is, the 

total amount of levoleucovorin drug product to be imported—would infringe the claims. Id.

The district court further found that Spectrum was 

precluded from asserting infringement under the doctrine 

of equivalents because of the inventors’ statements during 

prosecution. Summary Judgment Order at *7–8. The 

court cited various instances in the prosecution history in 

which the applicants had distinguished Rees by emphasizing that the application claims (that issued as claims 

5–9) had “more stringent quantity limitations” than claim 

1. Id. at *7. As a result, the court found “a clear and 

unmistakable surrender of subject matter covering pharmaceutical composition quantities less than what is 

required to provide two or more doses of, at minimum, 

2000 mg per dose of the mixture.” Id. at *8. Because 

Spectrum did not raise a genuine issue of material fact as 

to literal infringement or infringement under the doctrine 

of equivalents of claims 5–9, the court granted summary 

judgment of noninfringement of those claims. 

Sandoz stipulated to infringement of claims 1 and 2, 

and the district court subsequently conducted a bench 

trial only on the validity of those claims. The court found 

that the prior art disclosed: (i) leucovorin as a mixture of 

(6R) and (6S) diastereoisomers; (ii) that the therapeutic 

usefulness of leucovorin derives wholly from the (6S) 

isomer; and (iii) a rationale for investigating a purified 

(6S) isomer product for use in 5-FU combination therapy. 

Trial Order at *6–8, *13–14. The court also found that

preparations of purified (6S) isomer by an enzymatic 

synthesis method and by separation methods had been 

publicly reported before the ’829 patent’s priority date. 

Id. at *6–7. In particular, the court analyzed two related 

prior art references that disclosed a process for separating 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 7

the diastereoisomers using the solubility differential of 

the (6S) and (6R) isomer salts, i.e., fractional crystallization. See id. at *11–13 (findings relating to Donna B. 

Cosulich, Diastereoisomers of Leucovorin, 74 J. Am. 

Chemical Soc’y 4215–16 (1952) and U.S. Patent 2,688,018

(collectively, “Cosulich” or “the Cosulich references”)). 

The district court further found that the process

taught by Cosulich would have “invariably” produced a 

mixture containing the (6R) isomer as an impurity, and 

that the data in the Cosulich references demonstrated 

that Dr. Cosulich also obtained a highly pure (6S) isomer 

compound. Trial Order at *10–12. The court concluded 

that those facts alone made the subject matter of the 

claims prima facie obvious in light of the prior art. The 

court also rejected Spectrum’s argument that using the 

Rees method would not have produced sufficient quantities of the (6S) isomer, because the applicants had submitted a declaration during prosecution stating that the 

reaction could have been scaled up to produce about 500

grams of the (6S) isomer per year. Id. at *15–16. 

The district court then found that Spectrum did not 

rebut the prima facie case of obviousness because it failed 

to prove any nexus between what was claimed and the socalled secondary factors, much less prove a long-felt need 

or successful licensing. Id. at *25–27. In particular, the 

court found that the only “distinguishing feature” of the 

claims compared to the prior art was “the small presence 

of the unwanted (6R) isomer,” and that Spectrum did not 

prove a nexus between that amount and any secondary 

consideration. Id. at *25. Moreover, as leucovorin was 

not used in 5-FU combination therapy until much later 

than the claimed uses (and thus the effect of the 

(6R) isomer was not previously a concern), the court found 

that no nexus was shown between the claims and the 

asserted long-felt need. Id. The court found that even if 

there were a nexus and a long-felt need, the invention 

would not have satisfied the need because substantially 
8 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

pure levoleucovorin is clinically interchangeable with the 

prior art leucovorin. Id. at *26. The district court also 

rejected Spectrum’s proof of commercial success. Trial 

Order at *26–27. The court thus concluded that the 

evidence as a whole showed that claims 1 and 2 were 

invalid as obvious. Id. The district court accordingly 

entered final judgment in favor of Sandoz. 

Spectrum timely appealed to this court. We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

DISCUSSION

On appeal from a bench trial, we review a district 

court’s conclusions of law de novo and its findings of fact 

for clear error. Golden Blount, Inc. v. Robert H. Peterson 

Co., 365 F.3d 1054, 1058 (Fed. Cir. 2004). A factual 

finding is only clearly erroneous if, despite some supporting evidence, we are left with the definite and firm conviction that a mistake has been made. United States v. U.S. 

Gypsum Co., 333 U.S. 364, 395 (1948); see also Polaroid 

Corp. v. Eastman Kodak Co., 789 F.2d 1556, 1559 (Fed. 

Cir. 1986) (“The burden of overcoming the district court’s 

factual findings is, as it should be, a heavy one.”).

At the summary judgment stage, we review the grant 

of summary judgment under the law of the regional 

circuit in which the district court sits, here the Ninth 

Circuit. Classen Immunotherapies, Inc. v. Elan Pharm., 

Inc., 786 F.3d 892, 896 (Fed. Cir. 2015). Applying the law 

of the Ninth Circuit, we review a district court’s grant of 

summary judgment de novo. Burke v. Cty. of Alameda, 

586 F.3d 725, 730 (9th Cir. 2009). Summary judgment is 

appropriate when, drawing all reasonable inferences in 

favor of the nonmovant, there is “no genuine dispute as to 

any material fact and the movant is entitled to judgment 

as a matter of law.” Fed. R. Civ. P. 56(a); see Anderson v. 

Liberty Lobby, Inc., 477 U.S. 242, 255 (1986). 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 9

This appeal raises questions of validity and infringement, but, unlike most such appeals, does not challenge 

the district court’s claim construction. As we find no 

reason to disturb the district court’s claim construction in 

these cases, we will only address the issues raised.

I. Invalidity

We first address Spectrum’s argument that the district court erred in holding claims 1 and 2 of the ’829

patent invalid as obvious.

Patents are presumed to be valid, and overcoming 

that presumption requires clear and convincing evidence. 

35 U.S.C. § 282; Microsoft Corp. v. i4i Ltd. P’ship, 564 

U.S. __, 131 S. Ct. 2238, 2242 (2011). A patent claim is 

invalid as obvious if an alleged infringer proves that the 

differences between the claims and the prior art are such 

that “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.” 35 U.S.C. § 103(a) 

(2006).1

Obviousness is ultimately a conclusion of law premised on underlying findings of fact, including the scope 

and content of the prior art, the differences between the 

claimed invention and the prior art, and the level of 

ordinary skill in the pertinent art. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007); Graham v. John Deere 

Co., 383 U.S. 1, 17–18 (1966). “The presence or absence of 

a motivation to combine references in an obviousness 

determination is a pure question of fact.” Alza Corp. v. 

Mylan Labs., 464 F.3d 1286, 1289 (Fed. Cir. 2006). In 

addition to common knowledge or teachings in the prior 

1 Because the ’829 patent was filed before the effective date of the America Invents Act, the earlier, pre-Act 

version of § 103(a) applies. See Leahy–Smith America 

Invents Act, Pub. L. No. 112-29, 125 Stat. 284, 293 (2011).

 
10 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

art itself, a “design need or market pressure or other 

motivation” may provide a suggestion or motivation to 

combine prior art elements in the manner claimed. Rolls 

Royce, PLC v. United Techs. Corp., 603 F.3d 1325, 1339 

(Fed. Cir. 2010); accord KSR, 550 U.S. at 420. These 

principles are relevant here.

Spectrum asserts that the district court improperly 

used hindsight to provide a reason or motivation to modify the prior art pure (6S) isomer compound to obtain a 

slightly impure compound. Even though one of skill in 

the art admittedly could have added some (6R) isomer to 

contaminate the 100% pure (6S) isomer disclosed by Rees 

to produce the claimed substantially pure compound, 

Spectrum argues that none of the record evidence supplied a logical motivation to do so.

Sandoz responds that the district court correctly 

found that one of skill would have been motivated to 

make substantially pure (6S) leucovorin starting with the 

50/50 mixture to have a more effective pharmaceutical 

treatment, and would have reasonably expected to succeed in doing so. Sandoz contends that it had no burden 

to show a motivation to contaminate the prior art pure

(6S) isomer compound, because the court’s analysis began 

with the 50/50 mixture and rejected Spectrum’s arguments on the inoperability of the prior art. Moreover, 

Sandoz argues, the court found no patentable difference 

between the claimed substantially pure compound and 

the prior art pure compound, which presented a prima 

facie case of obviousness that Spectrum failed to rebut.

Most issues relating to purified diastereoisomers or 

enantiomers involve the question whether a pure, resolved compound would have been obvious over the corresponding mixture. See, e.g., Aventis Pharma Deutschland 

GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301–03 (Fed. Cir. 

2007); see also Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 

1075, 1086–90 (Fed. Cir. 2008); Forest Labs., Inc. v. Ivax 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 11

Pharm., Inc., 501 F.3d 1263, 1269 (Fed. Cir. 2007); In re 

Adamson, 275 F.2d 952, 953–54 (CCPA 1960); In re 

Anthony, 414 F.2d 1383, 1386 (CCPA 1969). This case is 

unusual in involving a slightly different question, namely, 

whether a substantially pure compound would have been 

obvious when both the 50/50 mixture and the pure compound were known in the art. We agree with the district 

court that the claimed substantially pure compound 

would have been obvious over both the 50/50 mixture and 

the pure (6S) isomer compound in the prior art. 

First, the district court did not clearly err in finding 

that one of skill would have been motivated to modify the 

prior art 50/50 mixture to make the claimed mixture. If it 

is known that the desired activity all lies in one isomer, 

surely, it is better, and there is generally motivation, to 

try to obtain the purest compound possible. See Aventis, 

499 F.3d at 1301 (“[A] purified compound is not always 

prima facie obvious over the mixture; . . . [h]owever, if it is 

known that some desirable property of a mixture derives 

in whole or in part from a particular one of its components, . . . the purified compound is prima facie obvious 

over the mixture even without an explicit teaching that 

the ingredient should be concentrated or purified.”). A 

physician would not likely want to administer a contaminant or a less pure material to a patient if one could use a 

pure material. Thus, there is always in such cases a 

motivation to aim for obtaining a pure, resolved material.

Conversely, if the pure material is known, no reason 

has been shown why one would want to have an impure 

material. Although one may not be motivated to obtain 

an impure material and, in effect, it therefore can be 

argued to have been nonobvious—which is Spectrum’s 

position here, that the 92–95% pure material was nonobvious over the known pure material—that position, despite its superficial appeal, is not persuasive. As the 

district court correctly decided, because the desirable 

properties of the prior art 50/50 mixture are attributable 
12 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

to only one component, and the slightly impure mixture—

one that contains the substantially pure (6S) isomer in an 

amount of at least 92–95%—has not been shown to possess unexpected advantages over the prior art pure material, the less-than-pure material, and any others of 

similar concentration, cannot be found to have been 

nonobvious. 

We also agree with the district court that, given the 

50/50 mixture, there would have been a motivation to 

pursue the goal of obtaining either pure or the clinically 

interchangeable substantially pure (6S) isomer. A person 

of skill knew that the desired activity of leucovorin came 

from the (6S) isomer, which therefore provided a motivation to purify the (6S) isomer, even without an explicit 

teaching. Although the claimed compounds are not 100% 

pure, they are described as “substantially pure” and as 

not patentably different from pure material. 

The evidence showed that “numerous other research 

groups had responded to the motivation to obtain a pure 

isomer and were pursuing purified (6S) leucovorin prior to 

the priority date for the ’829 patent,” and, as the district 

court noted, “[i]n short time, many succeeded.” Trial 

Order at *14–15 (citation omitted). As in Aventis, here 

there was no need to find an express teaching to prove 

sufficient motivation to modify the prior art to arrive at 

the claimed invention, where various techniques to purify

the isomers were reported in the art and, importantly, it 

was known that the (6S) isomer alone provided the therapeutic effect.

In the face of that evidence of obviousness, Spectrum 

did not provide any evidence of unexpected results for the 

substantially pure compound as compared to the 50/50 

mixture or the 100% pure compound. The district court 

found that “clinical trials have established that purified 

(6S) leucovorin and leucovorin are clinically interchangeable” and that one of skill in the art “would not have 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 13

expected there to be any differences in the biological 

properties between purified (6S) leucovorin with or without a small amount of (6R) impurity . . . because small 

amounts of the inactive isomer would not be noticeable in 

terms of therapeutic effects.” Trial Order at *16. 

The district court also found that the prior art as a 

whole enabled one of skill in the art to make and use the 

claimed invention. Spectrum asserts that the court made 

no explicit finding that Cosulich was enabling, and therefore nothing in the record showed that one of skill in the 

art had the means to separate the (6S) and (6R) isomers 

from a 50/50 mixture. Accordingly, Spectrum argues,

because the ’829 patent enabled one of skill in the art to 

produce viable quantities of the substantially pure (6S) 

isomer, the claims are directed to both the compound and

the method of making that compound. 

Sandoz responds that the district court made factual 

findings that the prior art was enabling because multiple 

teams independently developed different methods for 

purifying a (6S) isomer compound around the time of the 

claimed invention, and that the specification admits that 

the prior art methods worked. Sandoz also notes that the 

court acknowledged the evidence of failures to repeat the

results of the method disclosed in Cosulich, but did not 

find that the purification could not be accomplished. 

Regardless whether the Cosulich references were enabling or not, the whole spectrum of prior art available 

before the invention was made would have enabled one of 

skill in the art to make and use the claimed substantially 

pure leucovorin compound. We agree with the district 

court’s conclusion on that point.

Finally, the district court found that the objective indicia did not rebut the prima facie case of obviousness. 

Spectrum argues that the district court erred by finding 

that, despite the motivation to purify the prior art 50/50 

mixture and the knowledge in the art that the (6R) isomer 
14 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

was undesirable, there was not a long-felt but unmet 

need. Spectrum also asserts that the district court improperly used evidence of later clinical studies. Sandoz 

responds that such a need does not always exist whenever 

there is a motivation to modify the prior art, and that 

post-filing evidence is usually required to determine if the 

claimed invention satisfied the alleged long-felt need.

We agree that the district court did not clearly err in 

finding that there was no long-felt but unmet need. 

Moreover, even if there were a long-felt need, the district 

court found that a purified (6S) isomer compound would 

not have satisfied that need because it was shown to be 

clinically interchangeable with the 50/50 mixture. Id. at 

*18. The court also credited expert testimony, including 

that of Spectrum’s expert, that the claimed substantially 

pure (6S) isomer compound “offers no meaningful difference” from the pure (6S) isomer compound. Id. at *16. As

a long-felt but unmet need was the only indicium argued 

on appeal, we agree with the district court that Spectrum

did not provide evidence of objective indicia of nonobviousness.

We owe the district court’s factual findings considerable deference on appeal, and we see no clear error based 

on the record before us. Based on those findings, we 

affirm the district court’s conclusion that Sandoz proved 

by clear and convincing evidence that claims 1 and 2 of 

the ’829 patent are invalid as obvious.

II. Noninfringement

We also address the district court’s finding that 

claims 5–9 of the ’829 patent would not be infringed by 

Sandoz’s ANDA product. The key language at issue in 

claim 5, and by extension in dependent claims 6–9, is

“said composition being of a quantity at least sufficient to 

provide multiple doses of said mixture of (6S) and (6R) 

diastereoisomers in an amount of 2000 mg per dose.” ’829 

patent col. 10 ll. 10–24 (emphasis added). Based on its 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 15

claim construction, the district court found that Sandoz’s 

ANDA product, in vials of 175 mg or 250 mg of levoleucovorin, would not meet the limitation of at least two doses 

of 2000 mg each. The court also found that the patent 

applicant had explicitly disclaimed smaller dosage

amounts during prosecution. The district court therefore 

decided that no genuine issue of material fact on the 

infringement question had been raised, finding that 

Spectrum had not shown literal infringement and was 

estopped from applying the doctrine of equivalents.

Under the framework of the Hatch–Waxman Act, the 

infringement inquiry focuses on a comparison of the 

asserted patent claims against the ANDA product that is 

likely to be sold following FDA approval. Warner–

Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1365–66 

(Fed. Cir. 2003) (citing Glaxo, Inc. v. Novopharm, Ltd., 

110 F.3d 1562, 1567–68 (Fed. Cir. 1997)). The burden of 

proving infringement by a preponderance of the evidence 

remains on the patentee. Id. Evaluating the grant of 

summary judgment of noninfringement requires two 

steps: (1) claim construction, where contested, and (2) 

comparison of the properly construed claims to the accused product. Abbott Labs. v. Sandoz, Inc., 566 F.3d 

1282, 1288 (Fed. Cir. 2009). The second step of the analysis is a question of fact. Bai v. L&L Wings, Inc., 160 F.3d 

1350, 1353 (Fed. Cir. 1998). As such, it is amenable to 

summary judgment where no reasonable factfinder could 

find that the accused product contains every claim limitation or its equivalent. Id.; see Warner–Jenkinson Co. v. 

Hilton Davis Chem. Co., 520 U.S. 17, 29, 39 n.8 (1997). 

Even without literal infringement, a patentee may establish infringement under the doctrine of equivalents if 

an element of the accused product “performs substantially 

the same function in substantially the same way to obtain 

the same result as the claim limitation.” Pozen Inc. v. Par 

Pharm., Inc., 696 F.3d 1151, 1167 (Fed. Cir. 2012) (citation omitted). 
16 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

Whether prosecution history estoppel applies, and 

thus whether the doctrine of equivalents is available for a 

particular claim limitation, is a question of law reviewed 

de novo. Intervet Inc. v. Merial Ltd., 617 F.3d 1282, 1290–

91 (Fed. Cir. 2010). That situation arises when an applicant during prosecution either makes an argument evincing a “clear and unmistakable surrender” of subject 

matter, Elkay Mfg. Co. v. Ebco Mfg. Co., 192 F.3d 973, 

979 (Fed. Cir. 1999), or narrows a claim “to avoid the 

prior art, or otherwise to address a specific concern . . . 

that arguably would have rendered the claimed subject 

matter unpatentable,” Warner–Jenkinson, 520 U.S. at 30–

31. The applicant is then estopped from later invoking 

the doctrine of equivalents to recapture the surrendered 

subject matter. Festo Corp. v. Shoketsu Kinzoku Kogyo 

Kabushiki Co., 535 U.S. 722, 734 (2002). The patentee 

bears the burden of rebutting the application of prosecution history estoppel. Id. at 740–41.

Spectrum asserts that the claims do not require that 

the end product be distributed or administered in the 

packaged dosage. Because Sandoz stipulated to future

importation of more than 10 grams of its product, Spectrum argues that such importation will literally infringe

the claims. Spectrum also asserts that the court erred in

finding that prosecution history estoppel applied. Spectrum insists that the applicants did not surrender coverage of aggregate quantities of the mixture. Moreover, 

Spectrum argues, claim 5 was added by amendment in 

addition to, not in place of, the original claims, and was 

not amended to relinquish any claim scope.

Sandoz responds that the district court rejected Spectrum’s argument during claim construction that the “2000 

mg per dose” limitation could be satisfied by multiple 

doses as long as they added up to 4000 mg total, because 

that ignored the “per dose” language in the claim. Sandoz 

also contends that Spectrum is barred from asserting

infringement under the doctrine of equivalents because of 
SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 17

the statements of disclaimer made during prosecution

that were described as defining a significant aspect of the 

invention. Even without the disclaimer, Sandoz argues 

that amendment-based estoppel would apply because

those claims were added with the dosage limitation to 

overcome an obviousness rejection based on Rees.

Viewing the record in the light most favorable to 

Spectrum and drawing all reasonable inferences in its 

favor, we do not find the evidence in the record sufficient 

to prove infringement. The product that is likely to be 

sold following FDA approval is what Sandoz’s ANDA 

describes: single-use vials with 175 mg or 250 mg of 

substantially pure levoleucovorin, indicated only for 

methotrexate rescue at doses between 7.5 mg and 75 mg 

per dose, which would be far less than at least two doses 

of 2000 mg each. We discern no clear error in the district 

court’s finding that Sandoz’s approved product would not 

meet the dosage claim limitation, and thus would not 

literally infringe claims 5–9.

Moreover, by claim amendments and distinguishing

statements on the prior art during prosecution, Spectrum 

is now estopped from invoking the doctrine of equivalents 

to prove infringement. When submitting an amendment 

with the application claims that eventually issued as 

claims 5–9, the applicants asserted that the newly added 

claims “include specific limitations as to quantities of 

materials,” and distinguished the prior art by pointing to 

the “quantities of these specific mixtures specified in the 

claims.” J.A. 4904–05. Those claims were also added 

following an office action rejecting the previous original 

claims as obvious in view of Rees. The applicants again 

explicitly highlighted the significance of the dosage limitation during an appeal to the Board, their brief stating

that the claims “require a minimum of four grams,” the 

“quantity limitations set forth in the claims” which “define an aspect of the invention that is of great practical 

significance.” J.A. 4996–97. The applicants unequivocal-
18 SPECTRUM PHARMACEUTICALS, INC. v. SANDOZ INC. 

ly argued that Rees, which allegedly only produced experimental quantities, “do[es] not teach, suggest, or otherwise render obvious the claimed compositions in the 

quantity specified” in the application claims that became 

claims 5–9. J.A. 4998 (emphasis in original). Those 

statements are clear and unmistakable expressions of the 

applicants’ intent to surrender coverage of quantities of 

the compound in lower doses.

Accordingly, we agree with the district court that 

Spectrum did not sufficiently raise a genuine issue of 

material fact as to infringement to defeat the motion for 

summary judgment. The court did not clearly err in 

finding that Spectrum failed to prove that the approved 

product would literally infringe claims 5–9. The court 

also did not err in concluding that Spectrum was barred

from invoking the doctrine of equivalents by prosecution 

history estoppel. The district court thus did not err in 

granting summary judgment of noninfringement.

CONCLUSION

We have considered the remaining arguments and 

conclude that they are without merit. For the foregoing 

reasons, we conclude that the district court did not err in 

holding that claims 1–2 of the ’829 patent are invalid as 

obvious under 35 U.S.C. § 103, and we therefore affirm 

that decision. We further conclude that the district court 

did not err in holding that Spectrum failed to prove by a 

preponderance of the evidence that Sandoz’s ANDA 

product would infringe claims 5–9 of the ’829 patent, and 

we also affirm that decision. 

AFFIRMED