Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-15-01204/USCOURTS-ca13-15-01204-0/pdf.json

Parties Involved:
Cubist Pharmaceuticals, Inc.
Cross-Appellant
Hospira, Inc.
Appellant

Document Text:

United States Court of Appeals 

for the Federal Circuit ______________________ 

CUBIST PHARMACEUTICALS, INC.,

Plaintiff-Cross-Appellant

v.

HOSPIRA, INC.,

Defendant-Appellant

______________________ 

2015-1197, 2015-1204, 2015-1259

______________________ 

Appeals from the United States District Court for the 

District of Delaware in No. 1:12-cv-00367-GMS, Judge 

Gregory M. Sleet.

______________________ 

Decided: November 12, 2015 

______________________ 

WILLIAM F. LEE, Wilmer Cutler Pickering Hale and 

Dorr LLP, Boston, MA, argued for plaintiff-crossappellant. Also represented by MARK CHRISTOPHER 

FLEMING, LISA JON PIROZZOLO; WILLIAM G. MCELWAIN, 

Washington, DC.

JAMES F. HURST, Kirkland & Ellis LLP, Chicago, IL, 

argued for defendant-appellant. Also represented by JOHN 

C. O'QUINN, Washington, DC; LESLIE M. SCHMIDT, New 

York, NY; STEFFEN NATHANAEL JOHNSON, JOVIAL WONG, 

Winston & Strawn LLP, Washington, DC; JAMES 

MATTHEW HILMERT, TYLER JOHANNES, GEORGE C.

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2 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

LOMBARDI, Chicago, IL; STEPHEN R. SMEREK, Los Angeles, 

CA. 

______________________ 

Before WALLACH, BRYSON, and HUGHES, Circuit Judges.

BRYSON, Circuit Judge.

This case arises under the Hatch-Waxman Act, which 

governs certain patent disputes between pharmaceutical 

companies.1 The plaintiff, Cubist Pharmaceuticals, Inc., 

owns five patents that relate to the antibiotic daptomycin. 

The defendant, Hospira, Inc., sought authorization to sell 

a generic version of Cubist’s daptomycin product, which 

led Cubist to file this action charging Hospira with patent 

infringement.

Daptomycin was developed by Eli Lilly & Co. (“Lilly”). 

The original patent to daptomycin expired in 2002. The 

five patents at issue in this case are all follow-on patents 

owned by Cubist. The first is U.S. Patent No. RE39,071 

(“the ’071 patent”), which is a reissue of U.S. Patent No. 

5,912,226 (“the ’226 patent”) and is directed to antibiotic 

compounds, compositions, formulations, and methods of 

treating bacterial infections. The next two are U.S. 

Patent Nos. 6,852,689 and 6,468,967 (“the ’689 and ’967 

patents”), which are entitled “Methods for Administration 

of Antibiotics” and are directed to dosage regimens for 

administering daptomycin. The final two are U.S. Patent 

Nos. 8,058,238 and 8,129,342 (“the ’238 and ’342 patents”), which are entitled “High Purity Lipopeptides” and 

1 The Hatch-Waxman Act is the name commonly 

used to refer to the Drug Price Competition and Patent 

Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 

1585, the principal provisions of which are codified at 21 

U.S.C. § 355 and 35 U.S.C. §§ 156 and 271(e)(2). 

 

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are directed to the purification of daptomycin compositions. 

Cubist sells its daptomycin formulation under the 

trade name Cubicin. In 2011, Hospira filed an Abbreviated New Drug Application with the Food and Drug Administration seeking approval to manufacture and sell an 

equivalent daptomycin product prior to the expiration of 

Cubist’s patents. Pursuant to procedures set forth in the 

Hatch-Waxman Act, Cubist then filed an action in the 

United States District Court for the District of Delaware, 

alleging that Hospira had infringed all five of Cubist’s 

patents. Hospira responded by challenging the validity of 

the asserted claims of each of those patents. Two other 

related actions brought by Cubist were subsequently 

consolidated with the initial lawsuit. 

Following a bench trial, the district court held some of 

the asserted claims of four of Cubist’s patents invalid for 

anticipation and all the asserted claims of those patents 

invalid for obviousness. As for the fifth patent, the court 

held the two asserted claims not invalid and ruled that 

Hospira’s proposed products infringed those claims. Both 

parties appeal from the portions of the judgment adverse 

to them. We affirm the judgment of the district court, 

relying heavily on the factual findings made by the court 

following the trial.

I 

Hospira appeals from the district court’s ruling that 

Hospira infringed claims 18 and 26 of the ’071 patent and 

that those claims are not invalid. Hospira’s appeal focuses on a certificate of correction granted to Cubist with 

regard to the ’071 patent. The certificate corrected a 

diagram of the chemical structure of a compound described in the specification and recited in four of the 

claims of the ’071 patent, including claims 18 and 26.

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A 

1 

The asserted claims of the ’071 patent recite an antibiotic composition and a pharmaceutical formulation, 

each comprising a combination of three compounds. The 

first and second compounds in each claim are daptomycinrelated substances. The first is known as anhydrodaptomycin and the second is known as the beta isomer of 

daptomycin. The third compound, referred to as Formula

3, is the compound known in the art as daptomycin.2 

The specification of the ’071 patent describes the 

Formula 3 compound in three ways. First, it refers to the 

compound as “an A-21978C cyclic peptide.” According to 

the specification, A-21978C cyclic peptides “are prepared 

from the A-21978C antibiotics,” which are “a group of 

closely related, acidic peptide antibiotics” that are described in U.S. Patent No. 4,208,403 (“the ’403 patent”). 

’071 patent, col. 6, ll. 59-61; col. 7, ll. 41-42. The ’403 

patent in turn describes the A-21978C antibiotics as being 

produced by a process involving the fermentation of the 

bacterium Streptomyces roseosporus.

Second, the specification of the ’071 patent refers to 

the Formula 3 compound by the code name LY146032. 

That code name was assigned to the compound by Lilly 

and was known in the art to refer to daptomycin. 

Third, the specification states that the Formula 3 

compound has the following structure, where RN is ndecanoyl:

2 For clarity, we refer to “daptomycin” as the compound that is found in Cubicin and was the subject of 

Hospira’s Abbreviated New Drug Application.

 

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It turns out that the structural diagram of the compound identified as Formula 3 and depicting daptomycin

was inaccurate in one respect. The structure in the 

diagram contained 13 amino acids, including asparagine 

(abbreviated “Asn”). While the diagram accurately identified the amino acids and their location in the daptomycin 

molecule, it mistakenly identified the stereoisomer of the 

asparagine amino acid as the “L” stereoisomer of asparagine, rather than the “D” stereoisomer. 

At the time the application for the ’226 patent was 

filed, and until well after that patent was issued, it was 

universally believed that the asparagine amino acid in 

daptomycin was the L-isomer of asparagine, as set forth 

in the structural diagram. Years after the issuance of the 

’226 patent and after the reissue application for the ’071 

patent was filed, Lilly researchers discovered that daptomycin actually contains the D-isomer of asparagine, not 

the L-isomer. 

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In 2007, Cubist sought to correct the error by requesting a certificate of correction from the Patent and Trademark Office (“PTO”) pursuant to 35 U.S.C. § 255. Cubist 

explained that the mistake in the patent as to the identity 

of the stereoisomer of asparagine was “the result of the 

mischaracterization of one of the A-21978C factors described by Formula 3.” Specifically, Cubist explained, 

“the patentees erred in describing one amino acid’s stereochemistry as ‘L-Asn’ in the tail of the compound illustrated in Formula 3, when the correct stereochemistry of 

the disclosed and claimed amino acid is ‘D-Asn.’” Cubist 

further explained that the true nature of the stereochemistry of daptomycin was disclosed in a 2005 journal article 

by Vivian Miao et al. The Miao article, Cubist stated, 

“demonstrates that the A-21978C factors of Formula 3 

inherently contain the ‘D-Asn’ in the tail portion illustrated in Formula 3 when isolated from their native source, 

not an ‘L-Asn.’”

The examiner concluded that it was appropriate to 

use a certificate of correction to correct the error identified 

by Cubist. Accordingly, the examiner issued the certificate, correcting the diagram of Formula 3 in the specification and four of the claims of the ’071 patent by 

substituting “D-Asn” for “L-Asn” in the diagram.

2 

Before the district court, Hospira argued that the PTO 

had erred by issuing the certificate of correction because 

the change in the structural diagram of Formula 3 altered 

the substance of the claims, broadening their reach. 

Accordingly, Hospira argued, the ’071 patent should be 

construed to be limited to the variant of the daptomycin 

compound containing the L-isomer of asparagine. The 

compound with the L-isomer of asparagine is an antibiotic, but a much less potent one than daptomycin. 

Hospira’s expert testified that Formula 3 with the Lisomer of asparagine was an entirely different compound 

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from Formula 3 with the D-isomer of asparagine. He 

therefore concluded that the asserted claims did not read 

on daptomycin. The expert admitted, however, that he 

had not considered the specification of the ’071 patent in 

reaching his determination that the certificate of correction had the effect of broadening the claims of the patent 

to read on daptomycin for the first time.

Cubist’s expert testified that the specification made it 

clear that the claims of the ’071 patent were directed to 

daptomycin, not to the variant containing the L-isomer of 

asparagine. Because it was plain that the claims were 

directed to daptomycin, Cubist argued, it was appropriate 

for the PTO to correct the error in the structural diagram 

of Formula 3. 

The district court acknowledged that the chemical 

structure of Formula 3 in the corrected version of the ’071 

patent is different from that of the pre-correction version 

of the patent. However, the court characterized the PTO’s 

action as simply correcting an error in the diagram of 

Formula 3 without changing the scope of the patent. The 

court agreed with Cubist that the specification made clear 

that the patent claimed the daptomycin compound all 

along; the pre-correction version merely misidentified the 

stereoisomer of the asparagine amino acid found in that 

compound.

Based on the evidence summarized above, the district 

court concluded that Hospira had not satisfied its burden 

to show that the certificate of correction was invalid. In 

particular, the court ruled that the specification as a 

whole “confirms that the Formula 3 compound identified 

in the claims is truly D-asparagine daptomycin, the byproduct of the fermentation process” described in the 

specification. Accordingly, the court held, substituting Lasparagine for D-asparagine in the Formula 3 chemical 

structure was “a correction of minor character because it 

did not result in ‘the new version cover[ing] territory the 

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old one did not.’” Contrary to Hospira’s contention, the 

court explained, “D-asparagine was covered both before 

and after correction.”

3 

On appeal, Hospira argues that the change in the ’071 

patent made by way of the certificate of correction was not 

a change “of minor character,” as provided for in section 

255, because the change broadened the scope of the asserted claims. See Superior Fireplace Co. v. Majestic 

Prods. Co., 270 F.3d 1358, 1375 (Fed. Cir. 2001) (“A 

mistake that, if corrected, would broaden the scope of a 

claim must thus be viewed as highly important and thus 

cannot be a mistake of ‘minor character.’”). In Hospira’s 

view, because the change from L-Asn to D-Asn in the 

structural diagram broadened the scope of the claims to 

read on daptomycin rather than the L-Asn variant of 

daptomycin, the certificate of correction was invalid.

Once the PTO has issued a certificate of correction, a 

court may invalidate the certificate only upon a showing 

of clear and convincing evidence that it was improperly 

issued. Superior Fireplace Co., 270 F.3d at 1367. In this 

case, no such showing has been made.

The problem with Hospira’s argument is that the 

district court did not view the change in the diagram as 

changing the scope of the claims at all. Instead, the court 

regarded the change as simply conforming the structural 

diagram of Formula 3 to the compound described in the 

specification and covered by the claims.

Contrary to Hospira’s argument, the original structural diagram in the ’071 patent did not establish that the 

patent was directed to a compound other than daptomycin. As this court has noted, a chemical structure is 

“simply a means of describing a compound; it is not the 

invention itself.” Regents of Univ. of N.M. v. Knight, 321 

F.3d 1111, 1122 (Fed. Cir. 2003). In determining what 

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compound the patent claims were directed to, the proper 

focus is not limited to the chemical structure depicted in 

the diagram. Instead, the specification as a whole must 

be considered. As the district court explained, the Formula 3 compound is defined not only by the structural diagram, but also by other portions of the specification.

The specification of the ’071 patent does not rely exclusively on the structural diagram of Formula 3 to describe the subject compound. By reference to a co-pending 

application (later issued as U.S. Patent No. 4,885,243), 

the specification teaches that daptomycin is obtained 

through fermentation of Streptomyces roseosporus. That 

fermentation process necessarily results in daptomycin, 

not the variant with the L-isomer of asparagine. The 

evidence at trial established that the L-isomer variant 

cannot be produced by fermentation and can only be 

produced synthetically. 

In addition, the specification describes the claimed 

compound by the code name given to it by Lilly—the 

designation LY146032. Evidence introduced by Cubist at 

trial showed that the code name LY146032 refers to 

daptomycin, not the variant of daptomycin with the Lisomer of asparagine.

Finally, at the time of the original application that 

matured into the ’226 patent, it was universally believed 

that the asparagine amino acid in daptomycin was the Lisomer of asparagine, not the D-isomer. It was not until 

well after the filing of the original ’226 patent (in 1991), 

the issuance of that patent (in 1999), and the filing of the 

reissue application (in 2000) that Lilly researchers determined that the previous understanding of the structure of 

daptomycin was mistaken, and that the asparagine amino 

acid in daptomycin is the D-isomer of asparagine, not the

L-isomer, as previously thought. Even though researchers had previously been mistaken about the precise 

chemical structure of daptomycin, it was nonetheless 

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clear from the specification that the patentees possessed 

daptomycin (with the D-isomer of asparagine) and that 

the references to Formula 3 in the claims of the ’071 

patent were directed to daptomycin. 

4 

Hospira relies heavily on this court’s decision in Bayer 

v. Dow Agrosciences LLC, 728 F.3d 1324 (Fed. Cir. 2013). 

That case, however, is different in important ways from 

this one. The patentee in Bayer claimed, in pertinent 

part, a recombinant gene comprising a DNA sequence 

encoding for a polypeptide “having the biological activity 

of 2,4-D monooxygenase.” Id. at 1326. Although it was 

determined long before Bayer’s patent issued that the 

gene Bayer had sequenced encoded for an enzyme that 

was a dioxygenase, not a monooxygenase, Bayer did not 

seek to change the claim language to reflect the error. 

Instead, Bayer argued that the claim language should be 

interpreted to cover any DNA sequence that codes for an

enzyme that alters a common herbicide known as 2,4-D by 

cleaving its side chain, regardless of whether the cleaving 

enzyme is a monooxygenase or a dioxygenase. Id. at 

1327.

This court rejected that argument as a matter of claim 

construction. We explained that Bayer’s proposed construction would be inconsistent with the “strong accepted 

scientific meaning” of the claim language by “strip[ping] 

the monooxygenase half of the claim phrase of its accepted descriptive meaning” and “assert[ing] a specification 

‘definition’ of the biological-activity half.” 728 F.3d at 

1330. Beyond that, Bayer’s proposed claim construction 

would have raised serious doubts about the validity of 

Bayer’s claim by broadening the claim to cover the enzymatic function of causing the cleavage of the side chain of 

2,4-D, but not “providing even an indirect structural 

identification of all that would be within the claim’s 

scope.” Id. at 1331.

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In this case, unlike in Bayer, the applicants sought a 

certificate of correction to correct the structural diagram, 

which was based on a previous misunderstanding of the 

chemical structure of the claimed compound. Given the 

other descriptions of the claimed compound in the specification, the PTO and the district court concluded that the 

reference to the L-isomer of asparagine was an error and 

that the claimed compound was the compound with the Disomer of asparagine. In Bayer, by contrast, the patentee 

sought a broad, functional claim construction based on the 

original claim language. We found that claim construction to be seriously flawed and rejected it. Given the very 

different approaches employed by the patentees in the 

two cases, as well as the strong indications in the specification of the ’071 patent that Formula 3 was in fact 

daptomycin (despite the error in the structural diagram), 

the outcome of this case is not controlled by Bayer. 

In light of the heavy burden on a party seeking to invalidate a certificate of correction, we uphold the district 

court’s conclusion that the certificate of correction did not 

alter the scope of the patent, but merely corrected an 

error as to the chemical structure of daptomycin. We 

therefore reject Hospira’s argument that the asserted 

claims of the ’071 patent should be limited to the variant 

of daptomycin containing the L-isomer of asparagine. 

B 

Hospira next argues that if the validity of the certificate of correction is sustained, the asserted claims of the 

’071 patent should be held invalid for violating the written description requirement of 35 U.S.C. § 112. Like the 

district court, we reject that argument, and for the same 

reasons.

Hospira contends that the written description requirement was not satisfied because the specification did 

not disclose the features or structure of daptomycin 

(containing the D-isomer of asparagine), and thus the 

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specification provided no indication that the inventors 

knew they were working with daptomycin having that 

structure. 

The district court found as a matter of fact that the 

disclosure of the specification reasonably conveyed to 

those skilled in the art that the inventors had possession 

of the claimed subject matter as of the filing date, i.e., 

that the specification described “an invention understandable to [a] skilled artisan and show[ed] that the 

inventor actually invented the invention claimed.” Ariad 

Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. 

Cir. 2010) (en banc). Notwithstanding the error in the 

structural diagram of Formula 3, the court concluded that 

one skilled in the art would have understood that the 

inventors possessed and were working with the naturally 

occurring fermentation product, i.e., the daptomycin 

molecule containing D-asparagine. For that reason, the 

court held that Hospira had failed to show, by clear and 

convincing evidence, that the ’071 patent was invalid for 

lack of an adequate written description.

Hospira has not shown that the district court committed clear error in finding that the written description 

requirement was satisfied. The references in the specification to the “A21978C cyclic peptide,” and to LY146032, 

Lilly’s codename for daptomycin, would have demonstrated to a person of skill in the art that the inventors were in 

possession of daptomycin, the product of the fermentation 

of Streptomyces roseosporus, in spite of the error in the 

structural diagram.

The fact that the inventors were mistaken as to one 

aspect of the structure of daptomycin at the time the 

application for the original ’226 patent was filed does not 

render the specification inadequate to satisfy the written 

description requirement. It was enough that the specification disclosed relevant identifying characteristics that 

distinguished daptomycin from other compounds and thus 

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showed that the inventors had possession of daptomycin, 

even though they may not have had an accurate picture of 

the entire chemical structure of that compound. See

Invitrogen Corp. v. Clontech Labs., Inc., 429 F.3d 1052, 

1072 (Fed. Cir. 2005).

Hospira relies on In re Wallach, 378 F.3d 1330 (Fed. 

Cir. 2004), in support of its written description argument, 

but that case has little in common with this one. In 

Wallach, the applicants were in possession of only about 

5% of the amino acids of the nucleic acid encoding a 

particular protein, but they sought to claim all DNA 

molecules that would code for the protein. That is, they

claimed the entire nucleotide sequence of any DNA molecule that would code for the protein, even though they 

were in possession of only a small portion of one such 

nucleotide sequence. This court upheld the PTO’s decision rejecting the applicants’ claims. 

The applicants in Wallach argued that they were entitled to patent protection for the claimed DNA molecules 

because they had shown that they were in possession of 

the protein. This court noted, however, that whether the 

applicants “were in possession of the protein says nothing 

about whether they were in possession of the protein’s 

amino acid sequence.” 378 F.3d at 1334. 

Because the applicants had not “provided any evidence that the full amino acid sequence of a protein can 

be deduced from a partial sequence and the limited additional physical characteristics that they have identified,” 

the court concluded that the applicants had not shown 

that they were in possession of the claimed nucleic acid 

sequences. Id. at 1335. The court summed up its ruling 

by stating that the applicants had not shown “that there

is any known or disclosed correlation between the combination of a partial structure of a protein, the protein’s 

biological activity, and the protein’s molecular weight, on 

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the one hand, and the structure of the DNA encoding the 

protein on the other.” Id.

In this case, the applicants claimed only what they 

had produced—the daptomycin molecule—which they 

identified in several ways. The district court found that 

the identification of the molecule in the specification was 

sufficient to inform a person skilled in the art that the 

inventors were in possession of the daptomycin molecule, 

even though the structure that they ascribed to it was 

inaccurate in one respect. The description of the molecule 

provided in the specification in this case was far greater 

than the very limited description of the DNA sequence in 

the Wallach case, and the claims in this case, unlike those 

at issue in Wallach, were limited to the compound itself. 

We therefore uphold the district court’s finding that the 

specification of the ’071 patent contained the written 

description required by 35 U.S.C. § 112 and that the 

asserted claims are not invalid for lack of adequate written description. 

C 

Finally, Hospira argues that the asserted claims of 

the ’071 patent are invalid because they violate the “recapture rule” applicable to reissued patents. Relying on 

the proposition that a patentee may not “regain[] through 

reissue the subject matter that he surrendered in an 

effort to obtain allowance of the original claims,” Pannu v. 

Storz Instruments, Inc., 258 F.3d 1366, 1370-71 (Fed. Cir. 

2001), Hospira argues that the claims of the reissued ’071 

patent are impermissibly broader than the corresponding 

original claims of the ’226 patent. 

The recapture rule applies if (1) the reissue claims are 

broader than the original patent claims; and (2) the 

broader aspects of the reissued claims relate to subject 

matter that was surrendered in the prosecution of the 

original patent. In re Youman, 679 F.3d 1335, 1345 (Fed. 

Cir. 2012); In re Mostafazadeh, 643 F.3d 1353, 1358 (Fed. 

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Cir. 2011); In re Clement, 131 F.3d 1464, 1469 (Fed. Cir. 

1997). The recapture rule does not apply if the reissue 

claims were materially narrowed compared to the original 

claims “such that full or substantial recapture of the 

subject matter surrendered during prosecution is avoided.” In re Mostafazadeh, 643 F.3d at 1358. Moreover, the 

recapture rule applies only if the patentee surrendered

subject matter in the original prosecution in order to 

overcome a prior art rejection. In re Clement, 131 F.3d at

1469. 

The reissue claims here did not violate the recapture 

rule. Besides the fact that reissue claims 18 and 26 are 

narrower than original claim 24 by requiring the presence 

of the Formula 1 and Formula 2 compounds, which are 

not required by original claim 24, the evidence shows that 

the applicants did not surrender subject matter in the 

prosecution of the ’226 patent to avoid prior art. 

In the course of the prosecution of the application that 

matured into the ’226 patent, the examiner rejected claim 

24 on three occasions, each time on indefiniteness 

grounds. In response to the third rejection, the applicants 

cancelled claim 24. Although the applicants stated that 

claim 24 was nonobvious, that statement was made in the 

context of an argument that a large number of the claims 

of the application, including claim 24, were nonobvious. 

The applicants did not cancel the other claims, but they

cancelled claim 24, which was the only claim rejected on 

indefiniteness grounds. The applicants ultimately succeeded in overcoming the obviousness objection to the 

other claims.

The prosecution history thus makes it clear that the 

applicants withdrew claim 24 from the application because of the indefiniteness rejection, not to avoid prior art. 

Accordingly, the recapture rule does not render claims 18 

and 26 of the ’071 patent invalid.

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For the foregoing reasons, we hold that the asserted 

claims of the ’071 patent are not invalid. Because Hospira 

does not contest the district court’s ruling that its products infringe the ’071 claims if the certificate of correction 

was properly issued and the patent is otherwise valid, we 

sustain the district court’s judgment of infringement as to 

the ’071 patent. 

II

Cubist has cross-appealed from the portions of the 

district court’s judgment invalidating the other four 

patents at issue in this case: the two patents that the 

district court referred to as the “dosing patents” (the ’967 

patent and the ’689 patent) and the two patents that the 

district court referred to as the “purity patents” (the ’238 

patent and the ’342 patent). We affirm the district court’s 

decision that all four of those patents are invalid for 

obviousness.

A 

1 

In the 1980s, Lilly researchers who were looking for 

an antibiotic effective against Staphylococcus aureus (“S. 

aureus”) infections discovered daptomycin. At the time, 

Lilly’s drug vancomycin was the only available treatment 

for infections caused by methicillin-resistant S. aureus

bacteria. While sufficiently high doses of daptomycin 

proved effective against such infections, the researchers 

discovered that high doses of daptomycin administered 

every twelve hours resulted in skeletal muscle toxicity in 

some patients. When the Lilly researchers encountered 

the toxicity problem, they suspended further testing of 

daptomycin.

Cubist subsequently licensed the daptomycin compound from Lilly and conducted studies designed to 

overcome the problem of skeletal muscle toxicity that 

Lilly had encountered. Cubist researchers discovered 

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that the toxic side effects of daptomycin could be reduced 

by administering the drug less frequently than twice 

daily. They subsequently sought patent protection for 

treatment methods involving large doses of daptomycin 

and large intervals between doses. 

2 

Asserted claims 16, 17, 34, and 35 of the ’967 patent 

and asserted claims 51 and 52 of the ’689 patent recite 

dosage regimens. The claims of the ’967 patent recite a 

method of administering daptomycin at a dosage interval 

that minimizes skeletal muscle toxicity; the recited dosage is 4 or 6 milligrams per kilogram of patient weight 

(abbreviated as “mg/kg”) and the recited dosage interval is 

once every 24 hours. The claims of the ’689 patent recite 

administering daptomycin in doses of 4 or 6 mg/kg once 

every 48 hours.

At trial, Hospira sought to prove that the asserted 

claims of the ’967 patent are anticipated by a 1991 journal 

article by James Woodworth et al. The Woodworth article 

stated that, based on the pharmacokinetics and antibacterial activity of daptomycin, “doses of 4 to 6 mg/kg/day, 

possibly in divided doses, are predicted to be effective.” 

The article added that the reported data “suggest that 

good antibacterial activity would be produced from single 

doses of 4 to 6 mg/kg,” and that the drug’s long half-life in 

the body would “allow[] once- or twice-daily administration with the proper doses.” 

Although the Woodworth article did not mention the 

objective of minimizing skeletal muscle toxicity, the 

district court found that the effect of minimizing skeletal 

toxicity was inherently disclosed by Woodworth’s suggestion to administer 4 or 6 mg/kg of daptomycin once a day. 

That is, the court found that minimizing skeletal toxicity 

was “a necessary accompaniment to the other disclosed 

claimed limitations and therefore was inherently disclosed by the Woodworth article.”

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18 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

In response to Cubist’s argument that the Woodworth 

article was not enabling, the court found that Woodworth 

“identified the exact dosage amounts and interval claimed 

by the ’967 patent: 4 mg/kg/day and 6 mg/kg/day.” The 

dosage level and timing, the court found, “were two major 

variables that required no additional experimentation.” 

Accordingly, the court found that Cubist had failed to 

rebut the presumption that the Woodworth article enabled the disclosed invention.3

The court also found the asserted claims of the ’967 

patent to be invalid for obviousness based on the Woodworth article and the ’226 patent, in view of the known 

properties of daptomycin. The court explained that the 

Woodworth article and the ’226 patent contained disclosures “indicating that the claimed dosage levels would be 

effective.” Beyond that, the known properties of daptomycin provided “additional support for why one skilled 

in the art would find daily dosing to be preferable and 

obvious.” In particular, the court found, it was known 

that daptomycin’s effectiveness is concentrationdependent, which suggests that less frequent and more 

concentrated treatments would be more effective than 

smaller doses of the drug administered at more frequent 

intervals.

The court reached the same conclusion with respect to 

the ’689 patent, which provides for doses of daptomycin to 

be administered every 48 hours. The court explained that 

a person of skill in the art would know that in treating 

patients with impaired renal function, either the doses

would have to be reduced or the dosage intervals increased. In light of the concentration-dependent killing 

capacity of daptomycin, the court concluded, it would have 

3 Hospira argued that the ’226 patent also anticipated the asserted claims of the dosing patents, but the 

district court rejected that argument. 

 

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been obvious to consider doubling the dosage interval for 

a patient with impaired kidney function, such as 50% of 

normal. 

Finally, the district court analyzed the secondary 

considerations invoked by Cubist, but found them insufficient to overcome the showing of obviousness based on the 

cited prior art references.

3 

Focusing largely on the Woodworth reference, Cubist 

challenges the district court’s ruling that the asserted 

claims of the dosing patents would have been obvious. We 

hold that the district court did not commit legal error and 

that the findings underlying the court’s obviousness 

ruling were not clearly erroneous. Because we uphold the 

district court’s obviousness ruling with respect to the 

dosing patents, it is not necessary for us to address Cubist’s challenge to the court’s ruling on anticipation.

In challenging the district court’s finding of obviousness, Cubist places great weight on the fact that the 

Woodworth reference does not mention skeletal muscle 

toxicity. In addition, Cubist argues that the court’s 

reliance on the once-daily administration of other similar 

antibiotics to reduce toxic side-effects is too remote to 

support the court’s obviousness finding as to the oncedaily administration of daptomycin. Finally, Cubist 

complains that the district court ignored secondary evidence of non-obviousness, including evidence of long-felt 

but unmet need, failure of others, commercial success, 

and unexpected results. 

4 

Cubist did not discover daptomycin, nor did it invent 

the use of daptomycin for treating bacterial infections. 

Beginning in the 1980s, Lilly tested daptomycin treatment protocols including once-daily doses of 2mg/kg, and 

twice-daily doses of 3 mg/kg. Both of those protocols were 

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20 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

determined to be effective against some infections, although they were not as effective as conventional therapies in treating the most serious targeted infection, S. 

aureus endocarditis (“SAE”). Lilly researchers concluded 

that the dosages used in those studies did not result in 

enough free daptomycin in the bloodstream to kill the 

targeted bacteria. Lilly conducted a follow-up study in 

which subjects were given up to 4 mg/kg of daptomycin 

every 12 hours. At that dosage level, however, several 

subjects developed symptoms of skeletal muscle toxicity, 

and the study was abandoned. 

The dosing patents proposed the administration of 

doses of either 4mg/kg or 6mg/kg, similar to the dosage in 

the Lilly follow-up study, but given only once per day or 

once every 48 hours. Given what was previously known 

about daptomycin and related compounds, the district 

court reasonably concluded that the treatment protocols

claimed in the dosing patents would have been obvious in 

light of the prior art.

As the district court observed, the Woodworth article 

clearly pointed to the use of once daily administration of 

daptomycin in doses of 4 to 6 mg/kg per day. It did so in 

the abstract of the article, where the authors predicted 

that doses of 4 to 6 mg/kg per day would be expected to be 

effective either in single doses or “possibly in divided 

doses.” It also did so in the body of the article, where the 

authors specifically noted that the long half-life of daptomycin would allow the administration of daptomycin 

once or twice a day, and that anti-bacterial effects could 

be achieved from single daily doses of 4mg/kg to 6 mg/kg, 

exactly the doses set forth in the dosing patents. Similarly, the ’226 patent discloses that a “typical daily dose for 

an adult human” of about 1.4 mg/kg to 14 mg/kg “can be 

administered as a single daily dose or in multiple doses 

per day.” ’226 patent, col. 10, ll. 56-61. The district court 

found that the ’226 patent, like the Woodworth article, 

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disclosed that the claimed dosage levels would be effective, “either through daily or divided administrations.”

Cubist takes issue with the Woodworth reference on 

two grounds: first, that it is based on laboratory studies, 

not clinical trials, and is thus predictive in nature with 

respect to the likely effects of the drug in patients; and 

second, that it does not advert to minimizing skeletal 

muscle toxicity, which is an objective expressly set forth 

in the asserted claims. 

While it is true that the Woodworth reference is 

predictive in nature, it is based on extensive laboratory 

research, and its predictions of the efficacy of a dosage 

regimen of 4 mg/kg to 6 mg/kg at daily intervals give rise 

to a reasonable expectation that dosages in that amount 

would be effective in patients. Moreover, published 

accounts of Lilly’s clinical trials indicated a dosage level of 

2 mg/kg administered once daily produced no reported 

side effects and a dosage level of 3 mg/kg administered 

twice daily produced no symptoms of skeletal muscle 

toxicity, but were not highly effective against SAE. Those 

results would have given rise to a reasonable expectation 

that somewhat higher doses administered less frequently 

than twice daily could be expected to be both safe and 

effective. 

The district court’s obviousness finding is also supported by evidence of the known properties of daptomycin, 

from which persons of skill in the art could reasonably 

conclude not only that doses given once per day or even 

less frequently would be effective, but also that increased 

dosage intervals would result in less risk of skeletal 

muscle toxicity. 

That evidence included four characteristics of daptomycin that suggested the use of high dosages of daptomycin with long intervals between doses. First, 

daptomycin is especially effective at killing bacteria when 

it is found in high concentrations in the patient’s body. 

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Second, daptomycin has a long half-life, which allows it to 

act in the body over an extended period of time before 

being cleared by the kidneys. Third, daptomycin has a 

long post-antibiotic effect, i.e., it continues to suppress 

bacteria after leaving the body. Those three characteristics suggest that it is not necessary to administer daptomycin frequently. Fourth, muscle toxicity resulting 

from daptomycin was known to be reversible in most 

cases. That characteristic suggests that administering 

doses at greater intervals would allow the muscles more 

time to repair between doses, thus reducing the cumulative toxic effect of the drug.

The district court’s finding is also supported by evidence pertaining to aminoglycosides, a group of antibiotic 

compounds similar to daptomycin. The court found

aminoglycosides to be “within the relevant prior art” that 

“would have been considered by one skilled in the art,” 

and it found that aminoglycosides share many properties 

with daptomycin. Like daptomycin, aminoglycosides 

exhibit concentration-dependent killing, long-lasting postantibiotic effects, and reversible toxicity. And the evidence showed that less frequent dosing resulted in the 

avoidance of toxicity problems with aminoglycosides. 

Those characteristics, the district court found, would have 

led one of skill in the art to believe that increasing the 

dosage intervals for daptomycin would give rise to a 

reasonable expectation of increased efficacy while minimizing the toxic side effects of the drug.

Cubist does not separately argue the validity of the 

asserted claims of the ’689 patent; in any event, however,

we agree with the district court that those claims, which 

recite dosage intervals of 48 hours, would have been 

obvious based on the same analysis that applies to the 

claims of the ’967 patent. The ’689 patent notes that 

longer dosage intervals are appropriate for patients with 

impaired renal function or requiring dialysis. ’689 patent, 

col. 5, line 63, to col. 6, line 5. The district court explained 

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that it is known that patients with compromised renal 

function do not clear drugs such as daptomycin from their 

systems as quickly as persons with healthy kidneys. 

Accordingly, it was reasonable for the court to conclude 

that a person of skill in the art would expect that for such 

a patient a longer dosage interval would be equally effective against bacteria and would be necessary to avoid 

building up concentrations of daptomycin in the patient’s 

body that could lead to skeletal muscle toxicity.

5 

Cubist relies heavily on secondary consideration evidence to support its argument that the asserted claims of 

the dosing patents would not have been obvious. The 

district court acknowledged that secondary consideration 

evidence must be weighed in the obviousness analysis, 

but the court concluded that “any weight certain factors 

may have does not overcome Hospira’s prima facie showing of obviousness.”

Cubist argues that, prior to the invention claimed in 

the dosing patents, there was a long-felt but unmet need 

for such a treatment regimen and that the success of 

Cubist’s invention was unexpected. As the district court 

pointed out, however, daptomycin treatment regimens 

that were only slightly different from Cubist’s had previously been shown to be effective against a variety of 

bacterial infections. Although the prior art daptomycin 

treatment methods had not proved effective for SAE, the 

court noted that SAE is the target infection in only about 

5% of the cases in which daptomycin is administered. 

Accordingly, the court concluded that any “long-felt need”

or “unexpected results” applied only to the small percentage of cases in which daptomycin was used to treat SAE. 

The court made the same observation with regard to 

Cubist’s argument regarding the commercial success of 

Cubist’s daptomycin product, Cubicin. Although Cubist 

attributes the success of Cubicin to the invention of the 

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24 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

’967 and ’689 patents, the district court concluded that 

Cubicin’s commercial success is mainly attributable to 

daptomycin itself; it is attributable only in small measure 

to the dosage and interval protocols disclosed in the 

dosing patents. For Cubicin’s use in treating other infections that make up the bulk of the market, the court 

found, “Cubist was unable to establish that the claimed 

features drove market success.” The court likewise found 

that any “unexpected results” obtained from the dosing 

patents were limited to the treatment of serious infections 

such as SAE. 

Cubist sought to show the failure of others by pointing 

to Lilly’s failure to develop the dosing regimens set forth 

in the dosing patents. The court, however, found that 

Cubist’s showing was undercut by the fact that Lilly 

owned and marketed vancomycin, which was regarded as 

the “gold standard” for treating many serious infections 

such as infections caused by methicillin-resistant S. 

aureus bacteria. Referring to vancomycin, Hospira’s 

expert on secondary considerations testified that Lilly 

“had a drug that was generating four to five hundred 

million dollars a year in the late eighties and early 1990s. 

They would have very little incentive to cannibalize those 

sales by the introduction of a substitutable drug.” Therefore, the court concluded, “economic considerations, and 

not merely difficulties in the lab, weighed on Eli Lilly’s 

decision to ‘shelve’ daptomycin development.” 

We are not persuaded that the district court committed legal error in its analysis of the secondary consideration evidence. The court weighed the secondary 

consideration evidence against the other evidence of 

obviousness and concluded that the secondary consideration evidence was not sufficiently strong to overcome the 

showing of obviousness arising from an analysis of the 

prior art. That conclusion was not clearly erroneous. We 

therefore sustain the district court’s judgment that the 

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asserted claims of the dosing patents are invalid for 

obviousness.

B 

The second portion of Cubist’s cross-appeal is its challenge to the district court’s ruling that the asserted claims 

of the purity patents (the ’238 and ’342 patents) are 

invalid. The district court held that claim 98 of the ’238 

patent is anticipated by Lilly’s U.S. Patent No. 4,874,843 

(“the ’843 patent”), and that all of the asserted claims of 

the two purity patents are invalid for obviousness. Because we sustain the district court’s ruling that all of the 

asserted claims of the purity patents are invalid on 

grounds of obviousness, we do not need to address the 

issue of anticipation. 

1 

Of the three asserted claims of the ’238 patent, claim 

91 recites a method of preparing a pharmaceutical daptomycin composition that is essentially free of each of 14 

identified impurities, i.e., in which the composition has 

less than 0.5% of each impurity and is obtained by a 

process comprising the step of forming an aggregate 

containing daptomycin. Claim 98 recites a daptomycin 

composition that is at least 93% pure, in which the composition is obtained by the steps of forming a daptomycin 

aggregate, separating the aggregate from low molecular 

weight contaminants, causing the aggregate to dissociate 

into monomers, and separating the daptomycin monomers 

from high molecular weight contaminants by a size selection technique of either ultrafiltration or size exclusion 

chromatography. Claim 187 recites a daptomycin composition that is at least 97% pure relative to certain daptomycin-related impurities, in which the composition is 

obtained from a lipopeptide aggregate containing daptomycin. 

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Of the two asserted claims of the ’342 patent, claim 23

recites a pharmaceutical daptomycin composition that is 

at least 93% pure with respect to certain daptomycinrelated impurities and has less than 4% each of anhydrodaptomycin and the beta isomer of daptomycin, in which 

the composition is prepared by a process comprising the 

steps of subjecting the daptomycin to anion exchange 

chromatography, forming a daptomycin aggregate, and 

obtaining the daptomycin from the daptomycin aggregate 

by a method comprising the steps of filtering the daptomycin aggregate so that the aggregate is retained on the 

filter and collecting the aggregate. Claim 53 recites a 

daptomycin lyophilized powder pharmaceutical composition that is 94 to 96% pure relative to certain daptomycinrelated impurities and has less than 1% of the lactone 

hydrolysis product of daptomycin and less than 4% each of 

anhydro-daptomycin and the beta isomer of daptomycin,

in which the composition is prepared by a process comprising the steps of forming a daptomycin aggregate, 

converting the aggregate to monomers by a process including either anion exchange chromatography or hydrophobic interaction chromatography. 

2 

In its obviousness analysis, the court focused on the 

two primary purification steps recited in the asserted 

claims: (1) micelle or aggregation filtration and (2) anion 

exchange chromatography. Those steps, the court explained, enable the daptomycin to be separated from 

impurities such as saponins and endotoxins. Saponins 

are found in the soy commonly used in daptomycin fermentation, and endotoxins are segments of the cell walls 

of certain bacteria that are left over after the fermentation process that is used to produce daptomycin. 

With respect to micelle filtration, the district court 

explained that in an acidic solution, daptomycin forms 

micelles, or aggregates, of daptomycin molecules. The 

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formation of the micelles effectively increases the size of 

the particles of daptomycin, so that the daptomycin will 

not pass through the pores of certain filters. Because 

smaller impurities such as saponins can pass through the 

filters and be discarded, the process of forming micelles 

enables the filters to separate the saponins from the 

daptomycin.

After that filtration step is completed and the saponins are discarded, the solution is neutralized. That step 

causes the daptomycin aggregates to break apart into 

individual daptomycin molecules, which are small enough 

to pass through the filters’ pores. Larger molecules, such 

as endotoxins, cannot pass through the filters, resulting 

in the separation of the daptomycin from the endotoxins. 

As a result of the two-step filtering process, the daptomycin solution is free of both saponins and endotoxins. 

The district court held that the use of micelle filtration would have been obvious to a person of skill in the art 

based on two references: a 1997 publication by Sung-Chyr 

Lin et al. that showed that it was possible to employ 

micelle filtration for the recovery and purification of most 

surfactants; and a 1988 reference by Jeremy H. Lakey et 

al. teaching one skilled in the art that daptomycin displays the properties of a surfactant. 

With respect to anion exchange chromatography, the 

district court found that the technique was a familiar one, 

and that it was well understood in the industry that it 

could be used to filter out impurities similar to daptomycin in size but differing in chemical structure. The court 

found that anion exchange chromatography would have 

been an obvious method of purification to one of skill in 

the art after solving the problem of removing saponins.

As in the case of the dosing patents, the court reviewed Cubist’s secondary consideration evidence in 

detail and concluded that the secondary consideration 

evidence did not undermine Hospira’s showing that the 

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purity patents would have been obvious to a person of 

skill in the art. Accordingly, the court held the asserted 

claims of the purity patents invalid for obviousness.

3 

In its brief, Cubist does not directly address the 

district court’s analysis of the micelle filtration and anion 

exchange chromatography limitations of the asserted 

claims. Instead, Cubist argues that the court failed to 

analyze obviousness on a claim-by-claim basis and failed 

to conduct an analysis of each of the limitations of the 

asserted claims. In doing so, Cubist asserts, the court 

“did not address a number of limitations that were material to the obviousness analysis.” Focusing on claim 187 

of the ’238 patent and claims 23 and 53 of the ’342 patent, 

Cubist argues that the court ignored the claim limitations 

requiring greater than 93% purity with respect to daptomycin-related substances. Cubist also contends that 

the district court ignored the requirement of claim 91 of 

the ’238 patent that the daptomycin be “essentially free” 

of 14 daptomycin-related impurities, which has the effect 

of requiring that the claimed daptomycin composition 

contain no more than 0.5% of each of the impurities 

referred to in the patent. See ’238 patent, col. 7, ll. 52-56.

Although the district court focused on the two limitations relating to the mechanics of the purification process, 

the court’s focus on those limitations does not undermine 

its obviousness analysis. The use of the two techniques 

set forth in those limitations—micelle filtration and anion 

exchange chromatography—are the keys to the purification process described in the specifications of the purity 

patents and recited in each of the asserted claims. The 

purity patents do not point to any additional techniques 

that are necessary to obtain the recited purity levels in 

each of the claims. Once the saponins and endotoxins are

eliminated from the daptomycin composition by micelle 

filtration, the desired purification levels can be obtained 

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by what the district court referred to as “the simple 

concept” of ion exchange purification.

Cubist contrasts its purification process with the 

process used by Lilly, which is described in Lilly’s ’843 

patent. That process produced daptomycin that was 

approximately 93% pure relative to daptomycin-related 

impurities. Cubist argues that its claimed process of 

micelle filtration followed by anion exchange chromatography constituted a breakthrough for the purification of 

daptomycin compositions, providing a means both for 

filtering out endotoxins and saponins, and for obtaining 

levels of purity relative to daptomycin-related substances 

that were significantly higher than the 93% achieved by 

Lilly’s process. 

Although Cubist argues that the techniques for obtaining purity levels of up to 97% with respect to daptomycin-related substances (as in claim 187 of the ’238 

patent) and levels of less than 0.5% for each of 14 daptomycin-related impurities (as in claim 91 of the ’238 

patent) would not have been obvious, the district court 

found that it would have been obvious to use both micelle 

filtration and anion exchange chromatography and that 

by using those steps the desired purity levels could easily 

be achieved.

The court’s obviousness finding as to micelle filtration 

was soundly based on its reliance on the Lin and Lakey 

prior art references. Given the similarities between 

daptomycin and surfactants, and the known utility of 

micelle filtration of surfactants, the court permissibly 

found that a person of skill in the art would have looked 

to micelle filtration to remove saponins and endotoxins 

from the daptomycin composition. 

The court’s findings as to the obviousness of anion exchange chromatography were also well supported. Based 

on evidence that ion exchange chromatography “was 

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30 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

niques in the field,” the court found that ion exchange 

techniques, and in particular anion exchange chromatography, “would have been an obvious method of purification to one skilled in the art, after solving the problem of 

removing saponins.” That technique, the court found, 

could produce the high purity levels recited in each of the 

asserted claims.4 The court rejected Cubist’s argument 

that those skilled in the art believed there was an upper 

limit on the obtainable purity level of daptomycin, a belief 

that that would have “discouraged one skilled in the art 

from applying a common purification technique after the 

saponin problem was resolved.” The court’s findings as to 

anion exchange chromatography and the purity results 

obtainable from its use were not clearly erroneous.

4 

Finally, Cubist argues that the district court erred by 

failing to give sufficient weight to the secondary considerations of nonobviousness, in particular the long-felt need 

for a commercial-scale purification process for daptomycin 

and the unexpected result that daptomycin would form 

4 Cubist complains that by referring to the observation in the purity patents that “running samples obtained 

via the ’843 Patent process through an anion exchange 

column yielded a very high purity,” the district court 

improperly relied on disclosures in the patent in suit to 

buttress the case of obviousness. To the contrary, the 

court made the observation about the high purity levels 

obtained by anion exchange chromatography to show that 

once the saponins had been removed by micelle filtration, 

that well-known technique was sufficient by itself to 

achieve the purity levels claimed in the purity patents, 

and that the purity patents added nothing to what was 

known in the art. As the court explained, the purity 

patents “do not claim anything other than this simple 

concept.”

 

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reversible micelles under conditions compatible with 

purification. 

The district court considered the evidence of secondary considerations but did not find that evidence sufficiently strong to overcome the proof of obviousness based 

on the prior art. As for Cubist’s claim that there was a 

long-felt need for a commercial-scale purification process 

for daptomycin, the court noted that the asserted claims 

did not refer to production-scale purification, but were 

simply directed to purification “whether produced in an 

economical or wasteful manner.” The court added that it 

was not persuaded by Cubist’s argument that there was a 

long-felt need for an efficient method of purifying daptomycin, particularly in light of the evidence that many 

believed daptomycin was a “dead drug.” 

As for Cubist’s assertion that the propensity to form 

micelles was an unexpected property of daptomycin, the 

district court acknowledged that “Cubist’s being the first 

to observe daptomycin’s micelle-forming properties offers 

some objective evidence of non-obviousness.” However, in 

light of the evidence that it was known that daptomycin 

behaves like surfactants, which in turn were known to 

form micelles, the court concluded that the unexpected 

results argument was not “entitled to serious weight.” 

Ultimately, the court found that the secondary considerations relied on by Cubist were not sufficiently strong to 

“upset Hospira’s prima facie showing that the asserted 

claims of the purity patents are obvious.” 

We sustain the district court’s determination that the 

secondary consideration evidence did not overcome the 

showing of obviousness based on the prior art. With 

respect to Cubist’s claim of a long-felt need, the evidence 

showed that Lilly’s decision not to pursue its research into 

daptomycin was based on economic considerations, not on 

the absence of methods of obtaining sufficiently high 

purity levels. With respect to Cubist’s claim that it was 

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32 CUBIST PHARMACEUTICALS, INC. v. HOSPIRA, INC. 

unexpected that daptomycin would form “reversible 

micelles,” the district court did not clearly err in rejecting 

that argument in light of the Lakey reference that taught 

that daptomycin behaves like a surfactant and the Lin 

reference that taught that surfactants form micelles 

under the proper conditions. We therefore uphold the 

district court’s ruling that the asserted claims of Cubist’s 

purity patents are invalid for obviousness.

Each party shall bear its own costs for these appeals.

AFFIRMED

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