IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

CUBIST PHARMACEUTICALS, INC.,

)))

Plaintiff, ))

v. ))

Civil Action No. 12-367 (GMS) (CONSOLIDATED)

HOSPIRA, INC., ))

Defendant. ))

HOSPIRA, INC.’S ANSWERING CLAIM CONSTRUCTION BRIEF

OF COUNSEL: James F. Hurst WINSTON & STRAWN LLP 35 W. Wacker Drive Chicago, Illinois 60601 (312) 558-5600 E-mail: jhurst@winston.com Gail J. Standish Peter E. Perkowski WINSTON & STRAWN LLP 333 S. Grand Avenue, Suite 3800 Los Angeles, California 90071 (213) 615-1700 E-mail:gstandish@winston.com E-mail: pperkowski@winston.com

John C. Phillips, Jr. (No. 110) Megan C. Haney (No. 5016) PHILLIPS, GOLDMAN & SPENCE, P.A. 1200 North Broom Street Wilmington, DE 19806 Tel. (302) 655-4200 Fax (302) 655-4210 jcp@pgslaw.com mch@pgslaw.com Attorneys for Defendant and Counterclaim Plaintiff HOSPIRA, INC

Jovial Wong Neema Kumar WINSTON & STRAWN LLP 1700 K Street, NW Washington, DC 20006 (202) 282-5000 E-mail: jwong@winston.com E-mail: nkumar@winston.com March 8, 2013

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TABLE OF CONTENTS

Page

INTRODUCTION ........................................................................................................................1 

ARGUMENT ................................................................................................................................3 

I.  Cubist’s Proposed Construction Contradicts Four Major Tenets Of Claim Construction. .....................................................................................................................3 

A.  Claims Are Construed Based On How They Are Understood At The Time Of Filing. ...............................................................................................................4 

B.  Extrinsic Evidence Cannot Trump Intrinsic Evidence. .........................................6 

C.  A Process Limitation Based On An Admittedly Optional Method Cannot Be Incorporated Into A Product Claim. ................................................................9 

D.  Drug Molecules Must Be Defined By Their Structure, Not By Their Function. .............................................................................................................13 

II.  Cubist Cannot Support Its D-Asn Construction Of “Formula 3” Except By Asking The Court To Put Blinders On And Ignore That The CoC Is Invalid As A Matter Of Law. ...........................................................................................................................16 

CONCLUSION ...........................................................................................................................18 

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TABLE OF AUTHORITIES

Page(s) CASES

Advanced Tech. Incubator, Inc. v. Sharp Corp., 2009 WL 4403314 (E.D. Tex. June 26, 2009) ...................................................................16, 17

Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927 F.2d 1200 (Fed. Cir. 1991)................................................................................................13

Atlanta Attachment Co. v. Leggett & Platt, Inc., 516 F.3d 1361 (Fed. Cir. 2008)..................................................................................................6

Bayer Cropscience AG v. Dow Agrosciences LLC, No. 10-1045 RMB/JS, 2012 WL 4498527 at *2 (D. Del. Sep. 27, 2012) ...................10, 14, 15

Biovail Corp. Int’l v. Andrx Pharm., Inc., 239 F.3d 1297 (Fed. Cir. 2001)..................................................................................................9

Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223 (Fed. Cir. 1994)..................................................................................................13

Chef Am., Inc. v. Lamb-Weston, Inc., 358 F.3d 1371 (Fed. Cir. 2004)..........................................................................................3, 8, 9

Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002)..................................................................................................13

Eon Corp. IP Holdings, LLC v. T-Mobile USA, Inc., 2012 WL 405492 (E.D. Tex. Feb. 8 2012) ........................................................................16, 17

Finisar Corp. v. DirecTV Group, Inc., 523 F.3d 1323 (Fed. Cir. 2008)..................................................................................................6

Kara Tech. Inc. v. Stamps.com Inc., 582 F.3d 1341 (Fed. Cir. 2009)..................................................................................................7

Karlin Tech., Inc. v. Surgical Dynamics, Inc., 177 F.3d 968 (Fed. Cir. 1999)..................................................................................................11

Kumar v. Ovonic Battery Co., 351 F.3d 1364 (Fed. Cir. 2003)..................................................................................................5

Lacks Indus., Inc. v. McKechnie Vehicle Components, USA, Inc., 322 F.3d 1335 (Fed. Cir. 2003)..................................................................................................8

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Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898 (Fed. Cir. 2004)....................................................................................................9

Lucent Tech., Inc. v. Gateway, Inc., 525 F.3d 1200 (Fed. Cir. 2008)..............................................................................................3, 8

Merrill v. Yeomans, 94 U.S. 568 (1876) ...............................................................................................................3, 15

Optivus Tech., Inc. v. Ion Beam Applications S.A., 2004 WL 5700631 (C.D. Cal. Aug. 31, 2004) ...........................................................................7

PC Connector Solutions LLC v. SmartDisk Corp., 406 F.3d 1359 (Fed. Cir. 2005)..................................................................................................4

Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005)........................................................................................1, 3, 16

Schultz v. iGPS Co. LLC, No. 10 C 0071, 2013 WL 212927 (N.D. Ill. Jan. 17, 2013) ......................................................7

Superior Fireplace Co. v. Majestic Prods. Co., 270 F.3d 1358 (Fed. Cir. 2001)................................................................................................17

Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 (Fed. Cir. 2004)..................................................................................................13

Vanguard Prods. Corp. v. Parker Hannifin Corp., 234 F.3d 1370 (Fed. Cir. 2000)..............................................................................................1, 9

Wright Asphalt Prod. Co. v. Pelican Refining Co., LLC, No. H-09-1145, 2011 WL 845917 (S.D. Tex. Mar. 7, 2011) ..................................................10

STATUTES

35 U.S.C. § 102(b) ...........................................................................................................................6

INTRODUCTION

Cubist’s Opening Brief ignores the central issue before this Court: how the disputed claim

terms would have been understood “as of the effective filing date of the patent application.”

Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en banc) (emphasis added).

Nowhere in its brief does Cubist even acknowledge that temporal requirement. Nor does Cubist

dispute that at the relevant time, scientists would have understood the disputed terms exactly as

Hospira proposes: daptomycin with an L-Asn amino acid.

Without even acknowledging the legally mandated temporal limitation, Cubist mainly

argues that scientists would have construed “daptomycin” as the version of that antibiotic that

“could be obtained by fermenting bacteria.” (D.I. 39 “Cubist Br.” 1 (emphasis removed).) But at

the relevant time period—as confirmed by both the patent specifications and the prior art cited

therein—scientists would have understood and believed, without question, that the fermentation

process produced daptomycin with L-Asn (as Hospira proposes), not daptomycin with D-Asn (as

Cubist proposes).

Indeed, nobody would have believed Cubist’s proposed construction until 2005—when

scientists first discovered the D-Asn configuration—which is far too late for claim construction

purposes. And it is also irrelevant that at the time of filing, scientists could have conducted private

experimentation to determine whether fermentation produced daptomycin with D-Asn or L-Asn,

because any such hypothetical extrinsic evidence would be “inconsistent with the intrinsic record”

(Cubist Br. 5) which definitively defines daptomycin as Hospira proposes.

Yet another problem—among many others—is that Cubist is attempting to import a

fermentation process limitation to a product claim, which the law unequivocally forbids under these

circumstances, particularly because fermentation was just one way of making the claimed

compound. Vanguard Prods. Corp. v. Parker Hannifin Corp., 234 F.3d 1370, 1372-73 (Fed. Cir.

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2000). At the relevant time and as Cubist admits, scientists could have avoided fermentation

altogether by using a synthetic method to make daptomycin with L-Asn, which is what Cubist

actually claimed.

In a further attempt to avoid all these glaring problems, Cubist asserts that scientists ignore

stereochemistry when defining natural compounds. Based on that assertion, Cubist proposes

defining “daptomycin” based not only on a process limitation, but also on its chemical structure

without its stereochemistry. This is nonsense. Scientists cannot and do not ignore stereochemistry.

Compounds that are otherwise identical but for different stereochemistry are different compounds,

often with drastically different properties, like here where daptomycin with L-Asn is ten times less

potent than daptomycin with D-Asn. Stereochemistry must be included when defining a compound

to precisely identify the correct compound. Cubist knows this, as evidenced by the fact that it

proposes defining “formula 3” with a full chemical structure including stereochemistry (though the

wrong stereochemistry as understood at the time of filing).

As an alternative to its proposed process limitation, Cubist argues that scientists would have

construed the disputed terms as the version of “daptomycin” that had been “demonstrated to have

antibiotic properties in clinical trials.” (Cubist Br. 1 (emphasis removed).) But this argument is

similarly problematic because before 2005, the intrinsic evidence would have definitively shown

that the compound achieving such antibiotic properties was understood and believed to be

daptomycin with L-Asn, not daptomycin with D-Asn. Belated extrinsic evidence from 2005 cannot

retroactively change what scientists understood at the relevant time.

Under the law, the meaning of the disputed terms at the time of filing is what controls,

regardless of whether that meaning was proven incorrect years later in 2005. Notice to the public is

the keystone of patent law, because “nothing can be more just and fair, both to the patentee and the

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public, than that the former should understand, and correctly describe, just what he has invented,

and for what he claims a patent.” Merrill v. Yeomans, 94 U.S. 568, 573-74 (1876) (emphasis added).

Given this, courts “may not redraft claims to cure a drafting error made by the patentee” (Lucent

Tech., Inc. v. Gateway, Inc., 525 F.3d 1200, 1215 (Fed. Cir. 2008)), because a claim is construed

“as written, not as the patentee[] wish[ed] [it] had written it.” Chef Am., Inc. v. Lamb-Weston, Inc.,

358 F.3d 1371, 1374 (Fed. Cir. 2004). The Court thus should adopt Hospira’s proposed

constructions, which are confirmed by the specifications, the file history, and the prior art cited in

the specifications.

ARGUMENT

As detailed below, Cubist’s arguments run afoul of many major tenets of claim construction,

most of which they do not even acknowledge and which mandate adoption of Hospira’s proposed

constructions of “formula 3” and “daptomycin.” Additionally, as also detailed below, delaying the

resolution of the threshold Certification of Correction (CoC) issue, as Cubist proposes, would be

utterly wasteful, because the Court will be addressing the same issues, arguments, and evidence

anyway when construing the disputed claim terms.

I. Cubist’s Proposed Construction Contradicts Four Major Tenets Of Claim Construction.

Cubist’s proposed construction defies four bedrock principles of claim construction: (1)

claims must be interpreted as of their effective filings dates, not later; (2) extrinsic evidence cannot

trump intrinsic evidence; (3) absent a clear disavowal of claim scope, a process limitation cannot be

read into a claim; and (4) drug molecules cannot be defined solely by function. Taken individually

or together, these tenets of patent law mandate adoption of Hospira’s proposed constructions.

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A. Claims Are Construed Based On How They Are Understood At The Time Of Filing.

Cubist’s brief entirely ignores that claims must be construed as of their priority dates.

Phillips, 415 F.3d at 1312-13. Cubist also ignores the corollary principle that a “claim cannot have

different meanings at different times,” because the meaning of a claim term is “time-dependent.”

PC Connector Solutions LLC v. SmartDisk Corp., 406 F.3d 1359, 1363 (Fed. Cir. 2005). Cubist’s

oversight cannot be ignored, especially considering that it is the central reason Hospira’s proposed

construction is so obviously correct.

As of the effective filing dates for each asserted patent, there is no dispute that the structure

of daptomycin was understood to have an L-asparagine. For the latest of the patents, Cubist admits

that the relevant filing date is no later than January 20, 2000. (Ex. 1, Cubist’s Resp. to Interrogatory

No. 11.) Cubist also admits, as it must, that as of that time, many prior art references, including

those related to dosing and purity—and even to methods of producing of daptomycin—repeat this

L-Asn configuration, “because that was the best available information at the time they were filed.”

(Cubist Br. 15 (emphasis added).)

Cubist could not avoid this admission. All of the intrinsic evidence supports Hospira’s

construction, and none shows the D-Asn structure that Cubist seeks to import into its claims. (See

Cubist Br. 11-12, 15, 16; Gerwick Decl. ¶¶ 21-22; Guglielmo Decl. ¶ 12; see also D.I. 38, 2/15/13

Declaration of Bruce Ganem, Ph.D. (“Ganem Decl. I”) ¶¶ 22-25, n.2.) In fact, Cubist affirmatively

argues that “daptomycin” is synonymous with LY 146032 (Cubist Br. 14 (citing ’238 patent, at col.

7:24-27 (JA at 50))), which all the prior art defines as having the L-Asn structure. For example, the

figures below makes this plain, equating “daptomycin” with “LY 146032” and showing the L-Asn

stereochemical structure.

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BALTZ 1997 AT FIG. 1(A) (EMPHASIS ADDED) DEBONO 1988 AT 1094, FIG. 1 (EMPHASIS ADDED) (JA459) (GANEM DECL. I, EX. D AT 1094)

Cubist tries to dismiss the Baltz and Tally references—which explicitly depict the

daptomycin with L-Asn—because they are in the prior art rather than in the specification itself.

(See Cubist Br. 10.) But both are actually cited (and discussed) in the specifications of each of the

method of treatment and purity patents. Because “intrinsic evidence” includes “prior art cited in a

patent,” the Baltz and Tally references are intrinsic evidence. Kumar v. Ovonic Battery Co., 351

F.3d 1364, 1368 (Fed. Cir. 2003). In fact, prior art has “particular value as a guide to the proper

construction of the term” when “cited by the patentee” because it may “indicate not only the

meaning of the term to persons skilled in the art, but also that the patentee intended to adopt that

meaning.’” Id. (quoting Arthur A. Collins, Inc. v. N. Telecom Ltd., 216 F.3d 1042, 1045 (Fed. Cir.

2000)) (emphasis added).

In addition to the art cited in the specification, other prior art references make clear that both

“daptomycin” and “formula 3” were synonymous with LY146032 and were understood to have the

L-Asn configuration. (Ex. E to Ganem Decl. I, Baltz (1997) at Fig. 1; Ex. F to Ganem Decl. I, Tally

(2000) at Fig. 1; Ex. H to Ganem Decl. I, Jeu (2004) at 1729; JA107, JA110, JA114-19, RE ’071

1:25-35, 2:29-31, 7:1-60, 8:50-60; claims 18, 20, 26, and 30.)

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Instead of relying on art that existed as of the relevant filing dates, Cubist relies on

information scientists discovered in 2005, specifically arguing that the 2005 Miao paper was

“considered” by the PTO examiner (actually, it was cited on an IDS submitted in 2010, but never

referenced or discussed by either the patentee or examiner). That argument is meritless. The 2005

Miao paper did not even exist at the relevant time, and thus is irrelevant to a proper claim

construction, which again is based on how the claims would be construed as of the filing date.

In any event, if the 2005 paper was necessary to construe “daptomycin” or “formula 3” as

having D-Asn instead of L-Asn, all of Cubist’s patents would be blatantly invalid. Drastically

changing claim scope—from one compound to a different compound—based on a 2005 publication

would result in (at best) a 2005 priority date. Consequently, all of Cubist’s claims would be invalid,

at least as anticipated by sales and use of their own commercial product in 2003, two years earlier.

See 35 U.S.C. § 102(b). “Our patent laws deny a patent to an inventor who applies for a patent

more than one year after making an attempt to profit from his invention by putting it on sale.” Atl.

Attachment Co. v. Leggett & Platt, Inc., 516 F.3d 1361, 1365 (Fed. Cir. 2008). Stuck between a

rock and a hard place, Cubist has chosen the early priority dates and thus must live with the state of

the art and a scientist’s understanding of “daptomycin” before the Miao 2005 discovery.

B. Extrinsic Evidence Cannot Trump Intrinsic Evidence.

Another problem with Cubist’s arguments is that they rely entirely on extrinsic evidence that

is inconsistent with the overwhelming abundance of intrinsic evidence. As even Cubist admits,

“extrinsic evidence” is relevant only “when not inconsistent with the intrinsic record.” (Cubist Br. 5

(emphasis added), citing Phillips, 415 F.3d at 1318); accord Finisar Corp. v. DirecTV Group, Inc.,

523 F.3d 1323, 1328 (Fed. Cir. 2008) (extrinsic evidence cannot “overcome more persuasive

intrinsic evidence”); Kara Tech. Inc. v. Stamps.com Inc., 582 F.3d 1341, 1348 (Fed. Cir. 2009)

(“extrinsic evidence such as expert testimony is ‘less significant than the intrinsic record in

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determining the legally operative meaning of claim language’”); Schultz v. iGPS Co. LLC, No. 10 C

0071, 2013 WL 212927, at *5 (N.D. Ill. Jan. 17, 2013) (“intrinsic evidence from the patent itself

trumps any contradictory extrinsic evidence”); Optivus Tech., Inc. v. Ion Beam Applications S.A.,

2004 WL 5700631, at *8 (C.D. Cal. Aug. 31, 2004) (Federal Circuit cases “clearly state it would be

error to allow expert testimony to trump intrinsic evidence or the plain meaning of the claim terms”)

(citing Vitronics, 90 F.3d at 1583; Texas Digital Systems, 308 F.3d at 1202–03)).

Contrary to this settled law, Cubist asks this Court to retroactively correct the definition of

its claimed compound, which is dictated by the intrinsic evidence, based solely on contradictory and

after-acquired extrinsic evidence. Specifically, accordingly to Cubist, scientists now allegedly

know that the referenced compound must have been daptomycin with D-Asn all along, because that

compound (rather than daptomycin with L-Asn) is the one that can be “obtained by fermenting

bacteria” and has been “demonstrated to have antibiotic properties in clinical trials.” (Cubist Br. 1.)

But what scientists allegedly “know” now is based only on post-2005 extrinsic evidence that

contradicts the intrinsic evidence. Before 2005, as discussed above, the intrinsic evidence

uniformly and definitively taught that the biologically active daptomycin produced by fermentation

had the L-Asn configuration. For example, U.S. Patent No. 4,208,403 (reissued as RE 32,333) is an

early patent claiming daptomycin that is incorporated by reference in the RE ’071 and its ’333

reissue is cited in the purity patents and on the face of the method of treatment patents. The RE

’333 patent claims the fermentation product of S. roseosporus bacteria and specifically claims the

structure of that product as having the L-Asn configuration. (See JA298, ’333 patent, claim 11.)

Along similar lines, Cubist asks the Court to reject Hospira’s proposed construction because

it would exclude some of the preferred embodiments in the patents, and such constructions are

“rarely correct.” (Cubist Br. 9.) Cubist’s flawed reasoning is as follows: Since the fermentation

8

process inherently produces the D-Asn configuration, adopting Hospira’s construction would

exclude “preferred” examples showing the use of fermentation to produce daptomycin.

But, again, this argument depends entirely on after-acquired extrinsic evidence. At the

relevant time, a scientist reading the intrinsic evidence, including the specification and the cited

prior art, would not have believed any “preferred” examples were excluded by Hospira’s

construction. On the contrary, they would have understood Hospira’s proposed construction to

exactly match the disclosure, because they would have understood that the product of fermentation

was daptomycin with the L-Asn structure. In any event, even a “claim interpretation, which

operate[s] to exclude the preferred embodiment” “can be mandated by clear intrinsic evidence,” as

it is here. Lacks Indus., Inc. v. McKechnie Vehicle Components, USA, Inc., 322 F.3d 1335, 1356

(Fed. Cir. 2003).

Cubist’s real issue is that its claims—as properly construed—are partially inoperative, in the

sense that they cover an antibiotic with the L-Asn configuration that allegedly is not as “potent” as

stated in the specification. But that is irrelevant. Courts may not “redraft claims to cure a drafting

error made by the patentee, whether to make them operable or to sustain their validity.” Lucent

Tech., Inc. v. Gateway, Inc., 525 F.3d 1200, 1215 (Fed. Cir. 2008). The Federal Circuit has

“repeatedly and consistently . . . recognized” that principle. Chef Am., Inc. v. Lamb-Weston, Inc.,

358 F.3d 1371, 1374 (Fed. Cir. 2004) (citing many cases). In fact, even “a nonsensical result does

not require the court to redraft the claims” when the “claims are susceptible to only one reasonable

interpretation.” Id. (quoting Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357

(Fed. Cir. 1999)). Courts “must construe the claims based on the patentee’s version of the claim as

he himself drafted it.” Id.

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In sum, because the specific stereochemical structure of daptomycin was clearly and

intentionally defined with L-Asn at the relevant time, a scientist would look no further than the

intrinsic evidence to understand what molecule was being claimed. Under the law, after-acquired

and contradictory extrinsic evidence cannot change the meaning dictated by the intrinsic evidence.

C. A Process Limitation Based On An Admittedly Optional Method Cannot Be Incorporated Into A Product Claim.

Yet another problem with Cubist’s proposed construction is that Cubist is improperly

attempting to incorporate a process limitation into a product claim1—a limitation found nowhere in

the asserted claims themselves. Specifically, Cubist proposes reading into each claim a process

limitation requiring that the drug be “derived from the fermentation of Streptomyces roseosporus.”

In support, Cubist asserts that scientists would ignore the claimed compound’s chemical structure

(including its stereochemistry) in favor of focusing on “how” that compound “can be” made.

(Cubist Br. 8-9, 15.) Any such reasoning is flatly prohibited by the law and the facts.

“As a general proposition, a limitation that does not exist in a claim should not be read into

that claim.” Biovail Corp. Int’l v. Andrx Pharm., Inc., 239 F.3d 1297, 1301 (Fed. Cir. 2001). And

attempting to add a nonexistent process limitation to a product claim is particularly inappropriate.

“The method of manufacture, even when cited as advantageous, does not of itself convert product

claims into claims limited to a particular process.” Vanguard Prods. Corp. v. Parker Hannifin

Corp., 234 F.3d 1370, 1372-73 (Fed. Cir. 2000).

1 The asserted claims of the method of treatment and purity patents are either claims to methods of using daptomycin or claims to daptomycin purified by particular process steps. The disputed term in these claims is the product “daptomycin,” and Cubist is trying to improperly limit daptomycin to a specific process by which it is made.

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Under certain rare circumstances, courts will add process limitations to product claims, but

only when the patentee has excluded all other possible processes during prosecution as confirmed

by “a clear intention to limit the claim scope using ‘words or expressions of manifest exclusion or

restriction.’” Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898, 906 (Fed. Cir. 2004) (quoting

Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1327 (Fed. Cir. 2002)); see also Bayer, 2012

WL 4498527, at *5 (same); Wright Asphalt Prod. Co. v. Pelican Refining Co., LLC, No. H-09-

1145, 2011 WL 845917, at *13-14 (S.D. Tex. Mar. 7, 2011) (product claims not limited to same

scope as product-by-process claims).

Here, Cubist does not even argue—nor could it—that the intrinsic evidence demonstrates a

“clear intention” to exclude all processes other than fermentation. On the contrary, as noted in

Hospira’s Opening Brief (D.I. 37, “Hospira Br.” 19), Cubist made it clear that fermentation was

only one option that “can be” used to make the antibiotic, which stands in stark contrast to its

proposed claim construction:

Cubists’ Proposed Construction Disclosure in Patent Specification2 The cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus, comprised of a decanoyl side chain linked to the N-terminal tryptophan of a cyclic 13 amino acid peptide

Daptomycin is a cyclic lipopeptide that can be derived from the fermentation of Streptomyces roseosporus. It is composed of a decanoyl side chain linked to the N-terminal tryphtophan of a cyclic 13 amino-acid peptide

Cubist’s brief actually confirms that fermentation is optional rather than required. Cubist

describes fermentation as the “preferred” method, which means it “can be” made other ways too.

(Cubist Br. 9, 14.) Cubist explicitly admits that at all relevant times, there was another, known

method of making daptomycin: synthesis. Additionally, Cubist’s expert specifically acknowledges

(and the file history of the RE ’071 patent confirms) that skilled artisans could synthesize

daptomycin to obtain its then known L-Asn configuration, just as Miao did later, with well-known

2 See, e.g, JA007, ‘967 patent at 1:39-47; JA047, ‘238 patent at 1:58-66.

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techniques available for decades and, more importantly, as of the filing dates of the asserted patents.

(Gerwick Decl. ¶ 13; JA453, 12/12/89 Office Action at 4; see also Ganem Decl. I ¶¶ 26-28.)

Cubist points to nothing in the patent specification or file history where the inventors

disclaim the use or purification of synthetic daptomycin. On the contrary, Cubist notes that some

claims refer only to “daptomycin” while other, unasserted claims require the claimed daptomycin be

made by fermentation. (Cubist Br. at 12-13.) Based on the doctrine of claim differentiation—as

explained in Hospira’s Opening Brief at page 19—this distinction only serves to make abundantly

clear that the term “daptomycin” alone is not limited to daptomycin made by fermentation. See

Karlin Tech., Inc. v. Surgical Dynamics, Inc., 177 F.3d 968, 971-72 (Fed. Cir. 1999). When the

inventors wanted to add that further process limitation, they knew how to do so, and did so

explicitly.

It would be both legally and factually inappropriate to use a new process limitation, as

Cubist proposes, to somehow trump the well-known stereochemistry of daptomycin that persisted

through (and beyond) the latest effective filing date. In an effort to include a process limitation and

exclude the drug’s stereochemistry, Cubist falsely downplays the critical importance of

stereochemistry.

For instance, in its brief, Cubist claims that the dosing patents “Do Not Refer To

Stereochemistry.” (Cubist Br. 8.) That is not true. The very paragraph that Cubist quotes defines

daptomycin and concludes by specifically referring to “see Baltz, Fig. 1a,” which (as seen above) is

a diagram of the complete molecular structure including its stereochemical configuration.

Despite this, Cubist strains credulity by arguing that skilled scientists would not care about

the stereochemistry of the molecule with which they were working (see Guglielmo Decl. ¶ 12;

Gerwick Decl. ¶¶ 17, 23)—an argument squarely contradicted by the fact that numerous prior art

12

articles authored by scientists repeatedly and expressly disclose daptomycin’s stereochemistry. (See

Ganem Decl. I ¶¶ 22-25, n.2.) In reality, persons skilled in the art with respect to the method of

treatment patents would consider a drug’s chemistry, including its stereochemistry, crucial to fully

understanding its clinical applicability. (See also Chandrasekar Decl. ¶¶ 9-11.) Indeed, as noted

above, otherwise identical compounds with different stereochemistry are different compounds, with

sometimes massively different properties, including differences that can turn an effective compound

into a deadly compound. (See Ganem Decl. I ¶ 12.) As Miao similarly proved, the physical and

chemical properties of compounds with different stereochemistry—even, like daptomycin, where

only one amino acid is changed—can result in dramatic differences such as a ten-fold change in

potency. (JA507, Miao (2005) at 1520.) Those properties similarly affect how and under what

conditions a purification process would or would not work, and thus stereochemistry would also be

important to the skilled scientist with respect to the purity patents. (3/8/13 Declaration of Bruce

Ganem, Ph.D. (Ganem Decl. II) ¶ 7; Ganem Decl. I ¶ 13.)

When arguing otherwise, Cubist’s expert, Dr. Gerwick, asserts that stereochemical mistakes

with natural compounds are so common that skilled scientists would dismiss the published

stereochemistry as unreliable. (Gerwick Decl. ¶¶ 16-17.) But Dr. Gerwick’s own patent—

obviously not prepared for litigation—emphasizes the importance of determining the

stereochemistry of natural products in connection with “structure activity relationship studies and/or

drug development (e.g., increase bioavailability and/or decrease toxicity).” (Ganem Decl. II, ¶ 8

and Ex. B (U.S. Pat. No. 8,034,780, col. 19, lines 45-52).)

Cubist also asserts that scientists would ignore the stereochemistry because it was only

“tentative” when the patents were filed. (Cubist Br. 16.) Not so. Cubist cites nothing calling

daptomycin’s stereochemistry “tentative.” While the reported stereochemistry turned out to be

13

wrong, the intrinsic evidence cited by both Hospira and Cubist proves it was anything but tentative.

Instead, the stereochemistry of daptomycin was carefully established, repeatedly reported, and

never questioned until Miao “unexpectedly” discovered in 2005 that one of the “key” amino acids

had been assigned the incorrect configuration.

For these reasons, there is no basis to construe the claims to include a process limitation that

is found nowhere in the claims.

D. Drug Molecules Must Be Defined By Their Structure, Not By Their Function.

Finally, Cubist also contends that skilled scientists would ignore the specific stereochemistry

incorporated into the patents and instead define “daptomycin” by reference to its function as (in

Cubist’s words) a “highly potent antibiotic.” (Cubist Br. 8-9.) This approach, too, is flatly

prohibited by a fundamental tenet of claim construction: compounds are defined by their structure,

not by their function. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927 F.2d 1200, 1206 (Fed. Cir.

1991).

A drug molecule must be defined by “sufficient structure” to distinguish the molecule from

all others. MPEP 2163, II.A.3(a)(i)(C)(2); Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d

1223, 1229-30 (Fed. Cir. 1994) (a “chemical substance” is described and conceived under patent

law based on “knowledge of both the specific chemical structure of the compound and an operative

method of making it.”) (emphasis added). In fact, it is “not sufficient to define [a chemical] solely

by its principal biological activity,” Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1206 (Fed.

Cir. 1991), as Cubist requests, unless “there is a well-established correlation between structure and

function. In contrast, without such a correlation, the capability to recognize or understand the

structure from the mere recitation of function and minimal structure is highly unlikely.”

MPEP 2163, II.A.3(a)(i) (requirements to satisfy written description requirement for chemical

compounds); see also Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 925 (Fed. Cir.

14

2004) (written description requirement met only if “functional characteristics are coupled with a

known or disclosed correlation between function and structure”); Enzo Biochem, Inc. v. Gen-Probe

Inc., 323 F3d 956, 964 (Fed. Cir. 2002) (adopting MPEP guidelines and requiring “disclosed

correlation between that function and a structure that is sufficiently known or disclosed”) (italics in

original).

Here, with daptomycin, there was no well-known correlation between structure and

function. The opposite was true, as the “unexpected” change in one structural element significantly

changed the level of function. Moreover, it is true that the L-Asn form may not be as potent as the

D-Asn form. But there is no evidence that it is not also a “potent” antibiotic. Some of the method

of treatment claims require only that daptomycin be administered until an infection is “treated or

eradicated.” (See, e.g., JA014, ’967 patent at claim 26; JA032, ’689 patent at claim 27.) L-Asn

daptomycin may very well be capable of “treating” or “eradicating” an infection, and Cubist

presents no evidence to the contrary. The point is that a person of ordinary skill reading the

treatment patents on the critical date would have no reason to question that L-Asn daptomycin was

perfectly capable of being an effective antibiotic.

In addition, the Bayer court was faced with, and resoundingly rejected, the same argument

Cubist makes here. There, just like here, the patentee requested a functional definition based on

“biological activity” to attempt to correct a mistake in its patent. On the relevant filing date in

1989, the claimed gene coded for an enzyme that “was wrongly believed to be a monooxygenase,

not a dioxygenase.” Bayer Cropscience AG v. Dow Agrosciences LLC, Civ. No. 10-1045 RMB/JS,

2012 WL 4498527 at *2 (D. Del. Sep. 27, 2012) (emphasis in original). Four years later, in 1993, a

published paper “identified this error.” Id. at *2 n.4. To attempt to retroactively fix the error, the

15

patentee sought a functional definition focusing on “biological activity” that would have covered

the correct “dioxygenase” enzyme. The Court rejected this argument:

It is immaterial that persons of ordinary skill in the art at the time of the invention erroneously understood the claim terms ‘2,4-D monooxygenase’ to include the TfdA enzyme. That misimpression was not based on a misunderstanding of what it meant to be a 2,4-D monooxygenase, but the mistaken belief that the TfdA enzyme qualified as a 2,4-D monooxygenase. What is material is that 2,4-D monooxygenase had a specific meaning to persons of ordinary skill in the art at the time . . . . ; that meaning would not capture the TfdA enzyme, as the parties agree that TfdA is a dioxygenase.”

Id. at *5 (emphasis added). Here, “what is material is that” the L-Asn daptomycin structure set

forth in the patent specifications “had a specific meaning to persons of ordinary skill in the art at the

time,” and it is “immaterial” that scientists were “erroneous[]” in their belief that daptomycin had

that structure.

Thus, the Court should reject Cubist’s effort to define daptomycin based on its function.

Disclosure of the drug as an antibiotic, even in combination with a way it could be made, is

insufficient to distinguish the molecule from all others, and it is certainly insufficient to overcome

the specific L-Asn structure expressly incorporated by reference into both the method of treatment

and purity patents.

* * *

In sum, the facts do not support, and the law does not allow, Cubist’s construction of

daptomycin. That construction is nothing but an attempt to make an end run around the fact that, on

the filing date for each of the patents, skilled scientists understood daptomycin to be a specific drug

molecule containing an L-asparagine.

16

There is simply no provision in the patent law that permits Cubist’s constructions to be

adopted. Courts may not rewrite the claims to cover what the patentee allegedly had in hand at the

time (if indeed, Cubist always had D-Asn daptomycin “in hand”) rather than what it told the public

was its claimed invention. Notice to the public is the keystone of patent law, because “nothing can

be more just and fair, both to the patentee and the public, than that the former should understand,

and correctly describe, just what he has invented, and for what he claims a patent.” Merrill v.

Yeomans, 94 U.S. 568, 573-74 (1876) (emphasis added). “Because the patentee is required to

‘define precisely what his invention is,’ … it is ‘unjust to the public, as well as an evasion of the

law, to construe it in a manner different from the plain import of its terms.’” Phillips, 415 F.3d at

1312 (quoting White v. Dunbar, 119 U.S. 47, 52 (1886)). But that is precisely what Cubist asks the

Court to do here—to construe the disputed terms in a manner plainly at odds with what the

inventors told the public they had invented. The Court should reject this invitation.

II. Cubist Cannot Support Its D-Asn Construction Of “Formula 3” Except By Asking The Court To Put Blinders On And Ignore That The CoC Is Invalid As A Matter Of Law.

Even though it is a critical threshold issue to a proper claim construction—an issue that

drives whether this Court construes the original or corrected claims in the RE ’071 patent—Cubist

asks this Court to delay deciding whether the CoC is valid. But as explained in Hospira’s Opening

Brief, any such delay would be utterly wasteful because resolving that question is a pure issue of

law, one that turns entirely on (1) whether the corrected claims are “broader” than the original

claims, and (2) the same intrinsic record that Court is already addressing when construing the

disputed “daptomycin” term. (See Hospira Br. 12.)

In support of its position, Cubist’s cites two cases from the Eastern District of Texas. See

Eon Corp. IP Holdings, LLC v. T-Mobile USA, Inc., 2012 WL 405492, at *19 (E.D. Tex. Feb. 8

2012); Advanced Tech. Incubator, Inc. v. Sharp Corp., 2009 WL 4403314, at *19 (E.D. Tex. June

17

26, 2009). But those cases support Hospira’s position, not Cubist’s.

As the Court in Eon Corporation explained, the CoC validity inquiry is a two-part inquiry,

requiring proof that “‘(1) the corrected claims are broader than the original claims; and (2) the

presence of the clerical error, or how to correct that error, is not clearly evidenced to one of skill in

the art.’ . . . The first element is a question of law; however, the second element is a question of

fact.” Eon Corp., 2012 WL 405492 at *19 (quoting Central Admixture Pharmacy Servs., Inc. v.

Advanced Cardiac, 482 F.3d 1347, 1353-56 (Fed. Cir. 2007)). The Court then declined to resolve

the issue as a matter of law solely based on disputed factual issues regarding the second part of the

inquiry, specifically whether the alleged mistake of a clerical or typographical nature would be

recognized as such by a person of ordinary skill in the art and whether, even if recognized, it would

be apparent to a person of skill on the effective filing date how to correct it. Id. at *19; accord;

Advanced Tech. Incubator, 2009 WL 4403314, at *19 (declining to address validity of CoC, while

nevertheless construing both sets of claims, because the court found that “factual findings beyond

the scope of claim construction would be required”).

Here, by contrast, there are no factual issues to address. The “second element” of the CoC

inquiry is not part of this case because Cubist does not contend, nor can it, that the mistake at issue

is of a clerical or typographical nature. As explained in Hospira’s Opening Brief and confirmed by

Cubist’s expert (see Hospira Br. 12-13; Gerwick Decl. ¶¶ 16-17, 21-22), Cubist admits that the

scientific mistake made in assigning the wrong stereochemistry to daptomycin’s asparagine amino

acid was not a “clerical” or “typographical” mistake. (See also D.I. 37, Ex. 1, Cubist’s Resp. to

RFAs 1, 2.)

Thus, the only inquiry for the Court is a pure matter of law: Are the new claims broader

than the old? If the answer to this question is “yes,” then the CoC is invalid because “a mistake the

18

correction of which broadens a claim is not a ‘mistake of . . . minor character’” subject to correction

under § 255. Superior Fireplace Co. v. Majestic Prods. Co., 270 F.3d 1358, 1376 (Fed. Cir. 2001).

That inquiry is not only a pure question of law, it is a question of claim construction, requiring that

the Court construe both sets of claims and compare their scope. (Hospira Br. 12, and cited cases.)

Here, Cubist’s delisting and then relisting of the RE ’071 patent from the FDA’s Orange Book by

itself answers that question—although even this evidence is unnecessary—because the original

claims on their face did not cover the D-Asn molecule while the corrected claims do. This is the

very definition of broadening.

Notably, Cubist makes no attempt to explain why it would be more efficient for the Court to

delay claim construction by declining to address the broadening issue now. In fact, it would be

highly inefficient to do so, requiring the Court to revisit the very same issues it is addressing now in

construing the term “daptomycin” from the method of treatment and purity patents. Hospira

respectfully submits that the Court should find the CoC invalid and proceed to construe the

uncorrected claims, which plainly set forth “formula 3” with the L-Asn configuration.

CONCLUSION

For the reasons stated above and in Hospira’s Opening Brief, Hospira respectfully requests

that the Court reject Cubist’s attempt to rewrite history with extrinsic evidence. Instead, the Court

should construe the two disputed claim terms as the intrinsic evidence proves they would have been

understood by scientists on the effective filing dates of the patents to require “daptomycin” and

“formula 3” to contain L-asparagine.

19

Dated: March 8, 2013 HOSPIRA, INC. By: /s/ John C. Phillips, Jr.

OF COUNSEL: James F. Hurst WINSTON & STRAWN LLP 35 W. Wacker Drive Chicago, Illinois 60601 (312) 558-5600 E-mail: jhurst@winston.com Gail J. Standish Peter E. Perkowski WINSTON & STRAWN LLP 333 S. Grand Avenue, Suite 3800 Los Angeles, California 90071 (213) 615-1700 E-mail:gstandish@winston.com E-mail: pperkowski@winston.com

John C. Phillips, Jr. (No. 110) Megan C. Haney (No. 5016) PHILLIPS, GOLDMAN & SPENCE, P.A. 1200 North Broom Street Wilmington, DE 19806 Tel. (302) 655-4200 Fax (302) 655-4210 jcp@pgslaw.com mch@pgslaw.com Attorneys for Defendant and Counterclaim Plaintiff HOSPIRA, INC

Jovial Wong Neema Kumar WINSTON & STRAWN LLP 1700 K Street, NW Washington, DC 20006 (202) 282-5000 E-mail: jwong@winston.com E-mail: nkumar@winston.com

CERTIFICATE OF SERVICE I, Megan C. Haney, hereby certify that on March 8, 2013, I caused true and correct copies of the foregoing HOSPIRA’S ANSWERING CLAIM CONSTRUCTION BRIEF to be served upon the following counsel of record in the manner indicated: VIA E-MAIL AND ECF: Jack B. Blumenfeld Maryellen Noreika Morris, Nichols, Arsht & Tunnell LLP jblumenfeld@mnat.com mnoreika@mnat.com William F. Lee Lisa J. Pirozzolo Emily R. Whelan Ryann M. Muir Andrew Scott Dulberg Wilmer Cutler Pickering Hale and Dorr LLP 60 State Street Boston, MA 02109 william.lee@wilmerhale.com lisa.pirozzolo@wilmerhale.com emily.whelan@wilmerhale.com ryann.muir@wilmerhale.com andrew.dulberg@wilmerhale.com Andrew Zoltan Wilmer Cutler Pickering Hale and Dorr LLP 7 World Trade Center 250 Greenwich Street New York, NY 10007 andrew.zoltan@wilmerhale.com /s/ Megan C. Haney Megan C. Haney (No. 5016)