IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE ) ) ) ) ) ) Civil Action No.

12-367 (GMS) ) (CONSOLIDATED) ) ) ) )

CUBIST PHARMACEUTICALS, INC., Plaintiff, v. HOSPIRA, INC., Defendant.

HOSPIRA, INC.’S OPENING CLAIM CONSTRUCTION BRIEF 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

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 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 February 15, 2013

TABLE OF CONTENTS INTRODUCTION .......................................................................................................................1 FACTUAL BACKGROUND ......................................................................................................3 A. B. C. D. E. Eli Lilly Invented Daptomycin In The Late 1970’s, But Mistakenly Described The Wrong Configuration For The Compound. ............................................................3 The Prior Art Repeated Lilly’s Mistaken Configuration For Daptomycin. ...................4 Cubist Repeated Lilly’s Mistake When Filing Its Patent Applications. ........................5 Cubist Finally Discovered Lilly’s Mistake In 2005. ......................................................7 After Discovering the Mistake, Cubist Delisted The Re ‘071 Patent From The FDA Orange Book. ........................................................................................................7

ARGUMENT ...............................................................................................................................8 A. B. Claims Are Construed As They Would Have Been Understood By Skilled Scientists On The Effective Filing Date Of The Patent. ................................................8 On The Effective Filing Dates, Both Disputed Terms Would Have Been Understood As L-Asn Daptomycin. ..............................................................................9 1. 2. The RE ‘071 Patent Claim Term “Formula 3 Compound/Compound of Formula 3” Means L-Asn Daptomycin..............................................................9 “Daptomycin” Should Be Construed as Described in the Prior Art Expressly Referenced in the Patent Specifications Of The Method And Purity Patents. ..................................................................................................15 a. b. The intrinsic record requires that “daptomycin” be construed as having L-Asn. ......................................................................................16 Cubist’s proposed construction seeks to impermissibly read a process limitation into the claims. .......................................................17

CONCLUSION ..........................................................................................................................20

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TABLE OF AUTHORITIES Page(s) CASES Adv. Tech. Incubator, Inc. v. Sharp Corp., No. 2:07-CV-468, 2009 WL 4670942 (E.D. Tex. Sept. 18, 2009) ..........................................14 Arthur A. Collins, Inc. v. N. Telecom Ltd., 216 F.3d 1042 (Fed. Cir. 2000)..................................................................................................9 Bayer Cropscience, AG v. Dow Agrosciences LLC, Civ. No. 10-1045 RMB/JS, 2012 WL 4498527 (D. Del. Sep. 27, 2012) ..........................14, 18 Biovail Corp. Int’l v. Andrx Pharm., Inc., 239 F.3d 1297 (Fed. Cir. 2001)................................................................................................18 Bristol-Myers Squibb Co. v. Ben Venue Labs, Inc., 246 F.3d 1368 (Fed. Cir. 2001)................................................................................................11 Central Admixture Pharm. Servs., Inc. v. Advanced Cardiac Solutions, P.C., 482 F.3d 1347 (Fed. Cir. 2007)....................................................................................12, 13, 14 Chef Am., Inc. v. Lamb-Weston, Inc., 358 F.3d 1371 (Fed. Cir. 2004)............................................................................................2, 14 Chimie v. PPG Indus., 402 F.3d 1371 (Fed. Cir. 2005)..................................................................................................9 Cordis Corp. v. Boston Scientific Corp., 561 F.3d 1319 (Fed. Cir. 2009)................................................................................................18 Kara Tech. Inc. v. Stamps.com Inc., 582 F.3d 1341 (Fed. Cir. 2009)................................................................................................17 Karlin Tech., Inc. v. Surgical Dynamics, Inc., 177 F.3d 968 (Fed. Cir. 1999)..................................................................................................19 Kumar v. Ovonic Battery Co., 351 F.3d 1364 (Fed. Cir. 2003)............................................................................................9, 16 Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898 (Fed. Cir. 2004)..................................................................................................18 Lucent Tech., Inc. v. Gateway, Inc., 525 F.3d 1200 (Fed. Cir. 2008)............................................................................................2, 18

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Markman v. Westview Instruments Inc., 52 F.3d 967 (Fed. Cir. 1995)..........................................................................................9, 12, 15 Monsanto Co. v. Bayer Bioscience N.V., 363 F.3d 1235 (Fed. Cir. 2004)................................................................................................19 Novo Indus., L.P. v. Micro Molds Corp., 350 F.3d 1348) (Fed. Cir. 2003) ..............................................................................................14 Nystrom v. Trex Co., 424 F.3d 1136 (Fed. Cir. 2005)..................................................................................................9 PC Connector Solutions LLC v. SmartDisk Corp., 406 F.3d 1359 (Fed. Cir. 2005)..................................................................................................8 Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ...................................................................................1, 8, 9, 17 Schultz v. iGPS Co. LLC, No. 10 C 0071, 2013 WL 212927 (N.D. Ill. Jan. 17, 2013) ....................................................17 Superior Fireplace Co. v. Majestic Prods. Co., 270 F.3d 1358 (Fed. Cir. 2001)............................................................................................2, 12 Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313 (Fed. Cir. 2002)................................................................................................18 Tillotson, Ltd v. Walbro Corp., 831 F.2d 1033 (Fed. Cir. 1987)................................................................................................12 Vanguard Prods. Corp. v. Parker Hannifin Corp., 234 F.3d 1370 (Fed. Cir. 2000)................................................................................................18 Wright Asphalt Prod. Co. v. Pelican Refining Co., LLC, No. H-09-1145, 2011 WL 845917 (S.D. Tex. Mar. 7, 2011) ..................................................19 STATUTES 35 U.S.C. § 255 ..........................................................................................................................2, 12 OTHER AUTHORITIES 21 C.F.R. § 314.53(b) ..................................................................................................................1, 7

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INTRODUCTION Though there are over 100 asserted claims from five asserted patents, the parties dispute the meaning of only two terms: “formula 3 compound” and “daptomycin.” The proper construction of these related terms go to a central issue in this case, because all five patents claim the wrong drug. When filing their original patent application, the inventors described and claimed the wrong molecule, not the active ingredient in Cubist’s or Hospira’s product. Eli Lilly originally made the antibiotic “daptomycin” (in quotes because its meaning has changed over time) around 1978. At that time, and for over two decades after, the inventors—and all ordinarily skilled scientists—were mistaken about the drug’s physical configuration. The patent specifications and the prior art repeatedly reported the mistaken configuration. And that mistake had important implications. The difference in configuration not only results in a completely different drug, but the antibiotic the inventors actually claimed is ten times less potent than the active ingredient in Hospira’s product. Nobody discovered the mistaken configuration until 2005, too late for claim construction. Courts construe patent terms from the perspective of “a person of ordinary skill in the art in question at the time of the invention, i.e., 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). And at that time, as confirmed by the specifications and prior art, scientists understood the term “daptomycin” to mean a specific drug with a specific (yet mistaken) configuration. How scientists understood the term back then—not now—is what matters for claim construction purposes. Cubist knows this. When the mistaken configuration was uncovered in 2005 (two years after its product hit the market), Cubist responded by delisting its main patent from the FDA’s Orange Book—a necessity since a patent can be listed only if it “claims the drug or a method of using the drug” that is the subject of an FDA-approved application. 21 C.F.R. § 314.53(b). The patent had to be delisted because it did not “claim[] the drug” in Cubist’s FDA-approved product.

Cubist then obtained a Certificate of Correction (“CoC”) from the PTO that purported to “correct” the configuration of the claimed “formula 3 compound.” But that CoC is ineffective: a CoC can only correct “a mistake of a clerical or typographical nature, or of minor character” (35 U.S.C. § 255), which as a matter of law does not apply to “errors” that, as here, broaden the claim scope and are “not clearly evident from the specification, drawings, and prosecution history.” Superior Fireplace Co. v. Majestic Prods. Co., 270 F.3d 1358, 1376 (Fed. Cir. 2001). The other four asserted patents have the same defect; Cubist never even tried to “correct” them. Two of them claim methods of using “daptomycin,” and the other two claim “daptomycin” of certain purity levels. Each unambiguously defines “daptomycin” by reference to the pre-2005 prior art, which again sets forth the wrong configuration. On the relevant filing dates in 1999 and 2000, a skilled scientist would have had no idea the inventors intended to claim a different drug that was not even identified until 2005. As a pure matter of claim construction, therefore, “daptomycin” means the antibiotic drug described in the patents’ specifications and the pre-2005 prior art. Through its proposed claim construction, Cubist asks this Court to revise history by retroactively correcting the inventors’ scientific mistake, or otherwise construing the claims inconsistently with how skilled scientists, and even the inventors themselves, understood them on the relevant filing dates. But there is no provision in the patent law that allows for such an exercise. “[C]ourts 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). 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). To do otherwise would flout the primary purpose of patent claims, which is to give the public notice of the bounds of the claimed invention. Here, the terms “formula 3 compound” and “daptomycin” had well-understood meanings at the time of filing based

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on the patents’ claims, the specifications, the file histories, and decades of scientific references. Those meanings control here, and should be adopted by the Court. FACTUAL BACKGROUND A. Eli Lilly Invented Daptomycin In The Late 1970’s, But Mistakenly Described The Wrong Configuration For The Compound. Cubist has asserted five patents, all of which relate to an antibiotic known as “daptomycin.” Daptomycin belongs to a class of drugs originally invented by Eli Lilly in the late 1970s. (JA121, ‘403 patent; Declaration of Bruce Ganem, Ph.D. ¶¶ 16-18.) Lilly first disclosed and claimed daptomycin as part of a class of antibiotics described in a patent application filed in 1982, which eventually issued into U.S. Pat. No. 4,537,717 in 1985. (JA199, ‘717 patent.) That patent—the original daptomycin patent—sets forth the structure of a compound Lilly called “LY 146032,” which was later renamed “daptomycin.” (JA201, JA216, id. at 3:1-28, claims 8, 30.) All of the scientific literature equates “LY 146032” with “daptomycin.” (E.g., JA110, RE ‘071 patent at 7:56-60; JA457, Baltz 1997 at 415.) Lilly’s patent disclosed that daptomycin has 13 “amino acids,” which are simple organic compounds that can be combined to form larger compounds. (Ganem Decl. ¶¶ 10-15.) When part of a larger compound, an amino acid’s three-dimensional orientation, or its “stereochemical configuration,” can be critical to the compound’s activity. (Id.; JA439-440, 11/4/88 Resp. at 5-6; JA444, 11/5/91 Amendment at 3.) The important amino acid for this case—which Cubist later called a “key” amino acid (JA507, Miao at 1520)—is asparagine (“Asn”). For its stereochemical configuration, Lilly stated that Asn has an “L” configuration (“L-Asn”) rather than the alternate “D” configuration (“D-Asn”). (JA201, ‘717 patent at 3:1-25.) But in fact, the Asn amino acid in daptomycin is known today to have the D configuration. (JA494, JA507, Miao at Abstract, 1520.) Nevertheless, related Lilly patents repeated the mistaken

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L-Asn for literally decades. For instance, Lilly obtained U.S. Pat. No. RE 39, 071 (“the RE ‘071 patent”) in April 2006, stemming from a 1987 application and describing the same mistaken daptomycin structure. Specifically, the RE ’071 patent includes a graphic entitled “formula 3”—reproduced at right—setting forth the configuration of each amino acid in the relevant antibiotic class, including L-Asn for the “key” Asn amino acid. (JA110, JA114, RE ’071 patent at 7:1-26, claim 18.). When “RN” at the bottom is n-decanoyl, the formula 3 compound is LY 146032 (a.k.a. daptomycin). (JA110, RE ’071 patent at 7:56-60.) Lilly later assigned the RE ‘071 patent to Cubist, which has now asserted that patent against Hospira. The RE ‘071 patent generally relates to “impurity levels” in a daptomycin formulation. (JA106, RE ’071 patent at Abstract.) As explained further below, the RE ‘071 patent was allegedly “corrected” to change the L-Asn to the D-Asn in 2007. B. The Prior Art Repeated Lilly’s Mistaken Configuration For Daptomycin. For years after Lilly’s original work in the late 1970s, the prior art consistently and repeatedly reported the mistaken structure of daptomycin with L-Asn. Two important examples are articles authored by Lilly and Cubist scientists, both of which are cited in the specification of the four other patents at issue in this case. The articles—Baltz (1997) and Tally (1999)—each contain a figure that unambiguously shows the mistaken structure of daptomycin with L-Asn. (JA459, Baltz 1997 at Fig. 1(a); JA479, Tally 1999 at Fig. 1.) Before 2005, the L-Asn configuration was well accepted. This was no typographical or clerical error. It was intentional, and repeated dozens of times.1 And there was never any reason for

See, e.g., JA201, ‘717 patent (1985) at 3:1-25; JA286, RE ‘333 patent (1987) at 4:1-30; JA254, RE ‘311 patent (1986) at 3:28-52; JA308, RE ‘455 patent (1987) at 4:1-25; JA240, RE’ 310 patent 4

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scientists to doubt its accuracy, particularly because the “D” configuration is exceedingly rare. One review article studying naturally-occurring compounds dating back to at least 1971 found only two experimentally-validated occurrences of asparagine with the “D” configuration out of almost 200 million chemical structures. (Ganem Decl. ¶ 25, Ex. I, Khoury et al. at Table 2.) C. Cubist Repeated Lilly’s Mistake When Filing Its Patent Applications. Cubist repeated the same mistake when filing for its own patents now at issue. In addition to the RE ‘071 patent (assigned from Lilly), Cubist obtained four daptomycin patents that it has now asserted against Hospira. The first two patents—U.S. Pat. No. 6,468,967 (“the ‘967 patent”) and U.S. Pat. No. 6,852,689 (“the ‘689 patent”)—have identical specifications and are both titled “Methods for Administration of Daptomycin.” (JA001, JA015.) These method patents, which relate generally to dosing regimens intended to reduce toxicity when treating patients with daptomycin, issued from an original application filed on September 24, 1999. (Id.) The second two patents—U.S. Pat. No. 8,058,238 (“the ‘238 patent”) and U.S. 8,129,342 (“the ‘342 patent”)—also have identical specifications. They are both titled “High Purity Lipopeptides” and relate generally to highly purified compositions of daptomycin. (JA034, JA072.) Both issued from a series of applications (with identical specifications), the earliest of which was filed on November 28, 2000. (Id.) All of Cubist’s patents repeat Lilly’s mistake in unambiguous terms. The original applications for all four patents (and the issued specifications) define “daptomycin” by referring to the prior art. For instance, the specifications repeatedly cite Baltz 1997, a reference that, as noted (1986) at 4:1-32; JA158, ‘487 patent (1984) at 4:1-32; JA183, ‘135 patent (1985) at 4:1-25; JA233, ‘226 patent (1999) at 7:1-30; Ganem Decl. ¶¶ 22, 34, Ex. C (Debono 1987 at Fig. 6), Ex. D (Debono 1988 at Fig. 1), Ex. E (Baltz 1997 at Fig. 1), Ex. F (Tally 2000 at Fig. 1); Ex. G (Shu 2004 at Fig. 2); Ex. H (Jeu 1998 at 1729).

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above, describes daptomycin with L-Asn. (See, e.g., JA007, ‘967 patent at 1:40-2:19; JA047, ‘238 patent at 1:58-66.) The two purity patents include this disclosure: Daptomycin is described in Baltz in Biotechnology of Antibiotics, 2nd Ed., ed. by W.R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435, hereafter “Baltz.” Daptomycin, also known as LY 146032, is a cyclic lipopeptide that can be derived from the fermentation of Streptomyces roseosporus. (See, e.g, JA047, ‘238 patent at 1:58-63 (emphasis added).) Similarly, the two method patents state: Daptomycin is described in Baltz in Biotechnology of Antibiotics, 2nd Ed., ed. by W.R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435, hereafter “Baltz.” 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 tryptophan of a cyclic 13 amino-acid peptide (see FIG 1a. Baltz et al, supra). (See, e.g, JA007, ‘967 patent at 1:39-47 (emphasis added).) The referenced “FIG 1a” in the Baltz article, reproduced to the right, shows that daptomycin has L-Asn. (JA459, Baltz 1997 at Fig. 1(a) (emphasis added).) Figure 1(a) also equates “daptomycin” with the Lilly designation “LY146032,” which as noted, is the term used in the RE ‘071 patent to describe the “formula 3 compound” when RN is n-decanoyl (a.k.a. daptomycin). (JA110, RE ’071 patent at 7:56-60.) All of the Cubist patent specifications also cite the Tally 1999 article, which again also discloses daptomycin with L-Asn. (See, e.g, JA047, ‘238 patent at 1:42-57; JA007, ‘967 patent at 1:25-35.) Like Baltz, Tally includes a Figure 1 specifically depicting daptomycin with L-Asn. (JA479, Tally 1999 at Fig. 1.) And the patents also cite the various other prior art references discussed above that make the same mistake. (See, e.g, JA047-48, ‘238 patent at 2:9-3:46.) In addition to everything else, the purity patents provide a very specific definition for

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“daptomycin,” stating: “The term ‘daptomycin’ refers to the n-decanoyl derivative of the factor A21978 C0 type antibiotic, or a pharmaceutical acceptable salt thereof. “Daptomycin” is synonymous with LY146032. See Fig. 1.” (See, e.g, JA050, ’238 patent at 7:24-27 (emphasis added).) Again, LY140632 is consistently described in the prior art as daptomycin with L-Asn. D. Cubist Finally Discovered Lilly’s Mistake In 2005. Cubist scientists, including one named Vivian Miao, finally discovered the mistaken configuration for daptomycin in 2005. (JA494, Miao at Abstract.) Certain data they collected from a genetic test made them question the L-Asn configuration. So they synthesized the molecule with both the L-Asn and D-Asn configurations and compared the two. They found not only that the Lilly inventors had been wrong all along, but there was a 10-fold difference in the potency of the two drugs. (JA507, Miao at 1520; Ganem Decl. ¶¶ 29-33.) That is, the D-Asn molecule is an order of magnitude more effective than the previously described and claimed L-Asn molecule. Though there was no reason to question the L-Asn configuration before, the inventors or anybody else could have made this same comparison any time after daptomycin’s discovery. (JA507, Miao at 1520 (citing “standard” methods known by 1989); JA453, 12/12/89 Office Action at 4; Ganem Decl. ¶¶ 26-28.) E. After Discovering the Mistake, Cubist Delisted The Re ‘071 Patent From The FDA Orange Book. In September 2007, after the Miao paper published, Cubist delisted the RE ‘071 patent from the FDA Orange Book, thus admitting that it did not cover Cubist’s own CUBICIN® brand product, which had been on the market since 2003. (Ex. 1, Cubist’s Resp. to RFA 84.) The delisting was necessary under the controlling regulations, which permit a patent to be listed for FDA-approved products only when it “claims the drug or a method of using the drug” that was the subject of the approved “new drug application,” and “with respect to which a claim of patent infringement could reasonably be asserted” against a generic equivalent. 21 C.F.R. § 314.53(b).

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Obviously, the RE ‘071 patent covering daptomycin with L-Asn did not claim, and could not be asserted against, a product containing daptomycin with D-Asn. In October 2007, Cubist purported to “correct” the RE ‘071 patent by changing L-Asn in the formula 3 compound to D-Asn where it appeared in the specification and claims. (JA362, 10/18/07 CoC Request.) But Cubist did not “correct” the numerous references throughout the specification— such as citations to Lilly’s earlier patents and publications––which made clear that the referenced compound had L-Asn. (See JA110, RE ’071 patent at 7:42-60.) After that “correction,” Cubist relisted the patent in the FDA Orange Book. (Ex. 1, Cubist’s Resp. to RFA 87.) Importantly, Cubist never attempted to “correct” the method and purity patents. In sum, at all times relevant to claim construction—the effective filing date for each patent—a skilled scientist understood, without question, that (1) the drug “daptomycin” had L-Asn and (2) the “formula 3 compound” in the RE ‘071 patent depicted, and was intended to depict, the same daptomycin structure with L-Asn that was consistently reported in the original daptomycin patent and other prior art references. ARGUMENT A. Claims Are Construed As They Would Have Been Understood By Skilled Scientists On The Effective Filing Date Of The Patent. When construing claim terms—a purely legal issue—courts “generally” give the disputed terms “their ordinary and customary meaning,” which, critically for this case, is “the meaning that the term would have to a person of ordinary skill in the art in question at the time of the invention, i.e., 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). “A claim cannot have different meanings at different times; its meaning must be interpreted as of its effective filing date.” PC Connector Solutions LLC v. SmartDisk Corp., 406 F.3d 1359, 1363 (Fed. Cir. 2005).

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The proper claim construction turns primarily on the often “dispositive” intrinsic evidence (the claim language, specification, and prosecution history). Markman v. Westview Instruments Inc., 52 F.3d 967, 970-71, 978 (Fed. Cir. 1995) (en banc). “The patent system is based on the proposition that claims cover only the invented subject matter.” Phillips, 415 F.3d at 1321. A patentee “is not entitled to a claim construction divorced from the context of the written description and prosecution history.” Nystrom v. Trex Co., 424 F.3d 1136, 1144-45 (Fed. Cir. 2005). Also critical for this case, the “intrinsic evidence” includes “prior art cited in a patent,” which here would include the Baltz and Tally references. Kumar v. Ovonic Battery Co., 351 F.3d 1364, 1368 (Fed. Cir. 2003). “‘When prior art that sheds light on the meaning of a term is cited by the patentee, it can have particular value as a guide to the proper construction of the term, because it may indicate not only the meaning of the term to persons of skill 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)); see also Chimie v. PPG Indus., 402 F.3d 1371, 1380 (Fed. Cir. 2005) (affirming reliance on patent disclosure where patentee “chose to define [claim] term . . . solely by reference to the characteristics of the prior art”). B. On The Effective Filing Dates, Both Disputed Terms Would Have Been Understood As L-Asn Daptomycin. Both disputed terms should be construed as they would have been understood at the time of filing—that is, daptomycin with L-Asn—as dictated by the specifications and the cited prior art. 1. The RE ‘071 Patent Claim Terms “Formula 3 Compound/Compound of Formula 3” Mean L-Asn Daptomycin.

The disputed claim terms in the RE ‘071 patent are “formula 3 compound” and “compound of formula 3.”

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Claim Term 
“formula 3 compound”/ ”compound of formula 3”

Hospira’s Proposal
The FORMULA 3 compound as recited in claims 18 and 26 that re-issued on April 18, 2006, i.e.,

Cubist’s Proposal
An A21978C cyclic peptide of FORMULA 3

wherein RN is n-decanoyl (i.e. LY146032)

All of the intrinsic evidence supports Hospira’s construction. Critically, the uncorrected formula 3 compound includes L-Asn (not D-Asn), and that same figure is also depicted in Lilly’s original daptomycin patent, which is cited and relied on by the RE ‘071 patent to describe the drug. (JA110, RE ’071 patent at 7:42-60 (discussing the ‘717 patent); JA201, ‘717 patent at 3:1-25.) The inventors clearly intended to define the claimed compound by referencing the original daptomycin patent, and then specifically repeated the figure from that patent as the “formula 3” compound in their specification. This intrinsic evidence cannot be controverted. In fact, the inventors re-filed the same specification, with the same formula 3 figure showing L-Asn, in March 1991, December 1991, and April 2000. (JA106, RE ‘071 patent (showing history of continuation applications.) The extrinsic evidence also supports this construction. As of the RE ‘071 patent’s priority date (June 10, 1987), a skilled scientist would have understood that the compound described and claimed was L-Asn daptomycin, not D-Asn daptomycin. Later references back this up, confirming the state of the art at the time of the application leading to the patent. (Ganem Decl. ¶¶ 22, 34, Ex. C (Debono 1987 at Fig. 6), Ex. D (Debono 1988 at Fig. 1), Ex. E (Baltz 1997 at Fig. 1), Ex. F

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(Tally 2000 at Fig. 1); Ex. G (Shu 2004 at Fig. 2); Ex. H (Jeu 1998 at 1729).) Bristol-Myers Squibb Co. v. Ben Venue Labs, Inc., 246 F.3d 1368, 1379 (Fed. Cir. 2001) (later references can show state of the art at earlier time). Indeed, the same “formula 3” structure appears in Lilly and Cubist’s own Baltz 1997 and Tally 1999 articles. (JA459, Baltz 1997 at Fig. 1(a); JA479, Tally 1999 at Fig. 1.) For its contrary interpretation, Cubist relies solely on the corrected claims and specification. It has offered nothing else in support of its proposal. This argument fails for two reasons. First, even after the correction, a skilled scientist faced with conflicting evidence would still have concluded that the claimed compound was L-Asn daptomycin, not D-Asn daptomycin. This is because a skilled scientist looking at the entire specification, and through the lens of the relevant prior art, would simply not believe that the formula 3 molecule included D-Asn. There is absolutely no teaching in the patent specification or other intrinsic evidence that a D-Asn antibiotic drug was what the inventors thought they had discovered. There was overwhelming, universally accepted evidence to the contrary, including the original daptomycin patent (made part of the intrinsic record by the inventors) and several other prior art references. (JA109-110, RE ’071 patent at 6:56-7:60 (discussing the ‘403 and ‘717 patents).) Moreover, skilled scientists would have known, as the inventors themselves acknowledged, that it would have been highly unusual to find Asn with the “D” configuration: another patent by daptomycin inventor Manuel Debono refers to the “natural configuration (L-configuration) and unnatural configuration (D-configuration).” (JA261, RE ‘311 patent at 17:39-45; Ganem Decl. ¶ 25 (same, citing Ex. I).) From its earliest filing date in 1987 and even through the issuance of the RE ‘071 patent in 2006, there is simply no intrinsic evidence to support the formula 3 compound with D-Asn. In sum, on the effective filing date, it was a scientifically accepted fact—though one proved wrong 20 years later—that LY146032/daptomycin had L-Asn. Thus, the “corrected” formula 3

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compound with D-Asn would have been considered a mistake as of the RE ‘071 patent’s effective filing date. Second, Cubist’s CoC is ineffective and, thus, the Court should be construing the original claims, not the corrected claims. A CoC may be used only to correct “a mistake of a clerical or typographical nature, or of minor character.” 35 U.S.C. § 255. If the allegedly corrected mistake is not a clerical or typographical error, then the only question to address is whether the CoC results in broader claims, because the Federal Circuit has held “that a mistake the 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) (correction held ineffective as a matter of law because changing “rear walls” to “rear wall” broadened claim). Whether a claim is “broadened through correction requires interpreting the old and new versions of that claim, and then determining whether the new version covers territory that the old one did not.” Central Admixture Pharm. Servs., Inc. v. Advanced Cardiac Solutions, P.C., 482 F.3d 1347, 1353 (Fed. Cir. 2007). Put simply, a claim is “broader in scope than the original claim[] if it contains within its scope any conceivable apparatus or process which would not have infringed the original [claim].” Tillotson, Ltd v. Walbro Corp., 831 F.2d 1033, 1037 n.2 (Fed. Cir. 1987). Whether “the corrected claims are broader than the original claims” is a “question of law, since the correct scope and meaning of a claim is an issue for the court to decide.” Central Admixture, 482 F.3d at 1353 (citing Markman, 52 F.3d at 979). Cubist does not contend, nor can it, that the description of the formula 3 compound with LAsn was a clerical or typographical mistake. (Ex. 1, Cubist’s Resp. to RFAs 1, 2.) Both the patent specification and the prior art repeatedly describe the compound that way, so it was obviously an intentional description (though it later turned out to be wrong).

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So to save the CoC here, the allegedly corrected mistake must be “of minor character,” which again is not the case if the CoC resulted in “broader” claims. That legal issue boils down to a simple inquiry: Is there any product that would infringe claims directed to D-Asn daptomycin that would not infringe original claims to L-Asn daptomycin? Of course there is. D-Asn daptomycin would not have infringed the original “formula 3 compound” claims, but would infringe the corrected claims (assuming any other claim limitations claims are met). Cubist’s and Hospira’s products are real world examples, because both contain D-Asn daptomycin. Before the CoC, when the “formula 3 compound” was directed to L-Asn daptomycin, a commercial product with D-Asn daptomycin was not covered by the claims, as Cubist admitted when delisting the RE ‘071 patent from the FDA’s Orange Book for its own D-Asn daptomycin commercial product. Case law from the Federal Circuit is directly on point. In Central Admixture Pharmacy Services, Inc. v. Advanced Cardiac Solutions, P.C., 482 F.3d 1347 (Fed. Cir. 2007), the patentee obtained a CoC replacing all references to the term “osmolarity” with the term “osmolality,” a term that was “related but subtly different in meaning.” Id. at 1350. Both referred to the concentration of solute in a solvent, but one measured the amount of solute per liter, while the other measured per kilogram. Id. As a result, the “corrected” claims covered different ranges of concentrations, and some products that would not have infringed the original claims might have infringed the corrected claims. Id. at 1350-51. The Federal Circuit invalidated the CoC as a matter of law, stating that “[c]laims mean precisely what they say,” and that “[s]ince the error corrected . . . was not clearly evident to one of skill in the art and the result of its correction was to broaden the claims,” the patent “continue[d] to read as it did prior to the issuance of the certificate.” Id. at 1355. The same is true here: the L-Asn “error” was not evident; it was intentional, and skilled scientists accepted the L-Asn configuration as correct. And the correction plainly resulted in broader claims. As in

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Central Admixture, the CoC is invalid. See also Adv. Tech. Incubator, Inc. v. Sharp Corp., No. 2:07-CV-468, 2009 WL 4670942 (E.D. Tex. Sept. 18, 2009) (change from “the opening” to “an opening” broadened claim and thus invalidated CoC). Bayer Cropscience, AG v. Dow Agrosciences LLC, Civ. No. 10-1045 RMB/JS, 2012 WL 4498527 (D. Del. Sep. 27, 2012), is factually on point, and demonstrates that even the Court— which has limited “correction authority” to fix “certain obvious errors in the patent” (Novo Indus., L.P. v. Micro Molds Corp., 350 F.3d 1348, 1355) (Fed. Cir. 2003))—cannot correct Cubist’s scientific mistake to save the RE ‘071 (or the method or purity) patent claims. The inventors in Bayer, when filing their application, mistakenly believed that the enzyme of their invention was a monooxygenase. As here, “[c]onsistent with that mistaken belief,” the patent “repeatedly describe[d] [the claimed enzyme] as a monooxygenase.” Id. at *2. A few years later, scientists discovered that the claimed molecule was actually a dioxygenase, not a monooxygenase. The inventors sought a broad construction that would cover the dioxygenase in the defendant’s product. But the Bayer court rejected that construction, stating: “In the final analysis, even though the inventors erroneously believed that [the claimed molecule] was a monooxygenase, the Court should construe the claim ‘as written, not as the patentee[] wish[ed] [it] had written it.” Bayer, 2012 WL 4498527, at *7 (quoting Chef Am., Inc. v. Lamb-Weston, Inc., 358 F.3d 1371, 1374 (Fed. Cir. 2004)). The type of scientific mistake the Lilly and Cubist inventors made here simply is not amenable to correction, by CoC or through claim construction. Based on the uncontroverted intrinsic record, even the corrected claims of the RE ‘071 patent would not have been understood as covering D-Asn daptomycin as of the 1987 effective filing date. But given the controlling case law, the Court should hold the CoC invalid and proceed

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to construe the uncorrected claims, which must be read to mean L-Asn daptomycin.2 2. “Daptomycin” Should Be Construed as Described in the Prior Art Expressly Referenced in the Patent Specifications Of The Method And Purity Patents.

The term “daptomycin” is used in each of the asserted claims of both the method patents (‘967 and ‘689 patents) and the purity patents (‘238 and ‘342 patents). The specifications of all four patents expressly describe “daptomycin” by reference to the same prior art (the Baltz and Tally articles). While the parties’ dispute centers around the meaning of “daptomycin,” they agree that “daptomycin” should be construed consistently for all of the asserted claims in all of the patents. Claim Term 
“daptomycin”

Hospira’s Proposal
The compound described in the Baltz article at Fig. 1a (Biotechnology of Antibiotics, 2nd Ed., ed. by Strohl, 415-435 (1997)) and in the Tally article at Fig. 1 (Exp. Opin. Invest. Drugs, 8:1223-1238 (1999)), i.e.,

Cubist’s Proposal
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, i.e.,

(LY146032) or a pharmaceutically acceptable salt thereof

Cubist objected to addressing this CoC issue during Markman proceedings. But delaying the resolution of this issue would be utterly wasteful. First, deciding whether the CoC is valid is a critical threshold issue to proper claim construction, because the Court needs to resolve that issue before determining whether the original or corrected claims control. Second, as already explained, the CoC question is a pure matter of law—specifically, of claim construction—turning on whether the corrected claim is “broader” than the original claim, and that legal question turns entirely on the intrinsic record just like Markman issues. Third, the Court has to address the same issue anyway— that is, how a skilled scientist would construe the claims before the “unexpected” 2005 discovery of the mistaken configuration—as part of the “pure” claim construction issue presented by the remaining four, uncorrected patents. See infra Section B.2. Importantly, Hospira is not presently seeking summary judgment of non-infringement or invalidity of any of the asserted patents.

2

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As with the dispute regarding “the formula 3 compound” in the RE ‘071 patent claims, the key difference here between the parties’ proposed constructions relates to the L-Asn vs. D-Asn structure of the claimed molecule. Hospira’s proposal addresses this explicitly by showing the LAsn stereochemical structure of the drug, while Cubist’s interpretation is silent on the issue but instead adds a process limitation relating to how the drug is allegedly created (“derived from the fermentation of Streptomyces roseosporus”). a. The intrinsic record requires that “daptomycin” be construed as having L-Asn.

The inventors of both the method and purity patents clearly intended that their citations to, and detailed descriptions of, the prior art—specifically the Baltz and Tally articles—define “daptomycin.” For instance, they state that “Daptomycin is described in Baltz” (which describes LAsn daptomycin), that daptomycin is depicted in “FIG 1a. Baltz” (which likewise depicts the LAsn daptomycin), and that “’Daptomycin’ is synonymous with LY146032.” (which was always described and depicted with L-Asn). (See, e.g, JA047, ‘238 patent at 1:58-63; JA007, ‘967 patent at 1:39-47 (emphasis added).) These references “have particular value as a guide to the proper construction of the term, because [they] may indicate not only the meaning of the term to persons skilled in the art, but also [demonstrate] that the patentee[s] intended to adopt that meaning.” Kumar, 351 F.3d at 1368 (adopting definition of “amorphous” in cited prior art patent even where it was at odds with dictionary definition). Importantly, the method and purity patents have two different, nonoverlapping sets of inventors and, yet, they both cited the Baltz and Tally articles to define and describe “daptomycin.” This leaves the Court with a simple application of the law. Under the law, “daptomycin” must be construed as it would have been understood by a skilled scientist at the time the patent

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applications were filed. Phillips, 415 F.3d at 1312-13. And at that time—September 1999 for the method patents and November 2000 for the purity patents—the specifications and all the cited prior art consistently described daptomycin with L-Asn. A skilled scientist would have no reason to doubt that configuration, and it was not until 2005 that Cubist first discovered that daptomycin actually had D-Asn. Accordingly, the Court should adopt Hospira’s construction. b. Cubist’s proposed construction seeks to impermissibly read a process limitation into the claims.

Faced with such inescapable evidence from the intrinsic record, Cubist’s proposal seeks to import a limitation into the claims—that “daptomycin” be obtained by a particular process that would inherently produce D-Asn daptomycin—in order to have the claims cover the D-Asn rather than L-Asn drug. Specifically, Cubist proposes reading into each of the claims a specific process limitation requiring that the drug be “derived from the fermentation of Streptomyces roseosporus.” This argument fails for several independent reasons. First, “extrinsic sources like expert testimony cannot overcome more persuasive intrinsic evidence.” Kara Tech. Inc. v. Stamps.com Inc., 582 F.3d 1341, 1348 (Fed. Cir. 2009); accord 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”) (citing Kara Tech. Inc., 582 F.3d at 1348). Here, the intrinsic evidence from patents’ specification states that “Daptomycin . . . can be”—not “is”—“derived from the fermentation of Streptomyces roseosporus.” (See, e.g, JA007, ‘967 patent at 1:39-47.) And the intrinsic evidence also teaches, expressly, that the result of that process is L-Asn—confirmed, for instance, by the very next line of the method patents stating that the resulting daptomycin is depicted in “FIG 1a. Baltz” showing the L-Asn daptomycin. That definitive intrinsic evidence cannot be trumped by extrinsic evidence in the form of private experiments done by scientists years after the invention.

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Second, Cubist is trying to add a process limitation mentioned nowhere in the claims, which do not expressly or implicitly reference how the claimed daptomycin is created. “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); accord Lucent Tech., Inc. v. Gateway, Inc., 525 F.3d 1200, 1215 (Fed. Cir. 2008) (“[C]ourts may not redraft claims to cure a drafting error made by the patentee, whether to make them operable or to sustain their validity”; rather, claims must be construed “as the patentee drafted them.”); see also Bayer, 2012 WL 4498527, at *5 (rejecting attempt to import functional limitation into claims as an “alternate definition” to plain meaning of “monooxygenase” in order to cover dioxygenase molecules). Third, the ordinary meaning of the claims cover “daptomycin” made by any method, not just by the “fermentation” process. And there is no legal basis to limit the claim scope to daptomycin made only by the “fermentation” process and not by any other method, such as chemical synthesis, which could be used to produce L-Asn daptomycin. (See JA453, 12/12/89 Office Action at 4; Ganem Decl. ¶¶ 26-28.) To be viable, any such alleged limitation would have to be “clear and unmistakable.” Cordis Corp. v. Boston Scientific Corp., 561 F.3d 1319, 1329 (Fed. Cir. 2009). Disavowal of claim scope requires evidence of “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)).

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There is no such evidence here. Cubists’ inventors did not clearly and unmistakably disavow coverage over daptomycin made by any process other than “fermentation.” On the contrary, the specification merely recites “fermentation” as one way the drug “can be” made without remotely disclaiming other ways. This is clear from a comparison of Cubist’s proposed construction to the actual disclosure in the specifications, where Cubist selectively edits out the words “can be:” Cubists’ Proposed Construction
The cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus, comprised of a decanoyl side chain linked to the Nterminal tryptophan of a cyclic 13 amino acid peptide

Disclosure in Patent Specification3
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 selective editing of “can be” is fatal to its proposed construction. See Monsanto Co. v. Bayer Bioscience N.V., 363 F.3d 1235, 1245-47 (Fed. Cir. 2004) (holding that court incorrectly construed claimed chemical compound as being derived from a particular bacterial source, even though the specification said the compound “could be produced” using that source). Finally, the doctrine of claim differentiation further supports Hospira’s proposed construction. That doctrine is “based on the common sense notion that different words or phrases used in separate claims are presumed to indicate that the claims have different meanings and scope.” Karlin Tech., Inc. v. Surgical Dynamics, Inc., 177 F.3d 968, 971-72 (Fed. Cir. 1999); see also 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, unasserted claims 66 and 191 of the ‘238 purity patent expressly require the process step of “fermenting Streptomyces roseosporus… to produce daptomycin.” (JA067, JA071, ‘238 patent at claims 66, 191.) Thus, where the inventors wanted to limit their invention by requiring that daptomycin be made from the fermentation process, they did so. They did not do so for the

3

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

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asserted claims, which makes it doubly clear that the term “daptomycin” means daptomycin made by any process. CONCLUSION For these reasons, Hospira respectfully requests that the Court reject Cubist’s attempt to rewrite history, and instead construe the two disputed claim terms, consistent with all of the intrinsic evidence, as proposed by Hospira. Dated: February 15, 2013 HOSPIRA, INC. By: /s/ John C. Phillips, Jr. 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

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 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

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CERTIFICATE OF SERVICE I, Megan C. Haney, hereby certify that on February 15, 2013, I caused true and correct copies of the foregoing HOSPIRA’S OPENING 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)

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