## United States Court of Appeals for the Federal Circuit

06-1613

SANOFI-SYNTHELABO, SANOFI-SYNTHELABO, INC., and BRISTOL-MYERS SQUIBB SANOF I PHARMACEUTICALS HOLDING PARTNERSHIP, Plaintiffs-Appellees,

v.

APOTEX, INC. and APOTEX CORP., Defendants-Appellants.

Evan R. Chesler , Cravath, Swaine & Moore, LLP, of New York, New York, argued for plaintiffs-appellees. With him on the brief were Richard J. Stark and David Greenwald . Of counsel on the brief were Robert L. Baechtold , John D. Murnane , and William E. Solander , Fitzpatrick, Cella, Harper & Scinto, of New York, New York. Bruce J. Chasan , Caesar, Rivise, Bernstein, Cohen & Pokotilow, Ltd., of Philadelphia, Pennsylvania, argued for defendants-appellants. With him on the brief were Robert S. Silver , Manny D. Pokotilow , Mona Gupta , and Lynn M. Terrebonne

. Anthony F. Lo Cicero , Amster, Rothstein & Ebenste in LLP, of New York, New York, for amicus curiae, Generic Pharmaceutic al Association. With him on the brief was Richard S. Mandaro

. David H. Weinstein , Weinstein Kitchenoff & Asher LLC, of Philadelphia, Pennsylvania, for amicus curiae, Medco Health Solutions, Inc. Jeffrey Light , Patients Not Patents, Inc., of Wa shington, DC, for amicus curiae, Patients Not Patents, Inc. Appealed from: United States District Cour t for the Southern District of New York Judge Sidney H. Stein

## United States Court of Appeals for the Federal Circuit

06-1613 SANOFI-SYNTHELABO, SANOFI-SYNTHELABO, INC. and BRISTOL-MYERS SQUIBB SANOFI PHARMACEUTICALS HOLDING PARTNERSHIP, Plaintiffs-Appellees,

v. APOTEX, INC. and APOTEX CORP., Defendants-Appellants.

_____________________ DECIDED: December 8, 2006

_____________________

Before LOURIE, Circuit Judge , CLEVENGER, Senior Circuit Judge , and BRYSON, Circuit Judge

. LOURIE, Circuit Judge

. Apotex, Inc. and Apotex Corp. (collectiv ely referred to as “Apotex”) appeal from the decision of the United Stat es District Court for the Southern District of New York granting a preliminary injunc tion in favor of Sanofi-Synt helabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb (“BMS”) Sanofi P harmaceuticals Holding Partnership (collectively referred to as “Sanofi”). Becaus e we conclude that the district court did not abuse its discretion in granting the pr eliminary injunction, we affirm.BACKGROUND Sanofi markets Plavix ® , a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and st rokes. The active ingredient in Plavix ® is clopidogrel bisulfate, which is covered by Sanofi’s patent, U.S. Patent 4,847,265 (“the ’265 patent”), which will expire on November 17, 2011. To understand the issues presented in th is appeal, it is necessary to have a generalized understanding of stereoc hemistry. Stereochemistr y refers to the threedimensional spatial arrangement of a molecule’s constituent atoms. Molecules that have the same chemical substi tuents, but different spatial arrangements, are referred to as stereoisomers. If they contain an asy mmetrical carbon atom, they exist as nonsuperimposable mirror images of each other and are referred to as enantiomers. Enantiomers are optically active because t hey are capable of rotating plane-polarized light; enantiomers that rotate polarized light to the right are referred to as dextrorotatory enantiomers, or d-enantiomers; enantiomers ro tating polarized light to the left are referred to as levorotatory enantiomers, or l-enantiomers. 1 A mixture of equal amounts of both types of enantiomers is referred to as a racemic mixture, or racemate, and it exhibits no optical activity. Clopidogrel is the dextrorotat ory enantiomer of the free base methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)th ienopyridyl)-(2-chlorophenyl) acetate, which the parties refer to as “MATTPCA.” The active ingredient in Plavix ® is the bisulfate salt of the d-enantiomer of MATTPCA, which is spec ifically recited in claim 3 of the ’265 patent.

1 Other nomenclature conventions are used to signify dextrorotatory and levorotatory enantiomers. For example, the pr efixes (R-) or (+) re fer to d-enantiomers, and (L-) or (-) refer to l-enantiomers.

06-1613 2In November 2001, Apotex filed an A bbreviated New Drug Application (“ANDA”) pursuant to the Hatch-Waxman Act seeki ng U.S. Food and Drug Administration (“FDA”) approval to manufacture and sell a generic versi on of clopidogrel bisulf ate. Apotex filed a Paragraph IV certification with its ANDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), asserting that the ’265 patent is invalid. In response, Sanofi sued Apotex on March 21, 2002, claiming that the filing of the A NDA infringed the ’265 patent. Apotex counterclaimed, asserting t hat the patent is invalid and unenforceable. A thirty-month stay of FDA approval for the A NDA was triggered when the suit was filed in the district court, pursuant to 21 U.S.C. § 355(j)(5)(B)(iii) . The stay expired May 17, 2005, and on January 20, 2006, the FDA approved the ANDA. Several days before the ANDA was approved, Sanofi and Apotex began settlement negotiations in an effort to resolv e the litigation. On March 17, 2006, the parties reached a first settlem ent agreement that was subjec t to the approval of the Federal Trade Commission and a consortium of state attorneys general pursuant to an order issued in another litigation involving BMS. In May 2006, the state attorneys general notified the parties t hat they would not approve t he settlement. The parties negotiated a second agreement (“the May agreem ent”). The May agreement included provisions specifying, inter alia , actions that could be taken by the parties in the event that the settlement failed to receive regul atory approval. In Ju ly 2006, the state attorneys general again informed the parties t hat they would not approve the settlement. Apotex then declared “regulatory denial” on July 31, 2006, as permitted under the settlement agreement, which meant, inter alia , “a denial of approval by either the FTC or

06-1613 3a state attorney general as to which neither party seeks further review.” Under the agreement, litigation would resume in the event of “regulatory denial.” Pursuant to the aforementioned agreem ent, Apotex launched its generic clopidogrel bisulfate product on August 8, 2006. In accordance with the provisions in the settlement agreement, Sanofi not ified Apotex of its intent to move for a preliminary injunction in the time fram e permitted by the agreement, viz. , five business days after the generic launch. 2 Sanofi filed its motion for a pr eliminary injunction on August 15, 2006, and requested a recall of Apotex’s products that were already distributed. After a two-day evidentiary hearing, the district cour t granted the motion for injunctive relief on August 31, 2006, but denied the request for re call. During the period between the generic launch and the entry of the preliminary injunction, Apotex shipped a six-month supply of its product to distri butors in the United States. In reaching its decision, the district c ourt applied the established four-factor test for preliminary injunctive relief, and found t hat the factors weighed in favor of an injunction. Regarding the likelihood of su ccess on the merits, the court noted that Apotex conceded that its accused products in fringe claim 3 of the ’265 patent. The court then found that Apotex failed to establis h a likelihood of proving invalidity at trial— rejecting its anticipation, obviousness, and obviousness-type double patenting invalidity defenses. The court also dete rmined that Apotex failed to raise a substantial question as to whether the ’265 patent is unenforceabl e due to inequitable conduct. Additionally, the court found that the rema ining three factors of the test favored issuance of a

2 Sanofi moved for a temporary restrain ing order (“TRO”) prior to that date, but the request was denied in light of Sanofi’s agreement not to seek a TRO before the expiration of the five-day period. Sanofi-Synthelabo v. Apotex , No. 02-2255, slip op. at 10 (S.D.N.Y. Aug. 31, 2006).

06-1613 4preliminary injunction. As for Apotex’s other defenses, the cour t concluded that the doctrine of laches was inapp licable, and it rejected Apotex’s unclean hands defense. The court set bond in the am ount of $400 million. Trial is scheduled to commence on January 22, 2007. Apotex moved for a stay of the injunc tion, which we denied on September 21, 2006, and it filed its appeal from t he district court’s grant of the preliminary injunction. An expedited briefing schedule was set, and oral argument was heard on October 31, 2006. We have jurisdiction pursuant to 28 U.S. C. § 1292(c) in view of §§ 1292(a) and 1295(a)(1). DISCUSSION A decision to grant or deny a preliminary injunction pursuant to 35 U.S.C. § 283 is within the sound discret ion of the district court, and we review such a decision for an abuse of discretion. Amazon.com, Inc. v. Barnesandnoble.com, Inc. , 239 F.3d 1343, 1350 (Fed. Cir. 2001). Thus, a decision gr anting a preliminary injunction will be overturned on appeal only if it is establis hed “that the court made a clear error of judgment in weighing relevant factors or exercised its discretion based upon an error of law or clearly erroneous factual findings.” Genentech, Inc. v. Novo Nordisk A/S , 108 F.3d 1361, 1364 (Fed. Cir. 1997). To the extent the court’s decision is based upon an issue of law, we review that issue de novo

. Tate Access Floors, Inc. v. Interface Architectural Res., Inc. , 279 F.3d 1357, 1364 (Fed. Cir. 2002). Sanofi, as the moving party, may be entitl ed to a preliminary injunction if it establishes four factors: “(1) a reasonable likelihood of its success on the merits; (2) irreparable harm if an injunction is not granted; (3) a balance of hardships tipping in its

06-1613 5favor; and (4) the injunction’s . . . impact on the public interest.” Amazon.com , 239 F.3d at 1350. A. Likelihood of Success on the Merits In order to satisfy the first element of the test, Sanofi must demonstrate that, “in light of the presumptions and burdens that will inhere at trial on the merits,” Amazon.com , 239 F.3d at 1350, Sanofi will likely prove that Apotex ’s product infringes the ’265 patent and that it will withstand Apotex’s chall enges to the validity and enforceability of the ’265 patent. Because A potex stipulated to in fringement, only the second inquiry is at issue in this case. Thus, the first element was properly found satisfied if Apotex failed to raise a “subst antial question” with regar d to the validity or enforceability of the ’265 pat ent—or, if it succeeded in doing so, Sanofi demonstrated that those defenses “lack substantial merit.” Genentech , 108 F.3d at 1364. On appeal, Apotex challenges the district court’s rulings with respect to anticipation, obviousness, obviousness-type double patenting, and enforceability. 1. Validity of the ’265 Patent

a. Anticipation We first consider whether t he district court clearly err ed in its determination that Sanofi will likely withstand Apotex’s challenge to the validity of the ’265 patent based on anticipation. Apotex assert ed that U.S. Patent 4,529,596 (“the ’596 patent”) anticipates claim 3 of the ’265 patent. The district court rejected Apotex’s argument on two grounds. First, the court found that the ’596 patent does not describe clopidogrel bisulfate. Second, the c ourt determined that the ’596 pat ent does not enable a person of ordinary skill in the art to make clopi dogrel bisulfate without undue experimentation.

06-1613 6On appeal, Apotex argues that the district court erred by improperly focusing its anticipation analysis on claim 1 of the ’ 596 patent, which claims a broad genus of compounds, and by failing to consider clai m 2, which claims the free base of clopidogrel, MATTPCA. Accordi ng to Apotex, claim 2 descri bes clopidogrel bisulfate and thus anticipates clai m 3 of the ’265 patent. 3 Apotex advances two main arguments in support of this position. First, Apotex ar gues that a person of or dinary skill in the art would interpret claim 2 of t he ’596 patent in light of t he specification as not only disclosing the racemate free base, but al so the dextrorotatory and levorotatory enantiomers, as well as pharmaceutically acc eptable salts, including the bisulfate. Second, Apotex contends that the district court erred by failing to address controlling precedent, specifically In re Petering , 301 F.2d 676 (C.C.P.A. 1962), and In re Schaumann , 572 F.2d 312 (C.C.P.A. 1978), which relate to genus/species anticipation. According to Apotex, those cases establish that the genus disclosed in claim 2 of the ’596 patent is a small class to which clopi dogrel bisulfate belongs, which describes all members of that class. Sanofi responds that the district cour t correctly concluded that Apotex’s anticipation challenge lacks substantial meri t. Sanofi contends that Apotex engages in an impermissible, hindsight-driven, “dissect ion and recombination” analysis of the ’596 specification in arguing that a person of ordinary skill in the ar t would interpret the claim, which only recites the racemate free base, as disclosing the bisulfate salt of the d-

3 In this appeal, we are faced with the unusual situation of an anticipating disclosure being argued to be a claim, rather than other descriptive material in a specification. No doubt appe llants argued what they consi dered to be their strongest case.

06-1613 7enantiomer. Sanofi further argues that the district court di d not abuse its discretion in not addressing Petering because it does not apply in this case. As a preliminary matter, we note that the ’596 patent was bef ore the Examiner during prosecution, which make s Apotex’s burden of proving in validity at trial “especially difficult.” Glaxo Group Ltd. v. Apotex, Inc., 376 F.3d 1339, 1348 (Fed. Cir. 2004). Thus, in light of the defer ential standard we apply in reviewing grants or denials of preliminary injunctions, and mindful that “a patent is presumed valid, and th is presumption exists at every stage of the litigation,” Canon Computer Sys., Inc. v. Nu-Kote Int’l., Inc. , 134 F.3d 1085, 1088 (Fed. Cir. 1998), we conclude that the district court did not clearly err in finding that Apotex’s anticipati on defense lacks substantial merit. 4 A determination that a patent is invalid as being anticipated under 35 U.S.C. § 102 requires a finding that “each and every limitation is found ei ther expressly or inherently in a single prior art reference.” Celeritas Techs. Ltd. v. Rockwell Int'l Corp. , 150 F.3d 1354, 1361 (Fed. Cir. 1998). Claim 3 of the ’265 patent reads as follows: 3. Hydrogen sulfate of the dextr o-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thienopyridyl) (2- chlorophenyl) - acetate subst antially separated from the levo-rotatory isomer. ’265 patent col.12 ll.37-40. Thus, the claim cons ists of the following key limitations: 1) the d-enantiomer; 2) of the compound MATTP CA; 3) the bisulfate salt; and 4) substantial separation from the levorotatory isomer.

4 In its moving brief and as counsel clarified at oral argument, Apotex’s anticipation argument on appeal is solely prem ised on claim 2 of the ’596 patent. Thus, we limit our discussion to the narrow issue whet her there is substantial merit to Apotex’s assertion that claim 3 of t he ’265 patent is unpatentable in vi ew of claim 2 of the ’596 patent.

06-1613 8Claim 2 of the ’596 patent, in contrast, reads as follows: 2. Methyl α -(4,5,6,7-tetrahydro-th ieno(3,2-c)-5-pyridyl)- o.chlorophenyl-acetate. 5 ’596 patent, col.13, ll.20-21. Thus, the plai n language of claim 2 only recites the free base, MATTPCA, and does not expressly descri be the dextrorotatory or levorotatory enantiomers or any salt. Because claim 2 fa ils to describe each and every limitation of claim 3 on its face, claim 2 does not anticipate claim 3. Apotex argues that the two missing limitations, viz. , the d-enantiomer and the bisulfate salt, are inherently disclosed in the claim. With regard to the bisulfate salt limitation, Apotex seeks to import into the scope of claim 2 a statement in the specification that the invent ion includes “addition salts with pharmaceutically acceptable mineral or organic acids.” Id. , col.1 ll.42-43. Apotex furt her argues that the ’596 patent discloses a preference for bisulfate salt. The district court, however, considered that argument and rejected it. After careful consideration of the record before it, the court f ound that a person of ordinary skill in the art would not be led to the bisulfate salt for several reasons. Based on the testimony of Sanofi’s expert, Dr. Byrn, the c ourt noted that a chemist would actually be dissuaded from preparing the bisulf ate salt in light of Exam ple 1, which describes the hydrochloride salt of the racemate, bec ause a chemist would believe that the hydrochloride, as opposed to t he bisulfate, is the preferr ed salt for clopidogrel. The

5 The parties do not dispute that “methyl α -(4,5,6,7-tetrahydro-thieno(3,2-c)-5- pyridyl)-o.chlorophenyl-acetate” recited in claim 2 of the ’596 patent is the same compound as “methyl alpha-5 (4,5,6,7-tetrahy dro (3,2-c) thienopyridyl) (2-chlorophenyl)- acetate” recited in claim 3 of the ’265 paten t. Both names, although slightly different in form, refer to the same free base, MATTPCA. The punctuation of th e names is as it appears in the particular patents.

06-1613 9court also credited Dr. Byrn’s additional testimony that salt formation with a new compound is an “unpredictable exercise.” In addition, the court not ed that a chemist theoretically had at least fifty different pharma ceutically acceptable salts from which he could have chosen for formulation. Based on that evidence, the court found that “disclosing bisulfate in the ’596 patent was in sufficient to disclose a single enantiomer of a compound as a bisulfate salt.” Sanofi-Synthelabo , slip op. at 26. Because we find that the district court did not clearly err in its fact-finding as to this issue, we reject Apotex’s argument that claim 2 of the ’596 pat ent inherently discloses the bisulfate salt. 6 Apotex argues that the holding in In re May , 574 F.2d 1082 (C.C.P.A 1978), specifically with respect to claim 6—a cl aim that the Court of Customs and Patent Appeals found anticipated by prior art—mandates a finding of antici pation here. That case, however, is distinguis hable from this case. In May , our predecessor court held that claim 6, which claimed the hydrochloride salt of a class of compounds, or genus, was anticipated by a prior art pat ent that expressly disclosed the hydrobromide salt of a species included within the genus. The appellant argued that the prio r art patent did not anticipate the hydrochloride bec ause it did not “specifically describe” it. The court disagreed in light of a statem ent in the specification that the compounds of the genus were “preferably administered in the form of their salts, ‘the hydrobromide and hydrochloride salts being especially suitable.’” Id. at 1090 (emphases added). The court found that that st atement “coupled with the ex press disclosure of the

6 Apotex cites In re Adamson , 275 F.2d 952, 954 (C.C.P.A. 1960), for the proposition that the disclos ure of a racemic compound inherently discloses its enantiomers. Thus, Apotex argues that t he d-enantiomer of MATTPCA is inherently disclosed by claim 2. Because we conclude that the district court did not err in finding that the bisulfate salt limitation is not disclosed in t he claim, and thus cannot anticipate claim 3, we need not address this contention.

06-1613 10hydrobromide salt of the [species compound]” constituted an anticipation of claim 6. Id. Here, however, there is no clear statement in the specification that the bisulfate salt is “especially suitable” for administering co mpounds of the genus including clopidogrel. On the contrary, as discussed above, the spec ification of the ’596 patent discloses a number of potentially acceptabl e salts and discloses the racemate of clopidogrel in Example 1 only as a hydrochloride salt. T hus, we find the facts in the present case distinguishable from those in May

. Further, we are not persuaded by Apotex ’s argument that the holdings of In re Petering and In re Schaumann warrant reversal of the district court’s decision. In Petering , the Court of Customs and Patent Appeals upheld the board’s § 102(b) anticipation rejection of a claim that cover ed specific chemical co mpounds in light of a prior art patent that disclosed a class of compounds of which those specific compounds were members. 301 F.2d at 682. In reachi ng its conclusion, the court noted that, while the generic formula in Petering was quite broad, “specific pr eferences” were described. Based on those disclosed preferences, t he court found that the narrowed generic formula essentially disclosed a limited cla ss of approximately twenty compounds. Each was held to have been disclosed by the genus. Similarly, in Schaumann , the Court of Customs and Patent Appeals affirmed the rejection of claims that covered a specif ic compound and certain compatible salts in light of a prior art patent t hat disclosed a generic formula with a single variable. The court found that the prior art patent disclos ed a limited class of compounds based on a disclosed preference for that variable subs tituent. The court concluded that the

06-1613 11compound in the rejected claim fell within t he scope of that limit ed class of compounds, and thus was anticipated by the prior art patent. Here, however, we do not find that the ’596 patent discloses a “pattern of preferences” akin to the disclosures in Petering and Schaumann that would limit the generic formula of MATTPCA in claim 2 of the ’596 patent to a narrow class of compounds that includes clopidogrel bisulfate. The principal, obvious distinction is that the generic formula of claim 2 does not include a salt. On this basis alone, we find that clopidogrel bisulfate is not a species of any genus comprised by claim 2 of the ’596 patent. In addition, our predecessor court found a “pattern of preferences” in Petering and Schaumann . In this case, however, there is no such clear “pattern of preferences” that serves to narrow the genus in claim 2 to a narrow class that includes clopidogrel bisulfate. Even had claim 2 included sa lts generically, there was no expressed preference for clopidogrel bisulfate. The ’ 596 patent specification discloses twenty-one exemplary compounds that are thienopyridi nes—not just MATTPCA. The examples describe hydrochloride salts, hydrobromide salts, a sodium salt, an oxalate, and a free base, as well as bisulfates, not showing a pr eference for bisulfates. Thus, we find this case distinguishable from Petering and Schaumann on that additional basis, viz. , that the ’596 patent does not point to bisulfates as preferred salts for clopidogrel. We therefore reject Apotex’s assertion t hat clopidogrel bisulfate is a species of the genus in claim 2 of the ’596 patent, and that the district court cl early erred by failing to so find. In light of this holding, we need not address the enablement issue. Accordingly, we conclude that the district court did not clearly err in finding no

06-1613 12substantial merit to Apotex’s assertion that claim 3 of the ’265 paten t is anticipated by the ’596 patent. 7
b. Obviousness We next consider Apotex’s a ssertion that claim 3 of the ’265 patent is invalid as obvious. Apotex argues that the district c ourt erred in concluding that its obviousness defense failed to raise a substantial question with regard to the va lidity of the ’265 patent. Apotex primarily argues that it would have been obvi ous to a person of ordinary skill in the art to prepare clopi dogrel bisulfate based on the di sclosure of the ’596 patent. Additionally, Apotex asserts that the “unexpected results” upon which Sanofi relied to establish the nonobviousness of clopidogrel bisu lfate were not “unexpected” to a person of ordinary skill in the art. Moreover, Apotex contends that the cour t erred by failing to cite Adamson in its obviousness analysis—a case t hat, according to Apotex, stands for the proposition that enantiomers are prima facie obvious over disclosures of their
racemates. Sanofi responds that the district court co rrectly concluded that it would not have been obvious to prepare clopidogrel bisulfate in view of the ’596 patent, particularly in light of the effort Sanofi actually had to expend in developing clopidogrel bisulfate, including the four years and millions of dollars that were allocated to the development of the racemate before efforts were redirected toward isolating the d-enantiomer. Sanofi

7 To the extent that A potex argues that portions of the ’596 patent other than claim 2 anticipate clopidogrel bisu lfate, we reject that argum ent. Although several of the examples in the ’596 patent ar e salts of esters, the specification does not identify as a class esters in salt form. This case is therefore unlike Petering , in which the prior art reference named a class, exam ples of which were then taken as expressing preferred species of that class. Similarly, because no class-wide salt pref erences are disclosed, May does not support a finding of anticipation.

06-1613 13further argues that any prim a facie obviousness resulting from the disclosure of the racemate in the prior art was rebutted by the unexpected properties of clopidogrel bisulfate—specifically, high pharmacological activity and low toxicity—two properties that are not necessarily generally associated with one enantiomer. We agree with Sanofi that the court did not clearly err in finding that Apotex failed to raise a substantial question in its obvious ness defense. First, we reject Apotex’s contention that it would hav e been obvious to a person of ordinary skill in the art to prepare clopidogrel bisulfate bas ed on the disclosures of the ’596 patent. The district court rejected that position after consi dering extensive argument, testimony, and references presented by both parties. In reac hing that determination, the district court noted that there was “nothi ng obvious about arriving at clopidogrel bisulfate by separating the enantiomers of [MATTP CA] and preparing t he dextrorotatory [enantiomer] as a bisulfate salt.” Sanofi-Synthelabo , slip op. at 31-32. The court determined that nothing existed in the pr ior art that would make pursuing the enantiomer of MATTPCA an obvious choice, particu larly in light of t he unpredictability of the pharmaceutical properties of the enantio mers and the potential for enantiomers to racemize in the body. The court also found that the extensive time and money Sanofi spent developing the racemate before redirecting its e fforts toward the enantiomer, and the unpredictability of salt formation, were indica tors of nonobviousness. The court credited the testimony of Apotex’s own expert, Dr. McClelland, who agreed that salt formation was an unpredictable exerci se that would require a chemist “to engage in experimentation to determine which salt would in fact be suitable.” Id. at 33. The court

06-1613 14also noted that a named inventor, Dr. Bador c, tested twenty different salts before discovering that bisulfate had the most desirabl e properties. Thus, the court found that it would not have been obvious to a person of ordinary skill in the art to prepare clopidogrel bisulfate from reading the ’596 patent in light of the extensive experimentation that was required to arrive at that particular compound. We discern no clear error with respect to those factual det erminations or the legal conclusion. We also reject Apotex’s assertion that a person of ordinary sk ill in the art would have been led to the active enantiomer of MATTPCA after reading the ’596 patent. Apotex merely asserts that one would hav e been motivated “because the patent directs [a person of ordinary skill in the art] to enantiomers and pharmaceutical salts.” We have noted that it is insufficient to merely identif y each element in the pr ior art to establish unpatentability of the combined s ubject matter as a whole. Abbott Labs. v. Andrx Pharm., Inc. , 452 F.3d 1331, 1336 (Fed. Cir. 2006). Inst ead, “a party alleging invalidity due to obviousness must articulate the reas ons one of ordinary sk ill in the art would have been motivated to select the referenc es and to combine them to render the claimed invention obvious.” Id. Apotex’s conclusory assertion that the ’596 patent directs a chemist to the enantiomers and salts is insufficient to satisfy this requirement. Certainly nothing directed a chemist to t he particular enantiomer and salt, clopidogrel bisulfate, which is the limited subject matter of claim 3. Second, while Apotex disagrees with t he district court’s assessment of the evidence relating to the “unexpected results” obtained with clopidogrel bisulfate, we review that assessment, which is based on fa ctual findings made by the district court,

06-1613 15for clear error. Based on the record befor e us, we find no basis to conclude that the district court clearly erred in it s evaluation of that evidence. Finally, we are unpersuaded by Apotex’s argum ent that the court clearly erred by failing to consider Adamson in its obviousness analysis. In Adamson , the CCPA affirmed the Board’s rejection of claims t hat covered the l-enantiomer of a specific compound and its addition salts as obvious in view of certain prior art references. One prior art reference disclosed “synthetica lly produced compounds of the same formula claimed,” but did not state whether t he compounds were racemic mixtures or enantiomers. Adamson , 275 F.2d at 953. A nother prior art reference, an organic chemistry textbook, taught, inter alia , that racemates may be separated into their enantiomers by various methods, and that enantiomers often possess substantially different physiological properties in comparis on to each other. Thus, the court found the claimed l-enantiomer salt unpatent able despite the fact that that enantiomer exhibited substantially greater spasmolytic activity than its dextrorotatory counterpart. Apotex contends that Adamson is “no different” from the present case. We disagree. This case is distinguishable on at least two grounds. First, it was undisputed in Adamson that the primary reference disclosed the racemic mixtures of the isomers and the acid addition salts. Id. at 954. Here, and most importantly, the ’596 patent does not disclose the bisulfat e salt of the d-enantiomer of MATTPCA. Resolution of a racemic free base does not lead to a particular unnamed salt. Second, the Adamson court observed that it w ould have been expected by one of skill in the art that enantiomers would have different pharmacologica l activity and that the toxicity of the
racemate would lie somewhere between that of its isomers. In this case, the district

06-1613 16court made factual findings that resolvi ng the racemate was not mere routine experimentation and that it wa s unexpected that the desirable activity of clopidogrel would be found only in the d-enantiomer. We do not consider that those findings are clearly erroneous. Accordingly, Adamson is distinguishable on that additional basis. Based on the preliminary record before us, we thus find t hat the district court did not err in determining that Apotex failed to ra ise a substantial question as to the validity of claim 3 based on obviousness.

c. Obviousness-Type Double Patenting In the district court, Apotex also cha llenged the validity of cl aim 3 of the ’265 patent based on obviousness-ty pe double patenting. Apotex argues that the court committed clear error in concluding that t he double patenting inquiry was subsumed by the broader obviousness inquiry, and by failing to specifically address this claim. Apotex asserts that an obviousness inquiry is distinct from the double patenting inquiry and should have been independently analyzed. Sanof i responds that the court correctly concluded that nothing in the prior art, in cluding the ’596 patent, rendered claim 3 obvious. Claim 2 of the ’596 patent especia lly did not render claim 3 obvious. While Apotex asserts that the court erred by failing to separately address its double patenting defense, Apotex fails to set forth any arguments on ap peal that raise a substantial question with respect to the va lidity of claim 3 bas ed on that defense. Accordingly, we reject Apotex’s argument t hat the grant of the pr eliminary injunction should be reversed on that basis.

06-1613 172. Enforceability of the ’265 Patent Apotex argues that the di strict court abused its discret ion in finding that Apotex failed to raise a substantial question as to the enforceability of t he ’265 patent. Apotex identifies separate bases upon which it asserts inequitable conduct should have been found. They include incorrect inventorship , concealment of research regarding other compounds that were tested by Sanofi, and purported false statem ents concerning the “unexpected results” of clopi dogrel bisulfate and the “less well-tolerated” statement referring to the l-enantiomer. Sanofi res ponds to each of Apotex’s assertions, explaining why none of Apotex’s arguments rais es a substantial question as to the ’265 patent’s enforceability. “A patent may be rendered unenforceable fo r inequitable conduct if an applicant, with intent to mislead or deceive the examiner , fails to disclose ma terial information or submits materially false information to the PTO during prosecution.” Digital Control, Inc. v. Charles Mach. Works , 437 F.3d 1309, 1313 (Fed. Cir. 2006 ). “The party asserting inequitable conduct must prove a threshold le vel of materiality and intent by clear and convincing evidence.” Id. Further, “materiality does not presume intent, which is a separate and essential component of inequitable conduct.” GFI, Inc. v. Franklin Corp. , 265 F.3d 1268, 1274 (Fed. Cir. 2001) (quoting Manville Sales Corp. v. Paramount Sys., Inc. , 917 F.2d 544, 552 (Fed. Cir. 1990)). While Apotex devotes a significant porti on of its briefs to argue its inequitable conduct contentions, virtually none of its discussion is devoted to identifying any evidence that would support a finding of deceptive intent. Apotex’s evidence of intent is limited to a statement in Apot ex’s reply brief that the in ventors’ declaration, which

06-1613 18excluded Dr. Maffrand as an inventor, is evidenc e of intent. Moreover, Apotex suggests that intent can be inferred because “Sanofi was motivated to extend its patent monopoly beyond the ’596 patent term by patenting the enantiomer, and it needed to conjure up ‘unexpected’ results.” Such generalized allegat ions lack the particularity required to meet the threshold level of deceptive intent necessary for a finding of inequitable conduct. Thus, based on the record before us, A potex clearly fails to raise a substantial question as to the enforc eability of the ’265 patent. 8 Accordingly, we find no abuse of discretion with regard to that issue. B. Other Preliminary Injunction Factors We next consider the remaining elements of the preliminary injunction test. The district court applied a presumption of irrepar able harm in light of its conclusion that Sanofi established a likelihood of success on t he merits. The court also found that Sanofi proffered substantial evidence est ablishing other forms of irreparable harm, including irreversible price erosion, lo ss of good will, potential lay-offs of Sanofi employees, and the discontinuance of clinical tr ials that are devoted to other medical uses for Plavix ®

. Apotex argues that the dist rict court clearly erred in concluding that Sanofi would suffer irreparable harm in the absence of an injunction. According to Apotex, the settlement agreement entered into by Sanofi and Apotex negated any finding of irreparable harm. Apotex c ontends that Sanofi quantified in the May agreement the measure of harm it would suffer in t he event Apotex marketed a generic product—

8 Because both materiality and intent are required to establish inequitable conduct, we need not address the materiality of the purported false statement or omissions that Apotex describes in its briefs.

06-1613 19specifically, 40%-50% of Apotex ’s net sales. Additionally, Apotex challenges the court’s findings with regard to the other kinds of irreparable harm established by Sanofi. In response, Sanofi argues that it did not contractually surrender its right to prove irreparable harm by entering into the May agr eement. Moreover, Sanofi asserts that the court did not clearly err by crediting the evi dence it proffered establishing the additional kinds of irreparable harm it would suffer if A potex were allowed to continue selling its generic product. We conclude that the district court di d not clearly err in finding that Sanofi satisfied this factor. We are not persuaded by Apotex’s assertion that Sanofi contracted away its right to prove irreparable harm by entering into the May agreement, which includes a provision that capped damages for infr ingement by Apotex. In support of this argument, Apotex refers to the following provision: 14. In the event of Regulator y Denial, the litigations will be resumed as further described in paragraph 15 hereof, and: * * * (ii) If the litigation results in a judgment that the ’265 patent is not invalid or unenforceable, Sanofi agrees that its actual damages for any past infringement by Apotex, up to the date on which Apotex is enjoined, will be 50% of Apotex’s net sales of clopidogrel products if Sanofi has not launched an authorized generic and 40% of Apot ex’s net sales if Sanofi has launched an authorized generic . Sanofi further agrees that it will not seek increased damages under 35. U.S.C. § 284. May agreement, ¶ 14. We think that the above provision favors Sanofi, not Apotex. We disagree with Apotex that by entering in to that agreement, Sanofi bargained away its right to seek preliminary injunctive relief, and thus its right to prove irreparable harm, in the event the settlement was not approved. The above provisi on itself contemplates an injunction in

06-1613 20referring to “up to the date on which Apotex is enjoined” and speaks only of damages for past infringement. In addition, based on other provisions in the agreement, it is clear that the parties contemplated the possibility of a preliminar y injunction in the event of regulatory denial. Paragraph 15 of the agreement, for example, sets forth the procedural steps the parties must follow when seeking a preliminary injunction. Moreover, merely because a patentee is able to identify a monetary amount that it deems sufficient to avoid or end litigati on does not necessar ily mean that it automatically foregoes its right to seek a preliminary inj unction or that any potential irreparable injury ceases to exist if infri ngement resumes. Thus, Apotex’s argument is unsound. Further, we reject Apotex’s assertion that the district court abused its discretion in concluding that Sanofi would suffer irreversib le price erosion if an injunction were not entered. Based on the ev idence Sanofi adduced, includi ng the testimony of its economics expert, Professor Hausman, and a declaration from a Sanofi executive, Hugh O’Neill, the court found that Sanofi would suffer irreversible price erosion in light of a complex pricing scheme that is direct ly affected by the pr esence of the generic product in the market. In particular, the court found that since Apotex’s generic product entered the market, Sanofi has been forced to offer discounted rates and price concessions to third-party payors, such as health maintenance organizations, in order to keep Plavix ® on a favorable pricing tier, which gov erns what consumers pay for that drug. The court found that the availabilit y of a generic product encourages third party payors to place Plavix ® on a less favorable tier, thereby requiring consumers to pay a higher co-pay, and perhaps deterring them from purchasing Plavix ® . The court

06-1613 21identified additional consequences of unfavorabl e tier placement, including a decrease in demand for Plavix ® . According to Sanofi, it is nearly impossible to restore Plavix ® to its pre-launch price since the gener ic product entered the market. Apotex does not argue that price erosion is not a valid ground for finding irreparable harm, but rather challenges the distri ct court’s findings as to price erosion. We conclude that the district court did not clearly err in it s evaluation of the evidence relating to price erosion. While Apotex a sserts that price erosion had already occurred, and thus an injunction is not necessary because it cannot ameliorate Sanofi’s position, Apotex fails to identify clear errors in the district court’s analysis, and fails to proffer evidence of its own sufficient to rebut the court’s findings. Apotex also fails to demonstrate that the court clearly erred in its findings with respect to the additional factors that established irreparable harm, including loss of good will, the potential reduction in work force, and t he discontinuation of clinical trials. Accordingly, we conclude that the district court did not clearly err in finding irreparable harm. 9 As to the third factor of the test, Apotex argues that the court erred in balancing the hardships because it ignored the harm A potex would face if an injunction were granted, particularly in light of the settlem ent agreement which, according to Apotex, demonstrates that the harms S anofi would suffer are a result of its own conduct. Sanofi responds that the court did not abuse its discr etion in finding that that factor favored

9 Apotex also argues that the district court erred by applyi ng a presumption of irreparable harm because Sanofi established a likelihood of success on the merits. Apotex contends that applying su ch a presumption is in direct contravention of the Supreme Court’s decision in eBay Inc. v. MercExchange, L.L.C. , 126 S. Ct. 1837 (2006). Because we conclude that the district court did not clearly err in finding that Sanofi established several kinds of irreparable harm, including irreversible price erosion, we need not address this contention.

06-1613 22Sanofi, particularly because it was Apotex’s own decision to engage in an at-risk launch that would trigger its 180-day exclusivity period before reachi ng the merits of the case. Based on the record on appeal, we conclude that the court did not clearly err in finding that Apotex’s harms were “almost entirely pr eventable” and were t he result of its own calculated risk to launch its product pre-judgment. Sanofi-Synthelabo , slip op. at 48. Accordingly, the court did not abuse its discretion in finding that the balance of hardships tipped in Sanofi’s favor. The fourth factor we consider is the pub lic interest, which the court found tips in favor of Sanofi, albeit slightly. Apotex, as well as amici, 10 argue that the district court erred in failing to consider certain public harms that would result if an injunction issues. Apotex, in particular, contends that if the generic products were removed from the market, consumers would be inclined not to purchase their medication because of the accompanying price increase for the brand name drug, leading to possible deaths. Apotex further argues that significant cons umer confusion may ensue because of the six-month supply that was shipped to the American market, which was not equally distributed among vendors. Sanofi responds that the court did not clearly err in finding that the interest in encouraging pharmaceutic al research and development outweighed the public interest advanced by Apotex. We agree with Sanofi. While Apotex raises legitimate concerns, the district court did not abuse its discretion in concluding t hat those concerns were outweighed by the public interests identified by Sanofi. We have long acknowledged the importance of the

10 Medco Health Solutions, Inc., Pati ents Not Patents, Inc., and the Generic Pharmaceutical Association submitted amicus curiae briefs arguing for reversal of the grant of the preliminary injunction.

06-1613 23patent system in encouraging innovation. Indeed, the “encouragement of investmentbased risk is the fundamental purpose of the patent grant, and is based directly on the right to exclude.” Patlex Corp. v. Mossinghoff , 758 F.2d 594, 599 (Fed. Cir. 1985). The district court relied on the testimony of Dr. Hausman in finding that the average cost of developing a blockbuster drug is $800 million. Importantly, the pat ent system provides incentive to the innovative drug companies to continue costly devel opment efforts. We therefore find that the court di d not clearly err in concluding that the significant “public interest in encouraging investment in drug development and protecting the exclusionary rights conveyed in valid pharmaceutical patents” tips the scales in favor of Sanofi. Sanofi-Synthelabo , slip. op. at 51. C. Unclean Hands Having concluded that ther e was no abuse of discreti on in the trial judge’s determination that the four fact ors of the preliminary injuncti on test favor an injunction, we next consider Apotex’s argument concer ning unclean hands. Apotex argues that the district court erred by precluding Apotex fr om introducing evidence that counsel for BMS and Sanofi allegedly engaged in fraudulent mi sconduct during settlement negotiations by concealing oral side agreem ents from regulators and fals ely certifying that such agreements did not exist. The district court excluded that evidence from the preliminary injunction hearing, reasoning that the “c onduct of the parties during settlement negotiations does not affect the validity of the patent or the veracity of submissions to [the district court], and therefore has no relevance to the question of whether a preliminary injunction should issue.” Id. at 55.

06-1613 24We conclude that the district court did not abuse its discr etion by precluding Apotex from asserting this defense. Apotex contends the court clearly erred by disregarding Precision Instrument Manufacturing Co. v. Automotive Maintenance Machinery Co. , 324 U.S. 806 (1945). That case, how ever, is not on point. There the plaintiff sought to enforce several patents and contracts that were obtained as a result of a settlement agreement entered into by the parties in order to resolve an interference proceeding, during which the par ties either committed perjury before the Patent Office or concealed their knowledge of the perjury. The Supreme Court applied the unclean hands doctrine and dismissed plaintiff’s pat ent infringement and br each of contract claims. In doing so, the Court noted the public policy interest against asserting and enforcing patent claims that are “infected with fraud and perjury.” Id. at 819. Apotex’s unclean hands defense, however, is not based on fraud or perjury that counsel for BMS or Sanofi allegedly commi tted while obtaining the ’265 patent, but instead relates to the settlement agreement entered into between Sanofi and Apotex well after the patent was obtained. Because t he claims at issue in the grant of the preliminary injunction concern infringement and validity of the ’265 patent, as opposed to issues relating to the settlement agreement itself, we find that the court did not abuse its discretion in excluding such evidence in the context of the pr eliminary injunction motion. See Keystone Driller Co. v. Gen. Excavator Co. , 290 U.S. 240, 245 (1933) (noting the court’s discretion in applying the unclean hands doctrine when a plaintiff’s alleged misconduct “has no relation to anything involved in the suit”).

06-1613 25D. Bond Lastly, Apotex challenges the court’s dec ision to set bond in the amount of $400 million, which it asserts fails to provide su fficient security because it represents only 10% of the annual market and ignor es Apotex’s loss of market share. Sanofi responds that the amount far exceeds any damage Apotex may face, particularly in light of the fact that there was no recall of Apotex’s generic product after it launched its product on August 8, 2006. The posting of a bond is governed by Federal Rule of Civil Procedure 65(c) which provides that: No restraining order or pre liminary injunction shall issue except upon the giving of securi ty by the applicant, in such sum as the court deems proper, for the payment of such costs and damages as may be incurred or suffered by any party who is found to have been wrongfully enjoined or restrained. Fed. R. Civ. P. 65(c). T he amount of a bond is a determi nation that rests within the sound discretion of a trial court. Doctor’s Assocs., Inc. v. Distajo , 107 F.3d 126, 136 (2d Cir. 1997) (noting that a distri ct court has wide discretion under Rule 65(c) in setting the amount of a bond). The cour t based its determination on ev idence presented before the court that concerned Apotex’s “potential lost profits, lost market share and associated costs of relaunch” in the ev ent of wrongful enjoinment. Sanofi-Synthelabo , slip op. at 57. We find no basis for disturbing the c ourt’s assessment of the facts, and thus conclude that the court did not abuse its discretion in setting the bond amount. CONCLUSION We have considered Apotex’s remaining ar guments with respect to the myriad of issues it has raised on appeal and find them unper suasive. We therefore conclude that

06-1613 26the district court did not abus e its discretion in granting pr eliminary injunctive relief. Accordingly, for the foregoing reasons, we affirm the district c ourt’s grant of the preliminary injunction. We wish to note tha t, while we have carefully considered all of the arguments presented to us in reviewing the district cour t’s grant of the preliminary injunction, we have done so in the context of the standard of review applicable to grant of preliminary injunctions, and that the district court is not bound to its earlier conclusions on full trial on the merits. We l eave to that court the conduct of any further proceedings.

AFFIRMED

.

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