1 UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

ViroPharma, Inc., Plaintiff ,

v. Margaret A. Hamburg, M.D., in her official capacity as Commissioner, Food and Drug Administration, et al. , Defendants , and Akorn, Inc., et al. , Defendants-intervenors. Civil Action No. 12-0584 (ESH)

MEMORANDUM OPINION ViroPharma, Inc., manufactures the antibiotic Vancocin ® . On April 13, 2012, ViroPharma sued Margaret Hamburg, in her offi cial capacity as the Commissioner of the Food and Drug Administration; Kathleen Sebelius, in her official cap acity as the Secretary of the Department of Health and Human Services; and the agencies themselves (collectively, the “FDA”) to challenge the FDA’s approval, on April 9, 2012, of three Abbreviated New Drug Applications (“ANDAs”) permitting the marketing of generic versions of Vancocin (vancomycin hydrochloride capsules or “vancomycin”). ( See Complaint, April 13, 2012 [Dkt. No. 1] (“Compl.”).) ViroPharma alleges that the F DA approved the three ANDAs (1) in violation of ViroPharma’s statutory right under the Fede ral Food, Drug, and Cosmetic Act (“FFDCA”), 21 U.S.C. §§ 301 et seq. , to a three-year peri od of exclusivity for Va ncocin, extending through2 December 15, 2014; and (2) based solely on in vitro (laboratory) bioequivalence testing in

violation of the FDA’s own regulations requiring in vivo (human) bioequiv alence testing. ( Id. ¶ 2.) The Court will refer to these as Viro Pharma’s “statutory exclusivity claim” ( see id. ¶¶ 75–78 (Count II)) and its “bioeq uivalence claim.” ( See id. ¶¶ 69–74 (Count I).)

Before the Court is ViroPharma’s motion fo r a preliminary injunction to require the FDA to withdraw its approval of the three vanc omycin ANDAs and to refuse to approve any additional vancomycin ANDAs until ViroPharma’s claims are adjudicated on the merits. ( See Motion for a Temporary Restrain ing Order and/or Preliminary Injunction, April 13, 2012 [Dkt. No. 4] (“Pl.’s Mot.”). 1 ) The FDA has opposed ViroPharma’s motion ( see Federal Defendants’ Memorandum in Opposition to Plaintiff’s Motio n for Temporary Restraining Order and/or Preliminary Injunction, April 17, 2012 [Dkt. No . 22] (“FDA Opp’n”)), as have defendantsintervenors, the three generi c manufacturers whose vancomycin ANDAs have been approved. ( See Intervenor-Defendant Akorn’s Memorandum in Opposition to ViroPharma Incorporated’s Motion for a Temporary Restraining Order, April 17, 2012 [Dkt. No. 23] (“Akorn Opp’n”); Alvogen, Inc.’s Memorandum in Opposition to Plaintiff ViroPharma Inc.’s Motion for Temporary Restraining Order and/or Prelimin ary Injunction, April 17, 2012 [Dkt. No. 24] (“Alvogen Opp’n”); Opposition of De fendant-Intervenor Watson Laborat ories, Inc. to Plaintiff’s Motion for Temporary Restraini ng Order and/or Preliminary In junction and Expedited Hearing, April 17, 2012 [Dkt. No. 25] (“Watson Opp’n”).) Following a hearing held on April 19, 2012, and having considered a ll of the parties’ arguments and pleadings, including the repl y filed by plaintiff after the hearing ( see Reply, April

1 With the parties’ consent, the Court has collapsed ViroPhar ma’s requests for a temporary restraining order and a preliminary injunction.3 20, 2012 [Dkt. No. 32] (“Pl.’s Reply”)), the C ourt concludes that ViroPharma has not demonstrated that it is entitled to a preliminary injunction. Therefore, its motion will be denied.

BACKGROUND Prior opinions of this Court and others desc ribe the background relevant to ViroPharma’s statutory exclusivity an d bioequivalence claims.

I. STATUTORY AND REGULATORY FRAMEWORK

A. ViroPharma’s Stat utory Exclusivity Claim Prior to 1997 and the passage of th e [Food and Drug Modernization Act of 1997 (“FDAMA”), Pub. L. No. 105–115, 111 Stat. 2296], “antibiotic” drugs were approved under Section 507 of the FFDCA, 21 U.S.C. § 357 (“Section 507”), and non-antibiotic drugs were approved unde r Section 505, 21 U.S.C. § 355 (“Section 505”). This difference had a long histor y, dating back to th e development of penicillin, the first drug to have the capacity to kill microbes, i.e. , be “anti-biotic.” Because penicillin was manufactured in batches through fermentation, its strength and efficacy could vary depending on the ri gor of that process. Congress required that FDA test all batches of penicillin to ensure that appropriate doses were administered to the military during Worl d War II. Initially, Section 507 applied only to penicillin or any derivative of penicillin; other named antibiotic drugs were added to the statute as they were developed. When the FFDCA was amended in 1962, a more generalized defin ition was added so that the law would not need amending with each new di scovery of an antibiotic drug. [ See Drug Amendments of 1962, Pub. L. No. 87-781, 76 Stat. 780.] Two key consequences arose from thes e different treatments. Applicants for generic versions of antibiotic drugs were only requested to show conformance with statutorily-mandated, published standa rds of identity, strength, quality, and purity for the antibiotic s ubstance, as reflected in antibiotic “monographs” published by FDA. Pharmaceutical companies did not have to submit the safety and efficacy data that was required for pi oneer and generic non-antibiotic drugs. Therefore, generic antibiotics were de veloped and marketed fairly readily. See Glaxo, Inc. v. Heckler , 623 F. Supp. 69, 72 (E.D.N.C. 1985); Abbreviated New Drug Applications, Proposed Rule , 54 Fed. Reg. 28,872, 28,878 (July 10, 1989). However, antibiotic drugs did not receive the patent listing, pa tent certification, and marketing exclusivity benefits availa ble to pioneer and n on-antibiotic drugs after enactment of the Drug Price Competition and Patent Term Restoration Act (“Hatch-Waxman”), Pub. L. No. 98–417, 98 Stat. 1585 (1984). . . . The significance of the Hatch-Waxman Amendments to FFDCA cannot be understated. Prior to 1984, a ll applicants seeking to market pioneer drugs or generic non-antibiotic drugs had to fi le [a new drug application (“NDA”)]4 containing, inter alia , extensive scientific data demonstrating the safety and effectiveness of the drug. See 21 U.S.C. § 355(a)–(b); 21 C.F.R. § 314.50. As a result, few generic non-antibiotic dr ugs were approved by [the] FDA. See Glaxo , 623 F. Supp. at 72. Hatch–Waxman create d an abbreviated approval process for generic non-antibiotic drugs, wh ile retaining incentives for pioneer drugs, such as marketing exclusivity and patent protections. See 21 U.S.C. § 355(jj). The abbreviated new drug application (“ANDA”) process shortens the time and effort needed for approval of a generic drug by allowing the applicant to merely demonstrate its product’s bioequivale nce to the NDA drug, without reproducing the entirety of the NDA’s exte nsive scientific research. See Eli Lilly and Co. v. Medtronic, Inc. , 496 U.S. 661, 676 (1990) (describing the ANDA process). Because Congress still wanted to provide incentives for new drug development, alongside the ANDA process th at eased the marketing of generic drugs, Hatch-Waxman entitles an NDA appli cant to a period of market exclusivity (3 or 5 years, depending on the degree of innovation reflected in the NDA) which bars FDA approval of a generic ANDA for the NDA product. See 21 U.S.C. § 355(c)(3)(D)(ii)–(iv), (j)(5)(D)(ii)–(iv). Allergan, Inc. v. Crawford , 398 F. Supp. 2d 13, 16–17 (D.D.C. 2005) (footnotes omitted, citation formats altered). Thus, pursuant to Hatch-Waxman’s provisions, “pioneer drug companies are entitled to certain periods of marketing exclusivity dur ing which they are protected from generic competition.” AstraZeneca Pharm. LP v. FDA , --- F. Supp. 2d ----, ----, 2012 WL 983481, at *2 (D.D.C. 2012). “Included among th ese various exclusivity periods is what is sometimes referred to as a ‘new patient population’ or ‘new indicatio n’ exclusivity because it frequently arises when a pioneer drug company conducts post-approval clinical studies, submits a supplemental application to the FDA [(an “sNDA”)], and secure s the FDA’s approval to market an approved drug to a new population or for a new indication.” Id. Specifically, if an sNDA is approved and

it contains reports of new clin ical investigations (other than bioavailability studies) essential to the approval of the [sNDA] and conducted or sponsored by the person submitting the [sNDA], the [FDA] may not make the approval of an [ANDA] submitted . . . for a change approved in the supplement effective before the expiration of three years from the da te of the approval of the [sNDA].5 21 U.S.C. § 355(j)(5)(F)(iv). Although referred to “new indication ex clusivity,” this provision applies beyond situations where an existing drug is approved for the treatment of a disease for which it had not been approved before. “The FDA has interp reted [§ 355(j)(5)(F)(i v)] as establishing a relationship between the information obtained fr om the clinical inve stigation, the change approved through the pioneer drug company’s [sNDA], and the scope of the information relied upon by a generic competitor in a specific ANDA.” AstraZeneca , 2012 WL 983481, at *3. Therefore, labeling changes approved in an sNDA can qualify for exclusivity under § 355(j)(5)(F)(iv) as well. As relevant here, if an sNDA that prescribes labeling changes is approved on the basis of “new clinical investigat ions (other than bioava ilability studies) . . . conducted or sponsored by the person submitting the [sNDA],” then an ANDA that includes the labeling changes may only be approved three year s thereafter. 21 U.S.C. § 355(j)(5)(F)(iv). And because a generic drug product may not be approved unless its label is (w ith certain exceptions not relevant here) the “same as ” the brand-name drug’s label, id. § 355(j)(2)(A)(v); 21 C.F.R. § 2314.94(a)(8)(iv), if an approved sNDA prescribing labeling cha nges qualifies under 21 U.S.C. § 355(j)(5)(F)(iv), then the three y ears of labeling exclusivity the statute provides can in practice amount to an exclusive right to market the drug for that time period. As described above, however, when Hatc h-Waxman was enacted, its exclusivity provisions did not apply to antibi otics such as Vancocin. In 1997, with the enactment of the FDAMA, Congress extended Hatch-Waxm an to antibiotics by repealing Section 507 of the FFDCA and requir[ing] that all applications for antibiotic drugs be submitted under Section 505. FDAMA § 125(d)(1) (Transition). In subsection (d)(1), the Transition provided that applications for antibiotic drugs approved under Section 507 before FDAMA would be considered approved under6 Section 505. Id. However, subsection (d)(2) added the provision that when “the drug that is the subject of the applicat ion contains an antibiotic drug and the antibiotic drug was the subject of any application” r eceived by FDA before the enactment of FDAMA, it is exempt from Hatch-Waxman benefits. FDAMA § 125(d)(2); Proposed Rule: Marketing Ex clusivity and Pate nt Provisions for Certain Antibiotic Drugs, 65 Fed. Reg. 3,623, 3,624–25 (Jan. 24, 2000); Section 507 Repeal Guidance at 2. Specifica lly, § 125(d)(2) exempts from Hatch– Waxman: any application for marketing in wh ich the drug that is the subject of the application contains an an tibiotic drug and the antibiotic drug was the subject of any applic ation for marketing received by the Secretary of Health and Huma n Services under section 507 of such Act (21 U.S.C. § 357 [Section 507]) before the date of enactment of this Act. Pub. L. No. 105–115, 111 Stat. 2327 (1997), § 125(d)(2) ( reprinted in 21 U.S.C.A. § 355 Historical a nd Statutory Notes, “Transition”). Antibiotic drugs that were the subject of pre-FDAM A applications are known as “[O]ld [A]ntibiotics” and will be so referenced here. Allergan , 398 F. Supp. 2d at 17–18. Thus, with the enactment of the FDAMA in 1997, Congress eliminated the separate approval pathway fo r antibiotics and made antibiotics approved after the statute’s effective date, but not Old Antibiotics , eligible for exclusivity provided the other statutory criteria were met. As discussed below, ViroPharma’s Vancocin is an Old Antibiotic. Congress closed this gap when it enacted the QI Program Supplemental Funding Act of 2008, Pub. L. No. 110-379, 122 Stat. 4075 (the “QI Act” ). Section 4 of the QI Act, entitled “Incentives for the Development of, and Access to, Certain Antibiotics,” amended the FFDCA to make Old Antibiotics eligible for exclusivity. Id. § 4. Thus, the FFDCA now provides: Notwithstanding any provision of the [FDA MA] or any other pr ovision of law, a sponsor of [an Old Antibiotic] shall be elig ible for, with resp ect to the drug, the 3- year exclusivity period referred to unde r clauses (iii) and (iv) of subsection (c)(3)(E) and under cl auses (iii) and (iv) of subsec tion (j)(5)(F), subject to the requirements of such clauses, as applicable. 21 U.S.C. § 355(v)(1)(A). However, Section 4 of the QI Act also provides that the 3-year7 exclusivity period provided in 21 U.S.C. § 355(j)(5 )(F)(iv) is not available for “any condition of use for which the [Old Antibiotic] . . . was approved before the date of the enactment [of the QI Act].” Id. § 355(v)(3)(B). The FDA’s interpretati on of this exemption is the focus of ViroPharma’s statutory exclusivity claim. B. ViroPharma’s Bioequivalence Claim Under the FFDCA, in order for a generic appl icant to rely on the record of safety and effectiveness demonstrated by a pioneer drug, kn own as the “reference lis ted drug” (“RLD”) for purposes of the process by which a generic copy gains approval,

an ANDA must include information demons trating that the generic drug is the same as the RLD in a number of specified ways. 21 U.S.C. § 355(j)(2)(A). Of particular relevance here, the ANDA must demonstrate that the generic is the “bioequivalent” of the RLD, and is ther efore absorbed into the body at the same rate and to the same extent as the innovator drug. [ Id. ] § 355(j)(2)(A)(iv). 2 Where . . . “a drug . . . is not intended to be absorbed into the bloodstream, the Secretary may establish a lternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the [RLD] in safety and therapeutic effect.” [ Id. ] § 355(j)(8)(C). Depending on the circumstances and th e particular drug in question, the FDA may require an applicant [to] use one or more of a variety of different methodologies in order to demonstrate bi oequivalence. In general, however, methodologies for demonstrating bioequiva lence may be classified as either in vivo ( i.e. , through human testing) or in vitro ( i.e. , laboratory testing). ViroPharma, Inc. v. Hamburg , 777 F. Supp. 2d 140, 143 (D.D.C. 2011) (“ ViroPharma I ”) (some

2 FDA regulations define bioequi valence as “the absence of a significant difference [as between the generic drug and the RLD] in the rate and ex tent to which the active ingredient or active moiety . . . becomes available at the site of drug action.” 21 C. F.R. § 320.1(e). The rate of absorption itself is referred to as “bioavailability.” Id. § 320.1(a) (“Bioavailability means the rate and extent to which the active ingredient or active moiety . . . becomes available at the site of action.”). In approving an NDA, the FDA requires applicants to submit data on bioavailability

. Id. § 320.21(a). In approving an ANDA, as discussed below, the FDA requires data on bioequivalence to show that the proposed generic has the same bioavailability as the RLD. Id. § 320.21(b).8 alterations in the original; citations and some internal quotation marks omitted), 3 aff’d , No. 11- 5143, 2012 WL 1138803 (D.C. Cir. Mar. 21, 2012); see 21 C.F.R. Part 320 (FDA regulations regarding bioequivalence). The FDA’s interpre tation of various regulatory provisions in 21

C.F.R. Part 320 is the focus of Vi roPharma’s bioequivalence claim.

II. FACTUAL AND PROCED URAL BACKGROUND

A. ViroPharma and Vancocin ViroPharma, founded in September 2004, is a small pharmaceutical company headquartered in Exton, Pennsylvania. (Com pl. ¶ 6; Pl.’s Mot., Ex. A (“Rowland Decl.” 4 ) ¶ 4.) In addition to Vancocin, ViroPharma currently sells three other drugs and biologic products: Cinryze TM , Buccolam ® , and Diamorphine. (Pl.’s Mot. at 2; Rowland Decl. ¶ 7.) Prior to the FDA’s approval of generic vancomycin ANDAs , Vancocin represented “roughly half” of ViroPharma’s revenue. (Compl. ¶ 18; see Rowland Decl. ¶ 8 (“In 2011, Vancocin sales were $389 million and accounted for 53% of ViroPharma’s total revenue.”).) Vancocin was developed by Eli Lilly and Company and approved by the FDA in April 1986 for the treatment of, inter alia , “a dangerous gastrointes tinal infection” called Clostridium difficile associated diarrhea (or “CDAD”). 5 ViroPharma Inc. v. Dep’t of Health & Human

Servs. , --- F. Supp. 2d ----, ----, 2012 WL 892926, at *1 (D.D.C. 2012) (“ ViroPharma II ”). 6 ( See

3 In ViroPharma I , this Court concluded that ViroPharma lacked standing to sue on its bioequivalence claims where the FDA had not yet granted any vancomycin ANDAs. 777 F. Supp. 2d at 148.

4 Charles Rowland is ViroPharma’s Chief Financial Officer. (Rowland Decl. ¶ 1.)

5 Because Vancocin was first approved by the F DA prior to the enactment of the FDAMA, it qualifies as an Old Antibiotic. See Allergan , 398 F. Supp. 2d at 17–18.

6 In ViroPharma II , Judge Friedman addressed cross-moti ons for summary judgment in a FOIA9 Rowland Decl. ¶¶ 16–19, 22; Compl., Ex. A (“CP Response”) 7 at 8.) Vancocin, delivered orally in capsule form, releases the antibiotic vancomycin into the gastrointestinal tract where the drug

acts to attack C. difficile bacteria. (Rowland Decl. ¶ 20.) A ccordingly, Vancocin is a “locally acting” drug; it acts in the GI tr act but is not systemically abso rbed into the bloodstream or the rest of the body. ( Id. ; see CP Response at 3 (“Vancomycin acts lo cally in the GI tract . . . and is poorly absorbed after oral administration, mean ing it does not enter the body systemically.”).) In November 2004, ViroPharma “exclusively licensed from Eli Lilly the right to manufacture, market, and sell Vancocin in the Un ited States and its territo ries.” (Rowland Decl. ¶ 22.) However, Vancocin’s last core patent expired in 1996. ( Id. ¶ 23.) Therefore, “absent statutory exclusivity, the mark et for Vancocin is open to generic substitutes upon FDA approval.” ( Id. )

B. ViroPharma’s Efforts To Forestall the Approval of a Generic Vancomycin ViroPharma presented its stat utory exclusivity and bioequivale nce claims to the FDA in a series of filings commencing in 2006. As th e basis for its statutor y exclusivity claim,

ViroPharma cited the fact that on December 14, 2011, the FDA approved an sNDA for Vancocin that, according to plaintiff, “fundamentally ch anged the labeling” for the drug by adding “new conditions of use relating to Clinical Studies, Ad verse Reactions: Clinical Trials, Nephrotoxicity,

action brought by ViroPharma related to the FDA’s deliberations a nd decisions regarding Vancocin and potential generic va ncomycin ANDAs. 2012 WL 892926, at *1–2.

7 As discussed further below, CP Response consis ts of a single-spaced, eighty-five page letter from the FDA to ViroPharma denying the “citize n petition” through which ViroPharma raised, inter alia , its statutory exclusivity and bioequivalence claims before the agency. ( See infra n.11 (describing the “citizen petition” process).) The Court refe rences the letter ruling’s comprehensive treatment of the history of th is dispute for purposes of providing relevant background information.10 and Geriatric Use, by modifying Vancocin’s indication, and by specifying a recommended dosing regimen.” ( Id. ¶ 24.) These changes “were based on ne w clinical safety and efficacy data to which ViroPharma has exclusive rights.” 8 ( Id. ) Accordingly, ViroPharma argued that Vancocin is entitled to a three-year period of exclusivity to run through December 15, 2014. See 21 U.S.C. § 355(j)(5)(F)(iv). ViroPharma’s bioequivalence claim relies on a more complicated regulatory backdrop. Because Vancocin is the only RLD for vancom ycin, any ANDA for generic vancomycin must establish bioequivalence to Vancocin to gain approval from the FDA. (CP Response at 8.) “Prior to 2006 the FDA recommended using in vivo studies . . . to establ ish the bioequivalence of generic versions of vancomycin.” ViroPharma II , 2012 WL 892926, at *1. (See CP Response at 9 (“FDA’s initial recommendation for sponsors to establish bioequivalence to [Vancocin] was to

conduct in vivo studies with clinical e ndpoints.”).) However, generic manufacturers told the FDA that it was “nearly impossible to do” an in vivo bioequivalence study of a proposed generic for Vancocin. (Pl.’s Mot., Ex. A (“McCalips Decl.”), Ex. 5 at 1. 9 ) As of 2006 there had been no ANDAs submitted for the drug, and therefore no generic products competed with it. ( Id .)

8 ViroPharma’s data was based on two clinical safety and effica cy studies for an unsuccessful drug, tolevamer. (McCalips Decl., Ex. 2 at 4.) ViroPharma had purchased the rights to those studies from their sponsor, Genzyme Corporation. ( Id. ) In those studies, Vancocin was administered to the control group, in accordance w ith its labeled use in populations for which Vancocin had previously been approved. ( Id. at 4–5.)

9 Indeed, in considering Eli Lilly’s NDA for Va ncocin in the 1980s, the “FDA concluded that it could not assess systemic bioavaila bility of [the drug] from the in vivo bioavailability data Lilly had submitted because of low absorption of the capsule product.” (CP Response at 8; see supra n.2 (discussing bioavailability).) The FDA nonetheless approved the NDA by waiving the in vivo bioavailability data requirement pursuant to a re gulatory provision that is not relevant to the present dispute. (CP Response at 8.) Still, it is worth emphasizing that the FDA approved the Vancocin NDA based largely on the same kind of dissolution data which ViroPharma now argues is insufficient for the approval of an ANDA. ( See id. at 8 & n.8.)11 In February of that year, the FDA “ch anged its bioequivalence recommendation for vancomycin” and began to permit generic applican ts “to establish bioequivalence with certain in

vitro dissolution stud ies in lieu of in vivo data.” (CP Response at 9.) The FDA maintains that its

revised recommendation was based on 1) guidance it had issued in August 2000 which provided

for the waiver of in vivo data requirements for RLDs whic h were rapidly dissolving, highly soluble, and highly permeable (the “BCS Guidance”); 2) draf t guidance it issued shortly thereafter noting “that bioequivale nce for orally administered dr ugs intended for local action in the GI tract” could be demonstrated by in vitro studies in certain circum stances; 3) an ANDA for vancomycin submitted in late 2004 which “purport ed to show” that Vancocin was “‘rapidly dissolving’ under the BCS Guidance defini tion thereby justifying waiver of the in vivo clinical data requirement in place at that time;” and 4) independent FDA analysis confirming that vancomycin is highly soluble. 10 (CP Response at 9–11.) The revised recommendation provided “that ‘[v]ancomycin is a highly soluble drug and [Vancocin] is rapidly dissolving. Waivers of in

vivo bioequivalence testing can be requested in [ANDAs], provided that the test product is rapidly dissolving at the conditions specified in th e [BCS Guidance].’” ( Id. at 12 (some alterations in the original) (quoting a letter from the FDA to an interested party).) The “FDA did not publicly announce the change in policy, bu t provided information to companies that submitted inquiries regarding the bioequivalence standards for vancomycin.” ViroPharma II , 2012 WL 892926, at *1. ( See Pl.’s Mot. at 7; CP Response at 9, 11.) When one company publicized the new standards, the value of ViroPharma’s stock dropped by “roughly 40%.”

ViroPharma II , 2012 WL 892926, at *1. ( See Compl. ¶ 41.)

10 The FDA “did not independently assess th e ANDA applicant’s disso lution data.” (CP Response at 11.)12 On March 17, 2006, ViroPharma filed a citizen petition 11 to stay the approval of any vancomycin ANDA under the FDA’s ne w bioequivalence testing method. ( See McCalips Decl. ¶ 2; id. , Ex. 1 (ViroPharma’s Petition for Stay of Action, Docket No. FDA-2006-P-007 (as amended, “Citizen Petition”)).) Shortly thereafte r, ViroPharma supplemented its petition to include data purporting to show that Vancocin is not rapidly dissolving. 12 (CP Response at 13.) In response to this supplement, the FDA commis sioned a study which ultimately confirmed “that Vancocin is not ‘rapidly dissolving’ as defined in the BCS Guidance.” ( Id. ) Nonetheless, on December 16, 2008, and while ViroPharma’s Citizen Petition remained pending, the FDA issued a “draft guidance for industry entitled ‘Bioequivalence Recommendation for Vancomycin HCl,’” Notice, 73 Fed. Reg. 76,362, 76,362 (Dec. 16, 2008), that allowed generic applicants to demonstrate bioequivalence through in vitro testing if their proposed vancomycin capsules contained inactiv e ingredients which were qualitatively and quantitatively the same as Vancocin. See ViroPharma II , 2012 WL 892926, at *1. ViroPharma alleges that “[n]either the notic e of the Draft Guidance published in the Federal Register, nor the Draft Guidance itself, iden tified the regulatory authority for the recommendation.” (Pl.’s Mot. at 8; see Compl. ¶ 50.) “[T]wo key factors” led the FDA to th e conclusion “that notwithstanding that

11 When the FDA is considering an ANDA, those w ith rights to or scie ntific knowledge of the innovator drug may provide techni cal information relating to th e generic drug’s bioequivalence by filing a “citizen petition” with the FDA. See AstraZeneca Pharm. , 2012 WL 983481, at *3; Biovail Corp. v. FDA , 448 F. Supp. 2d 154, 157 n.2 (D.D.C . 2006); 21 C.F.R. §§ 10.25(a), 10.30(e).

12 After ViroPharma’s sNDA was approved on December 14, 2011, ViroPharma filed another supplement to its Citizen Petition requesting three years of exclus ivity pursuant to 21 U.S.C. § 355(j)(5)(F)(iv). ( See McCalips Decl., Ex. 2.) All told, the FDA maintains that “ViroPharma has . . . supplemented and/or amended its peti tion twenty times.” (FDA Opp’n at 9 (emphasis deleted).)13 vancomycin capsules are not ‘rapidly dissolving’ under the BCS Guidance, in vitro dissolution studies still are an appropri ate method of demonstrating bioequivalence for vancomycin capsules”: First, vancomycin acts primarily in the colon, and GI transit times for drugs to reach the colon average 3 to 4 hours. Dissolution even at 60 minutes, which all but one Vancocin lot demonstrated in [a 2008 study conducted by the FDA], ensures that even in patients with fast er transit times than healthy subjects, vancomycin will be completely dissolved when it reaches the colon. Second, . . . similar dissolution profiles across the pH ranges recommended in the bioequivalence recommendation ensure that generic and reference products will have equivalent release even in patients w ith extremely short GI transit times or in conditions that would not permit either the [RLD] or the generic product to completely dissolve. (CP Response at 14.) However, in noticing the 2008 Draft Guidance in th e Federal Register, the FDA stressed that it represented only the agency’s “current thinking on this t opic” and stated that “an alternate approach” to bioequivalence may be used if the approach satisfied “the requirements of the applicable statutes and regulations.” 73 Fed. Reg. at 76,363. According to the FDA, it then “received and carefully considered comments” on the Draft Guidance “from a variety of parties, ” including ViroPharma, other innovator drug manufacturers, generic drug ma nufacturers, doctors, patients , patient advocacy groups, and concerned citizens. (CP Response at 16. 13 ) In 2009, FDA convened its Advisory Committee for Pharmaceutical Science to consider the Draft Guidance. ( Id. at 17.) The FDA and industry representatives, including repres entatives of ViroPharma, presente d materials at the meeting, and members of the public also had an opportunity to comment. ( Id. at 18.) After “an extensive

discussion of the scientific bases for the bioe quivalence recommendation” in the Draft Guidance,

13 See Docket Folder Summary, Draft Guid ance for Industry on Bioequivalence Recommendation for Vancomycin HCl, http ://www.regulations.gov/#!docketDetail;D=FDA2008-D-0626 (last visited April 23, 2012).14 the Committee “voted unanimously in favor of endorsing” it. ( Id. ) C. The FDA’s Response to Vi roPharma’s Citizen Petition On April 9, 2012, the FDA denied ViroPharma ’s Citizen Petition in a comprehensive letter ruling, concluding that Vancocin was not entitled to statutory exclusivity ( see id. at 66–73; infra Section II.C.1) and that ViroPharma ’s bioequivalence claims failed. ( See CP Response at 52–60; infra Section II.C.2.)

1. ViroPharma’s Statutor y Exclusivity Claim In denying ViroPharma’s Citizen Petition, th e FDA determined that Vancocin was not entitled to statutory exclusivity under 21 U.S.C. § 355(j)(5)(F)(iv) “due to the limitation on such exclusivity for certain antibiotic products set forth in” 21 U.S.C. § 355(v)(3)(B). (CP Response at 67.) The FDA reasoned th at the QI Act created “a limited opportunity for an application containing an Old Antibiotic to obtain Hatch-Waxman exclusiv ity, if that application (or supplemental application) was submitted after” the Act’s enactment in 2008. (CP Response at 68–69 (emphasis added).) As described above, § 355(v)(3)(B) provides that exclusivity “is not available for ‘any condition of use for which the [O ld Antibiotic] . . . was approved before’” the QI Act’s enactment. ( Id. at 69 (quoting 21 U.S.C. § 355(v)(3)(B)).) Noting that “[t]he QI Act does not expre ssly define what constitutes a ‘condition of use . . . approved before the date of enactment ,’” the FDA first conclu ded that Congress must

have intended for the limitation to have some me aning; it “must exclude from exclusivity some applications and supplements containing new clin ical studies that othe rwise would qualify a nonOld Antibiotic product for 3-year Hatch-Waxman exclusivity,” for, “[t]o conclude otherwise would render [it] meaningless” by “exclud[ing] from” exclusivity “only those studies that already do not qualify for” it. ( Id. ) “To give content to this li mitation,” the FDA concluded that15 it “must find that there is a highe r hurdle for exclusivity for an Old Antibiotic than there is for another kind of product seeki ng 3-year exclusivity.” ( Id. ) Turning to the QI Act’s legi slative history, the FDA determined that the Act was passed “to encourage development of truly novelantibiotics and novel uses of Old Antibiotics.” ( Id. (emphasis added); see id. at 69–70 & nn.333–36 (surveying the legislative history).) Accordingly, the FDA announced that it would in terpret § 355(v)(3)(B) “to permit 3-year HatchWaxman exclusivity for Old Antibiotics only for a significant new use for an Old Antibiotic (such as a new indication for a previously appr oved antibiotic . . .), not for refinements in labeling related to previously approv ed uses for Old Antibiotics.” ( Id. at 70 (emphasis added).) The FDA justified its interpretati on as “consistent with the balance sought by Congress in the QI Act to reward and provide incentives for comp anies to develop innovative new uses of Old

Antibiotics while also facilita ting antibiotic acces s generally through generic approvals and limiting the time period in which the innovator pr oduct is the only product on the market.” ( Id. ) Applying its interpretation, the FDA then dete rmined that Vancocin was not eligible for Hatch-Waxman exclusivity because the December 2011 approval of ViroPharma’s sNDA did not constitute approval of a signi ficant new use for the drug. ( Id. at 70–73.) With respect to the three changes to the Vancocin label on which ViroPharma based its claim of exclusivity, the FDA concluded that granting such exclusiv ity would violate § 355(v)(3)(B). The FDA determined that the inclusion of (1) more speci fic dosing information that was within the range specified on the prior label and was consistent with the well-established standard dosage, (2) new instructions on monitoring patients’ renal function, and (3) new in structions for the continuation of treatment in older patents serv ed only “to incorporate clinical data that supports and refines labeling regarding already approve d conditions of use” and to bri ng the labeling into compliance16 with the “Physician Labe ling Rule” (or “PLR”). ( Id. at 66, 71.) The labeling changes did not effect a “significant new use” for Vancocin because they only “refine[d] the currently approved

indication for treatment of CDAD in alre ady identified patient populations.” ( Id. at 71–72.) In support of its analysis, the FDA cited the fact th at had ViroPharma “intended to seek approval for a new indication or a new dosing regimen,” it s sNDA would have had to comply with certain other statutory requirement s, which it did not. ( Id. at 72 & n.344.) Thus, the FDA concluded that the sNDA did not constitute approval for a ne w “condition of use” as that term is used in § 355(v)(3)(B). ( Id. at 71.) The agency stated that it encouraged pion eer manufacturers’ efforts “to modify labeling to provide doctors and patients with current information based on clinical data” and “to bring their labels into compliance with the PLR.” ( Id. at 73.) However, it concluded that “[r]evising the labeling and providing clini cal data that supports or, at most, refines information about already approved conditions of use . . . does not gi ve rise to an approval for a condition of use that has not been previously approved and therefore merits the limited 3-year exclusivity available for an Old Antibiotic product.” ( Id. )

2. ViroPharma’s Bioequivalence Claim The FDA also rejected ViroPharma’s bioequ ivalence claim. (See CP Response at 52– 56, 59.) ViroPharma had argued that 21 C.F.R § 320.21(b) establishes a default requirement that bioequivalence be demonstrated through in vivo testing, 14 subject to the waiver criteria set forth

14 21 C.F.R. § 320.21(b) provides that “[a]ny person submitting an abbreviated new drug application to FDA shall include in the applica tion either: (1) Evidence demonstrating that the drug product that is the subject of the abbreviate d new drug application is bioequivalent to the [RLD]” or “(2) Information to s how that the drug product is bioequi valent to the reference listed drug which would permit FDA to waive th e submission of evidence demonstrating in vivo bioequivalence as provided in paragraph (f) of th is section.” Subsection (f) is described below.17 in 21 C.F.R. § 320.22, which permits in vitro testing in limited circumstances. 15 On the basis of a lengthy analysis of the relevant regulations, which assessed their text, structure, and history, the

FDA concluded that there is no such default re quirement. For example, the agency cited 21 C.F.R. § 320.24(a), which provides that the agency “may require in vivo or in vitro testing, or both, to . . . establish the bioe quivalence of specific drug prod ucts.” 21 C.F.R. § 320.24(a). 16 Overruling ViroPharma’s objection that § 320.24 merely lists the various approaches for establishing either in vivo or in vitro bioequivalence, depending on wh ich of those two types of testing is otherwise required by the regulati ons, the FDA asserted in its response to

ViroPharma’s Citizen Petition th at § 320.24 provides the agency with discretion to determine, on a case-by-case basis, whether it will require in vivo testing, in vitro testing, or both. (CP Response at 52–54.) Exercising that discretion, and having gone to great lengths to buttress the scientific propriety and necessity of its appr oach, the FDA “determined . . .that the most

15 21 C.F.R. § 320.21(f), referenced in § 320.21(b)(2 ) as instructing an applicant as to the information “which would permit FDA to waive the submission of evidence demonstrating in vivo bioequivalence,” cross-references § 320.22. Subs ections (b), (c), (d), and (e) of § 320.22, in turn, enumerate the relevant criteria and circumstances.

16 21 C.F.R. § 320.24 is entitled “Types of evidence to measure bioavailability or establish bioequivalence.” Section 320.24(a) begins by stating that “bioequi valence may be demonstrated by several in vivo and in vitro methods,” and goes on to provide that “[t]he selection of the method used to meet an in vivo or in vitro testing requirement depe nds upon the purpose of the study, the analytical methods avai lable, and the nature of th e drug product.” Section 320.24(a) concludes by specifying that generic “[a]pplicants shall conduct . . . bioe quivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in” section 320.24(b). Section 320.24(b), in turn, lists “ in vivo and in vitro approaches, in descending order of accuracy, sensitivity, a nd reprudicity,” which are “acceptable for determining the . . . bioequivalence of a drug produc t.” Subsections (1)(i), (2), and (3) describe specific in vivo testing approaches; su bsections (1)(ii) and (5 ) describe specific in vitro testing approaches; subsection (4) refers to “[w]ell-controlled clinical trials”; and subsection (6) allows “[a]ny other approach deemed adequate by FDA to . . . establish bioequivalence.” 21 C.F.R. 320.24(b).18 accurate, sensitive, and reproducible approach available for demonstrating vancomycin capsule bioequivalence is one using in vitro dissolution data, and not clinical study data, which is the least sensitive for this product.” ( Id. at 53; see id. at 19–51 (providing the sc ientific rationale).) In the alternative, the FDA f ound that even if it lacked this discretion, it had “determined that [it] would waive [any in vivo data] requirement for generic va ncomycin applicants that meet

the criteria for in vitro data set forth” in 21 C.F.R. § 320.22(e). (CP Response at 59.) That provision allows the FDA to waive an in vivo bioequivalence testing requirement “for good cause . . . if waiver is compatible with the protection of the public health.” 21 C.F.R. § 320.22(e). The FDA concluded “that such a wa iver would be” appropriate “for generic vancomycin capsules for several reasons,” especi ally in light of its prior conclusion that in vivo bioequivalence testing was scient ifically unsound in this ap plication. (CP Response at 59. 17 ) On the same day that it issued its respons e to ViroPharma’s Citizen Petition, the FDA approved ANDAs for generic vancomycin submitted by Akorn, Alvogen, and Watson Laboratories. ( Id. at 2 n.6.) ViroPharma brought this ac tion four days later, on April 13, 2012.

17 Specifically, the FDA stated that: [V]ancomycin is one of only two FDA- approved treatments for the fast-moving, life-threatening colitis associated with CDAD. . . . [I]ncr eased incidence of CDAD infections as well as more seve re instances of the disease have been extensively reported in the medical lite rature and general media. Medical literature also indicates that in light of the high demand and high cost of Vancocin . . ., doctors and hospitals have begun administering vancomycin parenteral solution[, an alternative formula tion of the antibiotic that is injectable,] to patients orally to treat CDAD. This formulation has never been approved for oral use or for use in this fashion, and thus raises potential pub lic health concerns including a risk of dosage errors. The av ailability of safe and effective generic vancomycin capsules would mitigate these concerns consistent with the fundamental purposes of Hatch-Waxman: to make available to consumers safe and effective generic drug products. (CP Response at 59–60. But see infra n.26.)19 ViroPharma claims that the FDA’s rejection of its statutory exclusiv ity claim violated the FFDCA, and that the agency’s re jection of its bioequivalence cl aim violated the agency’s own regulations.

ANALYSIS The Supreme Court has described the relief sought by ViroPharma as “an extraordinary and drastic remedy.” Munaf v. Geren , 553 U.S. 674, 689–90 (2008) (int ernal quotation marks and citation omitted). To obtain a preliminary inj unction, a plaintiff “must establish that he is likely to succeed on the merits, that he is likely to suffer irreparable harm in the absence of preliminary relief, that the balance of equities tips in his favor, and that an injunction is in the public interest.” Winter v. Natural Resources Defense Council, Inc. , 555 U.S. 7, 20 (2008) (citing, inter alia , Munaf , 553 U.S. at 689–90). The movant “bears the burden of persuasion and must demonstrate, ‘by a clea r showing,’ that the request ed relief is warranted.” McGinn, Smith & Co., Inc. v. Fin. Indus. Regulatory Auth. , 786 F. Supp. 2d 139, 144 (D.D.C. 2011) (quoting Chaplaincy of Full Gospel Churches v. England , 454 F.3d 290, 297 (D.C. Cir. 2007)). 18

While the four factors Winter recites “have typically been evaluated on a sliding scale,” Davis v. Pension Benefit Guaranty Corp. , 571 F.3d 1288, 1291 (D.C. Cir. 2009) (internal quotation marks and citation omitted), “‘[i]t is particularly important for [the movant] to

demonstrate a substantial likelihood of success on the merits.’” McGinn , 786 F. Supp. 2d at 144 (quoting Barton v. Dist. of Columbia , 131 F. Supp. 2d 236, 242 (D.D.C. 2001)); see Sherley v.

18 Where a plaintiff seek s a mandatory injunction, i.e. , one that would alter, rather than preserve, the status quo, some courts have appl ied an even more exacting standard. See Allina Health Servs. v. Sebelius , 756 F. Supp. 2d 61, 69–70 & n.5 (D.D.C. 2010) (collecting cases). However, “the D.C. Circuit has yet to address this question,” id. at 70, and the Court does not need to here because ViroPharma’s claims fail under either standard.20 Sebelius , 644 F.3d 388, 393 (D.C. Cir. 2011) (“[W]e read Winter at least to suggest if not to hold ‘that a likelihood of success is an independent , free-standing requirement for a preliminary injunction.’” (quoting Davis , 571 F.3d at 1296 (Kavanaugh, J., concurring))). Moreover, the

movant must demonstrate an actual “likelihood” of success, not mere ly the existence of “questions so serious, substantial, difficult a nd doubtful, as to make them fair ground for litigation.” Munaf , 553 U.S. at 690 (internal quota tion marks and citation omitted).

III. LIKELIHOOD OF SUCCESS ON THE MERITS

Because the FDA’s denial of ViroPharma’s C itizen Petition is subject to review under the Administrative Procedure Act, 5 U.S.C. §§ 701 et seq ., ViroPharma will only succeed on the

merits if it demonstrates that the FDA’s deci sion was “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.” Id. § 706(2)(A). 19 This standard of review is narrow and highly deferential; it presumes ag ency action to be valid, and it prohibits a court from substituting its judgment for that of the agency. Citizens to Preserve Overton Park, Inc. v. Volpe , 401 U.S. 402, 416 (1971); Int’l Fabricare Inst. v. EPA , 972 F.2d 384, 389 (D.C. Cir. 1992). It bears emphasis that “[i]n an area as complex as” the regulatory “system” for pharmaceuticals, “the agency Congress vests with administrative responsibility must be able to

19 ViroPharma’s complaint states two counts, both of which center on the FDA’s denial of ViroPharma’s Citizen Petition and its approval of generic vancomycin ANDAs. Count I, entitled “Agency Action Not in Accordance with Regula tions,” alleges that the FDA violated its governing regulations and states Viro Pharma’s bioequivalence claim. ( See Compl. ¶¶ 69–74). Count II, entitled “Agency Action Not in Accordance with Statute, alleges that the FDA violated the FFDCA and states ViroPharma’s statutory exclusivity claim. ( See id. ¶¶ 75–78.) Neither count challenges the substance of the FDA’s scie ntific analysis. Accordingly, ViroPharma’s claims relate only to whether the FDA’s actions were “in accordance with law.” 5 U.S.C. § 706(2)(A). Therefore, as counsel for all parties agreed at oral argument, this Court may assess them without recourse to the administrative record. See Am. Bankers Ass’n v. Nat’l Credit Union Admin. , 271 F.3d 262, 266–67 (D.C. Cir. 2001); Hosp. Partners, L.P. v. Sebelius , 794 F. Supp. 2d 162, 171 (D.D.C. 2011).21 exercise its authority to meet ch anging conditions and new problems.” Bob Jones Univ. v.

United States , 461 U.S. 574, 596 (1983); see Mylan Labs., Inc. v. Thompson , 389 F.3d 1272, 1280 (D.C. Cir. 2004) (“There is no denying the co mplexity of the statutory regime under which the FDA operates . . . .”).

A. ViroPharma’s Statutor y Exclusivity Claim ViroPharma’s statutory exclusivity claim, which alleges that the FDA’s letter ruling denying ViroPharma’s Citizen Petition and its a pproval of vancomycin ANDAs are inconsistent with the FFDCA, presents an issue of first impr ession. To address it, the Court begins “with the first step of the two-part framework announced in Chevron . . . and asks[s] whether Congress has ‘directly addressed the preci se question at issue.’” Mayo Found. for Med. Educ. & Research v.

United States , 131 S. Ct. 704, 711 (2011) (quoting Chevron, U.S.A., Inc. v. Natural Resources Defense Council , 467 U.S. 837, 843 (1984)). If the st atutory language in 21 U.S.C. § 355(v)(3)(B) is unambiguous and “the intent of Congr ess is clear, that is the end of the matter; for the [C]ourt, as well as the agency, must give effect to the unambiguously expressed intent of Congress.” Chevron , 467 U.S. at 842–43. However, “if the st atute is silent or ambiguous with respect to the specific issue,” the Court will proceed to the second step of the Chevron analysis

and ask whether the FDA’s inte rpretation is “permissible.” Id. at 843. At this step, the interpretation is “given control ling weight unless” it is “manifestly contrary to the statute.” Id. at

844. Despite these bedrock principles, ViroPharma states, without elabor ation, that the FDA’s interpretation of 21 U.S.C. § 355(v)(3)(b) is not entitled to Chevron deference because the agency’s letter ruling denying its Citizen Petition is an “informal agency pronouncement . . . that

lacks the force of law.” (Pl.’s Mot. at 19 n.9 (citing United States v. Mead Corp. 553, U.S. 219,22 229 (2001).) This contention is meritless. Firs t, ViroPharma does not, and cannot, challenge the FDA’s authority to issue lett er rulings and approve ANDAs. Second, agency interpretations reached through means less formal than notice and comment rulemaking are not automatically deprived of the judicial deferen ce that they are otherwise due. Barnhart v. Walton , 535 U.S. 212, 221 (2002). Rather, “whether a c ourt should give such deference depends in significant part upon the interpretive method used and the nature of the question at issue.” Id. at 222 (citing

Mead , 533 U.S. at 229–31). In Barnhart , the Court concluded that “the interstitial nature of the legal question, the related e xpertise of the [a]gency, the importance of the question to administration of the statute, th e complexity of that administra tion, and the careful consideration the [a]gency has given the question over a long period of time all indicate that Chevron provides the appropriate legal lens through which to view the legality of the [a]g ency interpretation” it was reviewing. Id. Pursuant to Barnhart , the D.C. Circuit has consistently accorded Chevron deference to the FDA’s letter rulings, including its responses to citizen petitions. See Mylan

Labs. , 389 F.3d at 1280 (collecting cases); accord Apotex, Inc. v. FDA , No. 06-5060, 226 Fed. App’x 4, 5 (D.C. Cir. Feb. 23, 2007); Teva Pharm. Indus. Ltd. v. Crawford , 410 F.3d 51, 53 (D.C. Cir. 2005). Chevron applies here. 20 Finally, ViroPharma is wrong to suggest that Chevron deference should not apply because the FDA issued its interpretation “after the commencement of litigation with ViroPharma.” (Pl.’s Mot. at 19 n.9.) Neither Vancocin’s e ligibility for 3-year statutory exclusivity in general nor the FDA’s specific interpretation of 21 U.S.C. § 355(v)(3)(b) were at issue in the prior litigation. See ViroPharma I , 777 F. Supp. 2d 140. Moreover, the Circuit has

20 Regardless, as did the Circuit in Mylan Laboratories , the Court concludes that “[e]ven were the FDA’s decision subject only to Skidmore deference, the result would likely be the same.” 389 F.3d at 1280 n.6.23 applied Chevron to the FDA’s response to a citizen pet ition even though the FDA acted after the plaintiff “had already moved for injunc tive relief in the district court.” Serono Labs., Inc. v.

Shalala , 158 F.3d 1313, 1325 (D.C. Cir. 1998). In Serono , the Circuit characterized the FDA’s letter ruling as “represent[ing] the considered views of the agency decisionmaker . . ., announced at the usual point in the agency’s decision-maki ng process (the end), rath er than the views of litigation counsel trying to come up with an explanation after the fact.” Id. In such circumstances, the Circuit held, “‘[t]here is si mply no reason to suspect that the interpretation does not reflect the agency’s fair and consid ered judgment on the ma tter in question.’” Id. (quoting Auer v. Robbins , 519 U.S. 452, 462 (1997)). Therefore, the Court proceeds to Chevron ’s step one and applies “the traditional tools of statutory construction in order to discern whether Congress has spoke n directly to the question at

issue.” Eagle Broad. Grp., Ltd. v. FCC , 563 F.3d 543, 552 (D.C. Cir. 2009). The Court finds it likely that the statute is ambiguous. The FFDCA does not address what constitutes a “condition of use . . . approved before” the date of the QI Act’s enactment. 21 U.S.C. § 355(v)(3)(B). Starting with the plain meaning of the text and looking to the language itself, Blackman v. Dist. of Columbia , 456 F.3d 167, 176 (D.C. Cir. 2006), “condition of use” is not defined in the

FFDCA. And while the mere “absence of a st atutory definition does not render a [phrase] ambiguous,” Natural Resources Defense Council v. EPA , 489 F.3d 1364, 1373 (D.C. Cir. 2007), nothing about “the specific context in which [the phrase] is used” or “the broader context of the statute as a whole” is likely to compel the conclusion that the phrase has a definite meaning.

Blackman , 456 F.3d at 176 (internal quotation mark s omitted). ViroPharma’s strongest argument is that “conditions of use” is used th roughout the FFDCA and in the FDA’s regulations to unambiguously include a variety of aspects of a drug and its administration that go beyond the24 “significant new uses” contem plated by the FDA’s interpretation of § 355(v)(3)(B). ( See Pl.’s Mot. at 15, 20–23 (citing 21 U.S.C. §§ 321(p), 355(d)(1 ),(5), 355(j)(2)(A)(i)).) Yet, that fact is

of little moment where the term is far from unambiguous no matter the application. 21 Neither its repetition in the FFDCA nor, as counsel for Viro Pharma pressed at oral argument, its common usage in industry transforms it into a clear term. More importantly, although it is true that “[w]hen Congress uses the same [phrase] in different parts of a statute, it usually means th e same thing,” the Circuit has instructed that “statutory interpretation is not just about logic” and a statute’ s terms “should be read in context, the statute’s place in the overa ll statutory scheme should be considered, and the problem Congress sought to solve should be taken into account.” PDK Labs. Inc. v. DEA , 362 F.3d 786, 796 (D.C. Cir. 2004) (internal quotation marks and citations committed). With respect to this final admonition, the FDA has demonstrated that when § 355(v)(3)(B) was promulgated as part of the QI Act, Congress sought to address a problem much more specific th an that motivating the FFDCA as a whole. This alone is enough to di fferentiate “conditions of use” as employed in § 355(v)(3)(B) from the employment of that sa me term in unrelated statutory provisions. Cf. Abbott Labs. v. Young , 920 F.2d 984, 987 (D.C. Cir. 1990) (“ it is not impermissible under

Chevron for an agency to interpret an imprecise term differently in two separate sections of a statute which have different purpos es”). Moreover, “[i]t was only years” after the enactment of the QI ACT in 2008 “that the” specific issue ad dressed by the agency in 2012—whether a drug

manufacturer is entitled to rene wed exclusivity where it makes ch anges to the drug’s label that

21 ViroPharma’s appeal to the FDA’s definition of “condition of us e” in a regulation not related to the issues before this Court ( see Pl.’s Mot. at 20 (citing 21 C.F.R. § 314.53(d)(2)(B)) undercuts its argument. If the statute is as una mbiguous as ViroPharma co ntends, then reference to an unrelated regulatory de finition would be unnecessary.25 the agency deems minor—arose. PDK Labs. , 362 F.3d at 796

. “This is at least some indication that Congress, in [§ 355(v)(3)(B)], did ‘not directly address[] the precise ques tion at issue’ in this

case.” Id . (quoting Chevron , 467 U.S. at 843). 22 Furthermore, ViroPharma provides scant suppor t for its contention th at the “ordinary and natural meaning [of ‘conditions of use’] plainly encompasses any qualifications concerning the proper usage of the drug for its intended purpose, most obviously in the form of instructions or recommendations to the users of the drug.” (Pl.’s Mot. at 14 (emphasis added).) Where courts address a complex statutory regime, laden with scientific language a nd other terms of art, dictionary definitions do not suffi ce to show an unambiguous meaning. See, e.g. , Emerson v. Steffen , 959 F.2d 119, 121 (8th Cir. 1992) (holding that a provision of Title XIX of the Social Security Act remained ambiguous even though a key phrase was defined by Webster’s Third New International Dictionary because, “[w]hile we do not dispute the correctness of this definition, we do not believe that our agreement w ith the dictionary neces sitates agreement with the plaintiffs”). 23 And the fact “[t]hat a statute is sus ceptible of one constr uction does not render its meaning plain if it is also susceptible of another, plausible construction,” as the Court concludes § 355(v)(3)(B) is. PDK Labs. , 362 F.3d at 796.

22 Tellingly, ViroPharma has not cited any agency or court decisions conferring Hatch-Waxman exclusivity in response to changes of the type th at were made to Vancocin’s labeling after the company’s sNDA was approved in December 2011.

23 Cf. A.T. Massey Coal Co. v. Holland , 472 F.3d 148, 160 (4th Cir. 2006) (concluding that, although a certain term had “several meanings, as demonstrated by . . . dictionary definitions,” the provision at issue was not ambiguous because “s tatutory context and historical context . . . both reveal[ed] a uniform and precise meaning of the term”); New Castle Cnty. v. Hartford Accident & Indem. Co. , 933 F.2d 1162, 1193–94 (3d Cir. 1991) (“Although dictionaries are helpful insofar as they set forth the ordinar y, usual meaning of words, they are imperfect yardsticks of ambiguity” because they “define words in the abstract, whereas” courts “must ascertain whether [a specific term] is am biguous in the contex t of a” statute.).26 Nor would an examination of the QI Act’s purpose and legislativ e history undercut the FDA’s interpretation. See Nat’l Cable & Telecomms. Ass’n v. FCC , 567 F.3d 659, 663 (D.C. Cir. 2009) (instructing courts to use “all ‘traditional to ols of statutory inte rpretation,’ including ‘text, structure, purpose, and legislative hi story,’ to ascertain Congress’ intent at Chevron step one” (quoting Pharm. Research & Mfrs. of Am. v. Thompson , 251 F.3d 219, 224 (D.C. Cir. 2001))); PDK Labs. , 362 F.2d at 798 n.4. To the contrary, as the Court’s Chevron step-two analysis demonstrates, the FDA’s interpretation is reasonable in large part because it furthers Congress’s express purpose. Having concluded that § 355(v)(3)(B) is ambiguous, the Court will move to Chevron ’s second step and defer to the agen cy’s reasonable interpretation of the provision as set forth in its response to ViroPharma’s Citizen Petition. While ViroPharma may argue with that interpretation on policy grounds an d present alternative readings of the provision’s purpose and legislative history, such claims fail in the face of the agency’s carefully considered decision. See

Serono Labs. , 158 F.3d at 1321 (under Chevron step two, “courts are bound to uphold an agency interpretation as long as it is reasonable—regard less whether there may be other reasonable, or even more reasonable, views”); Bush-Quayle ’92 Primary Cmty., Inc. v. FEC , 104 F.3d 448, 453 (D.C. Cir. 1997) (“When confronted with alterna tive sensible readings of an ambiguous statute the court is directed by Chevron to adopt the one the ag ency presents.” (citing Chevron , 467 U.S. at 844)). First, the legislative histor y supports the FDA’s conclusion that Congress’s purpose in the QI Act was to “balance the need to encourage development of new antibiotic drugs to combat the growing number of disease-resistant bacterial in fections and the desire to ensure access to previously approved antibiotics th rough approval of generic versions of such antibiotics.” (CP27 Response at 69.) See, e.g. , 154 Cong. Rec. S9638, 9638 (daily ed. Sept. 26, 2008) (statement of Sen. Burr) (“Section 4 of [the bill which eventually became the QI Act], entitled ‘Incentives for the Development of and Access to Certain Antibiotics, ’ is an important step forward to help spur research on new antibiotics and provide incentives for the creation of additional generic antibiotics.”); 153 Cong. Rec. S 5759, 5823 (daily ed. May 9, 2007) (statement of Sen. Kennedy) (in discussing what is now codified at § 355( v)(3)(B) when it was originally proposed in 2007, noting that the subsection “includes limits that would prevent pharmaceutical manufacturers from abusing the process to extend the life of old active ingredient drugs”); 153 Cong. Rec. S5630, 5630 (daily ed. May 7, 2007) (statement of Sen. Kennedy) (“The amendment strikes the right balance between innovation and access . . . .”). The FDA’s interpretation of § 355(v)(3)(B) also furthers Congress’s more general purpose of “‘increas[ing] competition in the drug industry by facilitating the approval of generic copies of drugs.’” Serono Labs. , 158 F.3d at 1319 (D.C. (quoting Mead Johnson Pharm. Grp. v. Bowen , 838 F.2d 1332, 1333 (D.C. Cir. 1988)). Second, especially in lig ht of this legislative history, th e FDA was within its discretion to apply a limiting principle so that Hatch-Waxm an’s exclusivity provi sions do not apply to all approved changes that are “new” (in that they deri ve from new clinical investigations). As the FDA explained ( see CP Response at 69), the genera l exclusivity pe riod provided in § 355(j)(5)(F)(iv), which was made applicable to Old Antibiotics by § 355( v)(1)(A), is itself limited to that which is “new” about the given dr ug. Thus, for § 355(v)(3)(B) to be something more than mere surplusage, it must impose a further limitation on the availability of three-year exclusivity. See, e.g. , TRW Inc. v. Andrews , 534 U.S. 19, 31 (2001) (“It is a cardinal principle of statutory construction that a statute ought . . . to be so construe d that . . . no clause, sentence, or word shall be superfluous, void, or insignifi cant.” (internal quotati on marks and citations28 omitted)). Third, once the FDA reasonably determined th at § 355(v)(3)(B) must impose a limitation, it was well-within the agency’s au thority to set the bounds of that limitation. “Such interpretive line drawing lies at the heart of Chevron deference.” Dickow v. United States , 654 F.3d 144, 151 (1st Cir. 2011). Here, be cause the line the FDA drew was eminently “reasonable, Chevron requires” the Court to accept it. Nat’l Cable & Telecomms. Ass’n v. Brand X Internet Servs. , 545 U.S. 967, 981 (2005). The FDA, “[u]pon review[ing] the statute and the available legislative history,” stated that it interprets [§] 355(v)(3)(B) to permit 3- year Hatch-Waxman exclusivity for Old Antibiotics only for a significant new use for an Old Antibiotic (such as a new indication for a previously approved antibiotic, or a new approval for a submitted but never previously approved antibiotic), not for refinements in labeling related to previously approved uses for Old Antibiotics. (CP Response at 70.) ViroPharma has not demonstr ated that this interpretation of “conditions of use,” 21 U.S.C. § 355(v)(3)(B), is anything other than “‘a reasonable polic y choice for the [FDA] to [have made].’” Nat’l Cable , 545 U.S. at 986 (quoting Chevron , 467 U.S. at 845). ViroPharma protests that the agency has gone too far, that the stat ute contemplates some limitation on exclusivity but not on e with this much bite. In pa rticular, ViroPharma argues at length that the FDA’s letter ruling shows that th e agency will only allow exclusivity where an sNDA specifies a new indication for an Old Antibiotic. ( See Pl.’s Mot. at 19–24; Pl.’s Reply at 1–2.) But the Court “need not decide whether a c onstruction [of § 355(v)(3)(B)] that resulted in these consequences would be unreasonable because [it does] not believe that these results follow from the construction the [FDA] adopted.” Nat’l Cable , 545 U.S. at 997. The FDA cited a “new indication” only as an example of a “significant new use,” as evidenced by the fact that “new indication” is contained in a pa renthetical and introduced by the words “such as.” (CP Response29 at 70.) The crux of the agency’s interpretati on is “significant new use,” and by its terms it clearly includes more than just new indications. The FDA’s application of its interpretation to Vancocin underscores this point. In concluding that “the revision of the Vancocin label . . . does not constitute approval for a

condition of use that has not been ‘approved before the date of [the QI Act’s] enactment’ within the meaning of [§ 355(v)(3)(B)],” the FDA determin ed that the new label (1) did “not constitute a significant expansion in the conditions of use of the product” to new “patient populations;” (2) did not “support[] a changed indication;” and (3 ) did not prescribe “a new dosing regimen.” ( Id. at 71–72.) Only the second factor relates to new indications, whereas the first and third factors confirm that “significant new use” is broader. The FDA’s constructi on “does not leave all” changes in a drug’s labeling “exempt from” Hatch-Waxman exclusivity. Nat’l Cable , 545 U.S. at 997. As such, it is nowhere near as “radical ” as ViroPharma suggests in its motion. (Pl.’s

Mot. at 21. 24 ) Finally, given this Court’s conclusion that the FDA’s interpretation of § 355(v)(3)(B) is permissible under Chevron , it follows that ViroPharma’s protests regarding the purported significance of Vancocin’s new la bel are unavailing. ViroPharma has failed to demonstrate that Watson Laboratories is incorrect when it argues that “[u]nder the sNDA language, patients [are]

24 ViroPharma concedes as much in its reply br ief. There, ViroPharma acknowledges that the FDA, in opposing its motion be fore this Court, “offers a perfectly acceptable definition of ‘conditions of use’—they ‘encompass how, to wh om, and for which purposes a drug product is used,’” but argues that the agency, in denying its Citizen Petition, did not use this definition. (Pl.’s Reply at 1–2 (emphasis added) (quoting FDA Opp’n at 21; citing SEC v. Chenery Corp. , 318 U.S. 80, 93–94 (1943)).) As the foregoing disc ussion makes clear, the FDA indeed defined and applied “conditions of use” in terms of how a drug is used (the third factor above), to whom it is prescribed (the firs t factor), and for what purposes (the second factor). Furthermore, this shows that ViroPharma may not rely on Chenery , as in upholding the F DA’s interpretation, the Court has considered only the very “grounds upo n which the agency acted.” 318 U.S. at 94.30 being given the same drug, in the same dosage, an d in the same method of administration as had been given before the label was changed.” (Wats on Opp’n at 7.) Because the agency was within its discretion to interpret § 355(v)(3)(B) as denying exclusivity where a pioneer manufacturer puts forward only “refinements in labeling re lated to previously approved uses for Old Antibiotics” (CP Response at 70), then it was cert ainly entitled to conclude, on the basis of its expertise, that the changes to the Vancocin labeling do not hing more than “support[] and refine[]” materials “regarding alread y approved conditions of use.” ( Id. at 71.) The FDA’s decision “involve[s] a subject matter [tha t] is technical, complex, and dynamic,” Nat’l Cable , 545 U.S. at 1002–03 (internal quotation marks and citation omitted; some alterations in the original), and “rests on the ‘agency’ s evaluations of scientific data w ithin its area of expertise.’”

Serono Labs. , 158 F.3d at 1320 (quoting A.L. Pharma, Inc. v. Shalala , 62 F.3d 1484, 1490 (D.C. Cir. 1995); citing Schering Corp. v. FDA , 51 F.3d 390, 399–400 (3d Cir. 1995)). Accordingly, it “is entitled to a high level of de ference from” reviewing courts, id. (internal quotation marks and citation omitted), and appl ying this standard, the Court concl udes that ViroPharma is not likely to succeed on the merits of its statutory exclusivity claim.

B. ViroPharma’s Bioequivalence Claim The “FDA’s ‘judgment[] as to what is require d to ascertain the safety and efficacy of drugs,’” including its decisions rega rding bioequivalence, also “‘fall[ s] squarely within the ambit of the FDA’s expertise a nd merit[s] deference from’” reviewing courts. A.L. Pharma , 62 F.3d at 1490 (quoting Schering Corp. , 51 F.3d at 399); see Graceway Pharm., Inc. v. Sebelius , 783 F. Supp. 2d 104, 111 (D.D.C. 2011) (applying a “‘high degree of deference . . . to the FDA’s determinations regarding which methodologies it determines are needed to test the bioequivalency of a given generic’” (quoting Astellas Pharma U.S., Inc. v. FDA , 642 F. Supp. 2d31 10, 19 (D.D.C. 2009)). Moreover, it is undisputed that the FDA has broad statutory authority to establish bioequivalence standards, including permitting in vitro testing. 21 U.S.C. § 355(j)(8)(C). ( See Pl.’s Mot. at 33.) Nor does ViroPh arma challenge the FDA’s scientific

conclusion that in vitro testing is appropriate in these circ umstances or request that the Court ignore the well-established principl es of deference described above. Rather, ViroPharma argues that the FDA violated its regulations in approving vancomycin ANDAs without in vivo bioequivalence testing. This Court described the dispute in

ViroPharma I : According to ViroPharma, 21 C.F.R § 320.21( b) sets forth a general requirement that bioequivalence be demonstrated through in vivo testing, unless the drug product meets one of the waiver criteria set forth in 21 C.F.R. § 320.22. . . . The FDA, however, argues that there is no such default requirement for in vivo data to establish bioequivalence. . . . Instead, th e FDA relies on language in 21 C.F.R. § 320.24[(a)], which states that “FDA may require in vivo or in vitro testing, or both, to . . . establish the bioequivalence of specific drug products.” [The] FDA therefore asserts that it has discretion to determine, on a case-by-case basis, whether it will require in vivo testing, in vitro testing, or both in order to establish the bioequivalence of a drug product. According to ViroPharma, however, 21 C.F.R. § 320.24 merely lists the vari ous methods for establishing either in vivo or in vitro bioequivalence, depending on which of those two types of testing is otherwise required by the regulations. 777 F. Supp. 2d at 143. As described above ( see supra Section II.C.2), in denying ViroPharma’s Citizen Petition, the FDA rejected each of plaintiff’s arguments. ( See CP Response at 52–56.) The agency set forth its interpretation of its re gulations and justified that interpretation with reference to the regulatory text, structure, and history. The FDA carefully ex plained why the regulations contain no default requirement for in vivo bioequivalence data, and th erefore why no waiver was required for the vancomycin ANDAs. ( Id. ) The agency then stated that, in the alternative, even if such a waiver were required, it would issue it to generic vancomycin applicants “for good32 cause” and in order to “protect[] . . . th e public health.” 21 C.F.R. § 320.22(e). 25 ( See CP Response at 59–60.) The FDA expressly found that the waiver was appropriate because, among other factors, “vancomycin is one of only tw o FDA-approved treatments for the fast-moving, life-threatening colitis associated with CDAD,” such that “[t]he availability of safe and effective generic vancomycin capsules woul d” protect the public health and further “the fundamental purposes of Hatch-Waxman.” ( Id. 26 ) An agency’s interpretation of its own regula tions is “controlling” unless it is “plainly erroneous or inconsistent with the regulation.” Auer , 519 U.S. at 461 (internal quotation marks

25 ViroPharma tries to narrow the applicabil ity of 21 C.F.R. § 320.22(e) by relying on an explanatory statement accompanying th e provision’s promulgation in the Federal Register

. See Final Rule, 42 Fed. Reg. 1,624, 1,642 (Jan. 7, 1977). But contrary to ViroPharma’s arguments, its “alternative readi ng” of the regulation is not “com pelled” by any “indication[] of the [Commissioner’s] intent at the time of the regulation’s promulgation.” Gardebring v. Jenkins , 485 U.S. 415, 430 (1988). Rather, the explanatory statement confirms the FDA’s position that it will not insist on, or even permit, in vivo bioequivalence data where such data does not demonstrate a drug’s safety and effectiveness, bu t where it is otherwise known that the drug is suitable and needed. See 42 Fed. Reg. at 1,642 (section 320.22(e) allows the “FDA to permit the continued marketing of medically important dr ug products while adequate methodology is being developed or bioavailability studies are being co nducted”). Second, and more importantly, the statement predates the Hatch-Waxman generi c drug approval amendment and the attendant regulations that allow FDA to determine whic h bioequivalence testing is appropriate in a particular situation. See Final Rule, 57 Fed. Reg. 17,950, 17,951 (April 28, 1992) (implementing Hatch-Waxman and leaving in place the br oad language in 21 C.F.R. § 320.22(e)).

26 In its response to ViroPharma’s Citizen Petiti on, the FDA also stated that a waiver under 21 C.F.R. § 320.22(e) would protect the public health because the “high demand and high cost” of Vancocin had caused doctors to re sort to administering injectable vancomycin orally, despite the fact that the injectable “formula tion has never been approved for or al use.” (CP Response at 59.) At oral argument, counsel for ViroPharma argued that the FDA has, in fact, approved injectable vancomycin for oral use. The FDA subsequently admitted error. ( See Pl.’s Reply at 5 (“As the Government has now conceded, that reasoning . . . is ‘incorrect,’ as ‘t he FDA-approved labeling for the parenteral ( i.e. , injectable) dosage form of va ncomycin HCl provides for oral administration of the drug.’” (quoting an Ap ril 19, 2012 email from the FDA’s counsel)). Accordingly, in rejecting ViroPharma’s bioequ ivalence claim, the Court does not rely on the FDA’s erroneous second argument for waiver under 21 C.F.R. § 320.22(e).33 and citation omitted). Especially given the scientific expertise driving the FDA’s well-reasoned decision in this matter, see Serono Labs. , 158 F.3d at 1320, the Court co ncludes that ViroPharma is unlikely to prevail on the mer its of its bioequivalence claim. The FFDCA and a number of the FDA’s own regulations grant the agency wide discretion in “determin[ing] whether bioequivalence has b een established.” Bristol-Myers Squibb Co. v. Shalala , 923 F. Supp. 212, 217 (D.D.C. 1996). 27 Furthermore, in addition to the provi sion on which the agency specifically relied, 21 C.F.R. § 320.22(e), “waivers” of any in vivo bioequivalence requirement for ANDAs may be permitted pursuant to, inter alia , §§ 320.21(b)(2), 320.21(f), 320.22, and 320.24(b)(6). Where the regulations allow so many “waivers,” the “default” position that ViroPharma argues is

difficult to discern. 28 In light of the deference owed, th e Court has no basis for overruling the

27 At oral argument, counsel for ViroPharma acknowledged that Judge Urbina’s decision in Bristol-Myers supports the FDA’s position but argued th at it was wrongly decided. Counsel, however, could not cite any aut hority in support of ViroPharma’s reading of the regulations.

28 ViroPharma is of course correct that an agency ’s interpretation of its own regulations is owed no deference if that interpretation is inconsistent with the agency’s “int ent at the time of the regulation’s promulgation,” Gardebring , 485 U.S. at 430, and that “the preamble to a regulation is evidence of an agency’s contemporane ous understanding of its proposed rules.” Wyoming Outdoor Council v. U.S. Forest Serv. , 165 F.3d 43, 53 (D.C. Cir. 1997). ( See Pl.’s Reply at 5.) However, the FDA’s lengthy preamble to the rules at issue here contains statements that support both parties’ positions. ViroPharma points to th e agency’s statement that, “[i]n general, the submission of in vivo data is required.” 57 Fed. Reg. at 17,976. The FDA, on the other hand, relies on its statement that Bioequivalence can be established by pharmacodynamic measurement as well as by in vitro techniques and bioequivalence studies with clinical endpoints. The preferred method for establishment of bioe quivalence . . . is determined on a caseby-case basis, depending on the drug under study. 57 Fed. Reg. at 17,972. In the end, these dueli ng passages do little to illuminate the Secretary’s intent, and only underscore the fact that the regulations allow the FDA significant leeway to make decisions about bioequivalence based on its particular expertise.34 FDA’s interpretation of 21 C.F.R. Part 320. Whet her it is the “most natu ral” interpretation is

immaterial. Pauley v. BethEnergy Mines, Inc. , 501 U.S. 680, 702 (1991); see Young v. Cmty.

Nutrition Inst. , 476 U.S. 974, 980 (1986). Because it is not clearly erroneous, the Court must

defer to it.

IV. IRREPARABLE HARM ViroPharma’s showing of irreparable injury is especially unpersuasiv e. “The irreparable injury requirement erects a ve ry high bar for a movant.” Coal. for Common Sense in Gov’t

Procurement v. United States , 576 F. Supp. 2d 162, 168 (D.D.C. 2008). 29 The injury must “be both certain and great; it must be actual and not theoretical.” Wis. Gas Co. v. FERC , 758 F.2d 669, 674 (D.C. Cir. 1985) (per curiam). Of re levance here, economic loss qualifies only if it “threatens the very existen ce of the movant’s business,” id. , 30 or where the movant, in addition to making a very strong showing of likely success on the merits, “has little hope of obtaining ‘adequate compensatory or other co rrective relief at a later date’ if the injunction does not issue.” O’Donnell Constr. Co. v. Dist. of Columbia , 963 F.2d 420, 428 (D.C. Cir. 1992) (quoting Va.

Petroleum Jobbers Ass’n v. Fed. Power Comm’n , 259 F.2d 921, 925 (D.C. Cir. 1958)); cf. Chaplaincy , 454 F.3d at 297 (to be irreparable, an in jury “must be beyond remediation,” and

29 Albeit in a concurring opinion, two Circuit judges have stated that, notwithstanding courts’ traditional sliding scale analysis of the prelim inary injunction factors, the Supreme Court in Winter “ruled that the movant always must show a likelihood of irreparable harm.” Davis , 571 F.3d at 1296 (emphasis added) (Kavanaugh, J., concurring) (citing Winter , 555 U.S. at 21–22); accord Am. Trucking Ass’ns v. City of Los Angeles , 559 F.3d 1046, 1052 (9th Cir. 2009). At minimum, a party seeking a prelim inary injunction must “demonstrate at least ‘some injury’” to succeed on its motion “since ‘[t]he ba sis of injunctive relief in the federal courts has always been irreparable harm.’” CityFed Fin. Corp. v. Office of Thrift Supervision , 58 F.3d 738, 747 (D.C. Cir. 1995) (some internal quotation marks omitted) (quoting Sampson v. Murray , 415 U.S. 61, 88 (1974)).

30 See Astellas Pharma , 642 F. Supp. 2d at 22 (“[I]t is well-s ettled that economic loss alone will rarely constitute irreparable harm.” (citing Wis. Gas Co. , 758 F.2d at 674)).35 “‘[t]he possibility that adequate compensatory . . . relief will be available at a later date, in the ordinary course of litigation weighs heavily against a claim of irreparable harm’” (quoting Wis.

Gas Co. , 758 F.2d at 674)); accord Nat’l Med. Care, Inc. v. Shalala , No. 95-860, 1995 WL 465650, at *3 (D.D.C. June 6, 1995) (concluding that, where plain tiffs had demonstrated an “overwhelming likelihood that” th ey would prevail on the merits, they had also demonstrated irreparable injury despite alleging threatened economic harms because upon prevailing they would not be able to “bring an action to reco ver” their damages). Where a plaintiff cannot recover money damages from the government owi ng to sovereign immunity, for example, some courts have held that “any loss of inco me suffered by a plaintiff is irreparable per se .”

Feinerman v. Bernardi , 558 F. Supp. 2d 36, 51 (D.D.C. 2008) (citing United States v. New York , 708 F.2d 92, 93–94 (2d Cir. 1983)); accord Woerner v. U.S. Small Bus. Admin. , 739 F. Supp. 641, 650 (D.D.C. 1990) (finding economic loss co nstituted irreparable harm “because the government is immune from damage suits”). Yet, irreparability aside, it remains incumbent on plaintiffs to demonstr ate, first, that they

are threatened with serious injury

. See, e.g. , N. Air Cargo v. USPS , 756 F. Supp. 2d 116, 125 n.6 (D.D.C. 2010) (“While the Court agrees that irrecoverable financial loss may constitute irreparable injury in some cases, this Court is of the opinion that a party asserting such a loss is not relieved of its obligati on to demonstrate that its harm is ‘great.’” (quoting Wis. Gas Co. , 758 F.2d at 674)); Gulf Oil Corp. v. Dep’t of Energy , 514 F. Supp. 1019, 1026 (D.D.C. 1981) (to qualify, injury must be “more than simply irretrie vable; it must also be serious in terms of its effect on the plaintiff”). ViroPharma has not made the requisite showing here. It alleges that “if injunctive relief is not granted,” its “revenue from Vancocin will likely be significantly an d rapidly eroded, as its36 share of the market for vancomycin capsules is taken over by generic competition.” (Pl.’s Mot. at 41 (citing Rowland Decl. ¶¶ 26–32); see Rowland Decl. ¶ 26 (“If FDA approval to market generic copies of Vancocin is not immediately enjo ined and, as a result, if the generic companies continue marketing generic copies of Va ncocin, ViroPharma will suffer immediate and irreparable injury from a substantial decrease in ViroPharma’s sales of Vancocin.”).) Courts have consistently held, however, that such vague allegations do not sati sfy the high irreparable injury standard. See Astellas Pharma , 642 F. Supp. 2d at 21–23 (concluding that plaintiff pioneer drug company had not established irrepara ble injury where sales of the RLD constituted “approximately half of its total U.S. revenue fo r [a given] fiscal year” (collecting cases)). 31 ViroPharma cannot escape the fact that “‘[t]he mere existence of competition is not irreparable harm, in the absence of substantiation of severe economic impact.’” Bristol-Myers Squibb Co. , 923 F. Supp. at 221 (quoting Wash. Metro. Area Tran. Comm’n v. Holiday Tours, Inc. , 559 F.2d 841, 843 n.3 (D.C. Cir. 1977)).

31 Cases holding that “‘[w]here a plaintiff cannot recover damages from an agency because the agency has sovereign immunity, ‘ any loss of income suffered by [the] plaintiff is irreparable per se ’” are thus inapplicable here, where ViroPharma ’s allegations of injury are too vague to be credited. Smoking Everywhere, Inc. v. FDA , 680 F. Supp. 2d 62, 77 n.9 (D.D.C. 2010) (emphasis added) (quoting Feinerman , 558 F. Supp. 2d at 51). Smoking Everywhere is also distinguishable on its facts, as there the court’s irreparable injury determination was based in large part on the fact “that the potential ec onomic loss and loss of good will are substantial, especially for a fledgling company like [plaintiff, founded just one year prior,] that has only one product line.” Id. at 76. ViroPharma, by contrast, was founded in 1994 and has at least four product lines at present and is currently develo ping three more. (Rowland Decl. ¶¶ 4, 7, 10.) Finally, if Feinerman would hold that ViroPharma has show n irreparable injury because it has put forward some allegation of threatened ha rm, however vague, 558 F. Supp. 2d at 51,this Court is persuaded by Judge Sullivan that “prospectiv e injunctive relief would often cease to be an ‘extraordinary remedy’ in cases i nvolving government defendants.” N. Air Cargo , 756 F. Supp. 2d at n.6 (quoting Winter , 555 U.S. at 22); see also Gulf Oil Corp. , 514 F. Supp. at 1025–26 (surveying the case law and concluding that, alth ough “there is some appeal to the proposition that any damage, however slight, which cannot be made whole at a later time, should justify injunctive relief,” the better rule is to require plaintiffs to demo nstrate a “serious” injury because “some concept of magnitude . . . is implicit” in the standards governing prel iminary injunctions).37 ViroPharma also claims that it will suffer re putational injury if th e approved vancomycin generics prove “unsafe or ineffec tive.” (Pl.’s Mot. at 42.) This allegation is too speculative. See

Astellas Pharma , 642 F. Supp. 2d at 23 (finding no irrepara ble harm where “plaintiff’s concerns about the potential loss of goodw ill and reputation are founded enti rely on its belief that the approved generic [drug] may be more harmful than [its own brand-name drug], a belief that . . . lacks evidentiary support and is entirely speculative”); Bristol-Myers Squibb Co. , 923 F. Supp. at 221 (holding that the plaintiff fa iled to establish irreparable harm because “there is nothing

before the court which would lead it to conc lude that [the competing drug] will cause any harmful health effects”). Because ViroPharma ha s not alleged that there are in fact any quality or safety issues associated with generic vancom ycin products, its fear of reputational injury can be dismissed out of hand. Moreover, the sugges tion that patients and physicians would mistake generic vancomycin and any associated negative o ccurrences for Vancocin i gnores that fact that “[i]f some confusion were to occur, [ViroPharm a] has the tools that any manufacturer would have at its disposal to establis h its product uniquely in the minds of customers and their doctors.” Somerset Pharm., Inc. v. Shalala , 973 F. Supp. 443, 455 (D. Del. 1997). Most importantly, as to both its alleged economic and reputational harms, ViroPharma’s claims are belied by its own statements. The day after the vancomycin ANDAs were approved,

ViroPharma announced to investors that three other drugs, not Vancoci n, were the company’s “growth drivers.” ( See FDA Opp’n, Ex. A at 9 (transcr ipt of April 10, 2012 call with ViroPharma Chairman, President, and CEO Vi n Milano, other ViroPharma officials, and investor representatives); see id. at 13 (stating that Cinryze in particular is “the anchor and

remains the anchor with or w ithout Vancocin in the mix”); see also Rowland Decl. ¶ 31 (reporting that 2011 sales of Cinr yze amounted to “approximately $251 million and . . . 46% of38 ViroPharma’s revenue).) The company also announced that it would “be launching [its] own authorized generic” of Vancocin “soon.” (FDA Opp’n, Ex. A at 6. 32 ) Indeed, ViroPharma’s CEO stated that the company had been “prepar[ing] an authorized generi c for years” and that “the work [is] in place and essentially on the shelf waiti ng for the need to deploy it” and, in response to a question, clarified that “[t]here is no need to file an[] ANDA for an authorized generic.” ( Id. at 7.) He further stated that the company’ s officials had “spent [their] en tire lives assuming Vancocin was going to go away” and had “been building the co mpany expecting it someday to go away.” ( Id.

at 8. 33 ) In fact, not a day later—and two days be fore filing the present lawsuit—ViroPharma launched an authorized generic version of Vanc ocin to be sold by Pr asco Laboratories. ( See Watson Opp’n at 10; id. , Ex. 3 (April 11, 2012 press release fro m Prasco announcing that it “will exclusively sell and distribute the authorized gene ric version of Vancocin . . . as part of an agreement with ViroPharma” (capitalization altered)); see also Alvogen Opp’n, Hill Decl. ¶¶ 26– 29 (as of April 14, 2012, ViroPharma’s authorized generic for Vancocin had established itself as a dominant player in the newly form ed vancomycin generic market).) Perhaps most damning to ViroPharma’s positi on is its CEO’s rosy de scription, at the end

32 An “authorized generic” is a generic drug th at is marketed by the NDA-holder—in this case, ViroPharma—as opposed to a generic marketed by the ANDA-holder, such as defendantsintervenors. See 21 C.F.R. § 314.3(b).

33 See Altana Pharma AG v. Teva Pharm. USA, Inc. , 532 F. Supp. 2d 666, 682 (D.N.J. 2007) (concluding that there was no showing of irre parable injury where, “[a]lthough [the RLD] ma[de] up a large portion of [plaintiff’s] sales, [plaintiff] ha[d] known for over three years . . . that” its period of exclusivity would be ending; stating that “[i]t is difficult to accept that [plaintiff] does not have a business plan in pl ace to deal with the in troduction of a generic version of [the RLD], whether th at includes [plaintiff’s] marketi ng of its own authorized generic version of [the RLD] or so me other business strategy”); id. at 682 n.26 (relying in part on the plaintiff company’s executive’s statements to inve stors in order to discer n the plaintiff’s plans).39 of the April 10 call, of the company’s immediate future: [W]e have a very strong balance sheet. We have cash flow from the Cinryze business. We have a credit facility that allows us a low cost of capital . . . to pursue the acquisition of things that we believe fit the strategic intent of the company. And we still have Vancocin cash flow[;] it doesn’t go to zero. ( Id. at 13. 34 )

ViroPharma has failed to de monstrate irreparable injury. V. BALANCE OF EQUITIES In considering whether the balance of equities favors granting a preliminary injunction, courts consider whether an inj unction would “‘substantia lly injure other inte rested parties.’”

McGinn , 786 F. Supp. 2d at 144 (quoting Chaplaincy , 454 F.3d at 297); see Winter , 555 U.S. at 24 (courts ‘must balance the competing claims of injury and must consider the effect on each party of the granting or withholding of the requested relief.’” (quoting Amoco Prod. Co. v. Village of Gambell , 480 U.S. 531, 542 (1987)). Here, defendants-intervenors have all demonstrated that they would su ffer serious harm were the Cour t to grant the injunction that ViroPharma requests. First, the FFDCA entitles generic drug co mpanies to FDA approval of their ANDAs when all requisite conditions have been met, see 21 U.S.C. § 355(j)(4), and this Court has held that ViroPharma is unlikely to prevail on its claim that the generic vancomycin ANDAs were

34 While the CEO addressed ViroPharma’s future in terms of its entire drug portfolio, the company’s CFO, in the declaration that purports to substantiate plaintiff’ s claim to irreparable injury, carefully limited his statements to the market for Vancocin. ( See, e.g. , Rowland Decl. ¶ 29 (“ Without the revenue fr om Vancocin sales , ViroPharma will have a restricted ability to raise capital . . . .” (emphasis added)); id. ¶ 32 (“While ViroPharma may market an authorized generic form of Vancocin, in a fully gene ricized market ViroPharma believes that sales of Vancocin may amount to less than $20 million.” (e mphasis added)).) Moreover, the CFO’s figures do not account for any expected revenues fr om the authorized generic that ViroPharma has already begun to sell.40 somehow insufficient. ( See supra Section III.) Second, all thre e defendants-intervenors would lose the substantial benefits of their early entr y into this market, and furthermore would suffer significant costs, if the Court were to order th e FDA to withdraw approva l of their vancomycin products. ( See Akorn Opp’n, Bonaccorsi Decl. ¶¶ 16–17; Alvogen Opp’n, Hill Decl. ¶¶ 29, 32, 25, 37; Watson Opp’n, Boyer Decl. ¶ 8.) It is perhaps for this r eason that the parties have only been able to find one instance, among all the de cisions in this circuit addressing a pioneer drug manufacturer’s challenge to the FDA’s approval of an ANDA, where a court ordered the agency to withdraw its approval after the generic had hit the market. See Serono Labs., Inc. v. Shalala , 974 F. Supp. 29, 37 (D.D.C. 1997). There, the Circ uit immediately stayed the issuance of the preliminary injunction pending its resolution of defendants’ appeal, and ultimately reversed.

Serono Labs. , 158 F.3d at 1316, 1327. To the best of the parties’ and the Court’s knowledge, the extraordinary relief that ViroPharma s eeks is unprecedented in this jurisdiction. 35 Finally, the “effect of an injunction on [def endants-intervenors] would be dramatically greater than the harm to [ViroPharma].” Bristol-Myers Squibb Co. , 923 F. Supp. at 221. Regardless of whether this Court grants plaintiff th e relief it requests, ViroPharma will be able to continue selling both Vancocin and its authorized generic version. The same cannot be said for defendants-intervenors, all of whom expect to earn substantial revenues from vancomycin. ( See

35 Following oral argument, counsel for ViroPharma supplied two citations to cases from other circuits where courts issued preliminary injunc tions against already introduced generic drugs. ( See April 20, 2012 email from ViroPharma’s counsel (citing Sanofi-Synthelabo v. Apotex, Inc. , 488 F. Supp. 2d 317 (S.D.N.Y.), aff’d , 470 F.3d 1368 (Fed. Cir. 2006); Sciele Pharma Inc. v. Lupin Ltd. , No. 09-cv-037, 2011 WL 6097741 (D. Del. Dec. 6, 2011)).) As counsel acknowledged, however, “the se are patent cases” ( id. ), where a party that “clearly establishes likelihood of success on the merits ‘receives the benefit of a pr esumption on the [irreparable harm]’ factor,” and therefore an advantage on the balance of equities factor as well. SanofiSynthelabo , 488 F. Supp. 2d at 342 (quoting Reebok Int’l Ltd. v. J. Baker, Inc. , 32 F.3d 1552, 1556 (Fed. Cir. 1994)). Accordingly, these case s provide little guida nce to this Court.41 Akorn Opp’n, Bonaccorsi Decl. ¶¶ 7, 19; Al vogen Opp’n, Hill Decl. ¶ 24, 30–34; Watson Opp’n, Boyer Decl. ¶ 7.)

VI. THE PUBLIC INTEREST In exercising their “‘sound discretion’ ” when deciding a motion for a preliminary injunction, courts are instructed to “‘pay part icular regard for the public consequences in employing the extraordinary remedy of injunction.’” Winter , 555 U.S. at 24 (quoting Weinberger v. Romero-Barcelo , 456 U.S. 305, 312 (1982)). Here, as in Serono Laboratories , the public interest factor “is inextr icably linked with the merits of the case.” 158 F.3d at 1326. ViroPharma may be correct that “the public always has an interest in agency compliance with the law.” (Pl.’s Mot. at 44.) However, because this Court has held that ViroPharma “is not likely to establish that” the FDA erred in denying its Citizen Petition and approving ANDAs for generic vancomycin, “public interest considerat ions weigh against an injunction.” Serono , 158 F.3d at 1326. As discussed above, Hatch-Waxman and the QI Act aim to increase competition in the drug industry and “‘to make availabl e more low cost generic drugs.” Id. (quoting H.R. Rep. No. 98-857, pt. 1, at 14 (1984)). “Congress’ pur pose is directly implicated here,” id. , as generic vancomycin sells for considerably less than Vancocin. ( See Watson Opp’n, Boyer Decl. ¶ 9 (providing, under seal, proprietary, comparative pricing data for Watson’s vancomycin generic); Rowland Decl. ¶ 27 (“generics typically cost 50–70% less than the grand-name drug”); see also Akorn Opp’n, Bonaccorsi Decl. ¶ 26 (“Publicly av ailable documents reveal that ViroPharma has increased the price of Vancocin seven times since January 2009 to the present, from approximately $442 to $1284 per 20-unit box for 250 mg Vancocin . . . .”). 36 ) The public “has a

36 The FDA’s own guidance confirms the effect of the introduction of ge neric drugs on market prices. While the first generic competitor on th e market prices its product only slightly lower42 well-recognized interest in receiving generic co mpetition to brand-name drugs as soon as possible . . . and a delay in the marketing of [the generic] drug could easily be against the public interest in reduced prices.” Biovail Corp. v. FDA , 519 F. Supp. 2d 39, 50 (D.D.C. 007) (some alterations in the original; internal quotation mark s and citation omitted). Therefore, it is “not in the public interest for the Court to grant a prelim inary injunction preventing these generic drugs from being sold on the market.” Hill Dermaceuticals, Inc. v. FDA , --- F. Supp. 2d ----, ----, 2011 WL 6005195, at *10 (D.D.C. 2011).

CONCLUSION For these reasons, it is clear that ViroPharma is not entitled to a preliminary injunction.

ViroPharma has not demonstrated th at it is likely to succeed on the merits of its claims; it has not shown irreparable injury; and the balance of the e quities and the public interest both tilt against injunctive relief. The Court will deny ViroPhar ma’s motion. A separate Order accompanies this Memorandum Opinion.

/s/ ELLEN SEGAL HUVELLE United States District Judge Date: April 23, 2012

than that of the pioneer manuf acturer, “the appearance of a sec ond generic manufacturer reduces the average generic price to nearly half the bran d name price,” and if “a large number of generic drug manufacturers” enter the market, “the av erage generic drug price falls to 20% of the branded drug price and lower.” FDA, Generic Competition and Drug Prices, http://www.fda.gov/AboutFDA/CentersOffices/O fficeofMedicalProductsandTobacco/CDER/uc m129385.htm (last visited April 23, 2012).