Pfizer Inc

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235 East 42nd Street New York, NY 10017 Tel212 733 8721 Email: geoffrey.levitt@pfizer.com

• Corporate Legal- Regulatory Geoffrey Levitt Senior Vice President & Associate General Counsel

June 6, 2012

Division of Dockets Management (HFA 305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, Maryland 20852

CITIZEN PETITION

Pfizer Inc ("Pfizer") respectfully submits this citizen petition under 21 U.S.C. 351 and 355, and 21 C.F.R. 10.30, among other provisions of law, to request that the Commissioner of Food and Drugs take the actions desaibed below with respect to all abbreviated new drug applications ("ANDAs") that reference Pfizer's Lyrica® (pregabalin), including ANDA 91-025 ("the Actavis ANDA"), ANDAs 91-040 and 201989 ("the Lupin ANDAs"), and ANDA 91-222 ("the Wockhardt ANDA").

I. ACTION REQUESTED

The undersigned requests that the Commissioner take the following actions:

• Refuse to approve any ANDA referencing Lyrica that contains an isomeric impurity specification that includes a "not less than" minimum level or otherwise requires the generic product covered by the ANDA to contain an isomeric impurity.

• Refuse to accept any amendment that would change the R-isomer impurity specification for an ANDA referencing Lyrica unless the amendment includes a new patent certification under 21 U.S. C. 355(jX2XAXvii).

• Respond to this petition before June 30, 2012, the earliest date on which a regulatory stay applicable to a pending ANDA may expire.

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II. INTRODUCTION

Pfizer is currently engaged in patent litigation with a number of sponsors of ANDAs for proposed generic versions of Lyrica. As part of this litigation, Pfizer has learned that several generic sponsors have sought to amend their ANDAs or otheJWise act in a manner that defies well accepted conventions for establishing limits for impurities in drug substances. In particular, we understand that certain generic applicants are seeking to require a "ffoor" or minimum level for the R-isomer impurity of the active drug substance, for the sole purpose of trying to avoid a patent See Transcript Pfizer Inc., eta/. v. Teva Pharms. USA, Inc., eta/., Case No. 09-00307 (D. Del., Oct. 11-13, 2011) at 35:13-36:23 (redacted excerpts attached as Exhibit 1 ).

To our knowledge, the universal practice in the field of pharmaceutical chemistry and formulation is to limit drug substance impurities to the lowest level possible, and to set a maximum or "not more than" ("NMT") upper limit. Drug substance specifications must set "appropriate" criteria for accepting and rejecting batches of the product. A specification that would require the sponsor to reject a batch because the product fails to contain a certain impurity is nonsensical, inappropriate, and should not be tolerated by the agency. There is no scientific basis for allowing the generic sponsors to require their products to contain the R­isomer, a substance which often cannot even be detected in a typical, pharmaceutical-grade batch of pregabalin.

The impetus and only justification for the proposed changes to these ANDAs appears to be an attempt to avoid infringing one of Pfizer's listed patents. Under longstanding Food and Drug Administration ("FDA") policy, the agency has neither the authority nor the expertise to consider the patent claims, or a court's construction of those claims, as a basis for allowing a scientifically unsupported change to the proposed drug product See Section IV.A., below. Second, the agency may not consider an amendment relating to the isomeric impurity of the proposed drug unless the ANDA applicant includes a new paragraph IV certification. In a case such as this, where the amendment relates directly to the enforcement of a listed patent, FDA must require a "recertification" to the patent before it may consider the proposed change to the product. See Section IV.B., below.

Finally, Pfizer respectfully requests that FDA provide a response to the issues raised in this petition by June 30, 2012. This is the earliest date on which a regulatory stay may expire, allowing the agency to approve a pending pregabalin ANDA. Pfizer initially raised the impurity specification issue in informal correspondence with the FDA's Office of Generic Drugs ("OGD") in February 2012. Because the issue involved ANDA specifications submitted by individual applicants, Pfizer believed it was appropriate to raise the issue in this manner. Pfizer also provided copies of its correspondence with OGD to the relevant ANDA applicants, to provide each applicant with an opportunity to respond to Pfizer's concerns. By letter dated March 14, 2012, FDA requested that Pfizer submit the issue in the form of a citizen petition.

In the interim, on March 8, 2012, several of the ANDA applicants, who are also defendants in the patent litigation action described below ("Defendants"), filed a Motion to Redact certain testimony from the publicly available trial transcript, including testimony directly relevant to the revised R-isomer impurity specifications. This move followed the ANDA applicants' receipt of copies of Pfizer's February 2012 letter to FDA on this matter. On March 22, 2012, Pfizer filed a Response to Defendants' Motion, objecting to the breadth of the

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proposed redactions. Defendants filed a further Reply on April 5, 2012. This Motion is still pending. As a result, Pfszer must file this petition without the benefit of certain information that is currently the subject of the pending motion.

Ill. BACKGROUND

A. Product Background

C.P. Pharmaceuticals International, C.V.,1 is the sponsor of NDAs 21-446, 21-723, 21-724 and 22-488 for an array of strengths and dosage forms of Lyrica ("the Lyrica NDAs"). 2

Lyrica is approved for the treatment of fibromyalgia; management of postherpetic neuralgia; and as adjunctive therapy for adult patients with partial onset seizures.

The active drug substance in Lyrica is the chiral molecule known as (S)-3-(aminomethyt)-5-methylhexanoic acid (the "8-isomer"). This S-isomer can be manufactured to a very high level of purity, with only trace levels of the R-isomer enantiomeric impurity,3 including to a level below the limit of detection of many standard analytical methods. For purposes of obtaining FDA approval, Pfizer's specification established an upper limit for the R-isomer impurity of not more than 0.2% w/w.

Pfizer has listed multiple patents in FDA's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations ("the Orange Bookj. Of particular relevance to this petition is patent 6,197,819 ("the '819 patent"), which expires on December 30, 2018. FDA identifies the '819 patent in the Orange Book as a drug substance and drug product patent. The '819 patent claims, inter alia, "a compound of the formula S-(+)-4-amino-3-(2-methylpropyl) butanoic acid as a single optical isomer."

B. Factual Background

At least eight generic sponsors have submitted ANDAs referencing the Lyrica NDAs:

• Actavis (ANDA 91-025);

C.P. Pharmaceuticals International, C.V., is a wholly owned subsidiary of Pfizer. For convenience, all further references in this petition will be to Pfizer. 2 FDA approved new drug application ("NDA") 21-446 for lyrica on December 30, 2004. This NDA provided for the use of oral capsules in 25, 50, 75, 100, 150, 200, 225 and 300 mg strengths for the treatment of fibromyalgia. FDA subsequently approved addltionallyrica NDAs on December 30, 2004 (NDA 21-723 providing for the use of Lyrica oral capsules for management of postherpetic neuralgia); June 10, 2005 (NDA 21-724 providing for the use of Lyrica oral capsules as adjunctive therapy for adult patients with partial onset seizures); and January 4, 2010 (NDA 22-488 approving Lyrica oral solution 20 mg/ml for all of the above indications). 3 The US Pharmacopeia ("USP') defines a "Stereomeric Impurity" as N(a) compound with the same 2-dimensional chemical structure as the drug substance (that) differs in the 3-dimensional orientation of substituents at chiral centers within that structure. In those cases where all chiral centers are in the opposite orientation, the impurity is an enantiomer (enantiomeric impurity)." See USP 34, General Chapters§ 1086, Impurities in Drug Substances and Drug Products.

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• Cobalt (ANDA 91-221); • Lupin (ANDAs 91-040 and 201989~4

• Mylan (ANDA 91-228); • Sandoz (ANDA 91-229); • Sun (ANDA 91-157); • Teva (ANDAs 91-224 and 91-219);5 and • Wockhardt (ANDA 91-222).

Each of the above applicants notified Pfizer that its ANDA contains a paragraph IV certification to at least one of the Lyrica listed patents. Pfizer subsequently filed infringement actions against all eight generic sponsors; the suits have been consolidated into one action. See Stipulation and Order of Consolidation, Pfizer Inc., et al. v. Teva Pharms. USA, Inc., eta/., Case No. 09-00307 (D. Del., Sept. 3, 2009).6

Each of the identified ANDA applications includes a specification for the R-isomer impurity. According to unredacted testimony in the ongoing patent litigation, the ANDA applicants have specified an R-isomer impurity with appropriate "NMr upper limits. FDA has tentatively approved three of these applications: ANDA 91-040 (Lupin), ANDA 91-224 (Teva), and ANDA 91-219 (Teva).

As part of the patent litigation, the district court issued an order- known as a Markman ruling - that provides the court's construction of the terms used in the claims of each patent at issue. See Order Construing the Terms of U.S. Patent No. 6,197,819 ("Markman Order"), Pfizer Inc., et a/. v. Teva Pharms. USA, Inc., et al., Case No. 09-00307 (D. Del., Oct 13, 2010) (attached as Exhibit 2). As part of that ruling, the court interpreted the meaning of the phrase "S-(+)-4-amino-3-(2-methylpropyl) butanoic acid as a single optical isomer" in the '819 patent to mean "4-amino-3-(2-methylpropyl) butanoic acid in the single S-( +) isomer form only, free of the R(-) isomer form." /d.

Subsequent to the court's Markman Order, Pfizer learned that several of the ANDA applicants sought to amend their ANDAs, their drug master files ("DMFs"), or their drug substance supply agreements to require a minimum quantity of R-isomer in their proposed drug products. The portions of the trial transcript not subject to Defendants' Motion demonstrate that Lupin, Actavis and Wockhardt propose to require a "not less than" level of R-isomer and expect to argue that this minimum amount of R-isomer provides them an independent basis for non­infringement of the '819 patent See Transcript at 35:13-36:23; 127:3-11; 137:22-138:6, 188:24-189:2. Actavis, for example, originally submitted its ANDA with a standard "not more than" limit for the R-isomer but, presumably in response to the court's Markman Order, amended its ANDA

4 Lupin's two ANDAs cover different dosage forms, a capsule and oral solution form, respectively. See Transcript at 173:20. 5 Teva's two ANDAs cover different strengths. See Transcript at 109:25-110:5. 6 ANDAs have additionally been filed by the following entities: Novel (ANDA 202269), Alembic (ANDA 203459) and Apotex (ANDAs 202998 and 203022, which cover different dosage forms). The patent infringement actions related to those ANDAs were not consolidated with Case No. 09-00307, and discovery has yet to commence. We are, therefore, not aware of the R-isomer specification for each of those proposed products.

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to now include a "not less than" specification for the impurity. ld. at 35:13-36:23; 127:9-11; 137:22-138:6; 281:24-283:9; 468:7-10; 509:13-510:4.

C. Statutory and Regulatory Framework

As with an application for an innovator drug product, a generic drug product application must include complete chemistry, manufacturing and controls ("CMC") information. 21 U.S.C. 355(j)(2)(A)(vi) (an ANDA must contain the information required of NDAs under 21 U.S.C. 355(b)(1)(B)-(F)). Thus, an ANDA sponsor must provide FDA with a complete description of all componen1s of its drug product and the composition of its drug substance, as well as a "full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug." 21 U.S.C. 355(b)(1 )(B)-{D).

FDA's ANDA regulations likewise require an ANDA to meet the same CMC standards as an NDA. 21 C.F.R. 314.94(a)(9)(i) (an ANDA must contain the CMC information required of NDAs under 21 C.F.R. 314.50(d)(1 )). Among other requirements, an ANDA must contain a full description of the drug substance, the method of purification of the drug substance, and "the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance." 21 C.F.R. 314.50(d)(1 )(i).

Under the agency's Good Manufacturing Practice ("GMP") standards, all manufacturers must maintain strict control over their processes through, among other practices, "the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components. drug product containers, closures, in­process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity." 21 C.F.R. 211.160(b) (emphasis added); see also Draft Guidance for Industry, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, 65 Fed. Reg. 83041, 83042 (Dec. 29, 2000). In addition, acceptance criteria and specifications must include "appropriate acceptance levels and/or appropriate rejection levels." 21 C.F.R. 211.165(d) (emphases added).

An impurity, by definition, is an unintended component of a drug product or drug substance. According to the US Pharmacopeia, an impurity is any component that is "not the chemical entity defined as the drug substance" and "not a formulation ingredient." USP General Chapters § 1086, Impurities in Drug Substances and Drug Products (emphases added); see also Guidance for Industry, Q3B(R2), Impurities in New Drug Products (July 2006) (an impurity is "any component of the drug substance or drug product other than the chemical entity that makes up the drug substance or an excipient in the drug product").

As noted by FDA officials in a published article titled ''Toxicological Overview of Impurities in Pharmaceutical Products," the unintended nature of pharmaceutical impurities is what drives the regulatory and manufacturing approach to their control. As emphasized in that article, "impurities convey only risk with no associated benefit." D. Jacobson-Kram & T. McGovern, Toxicological Overview of Impurities in Pharmaceutical Products, 59 Aov. DRUG DELIV. REV. 38-42 (Jan. 10, 2007); see also Draft Guidance for Industry, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (Dec. 2008) at 3 ("impurities in drug substances and drug products generally do not have beneficial effects and may impose a risk without associated benefir). Where they cannot be eliminated

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entirely, impurities should be reduced to the minimum level possible under GMP. Jacobson­Kram & McGovern at 38.

Thus, the practice under FDA's governing GMP and CMC standards is to establish "not more than" limits on the presence of an impurity within a given drug substance, product, or manufacturing batch. As shown below, nowhere within FDA's governing statute, rules or guidance does the agency recognize the idea of setting "not less than" levels for impurities.

IV. STATEMENT OF GROUNDS

A. FDA Must Not Permit ANDA Applicants to Require their Products to Include the R-lsomer Impurity

An impurity specification must be based on sound science. The sponsor must be able to justify the specification, and the specification must provide a necessary and appropriate basis for accepting or rejecting a given batch of drug substance or drug product. Under this basic standard, there is no scientifically acceptable basis for requiring a minimum level of the R­isomer impurity in generic pregabalin products.

The attempt by the generic sponsors to set a lower boundary on the R-isomer impurity is rooted in patent litigation tactics, not science. The generic sponsors apparently believe that by gratuitously including R-isomer in their products, they may avoid the reach of one of Pfizer's Orange Book-listed patents. The agency, however, has no authority to consider or rely on a patent as the basis for accepting a drug substance specification. The agency's analysis must be driven solely by the science and, in particular, the scientific standards under the Food, Drug, and Cosmetic Act ("FDCA "). Patents are simply not a relevant factor for the agency to consider when determining whether an impurity specification is justified and appropriate.

1. Neither FDA Nor Any Other Standard-Setting Authority Contemplates the Use of Minimum Impurity Levels

As noted above, all relevant regulatory guidance documents for impurity specifications are directed toward reducing and qualifying impurities below a defined maximum limit, typically expressed with a "not more than" or "NMr upper limit. This logically and reasonably flows from the definition of an impurity, which is that of a substance with no intended purpose within the product.

After an extensive search of literature in the field, we have been unable to identify any authoritative body or figure that has recognized circumstances in which lower boundaries should be set for impurities. We reviewed relevant FDA guidance, including FDA's ICH Q3A; Q3B; and Q6A guidance documents; guidances on impurities in ANDAs; FDA statements regarding stereoisomeric drug substances: and general FDA CMC guidance documents. We also reviewed USP monographs and general chapters: ICH Guidelines and WHO Guidelines (including the WHO Technical Report Series); online scientific references and databases maintained by the National Center for Biotechnology Information; and other basic chemistry texts and general online searches and sources. We have even examined numerous FDA review documents for approved products and could find no instance in which a sponsor had set a "not less than" level for a given impurity.

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In sum, we did not find even a brief or passing reference to the idea of setting "not less than" levels for impurities in any regulatory document, text, or treatise we reviewed. For example, USP drug substance monographs set minimum and maximum potency levels for the active drug substance, but only maximum levels for impurities associated with the drug substance. See generally USP, Vol. 34.

With regard to FDA's own framework for managing impurities within drug substances, we reviewed every available statement we could locate. Without exception, we found that the agency only considers impurities from the perspective of minimizing their presence to the greatest extent possible. Thus, according to agency experts, impurities must be qualified based on establishing a maximum or NMT limit, and this approach is repeated consistently throughout all relevant guidance documents. For example:

• "For a given degradation product, its acceptance criterion should be established by taking into account its acceptance criterion in the drug substance (if applicable), its qualified level, its increase during stability studies, and the proposed shelf life and recommended storage conditions for the new drug product Furthermore, each acceptance criterion should be set no higher than the qualified level of the given degradation product." Guidance for Industry, Q3B(R2), Impurities in New Drug Products (July 2006) at 5 (emphases added)?

• "In establishing impurity acceptance criteria, the first critical consideration is whether an impurity is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified impurity, we recommend that the acceptance criterion be set no higher than the officiat compendia! limit." Guidance for Industry, ANDAs: Impurities in Drug Substances (June 2009) at 3 (emphases added).

• "An impurity is considered qualified when ... [t]he observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the reference listed drug product... [or] [t]he observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies." ld. at 5 (emphases added).

As these and other references make clear, impurity specifications must be derived based on data and science. The objective in establishing a specification and controlling the manufacturing process is to ensure the safety, efficacy, and quality of the finished drug product.

7 Although this guidance expressly excludes enantiomeric impurities, Guidance for Industry, Q3B(R2), Impurities in New Drug Products (July 2006) at 3, it supports the general proposition. Moreover, FDA has adopted ICH guidance under which enantiomeric impurities are expected to be controlled to the same level of rigor as all other types of impurities. See ICH Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, 65 Fed. Reg. 83041, 83046-47 (Dec. 29, 2000) ("Drug Substance: Impurities. For chiral drug substances that are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities.").

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Nowhere can we find authority for the idea that setting floors or minimum levels for impurities helps ensure that a product will be safe, effective, or of an appropriate quality.8

Finally, with regard to enantiomeric impurities, the approach is equally rigorous and equally focused on limiting the unintended isomer to the maximum extent possible. For example:

• "It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants on the compound tested preclinically that is intended for use in clinical trials. The maximum allowable level of impurity in a stereoisomeric product employed in clinical trials should not exceed that present in the material evaluated in nonclinical toxicity studies." Guidance for Industry, Development of New Stereoisomeric Drugs (May 1 , 1992) (emphases added).

As expected, the USP follows the same approach of controlling enantiomeric impurities to the maximum extent possible. USP General Chapters§ 1086, Impurities in Drug Substances and Drug Products. To the best of our knowledge, the current volume of the USP contains fourteen monographs that specify "enantiomeric purity" with a percentage acceptance criterion. Each is expressed only with a "NMr ("no more than") upper limit. See, e.g., USP Monograph for Esomeprazole Magnesium ("Acceptance criteria: NMT 0.2% of the R-enantiomer."). We also located three monographs that permit some racemization; these specify "enantiomeric purity" as a percentage, e.g., "97% pure." Again, they do not provide a boundary or limit that would essentially cap the level of purity of the drug substance.

2. There is No Scientific Justification for Requiring a Minimum Level of the R-lsorner Impurity in a Pregabalin Product

The R-isomer is a specified impurity in Pfizer's NDA for Lyrica, and has been qualified under agency guidance at levels less than or equal to 0.2% w/w. According to the agency's review documents in support of the approval of Lyrica, appropriate methods should be used to ensure adequate removal of the R-isomer.9 That is, the agency found no beneficial or functional role for the R-isomer impurity in the drug substance or finished drug product. In this light, there is no plausible scientific basis for a generic pregabalin sponsor to take steps to now require that its product affirmatively contain the R-isomer impurity.

8 At trial in the Lyrica patent litigation, Actavis's Director of Regulatory Affairs testified that Actavis had previously specified upper and lower limits for an impurity in an ANDA See Transcript at 509:13-17. Actavis apparently intended to use this testimony to suggest that the Office of Generic Drugs had, in a prior case, allowed a sponsor to set a minimum level for an impurity. However, the court immediately determined that the example was irrelevant and allowed no further testimony. /d. We have no information on whether OGD in that instance considered the issue of setting lower limits for impurities; whether the purported specification was scientifically justified; or whether the total amount of impurity was analyzed under the usual standards for setting limits on impurities. 9 See Lyrica NDA 21-446, Chemistry Review, at 17, available at htto:/lwww.accessdata.fcla.aov/drugsatfda docs/nda/2004/021446 lvrica%20Capsules chemr.PDF.

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The generic sponsors have in place manufacturing processes that are designed to produce $-isomer to the exclusion of the R-isomer impurity. In fact, Actavis's own testing shows that it was able to produce exhibit batches with no detectable levels of R-isomer. See, e.g., Transcript at 133:14-17. A specification that would now have them reject batches solely because they are free of an impurity - especially where there is no apparent scientific justification for requiring a minimum level of that impurity- is inconsistent with GMP.

3. FDA's Ministerial Role in Listing Patents Does Not Authorize the Agency to Consider the Scope of a Listed Patert in Reviewing ANDA CMC Specifications

FDA cannot consider the scope of a listed patent or the potential effects of agency actions on patent litigation as a basis for accepting an otherwise anomalous, and perhaps unprecedented, impurity specification. FDA's longstanding policy is that the agency's role with respect to patents is "ministerial":

A fundamental assumption of the Hatch-Waxman Amendments is that the courts are the appropriate mechanism for the resolution of disputes about the scope and validity of patents ...

In addition to the absence of any statutory basis for a substantive agency review of patents, we have long observed that we lack expertise in patent matters. An administrative process for reviewing patents, assessing patent challenges, and de-listing patents would involve patent law issues that are outside both our expertise and our authority. Although we will continue to relay questions about the accuracy of a patent submission to the NDA holder (see§ 314.53(f)), our patent listing role remains ministerial. Courts have upheld our determination that our role with respect to patent listing is ministerial.

Applications for FDA Approval to Market a New Drug: Patent Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug Is Invalid or Will Not Be Infringed, 68 Fed. Reg. 36,676, 36,683 (June 18, 2003) (codified at 21 C.F.R. part 314) (citations omitted); see also Alphapharm v. Thompson, 330 F.Supp.2d 1 (D.D.C. 2004) (recognizing that Congress unambiguously delegated to FDA only a ministerial duty to list patents). As the agency acknowledges, it has no expertise in patent law or in reading the claims of a patent.

FDA's primary responsibility in this area is administering the listing of patents by drug manufacturers and the publication of the Orange Book. In limited circumstances, where a patent includes "method of use" claims and the pioneer has summarized those claims for the agency, FDA may take the patent into account when approving the labeling for a generic drug. See 21 U.S.C. 3550)(2)(A)(viii); 21 C.F.R. 314.94(a)(8)(iv). The '819 patent at issue here does not, however, include a method of use claim. Rather, the '819 patent is a drug substance and drug product patent. See Orange Book. If the agency were to allow the ANDA applicants to establish "not less than" impurity specifications in this instance, because doing so may allow them to avoid a patent, then the agency will have stepped outside of its ministerial role. Even more, the agency will have allowed its scientific standards and judgment to be compromised on the basis of patent law.

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In short, the actions now being taken by certain ANDA sponsors are intended to address an issue that arises under patent law. Unless the proposed "not less than" impurity specifications are intended to improve the manufacturing processes or controls for the generic products, or to ensure a higher quality product. they should be denied. If the justification for setting an impurity floor is to evade a patent, then that is not a justification FDA may rely upon or accept.

B. The Agency Must Require ANDA Sponsors to Provide New Paragraph IV Certifications for any Proposed Changes to their Isomeric Impurity Specifications

The recent amendments to the ANDAs referencing Lyrica also fail on procedural grounds. For the agency to consider these amendments, they must be accompanied by new patent certifications to the '819 patent When an amendment to a pending ANDA changes the drug product in a manner related to the enforcement of a listed patent, FDA cannot consider that amendment without a new paragraph IV certification.

It has been FDA's longstanding position that a change in the formulation of an ANDA product triggers the need for the resubmission of patent certifications. See Letter from Paul D. Parkman ("Parkman Letter") (Oct. 31, 1986) at 5 (patent certifications required for formulation changes in ANDA supplements). It has also been FDA's practice to require patent certifications for formulation changes in pending ANDAs. See, e.g., Letter from FDA to G. Masoudi, Docket No. FDA-201Q-P-0223 (Oct. 19, 2010) at 3 (noting that FDA required ANDA applicant to recertify after amending its doxercalciferol injection product); Letter from FDA to S. Auten, Docket No. FDA-201Q-P-0632 (Sept 20, 2011) at 8 ("Cobrek Petition Response") (same); see a/so Paddock Labs., Inc., v. Ethypharm, S.A., 2011 WL 149860, *3 (D.N.J. 2011) (unpublished opinion) (noting that FDA required ANDA applicant to recertify after amending its ANDA to change formulation for fenofibrate capsule product) (attached as Exhibit 3).

As the agency recently explained, a recertification is necessary where the change to the ANDA product may be relevant to resolving any patent-related issues among the parties:

FDA's practice of generally requiring a resubmission of certification to listed patents at the time an ANDA applicant amends its application for a reformulation of its product is based on the premise that the patent holder should have notice relating to the formulation that is before FDA for approval, so that any patent issues related to the new formulation can be resolved. This requirement makes sense for all involved and implements the statutory objectives.

Cobrek Petition Response at 8. Recertification and notice provide an opportunity to litigate based on the most current and precise description of the proposed ANDA product, even where litigation between the innovator and the generic applicant is already ongoing. See Letter from FDA to C. Markus, Docket No. FDA-2011-P-0127 (June 7, 2011) ("Suprane Petition Response") at 7 ("The second patent infringement action is specific to the revised product described in Minrad's ANDA amendment. The fact that the court chose to consolidate the two infringement actions does not affect our reasoning.").

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The principles behind the recertification requirement extend beyond formulation changes to any other changes to the ANDA that may be relevant to the innovator's patents. For example, the agency recently determined that a recertification was necessary when an ANDA applicant proposed a change to its container closure system. Suprane Petition Response at 6-7. In that case, Minrad, Inc., ("Minrad") had submitted an ANDA for a generic desflurane product referencing Baxter's Suprane (desflurane). When it submitted its original ANDA, Minrad included a paragraph IV certification to a listed patent, the '906 patent. However, in June 2009, after patent litigation between Baxter and Minrad had already commenced, Minrad amended its ANDA to change its container closure system. According to information provided by Baxter in its citizen petition, the '906 patent claims "the finished dosage form of desflurane and a closure system that constitutes the drug product." ld. at 2 (citing Baxter Petition at 1-2) (emphasis added). Thus, FDA required Minrad to submit a new paragraph IV certification to the '906 patent, based on the change proposed in its ANDA amendment. As FDA made clear, "[w]hen Minrad changed the container closure system, it changed its product ... " ld. at 7. As a result, Minrad was required to recertify to the '906 patent and give notice to Baxter. /d. This, in turn, resulted in the entry of a new 30-month regulatory stay against Minrad, to provide the parties a fair opportunity to litigate the listed patent based on the amended ANDA.

Not every amendment to an ANDA would give rise to a new certification.10 However. an amendment that goes directly to the enforcement of an Orange Book-listed patent is certainly the type for which the agency must require recertification and notice to the innovator. As shown in section IV.A, above, the generic pregabalin sponsors have proposed changes to their ANDA products that relate directly to Pfizer's '819 patent. Indeed, there appears to be no justification for the remarkable "not less than" impurity specification discussed above, other than to try to avoid the '819 patent. In a case such as this, where the generic applicants are seeking to change the terms of their ANDAs in a manner that goes directly to the enforcement of a listed patent, recertification and notice must be given to ensure the "statutory objectives" are met. See Cobrek Petition Response at 8.

In short, the gambit by the generic sponsors to require their products to contain an impurity is contrary to good science, contrary to FDA's commitment to drug quality, and should

10 Early in its implementation of Hatch-Waxman, the agency recognized that post-market changes to ANDA products, such as changes in formulation, would generally give rise to the need for new patent certifications. See Parkman Letter at 5. The agency also recognized that there were limits to this approach:

The agency realizes, however, that not all supplements are for changes that could be patented. It appears unnecessary, for the purpose of carrying out the intent of the Act, to ask for patent certifications in supplements for such things as, for example, a change of manufacturing site, a change of equipment or a change in packaging. On the other hand some supplements may always involve changes that could be patented, e.g., supplements for new uses or other conditions of use, for these supplements certification appears to be necessary to carry out the intent of the Act.

ld. at 4-5. The essential premise -from the Parkman Letter to the Minrad decision- is to require new certifications where proposed changes to an ANDA drug product may be subject to patent protection and therefore impact the enforcement of a listed patent.

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be summarily rejected. To the extent the agency would even consider what the generic pregabalin applicants are proposing, an appropriate process must be followed, and that process begins with a new certification to the listed patents based on the newly proposed terms of the ANDAs.

IV. CONCLUSION

There is no credible scientific, medical or product quality rationale to allow generic sponsors to affirmatively include impurities in their products. FDA should refuse to approve any pregabalin ANDA that contains a specification for the R-isomer impurity that includes a "not less than" floor, or otherwise requires the generic product to contain the R-isomer impurity.

Moreover, FDA must also require a generic sponsor to submit a new paragraph IV certification to the '819 patent before the agency may consider whether to permit that generic sponsor to change its drug product to require a minimum level of the isomeric impurity.

V. ENVIRONMENTAL IMPACT

The actions requested in this petition are subject to categorical exclusion under 21 C.F.R. 25.31.

VI. ECONOMIC IMPACT

Information on the economic impact of this proposal will be submitted upon request of the Commissioner.

VII. CERTIFICAnON

I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: October 11, 2011. If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: Pfizer Inc. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.

Geoffli Levitt, Esq. Asso ate General Counsel Worldwide Regulatory and Policy Law Pfizer Inc

Division of Dockets Management June 6, 2012 Page 13 of 13

235 East 42nd Street New York, NY 10017 Tel: (212) 733-8721

Cc: Jane Axelrad Associate Director for Policy, COER

Elizabeth H. Dickinson Chief Counsel to the Food and Drug Administration

Keith 0. Webber, Ph. D. Acting Director Office of Generic Drugs

David M. Fox Hogan Lovells US LLP

John LaRocca VP, Legal Actavis Elizabeth LLC

Sofia Mumtaz Lupin Limited Lupin Pharmacet.mcals, Inc.

Jerome D. Jabbour U.S. General Counsel Wockhardt USA LLC

Enclosures