HOGAN & HARTSON APR -9 P4 :18 BY HAND DELIVERY

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1 HOGAN & HARTSON APR -9 P4 :18 Hogan & Hartson up Columbia Square 555 Thirteenth Street, NW Washington, DC Tel Fax Philip Katz Partner BY HAND DELIVERY Division of Dockets Management Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, Maryland CITIZEN PETITION On behalf of Abbott Laboratories ("Abbott"), Hogan & Hartson submits this citizen petition under 21 U.S.C. 355(b) and 355(q), as well as 21 C.F.R , to request that the Commissioner of Food and Drugs take the actions described below with respect to any new drug application ("NDA") submitted in accordance with section 505(b)(2) of the Food, Drug, and Cosmetic Act ("FDCA") that references Abbott's product, AndroGel (testosterone gel). Abbott recently acquired Solvay Pharmaceuticals ("Solvay") and through that transaction obtained AndroGel. The basis for Abbott's request is FDA's August 2009 response to a citizen petition submitted by Auxilium Pharmaceuticals ("Auxilium") regarding Testim (testosterone gel). In that response, FDA stated that certain differences in inactive ingredients between an approved testosterone gel and a proposed generic - including, but not limited to, different penetration enhancers - would trigger the need for skin transfer and hand washing studies. The Agency addressed the implications of that policy for any application for what might be considered a generic testosterone gel product : In short, we have determined that any application for a testosterone transdermal gel product that has different penetration enhancers than the reference listed drug will require transfer and hand-washing studies. The practical effect of this determination is that any application for a testosterone gel product that has different penetration enhancers than the reference listed drug cannot be submitted as an ANDA and, instead, will have to be submitted as an NDA under section 505(b) of the [FDCA]. Citizen Petition Response, Docket No. FDA-2009-P-0123 at 5 (Aug. 26, 2009) (emphasis added) ("Auxilium Response"). The Agency was clear in its response that the requirement of skin transfer and hand washing studies for a product with different penetration enhancers than the reference listed drug applies to all proposed testosterone gel products, not just those referencing Auxilium's Testim. Accordingly, Abbott understands the Agency's policy to apply to any proposed generic version of AndroGel that contains a different penetration enhancer than Abbott's product.

2 Page 2 In June 2009, Solvay received notice from Perrigo Israel Pharmaceuticals ("Perrigo") that the company had submitted two abbreviated new drug applications ("ANDAs") for generic versions of AndroGel.' Under FDA's enunciated policy, therefore, unless the Perrigo products contain the identical penetration enhancers found in the referenced AndroGel products, the applications for those products must contain data from skin transfer and hand washing studies, and cannot be submitted as ANDAs. Moreover, the law requires (a) FDA to refuse to approve any pending ANDA for a product containing a different penetration enhancer than AndroGel, and (b) the applicant to submit to the Office of New Drugs an application containing the required clinical data as an NDA in accordance with FDCA 505(b)(2). The law also would require FDA and the applicant to comply with all applicable procedures and regulatory requirements associated with submission of an NDA, including the assignment of a goal date under the Prescription Drug User Fee Act, and the submission of new certifications to all patents listed with AndroGel in the Orange Book. Although Abbott believes the Auxilium Response, statutory and regulatory imperatives, and past Agency practices are clear and consistent on these points, because of the importance of these issues, we are submitting this citizen petition to ask FDA to take the actions described below. I. ACTIONS REQUESTED Abbott respectfully requests that FDA take the following actions : " Require any applicant seeking to rely on AndroGel as the reference listed drug for a proposed product that does not contain the same penetration enhancers as AndroGel to conduct transfer and hand-washing studies (and the other required studies as set forth in the Auxilium Citizen Petition Response), and to seek approval by means of an NDA submitted in accordance with FDCA 505(b)(2), not an ANDA submitted under FDCA 505(j), unless the applicant has obtained a right of reference from Abbott. Require any NDA referencing AndroGel, including a 505(b)(2) NDA for a product that previously had been the subject of an ANDA referencing AndroGel, to contain new certifications to all patents listed with AndroGel in the Orange Book, and if any of those certifications assert that the patent is invalid, unenforceable, or will not be infringed, require the applicant to provide timely notification to Solvay, as provided for in FDCA 505(b)(3). II. STATEMENT OF GROUNDS A. Statutory and Regulatory Requirements The FDCA contains two provisions that allow an applicant to gain approval of a product by relying to some degree on FDA's previous determination that another drug product is safe and effective. FDCA 505(j) permits the approval of an ANDA based on FDA's prior approval of another product (the reference listed drug), so long as the proposed product has the same active ingredient, dosage form, route of administration, strength, and labeling (with important exceptions not relevant here) as the approved ' Perrigo was required to notify Solvay of the existence of the ANDAs, Nos and , because the applications contained Paragraph N certifications to a patent listed with AndroGel in the FDA publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book"). See 21 U.S.C. 355(j)(2)(B) ; 21 C.F.R

3 Page 3 drug. The proposed and approved products must also have the same bioavailability (i.e., they must be bioequivalent to one another). See 21 U.S.C. 355(j)(2)(A). With regard to inactive ingredients, FDCA 505(j) provides that FDA must not approve an ANDA unless information shows that the inactive ingredients in the proposed product are safe for use under the conditions described in the labeling. See 21 U.S.C. 355(j)(4)(H). The Agency has implemented this relatively simple statutory standard through detailed regulations that specify what types of changes to an approved product's formulation may raise questions about a generic's safety. See 21 C.F.R (a)(9) and (a)(8). With regard to topical drugs, FDA's regulations reflect the unique scientific challenges raised by such drugs, and generally require that generic versions of topical products contain the same inactive ingredients as their reference listed drugs. See 21 C.F.R (a)(9)(v). An ANDA applicant may seek approval of a topical product that contains different inactive ingredients than the listed drug, but must characterize those differences and demonstrate that they do not affect the safety of the proposed product. Importantly, however, FDCA 505(j) also includes a provision that prohibits FDA from reviewing clinical or other additional data in the context of an ANDA. See 21 U.S.C. 355(j)(2)(A). For this reason, if a demonstration of the safety of a generic product requires data - particularly clinical data - beyond what may be submitted in an ANDA, FDA must refuse to approve the application under FDCA 505(j). This prohibition on the review of clinical data under an ANDA was the basis for FDA's decision in the Auxilium Response that applications containing data from transfer and hand-washing studies cannot be submitted as ANDAs. When an applicant files an NDA under 505(b)(2) of the FDCA, the same limitations that apply to ANDAs under FDCA 505(j) do not apply. First, the two products do not have to be "the same," i.e., bioequivalent and with the same active ingredient, dosage form, route of administration, strength, and labeling. Second, a 505(b)(2) NDA may contain clinical and whatever other data as necessary to demonstrate the safety and effectiveness of the proposed product. See 21 U.S.C. 355(b)(2) ; 21 C.F.R Precisely what data are necessary to support the approval of a product under FDCA 505(b)(2) will depend on the extent and nature of any differences between that product and the reference listed drug. Although there are important differences between 505(b)(2) NDAs and ANDAs,2 the two applications are similar in some respects. For example, the Agency's 505(b)(2) NDA regulations contain provisions - not identical but parallel to those for ANDAs - regarding patent certifications, and 505(b)(2) applicants may be made subject to 30-month stays of approval if they submit Paragraph IV certifications. Compare 21 C.F.R (i)(1)(i), , and (a)(1)(vi) with 21 C.F.R (a)(12)(i) and ; see 21 C.F.R Similarly, both 505(b)(2) NDAs and ANDAs may be blocked by three- and fiveyear marketing exclusivities. Compare 21 U.S.C. 355(c)(3)(E) with 21 U.S.C. 3550)(5)(F) ; see 21 C.F.R As the above discussion demonstrates, although the patent certification, exclusivity, and other provisions for 505(b)(2) NDAs and ANDAs are similar, they are distinct, and each application carries with it independent obligations regarding, for instance, the patents listed in the Orange Book with the reference listed drug. Further, there is no statutory or regulatory authority permitting the Agency to allow an applicant to simply "convert" or "switch" an ANDA to a 505(b)(2) NDA and avoid the various 2 In addition to the fact that a 505(b)(2) NDA may contain clinical data, for example, a 505(b)(2) NDA must demonstrate the subject product's safety and effectiveness, not just its sameness and bioequivalence to the reference listed drug.

4 Page 4 obligations attendant to a new submission.3 This makes sense, in part because NDAs and ANDAs are reviewed by different agency components and under different standards. NDAs are reviewed by personnel within the relevant division within the Office of New Drugs, and must demonstrate, inter alia, a product's safety and effectiveness. See 21 U.S.C. 355(c) and 355(d). ANDAs are reviewed by the Office of Generic Drugs, and must generally demonstrate, inter alia, that a proposed product and the reference listed drug have the same active ingredient, route of administration, dosage form, and strength, and bioavailability. See 21 U.S.C. 355(j)(4) 4 B. FDA Precedents The procedural path set forth here for applicants who file a 505(b)(2) NDA after having filed and withdrawn an ANDA referencing AndroGel tracks FDA's actions in similar situations. We are aware of several instances in which a 505(b)(2) NDA submitted after the rejection or withdrawal of an ANDA for the same drug product was treated as a new application, subject to the procedures and requirements of initial NDA submissions, including the submission of new patent certifications under 21 U.S.C. 355(b)(2) and 21 C.F.R (i)(1)(i) and (a)(1)(vi). These detailed requirements were not waived simply because the products had previously been the subject of ANDAs that were rejected or withdrawn prior to approval. In December 1999, for example, Andrx Pharmaceuticals ("Andrx") submitted an ANDA for a proposed generic version of Depakote (divalproex sodium delayed release tablets), including Paragraph N certifications to two patents. See Joint Status Report and Motion to Extend Stay, Abbott Labs. v. Andrx Corp., Case No CN-HIGHSMITH/GARBER at 1 (S.D. Fla. Oct. 8, 2002) (unsealed Dec. 4, 2003) (attached as Exhibit A). In January 2001, and again in July 2002, FDA sent Andrx letters notifying the applicant that the ANDA could not be approved, because the product contained a different active ingredient than the reference listed drug. See id. at 2. In the 2002 letter, FDA suggested that the applicant explore submitting an NDA under section 505(b). See id. at 9 (enclosing a letter from FDA to Andrx). Andrx did so, submitting new Paragraph IV certifications to the same two patents at some point between November 2002 and March 2003, and received tentative approval in May 2004 (i.e., after a standard period of review). See Citizen Petition, Docket No. 2004P-0320 at 4 (July 15, 2004). The applicant also provided new Paragraph IV notifications to Abbott, in March See id. at 4. Similarly, Penederm ("Penederm") submitted an ANDA in May 1991 for a proposed generic version of Retin-A (tretinoin gel). See Letter from Penederm to FDA at 2 (Sept. 24, 1993) (attached as Exhibit B). Although FDA initially received the ANDA for review, the agency informed the applicant in August 1992 that the application was not acceptable as an ANDA because the product contained an excipient not in the reference listed drug and not previously approved. See id. Penederm withdrew the ANDA at FDA's request, and submitted a 505(b)(2) NDA in September 1993, with a new Paragraph IV certification (and new notification to the NDA and patent holders). See id. ; see also Patent Certification submitted with NDA (Sept. 16, 1993) (attached as Exhibit C). After issuing several not approvable letters, FDA 3 Although there are rules permitting applicants to request waivers of various requirements for 505(b)(2) NDAs and ANDAs, see 21 C.F.R and (b), those regulations are not applicable here, because they only apply where compliance with existing requirements is unnecessary, impossible, etc. We are unaware of these waiver provisions ever being used to waive the requirement that applicants submit appropriate patent certifications. Moreover, because any waiver of such a requirement would significantly disadvantage Abbott, as well as other applicants, public notice of FDA consideration of a waiver should be required. 4 For these reasons, moving from an ANDA to a 505(b)(2) NDA is not the same as moving from an NDA submitted under FDCA 505(b)(1) (i.e., a "full" NDA) to a 505(b)(2) NDA, or vice versa.

5 Page 5 approved the NDA in January Exhibit D). See Approval Letter for NDA (Jan. 29, 1998) (attached as Another example is the ANDA for a proposed generic version of 3M Pharmaceuticals' MetroGel Vaginal (metronidazole gel) that Teva Pharmaceuticals ("Teva") submitted in February In April 2002, the Agency refused to receive the ANDA, because the proposed product was not bioequivalent to the reference listed drug ; a second refusal letter was sent in June See Medical Review for NDA at 2 (May 19, 2005) (attached as Exhibit E). In October 2003, FDA sent Teva a letter requesting that the ANDA be withdrawn. See id. Teva withdrew the ANDA in November 2003, and submitted a 505(b)(2) NDA in July See Regulatory Filing Review for NDA at 1 (May 5, 2005) (attached as Exhibit F). That application, which contained new Paragraph III certifications to three listed patents, was accepted for filing as of September 2004, and was assigned a standard, ten-month review clock. See id. at l, 4. These precedents are consistent with applicable law, the animating principles of the Hatch Waxman Act, and the careful compromise between pioneer and generic drug manufacturers that the Act has come to represent. Any 505(b)(2) NDA applicant that does not submit new patent certifications, for example, should not be considered to have met the requirements for filing, let alone approval. See 21 C.F.R (i)(1)(i) and (a)(1)(vi) ; see also Exhibit F at 4-5 (requiring certifications to be made under 21 C.F.R ). In addition to contravening the explicit language of the statute and FDA regulations, not requiring a 505(b)(2) NDA applicant to submit new certifications would unjustly provide that applicant with a significant advantage over other applicants, and could deprive the sponsor of the reference listed drug of important statutory protections, because it could effectively eliminate the sponsor's ability to sue and obtain a 30-month stay of approval. See 21 U.S.C. 355(c)(3)(C) and 355(j)(5)(B)(iii) (providing for 30-month stays only for patents submitted to FDA before the date on which the application was submitted).' C. Conclusion Abbott believes the FDCA, FDA regulations, and previous Agency actions regarding similarly situated entities require any new 505(b)(2) NDA - regardless of the proposed product's history - to satisfy all applicable statutory and regulatory requirements, including the submission of new patent certifications under 21 U.S.C. 355(b)(2)(A). Accordingly, we respectfully submit this citizen petition to confirm FDA's policies in this regard and their application to 505(b)(2) NDAs for products that seek to rely on AndroGel as the reference listed drug. III. ENVIRONMENTAL IMPACT The actions requested in this petition are subject to categorical exclusions under 21 C.F.R and IV. ECONOMIC IMPACT Information on the economic impact of this petition will be submitted upon request of the Commissioner of Food and Drugs. 5 Requiring new patent certifications is also consistent with the concept that it is the submission of the application itself - an ANDA, a 505(b)(2) NDA, or one after the other - that is the act of patent infringement. See 35 U.S.C. 271(e)(2)(A).

6 Page 6 V. CERTIFICATION 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 that are unfavorable to the petition ; and (c) I have taken reasonable steps to ensure that any representative data and/or information that 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 : September 3, 2009, after FDA's August 27, 2009, response to the Auxilium petition was made public. 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 : Abbott Laboratories. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. Attachments cc : Jane Axelrad, Esq., Office of Regulatory Policy Elizabeth Dickinson, Esq., Office of Chief Counsel John Jenkins, M.D., Office of New Drugs Keith Webber, Ph.D., Office of Generic Drugs Steven N. Gersten, Esq., Abbott Laboratories

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