o 1205 Culbreth Dr., Suite 200, Wilmington, NC Phone : Facsimile :

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1 Osmotica Pharmaceutical 1?54,Lt. 27 P2 :05 BY HAND DELIVERY Division of Dockets Management Food and Drug Administration Department of Health and Human Services 563"0 Fishers Lane, Room 1061 Rockville, MD RE : Abbreviated New Drug Applications for Venlafaxine HCl Extended- Release Tablets Should Include Certifications for all Orange Book- Listed Patents for Effexor XR Capsules. Dear Sir or Madam : CITIZEN PETITION Osmotica Pharmaceutical Corp. ("Osmotica") submits this Citizen Petition pursuant to section 505(q) of the Federal Food, Drug, and Cosmetic Act ("FDC Act" or "the Act"), among other provisions of law, and the Food and Drug Administration's ("FDA's" or "Agency's") implementing regulations set forth at 21 C.F.R Osmotica requests that FDA require that any company with a pending Abbreviated New Drug Application ("ANDA") for Venlafaxine HCl Extended-Release Tablets, in particular Sun Pharmaceutical Industries Ltd. ("Sun"), submit a new ANDA that includes certifications to all applicable patents listed in FDA's Approved Drug; Products with Therapeutic Equivalence Evaluations (the "Orange Book"), for the reference listed drug ("RLD"), Osmotica's Venlafaxine HCl Extended-Release Tablets, and those patents that apply to the drug product on which Osmotica's application relied, namely Wyeth Pharmaceuticals, Inc.'s ("Wyeth's") Effexor XR (venlafaxine HCl) Extended-Release Capsules. o 1205 Culbreth Dr., Suite 200, Wilmington, NC Phone : Facsimile : info@osmotica.com - ep

2 Page 2 The action requested is consistent with existing FDA policy that prohibits applicants from procedurally circumventing statutory patent certification and notification requirements. I. ACTION REOVESTED (1) Clarify that when an ANDA applicant relies on an RLD, the approval of which was pursuant to a new drug application ("NDA") that is described in section 505(b)(2) of the Act (a "505(b)(2) application"), and that 505(b)(2) application itself relied on an earlier approved NDA, the ANDA applicant must certify not only to the Orange Book-listed patents that cover the 505(b)(2) listed drug on which it directly relied, but also to the Orange Book-listed patents that cover the earlier approval on which the 505(b)(2) applicant relied. (2) Specifically with regard to Sun, if the Venlafaxine HCl Extended-Release Tablets ANDA that is currently under review lacks all required patent certifications, it is deficient on its face and should not have been received by FDA. Therefore, we request that FDA require that Sun submit a new ANDA with appropriate certifications, including certifications to all Effexor XR Capsules Orange Book-listed patents. II. STATEMENT OF GROUNDS A. Background

3 Page 3 FDA approved Effexor XR, 37.5 mg, 75 mg, 100 mg, and 150 mg Extended- Release Capsules for the treatment of major depression under NDA No on October 20, Currently, Effexor XR is approved for multiple indications, including for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder. The Orange Book lists the following six patents with corresponding periods of patent exclusivity applicable to Effexor XR : U.S. Patent Nos. 5,916,293 (expires 2013) ; 6,274,171 (expires 2017) ; 6,310,101 (expires 2013) ; 6,403,120 (expires 2017) ; 6,419,958 (expires 2017) ; 6,444,708 (expires 2013). On March 30, 2005, FDA approved a suitability petition submitted pursuant to section 505(j)(2)(C) of the FDC Act for a dosage form change from Venlafaxine HCl Extended-Release Capsules to Venlafaxine HCl 37.5 mg, 75 mg, and 150 mg Extended- Release Tablets. See FDA Citizen Petition Response, FDA Docket No. 2003P-0159 (Mar. 30, 2005). Sun submitted an ANDA to FDA in May 2007 requesting approval for the company's proposed Venlafaxine HCl Extended-Release Tablets, 37.5 mg, 75 mg, 150 mg, drug products, citing Effexor XR Extended-Release Capsules as the RLD. Prior to the submission of the Sun ANDA, Osmotica submitted a 505(b)(2) application (NDA No ) for Venlafaxine HCl Extended-Release Tablets, 37.5 mg, 75 mg, 150 mg, and 225 mg. FDA approved Osmotica's 505(b)(2) application on May 20, 2008, based on the Agency's previous findings of safety and effectiveness for Effexor XR Extended-Release Capsules and Osmotica's bioequivalence data. The Orange Book lists two patents applicable to Osmotica's Venlafaxine HCl Extended-Release Tablets, U.S. Patent No. 6,403,120 ("the `120 patent") and U.S. Patent No. 6,419,958 ("the `958 patent"), both of which expire in The `120 and `958 patents, which are held by Wyeth, are also listed in the Orange Book for Effexor XR Capsules.

4 Page 4 On May 30, 2008, Osmotica submitted a citizen petition requesting that FDA : 1) refrain from approving any pending ANDA for Venlafaxine HCl Extended-Release Tablets that cites Effexor XR Capsules as the RLD and that was submitted based upon the March 30, 2005 approved suitability petition ; 2) require that any such pending ANDA applicant - specifically Sun - instead reference Osmotica's approved Venlafaxine HCl Extended-Release Tablets as the RLD and, as required by section 505(j)(2)(D)(i)1 of the Act, submit a new ANDA in order to make that change of the RLD ; and 3) require that the applicant conduct new bioequivalence studies comparing its proposed product to Osmotica's approved drug product. FDA granted Osmotica's petition in full on November 25, FDA Citizen Petition Response (regarding venlafaxine HCl), Docket No. FDA-2008-P-0329, at (Nov. 25, 2008). We believe that Sun's new ANDA, which Osmotica understands is currently under review, is deficient on its face in that it lacks certain required patent certifications, specifically certifications to all Orange Book-listed patents covering Wyeth's Effexor XR Capsules. If this is the case, FDA could not have lawfully received the ANDA in the first place, and Sun should now be required to submit a new ANDA that complies with the statutory certification and notification requirements. B. Analysis i The Medicare Prescription Drug Improvement and Modernization Act of 2003, Pub. L. No , 117 Stat (the "MMA"), amended section 505(j) of the Act to prohibit an ANDA applicant from amending an ANDA to change the RLD. FDC Act 505(j)(2)(D)(i). Any change to the RLD in an ANDA must be made by submission of a new ANDA.

5 Page 5 1. Sun cannot comply with the patent certification requirements of the Act without including in an ANDA for Yenlafaxine HCl Extended- Release Tablets certifications to all Orange Book-listed patents that apply to Effexor XR Capsules. There are at least three scenarios (outlined below) in which an applicant must, in order to comply with the statutory certification and notification requirements set forth in sections 505(b)(2)-(3) and 505(j)(2)(A)(vii)-(viii) and (B) of the Act, certify (and provide notice) to patents that relate to earlier-approved, underlying NDAs. This requirement is in addition to certifying to patents, if any, that cover the listed drug upon which the applicant has relied directly.2 FDA has already stated explicitly that this is the policy for two out of the three scenarios described below. The third scenario describes the current situation involving Sun, Osmotica, and Wyeth. To be consistent and treat similarly situated parties the same, the agency should announce and apply to Sun an analogous policy that prevents Sun from circumventing the statutory certification and notification requirements. FDA has recognized the importance of preventing applicants from taking advantage of certain procedural steps to circumvent the statutory certification and notification requirements. For example, with regard to Sun, in announcing the Agency's policy that a generic applicant with a pending ANDA subject to a suitability petition must submit a new ANDA citing the appropriate RLD once the drug product described in the z Alternatively under the statute, if any relevant patent is a method of use patent that does not claim a use for which the applicant is seeking approval, the applicant may make that statement in its application. FDC Act 505(b)(2)(B) and 505(j)(2)(A)(viii) (a "section viii statement").

6 Page 6 approved suitability petition has been approved in an NDA (i.e., Osmotica's Venlafaxine HCl Extended-Release Tablets), FDA explained : FDA's policy of requiring all pending ANDA applicants to change their basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition is intended to ensure that ANDA applicants do not circumvent the patent and certification requirements of section 5056)(2)(A) (vii)-(viii) of the Act through the suitability petition process. FDA Citizen Petition Response (regarding venlafaxine HCl), Docket No. FDA-2008-P- 0329, at (Nov. 25, 2008) (emphasis added). It is for the same reason (i.e., the need to adhere to statutory patent certification requirements) that FDA has announced the first two policies described below, and the Agency should now apply a similar policy to Sun. a. Scenario L Approved NDA --+ Approved Suitability Petition -+ ANDA (SP) --). Subsequent ANDA. It is well settled that FDA will require that an ANDA that is submitted subsequent to another ANDA that was itself approved based on a suitability petition include certifications to any Orange Book-listed patents that apply to the original NDA upon which approval of the suitability petition was based. In other words, a second ANDA applicant seeking approval based on a suitability petition cannot use that procedural step to avoid existing patent protection that covers the drug that was the basis for approval of the suitability petition in the first place.

7 Page 7 This policy is stated explicitly in the preface to the Orange Book : Patent Certification(s) Reference Listed Drug based upon a suitability petition. An [ANDA] that refers to a Reference Listed Drug (RLD) approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition. This concept also applies to an ANDA applicant that cites a RLD that was based upon an NDA that is still covered by patent(s) and/or exclusivity, e.g., a second RLD that was selected when the in vivo determination of bioequivalence of the original RLD is self-evident and the waiver of the in vivo determination of bioequivalence may be granted. Orange Book Annual Preface, 29th Ed. (2009). We understand that this situation was first addressed by FDA in January 2002, when the Agency had to rescind approval of WE Pharmaceuticals, Inc.'s ("WE's") ANDA No for prednisolone sodium phosphate oral solution for failure to meet the statutory patent certification and notification requirements. In the Agency's letter to WE rescinding approval of the ANDA, FDA explained the situation as follows : The ANDA submitted by [WE] does not meet the statutory requirements for approval, and did not do so at the time it was mistakenly approved by FDA. The mistake arose from the status of the WE ANDA as a subsequent ANDA to that approved for Ascent Pharmaceuticals Orapred (ANDA ). Both your ANDA and the Ascent ANDA are for drug products for which a suitability petition was approved for a change to a listed drug... The listed drug referenced in the approved suitability petition is [Celltech's] Pediapred (NDA ). The listed drug product referenced in [your] ANDA , by recent amendment, was Ascent's Orapred, which has no listed patent protection. Pediapred is subject to patent protection... Although the Agency considers Ascent's Orapred to be the reference listed drug for bioequivalence purposes, this does not obviate the need for WE to

8 Page 8 provide a patent certification and notification to the holder of the original listed drug upon which the approved suitability petition was based. Letter from Gary J. Bueler, Director, Office of Generic Drugs, to WE Pharmaceuticals, Inc. (Jan. 17, 2002) (rescinding the January 4, 2002 final approval of ANDA No ). But for the fact that Osmotica's Venlafaxine HCl Extended-Releast Tablets product was approved under a 505(b)(2) application, instead of an ANDA submitted subsequent to an approved suitability petition, the situation here is essentially the same. That is, FDA policy would not permit WE to circumvent the patent protection that remained attached to the Celltech product (Pediapred) by referencing the Ascent product (Orapred) for purposes of demonstrating bioequivalence. Likewise, to be consistent, FDA cannot permit Sun to circumvent the patent protection still attached to the Wyeth product, Effexor XR Capsules, because the company had to reference Osmotica's product for purposes of demonstrating bioequivalence. b. Scenario 2 : Approved NDA [(b) (1) or (b)(2)] --+ Approved 505(b) (2) (RLD) --+ Subsequent 505(b) (2) That Osmotica's product was approved under a 505(b)(2) application should not change the analysis. FDA has indicated that in the situation outlined above it would apply a policy that is analogous to the one the Agency stated when it rescinded the WE ANDA approval : where one 505(b)(2) application relies on another 505(b)(2) application, which itself relied on previous findings of safety and effectiveness of an earlier approved NDA, the second 505(b)(2) applicant must certify to patents that cover

9 Page 9 the drug that was approved under the earlier NDA and relied upon by the first 505(b)(2) applicant. FDA has explained this policy as follows : Where a 505(b)(2) application seeks to rely on the finding of safety or effectiveness for a listed drug that is [the subject ofj a 505(b)(2) NDA which, itself, relied on a previous finding of safety and effectiveness, the 505(b)(2) applicant should certify to the patents [that] the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied [on] for approval. This is analogous to the requirement that an ANDA applicant referencing an approved suitability petition (or another ANDA approved pursuant to a suitability petition [i.e., the WE scenario]) certify to the patents for the approved NDA upon which the suitability petition or ANDA approval was based. FDA Citizen Petition Response (regarding fenofibrate), Docket No. FDA-2004-P-0089 (formerly 2004P-0386), at 10 n.14 (Nov. 30, 2004). Again, Sun sits in the same position as the second 505(b)(2) applicant above, the only difference being that it seeks approval under section 505(j) instead of section 505(b). Sun should not be able to circumvent its statutory obligation to certify to all relevant patents (i.e., all patents that cover Wyeth's Effexor XR Capsules), just because Osmotica's product is the RLD for purposes of demonstrating bioequivalence. c. Scenario 3 : Wyeth - Osmotica - Sun : Approved NDA (Effexor XR) --* Approved 505(b) (2) (new RLD) (Osmotica's Venlafaxine HO Extended-Release Tablets) --> ANDA (Sun) Submitted Referencing the 505(b)(2) approved RLD

10 Page 10 The parties involved here are similarly situated to those in the other two scenarios, and as such FDA must apply consistent policy. FDA should announce and apply a similar policy here, where the ANDA applicant, Sun, relies on FDA's previous findings of safety and effectiveness of a listed drug (Osmotica's venlafaxine product) that was the subject of a 505(b)(2) application which, itself, relied on a previous finding of safety and effectiveness, namely FDA's finding of safety and effectiveness of Effexor XR Capsules. Therefore, Sun should be required to certify to those patents that cover the drug that was approved in the underlying NDA (as well as to those patents that cover Osmotica's approved drug product). In all three scenarios, the patent holders of the drug that was approved in the earlier, underlying NDAs are in the same position. FDA cannot lawfully subject such similarly situated parties to different treatment. The Administrative Procedure Act ("APA") provides that a court may hold unlawful "agency action, findings, and conclusions found to be arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with the law." 5 U.S.C. 706(2)(A). Under this "arbitrary and capricious" standard, courts have held that agency action that treats similarly situated parties in a different manner is a violation of the APA. See, e.g., Bracco Diagnostics, Inc. v. Shalala, 963 F. Supp. 20, 28 (D.D.C.1997) (stating with regard to FDA's application of different premarket review standards to two similar products regulated by two different centers that "[w]hat the FDA is not free to do, however, is to treat [similarly situated parties] dissimilarly and to permit two sets of similar products to run down two separate tracks, one more treacherous than the other"). To avoid exposure to an allegation of arbitrary and capricious action, FDA should apply here (and in any other similar pending or future situations) a consistent policy that

11 Page 11 prevents an applicant from circumventing the patent certification requirements of the Act. FDA should require that Sun certify to all Orange Book-listed patents that apply to Wyeth's Effexor XR and Osmotica's RLD. Moreover, Sun should be required to submit a new ANDA that includes all of those required certifications. 2. Sun must submit to FDA a new ANDA with all required patent certifications. Assuming it does not include certifications to all Orange Book-listed patents that cover Effexor XR Capsules, which we have reason to believe is the case, the Sun ANDA that is currently under review is deficient on its face, and it could not have been lawfully received by FDA in the first place. Without correcting this deficiency, FDA's review should not have proceeded because the ANDA fails to comply with the patent certification requirements of the Act. Pursuant to FDA regulations, upon submission of an ANDA, FDA performs an initial review to determine whether the application can be received for substantive review. When FDA designates an ANDA as "received," it means that the Agency has made a threshold determination that the ANDA is complete and that it can be reviewed substantively. 21 C.F.R The regulations include a list of reasons that FDA will refuse to receive an ANDA. One reason FDA will refuse to receive an ANDA is if the application is deficient on its face for failure to include information that is required by section 505(j) of the FDC Act. Id (d)(3). Pursuant to sections 505(j)(2)(A)(vii) and 505(j)(2)(B), an applicant is required to include in its ANDA the appropriate patent certifications, and in the case of a certification made under paragraph (A)(vii)(IV), a statement that the applicant will notify

12 Page 12 the patent and application holder. According to FDA regulations, an ANDA that lacks complete patent certifications, and where appropriate, statements of its intent to provide the appropriate notifications, is incomplete and deficient on its face. 21 C.F.R (d)(3). If the Sun ANDA currently under review is deficient in this manner, FDA should not have received it. The opportunity to correct the deficiency by amending the application has passed once FDA deems that the application has been received. Had FDA upon its initial review recognized the deficiency and so notified Sun, the application could have been amended. Id (b)(3). Without correcting the deficiency, however, it was unlawful for FDA to proceed with its substantive review. The regulations do not provide an opportunity for an application that was incomplete on its face upon submission to be amended after FDA has conducted its substantive review. The only appropriate action now is for FDA to rescind its receipt of the application and require that Sun submit a new ANDA that complies with all patent certification and notification requirements. 3. The Patent Owner's Rights are Being Prejudiced. Further, the deficiency in Sun's ANDA, if it lacks all appropriate patent certifications, is not merely an administrative error, it encroaches on Wyeth's intellectual property rights. If additional Paragraph IV Certifications and notifications are required and this omission is left uncorrected, Wyeth loses its ability to defend its Effexor XR patents. Upon notification of Paragraph IV Certifications, Wyeth has the statutory right to file suit for patent infringement and trigger a 30-month stay of approval, if it chooses to do so at that time. FDC Act 505(j)(5)(B)(iii). Even if Wyeth ultimately does not to sue, it has a statutory right to take 45 days to decide. FDA lacks any authority to presume what action Wyeth would take under these circumstances. The only lawful course of action is to require that Sun correct its error and certify to Orange Book-listed patents that

13 Page 13 apply not only to the RLD, Venlafaxine HCl Extended-Release Tablets, but also to Effexor XR Capsules. C. Conclusion For all the reasons stated above, Osmotica respectfully requests that FDA require that any ANDA applicant seeking approval of a Venlafaxine HCl Extended-Release Tablets drug product include in its ANDA the appropriate patent certifications (and statements of intent to notify) for all Orange Book-listed patents that apply not only to the RLD, Osmotica's Venlafaxine HCl Extended-Release Tablets, but also to Effexor XR Capsules. Failure to do so would be inconsistent with FDA's already stated policy that prohibits applicants from inappropriately circumventing the statutory certification and notification requirements. Failure to apply a consistent policy to Sun would amount to FDA treating similarly situated companies differently and could expose the Agency to allegations of arbitrary and capricious action. In addition, because Sun's ANDA that is currently under review appears to be deficient on its face, FDA should require that the company submit a new application that complies fully with the patent certification and notification provisions of the Act. Failure to require that Sun correct its omission will cause Wyeth to lose its statutory right to defend its Effexor XR patents. III. ENVIRONMENTAL IMPACT A claim for categorical exclusion from the requirements for an Environmental Assessment is made under 21 C.F.R (a) because the grant of the Citizen Petition would not have an effect on the environment.

14 Page 14 IV. ECONOMIC IMPACT Information on the economic impact of the action requested by this Citizen Petition will be submitted if requested by FDA. CERTIFICATION Pursuant to the Act 505(q)(1)(H), as added by Pub. L. No , Osmotica makes the following 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 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 : late June 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 : Osmotica. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. 3 Although Osmotica became aware of Sun's ANDA in March 2009 via Sun's Notice of Paragraph IV Certifications to the `120 and `958 patents, Osmotica did not become aware of certification requirements as to the other Effexor XR Capsules patents until late June 2009.

15 Page 15 Respectfully submitted, 'Mark S. Aikman, Pharm.D. Vice President, Regulatory Affairs and Quality Assurance Osmotica Pharmaceutical Corp.