1. AXINN, VELTROP & HARKRIDER LLP © 2007 | www.avhlaw.com How to Align the FDA Approval Process with PIV Strategy Chad A. Landmon 90 State House Square 1330 Connecticut Ave, N.W. cal@avhlaw.comcal@avhlaw.com Hartford, CT 06103Washington, D.C. 20036 (860) 275-8170(202) 721-5415 June 2, 2011

2. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 2 Overview I.Critical FDA Issues for Market Success II.Litigation Strategy to Optimize FDA Results III.Strategy to Address Exclusivity Grants

3. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 3 I. Critical FDA Issues for Market Success Major factors influencing FDA approval –Bioequivalence Strategies for using the FDA citizen petition process to optimize success –Ambien ® CR –ADHD drug citizen petitions –Abuse of the citizen petition process

4. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 4 Factors Influencing FDA Approval Bioequivalence (BE) –Required for FDA approval of an ANDA for the generic version of a brand name drug –FDA recommends substitution by state formularies only for bioequivalent products

5. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 5 Bioavailability Bioavailability is the rate and extent to which the active ingredient becomes available at the site of drug action. Bioavailability is typically measured as AUC and C max. C max measures the rate of absorption. AUC measures the extent of absorption.

6. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 6 Pharmacokinetic Studies: Key Measurements AUC: Area under the concentration- time curve C max: Maximum concentration T max: Time to maximum concentration Reference Listed Drug Generic Version Time Concentration C max T max AUC

7. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 7 FDA Requirements for Bioequivalence 125% 100% 80% Product A Bioequivalent Reference Listed Drug (RLD) Product B Not Bioequivalent Product A is bioequivalent to the RLD; its 90% confidence interval for AUC and C max fall within 80% to 125% of the RLD Product B is not bioequivalent to the RLD; its 90% confidence interval for AUC and C max fall outside of 80% to 125% of the RLD Pharmacokinetic Reference Range

8. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 8 Strategies for Using the FDA Citizen Petition Process The FDA citizen petition (CP) process may be used in order to delay the approval of generics –E.g., CP may challenge the BE testing criteria for certain generic products –Approval of generic products is delayed while FDA evaluates the CP –May be viewed as a less expensive alternative to litigation Generic filers may file a CP so as to adversely affect another generic competitor

9. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 9 Ambien CR ® Citizen Petition Brand company Sanofi-Aventis filed CP in June 2007; also filed comment on FDA BE Docket on Feb. 2009 –Sanofi argued that FDA should require more extensive BE measurements, specifically use of partial AUCs: AUC 0-3, AUC 3-6, AUC 6-inf August 2009 BE Guidance –Required AUC from time 0-1.5 hours after administration to meet the 80/125 test –Rationale: this was a sleep medication and effectiveness in the first 1.5 hours required a BE AUC

10. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 10 Wellbutrin XL ® Citizen Petition Biovail argued that FDA should require ANDA filers to conduct additional BE testing. –Sought comparisons to Wellbutrin IR and SR, in addition to Wellbutrin XL ® FDA rejected Biovail ’ s argument ANDA filers only need to prove BE to RLD.

11. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 11 ADHD Drug Citizen Petitions ADHD drugs: Concerta, extended-release (McNeil); Metadate ER (CellTech); Adderall ® XR (Shire) –Brand companies filed CPs in 2004 and 2005 Brand companies: Traditional BE metrics cannot account for different PK profiles. –ADHD drugs may appear BE based on standard metrics but are actually clinically inequivalent. –Shire: PK profile in the ANDAs must be superimposable on the profiles of the brand

12. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 12 Brand companies: –AUCpR is sensitive to early absorption profiles of certain classes of drugs AUCpR = area under the curve to the population median T max of the reference formulation –Safety concern: AUCpR can account for higher IR:ER ratios for ER methylphenidate drugs Brand companies ’ CPs have delayed ANDA approvals FDA has not rendered any decisions on these CPs ADHD Drug Citizen Petitions

13. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 13 Anticompetitive Conduct? A meritless CP submitted to impose delay may raise antitrust issues –On the eve of ANDA approvals relating to Arava ®, Sanofi- Aventis filed a CP for more stringent BE studies; the CP was denied by FDA six months later. –Drug wholesaler brought action under § 2 of the Sherman Act –Motion to dismiss denied and action allowed to continue Louisiana Wholesale Drug Co. v. Sanofi-Aventis, 2008 U.S. Dist. LEXIS 3611 (S.D.N.Y. Jan. 18, 2008)

14. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 14 II. Litigation Strategy to Optimize FDA Results Generic and brand strategies to prepare for PIV in light of FDA approval issues Brand company ’ s efforts to prolong exclusivity using the FDA process –Novo Nordisk and repaglinide Generic attempts to address various patent issues in the FDA approval process –Adding information to an ANDA specification to avoid infringement

15. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 15 Brand Strategies Evaluate potential FDA issues for generics –BE –“ sameness ” –labeling issues Prepare patent litigation team to issue spot Protective order issues regarding use and dissemination of information

16. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 16 Generic Strategies Fully evaluate ANDA and development history for FDA issues Prepare counsel to issue spot Prepare witnesses for FDA issues in depositions Protective order issues regarding use and dissemination of information Generic vs. generic strategies

17. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 17 Novo Nordisk ’ s Use of Repaglinide Novo Nordisk v. Caraco Pharm. Labs., Ltd., 601 F.3d 1359 (Fed. Cir. 2010) –Novo markets Prandin ® (repaglinide) for the treatment of diabetes –Three FDA-approved uses of Prandin: (1) repaglinide by itself; (2) repaglinide + metformin; and (3) repaglinide + thiazolidinediones –Novo ’ s OB-listed patent covers the use of repaglinide + metformin; patent ’ s use code was repaglinide + metformin to treat diabetes –Caraco filed ANDA for repaglinide Did not seek approval of repaglinide + metformin → filed section viii statement

18. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 18 Novo Nordisk ’ s Use of Repaglinide Novo Nordisk then updated the OB-listed patent ’ s use code to broadly cover the use of repaglinide to treat diabetes Caraco ’ s proposed carve-out label now overlapped with the OB patent ’ s use code → FDA denied Caraco ’ s section viii statement Caraco brought counterclaim to compel Novo to change the use code because the new use code was overbroad –Court: Hatch-Waxman Act did not support such a counterclaim The Act authorizes a counterclaim only where the listed patent does not claim any approved method of using the listed drug The statute authorizes a counterclaim to change the “ patent information, ” i.e., only the patent number and expiration date, not the use code July 29, 2010: Federal Circuit denied Caraco ’ s petition for rehearing en banc

19. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 19 Novo Nordisk Use of Repaglinide Novo Nordisk: OB Use Codes govern permissibility of section viii label carve-outs –Use Codes describing what the patent claims are created by brand (Forms 3542/3542a); not independently verified by FDA OB Use Codes can be used to thwart carve-outs –Use Codes can be vague to interfere with label carve-outs –This practice was sanctioned by Novo Nordisk

20. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 20 Post-Novo Nordisk Remedies for Use Code Abuse Post-MMA Delisting Counterclaim Provision –Applicable only where listed patents do not claim a drug product or any approved methods of use –Not an immediate remedy; can arise only in conjunction with PIV litigation –Counterclaims can only delete patents (or correct patent numbers and expiration dates); cannot change incorrect Use Codes Implications for the First Filer –Delisting can satisfy prong of failure-to-market provision

21. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 21 Adding to the ANDA to Avoid Infringement Where the ANDA defines it product in a way that directly addresses the question of infringement, the ANDA product cannot literally infringe under Section 271(e)(2) as a matter of law. The Federal Circuit has determined that the ANDA alone can “ mandate[] a finding of no literal infringement. ” –Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241 (Fed. Cir. 2000) –Tyco Healthcare Group LP v. Mut. Pharm. Co., No. 07-1299, 2009 U.S. Dist. LEXIS 68176 (D.N.J. Aug. 4, 2009) Hypothetical infringement inquiry is grounded in the ANDA application.

22. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 22 III. Strategy to Address Exclusivity Grants Ways to Maximize Exclusivity Strategy Challenges to the 180-day Exclusivity Period –Forfeiture –30-month Tentative Approval Issues

23. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 23 Optimizing a Brand ’ s Exclusivity Obtain additional patents –Claims directed to the formulation, PK properties, etc. Adjust the formulation –Controlled-release –Abuse-resistant Get approval for additional indications Product switching strategies –Immediate-release to extended-release dosage form –Basic drug molecule to a prodrug of the same drug molecule –Basic formulation to “ abuse-resistant ” formulation

24. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 24 Challenges to the 180-day Exclusivity Period: Forfeiture Failure to Market. The first applicant fails to market the drug by the later of – (aa) the earlier of the date that is – (AA) 75 days after the date on which the approval of the application of the first applicant is made effective under (B)(iii); or (BB) 30 months after the date of submission of the application of the first applicant; or (bb) with respect to the first applicant or any other applicant (which other applicant has received tentative approval), the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under (B)(iv), at least one of the following has occurred: (AA)... a court enters a final decision from which no appeal... has been or can be taken that the patent is invalid or not infringed. (BB)... a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed. (CC) The patent information submitted under (b) or (c) is withdrawn by the holder of the application approved under (b).

25. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 25 A First Applicant forfeits 180-day exclusivity if it fails to market by the later of: Regulatory EventsPatent Events THE EARLIER OF: With respect to the first applicant(s), or any other applicant with tentative approval, and with respect to each patent for which the first applicant(s) submitted a Paragraph IV Certification qualifying it for exclusivity, 75 days after any one of the following “has occurred": 75 days after final approval of the first applicant’s ANDA; or 30 months after submission of the first applicant’s ANDA. A court issues a final non-appealable decision that the patent(s) is/are invalid or not infringed (whether in an infringement action or a declaratory judgment action ); A court signs a settlement or consent decree that includes a finding that the patent(s) is invalid or not infringed; or The patent is withdrawn from the Orange Book

26. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 26 Other Forfeiture Events First applicant withdraws ANDA First applicant amends ANDA to withdraw PIV certifications First applicant fails to obtain tentative approval within 30 months from filing, unless the failure is caused by a change in or review of the approval requirements

27. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 27 Failure to Obtain Tentative Approval Added by Medicare Modernization Act Forfeiture occurs when “ [t]he first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed. ” 21 U.S.C. § 355(j)(5)(D)(i)(IV). Has not yet been litigated by either a first ANDA applicant who has forfeited 180-day exclusivity on these grounds or by a subsequent ANDA applicant challenging the first applicant ’ s retention of 180-day exclusivity

28. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 28 Failure to Obtain Tentative Approval In contrast to the “ failure to market ” provision, the “ failure to obtain tentative approval ” provision calculates the 30-month period from the date the ANDA is filed as opposed to the date of ANDA submission –Reasonable to use the date that qualifies the first ANDA applicant for 180-day exclusivity, i.e., the date that the ANDA is sufficiently complete to permit substantive review Rationale: 180-day exclusivity provided to the first applicant “ carries with it the requirement that – to maintain that eligibility – the first applicant must work diligently to obtain a tentative approval before the 30- month period expires. ”

29. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 29 Exceptions to Failure to Obtain Tentative Approval Provision Exception for a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed Acarbose: –CP filed relating to BE methodology for acarbose products after the 30-month period had run served to change the BE requirements –Filing and FDA evaluation of CP delayed approval of Cobalt ’ s ANDA –Cobalt did not forfeit its exclusivity for failure to obtain tentative approval Nateglinide: –At least one first ANDA applicant (of many) failed to obtain tentative approval within 30 months –If a first applicant loses 180-day exclusivity, its ANDA can still be approved during the 180-day period –Once any first applicant (eligible or ineligible for 180-day exclusivity) gets final approval and begins commercial marketing, the 180-day clock begins to run.

30. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 30 Where tentative approval is not received within 30 months, FDA may nevertheless defer making a decision on forfeiture unless and until another applicant becomes eligible for approval within 180 days after the first applicant begins commercial marketing. –Example: Triamcinolone Acetonide “ The agency notes that Barr failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed. See section 505(j)(5)(D)(i)(IV) of the Act. However, the agency is not making a formal determination at this time of Barr's eligibility for 180-day generic drug exclusivity. It will do so only if another applicant becomes eligible for approval within 180 days after Barr begins commercial marketing of Triamcinolone Acetonide Nasal Spray, 0.055 mg. ” Exceptions to Failure to Obtain Tentative Approval Provision

31. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 31 FDAAA Tolling Provision Enacted Sept. 27, 2007 “ [I]f the filing of an application resulted in first- applicant status... and approval of the application was delayed because of a petition, the 30-month period... is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates), without regard to whether the Secretary grants, in whole or in part, or denies, in whole or in part, the petition. ” 21 U.S.C. § 355(q)(1)(G).

32. AXINN │ VELTROP │ HARKRIDER │ LLP © 2011 | www.avhlaw.com 32 FDAAA Tolling Provision Any citizen petition submitted prior to Sept. 27, 2007 will not be subject to the provisions of FDCA 505(q)/21 U.S.C. § 355(q). –See Guidance for Industry: Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act 4 (Jan. 2009). FDA recommends that citizen petitions not be filed regarding BE guidances; instead, FDA requests comments on the BE docket (established for individual BE guidances).

33. AXINN, VELTROP & HARKRIDER LLP © 2007 | www.avhlaw.com Any questions? Chad A. Landmon cal@avhlaw.com (860) 275-8170 (202) 721-5415