1. Legal and Regulatory Considerations When Pursuing an ANDA Shaoyu Chen Managing Director China Food and Drug Practice Covington & Burling LLP Third DIA China Annual Conference Beijing, May 2011

2. 2 Some Context FDA approval needed NDA 505(b)(2) Two kinds of generics ANDA 505(b)(2) Two ways to market OTC Monographs (no approval needed) NDA Some generics FDA approval needed BLA Two kinds of generics Biosimilars Interchangeable biosimilars

3. 3 What’s the big deal anyway? Sales Time the Dreaded “Shark Fin” Curve generic entry

4. 4 Drug Price Competition & Patent Term Restoration Act of 1984 (a.k.a. “Hatch-Waxman Act”) Title I: abbreviated approval process for generic drugs Title II: patent term restoration

5. 5 Meet the Sponsors … Sen. Orrin Hatch (R-Utah) Rep. Henry Waxman (D-Calif.)

6. 6 A Little History (Pre-1984) … 1906 Food & Drugs Act 1938 FDCA 1962 Amendments 1984 H-W

7. 7 The Generic Drug Approval Process ANDA 090752, 4/15/2011 approval Amlodipine Besylate, 氨苯磺酸氯地平片 RLD: Norvasc®, Pfizer Frontage Lab, 方达医药技术有限公司 Beijing Second Pharmaceutical 北京赛科药业

8. 8 Generic Drug Approval Process Section 505(j) (21 U.S.C. 355(j)) Reference Listed Drug ANDA “Sameness” Bioequivalence CMC REMS Nothing addt’l

9. 9 Section 505(b)(2) Applications Successor to pre-1984 paper NDA policy Application must contain full safety and effectiveness information Section 505(b)(2) applies if the NDA contains one or more studies -- –Not conducted by or for the applicant –As to which applicant does not have a right of reference

10. 10 Patent Provisions

11. 11 ANDA/505(b)(2) Patent Certification All ANDA and 505(b)(2) applicants must certify to all patents listed in Orange Book for RLD: –Par. I: Patent information not filed –Par. II: Patents have expired –Par. III: Not seeking approval until patent expiry –Par. IV: Patents are is invalid/not infringed OR: “Little section viii statement” (omissions)

12. 12 Paragraph IV Process Notice to NDA holder and patent owner –Sent upon notice of acceptance of ANDA/505(b)(2) for filing –Detailed statement of factual and legal basis for opinion 45-day window to decide whether to sue Filing ANDA/505(b)(2) is an act of infringement

13. 13 Paragraph IV Process Timing of ANDA/505(b)(2) approval if patent litigation is brought –ANDA cannot be approved for 30 months while the litigation is pending –Court can shorten or lengthen the period if either party fails to cooperate in expediting the action –District court decision ends stay If patent upheld, ANDA/505(b)(2) converts to a par. III FDA review can proceed despite stay –ANDA will receive a “tentative approval”

14. 14 Multiple 30-Month Stays Under Prior Law  NDA/Patent holder sues -- 30-mo. Stay #2 NDA obtains & lists new patent(s) New ANDA Par. IV certification NDA w/ listed patent(s) ANDA w/ Par. IV certification  NDA/Patent holder sues -- 30-mo. stay #1

15. 15 MMA Rules for 30-Month Stays  NDA/Patent holder sues -- 30-mo. Stay #2 NDA obtains & lists new patent(s) New ANDA Par. IV cert’n NDA w/ listed patent(s) ANDA w/ Par. IV cert’n  NDA/Patent holder sues -- 30-mo. stay #1 X Only patents listed before ANDA/505(b)(2) can trigger stay

16. 16 Declaratory Judgments Affirmatively authorizes DJ after 45 days Courts shall have subject matter jurisdiction “to the extent consistent with the Constitution” –Legislative history supports “reasonable apprehension of suit” test Confidential right of access to ANDA/505(b)(2) as precondition to DJ –Non-infringement only

17. 17 Non-Patent Exclusivity

18. 18 Five-Year Protection for New Chemical Entities 5 year for new molecular entity 3 year for new use essential clinical data 7 year orphan drug (200,000 patients) 6 month: 1st generic challenging listed drug’s patent 6 month additional for pediatric indication

19. 19 180-Day Exclusivity Incentive to generic companies to challenge patents –First to file with paragraph IV Prohibits approval of subsequent ANDAs for 180 days from first commercial marketing Subject to forfeiture provisions –In essence, 75 days after ANDA approval or resolution of litigation, whichever is later

20. 20 Patent Term Restoration

21. 21 PTR Period 1/2 of IND time plus full NDA time Maximum period –Five years –Fourteen years of effective patent life Less any period during which applicant did not act with “due diligence” Rights under extension limited to approved product and uses

22. 22 Business & Practice Considerations

23. 23 Life Cycle Planning (f/k/a “Franchise Protection”) Regulatory opportunities –E.g., B-E standards, USP, product specs, labeling (incl. risk management) –Citizen petitions, letters, litigation Line extensions and enhancements –E.g., Combinations, XR, new actives (metabolites/enantiomers), OTC switches –Clinical advantage + IP/regulatory protection + time to introduce

24. 24 Life Cycle Planning (cont.) Maximize patent and exclusivity protections Begin early and plan throughout product life cycle Always with careful antitrust review –New waves of patent litigation follow-on antitrust cases

25. 25 Hot Topics Authorized generics Innovator/generic and generic/generic settlements QI Act Follow-on biologics

26. 26 Citations Statutory provisions –FD&C Act § 505(j) and (l) –FD&C Act § 505(b) and (c) –Patent Act § 271 –Patent Act § 156 Regulations –21 C.F.R. part 314 (patent, exclusivity and ANDA provisions) –21 C.F.R. part 320 (bioequivalence) Implementing regulations –Proposed regulations -- 54 Fed. Reg. 28872 (July 10, 1989) –Final procedural regulations -- 57 Fed. Reg. 17950 (April 28, 1992) –Final exclusivity/patent regulations -- 59 Fed. Reg. 50338 (Oct. 3, 1994) –Final revised patent listing regulations – 68 Fed. Reg. 36676 (June 18, 2003)

27. 27 Questions? C&B China Food and Drug Practice Attorneys: Shaoyu Chen schen@cov.com Eric Carlson ecarlson@cov.com Scott Cunningham scunningham@cov.com William Friedman wfriedman@cov.com Jason Ma jma@cov.comschen@cov.comecarlson@cov.comscunningham@cov.comwfriedman@cov.comjma@cov.com