1. Hatch-Waxman As Amended (MMA) Thomas O. Henteleff Kleinfeld, Kaplan and Becker, LLP November 9, 2005

2. 2 Hatch-Waxman

3. 3 Title I ANDAs 505(b)(2) Exclusivity Patent 5-year – New Chemical Entity 3-year – 180-day Other (orphan and pediatric)

4. 4 Title II Infringement of Patent Bolar exemption (not an act of infringement) Solely for uses Reasonably related to development and submission Under Federal law which regulates drugs An act of infringement to submit ANDA or 505(b)(2) Basis for Paragraph IV Litigation Injunction as to effective date of application No damages unless commercial marketing

5. 5 Title II Patent Extension NCE Up to 5 years No more than 14 years ½ IND + NDA – lack due diligence One per drug/per patent

6. 6 Patent Exclusivity Patent Listing Requirements: A patent that claims a drug or method of use to which a claim of patent infringement could reasonably be asserted Relates to 505(b)(1) and (b)(2) Failure to timely list is basis for withdrawal and/or loss of HW patent exclusivity Improper listing subject to delisting and anti-trust concerns

7. 7 Patent Listing Patents Covered Drug Substance (active ingredient) Subject to pending or approved Same/polymorph  Must certify test data showing perform the same  If listed, ANDA eligible Drug Product (formulation and composition) Subject to pending or approved Includes product by process

8. 8 Patent Listing Patents Covered Method of Use Must identify section of pending or approved labeling that corresponds Indications, dosing regimens, use in combination with other drugs- PK data

9. 9 Patent Listing Patents Not Covered Process patents Metabolites Intermediates Packaging

10. 10 Patent Listing – 314.53 When to submit If issued at time 505(b)(1) or (b)(2) is submitted or amended FDA Form 3542a Update within 30 days of approval FDA Form 3542 Orange Book listing/Public Display If Supplement that relates to change in formulation, indication, condition of use, route of administration, strength or any change that relates to a drug, drug product or method of use patent Within 30 days after issues Correction

11. 11 ANDA Prior to HW limited to generics of DESI-effective drugs (pre- 1962) Approval based upon establishing bio-equivalence to a reference listed drug (RLD) and CMC data Generally, must be the same as RLD with respect to active(s) and labeling, except: Approved Suitability Petition-strength, dosage form, route of administration, combination (21 CFR 314.93) Labeling differences due to different manufacturer (e.g., name, expiration dating), inactives or differencs resulting from outstanding exclusivity that do not render the drug product less safe or effective than the listed drug for any remaining non- protected conditions of use (21 CFR 314.94, 314.127, and 314.150(b)(10))

12. 12 ANDA Subject to patent and non-patent exclusivity Once filed cannot amend or supplement to refer to a different listed drug, except for new strength First to file a Paragraph IV potentially entitled to a 180-day exclusivity

13. 13 505(b)(2) Prior to HW “Paper NDA” Relies in part on investigations which were not conducted by or on behalf of the applicant and for which applicant has not obtained a right of reference Published literature (historical paper NDA) Relies on agency’s findings of safety and effectiveness of an approved listed drug If there is a listed drug which is pharmaceutically equivalent drug to proposed it should be identified as the RLD? Cannot be submitted if duplicate of listed and eligible for ANDA or if only difference is bio-equivalence profile relating to extent or unintentional rate Examples: NCE (different salt), new indication, OTC switch, strength, dosage form

14. 14 505(b)(2) Subject to patent and non-patent exclusivity (if rely on for safety and effectiveness data)* Potentially entitled to non-patent and patent exclusivity No 180-day exclusivity * King Pharmaceutical vs. FDA (July 2004)

15. 15 Patent Certification/Statement Paragraph I – Patent Information has not been filed No relevant patents Application may be made effective immediately Paragraph II – The listed patents have expired Application may be made effective immediately

16. 16 Patent Certification/Statement Paragraph III – The date the listed patents expire Application may be made effective on expiration date of patent Paragraph IV – The listed patent[s] are invalid, not- infringed or not enforceable License Agreement Application may be made effective immediately unless within 45 days of receipt of notice infringement action brought for a patent subject to certification and for which patent information was filed before ANDA or (b)(2) application (except amendments and supplements) deemed substantially complete Must provide certification for listed patent even if patent could not result in 30 month stay (i.e., filed after ANDA or (b)(2))

17. 17 Patent Certification/Statement viii Statement – The listed method of use patent does not claim the use for which the applicant seeking approval (carve-out) Limitation – Not permitted if renders generic less safe or effective than listed drug for remaining non-patented condition of use

18. 18 Paragraph IV Notification Must notify patent owner (designated representative) and holder of NDA for RLD Must include detailed statement of factual and legal basis Must give notice within 20 days after FDA notifies applicant that application has been filed If an Amendment or Supplement must be given at time filed Based on MMA FDA revoked rule that notice not required if applicant had already provided notice Must amend application to certify notice has been sent and provide for documented receipt (21 CFR 314.52, 314.95)

19. 19 30-Month Stay Conditions Patent listed before applicable ANDA or 505(b)(2) filed (MMA) MMA generally precludes multiple 30-month stays because only applies with respect to patents filed prior to ANDA or 505(b)(2)  New rule only applies to patents submitted after 8/13/03  Old rule if patent timely submitted ANDA would have to be amended if sued triggered a new 30-month stay (FDA by regulation tried to limit through notification)  Could be multiple 30-month stay under new rules if initially IV and III and convert III into IV

20. 20 30-Month Stay Paragraph IV Patent Owner on NDA holder sues within 45 days of notice Court may shorten or lengthen 30-month stay if either party to action fails to reasonably cooperate in expediting action Court may issue an injunction against commercial marketing until decides thereby effectively extending the 30-month stay

21. 21 30-Month Stay When Terminated District Court decision that patent invalid, not infringed or not enforceable (including any substantive determination that no cause of action) Date of Settlement or Consent degree that patent invalid not infringed Date of Court of Appeals decision reversing lower court decision of infringement

22. 22 30-Month Stay If 30-month stay expires and no finding of infringement ANDA/505(b)(2) may be made effective upon the expiration If Court finds infringement ANDA/505(b)(2) cannot receive effective approval until relevant patent expires

23. 23 180-Day Exclusivity First to submit a substantially complete ANDA with Paragraph IV for listed patent May be separate exclusivities for separate patents or shared exclusivity for filings on the same date Doesn’t apply to 505(b)(2) Prior to MMA (December 8, 2003) 180-day clock triggered by earlier of commercial marketing or court decision Paragraph IV filed prior to 12/08/03 court decision still triggers; however if court trigger occurs after 12/08/03 the triggering court decision is the court from which no appeal can be taken other than certiorari (Court of Appeals)

24. 24 180-Day Exclusivity Paragraph IV certification after MMA 180-day clock triggered by commercial marketing, however subject to forfeiture The 180-day clock is triggered if the first applicant markets the product subject to the certification or the listed drug-authorized generic

25. 25 180-Day Exclusivity Forfeiture Forfeited if fails to market the later of The earlier of 75 days of effective approval of first applicant or 30 months after submission of application entitling 180 days, or 75 days after any applicant (first to file or other) has obtained Tentative Approval and with respect to each patent subject to first applicants IV certification and at least one of the following has occurred: Infringement action brought against or a declaratory judgment brought by which results in a court from which no appeal can be taken (Court of Appeals) finding that patent invalid, not infringed or not enforceable A court signs a Settlement or Consent Decree and enters a final judgment finding invalid or not infringed* The patent information is withdrawn by the holder of the 505(b) application * Teva Pharmaceuticals v. FDA (October 2005)

26. 26 180-Day Exclusivity Forfeiture The first applicant withdraws its application or FDA considers application to have been withdrawn The first applicant amends or withdraws IV Certification for all patents qualifying for 180- day exclusivity Failure of the first applicant to obtain Tentative Approval within 30 months after the date filed unless failure due to change in review requirements

27. 27 180-Day Exclusivity Forfeiture Agreement with another applicant re marketing for which FTC or Attorney General files a complaint and there is a final judgment from which no appeal can be taken that the agreement violates anti-trust laws All patents as to which applicant submitted a certification for qualifying for 180-day exclusivity have expired

28. 28 Declaratory Judgment Action re Patents Conditions as necessary to pursue: After Paragraph IV notification 45 days have expired with no suit If based upon non-infringement made an offer as part of notice of confidential access to ANDA for determining whether action should be brought within 45 days No damages allowed MMA doesn’t change standard – still must show reasonable apprehension of suit

29. 29 Counterclaims In an infringement action may seek counterclaim to correct or delete listing because patent inappropriately listed No damage No independent cause of action

30. 30 Non-Patent Exclusivity 5-Years New Chemical Entity New Chemical entity – no active moiety (molecule (excluding salts or esters) responsible for physiological or pharmacological action) has been approved by FDA in any 505(b) application May not submit an ANDA or 505(b)(2) until exclusivity has expired, except May submit in 4 years if contains a Paragraph IV Certification

31. 31 Non-Patent Exclusivity 3-Year Exclusivity Applies to (b)(1) & (2) and Original and Supplements Application may be filed but effective approval cannot issue until exclusivity expires Scope (dosage form, dosage regimens)

32. 32 Non-Patent Exclusivity 3-Year Exclusivity Conditions: New clinical investigations (human studies (other than bio) which have not been relied upon by FDA to demonstrate substantial evidence of effectiveness or safety in a new population) Essential to approval (not duplicate or otherwise not essential) Conducted or sponsored by the applicant (filed 1571, provided substantial support (50% or more of funding) or predecessor in interest)

33. 33 Authorized Generic The NDA holder authorizes a generic to market product under its NDA Court have upheld validity* Can dilute the effectiveness of 180-day exclusivity FTC and Congress reviewing * Teva Pharmaceutical v. Crawford (6/3/05, Ct of Appeals) * Mylan Pharmaceuticals v. FDA (9/29/05)

34. 34 Conclusion