1. Safe Harbor or Not: Application of 271(e)(1) to Pioneering Drug Discovery Activities Susan Steele October 21, 2003

2. Typical Timeline in Life of Drug Pre-1984 Drug discovery at Pioneering Drug Company File patent Patent Granted Patent Expires Selection of Clinical Candidate File IND File NDA approved Generic Co. starts clinical trials 2 nd NDA

3. Roche v. Bolar Before patent expired, Bolar ordered 5 KG of drug. Began formulation and metabolism studies required for NDA. Fed. Cir. held that Bolar infringed patent under the 271(a) “use” prohibition. –Fed. Cir. declined to create a new judicial exception to the “use” prohibition for generic drug companies. –“We will not rewrite the patent laws here.”

4. Drug Price Competition and Patent Term Restoration Act of 1984 35 U.S.C. 156 –Allows for patent term extension of certain products subject to lengthy FDA approval. 35 U.S.C. 271(e)(1) Safe Harbor –Allows generic drug manufacturers to conduct research and development activities to generate data for ANDA before patent expires.

5. Typical Timeline in Life of Drug Post 1984 Drug discovery at Pioneering Drug Company File patent Patent Granted Patent Expires Selection of Clinical Candidate File IND File NDA approved Generic Co. starts clinical trials File ANDA

6. 35 U.S.C. 271(e)(1) It shall not be an act of infringement to make, use, offer to sell or sell within the US a patented invention solely for purposes reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs…

7. A Patented Invention 1.Patented invention is limited to drugs. 2.Patented invention is limited to products eligible for a term extension. 3.Patented invention is limited to products regulated by the FDA. 4.Patented invention refers to all patented inventions.

8. Eli Lilly v. Medtronic (1990) Patented invention was defibrillator eligible for term extension under 156. Supreme Court considered 156 and 271(e)(1) together to interpret scope of safe harbor. Opinion acknowledged there may be rare situations in which safe harbor would apply but not term extension.

9. Bristol-Myers Squibb v. Rhone-Poulenc Rorer RPR holds patent on key chemical intermediates in synthesis of taxol from natural product. BMS used patented chemical intermediates in research efforts to discover second generation taxol drug (eventual subject of IND).

10. BMS v. RPR Analysis of Patented Invention Fed. Cir. previously held that medical devices reviewed by FDA (but not subject to term extension) were patented inventions. District Court quickly concluded that “patented invention” means all patented inventions or discoveries.

11. 35 U.S.C. 271(e)(1) It shall not be an act of infringement to make, use, offer to sell or sell within the US a patented invention solely for purposes reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs…

12. Reasonably Related 1.Only activities that directly generate data submitted on an ANDA are immunized. 2.Activities that are reasonably expected to generate data submitted on an ANDA are immunized. 3.Activities that are reasonably expected to generate data submitted on an IND, NDA, ANDA. 4.Activities that identify drugs which are the subject of an FDA regulatory submission are immunized.

13. Intermedics v. Ventritex Would it have been reasonable, objectively, for a party…to believe that there was decent prospect that the “use” in question would contribute (relatively directly) to the generation of kinds information that was likely to be relevant in the process by which the FDA would decide whether to approve the product?

14. BMS v. RPR RPR argued that 271(e)(1) should not apply until drug candidate has been identified in FDA filing. Bristol countered that 271(e)(1) should apply “from first synthesis of an analog,” or otherwise “frustrate Congress’ intent” of promoting approval of drugs. District Court agreed with Bristol.

15. Integra v. Merck Integra owned patents on RGD peptides. –Research tool patents and composition of matter Merck developed and filed IND on cyclic RGD. Licensing negotiations filed; Integra sued. Integra did not allege infringement for period after clinical candidate was identified.

16. Integra v. Merck: Majority Consistent with Congress’ intent, “safe harbor covers those pre-expiration activities ‘reasonably related’ to acquiring FDA approval of a drug already on the market.” Majority believes Merck’s interpretation would wipe out the economic value of research tool patents. Characterizes RGD patents as research tool patents.

17. Integra v. Merck: Majority FDA does not require data in IND on analogs tested and rejected in discovery process. “Downstream clinical testing for FDA falls within safe harbor.”

18. Integra v. Merck: Dissent Characterizes RGD patents new compositions. Second comers can study patents under research exemption (in order to discover improvements). 271(e)(1) exception takes over where research exemption ends.