1. The Hatch-Waxman Act and How it Works: Balancing Incentives to Innovate with the Need for Affordable Drugs Minnesota Intellectual Property Association Biotech / Chem Law June 4, 2009

2. Drug Price Competition and Patent Term Restoration Act of 1984 Pub. L. No. 98-417 Codified at 15 U.S.C. §§ 68b-68c, 70b (1994); 21 U.S.C. §§ 301 note, 355, 360cc (1994); 28 U.S.C. § 2201

3. Balancing Innovation with Affordability “... the American people will save money, and yet receive the best medicine that pharmaceutical science can provide.” –President Reagan, Sept. 24, 1984

4. Background 1962 Amendments to FDCA required proof of safety and efficacy Lengthy approval period for innovators = defacto shortening of patent term Onerous approval requirements for generics = “off-patent” drugs with no generic competition

5. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

6. Generic Market Share Source: Gary Buehler presentation, FDA CDER; IMS Health 2009 study commissioned by GPhA

7. Generic Market Share In 2008, generic sales accounted for 69% of prescriptions written and 16% of all prescription dollars spent Source: IMS Health 2009 study commissioned by GPhA

8. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

9. Requirements for generic approval Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of use Compared to reference listed drug (RLD) - (brand name product)

10. Requirements for generic approval NDA 1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing 6.Animal Studies 7.Clinical Studies 8.Bioavailability ANDA 1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing 6.Bioequivalence

11. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

12. “Safe Harbor” for pre-approval activities before the Act, a generic manufacturer who used a patented drug during the patent term for the purpose of conducting tests to submit information to the FDA committed patent infringement Roche Products v. Bolar, 733 F.2d 858 (Fed. Cir. 1984)

13. “Safe Harbor” for pre-approval activities 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 United States or import into the United States a patented invention... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

14. “Safe Harbor” for pre-approval activities  Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005)  statutory text “provides a wide berth for the use of patented drugs in activities related to the federal regulatory process”  use of patented compounds in preclinical studies is protected... as long as there is a reasonable basis for believing that the experiments will produce “the types of information that are relevant to an IND or NDA.”

15. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

16. Patent Term Restoration  Formula Under 35 USC §156:  50% of the time spent in initial clinical trials (IND); PLUS  100% of the time spent in new drug application (NDA) approval process

17. Patent Term Restoration Under 35 USC §156  Other Requirements:  No more than 5 years or up to 14 years from date of FDA approval  Patent not expired  No previous extension under this provision  First permitted commercial marketing or use

18. Patent Term Restoration Under 35 USC §156  NOT the same as Patent Term Adjustment under § 154 (delays in PTO review)  Extension is in addition to any adjustment under § 154

19. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

20. Innovator Non-Patent Exclusivity  Exclusivity Regardless of Existence of Patent  NCE (New Chemical Entity): 5 years  New active ingredient, new molecules, new salts  FDA can’t even accept a generic application for 5 years (4 years if a PIV challenge)  Effectively 7 ½ years if there is a PIV challenge after 4 years  New product/new use /supplemental exclusivity: 3 years  (new clinical studies to support a new indication, formulation, salt, dosage regimen, etc.; enantiomers)

21. Innovator Non-Patent Exclusivity  Exclusivity Regardless of Existence of Patent  Orphan Drug: 7 years  If FDA approval is for disease affecting less than 200,000 U.S. citizens  Pediatric use: 6 months in addition to existing exclusivity or patent term  If pediatric study is undertaken in response to FDA written request

22. Key Features of the Hatch- Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

23.  NDA holder must notify FDA of any patent that claims a drug or method of using a drug and with respect to which a claim of infringement can reasonably be asserted  FDA publishes in “Orange Book”

24. Active Ingredient Search Results from "OB_Rx" table for query on "rosuvastatin." Appl No TE Code RL D Active Ingredient Dosage Form; Route Strength Proprietary Name Applicant 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 10MGCRESTORIPR 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 20MGCRESTORIPR 021366Yes ROSUVASTATIN CALCIUM TABLET; ORAL 40MGCRESTORIPR 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 5MGCRESTORIPR

25. Patent and Exclusivity Search Results from query on Appl No 021366 Product 002 in the OB_Rx list. Patent Data Appl No Prod No Patent No Patent Expiration Drug Substance Claim Drug Product Claim Patent Use Code Delist Requested 0213660026316460Aug 4, 2020Y 0213660026858618Dec 17, 2021U-618 021366002RE37314Jan 8, 2016Y Exclusivity Data Appl NoProd NoExclusivity CodeExclusivity Expiration 021366002NCEAug 12, 2008 021366002I-573Nov 6, 2011 021366002I-547Nov 8, 2010

26. Generic applicant patent certifications ANDA Certification Paragraph I: Paragraph II: Paragraph III: Paragraph IV: Patent status No Patent info in Orange Book Patent expired No product launch until patent expires Patent is invalid,unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted

27. Generic exclusivity First ANDA filer with para. IV certification gets:  180 days of exclusivity against other generics  Starts with first marketing or final appeals court decision

28. Notice Letter  Generic applicant who files a paragraph IV certification must notify the patent and NDA holder with a detailed statement  Patent/NDA holder has 45 days to sue  Generic applicant can file a declaratory judgment action if not sued

29. Submitting an ANDA with a PIV certification is an act of infringement 35 USC § 271: (a) direct infringement (b) induced infringement (c) contributory infringement (e)(1) safe harbor

30. Submitting an ANDA with a PIV certification is an act of infringement 35 USC § 271 (e)(2): It shall be an act of infringement to submit – (A) an [ANDA] Act for a drug claimed in a patent or the use of which is claimed in a patent...

31. Submitting an ANDA with a PIV certification is an act of infringement “somewhat artificial” act of infringement that vests district courts with jurisdiction –Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990)

32. Automatic Stay of FDA Approval Initiation of Lawsuit means FDA cannot approve an ANDA until:  Final court ruling;  Patent expires; or  30 months from notification

33. Remedies for infringement § 271(e) (4) For an act of infringement described in paragraph (2) — (A) court can set approval date as end of patent, (B) grant injunctive relief; (C) no damages unless there has been commercial manufacture, use, or sale. The remedies prescribed by subparagraphs (A), (B), and (C) are the only remedies which may be granted by a court for an act of infringement described in paragraph (2), except that a court may award attorney fees under section 285.

34. Hatch-Waxman Summary  Innovator gets:  Patent term extension/restoration  Guaranteed marketing exclusivity period  Automatic 30 month stay of FDA approval if litigation  Generic Gets:  Streamlined approval process  First-to-file 180-day marketing exclusivity  Safe harbor and possibility of definitive decision prior to launch

35. Example timeline: rosuvastatin 11/9/93 06/12/92 8/9/98 6/26/01 8/12/03 12/9/07 2/10/10 8/27/98 8/7/01 8/12/07 8/12/08 2/12/11 440 patent filing date IND becomes effective NDA filed NDA approved - product marketing begins infringement suits filed trial scheduled 440 patent issues reissue application Re 314 patent issues generic applicant first-to file date NCE marketing exclusivity expires 30 month automatic stay expires 6/12/12 1/8/16 Original patent expiration date patent expiration date following extension

36. By Edward J. Pardon