Presentation provides a brief overview of regulatory and patent market exclusivities for new drugs. Presentation also covers the types of intellectual property typically arising out of preclinical studies.

1. August 31, 2011 Intellectual Property Considerations During Nonclinical Drug Development Mary Breen Smith msmith@sbiplaw.com 1

3. drug discovery, preclinical work, Phase I/II/III clinical trials

4. Generics can “freeride” off of the work performed by innovator companies to gain market approval

5. How best to recoup these expenses and maximize profitability?

6. Regulatory statutes provide marketing exclusivity periods (e.g., exclude generic competition)

7. Patent statutes also provide exclusivity periods 2

11. 180 days granted for first applicant to file ANDA

12. Must wait at least fouryears after NCE NDA approval to apply for ANDA (Paragraph IV certification) or five years without certification4

14. No clinical work if substantially identical to a predicate device (Class I and II)

15. PMA, premarket approval necessary for Class III or non predicate Class I or II devices

16. No marketing exclusivity granted

17. Data exclusivity: follow on Class 3 devices cannot use original PMA data for six years but can use information from the published literature

18. Patents important5

21. Methods of use (e.g., to treat a disease, dosing methods, etc.)

22. Diagnostic methods

23. Devices

24. Manufacturing methods

25. Analytical methods

26. Patient populations7

28. (II)that such patent has expired,

29. (III) of the date on which such patent will expire, or

30. (IV)that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted INVALID: patent claims are not enforceable due to some legal deficiency NONINFRINGED: generic product is not within the scope of the patent’s claims 8

33. Applicable to a single patent chosen by the applicant upon regulatory approval of product for first indication10

34. Intersection Between Patent Regime and Regulatory Regime cont’d. 11 5 years 1 year

35. Case Study: Patent and Regulatory Exclusivity for Drug NDA approved xx/xx/2009 for Drug xx/xx/2025 US Patent B (use for label indication) expires (patent obtained later) xx/xx/2017 US patent A (composition of matter) expires xx/xx/2009 Marketing Approval xx/xx/2022 A Patent Term Extension (if granted) Expires NDA Filing US Patent A Patent Term A Patent Term Extension 6 Mo. PedE 2008 2009 2010 2011 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2012 2013 Paragraph IV Challenge (30-month stay) 2025 6 Mo. PedE Regulatory Exclusivity Periods - 6 Mo. pediatric exclusivity period attaches to the END of all existing marketing exclusivity and patent periods - Additional 3-Yr. data exclusivity period available for new indications 5-Yr. Data Exclusivity 1st ANDA Submitted (Yr. 4) 6 Mo. PedE 7-Yr. OD Exclusivity

37. Aim for patents having later expiration dates than regulatory exclusivity periods

38. Obtain multiple Orange book listable patents to require ANDA applications to certify against each (requires obtaining legal opinions for each)

40. Orphan indications (7 year)

41. Pediatric (6 months)Preclinical work can provide information/data to support new patent applications and new regulatory periods 13

42. Publication of Preclinical/toxStudies Patents have a “Novelty” requirement: must be new, i.e., not previously known. TRAP FOR THE UNWARY “Known” includes publications in technical journals, poster sessions, submitted abstracts for meetings, seminars, slides, lectures, etc. Disclosures to employees and to others (CROs) under a nondisclosure agreement (signed) are not public In the U.S., there is a “one year” grace period to file a patent application dated from when a public disclosure occurs Most countries require patent filing PRIOR to the first public disclosure I have clients who have ONLY U.S. rights to new inventions and have lost worldwide rights “oh, we already have a patent” Best practice: run by IP counsel all abstract s/posters and manuscripts sent by outside collaborators 14

43. Potential New Patentable Subject Matter from Preclinical/toxStudies Typical patent position going into preclinical studies is minimal A “composition of matter” patent may exist Often this is an older patent (close to expiration date) Or there may be no patent (in public domain because either unpatented or expired patent) University technology transfer groups may have cost restraints which may impact patent quality Preclinical work can provide new patentable subject matter If the subject matter is “nonobvious” over previous disclosures/patents, can obtain new patent with later expiration dates. GOOD NEWS! Even “obvious” subject matter can result in new patent claims, but may not have later expiration date. 15

44. Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d. Preclinical type of data supportive of new patent application Generally, pharmacology/toxicology showing “expected” results not separately patentable (also, may not be patentable subject matter) e.g., pharmacology results (compartment, half life, efficacy, tox) generally not patentable subject matter per se (although data confirming activity can be used to support existing patent application(s)) “Mechanism of action” generally not patentable Some types of data can be separately patentable Different indications (new activities) Example: panel of tumor cell lines, where activity in additional cell lines is observed (not predicted based on related compounds) New Method of Use patent New Supplemental NDA (new regulatory period) Orphan indication? Orange book listable (if claims cover “label”) 16

45. Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d. Preclinical type of data which can subject of new patent application Combination studies showing synergism between two compounds Potential new composition of matter patent Potential new method of use patent Potential new supplemental NDA Potential NCE (if neither separately approved) Orange book listable (if claims cover “label”) Biomarkers showing which patient populations are more responsive interest in these patents since biomarker can be included on label Potential new method of use patent Potential new supplemental NDA Orange book listable (if claims cover “label”) Improved analytical techniques (CRO-derived) Potential new method of use of patent 17

46. Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d. Separately patentable subject matter further includes: Dosing regimens that provide unexpectedly better results Generally, finding optimum dosing regime is “routine” experimentation New method of use patent Supplemental NDA Orange Book listable (if claims cover “label”) Other types of patentable subject matter (not generally derived from preclinical studies, though) New crystal forms/polymorphs (generally quite patentable) or new salt forms (often more difficult to patent without “unexpected” benefits) New composition of matter patent New method of use patent Supplemental NDA Orange book listable (if claims cover “label”) 18

47. Potential New Patentable Subject Matter from Preclinical/tox Studies cont’d. Other types of patentable subject matter (not generally derived from preclinical studies, though) Separated enantiomer (often difficult to patent for being obvious without “unexpectedly” better properties) New composition of matter patent New method of use patent Orange book listable Supplemental NDA New formulations (often difficult to patent without “unexpectedly” better properties) e.g., enteric coatings; orally active; extended release New composition of matter patent New method of use patent Orange book listable Supplemental NDA Improved manufacturing techniques Improved storage and handling techniques 19