Pharmaceutical Intellectual Property Summit Biosimilars Panel. Janis Fraser, moderator October 28, 2010 Princeton, NJ

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1 Pharmaceutical Intellectual Property Summit Biosimilars Panel Janis Fraser, moderator October 28, 2010 Princeton, NJ

2 Pharmaceutical Intellectual Property Summit Biosimilars Panel Terry G. Mahn October 28, 2010 Princeton, NJ

3 Hatch-Waxman vs. Biosimilars Legislation Generic Applications Biosimilar Applications 505(b)(2) ( paper NDA ) 505(j) (ANDA) 351(k)(2)(A) (biosimilar) 351(k)(2)(B) (interchangeable biosimilar) 3

4 Hatch-Waxman vs. Biosimilars Legislation Generic Definitions same active moiety required for generic approval same active ingredient, strength, dosage, route of administration all required for full substitutability Biosimilar Definitions Biosimilar means high similar to Pioneer notwithstanding minor differences in clinically inactive components; and no clinically meaningful differences with Pioneer in terms of safety, purity and potency. Interchangeable means a biological product found to be Biosimilar; that can be expected to produce the same clinical result as the Pioneer in any given patient; and if the product is administered more than once to an individual the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and the Pioneer is no greater than the risk of using the Pioneer without such alteration or switch. 4

5 Hatch-Waxman vs. Biosimilars Legislation Drugs 5 year filing* exclusivity available for new active moiety 3 year marketing exclusivity for new indication, dosage, etc., supported by clinicals Biologics 12 year marketing exclusivity (4 year filing exclusivity) for new biological structure but if application is filed by same sponsor or manufacturer of the Pioneer product (or a licensor, predecessor in interest or a related party), the changed biological structure must also result in a (1) change in indications, route of administration, dosing schedule, dosing form, delivery system, delivery device or strength or (2) change in safety, purity or potency No follow on exclusivity for same biological structure * Shortened to 4 years if OB patent challenged. 5

6 Hatch-Waxman vs. Biosimilars Legislation Drugs Orange Book listing of patents; certification by generic applicant; notice to NDA holder and patentees Automatic 30 month stay of FDA approval for OB patent challenge Biologics Private exchange of patent information; full disclosure of biosimilar application No automatic stay of FDA approval Pediatric exclusivity* adds 6 months to all exclusivities and Orange Book patent expirations pediatric exclusivity* adds 6 months to 12 year exclusivity, 4 year biosimilar filing restriction and Orphan Drug exclusivity *FDA must accept pediatric studies > 9 months before expiration of exclusivity or OB patents to qualify for extension 6

7 Hatch-Waxman vs. Biosimilars Legislation Drugs Generic Exclusivity first to file and to certify under Paragraph IV (challenging Orange Book patents) receives 6 months of generic exclusivity; can be forfeited under various conditions Biologics Biogeneric exclusivity first to obtain an interchangeable license receives exclusivity against any subsequent interchangeable license application for any condition of use in Pioneer product until: (1) one year after commercial marketing by first licensee; or (2) 18 months after court decision (appellate court, if appealed) on all patents or dismissal of action against first licensee; or (3) 42 months after first licensee approval if litigation is still pending, or 18 months after first licensee approval if no suit is filed (i.e., where 1 st licensee fails to market) 7

8 Biosimilar License Application Showing of biosimilar based on data from (1) analytical studies showing highly similar to Pioneer (different inactives allowed); (2) animal studies (including toxicity); and (3) clinical studies to demonstrate safety, purity and potency in one or more conditions of use. Must have same mechanism of action for conditions of use on label (if known), route of administration, dosage and strength as Pioneer product. Conditions of use on label must have been approved for Pioneer (allows for carve outs ) Production facilities must meet standards designed to assure product continues to be safe, pure and potent. 8

9 Biosimilar License Application - Interchangeable Must be biosimilar to Pioneer Must also show that (1) biosimilar can be expected to produce same clinical results as Pioneer in any given patient; and (2) any risk in terms of safety or diminished efficacy from switching between Pioneer and biosimilar is no greater than using Pioneer without switching Off-label substitution allowed? 9

10 FDA Guidance Documents for Biosimilarity Must be available for public comment Not required to approve Biosimilar application Can be product or product class-specific FDA can determine that science and experience do not allow approval of Biosimilar/Interchangeable for product or product class (but not for recombinant proteins) 10

11 FDA Guidance Documents for Biosimilarity Lovenox decision sameness test developed for uncharacterized large molecule drug requires equivalence showing for: - Physical and chemical properties - Source material - Methods of processing of source material - Nature and arrangement of components that constitute the drug - Laboratory measurements of drug activity - Certain aspects of the drug s effect in humans 11

12 Transition of Large Molecule Drugs Proteins (but not chemically synthesized polypeptides) are added to list of biologic products subject to Section 351 of PHS Act. Biologics approved under Section 505 may continue to be submitted under Section 505 for 10 years but not if a biologic approval under Section 351 could be the referenced Pioneer for the biologic if filed as a Biosimilar. After 10 years all Section 505 biologic products shall be deemed licensed under Section

13 The Patent Dance Reza Green, Ph.D., J.D. Chief IP Counsel Novo Nordisk Inc. 28 Oct

14 The Patent Dance Part I BLA provides FOB with list of patents BLA provides FOB with detailed response FDA Notifies FOB 20 d 60 d 60 d 60 d 15 d PARTIES TO NEGOTIATE FOB sends BLA dossier + manuf. info FOB provides BLA with detailed statements + counter-list of patents AGREEMENT 30 d BLA initiates lawsuit Simultaneous exchange of patents NO AGREEMENT? 5 d 30 d BLA initiates lawsuit FOB informs BLA of max # of patents 14

15 The Patent Dance Part II FOB notifies BLA 180 days prior to marketing BLA may seek PI /DJ on any patent included in original list not litigated in first phase 15

16 Issues No oversight of patent dance (e.g., no FDA involvement) Will relief lie in the courts? Sufficiency of disclosure no requirement for FOB to update BLA on changes in, e.g., manufacturing or formulation If relevant patent(s) are not owned by BLA but in-licensed, licensor must agree to be subject to statutory confidentiality provisions who is liable for breach of these obligations (i.e., is BLA liable because info flows from BLA to licensor?) Pre-litigation admissions statements to FOB: detailed claim-by-claim..factual and legal basis Good faith negotiations + timing not real-world Which patents to litigate in phase 1 (constitutionality?) BLA may be limited to 1 patent statute seems to allow FOB to require BLA to assert patents that BLA does not wish to enforce gaming by FOB? 16

17 Furthermore FOBs may try to file under 351(a) (esp. because they will have some clinical data) to avoid patent provisions FOBs may file under 359(k) to take advantage of patent dance, then withdraw and refile under 351(a) to avoid 12-y data exclusivity barrier 17

18 Preparing for the Patent Dance For each biologic, insure internal knowledge of all patents that could be infringed by a FOB product includes process patents (i.e., manufacturing) includes patents that innovator may not currently be using for its own products Review (and revise if necessary) in-license agreements covering innovator s biologics to ensure that statutory requirements are met Address need for single in-house patent attorney as recipient of ABLA; lock in suitable outside counsel and educate them about innovator s patent estate 18

19 Disclosure of Confidential Information for the Purpose of Patent Litigation Under the Biologics Price Competition and Innovation Act (BPCI) Charles M. Caruso International Patent Counsel Merck & Co., Inc.

20 Overview Contrast with Hatch Waxman ANDA litigation Evaluate immediate actions steps Discuss problems and solutions 20

21 Contrast with ANDA Litigation Orange Book patent listing publicly available excludes process patents certification by generic applicant automatic 30 month stay for listed patents short period before patent litigation ANDA may be provided under judicial protective order BPCI private exchange of information no automatic stay long period of information exchange before patent litigation biosimilar application provided before litigation under statutory protective order 21

22 Immediate Action Steps Biosimilar applicant ( BA ) required to provide reference product sponsor ( RPS ) with confidential access to biosimilar application within 20 days of FDA acceptance for review Sanction for failure RPS can bring DJ on any patent that claims the product or use (but not manufacture of product) 22

23 Immediate Action Steps Statutory protective order applies unless otherwise agreed by the parties Negotiate a pre-litigation protective order Identify who will receive BAs confidential information the people of RPS who decide which patents are in litigation 23

24 Identify Who Will Receive Confidential Information Under Statutory Protective Order One in-house attorney Does not formally or informally engage in patent prosecution related to the product Adequate scientific knowledge Walling off of this attorney One or more outside attorney Team of attorneys Adequate scientific knowledge Walls around team Conflicts Advance clearance Representative of patent owner for exclusively licensed-in patent, if Has right to participate in litigation, and Agrees to confidentiality provisions 24

25 Attorney Knowledge Base How to review biosimilar applications especially manufacturing section Technical details of RPS product, uses and manufacture RFP label Patent portfolio Claim construction Prior art and validity 25

26 Problems and Solutions Client refuses to provide biosimilar application to RFP File as novel BLA BLA may be disclosed in litigation under judicial protective order Negotiation of pre-litigation protective order is prolonged Offer reasonable terms and operate under proposed under while meeting statutory requirements Continue negotiation over prolonged patent information exchange period 26

27 Problems and Solutions Adequate Scientific and Patent Prosecution Knowledge Prepare in-house and outside attorneys before critical time period Prepare exclusive patent licensor before critical time period Expect the unexpected consequences of a new statute to arise during litigation 27

28 Pharmaceutical Intellectual Property Summit Biosimilars Panel Terry G. Mahn October 28, 2010 Princeton, NJ

29 Patent Exchange Procedures and Licensing Issues Disclosure of Biosimilar Application to Patent Owner - Confidential access may be provided to patent owner but only if patent is exclusively licensed to Pioneer and owner has retained right to assist the patentee or parties in the patent litigation - Owner or representative must notify Biosimilar applicant that it will be bound by confidentiality provision Disclosure of Patents to Biosimilar Applicant - Rights and responsibilities for disclosing existing and newly issued patents - Responsibilities for preparation of counter-statement - Time is of the essence clauses to ensure statutory timeframes are met 29

30 Patent Exchange Procedures and Licensing Issues Representations, Warranties, Indemnifications, Disclaimers and Limitations on Liability - Specify acts or omissions by patentee that could impact patent enforceability or timing of litigation (e.g., pre-launch) - Indemnification of Pioneer for confidentiality breach Control of Patent Litigation - Rights to assert, license and/or settle patent litigation - Require cooperation of patentee Patent Term Extension Rights 30

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