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1 Presenting a live 90-minute webinar with interactive Q&A Biosimilars: Navigating Current Legal and Regulatory Challenges Exploring How the First Biosimilar Cases are Shaping the Industry and Biologics Patents THURSDAY, APRIL 23, pm Eastern 12pm Central 11am Mountain 10am Pacific Today s faculty features: Nathaniel S. Edwards, Ph.D., IP Counsel, Biogen, Cambridge, Mass. Mary Henninger, Ph.D., Partner, McNeill Baur, Johns Creek, Ga. Sanya Sukduang, Partner, Finnegan Henderson Farabow Garrett & Dunner, Washington, D.C. The audio portion of the conference may be accessed via the telephone or by using your computer's speakers. Please refer to the instructions ed to registrants for additional information. If you have any questions, please contact Customer Service at ext. 10.

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4 Biosimilars: Navigating Current Legal and Regulatory Challenges Nathaniel Edwards, IP Counsel, Biogen Mary Henninger, Partner, McNeill Baur Sanya Sukduang, Partner, Finnegan April 23, 2015

5 BPCIA: The Sleeping Giant Awakes The BPCIA was signed into law on March 23, 2010, amended 351 of the PHSA (42 U.S.C. 262) 271(e) of the Patent Act Created a statutory framework for FDA approval of new product as biosimilar to or interchangeable with reference products Significant activity begins in Several biosimilar applications filed 1st series of litigations FDA responds to Citizen Petitions FDA approves 1st biosimilar 5

6 Today s Agenda Update in recent biosimilar litigations Regulatory developments Patent prosecution considerations Q&A 6

7 Update on BPCIA Litigations 7

8 BPCIA Litigation Hatch Waxman No Orange Book listing Biosimilar applicant has burden of identifying relevant patents during development work No limitation on types of patents to assert Hatch-Waxman limited to listing patents covering the active ingredient, formulations, and method of use patents BPCIA allows RPS to assert any patent that a claim of patent infringement could reasonably be asserted No 30 month stay upon filing suit No 180 day exclusivity for 1st filed biosimilar 180 day notice before 1st commercial marketing of biosimilar 8

9 Patent Litigation and FDA Approval Patent litigation process cannot start until four years after RP is first licensed Patent litigation process does not stay FDA approval of biosimilar application Even if biosimilar applicant indicates it will not market until after patent expiry, FDA can still approve application Only way to stop biosimilar product from coming onto the market is injunction from the court Timing will be critical 9

10 Patent Exchange Process Under 42 U.S.C. 262(l) Biosimilar files Application? Biosimilar Application accepted by FDA 20 days Biosimilar provides confidential info to RPS 60 days RPS provides patent list to Biosimilar 60 days Biosimilar provides RPS with patent list and detailed statement RPS & Biosimilar negotiate final list of patents to litigate 15 days RPS provides Biosimilar with detailed statement 60 days 30 days yes Agreement reached no Biosimilar identifies number of patents that can be asserted 5 days RPS files complaint Simultaneous exchange of patent lists 30 days RPS files complaint 180 days before Biosimilar commercialization must notify RPS 10

11 What happens if there is no biosimilar application on file? 11

12 Sandoz v. Amgen: Do You Need A Biosimilar Application? Sandoz Inc. v. Amgen Inc., No MMC, (ND Cal, ) Sandoz filed a DJ action: Two patents covering Enbrel are invalid/unenforceable and will not be infringed No biosimilar application for Enbrel but conducting Phase III trials Amgen moved to dismiss on two related grounds: No statutory authority to consider a patent dispute involving a biosimilar product until after such time as an application for FDA approval of the biosimilar product has been filed; and No case or controversy No immediacy No reality No standing Sandoz argued controversy is real and immediate 12

13 Sandoz v. Amgen: Do You Need A Biosimilar Application? Sandoz Inc. v. Amgen Inc., (ND Cal, ) District Court GRANTED Amgen s MTD for lack of SMJ 42 USC 262(l)(8): 180-Day notice of commercial marketing does not grant Sandoz right to file DJ action when no biosimilar application under 262(k) is on file; Even if 262(k) application on file, applicant cannot file DJ until complies with obligations under 262(l)(2)(A): copy of application and manufacturing information; No real and immediate injury to Sandoz Amgen never advised Sandoz it would sue and not in position make such a determination because no application on file; Amgen s prior statements on patent ownership do not constitute immediate threat to Sandoz 13

14 Sandoz v. Amgen: Do You Need A Biosimilar Application? Sandoz Inc. v. Amgen Inc., (ND Cal, ) Fed Circuit (773 F.3d 1274, Dec. 5, 2014) - AFFIRMED No case or controversy relying on traditional case or controversy case law Particular facts presented did not meet the requirements of immediacy and reality No immediacy because Sandoz was still conducting Phase III trials Infringement suit has uncertainties because Sandoz s product is not final Consistent with Hatch-Waxman precedent finding no DJ jurisdiction where ANDA application not yet on file No immediate and significant adverse impact on Sandoz at this time 14

15 Sandoz v. Amgen: Do You Need A Biosimilar Application? Sandoz Inc. v. Amgen Inc., (ND Cal, ) Federal Circuit did not comment on BPCIA: Our resolution of this case makes it unnecessary for us to address the district court's BPCIA rationale. We do not address distinct questions that may arise as Sandoz continues its efforts to develop and obtain approval to market an etanercept product. In particular, we do not address Sandoz's ability to seek a declaratory judgment if and when it files an FDA application under the BPCIA. 15

16 Celltrion v. Kennedy: Do You Need A Biosimilar Application? Celltrion Healthcare Co., Ltd. v. Kennedy, No PAC (SDNY ) Celltrion filed DJ complaint alleging patents covering its Remsima biosimilar (Remicade) are invalid Kennedy is a patent owner but not BLA holder Kennedy filed MTD for lack of SMJ No case or controversy Celltrion was in discussions with the FDA regarding its Remsima application but had not yet filed BPCIA prevents DJ action without an application In opposition, Celltrion argued Substantial preparation and investment including completion of clinical trial Kennedy has previously asserted patents in U.S. and foreign jurisdictions 16

17 Celltrion v. Kennedy: Do You Need A Biosimilar Application? Celltrion Healthcare Co., Ltd. v. Kennedy (SDNY ) District court GRANTED Kennedy s MTD Celltrion still too far from obtaining FDA approval No application on file Kennedy has not expressed clear intent to sue Celltrion BPCIA precludes DJ jurisdiction Even if the Court were to find that Celltrion had engaged in sufficient meaningful preparation to market Remsima and that the threat of injury was sufficiently demonstrable, the Court would still exercise its discretion to decline to hear this case in light of the existence of the BPCIA statutory framework for the resolution of patent disputes in the licensing of biosimilars. Skirting BPCIA while reaping its benefits improper Celltrion needs to use BPCIA against Janssen (BLA holder) before litigating against Kennedy 17

18 Does a biosimilar applicant need to disclose its application and manufacturing information? 18

19 Patent Exchange Process Under 42 U.S.C. 262(l) Biosimilar files Application? Biosimilar Application accepted by FDA 20 days Biosimilar provides confidential info to RPS 60 days RPS provides patent list to Biosimilar 60 days Biosimilar provides RPS with patent list and detailed statement RPS & Biosimilar negotiate final list of patents to litigate 15 days RPS provides Biosimilar with detailed statement 60 days 30 days yes Agreement reached no Biosimilar identifies number of patents that can be asserted 5 days RPS files complaint Simultaneous exchange of patent lists 30 days RPS files complaint 180 days before Biosimilar commercialization must notify RPS 19

20 Confidential Disclosure of Biosimilar Application Confidential information Within 20 days after Biosimilar applicant receives notice that application has been accepted for review, Biosimilar applicant shall provide : Copy of the application Information that describes the process used to manufacture the biological product and May provide other information requested by the RPS 42 U.S.C. 262(l)(2) 20

21 Confidential Disclosure of Biosimilar Application Access to confidential information 42 U.S.C. 262(l)(1)(B) One in-house RPS lawyer who does not prosecute patents related to RP Outside counsel who do not prosecute patents related to RP Owner of patent if not RPS and agrees to be bound by confidentiality provisions Limitation on disclosure 42 U.S.C. 262(l)(1)(C),(D), (F) No disclosure to anyone else without prior written consent Includes RPS employees, outside experts, or other outside counsel Information only used to determine identify relevant patents that a claim of patent infringement could reasonably be asserted Confidentiality provisions govern until court enters protective order 21

22 Confidential Disclosure of Biosimilar Application 42 U.S.C. 262(l)(9)(C): Subsection (k) application not provided: If a subsection (k) applicant fails to provide the application and information required under paragraph (2)(A), the reference product sponsor, but not the subsection (k) applicant, may bring an action under section 2201 of title 28 for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product Does this include patents covering methods of manufacturing? 22

23 Preliminary Injunctions Biosimilar applicant must give RPS 180-day notice before date of first commercial marketing of Biosimilar The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k). (42 U.S.C. 262(l(8)(A)) After receiving 180-day notice, and before commercial marketing by Biosimilar, RPS may seek a preliminary injunction with respect to any patent: Identified during patent exchange but Biosimilar applicant excluded from the list of patents to litigate RPS and Biosimilar applicant have a duty to cooperate in expediting discovery for purposes of preliminary injunction 23

24 Amgen v. Sandoz: Disclosure of Application Amgen Inc. v. Sandoz Inc., No. 3:14-cv EDL (ND Cal, ) Sandoz offered to provide a copy of its biosimilar application for Zarxio without confidentiality safeguards Amgen and Sandoz did not reach agreement on confidentiality Amgen files DJ complaint Infringement, conversion and unfair competition under CA law Amgen filed a PI motion (2/5/2015) Block commercial manufacture, use, offer to sell, sale within the United States, or importation into the United States until BPCIA says shall disclose application (42 U.S.C. 262(l)(2)) Sandoz s 180-day notice of commercial marketing premature because not before being licensed by FDA (42 U.S.C. 262(l)(8)) Provide a copy of the application, complete patent exchange process, provide notice of commercial marketing 24

25 Amgen v. Sandoz: Disclosure of Application Amgen Inc. v. Sandoz Inc., (ND Cal, ) Sandoz s opposition BPCIA does not require disclosure of application provides remedies (DJ suit) if application not provided Amgen can assert all relevant patents (35 U.S.C. 271 (2)(C)(ii)) 180 day notice of commercial manufacturing does not first require FDA approval: No irreparable harm Sandoz offered application with industry standard confidentiality obligations by Amgen refused Amgen had right to sue immediately after expiration of 20 day period to disclose application but waited 3 months Economic harm can be compensated with monetary damages 25

26 Amgen v. Sandoz: Disclosure of Application Mar. 19, 2015 (again on Apr. 15): D. Ct. denies Amgen s PI Disclosure of biosimilar application is optional Shall does not always mean mandatory particularly where the law provides remedies for failure to comply Biosimilar applicant confident with patent position can expedite litigation by refusing to comply with BPCIA 180-day notice can be provided before FDA approval Licensed does not require FDA approval prior to 180-day notice Before modifies first commercial marketing not licensed thus must give notice before marketing Waiting until FDA approval will give RPS an additional 6 months exclusivity not intended by BPCIA Denial of PI Amgen only raised speculative notions of irreparable harm Amgen did not provide any proofs of infringement 26

27 Amgen v. Sandoz: Disclosure of Application Amgen s Citizen s Petition Requests certification that applicant will comply with the disclosure obligations of the BPCIA (application and manufacturing process) Requests that FDA won t begin review until certification is received Momenta Pharmaceutical s comments FDA not part of information exchange Information exchange is optional BPCIA provides remedies if biosimilar applicant does not exchange information March 25, 2015: FDA denied Amgen s Citizen s Petition BPCIA does not require certification BPCIA does not describe FDA involvement in monitoring or enforcing information exchange Competing interpretations of information exchange are subject of current litigation 27

28 What Does This All Mean? No DJ jurisdiction until biosimilar application is filed Likely applies for both RPS, patent owners, and potential biosimilar applicants FDA will not get involved Intent on meeting 10 month approval goals FY2014: Review 70% of biosimilar applications w/i 10 months FY2015: Review 70% of biosimilar applications w/i 10 month Approval before litigation even starts? Ability to expedite litigation unless reversed by Fed. Cir. RPS must be ready to litigate immediately 35 USC 271(4)(D): cannot get injunction if biosimilar was approved prior to court decision on infringement and validity Engage experts on infringement and validity Gather evidence for PI including irreparable harm 28 28

29 Regulatory Developments 29

30 30

31 How We Got Here EMA approves Zarzio (Feb 2009) FDA draft guidance (Feb 2012) FDA draft guidance (May and August 2014) FDA public hearing re: Zarxio (Jan 2015) US enacts BPCIA (Mar 2010) FDA draft guidance (Mar 2013) FDA accepts Sandoz s 351(k) application for review (July 2014) FDA approves Zarxio (Mar 2015) 31

32 BPCIA & FDA Guidance 32

33 BPCIA Overview Allows for biosimilar products Allows for interchangeable products Provides ~ 1 year exclusivity period for first approved interchangeable product Provides 12 year exclusivity period for RP Allows biosimilar applicant to file application 4 years after RP is first licensed Potential for FDA guidance 33

34 BPCIA Definition of Biological Product A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings FDA definition of protein (FDA Q&A at 13): [A]ny alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size Compounds greater than 40 amino acids in size will be scrutinized to determine whether they are related to a natural peptide of shorter length and, if so, whether the additional amino acids raise any concerns about the risk/benefit profile of the product. 34

35 Biosimilar means: Biosimilar Products (A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. 42 U.S.C. 262(i)(2) Clinically meaningful differences could include a difference in the expected range of safety, purity, and potency of the proposed and reference products (Scientific Considerations at 8.) Non-clinically meaningful differences could include slight differences in rates of occurrence of adverse events between the two products. (Scientific Considerations at 8.) 35

36 FDA Draft Guidance Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 ( Q & A ; Feb 2012) Scientific Considerations in Demonstrating Biosimilarity to a Reference Product ( Scientific Considerations ; Feb 2012) Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product ( Quality Considerations ; Feb 2012) Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants ( Formal Meetings ; March 2013) Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product ( Pharmacology ; May 2014) Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act ( RP Exclusivity ; Aug 2014) 36

37 FDA Promises Additional Draft Guidance in 2015 Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Considerations in Demonstrating Interchangeability to a Reference Product Labeling for Biosimilar Biological Products Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity 37

38 Factors FDA Will Consider to Determine Whether Biosimilar Is Highly Similar Expression System Manufacturing Process Assessment of Physiochemical Properties Functional Activities Receptor Binding and Immunochemical Properties Impurities Reference Product and Reference Standards Finished Drug Product Stability 38

39 FDA Guidance on Establishing Biosimilarity Communication With FDA is Essential FDA encourages sponsors to consult extensively with the Agency after completion of comparative structural and functional analysis (before finalizing the clinical program), and throughout development as needed. (Scientific Considerations at 7-8.) FDA also advises sponsors intending to meet with FDA to present their product development plans and establish a schedule of milestones that will serve as landmarks for future discussions with the Agency. FDA anticipates that early discussions with FDA about product development plans and about the appropriate scientific justifications will facilitate biosimilar development. (Scientific Considerations at 21.) 39

40 FDA Guidance on Establishing Biosimilarity FDA intends to use a risk-based, totality-of-the evidence approach to evaluate all available data and information submitted in support of the biosimilarity of the proposed product. (Scientific Considerations at 8.) The type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis. (Id.) [M]any product-specific factors can influence the components of a product development program intended to establish that a proposed product is biosimilar to a reference product. Therefore, FDA will ordinarily provide feedback on a case-by-case basis on the components of a development program for a proposed product. (Id. at 21.) 40

41 FDA Guidance on Establishing Biosimilarity Structural and Functional Characterization The more comprehensive and robust the comparative structural and functional characterization... the more useful such characterization will be in determining what additional studies may be needed. (Scientific Considerations at 7.) Primary structures, such as amino acid sequence Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation) Enzymatic post-translational modifications, such as glycosylation and phosphorylation Other potential variants, such as protein deamidation and oxidation Intentional chemical modifications, such as PEGylation sites and characteristics (Id. at 9.) 41

42 FDA Guidance on Establishing Biosimilarity Animal data: The sponsor should then consider the role of animal data in assessing toxicity and, in some cases, in providing additional support for demonstrating biosimilarity and in contributing to the immunogenicity assessment. (Scientific Considerations at 7.) Animal Toxicity Studies: As a scientific matter, animal toxicity data are considered useful when, based on the results of extensive structural and functional characterization... Animal toxicity studies are generally not useful if there is no animal species that can provide pharmacologically relevant data for the protein product. (Scientific Considerations at 11.) Animal Immunogenicity Studies: Animal immunogenicity assessments generally do not predict potential immunogenic responses to protein products in humans. However, when differences in manufacturing (e.g., impurities or excipients) between the proposed product and the reference product may result in differences in immunogenicity, measurement of anti-protein antibody responses in animals may provide useful information relevant to patient safety. (Scientific Considerations at 12.) Animal PK and PD Measures: Under certain circumstances, a singledose study in animals comparing the proposed product and reference product using PK and PD measures may contribute to the totality of evidence that supports a demonstration of biosimilarity. (Scientific Considerations at 12.) 42

43 FDA Guidance on Establishing Biosimilarity Human Studies In general, the clinical program for a 351(k) application must include a clinical study or studies (including an assessment of immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product, as set forth in the PHS Act. The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies. (Scientific Considerations at 12.) 43

44 FDA Guidance on Establishing Biosimilarity Human Studies (cont.) PK / PD studies: We have determined that both PK and PD studies... generally will be expected to establish biosimilarity, unless a sponsor can scientifically justify that an element is unnecessary. (Scientific Considerations at 13.) Clinical immunogenicity studies: [A]t least one clinical study that includes a comparison of the immunogenicity of the proposed product to that of the reference product will generally be expected. (Scientific Considerations at 14.) Comparative clinical safety and effectiveness data If there are residual uncertainties about the biosimilarity of the two products after conducting structural and functional studies, animal toxicity studies, human PK and PD studies, and clinical immunogenicity assessment, the sponsor should then consider what comparative clinical safety and effectiveness data may be adequate. (Scientific Considerations at 7.) Clinical studies should be designed such that they can demonstrate that the proposed product has neither decreased nor increased activity compared to the reference product. (Scientific Considerations at 17.) 44

45 Interchangeable Products Interchangeable means: Biosimilar to RP and Can be expected to produce the same clinical result as the RP in any given patient, and For a biological product that 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 biological product and the RP is not greater than the risk of using the RP without such alteration or switch. 42 U.S.C. 262(k)(4) 45

46 Interchangeable Products What s the benefit for interchangeability? The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. A biosimilar product cannot be switched for RP without doctor intervention 42 U.S.C. 262(i)(3) FDA has not yet issued guidance on Interchangeability At this time it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application.... FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product. Q & A at

47 Interchangeable Products Exclusivity for first approved interchangeable product No subsequent FOB can be found to be interchangeable until earlier of 1 year after first commercial marketing of first interchangeable FOB 18 months after final court decision or dismissal with or without prejudice on patents involved in suit against first interchangeable FOB 42 months after approval of first interchangeable FOB if patent litigation is still ongoing within the 42 month period or 18 months after such approval if no patent suit was filed against first interchangeable FOB 42 U.S.C. 262(k)(6) 47

48 FDA Guidance Misc. Issues Reliance on Non-US Licensed Product Comparisons In general, a sponsor needs to provide information to demonstrate biosimilarity based on data directly comparing the proposed protein product with the reference product... However, under certain circumstances, a sponsor may seek to use data derived from animal or clinical studies comparing a proposed protein product with a non-u.s. licensed product... In such a case, the sponsor should provide adequate data or information to scientifically justify the relevance of this comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product. (Quality Considerations at 9.) 48

49 FDA Guidance Misc. Issues Extrapolating to Other Indications If the proposed product meets the statutory requirements for licensure as a biosimilar product under section 351(k)... the potential exists for the proposed product to be licensed for one or more additional conditions of use for which the reference product is licensed. However, the sponsor will need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought. (Scientific Considerations at 19; Q & A at 9.) 49

50 FDA s First Biosimilar Approval: Zarxio 50

51 First US Biosimilar Approved On March 6, 2015, FDA approved the first US biosimilar Zarxio is a biosimilar of Amgen Inc. s Neupogen G-CSF analog stimulates growth and differentiation of certain types of white blood cells Used to prevent infections during cancer therapy Relatively small/simple biologic 51

52 First FDA Hearing January 7, 2015, Oncologic Drug Advisory Committee Meeting First FDA hearing considering a biosimilar application Considered Sandoz s application for a filgrastim biosimilar Sandoz s proposed product = Zarxio Reference product = Amgen Inc. s Neupogen Committee agreed that Zarxio was biosimilar to Neupogen Committee agreed that Zarxio should be approved for the same 5 indications as Neupogen 52

53 First FDA Hearing FDA claims they are committed to an abbreviated approval process Still no mention of interchangeability Minor differences are OK Different ph buffer system patent considerations Case by case totality of the evidence Structural / functional characterization + clinical studies for a relatively simple product FDA cares about European history Committee without established European track record, it would have been a much closer call 53

54 The FDA Allowed Extrapolation to Other Indications The FDA approved Zarxio for the same indications as Neupogen: patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia. 54

55 Initial Implications The door is open FDA beats its goal of 10 month review Case by case, totality of the evidence Minor differences are OK Phase III head-to-head trials as the norm? European history matters Extrapolation is possible 55

56 Open Questions What about larger, more complex molecules? Data requirements Extrapolation Timelines Naming Interchangeability Limits on extrapolation? Structural differences? Promotion 56

57 Prosecution Considerations for Biologics 57

58 Current Biosimilar Applications Fusion proteins Amgen s Neupogen (Sandoz - approved) Amgen s Neulasta (Apotex) Amgen s Epogen and Janssen s Procrit (Hospira) Antibodies Janssen s Remicade (Celltrion) Likelihood of other classes of biosimilars? 58

59 Timing Considerations 12 year initial data exclusivity 6 months pediatric extension No new indication extension Biosimilar application may be filed 4 years after RP licensed (4.5 years if pediatric extension granted) USPTO is getting faster, resulting in less PTA Initial patent term versus preclinical development time 59

60 Definition: Biosimilarity The biological product is highly similar to the RP notwithstanding minor differences in clinically inactive components; and There are no clinically meaningful differences between the biological product and the RP in terms of the safety, purity, and potency of the product. 42 USC 262(i)(2) 60

61 Definition: Interchangeability The biological product is biosimilar to the RP; and can be expected to produce the same clinical result as the RP in any given patient; and For a biological product that 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 RP is not greater than the risk of using the RP without such alternation or switch. May be substituted for the RP without the intervention of the health care provider who prescribed the RP. 42 USC 262 (i)(3); (k)(4) 61

62 FDA View on Interchangeability J. Woodcock et al., Nature Reviews Drug Discovery 6: (2007) To establish that two protein products would be substitutable, the sponsor of a follow-on product would need to demonstrate through additional clinical data that repeated switches from the follow-on product to the referenced product (and vice versa) would have no negative effect on the safety and/or effectiveness of the products as a result of immunogenicity. For many follow-on protein products and in particular, the more complex proteins there is a significant potential for repeated switches between products to have a negative impact on the safety and/or effectiveness. Therefore, the ability to make determinations of substitutability for followon protein products may be limited. 62

63 Biosimilar Application Requirements Information demonstrating that the biological product: Is biosimilar to a RP; Utilizes the same mechanism(s) of action for the proposed condition(s) of use but only to the extent the mechanism(s) are known for the RP; Condition(s) of use proposed in labeling have been previously approved for the RP; Has the same route of administration, dosage form, and strength as the RP; and Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent. 42 USC 262 (k)(2)(a)(i) 63

64 Data Considered in Showing Biosimilarity Information demonstrating biosimilarity: Analytical studies demonstrating that the biological product is highly similar to the RP notwithstanding minor differences in clinically inactive components; Animal studies (including the assessment of toxicity); and A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the RP is licensed and for which licensure is sought for the biological product. 42 USC 262 (k)(2)(a)(i)(i) 64

65 FDA Factors for Determining Highly Similar Expression System Amino acid sequence if protein Manufacturing Process Assessment of Physiochemical Properties Functional Activities Receptor Binding and Immunochemical Properties Impurities Reference Product and Reference Standards Finished Drug Product Stability

66 Biologics Portfolio of Multiple Inventions Product (including product by process) Indications (including subpopulations) Route of administration Dosage form Dosage regime Safety Purity Potency Stability Immunogenicity Pharmacokinetics Pharmacodynamics Mechanism of action Methods of manufacture 66

67 Considerations for Product Inventions Demonstrate differences from known products Nonobvious CDR sequences or fusion proteins Nonobvious glycosylation and phosphorylation patterns Product by process of using nonobvious cell lines Stable and potent formulations Less may be more Consider initial prosecution of target species instead of genus Consider eliminating laundry lists of indications, routes of administration, dosage forms, dosage regimes, etc. Disclosure cuts both ways Consider maintaining as trade secret (e.g., proprietary cell lines) 67

68 Antibody Species Claims 1. An isolated monoclonal antibody that binds to protein X, wherein the antibody amino acid sequence comprises a heavy chain variable region sequence comprising a CDR1 comprising SEQ ID NO:1, a CDR2 comprising SEQ ID NO:2, and a CDR3 comprising SEQ ID NO:3, and comprises a light chain variable region comprising a CDR1 comprising SEQ ID NO:4, a CDR2 comprising SEQ ID NO:5, and a CDR3 comprising SEQ ID NO:6. 2. The antibody of claim 1, wherein the heavy chain variable region comprises an amino acid sequence at least 95% identical to SEQ ID NO:7. 3. The antibody of claim 1, wherein light chain variable region comprises an amino acid sequence at least 95% identical to SEQ ID NO:8. 68

69 Subpopulation Claims No Orange Book or skinny labeling Consider seeking claims to subpopulations A method of treating a lung cancer patient wherein the level of protein X in the patient s blood is at least 10 mg/kg, comprising administering to the patient an effective amount of drug Y. A method of treating a lung cancer patient, comprising ordering a test to determine the level of protein X in the patient s blood, and if the level is at least 10 mg/kg, administering to the patient an effective amount of drug Y. 69

70 Linking Inventions to Reference Product Prescribing Information 70

71 Enbrel Product Enbrel (etanercept) is a dimeric fusion protein consisting of the extracellular ligandbinding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the C H 2 domain, the C H 3 domain and hinge region, but not the C H 1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. 71

72 Enbrel Dosage Form The solution of Enbrel in the single-use prefilled syringe and the single-use prefilled SureClick autoinjector is clear and colorless, sterile, preservative-free, and is formulated at ph 6.3 ± 0.2. Enbrel is also supplied in a multiple-use vial as a sterile, white, preservative free, lyophilized powder. Reconstitution with 1 ml of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields a multiple-use, clear, and colorless solution with a ph of 7.4 ±

73 Enbrel Dosage Form 73

74 Enbrel Dosage Forms and Strengths 50 mg single-use prefilled syringe with 0.98 ml of a 50 mg/ml solution of etanercept 50 mg single-use prefilled SureClick Autoinjector with 0.98 ml of a 50 mg/ml solution of etanercept 25 mg single-use prefilled syringe with 0.51 ml of a 50 mg/ml solution of etanercept 25 mg multiple-use vial with 25 mg of etanercept 74

75 Enbrel Approved Uses and Dosing Regimes Solution administered by subcutaneous injection 50 mg once weekly with or without MTX for Adult RA and Psoriatic Arthritis 50 mg once weekly for Ankylosing Spondylitis 50 mg twice weekly for 3 months, followed by 50 mg once weekly for Adult Plaque Psoriasis 0.8 mg/kg weekly, with a maximum of 50 mg per week for Polyarticular Juvenile Idiopathic Arthritis in patients aged 2 years or older 75

76 Enbrel Pharmacokinetics In another study, serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (± standard deviation) C max, C min, and partial AUC were 2.4 ± 1.5 mcg/ml, 1.2 ± 0.7 mcg/ml, and 297 ± 166 mcg h/ml, respectively, for patients treated with 50 mg Enbrel once weekly (N = 21); and 2.6 ± 1.2 mcg/ml, 1.4 ± 0.7 mcg/ml, and 316 ± 135 mcg h/ml for patients treated with 25 mg Enbrel twice weekly (N = 16). 76

77 Enbrel Mechanism of Action Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds Enbrel) are not lysed in the presence or absence of complement. 77

78 Take Home Considerations To date, biosimilar applications are directed to antibodies and fusion proteins Consider competing development and exclusivity timelines when deciding when to file Consider patent protection of multiple inventions originating from RP information that will inevitably be disclosed to the public in the label and that are required to demonstrate biosimilarity Consider early prosecution of species claims BPCIA litigation is not equivalent to ANDA litigation; allows assertion of any patent that could reasonably be asserted 78

79 Thank You! Nathan Edwards is IP Counsel at Biogen and establishes and executes IP strategies for a portfolio of large molecules at all stages of development nathan.edwards1@biogen.com Mary Henninger is a Partner in the Georgia office of McNeill Baur and practices patent prosecution and client counseling in the areas of biotechnology and pharmaceuticals mary.henninger@mcneillbaur.com 79

80 Thank You! Sanya Sukduang is a Partner in the Washington, DC office of Finnegan and practices district court and appellate patent litigation in a variety of technologies, including pharmaceuticals and biotechnology. sanya.sukduang@finnegan.com

81 Disclaimer These materials are public information and have been prepared solely for educational and entertainment purposes to contribute to the understanding of U.S. intellectual property law. These materials reflect only the personal views of the authors and are not individualized legal advice. It is understood that each case is fact-specific, and that the appropriate solution in any case will vary. Therefore, these materials may or may not be relevant to any particular situation. Thus, the authors and Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Biogen, and McNeill Baur, PLLC cannot be bound either philosophically or as representatives of their various present and future clients to the comments expressed in these materials. The presentation of these materials does not establish any form of attorney-client relationship with the authors or Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Biogen, or McNeill Baur, PLLC. While every attempt was made to ensure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed. 81