An Update on Biosimilars and Biosimilar Litigation in the US

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1 An Update on Biosimilars and Biosimilar Litigation in the US Paul A. Calvo, Ph.D. 1 February nd Biologics and Biosimilars Congress - Berlin

2 Years of Nothing and Now 2

3 Biosimilar approvals in Europe* Product name Active substance Authorization date Manufacturer/ Company name Abasaglar (previously Abasria) insulin glargine 9 Sep 2014 Eli Lilly/Boehringer Ingelheim Abseamed epoetin alfa 28 Aug 2007 Medice Arzneimittel Pütter Accofil filgrastim 18 Sep 2014 Accord Healthcare Bemfola follitropin alfa 24 March 2014 Finox Biotech Binocrit epoetin alfa 28 Aug 2007 Sandoz Biograstim filgrastim 15 Sep 2008 CT Arzneimittel Epoetin alfa Hexal epoetin alfa 28 Aug 2007 Hexal Filgrastim Hexal filgrastim 6 Feb 2009 Hexal Filgrastim ratiopharm filgrastim 15 Sep 2008 Ratiopharm Withdrawn on 20 Apr 2011 Grastofil filgrastim 18 Oct 2013 Apotex Inflectra infliximab 10 Sep 2013 Hospira Nivestim filgrastim 8 Jun 2010 Hospira Omnitrope somatropin 12 Apr 2006 Sandoz Ovaleap follitropin alfa 27 Sep 2013 Teva Pharma Ratiograstim filgrastim 15 Sep 2008 Ratiopharm Remsima infliximab 10 Sep 2013 Celltrion Retacrit epoetin zeta 18 Dec 2007 Hospira Silapo epoetin zeta 18 Dec 2007 STADA R & D Tevagrastim filgrastim 15 Sep 2008 Teva Generics Valtropin somatropin 24 Apr 2006 BioPartners Withdrawn on 10 May 2012 Zarzio filgrastim 6 Feb 2009 Sandoz 3

4 Biosimilar approvals in US Product name Active substance Authorization date Manufacturer/ Company name Zarxio Filgrastim 6 March 2015 Sandoz 4 applications currently pending: Celltrion: infliximab Apotex: filgrastim Apotex: pegfilgrastim Hospira: epoetin alfa Amgen: adalimumab 4

5 FDA Issues Final Biosimilars Guidelines On April 28, 2015 FDA issued 3 final guidance documents on biosimilarity Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Documents reiterate use of a totality of the evidence approach for review of applications for biosimilar products Encourages a stepwise approach to demonstrating biosimilarity including comparison of proposed product with reference in terms of structure, function, animal toxicity, human PK/PD, clinical immunogenicity, and clinical safety/effectiveness with only rare exceptions. 5

6 FDA Issues Final Biosimilars Guidelines Changes from draft version of guidances Most of discussion of interchangeability was removed - separate guidance document that is forthcoming. Sponsor will need to provide information to demonstrate biosimilarity based on data directly comparing the proposed biosimilar product to reference product. Elaborate on the type of bridging data needed when a biosimilar applicant seeks to use a non-us licensed comparator product to support a demonstration of biosimilarity. 6

7 FDA Issues Final Biosimilars Guidelines 7 Changes from draft version of guidances cont d: Specific comments have been provided for biosimilar developers considering manufacturing/process changes after completing the initial analytical similarity assessment including a requirement to demonstrate comparability between the pre- and post-change proposed product. More detailed comments regarding animal toxicity studies were added. Previous Q and As relating to what constitutes the publicly-available information that should be included in a 351(k) application and whether an applicant can include a request for reference product exclusivity in its 351(a) application were deleted an indication that the FDA is still considering its position on these points.

8 What is coming in 2016? Considerations in Demonstrating Interchangeability With a Reference Product Labeling for Biosimilar Products Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity 8

9 Purple Book Lists of Licensed Biological Products with Reference Product Exclusivity Includes Biosimilarity or Interchangeability Evaluation Include date a biological product was licensed under 351(a) Whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) Biosimilar and interchangeable biological products licensed under section 351(k) will be listed under the reference product to which biosimilarity or interchangeability was demonstrated. Contains NO PATENT INFORMATION no plan to include patent information in the future. 9

10 State Anti-Substitution Bills 8 states Delaware, Florida, Indiana, Massachusetts, North Dakota, Oregon, Utah and Virginia have enacted laws that limit biosimilar substitution to those drugs that the FDA has deemed interchangeable. California, Illinois, Colorado, Maryland, New Jersey and North Carolina advancing legislation that would allow substitution of interchangeable biologics if the prescribing physician does not prohibit it, the pharmacist provides notification and details of the switch, the cost of the biosimilar is less, the patient is informed and written records are maintained. 10

11 Patent Exchange Timeline Applicant must notify RPS and provide copy of application 20 Days 60 Days 60 Days BA must provide RPS with detailed statement 60 Days Negotiations Negotiations fail 15 Days 5 Days Parties exchange lists of patents to be litigated 30 Days Biosimilar application accepted for FDA review RPS provides list of patents RPS provides own detailed statement BA notifies RPS of number of patents to be litigated RPS must bring suit 11

12 Litigation involving Patent Provisions Amgen Inc. et al. v. Sandoz Inc. et al., case number , in the U.S. Court of Appeals for the Federal Circuit Neupogen Patent exchange process is optional 180 Days Notice Prior to First Commercial Marketing Must Await Licensure Sandoz requested an extension to file a petition for a writ of certiorari to US Supreme Court. Deadline is now February 16,

13 Litigation involving Patent Provisions Janssen Biotech, Inc. et. al. v. Celltrion Healthcare Co., Ltd. et. al., Civil Action No. 1:15-cv-10698, U.S. District Court for the District of Massachusetts Remicade Janssen s motion to stay the proceedings with respect to U.S. patent 6,284,471 The cross motions for summary judgment in light of the Federal Circuit s Amgen v. Sandoz decision Janssen s motion to modify the protective order and Celltrion s alternative cross motion to stay Janssen s motion. 13

14 Litigation involving Patent Provisions Amgen v. Apotex, case number 15-cv-62081, in the U.S. District Court for the Southern District of Florida December 30, Apotex filed its opening appellate brief. Because the parties completed the patent dance under 42 U.S.C. 262(l)(2) (l)(5) prior to initiation of suit, notice of commercial marketing is not required Further, Apotex argues that making the 180-day notice period mandatory in all cases as opposed to just cases where the biosimilar applicant chooses not to participate in the patent dance would amount to a de facto extension of the 12-year exclusivity period granted under the BPCIA 14

15 15 Cancellation Proceedings at the USPTO AIA introduced new cancellation proceedings that are instituted at the USPTO Inter Partes Review Post Grant Review Increased interest due to filings of Kyle Bass Ampyra Acorda Therapeutics Imbruvica J & J and Pharmacyclics Lialda and Gattex Shire Thalomid Celgene Tecfidera - Biogen

16 Inter partes review at a glance Post-issuance nullity proceeding against any patent - ~120 bio/pharma; Based on novelty/obviousness of prior art patents and printed publications (not double patenting or ODP) Brought within 1 year of service of complaint against petitioner or counterclaim of infringement; exception in case of joinder ~80% of IPRs have parallel litigation 16

17 IPRs filed for biosimilars Hospira (IPR ) filed June 19, 2013 on US Pat. No. 6,747,002 Janssen Pharmaceuticals Challenged claims covering dosing regimen for EPO Janssen disclaimed the challenged claims petition is moot Boehringer Ingelheim (IPR , 417, and 418) filed December 15, 2014 on US Pat. Nos. 7,820,161, 7,976,838, and 8,329,172 Genentech Inc. and Biogen Inc. Institution of 2 of 3 petitions BI requested adverse judgment 17

18 IPR (Genzyme Corp.) (U.S. Patent No. 6,331,415) Petitioner: Genzyme Corp. IPRs filed for biosimilars Patent Title: Methods of Producing Immunoglobulins, Vectors and Transformed Host Cells for Use Therein Patent Owner: Genentech, Inc. and City of Hope IPR , (Boehringer Ingelheim) (U.S. Patent No. 8,889,135) Petitioner: Boehringer Ingelheim Corp., Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim USA Corp. Patent Title: Methods of Administering Anti-TNFα Antibodies Patent Owner: AbbVie Biotechnology Ltd. 18

19 First IPR FWD for biologic - Myozyme BioMarin Pharmaceutical Inc. v. Genzyme Therapeutic Products Ltd. Partnership, case numbers IPR and IPR , and BioMarin Pharmaceutical Inc. v. Duke University, case number IPR Myozyme 1. A method of treating a human patient with Pompe's disease, comprising intravenously administering biweekly to the patient a therapeutically effective amount of human acid alpha glucosidase, whereby the concentration of accumulated glycogen in the patient is reduced and/or further accumulation of glycogen is arrested. Obvious over two separate obviousness grounds 19

20 20 Myozyme - continued PTAB agreed that it could not have been predicted with "absolute certainty" that Pompe disease could be treated safely and effectively using GAA. However, there was sufficient motivation to pursue the clinical development of treatment as disclosed in prior art. Only missing element was the biweekly dosing schedule. But, experimentation needed to achieve this treatment regime was "nothing more than" routine. No nexus between the evidence related to long-felt but unmet need, skepticism, praise, and commercial success because PTAB characterized the invention as limited to biweekly administration feature. Because the secondary considerations related to the merits of the therapeutic compositions of GAA, they were inapplicable to the present invention.

21 IPRs filed for biosimilars PTAB Denies IPR Institution on AbbVie s Humira The PTAB denied institution on two of Amgen s IPR petitions (IPR , IPR ) against AbbVie s Humira. The patents, 8,916,157 and 8,916,158, are directed to formulations of Humira, that Amgen argued were obvious because they combined adalimumab, a known antibody, with known excipients for antibody formulations. PTAB held: Amgen has not persuaded us that [t]he skilled person would have had a reasonable expectation of success in applying the formulations commercially available and taught in the literature [to adalimumab]. 21

22 No presumption of validity Lower Burden of Proof Preponderance of the evidence standard to prove unpatentabiliity Compare with clear and convincing standard in district court to prove invalidity In re Baxter Intern., Inc., (Fed. Cir. 2012) a prior court decision in which a party has failed to prove a patent invalid does not bar the [PTO] from subsequently [finding] that the patent is, indeed, invalid. (O Malley J. concurring in denial of en banc) If the PTO later considers the validity of that same patent, it does so based on the evidence before it and under the lesser burden of proof that applies in reexamination proceedings. Id. 22

23 Expeditious Resolution and Patent Certainty IPR will most times be faster than district court Fast pace favors generic/biosimilar could nullify any delays Allows generic/biosimilar to be aggressor Force settlement 23

24 Bioproduction patents New IPR battleground? Any form of delay favors reference product sponsor be it a first biosimilar applicant or any subsequent filer Preemptive IPR filings (prior to 351(k) submission) could induce stay in DC pending resolution Timing could end up being quicker than exchange process PTAB technical expertise and broader claim construction heavily favors attack at USPTO rather than DC IPR challenges could limit reference product sponsor ability to go out and find additional IP to exclusively license to use in later attacks 24

25 Thank you Paul A. Calvo, Ph.D. Director Sterne, Kessler, Goldstein & Fox 1100 New York Avenue, NW Washington, DC Tel. no