1. From blockbusters to biosimilars – the Patent Perspective Dr. Thomas Friede Partner Patentanwalt & European Patent Attorney 2nd C5 Forum Biosimilars 2012

2. 2 Important biologics patents expire PharmaceuticalActive ingredientYear of expiry LantusInsulin2014 Remicade (infliximab)Monoclonal antibody2014 HerceptinMonoclonal antibody2014 NovoRapid/NovoLogInsulin2014 RituximabMonoclonal antibody2014 PegfilgrastimG-CSF2015 GardasilVaccine (HPV)2015 SynagisMonoclonal antibody2015 Erbitux (Cetuximab)Monoclonal antibody2016 HumiraMonoclonal antibody2018 LucentisMonoclonal antibody2018 AvastinMonoclonal antibody2019

3. 2nd C5 Forum Biosimilars 2012 3 Biosimilars approved in Europe BiosimilarActive ingredientYear of grant OmnitropeSomatotropin2006 ValtropinSomatotropin2006 BinocritEpoetin Alpha2007 Epoetin alpha HexalEpoetin Alpha2007 AbseamedEpoetin Alpha2007 RetacritEpoetin zeta2007 SilapoEpoetin zeta2007 RatiograstimFilgrastim2008 BiograstimFilgrastim2008 TevagrastimFilgrastim2009 Filgrastim (Sandoz)Filgrastim2009 Filgrastim HexalFilgrastim2009 ZarzioFilgrastim2009 NivestimFilgrastim2010

4. 2nd C5 Forum Biosimilars 2012 4 Biosimilars under current review by EMA Common name Therapeutic areaNumber of applications Originator product Originator company FilgrastimImmunostimulant (cancer/neutropenia) 1NeupogenAmgen Follitropin alpha Sex hormones and modulators of the genital system (IVF) 1Gonal-FMerck Serono InfliximabImmunosuppressant (arthritis) 2RemicadeMerck/Johnson & Johnson Insulin human Diabetes3HumalogEli Lilly Total7

5. 2nd C5 Forum Biosimilars 2012 5 Life cycle management - Evergreening  First generation: product patent  Second generation: process patents, derivatives, formulations, different medical uses  Decision of the Enlarged Board of Appeal G2/08 confirms the patentability of dosage regime  However: DE Federal Supreme Court „Carvedilol II“ December 19, 2006 dosage regime cannot be considered for novelty inventive step FR Decision of the Tribunal de Grande Instance Paris on September 28, 2010 „Actavis v. Merck“ dosage regime feature violates Art. 53c) EPC

6. 2nd C5 Forum Biosimilars 2012 6 Life cycle management – Evergreening (II)  Separate prosecution of different aspects of the same invention in parent and divisional is desirable (compounds, modes of administration, medical indications)  However: T 307/03: Prohibition of double patenting even if the compound claimed in the parent is only encompassed by the scope of the divisional application  Solution: Introduction of a Disclaimer  Decision G 2/10 of the EPO Enlarged Board of Appeal, Point 4 of the Reasons: A disclaimer is not only admissible based on prior art under Art. 54(2) and 54(3) EPC but also in other situations such as for non-patentability related reasons

7. 2nd C5 Forum Biosimilars 2012 7 Industrial Applicability- The Principles (i) The patent must disclose "a practical application" and "some profitable use" for the claimed substance, so that the ensuing monopoly "can be expected [to lead to] some … commercial benefit" (T 0870/04, para 4, T 0898/05, paras 2 and 4); (ii) A "concrete benefit", namely the invention's "use … in industrial practice" must be "derivable directly from the description", coupled with common general knowledge (T 0898/05, para 6, T 0604/04, para 15); (iii) A merely "speculative" use will not suffice, so "a vague and speculative indication of possible objectives that might or might not be achievable" will not do (T 0870/04, para 21 and T 0898/05, paras 6 and 21); (iv) The patent and common general knowledge must enable the skilled person "to reproduce" or "exploit" the claimed invention without "undue burden", or having to carry out "a research programme" (T 0604/04, para 22, T 0898/05, para 6)

8. 2nd C5 Forum Biosimilars 2012 8 Industrial Applicability (II) (v) The absence of any experimental or wet lab evidence of activity of the claimed protein is not fatal (T 0898/05, paras 21 and 31, T 1452/06, para 5); (vi) A "plausible" or "reasonably credible" claimed use, or an "educated guess", can suffice (T 1329/04, paras 6 and 11, T 0640/04, para 6, T 0898/05, paras 8, 21, 27 and 31, T 1452/06, para 6, T 1165/06 para 25); (vii) Such plausibility can be assisted by being confirmed by "later evidence", although later evidence on its own will not do (T 1329/04, para 12, T 0898/05, para 24, T 1452/06, para 6, T 1165/06, para 25)

9. 2nd C5 Forum Biosimilars 2012 9 Broad claims disclosure of a concept fit for generalisation required 1 Examiner has to substantiate reasons why he believes the effect cannot be achieved→ objections may be based on common general knowledge or prior art no general rules each case must be assessed on ist own merits 2 1 T 435/91, OJ EPO 1995, 188. 2 See T 694/92, OJ EPO 1997, 408 concerning a plant patent.

10. 2nd C5 Forum Biosimilars 2012 10 Harmonization of national Case law with EPO Case law UK Supreme Court HGS v Eli Lilly of November 2, 2011: “In a number of recent decisions of the House of Lords, attention has been drawn to "the importance of UK patent law aligning itself, so far as possible, with the jurisprudence of the EPO (and especially decisions of its Enlarged Boards of Appeal)", to quote Lord Walker in Generics (UK) Ltd v H Lundbeck A/S [2009] UKHL 12; [2009] RPC 13, para 35.”[2009] UKHL 12[2009] RPC 13 German Federal Supreme Court Xa ZB 10/09 of April 15, 2010: (“Walzenformgebungsmaschine”): “German courts have to comply with decisions handed down by the courts of the European Patent Office or by courts in other EPC contracting states and which essentially concern the same issue, and if necessary they have to address the grounds which led to a divergent result in the prior decision.”

11. 2nd C5 Forum Biosimilars 2012 11 Scope of Biotech Patents  Scope of EP patents governed by Art. 69 EPC and protocol on the interpretation of Art. 69 EPC  However: Interpretation by national Case Law  Germany: - known for broad claim interpretation (function-oriented approach) - applying the doctrine of equivalents

12. 2nd C5 Forum Biosimilars 2012 12 Scope of Biotech Patents The German Federal Supreme Court has developed three questions for the determination of equivalency: 1.Does the modified embodiment solve the problem underlying the invention with means that have objectively the same technical effect? 2.Was the person skilled in the art, using his specialist knowledge, able to find the modified means at the priority date as having the same effect? 3.Are the considerations that the person skilled in the art had to apply oriented to the technical teaching of the patent claim in such a way that the person skilled in the art took the modified embodiment into account as being an equivalent solution?

13. 2nd C5 Forum Biosimilars 2012 13 Scope of Biotech Patents  Federal Supreme Court X ZB 12/00 of March 12, 2002 („Custodiol I“) The indication of numerically defined ranges is generally binding. Figures outside the claimed range are not considered to be equivalent. Exception from the rule: tolerances due to limits in working precision

14. 2nd C5 Forum Biosimilars 2012 14 Scope of Biotech Patents Federal Supreme Court X ZR 16/09 of May 10, 2011 („Okklusionsvorrichtung“): Where the description discloses several ways of achieving a specific technical effect, as a rule, patent infringement by equivalent means is to be denied if only one of these ways is incorporated in the claim. Federal Supreme Court X ZR 69/10 of September 13, 2011 („Diglycidverbindung“): at least two requirements would have to be met for infringement under the doctrine of equivalence: (1) the specific effects of the variant are in accord with the claimed solution, and (2) the variant differs from the alternative merely outlined in the description but not in the claims in a similar fashion as the claimed solution differs from it.

15. 2nd C5 Forum Biosimilars 2012 15 Recent Biotech Patent Decisions of German Courts – thermostable DNA polymerase OLG Düsseldorf of January 14, 2010 I-2 U 69/08 Claim 1 of the Patent relates to a thermostable DNA polymerase having a molecular weight of 86.000 to 90.000 Da as determined by SDS page. The attacked embodiment: DNA polymerase having a molecular weight of 85.000 Da The attacked DNA polymerase was found not to infringe the patent. Court ruling: No equivalent infringement having regard to the Federal Supreme Court Schneidmesser and Custodiol decisions which rule that numerical ranges in claims are binding.

16. 2nd C5 Forum Biosimilars 2012 16 Recent Biotech Patent Decisions of German Courts – Ranibizumab LG Düsseldorf of November 18, 2011 4a O 143/10: MedImmune vs. Novartis (Ranibizumab) Representatives MedImmune: Johannes Heselberger, Thomas Friede  Litigation also in UK, FR, CH and NL  Claim 1 of the Patent relates to a method comprising Phage Display Technology  Ranibizumab is a Fab fragment specific for VEGF used for the treatment of AMD (age-related macula degeneration)  Annual Ranibizumab sales (Europe): US-$ 1.3 billion  Patent found to be infringed by import and sale of immediate product of the process

17. 2nd C5 Forum Biosimilars 2012 17 Recent Biotech Patent Decisions of German Courts - Ranibizumab Ranibizumab differs from the binding molecule actually obtained by the process by several substitutions introduced after the phage display step. However: Claim covers binding molecule, fragment or derivative with binding specificity for the target => Claim encompasses Ranibizumab.

18. 2nd C5 Forum Biosimilars 2012 18 Recent Biotech Patent Decisions of German Courts - Ranibizumab Narrowing claim construction by the Defendants: The Defendants argued that the core of the invention resides in a screening method which does not generate a product. Court reasoning: The claimed method is a manufacturing method since it comprises manufacturing steps.

19. 2nd C5 Forum Biosimilars 2012 19 Thank you for your attention ! Questions? Dr. Thomas Friede BARDEHLE PAGENBERG Prinzregentenplatz 7 81675 München thomas.friede@bardehle.de www.bardehle.com