1. P A T E N T A T T O R N E Y S The EPO‘s approach in assessing inventive step for antibody claims Dr. Andreas Hübel M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S

2. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Article 56 EPC – Inventive step An invention shall be considered as involving an inventive step if, having regard to the state of the art, it is not obvious to a person skilled in the art.

3. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 2. State of the art The state of the art may reside in the relevant common general knowledge, which need not necessarily be in writing and needs substantiation only if challenged (see T 939/92).

4. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.Problem-and-solution approach In the problem-and-solution approach, there are three main stages:

5. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.Problem-and-solution approach In the problem-and-solution approach, there are three main stages: (i)determining the "closest prior art",

6. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.Problem-and-solution approach In the problem-and-solution approach, there are three main stages: (i)determining the "closest prior art", (ii)establishing the "objective technical problem" to be solved, and

7. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.Problem-and-solution approach In the problem-and-solution approach, there are three main stages: (i)determining the "closest prior art", (ii)establishing the "objective technical problem" to be solved, and (iii)considering whether or not the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person.

8. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.1Determination of the closest prior art The closest prior art is that which in one single reference discloses the combination of features which constitutes the most promising starting point for an obvious development leading to the invention. … it should be directed to a similar purpose or effect as the invention or at least belong to the same or a closely related technical field as the claimed invention. In practice, the closest prior art is generally that which corresponds to a similar use and requires the minimum of structural and functional modifications to arrive at the claimed invention

9. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.2Formulation of the objective technical problem -determining the difference between the claimed invention and the closest prior art in terms of features;

10. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.2Formulation of the objective technical problem -determining the difference between the claimed invention and the closest prior art in terms of features; -identifying the technical effect resulting from the distinguishing features;

11. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.2Formulation of the objective technical problem -determining the difference between the claimed invention and the closest prior art in terms of features; -identifying the technical effect resulting from the distinguishing features; -then formulating the technical problem.

12. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.2Formulation of the objective technical problem -determining the difference between the claimed invention and the closest prior art in terms of features; -identifying the technical effect resulting from the distinguishing features; -then formulating the technical problem. The objective technical problem derived in this way may not be what the applicant presented as "the problem" in his application.

13. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.2Formulation of the objective technical problem The expression "technical problem" does not necessarily imply that the technical solution is a technical improvement over the prior art. Thus the problem could be simply to seek an alternative to a known device or process which provides the same or similar effects or is more cost-effective.

14. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Guidelines for Examination in the EPO – G VII 5.3Could-would approach Is there is any teaching in the prior art as a whole that would (not simply could, but would) have prompted the skilled person, faced with the objective technical problem, to modify or adapt the closest prior art while taking account of that teaching, thereby arriving at something falling within the terms of the claims, and thus achieving what the invention achieves.

15. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for antibody claims How does the EPO applies its problem-solution approach to antibody claims ? ?

16. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for antibody claims How does the EPO applies its problem-solution approach to antibody claims ?

17. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for antibody claims How does the EPO applies its problem-solution approach to small molecules ?

18. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for small molecules Compounds not structurally close to each other compound 1A compound 1B

19. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for small molecules Compounds not structurally close to each other compound 1A compound 1B

20. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventive step for small molecules Compounds not structurally close to each other compound 1A compound 1B Compound 1B does not have to exhibit advantages or surprising effects beyond those exhibited by compound 1A for being considered as being based on an inventive step.

21. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of small molecules Compounds structurally close to each other compound 2A compound 2B

22. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of small molecules Compounds structurally close to each other compound 2A compound 2B

23. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of small molecules Compounds structurally close to each other compound 2A compound 2B Compound 2B has to exhibit advantages or surprising effects beyond those exhibited by compound 2A for being considered as non-obvious.

24. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies How is the EPO’s assessment of inventive step for small molecules transferred to antibody claims ? www.protopedia.org

25. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Structure of antibodies www.protopedia.org

26. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Structure of antibodies

27. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Structure of antibodies

28. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Structure of antibodies

29. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies The vast majority of structural elements are the same in most antibodies. CDR‘s constitute the gist of a novel antibody, but constitute a small portion of the antibody structure. Amino acid sequences of the CDRs are not predictable. Amino acid sequence of a single CDR is often known.

30. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies If antigen A is novel, then an antibody against antigen A is usually considered to be novel AND inventive, provided that antigen A is well defined in the application.

31. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Prior Art: > monoclonal antibody (mAb) „X“, which binds protein „A“ > method for preparation (immunisation protocol, isolation) > functionality: neutralizing activity > characterized by the amino acid sequence of ist V H and V L - domains Claim: > monoclonal Ab „Y“ binding protein „A“, the mAB comprising the six CDRs as being those of SEQ ID NO: 1 to 6. (method of preparation is the same as in prior art, function is the same as prior art mAb) Novelty: > YES, due to structural characterization of the six CDRs Inventive:> Sequence of the six CDRs obvious ? YES or NO ?

32. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Prior Art: > monoclonal antibody (mAb) „X“, which binds protein „A“ > method for preparation (immunisation protocol, isolation) > functionality: neutralizing activity > characterized by the amino acid sequence of ist V H and V L - domains Claim: > monoclonal Ab „Y“ binding protein „A“, the mAB comprising the six CDRs as being those of SEQ ID NO: 1 to 6. (method of preparation is the same as in prior art, function is the same as prior art mAb) Novelty: > YES, due to structural characterization of the six CDRs Inventive:> Sequence of the six CDRs obvious ? YES ! pursuant to EPO

33. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies In small molecules, the skilled artisan could envisage changes here and there, however he would not do so with an expectation to succeed - unless prior art guides him in relation with non-active parts of the molecule which could be modified without consequences for the biological activity or - unless safe predictions can be made based on prior art structures. In Ab molecules, nature does it four you => once you have a method to produce one type of antibody, the skilled artisan knows that by routine techniques he would succeed to produce other Abs with equivalent functional properties, albeit different structure.

34. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies Methods of generating antibodies are known. Köhler, G. & Milstein, C. (1975): Continuous cultures of fused cells secreting antibody of predefined specificity. In: Nature. Bd. 256, S. 495–497. In 1979, hybridoma technology was considered not being routine (T 349/91). Today, hybridoma technology and phage display are considered technologies that are well mastered, no technical problems are expected. A single document describing the new technology thoroughly and reciting possible uses and advantages is sufficient to deny an inventive step.

35. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies A single document describing the new technology thoroughly and reciting possible uses and advantages is sufficient to deny an inventive step. Hence, producing single-domain antibodies („nanobodies“) be immunisation of llamas and generating Abs by hybridomas or generating phage display does not provide an inventive step for said nanobody if said nanobody does not have an unexpected effect.

36. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Inventiveness of antibodies As methods for generating antibodies are considered to be routine techniques today, the EPO deems that structure alone can not be the basis for acknowledging an inventive step, if the function of the novel antibody is the same as in the prior art antibody. The novel antibody has to have an unexpected technical effect for having an inventive step acknowledged by the EPO. e.g. antigen specificity, affinity, mode of action, immunogenicity, stability, neutralizing titer, epitope specificity, etc.

37. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Summary

38. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Summary If antigen A is novel, then an antibody against antigen A is usually considered to be novel AND inventive, provided that antigen A is well defined in the application.

39. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Summary If antigen A is novel, then an antibody against antigen A is usually considered to be novel AND inventive, provided that antigen A is well defined in the application. A generic antibody against a known target is not inventive.

40. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Summary If antigen A is novel, then an antibody against antigen A is usually considered to be novel AND inventive, provided that antigen A is well defined in the application. A generic antibody against a known target is not inventive. The provision of a novel antibody against a known antigen involves an inventive step only if the antibody shows unexpected properties or if it was unexpected that such an antibody could be produced at all.

41. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed

42. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed What is an unexpected property of a new antibody ?

43. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed What is an unexpected property of a new antibody ? Is it really nature doing it for us ?

44. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed What is an unexpected property of a new antibody ? Is it really nature doing it for us ? Is the basic nucleus of smalls molecule equivalent to the backbone or to the CDRs of Abs ?

45. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed What is an unexpected property of a new antibody ? Is it really nature doing it for us ? Is the basic nucleus of smalls molecule equivalent to the backbone or to the CDRs of Abs ? Is it appropriate to consider routine techniques in assessing inventive step of a product defined by its structure ?

46. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Questions to be discussed What is an unexpected property of a new antibody ? Is it really nature doing it for us ? Is the basic nucleus of smalls molecule equivalent to the backbone or to the CDRs of Abs ? Is it appropriate to consider routine techniques in assessing inventive step of a product defined by its structure ? Is the unpredictability of CDR sequences sufficiently considered ?

47. M I C H A L S K I H Ü T T E R M A N N P A T E N T A T T O R N E Y S Thank you very much for your kind attention. Michalski · Hüttermann & Partner www.mhpatent.de Büro Düsseldorf Neuer Zollhof 2 D-40221 Düsseldorf Fon +49 211 159 249 0 Fax +49 211 159 249 20 mail@mhpatent.de Büro München Nymphenburger Strasse 4 D-80335 München Fon +49 89 208027 274 Fax: +49 89 208027 275 muenchen@mhpatent.de