Post-published documents may lead to grant of a patent T 0957/18
|Date of decision:||24 September 2020|
|Case number:||T 0957/18|
|Title of application||Synergistic anti-CD47 therapy for hematologic cancers|
|Applicant name:||The Board of Trustees of the Leland Stanford Junior University|
In pre-grant proceedings, examination division didn’t discuss auxiliary requests of the appellant. The board viewed this act as a violation of right to be heard and as an exceptional circumstance, thereby accepting the amendment to the appellant’s claims after the notification of summons to oral proceedings. Art 13 (2) RPBA 2007
The appellant limits the scope of claim by amending the broad hematologic cancer class with diffuse large B cell lymphoma, which is a subcategory of the former. A further technichal feature is also added to the claim in view of novelty and inventive step assesment. Supporting evidence in the application as filed and further evidence from post published documents ragarding the effect of this technical feature determines the result of the case for the benefit of the appellant (CL II.C.6.8).
Invention of T 0957/18 relates to a treatment for diffuse large B cell lymphoma. A synergistic combination of agents are combined in a bispecific FcR-engaging antibody selective for CD47 and for CD20. Inventors found that bispecific FcR-engaging antibody is effective to reduce a potential antibody toxicity, while retaining the synergy effect, especially as CD47 is expressed in multiple normal tissues.
In pre-grant proceedings, the examining division (ED) held that main request (MR) and auxiliary request (AR) 1 did not meet the requirement of inventive step. ED didn’t discuss ARs 2 and 3 during the oral proceedings.
With the statement of grounds of appeal, the appellant submitted main request, AR 1-3 and a set of claims of a new AR 4. The board, inter alia, raised objections for novelty and clarity pursuant to G 10/93 : ( the board used its the power to examine whether the application meets the requirements of the EPC, including requirements which the examining division regarded as being met.)
After the notification of summons to oral proceedings , the appellant submitted a set of claims of a new MR. The board allowed the request pursuant to Article 13(2) RPBA 2007 (due to ED ‘s decision of not discussing ARs 2 and 3).
MR comprises only a single claim with the wording as follows
1.A synergistic combination of agents for use in the treatment of a hematologic cancer in a patient, - wherein the hematologic cancer is non-Hodgkin's lymphoma (NHL) and - wherein the NHL is a diffuse large B cell lymphoma, - wherein the combination of agents comprises a first agent that selectively blocks CD47 and a second agent that binds to CD20 - wherein the first and second agents are comprised in a bispecific FcR-engaging antibody selective for CD47 and for CD20.
Documents referred to in this decision:
D1: CD47 IS AN ADVERSE PROGNOSTIC FACTOR IN NON-HODGKIN LYMPHOMA AND A THERAPEUTIC ANTIBODY TARGET THAT SYNERGIZES WITH RITUXIMAB Authors:Chao M P, Alizadeh A, Tang C Z, Jan M, Levy R, Majeti R, Weissman I L Publication data:Experimental hematalogy, 20090901 Elsevier Inc, US Source info:Vol: 37, Nr: 9, Suppl, Page(s): S8 – S9 * abstract *
D2: WO2009091547 A1 (UNIV LELAND STANFORD JUNIOR [US], et al) – 23 July 2009 * The whole document, in particular §14 *
D9: A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells Authors:Emily C Piccione, Silvia Juarez, Jie Liu, Serena Tseng, Christine E Ryan, Cyndhavi Narayanan, Lijuan Wang, Kipp Weiskopf, Ravindra Majeti Publication data:mAbs, 20150903 Landes Bioscience, US Source info:Vol: 7, Nr: 5, Page(s): 946 – 956
D10: Bispecific T-cell engaging antibodies for cancer therapy Authors:BAEUERLE PATRICK A, REINHARDT CARSTEN Publication data:Cancer Research, 20090615 Source info:Vol: 69, Nr: 12, Page(s): 4941 – 4944
D11: Handbook of Therapeutic antibodies; Part III, Chapter 2 :Bispecific Antibodies Author:DAFNE MÜLLER AND ROLAND KONTERMANN Publication data:Handbook of Therapeutic Antibodies, 20080201 Wiley-VCH, Weinheim Source info:Page(s): 352 – 378
D13: Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies Authors:Elie Dheilly, Valéry Moine, Lucile Broyer, Susana Salgado-Pires, Zoë Johnson, Anne Papaioannou, Laura Cons, Sébastien Calloud, Stefano Majocchi, Robert Nelson, François Rousseau, Walter Ferlin, Marie Kosco-Vilbois, Nicolas Fischer, Krzysztof Masternak Publication data:Molecular Therapy, 20170201 Elsevier Inc, US Source info:Vol: 25, Nr: 2, Page(s): 523 – 533
🖤 The board didn’t raise any objections in regard to amendments, clarity and novelty for the MR of the apellant.
Assesment of inventive step
The board determined D1 as the closest prior art to the present invention. D1 elucidates the therapeutic potential of an anti-CD47 antibody alone and in combination with an anti-CD20 antibody for the treatment of Non-Hodgkin lymphoma (NHL). D1 reports a synergistic effect of the two separate antibodies in the treatment of NHL in a mouse model.
The difference of the present invention form D1 is that the first agent that selectively blocks CD47 and the second agent that binds to CD20 are combined in a bispecific FcR-engaging antibody selective for CD47 and for CD20. A further difference is that the Non-Hodgkin lymphoma is diffuse large B cell lymphoma.
The technical effect caused by this difference is the reduction of potential antibody toxicity, while retaining the synergy effect, especially as CD47 is expressed in multiple normal tissue.
According to above approach employed by the board, the objective technical problem of the present invention is thus a treatment for diffuse large B cell lymphoma having reduced antibody toxicity.
D1 does not mention the problem of a potential antibody toxicity due to ubiquitous CD47 expression. D10, D11 and common general knowledge don’t suggest the use of bispecific antibodies to reduce antibody toxicity due to off-target binding ( binding to non-cancer cells ).
Although D2 discloses therapies using combinations of monoclonal antibodies targeting CD47 which may be in the form of bispecific antibodies, it remains silent on a specific effect or purpose associated with such a bispecific antibody or the requirement that the bispecific antibody is FcR-engaging.
As to technical effect, the board arguments as the off-target binding (binding to non -cancer cells) was reduced by the preferential binding of the bispecific antibody to cells expressing both CD47 and CD20.
Board views that this effect was plausible and would seem “logical” to the skilled person, once informed about it in paragraph  of the application and in view of the data in Figure 17D, showing that anti-CD47 antibodies can cause cell-lysis of CD47-expressing cells. Moreover, D9 and D13 published after the application’s filing date confirmed selective binding of a bispecific FcR-engaging antibody specific for CD47 and CD20 to tumour cells and reduced binding to normal cells. The skilled person would also consider the statement in paragraph , that the bispecific antibody retained the synergistic effect relative to treatment with either anti-CD20 or anti-CD47 antibodies alone, and thus, evidence showing that the bispecific antibody retained the claimed synergistic effect could be taken into account, although it was published after the filing date.
In the end, the board concluded that the sole request involves an inventive step and remitted the case to ED in order to grant a patent.
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