Antibodies with variant Fc regions T 1856/16

Antibodies with variant Fc regions T 1856/16

Date of decision:24 August 2020
Case number: T 1856/16
Application number:04701279.4
Applicant name:MacroGenics, Inc.
  • Substantial Matters

    Claim is defined in broad structural terms, limited by a functional feature. The appellant referred to previous decisions (T 578/06, T 128/92 ) to convince the board that the examination division applied a too strict standart when stating that the invention fails to solve the technical problem.

The invention relates to antibodies comprising a variant Fc region. The interaction of antibody-antigen complexes with cells of the immune system results in a wide array of responses, ranging from so-called “effector” functions (e.g. such antibody-dependent cellular cytotoxicity -ADCC, mast cell degranulation, and phagocytosis). By modifying the affinity of the Fc region to its receptor, cellular responses to the antibody can be modulated.  

Technical problem to be solved by the invention is “the provision of alternative antibodies with improved effector function”. The solution of the inventor to this problem is the substitution of proline by leucine at position 396 (P396L) in the Fc region.   

1 Claims

With the statement of grounds of appeal, the appellant filed a set of 18 claims as a main request ( MR ). Furthermore, the appellant filed sets of claims of auxiliary requests (ARs) 1 to 5. The board stated the claims of AR 3 were considered to comply with the requirements of EPC and their subject-matter was considered to involve an inventive step.

Apellant promoted AR 3 as the new MR.

Claim 1 of MR

1. An antibody comprising a human IgG1 variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, such that said antibody specifically binds FcyRIIIA with a greater affinity than a comparable antibody comprising the wild-type Fc region, and wherein said at least one amino acid modification comprises a substitution at position 396 with leucine, wherein said numbering is according to the EU index as in Kabat.

2 Appellant’s arguments

In main request the appelant asserts that ED erroneously identified the technical problem to be solved as requiring enhanced antibody-dependent cellular cytotoxicity (ADCC), thereby ignoring that achieving enhanced ADCC was not an essential feature of the invention. The applicant also considered the second technical problem of “the provision of further Fc variants that bind FcγRIIIA with increased affinity compared to the wild-type” as a statement of the solution rather than the problem.

The applicant also objected to the findings of ED stating that the invention fails to solve the second problem.

“They (examining division) also applied too strict a standard when requiring multiple repeat experiments and the presentation of standard deviation or other statistical analysis.”

3 The Board’s decision

Cited documents:

D1| WO 99/51642 (1999) |

D2| WO 00/42072 (2000) |

D4| R. L. Shields et al., “High Resolution Mapping of the Binding Site on Human IgG1 for FcgammaRI, FcgammaRII, FcgammaRIII and FcRn and Design of IgG1 Variants with Improved Binding to the FcgammaR”, Journal of Biological Chemistry 276(9), 2001, 6591-6604|

D7| J. B. Stavenhagen et al., “Fc Optimization of Therapeutic Antibodies Enhances Their Ability to Kill Tumor Cells In vitro and Controls Tumor Expansion In vivo via Low-Affinity Activating Fcgamma Receptors”, Cancer Research 67(18), 2007, 8882-8890 |

3.1 Inventive step

  • Closest prior art (CPA): D4 discloses antibodies comprising a variant Fc region which binds the Fcγ receptor IIIA (FcγRIIIA) with greater affinity than a comparable unmodified antibody. The document also discloses that the “engineered antibodies may have important implications for improving antibody therapeutic efficacy”
  •  Difference from CPA: the specific position and nature of the mutation in the Fc region, i.e. the “substitution at position 396 with leucine”.
  • Technical effect: an improved effector function through increased binding for FcγRIIIA of the claimed antibody compared to an antibody lacking this mutation.
  • Technical problem: the provision of alternative antibodies with improved effector function.

 3.2 Obviousness

 D4 focuses on alanine substitutions and discloses only some substitutions with other amino acids, none of which involves leucine. A substitution of position 396 is not disclosed in document D4, apparently because this position was considered not to be surface-exposed, as predicted from its crystal structure. Close-by positions Lys392 and Leu398 were substituted by alanine, but these substitutions were found to have no effect on binding.

According to D7, P396 is neither surface-exposed nor directly involved in the interaction with FcyR and therefore, it would not have been possible to identify it as an important residue for FcγR binding using the approaches described in D4 (alanine-scanning of surface exposed residues).

The present application chose an approach different to the structure-guided mutation strategy disclosed in document D4, namely an empirical testing of random variants in a yeast display system. No indication can be found in document D4 or any other prior-art document that a different strategy could or should be used and would identify further mutations.

Neither of D1 and D2 provides to substitute position 396 with leucine or, alternatively, with a method to randomly mutate and screen positions in the Fc region so as to obtain antibody variants which bind FcγRIIIA with greater affinity.

The Board concludes that the identification of position 396 in the IgG1 Fc region of a human antibody and its substitution with leucine to obtain antibodies with improved effector function is not obvious.

🌑 You can read the whole decision by clicking on the case number.

🌑 Application number directs to European Patent Register

🌑 You can also read the legal texts by clicking on Article/Rule numbers.

🌕 CASE LAW MAIN PAGE

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