Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
Applicant’s amendment filed July 31, 2023 has been received and entered.
Claims 1-18 have been canceled.
Claims 19-45 have been added.
Claims 19-45 are pending and under consideration.
Priority
This application is a 371 of PCT/JP2021/013456 filed on March 30, 2021, which claims the benefit of Foreign Application JAPAN 2020-062357 filed on March 31, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on November 16, 2022, June 2, 2023, July 31, 2023, August 28, 2023, September 7, 2023, October 31, 2023, December 20, 2023, April 4, 2024, July 23, 2024, October 15, 2024, and January 3, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Interpretation
Claim 19 recites an Fc domain comprising a first Fc region subunit and a second Fc region subunit.
Claim 28 recites the multispecific antibody comprises a first Fab heavy chain and a first Fab light chain, and the second antigen binding moiety comprises a second Fab heavy chain and a second Fab light chain, wherein the C-terminus of the first Fab heavy chain is fused to the N-terminus of either the first Fc region subunit or the second Fc region subunit, and the C-terminus of the second Fab heavy chain is fused to the N-terminus of the remaining Fc region subunit.
The instant specification does not provide any other definition for an Fc region subunit. Therefore, a first or second Fc region subunit is interpreted as referring to the complete Fc region, comprising all or part of CH2 and CH3 domains, which pairs with the second Fc region (subunit) as shown in Figures 2 and 12-13. For example, see Fig. 2B.
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Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 22-36 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 22-24 recite the multispecific antigen-binding molecule comprises a first Fc region subunit with an amino acid sequence of SEQ ID NO: 317, and a second Fc region subunit with an amino acid sequence of SEQ ID NO: 323. However, claims 22-24 ultimately depend from claim 19 which recites that the first Fc region subunit comprises, at each of the following EU numbering positions, Ala at position 234, Ala at position 235, Ala at position 297, Cys at position 354, and Trp at position 366, and the second Fc region subunit comprises, at each of the following EU numbering positions, Ala at position 234, Ala at position 235, Ala at position 297, Cys at position 349, Ser at position 366, Ala at position 368, and Val at position 407.
It is unclear how the recited substitutions can occur at the positions indicated when the sequences for both the first and second Fc region subunits comprising SEQ ID NO: 317 and SEQ ID NO: 323, respectively, are only 220 amino acids in length.
Claims 25-36 are included in the rejection as they depend from or otherwise require all the limitations of the rejected claims and fail to clarify the issue.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 19-21 and 38-45 are rejected under 35 U.S.C. 103 as being obvious over Ho et al. (WO 2020/067419; cited on IDS 11/16/2022) (“Ho”). The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The instant claims are drawn to a multispecific antigen-binding molecule comprising: (i) a first antigen-binding moiety that binds to human CD3 and human CD137, but does not bind to human CD3 and human CD137 at the same time, wherein the first antigen-binding moiety comprises a set of heavy chain and light chain complementarity determining regions (CDR1-CDR3) selected from the sequences recited in claim 19 (a1) to (a3); and (ii) a second antigen-binding moiety that binds to human glypican-3 (GPC3) comprising heavy chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 235, 244, and 253, and light chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 268, 274, and 280; and (iii) an Fc domain comprising a first Fc region subunit and a second Fc region subunit that stably associate together, wherein the Fc domain exhibits reduced binding affinity to a human Fc gamma receptor compared to binding affinity of a native human IgG1 Fc domain to the human Fc gamma receptor, wherein the first Fc region subunit comprises the specific amino acids recited in claim 19. Further claimed is one or more polynucleotides that encode the multispecific antigen-binding molecule, a vector comprising the polynucleotide(s), a host cell comprising the polynucleotide(s), a method of producing a multispecific antigen-binding molecule by culturing, and a pharmaceutical composition.
Ho discloses an antigen-binding molecule comprising: an antibody variable region that is capable of binding to CD3 and CD137 (4-1BB), but does not bind to CD3 and CD137 at the same time; and a variable region binding to a third antigen expressed in a cancer tissue, preferably glypican-3 (GPC3). The trispecific antigen-binding molecules exhibit enhanced T-cell dependent cytotoxic activity induced by binding to the three different antigens without cross-linking different cells, which is considered to be responsible for adverse reactions caused by treatments with multispecific antigen-binding molecules [0016].
The multispecific antigen binding molecule is comprised of an antibody variable region that is capable of binding to CD3 and CD137 with a heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 6 and a light chain variable domain (VL) amino acid sequence of SEQ ID NO: 58 [pg. 19, (d6)] or a VH amino acid sequence of SEQ ID NO: 14 and a VL amino acid sequence of SEQ ID NO: 58 [pg. 20, 9d15)]. The third antigen glypican-3 (GPC3) of the multispecific antigen binding molecule comprises a VH amino acid sequence of SEQ ID NO: 206 and a VL amino acid sequence of SEQ ID NO: 207 [pg. 23, [7A-7B]].
The antigen-binding molecule further comprises an antibody Fc region with reduced binding activity against Fc gamma R as compared with the Fc region of a naturally occurring human IgG1 antibody [pg. 24, [9]]. Substitution of constituent amino acids can be made at several positions including L234A, L235A, N297A, D356C, T366S, L368A, and Y407V, which are residues involved in antigen binding [0379]. Specifically, Ho teaches substituting Ala for the amino acids at positions 234, 235, and 297 (EU numbering) to reduce Fc gamma binding [0341].
Ho generated anti-GPC3/CD3/human CD137 trispecific antibodies utilizing CrossMab and Fab-arm exchange (FAE) technology [0405]. Figure 2.2 shows the orientation of the VH and VL of first and second antigen-binding moieties with the Fc region.
Ho further discloses a pharmaceutical composition comprising the antigen-binding molecule and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition or the antigen-binding molecule is for use in the treatment of cancer [pg. 24, [10A-10C]].
In addition, Ho discloses an isolated polynucleotide comprising a nucleotide sequence that encodes the antigen-binding molecule, an expression vector comprising the polynucleotide, a host cell transformed or transfected with the polynucleotide or the expression vector, and a method of producing a multispecific antigen-binding molecule or a multispecific antibody comprising culturing the host cell [pg. 25, [11-14]].
The amino acid sequences for the CD3/CD137 arm heavy chain variable domain (VH) of SEQ ID NO: 6 and light chain variable domain (VL) of SEQ ID NO: 58 taught by Ho are 100% identical to the CD3/CD137 VH and VL amino acid sequences of recited in the instant claims, including the CDR regions. In addition, the GPC3 arm VH and VL amino acid sequences of SEQ ID NO: 206 and SEQ ID NO: 205, respectively, are 100% identical to the GPC3 VH and VL amino acid sequences of SEQ ID NO: 226 and SEQ ID NO: 262, respectively, as recited in the instant claims. As such the trispecific antibody that binds CD3/CD137 (but not at the same time) and GPC3 is identical to the trispecific antibody recited in the instant claims. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Additional References
The following pertinent prior art reference was found during examination but were not relied upon as grounds of rejection: WO2019/111871 (cited in IDS 11/16/2022) is drawn to a trispecific IgG antibody comprising a dual binding Fab that binds to human CD3 epsilon and human CD137, but
does not bind to human CD3 epsilon and human CD137 at the same time, and a second Fab comprising a second variable region that binds to GPC3, which has different amino acid sequences than the trispecific antigen-binding molecule recited in the instant claims.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Claims 22-24 recite the multispecific antigen binding molecule defined by the amino acid sequences recited in claim 19 comprises a first Fc region subunit with an amino acid sequence of SEQ ID NO: 317, and a second Fc region subunit with an amino acid sequence of SEQ ID NO: 323. There is no prior art that teaches or suggests multispecific antibody comprising Fc region subunits with the specific sequences recited in the instant claims. The closest prior art Ho et al. (WO 2020/067419) is directed towards a trispecific antibody having the identical antigen binding regions as recited in the instant claims as set forth above, however, does not teach or suggest the presently claimed Fc region subunits with specific sequences.
Claims 25-36 depend from or otherwise require all the limitations of the claims drawn to allowable subject matter.
REASONS FOR ALLOWANCE
The following is an examiner’s statement of reasons for allowance:
Claim 37 is directed to an antigen-binding molecule comprising a set of four polypeptide chains selected from sets (al) to (a6) below:(a1) chain 1 comprising the amino acid sequence of SEQ ID NO: 205, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 219, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225; (a2) chain 1 comprising the amino acid sequence of SEQ ID NO: 205, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 220, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225; (a3) chain 1 comprising the amino acid sequence of SEQ ID NO: 286, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 291, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225; (a4) chain 1 comprising the amino acid sequence of SEQ ID NO: 286, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 292, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225; (a5) chain 1 comprising the amino acid sequence of SEQ ID NO: 287, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 293, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225; and (a6) chain 1 comprising the amino acid sequence of SEQ ID NO: 287, chain 2 comprising the amino acid sequence of SEQ ID NO: 210, chain 3 comprising the amino acid sequence of SEQ ID NO: 294, and chain 4 comprising the amino acid sequence of SEQ ID NO: 225.
At least one polypeptide chain from each embodiment (a1) to (a6) are free of prior art. Specifically, amino acid sequences of SEQ ID NOs: 205, 286, 287, 291, and 292 are free of prior art. The closest prior art, Igawa et al. (WO 2020/067399; cited in IDS 11/16/2022), teaches anti-GPC3/CD3/human CD137 trispecific antibodies for the treatment of cancer comprising four polypeptides including polypeptides of SEQ ID NOs: 210 and 225 , however does not teach or suggest the presently claimed method with all of the specific polypeptide sequences recited in instant claim 37. Therefore, claim 37 is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644