DETAILED ACTION
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 .
Applicant’s remarks, filed 7/10/2026, are acknowledged and entered into the record. Applicants amended claims 1-2, canceled claims 3-24, and added new claims 25-51 in the remarks of 7/10/2026.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is a CON of PCT/IB2024/000774, filed 12/19/2024; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/611860, filed 12/19/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/27/2026 and 7/10/2026 have been considered by the examiner.
Status of Claims
Claims 1-2 and 25-51 are pending and are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112
The rejection of claims 1-24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. Applicants amended the claims to define the claimed CDRs of the various antibody species.
The rejection of claim 5 on the basis that it contains an improper Markush grouping of alternatives, is withdrawn. Applicants canceled claim 5, thus obviating the rejection.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3 and 16 under 35 U.S.C. 103 as being unpatentable over Afroz et al., (US 2025/0145695; priority to 2/16/2023), is withdrawn. Applicants amended claim 1 and canceled claims 3 and 16, in the remarks of 7/10/2026. However, applicants introduced the limitations of claims 3 and 16 in new claims 25 and 35. See below.
Claim Rejections – New, necessitated by amendment
Applicants canceled claims 3-24, and added new claims 25-51, in the remarks of 7/10/2026; thus necessitating the new rejections of record.
Claim Rejections - 35 USC § 103
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.
Claims 25 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Afroz et al., (US 2025/0145695; priority to 2/16/2023) and Abbvie (WO 2014/100542; published 6/26/2014).
Claim 25 recites an antibody that binds TDP-43, comprising the VH and VL of SEQ ID NOs: 70 and 88, respectively. Claim 35 recites a polynucleotide comprising a nucleotide sequence encoding an antibody comprising the VH and VL of SEQ ID NOs: 70 and 88, respectively. According to the Kabat numbering system, and described in Table 1(G) (Specifications, pg. 16); the HCDR1 is EYSMH, the HCDR2 is GINPNNGGTSYNQKFQG, and the HCDR3 is ES. The LCDR1 is KSSQSLLHSDGKTYLN, the LCDR2 is LVSKLKS, and the LCDR3 is MQGTHFPHT.
Afroz et al. teaches humanized anti-TDP-43 antibodies and methods of treating a disease associated with TDP-43 aggregates (abstract). Afroz teaches the anti-TDP-43 antibodies have HCDRs 1-2 of SEQ ID NOs: 21, 122, respectively, and a HCDR3 sequence of ES; and the LCDRs 1-3 of SEQ ID NOs: 25, 16 and 27 (pg. 56, claim 1). Thus, Afroz claims an anti-TGP-43 antibody wherein the HCD1 is EYSMH, the HCDR2 is GINPNNGGTSYNQKFQG, and the HCDR3 is ES; the LCDR1 is KSSQSLLHSDGKTYLN, the LCDR2 is LVSKLDS and the LCDR3 is WQGTHFPHT.
Thus, the HCDR1, HCDR2 and HCDR3, as well as the LCDR1, amino acid sequences of Afroz are 100% identical to those of instant claim 1. The LCDR2 and LCDR3 of Afroz are, each one, different from the instant claims by substitution of a single amino acid residue (bolded and underlined above). However, Afroz teaches that the chosen CDR sequences may be mutated at specific positions to avoid potential post-translational modification sites (pg. 4, para. 0023). Afroz teaches the LCDR2 can be mutated at D55 or S56, corresponding to the last 2 amino acids of LCDR2; and that LCDR3 can be mutated at W89, the first amino acid residue of LCDR3. Thus, making a D55K substitution to LCDR2 and a W89M mutation to LCDR3 would render the HCDRs 1-3 and LCDRs 1-3 of Afroz 100% identical to those of instant claim 1, wherein the VH and VL are SEQ ID NOs: 70 and 88, respectively.
It would have been obvious to one of skill in the art to modify the CDR sequences of the anti-TDP-43 antibodies of Afroz to have a D55K and W89M substitution in the LCDR2 and LCDR3 domains. One would have been motivated to do so in order to avoid potential post-translation modifications sites, as taught by Afroz et al. There would have been a reasonable expectation for success given that Afroz identifies the VL positions D55 and W89 as residues that will accept substitutions to avoid post-translational modifications, as taught by Afroz et al.
Afroz teaches humanizing the antibodies with acceptor framework regions of a heavy chain variable domain, such as IGHV3-43 and/or a light chain variable domain of IGKV2-28 (pg. 56, claim 1). However, Afroz does not teach whereby the humanization of the heavy chain is made with an IGHV1-46 acceptor framework region.
Abbvie teaches humanizing murine antibodies through a high-throughput antibody humanization process (abstract). Abbvie teaches grafting the CDRs of a rodent antibody onto a similar framework acceptor, including selecting a minimal number of key framework residues which may be back-mutated in order to maintain the original CDR conformation, and that such methods are known in the art (pg. 1, lines 28-31). Abbvie teaches potential human acceptor sequences for the CDRs of the donor VH or VL sequence may be compiled from databases of human IG germline sequences (pg. 33, lines 11-13), and that such sequences, for the VH, include IGHV3-43, or alternatively, IGHV1-46 (pg. 35, Table 3). Abbvie also teaches the potential acceptor framework regions for the VL include IGKV2-28 (pg. 37, Table 4). Abbvie also teaches the human germline framework 4 (FR4) sequences that may be used, including IGHJ1 for the VH and IGKJ4 for the VL (pg. 41, Table 7). Abbvie provides Figure 3 to demonstrate the process of matching a murine antibody sequence with the possible VH acceptor framework regions, including using IGHV1-46; as well as using the JH1 sequence for the FR4 (Fig. 4).
It would have been obvious to one of skill in the art to substitute the IGHV3-43 acceptor framework regions of the antibody comprising the HCDRs 1-3 and the LCDRs 1-3, of Afroz, with the alternative acceptor framework regions of IGHV1-46. One would have been motivated to do so in order to humanized the antibody. There would have been a reasonable expectation for success given that various human germline antibody domain sequences may be used to best map grafting the CDRs of a murine antibody, and that IGHV3-43 and IGHV1-46 are substitutable alternative framework domains for consideration, with a reasonable expectation for success.
Specifically, the VL of instant SEQ ID NO: 88 comprises the LCDR1, and the mutated LCDRs 2-3, as taught by Afroz (above), with the FR1-4 of the IGKV2 acceptor human framework domain, as taught by Afroz (pg. 56, claim 1), with 100% amino acid sequence identity, and not comprising back-mutations. Thus, Afroz makes obvious the VL of SEQ ID NO: 88 with 100% sequence identity. The VH of instant SEQ ID NO: 70 comprises the HCDRs 1-3 of Afroz with 100% sequence identity, and the acceptor human framework domain of IGHV1-46, as taught by Abbive, with 100% identity, except for a single back-mutation of Y-to-F at residue 27. However, Afroz teaches wherein the acceptor framework of the VH comprises a Y27F back-mutation (pg. 56, claim 2). Thus, the combination of Afroz and Abbvie makes obvious a humanized TDP-43 antibody comprising the VL of SEQ ID NO: 88 with 100% sequence identity and the VH of SEQ ID NO: 70 with 100% sequence identity. Therefore the combination of Afroz and Abbvie make obvious instant claim 25. Afroz teaches nucleic acids encoding the antibodies, viral vectors comprising the nucleotides, recombinant expression vectors, and host cells comprising the nucleic acids or vectors (pg. 61, claims 57-60). Thus the combination of Afroz and Abbvie make obvious the polynucleotides of instant claim 35.
Conclusion
Claims 25 and 35 are rejected; claims 1-2, 26-34 and 36-51 are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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