SINGLE CHAIN ANTIBODIES AND INTRABODIES TO MISFOLDED TDP-43 AND METHODS OF USE

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 Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 18, 2026 has been entered. RESPONSE TO AMENDMENT Status of Application/Amendments/claims 3. Applicant’s amendment filed September 18, 2026 is acknowledged. Claims1, 3-11, 15, 17-18, 20-22, 24-25, 27-29, 31-47 and 49-51 are canceled. Claims 2, 13-14, 23, 30, 48, 54 and 58 are amended. Claims 59-61 are newly added. Claims 2, 12-14, 16, 19, 23, 26, 30, 48, 52-58 and new claims 59-61 are pending in this application. Election was made without traverse in the reply filed on August 28, 2025. 4. Claims 2, 12-14, 16, 19, 23, 26, 30, 48 and 52-61 are under examination with respect to SEQ ID NOs: 16-18 and SEQ ID NOs: 19-21 for CDR-H1-3 and CDR-L1-3, SEQ ID NOs: 100 and 101 for VH and VL or encoded by SEQ ID NO:78 and 79 recited in b) of claim 2, SEQ ID NO:182 for linker, SEQ ID NO:174 for targeting moiety linker, SEQ ID NO:258 for nucleic acid sequence in this office action. 5. Applicant’s arguments filed on September 18, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below. Claim Rejections/Objections Withdrawn 6. The rejection of claims 2, 12-14, 16, 19, 23, 26, 30 and 48-58 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 49-51. The rejection of claims 49-51 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is moot because the claims are canceled. Claim Rejections/Objections Maintained In view of the amendment filed on September 18, 2026, the following rejections are maintained. Claim Objections 7. Claims 2, 12, 58 and 60 are objected to because of the following informalities: The recitations “heavy chain variable domain” and “light chain variable domain” recited in claims 2, 12, 58 and 60 in the limitation “wherein orientation of the heavy chain variable domain…the light chain variable domain is…” are inconsistent with the limitations “heavy chain variable region” and “light chain variable region”. Appropriate correction is required. Claim Rejections - 35 USC § 112 8. Claims 2, 12-14, 16, 19, 23, 26, 30, 48 and 52-61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained for the reasons of record and the reasons set forth below. Claims 2, 12-14, 16, 19, 23, 26, 30, 48 and 52-61 as amended encompass a genus of nucleic acid comprising a genus of variant sequences that are conservatively substituted sequences or humanized versions of SEQ ID NOs: 100 and 101 encoding a heavy chain variable region (VH) and a light chain variable region (VL) encompassed in a genus of single chain antibodies binding to at least the W residue in the context of DAGAWGNL (SEQ ID NO:1 or aa 65-71 of TDP-43) in misfolded TDP-43 (anti-Trp68-TDP-43 scAb), wherein the VH and the VL is linked by a linker, and wherein the linker comprises about 10-25 amino acids or is selected from recited SEQ ID NOs:. Claims 16 and 57 encompass a genus of nucleic acid further encoding a genus of targeting moiety and/or a genus of signal peptide and/or a genus of cell penetrating peptide. Claim 57 encompasses a genus of targeting moiety linker. Briefly, Applicant has not disclosed sufficient species for the broad genus of nucleic acid sequence variants of SEQ ID NOs: 100-101 encoding the VH and VL of the broad genus of anti-Trp68-TDP-43 scAbs; the broad genus of targeting moiety, signal peptide and/or cell penetrating peptide, and the broad genus of targeting moiety linker. The specification only describes: i) monoclonal antibodies 2F7, 1H3-1K3, 28H3-28K1 and 14H1-14K2 capable of binding to Trp68 in TDP-43 (tables 5 and 8; p. 39-40) and their amino acid sequences for VH and VL and HCDRs1-3 and LCDRs1-3, and DNA sequences for the VH and VL (see p. 30-35;Table 4, amino acid sequences for VH and VL; Table 2: amino acid sequence for HCDRs1-3 and LCDRs1-3, Table 3, DNA sequences for VH and VL); and ii) ScFv constructs: 1) with an N-terminal Flag tag lysosomal constructs: LYS-2F7, LYS-1H3-1K3, LYS-28H3-28K1 and LYS-14H1-14K2 comprising a lysosomal-targeting tag and their polynucleotide and amino acid sequences (table 9, p. 41-43); 2) C-terminal Flag-YPTL intrabodies YPTL-2F7, YPTL-1H3-1K3, YPTL-28H3-28K1 and YPTL-14H1-14K2 and their polynucleotide and amino acid sequences (table 10, p. 43-45); 3) C-terminal MYC tag constructs with a VL linked to a VH through a 15 amino acid linker: the VL sequence-15 amino acid ScFv linker sequence-VH-three amino acid MYC linker sequence-MYC tag: MYCL15H-2F7, MYC15H-1H3-1K3, MYCL15H-28H-288K1 and MYCL15H-14H1-14K2 and their polynucleotide and amino acid sequences (table 11; p. 45-47); 4) MYC constructs with a VH linked to a VL through a 15 amino acid linker: the VH sequence-15 amino acid ScFv linker sequence-the VL sequence-3 amino acid MYC linker sequence -MYC tag and their polynucleotide and amino acid sequences (table 12, p. 47-49); 5) MYC constructs with a VL linked to a VH through a 20 amino acid linker: the VL sequence-20 amino acid ScFv linker sequence-the VH sequence-three amino acid MYC linker sequence-MYC tag (table 13; p. 49-51); and 6) MYC construct with a VH linked to a VL through a 20 amino acid linker: the VH sequence-20 amino acid ScFv linker sequence-the VL sequence-three amino acid MYC linker sequence-MYC tag and their polynucleotide and amino acid sequences (table 14, p. 51-53). However, the specification provides no well-established structural and functional relationship or correlation between the claimed genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs: 100-101 for VH and VL and an undefined linker and the anti-Trp68-TDP-43 scAb comprising SEQ ID NO:100-101 for VH and VL or anti-Trp68-TDP-43 scAb with a specific lysosomal targeting moiety comprising the amino acid sequence of 209, 219 or 259. The specification provides no well-established structural and functional relationship or correlation between the claimed genus of structurally and functionally undefined nucleic acid sequence variants encoding variants of SEQ ID NOs: 100-101 for VH and VL of the broad genus of anti-Trp68-TDP-43 scAbs and the polynucleotides encoding anti-Trp68-TDP-43 scAbs comprising the amino acid sequences of SEQ ID NOs:100 and 101 for VH and VL or the polynucleotides of SEQ ID NO:208, 218 or 258 encoding the anti-Trp68-TDP-43 scAb with a specific lysosomal targeting sequence having the amino acid sequence of SEQ ID NO:209, 219 or 259. The specification also provides no sufficient description or information as to what other common structures and sequences are required by the claimed genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs:100-101 for a VH and a VL. The specification fails to teach what other common structures and sequences are required by the claimed genus of nucleic acid sequence encoding variants of SEQ ID NOs: 100-101 for VH and VL and with an undefined linker to the function of anti-Trp68-TDP-43 scAbs comprising SEQ ID NOs: 100-101 for VH and VL or to the function of anti-Trp68-TDP-43 scAbs with a specific lysosomal targeting moiety comprising SEQ ID NO: 209, 219 or 259 or encoded by polynucleotides of SEQ ID NO: 208, 218 or 258. The specification fails to provide sufficient description or information as to what other common structures and sequences are required by the claimed genus of targeting moiety, signal peptide and/or cell penetrating peptide, and targeting moiety linker. Since the common characteristics/features of other anti-Trp68-TDP-43 scAbs comprising variants of recited SEQ ID NOs: 100-101 for VH and VL or with an undefined linker or other nucleic acids encoding the anti-Trp6-TDP-43 scAbs variants, or other targeting moieties, signal peptides and/or cell penetrating peptides, and targeting moiety linkers are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention in view of Burgess et al. (J of Cell Bio. 1990, 111:2129-2138, cited previously), Bowie et al. (see col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310, cited previously), Pawson et al. (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452, cited previously), Alaoui-lsmaili et al. (see p. 502, right col., 2th paragraph; Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507, cited previously), Guo et al. (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210, cited previously) and Rudikoff et al. (see p. 1979; Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979, cited previously). Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of nucleic acid encoding the anti-Trp6-TDP-43 scAbs comprising variants of recited SEQ ID NOs: 100-101 for VH and VL or with an undefined linker, or the genus of targeting moiety, signal peptide and/or cell penetrating peptide, and the genus of targeting moiety linker. Therefore, the claimed nucleic acid has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163. Response to Amendment On p. 9 of the response, Applicant argues that the rejection is moot in view of amendment to the claims. Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of the claimed genus of nucleic acid comprising a genus of sequences encoding the genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NO: 100-101 for VH and VL and with a linker comprising structurally and functionally undefined 10-25 amino acids or the genus of targeting moiety, signal peptide and/or cell penetrating peptide, and targeting moiety linker because: i. There is no well-established structural and functional relationship or correlation between the claimed genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs: 100-101 that are conservatively substituted sequences thereof or humanized versions thereof for VH and VL and an undefined linker, and the anti-Trp68-TDP-43 scAb comprising SEQ ID NO:100-101 for VH and VL or anti-Trp68-TDP-43 scAb with a specific lysosomal targeting moiety comprising the amino acid sequence of 209, 219 or 259 or encoded by SEQ ID NO: 208, 218 or 258. There is no well-established structural and functional relationship or correlation between the claimed genus of structurally and functionally undefined nucleic acid sequence variants encoding variants of SEQ ID NOs: 100-101 for VH and VL of the broad genus of anti-Trp68-TDP-43 scAbs and the polynucleotides encoding anti-Trp68-TDP-43 scAbs comprising the amino acid sequences of SEQ ID NOs:100 and 101 for VH and VL or the polynucleotides of SEQ ID NO:208, 218 or 258 encoding the anti-Trp68-TDP-43 scAb with a specific lysosomal targeting sequence having the amino acid sequence of SEQ ID NO:209, 219 or 259. It is not known what other common structures and sequences are required by the claimed genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs:100-101 with conservatively substituted sequences for a VH and a VL. It is not known what can or cannot be changed or included within the claimed anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs:100-101 with conservatively substituted sequences for a VH and a VL. The specification provides no sufficient description or information as to what other common structures and sequences are required by the claimed genus of anti-Trp68-TDP-43 scAbs variants comprising variants of recited SEQ ID NOs:100-101 with conservatively substituted sequences for a VH and a VL. The specification fails to teach what other common structures and sequences are required by the claimed genus of nucleic acid sequence encoding variants of SEQ ID NOs: 100-101 for VH and VL and with an undefined linker to the function of anti-Trp68-TDP-43 scAbs comprising SEQ ID NOs: 100-101 for VH and VL or to the function of anti-Trp68-TDP-43 scAbs with a specific lysosomal targeting moiety comprising SEQ ID NO: 209, 219 or 259 or encoded by polynucleotides of SEQ ID NO: 208, 218 or 258. The specification fails to provide sufficient description or information as to what other common structures and sequences are required by the claimed genus of targeting moiety, signal peptide and/or cell penetrating peptide, and targeting moiety linker. The limitation “the lysosomal targeting sequence has an amino acid sequence….” recited in claim 53 encompasses fragments within the recited SEQ ID NO:. The specification provides no structural and functional relationship between fragments within the recited SEQ ID NOs: and the full length sequence of the recited SEQ ID NOs:. It is not known whether any fragments/sequences within the recited SEQ ID NOs: can function as lysosomal targeting. Since the common characteristics/features of other anti-Trp68-TDP-43 scAbs comprising variants of recited SEQ ID NOs: 100-101 for VH and VL or with an undefined linker or other nucleic acids encoding the anti-Trp6-TDP-43 scAbs variants, or other targeting moieties, signal peptides and/or cell penetrating peptides, and targeting moiety linkers are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention in view of Burgess et al. (J of Cell Bio. 1990, 111:2129-2138, cited previously), Bowie et al. (see col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310, cited previously), Pawson et al. (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452, cited previously), Alaoui-lsmaili et al. (see p. 502, right col., 2th paragraph; Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507, cited previously), Guo et al. (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210, cited previously) and Rudikoff et al. (see p. 1979; Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979, cited previously). Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of nucleic acid encoding the anti-Trp6-TDP-43 scAbs comprising variants of recited SEQ ID NOs: 100-101 for VH and VL or with an undefined linker, or the genus of targeting moiety, signal peptide and/or cell penetrating peptide, and the genus of targeting moiety linker. Therefore, the claimed nucleic acid has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163. Accordingly, the rejection of claims 2, 12-14, 16, 19, 23, 26, 30, 48 and 52-61 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained. New Grounds of Rejection Necessitated by the Amendment The following rejections are new grounds of rejections necessitated by the amendment filed on September 18, 2026. Claim Rejections - 35 USC § 112 8. 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. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 23 and 54 are rejected 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 pre-AIA the applicant regards as the invention. Claims 23 and 54 are indefinite because it is unclear what the limitation “the sequence i) encodes the antibody and linker portions of any of SEQ ID NOs: 209, 219 and/or 259, or ii) comprises….SEQ ID NOs: 208, 218 and/or 258” recited in claim 23 means and what sequence the limitation refer to. It is also unclear as to what the limitation “the sequence i) encodes the lysosomal targeting sequences of any of SEQ ID NOs: 209 and/or 219…ii) comprises….SEQ ID NOs: 208, 218 and/or 258” recited in claim 54 means and what sequence the limitation refer to. It is unclear what Applicant intended to include in the scope of the claims. The metes and bounds cannot be determined. A skilled artisan cannot envision what would be included and within the scope of the claims. Thus, the claims are indefinite. Conclusion 9. NO CLAIM IS ALLOWED. 10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. Chang-Yu Wang September 30, 2026 /CHANG-YU WANG/Primary Examiner, Art Unit 1675