DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority Claim
2. The instant application, filed on 25 May, 2023, claims domestic benefit to US provisional application no. 63/346,770, filed on 27 May, 2022.
Status of Application
3. The response filed on 25 May, 2023 has been entered in full. No amendments or withdrawals have been made. Therefore, claims 1-20 are pending and are the subject of this Office Action.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 19 December, 2025 has been considered by the examiner.
Claim Rejections - 35 USC § 112
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.
5. Claims 5-10 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, regards as the invention.
6. In regards to claims 5 and 10, claim 5 recites a therapeutic fusion protein comprising a truncated chlorotoxin, a VH domain of an antibody against CD3, and a VL domain of an antibody against CD3, “wherein a first amino acid linker sequence links the C-terminus of the VH domain to the antibody against CD3 to the N-terminus of the VL domain of the antibody against CD3 and a second amino acid linker sequence links the C-terminus of the truncated form of chlorotoxin to the N-terminus of the VH domain of an antibody against CD3.” As such claim 5 imparts a structural limitation to the fusion protein. However, the instant disclosure and the sequences encompassed in the claims do not convey a fusion protein representative of the claimed structure.
The structure of the instant disclosure (Figure 2A) and further the sequences (SEQ ID NOs: 4 and 5) listed in claim 10 which depends on claim 5 recite a fusion protein wherein a first amino acid linker sequence links the C-terminus of the VH- domain of an antibody against CD3 to the N-terminus of the VL- domain of the antibody against CD3 and a second amino acid linker sequence links the N-terminus of the truncated form of chlorotoxin to the C-terminus of the VL domain of an antibody against CD3 (See Figure 2A) and therefore it is unclear what is the claimed structure of the fusion protein of claims 5 and 10.
For the purposes of further examination, the structure outlined in Figure 2A will be used to interpret the claims.
Claims 6-9 are rejected due to their dependency on claim 5.
7. Claim 8 recites that SEQ ID NO: 3 refers to the VL domain of the antibody against CD3, however SEQ ID NO: 3 is a not a VL domain but a full fusion protein. Claims 9, 14, and 19 recite that SEQ ID NO: 4 refers to the amino acid sequence of the therapeutic fusion protein. SEQ ID NO: 3 and SEQ ID NO: 4 are identical and therefore it is unclear what is the claimed amino acid sequence of the VL domain of claim 8. For the purpose of further examination and in light of Figure 2A of the specification it will be interpreted that SEQ ID NO: 4 refers to the amino acid sequence of the therapeutic fusion protein and SEQ ID NO: 3 will refer to the amino acid sequence of the VL domain: QMTQSPSSL PASLGDRVTI NCQASQDISN YLNWYQQKPG KAPKLLIYYT NKLADGVPSR FSGSGSGRDS SFTISSLESE DIGSYYCQQY YNYPWTFGPG TKLEIKR which was extracted (see Examiner Figure 1, below) using the format of the fusion protein outlined in Figure 2A.
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Examiner Figure 1: Snapshot of the extracted VL domain amino acid sequence.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by the McGonigle et al. (WO 2019055840).
Claim 1 of the instant application refers to a polypeptide of 13-18 amino acid residues comprising a sequence with at least a 75% identity to SEQ ID NO:1. Claim 2 which relies upon claim 1 refers the polypeptide containing the entire sequence SEQ ID NO: 1. McGonigle anticipates these claims by teaching chlorotoxin polypeptide fragments (truncated chlorotoxin) and listing examples of chlorotoxin polypeptide sequences possible (Table 3) one of which the entirety matches SEQ ID NO: 1 of the instant application (SEQ ID NO: 81).
In regards to claim 3 McGonigle teaches that these chlorotoxin polypeptide fragments can be attached to therapeutic agents and the polypeptides bind to glioma cells (pg. 60/61 paragraph 0165 and pg. 177 paragraph 0521). Further in regards to claim 4 McGonigle teaches that it is obvious the attachment of the chlorotoxin polypeptide to the VH domain can occur at either the C-Terminus or the N-Terminus of the polypeptide (pg. 85 paragraph 0239).
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.
9. Claims 5-19 are rejected under 35 U.S.C. 103 as being obvious over McGonigle in view of Stuhler (WO2013104804).
In regards to claim 5-9, 13, and 14 McGonigle suggest the use of a fusion protein composed of a truncated form of chlorotoxin (Table 3, SEQ ID NO: 81 of McGonigle) the VH domain of an antibody and a VL domain of an antibody (pg. 4, paragraph 0013 and pg. 8, paragraph 0015). Further, McGonigle teaches the chlorotoxin polypeptides attachment to the fusion protein through its C terminus (pg. 85, paragraph 0241).
In regards to claim 11-14 McGonigle suggest using a fusion protein as a method to deliver the chlorotoxin polypeptide fragments for the treatment of cancers including glioblastoma (pg. 111 paragraph 0332) and further notes the binding ability and treatment potential of the chlorotoxin polypeptide fragment to glioma (pg.129, Example 8). McGonigle also teaches the truncated chlorotoxin sequence as outlined above.
In regards to claims 15, and 17-19 McGonigle teaches providing a polypeptide which is identical to SEQ ID NO: 1 of the instant application (Table 3, SEQ ID NO: 81 of McGonigle) and an antibody variable fragments (anti-glioma therapeutic agent) and linking them to produce a fusion protein (pg. 111 paragraph 0332), to bind to Neuropilin 1 (NRP1) on many tumor cells (including glioma) (pg. 38 paragraph 0126). Claims 17-19 which depend on claim 15 outline the same properties of a fusion protein taught in McGonigle as outlined above as applied to claims 5 and 10.
In regards to claim 16 McGonigle teaches that it is obvious the attachment of the chlorotoxin polypeptide to the VH domain can occur at either the C-Terminus or the N-Terminus of the polypeptide due to the various methods of blocking the N- of C- on the polypeptide (pg. 53 paragraph 0152).
McGonigle fails to teach a fusion protein comprising an antibody against CD3 and the attachment of the C Terminus of the VH domain to the N Terminus of the VL domain of claim 5, the fusion protein where in the VH domain of the antibody against CD3 comprises SEQ ID NO: 2 of the instant application, as well as a fusion protein wherein the VL of the antibody against CD3 comprises SEQ ID NO: 3 of the instant application of claims 7 and 8. Further McGonigle fails to teach amino acid linkers consisting of a least one glycine residue and at least one serine residue of claim 9, and the full fusion protein sequences of the fusion protein of claims 10, 14, and 19.
Stuhler however, teaches in regards to claim 5, the attachment of the of the C terminus of the VH domain to the N terminus of the VL domain (pg. 20, lines 4-23) and the use of antibodies against CD3 (claim 32).
In regards to claims 7 and 8 Stuhler teaches fusion protein where in the VH domain of the antibody against CD3 comprises SEQ ID NO: 2 (SEQ ID NO: 9 of Stuhler) of the instant application, as well as a fusion protein wherein the VL of the antibody against CD3 comprises SEQ ID NO: 3 (SEQ ID NO: 10 of Stuhler) of the instant application (claim 32).
In regards to claim 9 Stuhler teaches amino acid linkers which contain at glycine and serine residues (pg. 20, lines 26-28).
In regards to claims 10, 14, and 19 Stuhler teaches the VH and VL domains (claim 32) of SEQ ID NOs: 4 and 5 of the instant application, as well as the linkers of these sequences (pg. 20, lines 26-28). Further Stuhler teaches a His tag as an affinity tag and a stabilizing agent (pg. 8, section 8, lines 3-6). Therefore, a person of ordinary skill in the art before the effective filing date would have been able to construct the sequences for the fusion proteins of SEQ ID NOs: 4 and 5 of the instant application.
Thus, McGonigle teaches a fusion protein containing the VH and VL domains of an antibody, and truncated chlorotoxin polypeptide. McGonigle also teaches the attachment of a chlorotoxin polypeptide a method for targeting glioma. Stuhler teaches the sequences claimed for the VH and VL domains of the antibody against CD3 and further teaches all the components necessary to develop the entire fusion protein as claimed including the linkers and histidine tag, and also suggest the use of a fusion protein as a therapeutic composition to treat cancers. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to use the teachings of McGonigle and add the teachings of Stuhler with a reasonable expectation of success to develop a fusion protein using the claimed anti CD3 antibody domains and the truncated chlorotoxin which can target NRP1.
10. Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over McGonigle in view of Stuhler as applied to claim 5 and 10 above, and further in view of Novagen, pET system manual, 11th edition (2006) (hereafter, Novagen) and Engqvist and Nielsen (2015) ANT: Software for Generating and Evaluating Degenerate Codons for Natural and Expanded Genetic Codes ACS Synthetic Biology (4) 935-938 (hereafter, Engqvist).
McGonigle in view of Stuhler fails to teach a plasmid for expressing the therapeutic fusion protein of claim 10, with a plasmid sequence comprising SEQ ID NO:6.
However, SEQ ID NO: 6 when aligned with the commercially available pET11a plasmid aligns at the 358 (through the length of the plasmid) position of the plasmid which correlates with the NdeI restriction enzyme site (See Examiner Figure 2, below). Novagen teaches the method of using the pET-11a construct to create a vector including how to use restriction sites to cleave the plasmid for insertion of foreign DNA (Section C: Vector Preparation).
Novagen does not teach the DNA sequence that correlates to the fusion protein of claim 10 for insertion into pre-designed plasmid, however, Engvist teaches a software which can use the well-established degeneracy of the genetic code to translate amino acid sequences into nucleotide sequences by determining optimal degenerate codons (abstract).
Thus, McGonigle in view of Stuhler teaches the therapeutic fusion protein of claim 10, Novagen teaches the method of using a commercially available plasmid to create a custom vector, and Engvist teaches a software that would enable a person of ordinary skill in the art to translate an amino acid sequence from a protein into a nucleotide sequence using the degeneracy of the genetic code. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the therapeutic fusion protein of McGonigle in view of Stuhler with the plasmid of Novagen and method of determining the genetic sequence of the fusion protein of Engvist with a reasonable expectation of success to create a vector containing the nucleotide sequence that encodes a fusion protein.
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Examiner Figure 2: Snapshot of results of pET-11a and SEQ ID NO: 6 alignment
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
11. Claims 5-14, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, and 4-7 of U.S. Patent No. 10,745,478 (Sirianni of record (IDS 12/19/2025)) in view of McGonigle.
Claims 1, and 4-7 of the issued patent and claims 5-14, and 19 of the instant application both recite claim to a polypeptide composition containing two domains in which the first domain comprises a VH and VL domain of an anti-CD3 antibody and the second domain comprises a chlorotoxin peptide and/or a chlorotoxin-like peptide capable of binding to a neuroectodermal (glioma) cancer cell.
In SEQ ID NO: 9 of the issued patent claim 1 and SEQ ID NOs: 4 and 5 of the instant application claims 10, 14, and 19, refer to identical fusion proteins (it is noted that SEQ ID NO: 4 is identical to SEQ ID NO: 5 with the absence of the histidine tag on the N-terminus). Further the linkers in the issued patent’s fusion protein (SEQ ID NO: 9) contain at least one glycine residue and at least one serine residue as claimed in claim 9 of the instant application.
SEQ ID NO: 3 of claim 6 in the issued patent and SEQ ID NO: 3 of the instant application claim 8 refer to identical VL domains.
SEQ ID NO: 1 of claim 5 in the issued patent and SEQ ID NO: 2 of the instant application claim 7 refer to identical VH domains.
Claims 11 – 14, and 19 of the instant application refer to methods of use of the claimed fusion protein. The method claims do not preclude the compositions.
The issued patent and the instant application differ in the length of the chlorotoxin, with the issued patent having a chlorotoxin polypeptide which exceeds the limits of amino acids claimed in the instant application.
McGonigle, however, teaches of a truncated form of the chlorotoxin polypeptide which is capable to biding to glioma as outlined in the 102 and 103 rejections above. Therefore, a person of ordinary skill in the art in possession of the invention of issued patent before the effectively filed date would find it obvious to use the teachings of McGonigle, to replace the chlorotoxin domain of the issued patent with the truncated form of the chlorotoxin from McGonigle to get the therapeutic fusion protein of claims 5-14, and 19 of the instant application.
Conclusion
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 7am to 4:30pm. The examiner can also be reached on Fridays from 7am to 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.A.A/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647