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 .
Claim Status
Claim listing filed on November 20, 2025 is pending. Claim 1 is cancelled. Claims 2-10, 12-13, 15-18, and 20 are amended. Claims 21-25 are new. Claims 2-25 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on October 28, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claim 1 has rendered all previous rejections directed to this claim moot.
Applicant’s amendments to the specification and claims overcome all objections of record, and the specification objections and the claim objections are withdrawn.
The rejection of claims 6-8 and 16-18 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments.
Nucleotide and/or Amino Acid Sequence Disclosures (Maintained)
The sequence listing objection of record is maintained. In the remarks filed 11/20/2025, Applicant states that SEQ ID NO: 55 was added in the amended sequence listing; however, the amended sequence listing filed 11/20/2025 does not include SEQ ID NO: 55 (as pictured below). Appropriate correction is required.
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Solely to expedite prosecution, this Final rejection is being issued despite failure to comply with the sequence rules as set forth in the previous Office Action and reiterated above.
In response to this Final Action, Applicant is REQUIRED to fully comply with the sequence rules. Failure to do so will be considered a non-responsive reply.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claim 10 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 maintained.
Claim 10 is indefinite because wherein Z is “one or more amino acids of the original IL-10 sequence in continuity with the preceding amino acids on its C-terminal side” conflicts with what is defined in the specification. From SEQ ID NO: 1, the amino acid residues between SEQ ID NOs: 65 and 66 are MTMNNGGLDYLP. The specification defines that X may represent M, MT, MTM, or MTMN (page 9, paragraph 2) which is consistent with the section of SEQ ID NO: 1 between SEQ ID NOs: 65 and 66. However, the specification defines that Z may be LP, PEFA, or ELA (page 9, paragraph 3) wherein PEFA and ELA are not consistent with the section of SEQ ID NO: 1 between SEQ ID NOs: 65 and 66. Therefore, what is encompassed by the limitation wherein Z is “one or more amino acids of the original IL-10 sequence in continuity with the preceding amino acids on its C-terminal side” is unclear. Note, amino acid mutations that accommodate peptide linkers are understood in the art and often comprise lysine or cysteine residues (Gauthier et al. Chem. Commun., 2008; Abstract and section 2.2).
Applicant's arguments filed November 20, 2025 have been fully considered but they are not persuasive. Applicant argues that there is no inconsistency between the structural formula and the definitions of X and Z, because the claim expressly defines SEQ ID NOs: 65 and 66 as separated by X-(NtCt)-Z, wherein (NtCt) is a peptide linker. However, Examiner maintains that based on the amino acid residues between SEQ ID NOs: 65 and 66 (MTMNNGGLDYLP) and the definition of Z in Claim 10, Examiner would expect Z to consist of LP, YLP, DYLP, etc. However, the specification defines that Z may be PEFA or ELA (page 9, paragraph 3) wherein PEFA and ELA are not consistent with the C-terminal of MTMNNGGLDYLP. Because the definition of Z in Claim 10 and the definition of Z in the specification conflict, the metes and bounds of what amino acid residues are encompassed by Z are unclear. The rejection is maintained.
Claim Rejections - 35 USC § 112 (Modified, necessitated by amendment)
The rejection of Claims 2-25 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. 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Note, the original 112(a) rejection applied to Claims 1, 3, 5-6, 8-13, and 15-18 and now applies to Claims 2-25 due to Applicant’s amendments. Specifically, Examiner had on the record in the non-final office action filed 08/20/2025 (page 12) that Claims 2, 4, 14, and 19-20 were interpreted as a wild-type CSF1 monomer, a wild-type IL-10 monomer, and a single-chain dimeric IL-10 species known in the art prior to filing, because no amino acid mutations or variants were claimed. However, Applicant has applied a broader claim interpretation to Claims 2, 4, 14, and 19-20, because the amended dependent claims now recite wherein the CSF1 monomer, IL-10 monomer, and IL-10 dimer can all be mutant variations (Claims 3, 7-8, 12-13, 15, and 21-25). Therefore, in light of Applicant’s claim amendments, Examiner interprets that the CSF1 monomer, IL-10 monomer, and single-chain dimeric IL-10 defined in Claims 2 and 4 can broadly comprise wild-type proteins or any mutated variant thereof. If this interpretation is incorrect, then the claims would be subject to a potential rejection under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends or for failing to include all the limitations of the claim upon which it depends (MPEP § 608.01(n).III).
The claims encompass a genus of single chain polypeptides that can comprise any mutant variant of IL-10 linked to any mutant variant of CSF1. The single chain polypeptide of Claim 2 can comprise at least 85% or 95% sequence identity to one of SEQ ID NOs: 24-26 (Claims 3 and 21). The single chain polypeptide of Claim 4 can comprise at least 85% or 95% identity to SEQ ID NOs: 14, 16-19, 1, or 21-22 (Claims 15 and 25). The CSF1 monomer can comprise at least 85% or 95% identity to SEQ ID NOs: 9 or 10 (Claims 8 and 22). The single chain dimeric IL-10 can comprise at least 85% or 95% identity to SEQ ID NOs:1-5 (Claims 12-13 and 23-24). Claim 10 is directed to a single chain dimeric IL-10 comprising SEQ ID NO: 65-X-(NtCt)-Z-SEQ ID NO: 66 wherein SEQ ID NO: 65-X-(NtCt)-Z-SEQ ID NO: 66 itself is directed to a genus of possible dimeric IL-10 polypeptides. When the CSF1 monomer is defined as a wild-type CSF1 monomer (Claim 5), the IL-10 domain can still comprise any mutant variant. Further, the genus of claimed single chain polypeptides are required to maintain IL-10 and CSF1 activities (Claims 2 and 4) and have anti-inflammatory therapeutic effect (Claim 18).
Note, Claims 15 and 25 recite wherein the single chain polypeptide comprises SEQ ID NO: 1 and retains CSF1 activities; however, SEQ ID NO: 1 comprises Foldikine 10 but does not comprise CSF1 (page 42), and nothing in the specification or the art teaches that SEQ ID NO: 1 has CSF1 activity on its own.
Applicant's arguments filed November 20, 2025 have been fully considered but they are not persuasive. Applicant argues that amending “at least 80% identity” to “at least 85% identity” reduces the possible variability in the referred sequences. While the amendment decreases the amino acid variability encompassed by the claims, there is still substantial variation encompassed by “at least 85% identity.” For example, at least 85% identity to SEQ ID NO: 24 (Claim 3) means that any combination of 50 amino acid residues could be inserted, deleted, or substituted with any other conservative or non-conservative amino acid (15% of 337 amino acids). Further, at least 95% identity to SEQ ID NO: 24 (Claim 21) means that any combination of 16 amino acid residues could be inserted, deleted, or substituted with any other conservative or non-conservative amino acid (5% of 337 amino acids). The claims are still directed to a genus of single chain polypeptides that comprises millions of variants. How can 16 amino acid substitutions be made in the IL-10 monomer wherein IL-10 activity is still maintained? The specification provides no guidance or structure-to-function attributes for the genus of amino acid mutations claimed.
Applicant argues that the specification provides (i) full-length sequences; (ii) functional assay data; and (iii) explicit guidance for constructing and screening permitted variants. Applicant further argues that the specification discloses more than a representative number of species across both structural classes, demonstrating possession of the claims. Examiner maintains that the specification teaches specific species of CSF1-IL-10 fusion polypeptides comprising SEQ ID NOs: 24-26, 9-10, 1-5, 14, 16-19, 21-22 and SEQ ID NO: 12 with select CSF1 mutations (Tables 4-6) and dimeric IL-10 orientations (Tables 7-9). However, the examples provided in the specification do not adequately represent the genus of polypeptides claimed that comprises substantial variation. In Table 4, twenty-three CSF1 single point mutations are evaluated, but Claim 3 encompasses up to 50 CSF1 mutations in combination. Assuming 50 CSF1 amino acid residues were substituted at positions held constant, the genus would comprise 2050 ≈ 1064 possible variants. However, the instantly claimed genus is even broader because the positions are not held constant and the mutated residues can comprise any combination of positions. Twenty-three CSF1 single mutations does not provide adequate written description for a genus of CSF1 variants comprising well over a billion possibilities, and this analysis is only considering variation in half of the claimed polypeptide (the CSF1 domain and not the IL-10 domain). Therefore, the rejection is maintained. Examiner recommends directing the claims to the specific sequences and mutations evaluated in the specification to overcome the written description rejection.
Claims 2-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific species of polypeptides comprising SEQ ID NOs: 24-26, 9-10, 12, 1-5, 14, 16-19, and/or 21-22, does not reasonably provide enablement for the genus of polypeptides encompassed by the claims, specifically comprising 85% or 95% identity to different amino acid sequences. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. As stated above, the original 112(a) rejection applied to Claims 1, 3, 5-6, 8-13, and 15-18 and now applies to Claims 2-25 due to Applicant’s amendments.
Note, “treating” as recited in Claim 18 is not defined in the specification and is interpreted as alleviating the symptoms or complications of an established disease, delaying the progression of an established disease, and/or curing or eliminating an established disease.
The undue breadth of the claims and the lack of adequate guidance from the specification are both outlined in the written description record above and of record in the non-final office action filed 08/20/2025. One wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the single chain polypeptide variants encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims. Further, given that the nature of the claims is in vivo treatment (Claim 18), a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of treating inflammatory diseases by administering a representative number of IL-10-CSF1 fusion polypeptides in order to demonstrate the invention could be used with a reasonable expectation of success.
Applicant's arguments filed November 20, 2025 have been fully considered but they are not persuasive. Applicant argues that that the rejection of record is overcome by amending “at least 80% identity” to “at least 85% identity.” Applicant further argues that the specification teaches how to make and use the claimed polypeptides, provides working examples and functional assays, and instructs how to screen permissible variants which satisfies the Wands factors. The variants taught by the specification (CSF1 mutations - Tables 4-6 and dimeric IL-10 orientations - Tables 7-9) do not provide enablement for the genus of IL-10-CSF1 fusion proteins claimed that broadly encompasses well over a billion variants. Undue experimentation would be required by one of ordinary skill to make a representative number of IL-10-CSF1 fusion proteins, determine their functional characteristics, and use them in methods of treating inflammatory diseases in order for the invention to be used with a reasonable expectation of success. Therefore, the Wands factors are not satisfied, and the rejection is maintained.
Conclusion
No claim is 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 SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675