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 .
Claims 1-3, 7-14 and 16-27 are pending in the application. Claims 16-18, 20-24 are withdrawn. Claims 1-3, 7-14, 19 and 25-27 are currently under examination.
This office is in response to the amendment filed on 4/2/2026.
All previous rejection not reiterated in this office action are withdrawn.
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.
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.
Claim1-3, 8, 9-14, 19, 25-27 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the claim is indefinite because it is unclear whether limitation in parenthesis is part of the claim limitation. For example, is the OmpT leader sequence limited to SEQ ID NO: 16, or other sequence of OmpT leader fragment(s) or modified OmpT thereof?
Dependent claims 2-3, 8-14, 19, 25-27 are rejected for same reason because they depend on claim 1 but do not remedy the indefiniteness.
Note: For obviousness rejection discussed below, the claim is interpreted as not including the limitation in parenthesis.
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.
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.
Claim(s) 1-3, 9-14, 19, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Corti (cited previously), in view of Yang (Xiamen Daxue Xuebao, 2003, vol.42, no.4, p. 410-415, abstract). This is a new rejection necessitated by amendment.
Corti teaches a conjugation product between TNF and the CNGRC sequence, at the amino-terminal (N-terminus) of TNF through the spacer G (paragraph [0045]), which meets the limitation of protein attached with N terminus peptide SEQ ID NO: 1 (CNGRCG). Corti teaches modification may be made to the peptides to reduce immunogenicity, to increase circulatory half-life, to enhance bioavailability and/or to enhance efficacy and specificity (paragraph [0053]).
However, Corti does not specifically teach a compound X linked to N terminus of the peptide of SEQ ID NO:1, wherein X is (i) a serine, glycine, or alanine, or (ii) a chain of two or three amino acid residues selected from a serine, glycine and/or an alanine, or (iii) an amino acid sequence comprising the IEGR sequence or iv) the OmpT leader sequence or (v) the alpha mating factor secretion signal peptide.
Yang teaches a prokaryotic secretion expression vector, pTO-OT, comprising ompT leader sequence inserted in the MCS of PTO-T7. Yang teaches two foreign genes were cloned into pTO-OT and expressed efficiently in E. coli, and the mature protein showed excellent expression stability, suggesting PTO-OT was a practical vector for genetic engineering (abstract).
It would have been obvious to an ordinary skilled in the art that adding a N-terminus leader such as OmpT leader sequence to the conjugate taught by Corti would improve expression stability of protein in E.coli host based on the teaching from Yang. The ordinary skilled in the art would have been motivated to do so improve expression stability of the conjugates. The ordinary skilled in the art would have reasonable expectation of success to link the peptide to the N terminus of GNGRCG-protein following combined teaching from Corti and Yang. Therefore, the claimed invention of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 2, Corti teaches the conjugate is able to recognize CD13 receptor (paragraph [0047]).
Regarding claim 3 and 25, Corti teaches the protein is TNF (paragraph [0047]), which is a cytokine.
Regarding claim 9 and 10, Corti teach polynucleotide encoding the conjugates, and vectors comprising said polynucleotide (paragraph [0079] and [0081]).
Regarding claim 11, Corti teaches the conjugate may be prepared in the form of liposome (paragraph [0069]).
Regarding claim 12-14, Corti teaches the conjugate may be used with another anti-tumor agent such as doxorubicin and melphalan (paragraph [0072]).
Regarding claim 19, Corti teaches the pharmaceutical composition comprising the conjugates together with pharmaceutically acceptable carrier (paragraph [0063]).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Corti, in view of Yang, as applied to claim 1 above, further in view of Belczyk-Ciesielska et al (cited previously).
The teaching of Corti and Yang has been discussed above. However, neither Corti nor Yang teaches the conjugate contains a site for chemical or enzymatic cleavage of the bond between compound X and the peptide, X-C.
Belczyk-Ciesieska et al. teach the specific peptide bond hydrolysis induced by Ni(ii) ion within two complex His-tagged ZF metalloproteins without compromising the original metal ion binding sites (page 1095, 1st col., 1st paragraph). Belczyk-Ciesieska et al. teaches Ni(ii) induced peptide bond can be applied for the removal of any fusion protein such as affinity tags (page 1095, 2nd col., 1st paragraph).
The ordinary skilled in the art would recognize the leader sequence such as OmpT leader sequence would preferably be removed following protein expression to obtain mature protein for optimal protein activity and/or biological function. The ordinary skilled in the art would recognize that Belczyk-Ciesieska teaches a system for N(ii) induced cleavage of N terminus sequence without loss of functional structure. An ordinary skilled in the art would thus have reasonable expectation of success to add a site for cleavage between the leader sequence taught by Yang and the conjugate of Corti with a site that may be cleaved after protein expression following combined teaching from Corti, Yang and Belczyk-Ciesieska et al. Therefore, the claimed invention of 8 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Corti and Yang, as applied to claims 1 and 12 above, and further in view of Fallon et al (Oncotarget, 2017, vol., 8, no.13, pages 20558-20571).
The teaching from Corti and Yang have been discussed above.
However, neither reference teaches the antitumor agent is anti-PD-L1 antibody.
Fallon teaches that combining an IL-12 and avelumab, an anti-PD-L1 antibody yields a combinatorial benefit in multiple murine tumor models (title). Fallon teaches the combination enhances T cell activation and T cell effector functions within the tumor environment, significantly improving overall tumor regression, and these results should provide the rationale to examine the combination of these agents in clinical studies (abstract).
It would have been obvious to an ordinary skilled in the art that many different cytokines are used in antitumor therapy, including IL-12, TNF, IL-1…among others (Corti, paragraph [0002]). Even conjugates of TNF was used as an example, it would have been obvious that the invention also encompasses other cytokines conjugates such as IL-12 (paragraph 0062]). The ordinary skilled in the art reading Fallon would recognize that combination of IL-12 and anti-PD-L1 antibody would result in more effective antitumor treatment in animal model and worth exploring in clinical studies. The ordinary skilled in the art would thus be motivated to combine a conjugate of IL-12 with the peptide CNGRCG with anti-PD-L1 to further study such combination in clinical studies. Therefore, the claimed invention of claim 27 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Allowable Subject Matter
Claims 7 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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