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, 2, 8-12, 21, 24-27, 29, 30, 33-35, 37 and 45 are pending in the application.
Claims 30, 33-35 and 27 are withdrawn. Claims 1, 2, 8-12, 21, 24-27, 29 and 45 are currently under examination.
This office action is in response to the amendment filed on 11/10/2025.
All previous rejection not reiterated in this office action are withdrawn.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.
Claims 1, 2, 8-12, 21, 24-27 and 29 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 recitation of “a first peptide selected from an amino acid sequence having at least 80% identity to SEQ ID NO: 12, 10, 11 or 13 and a second peptide selected from an amino acid sequence having at least 80% identity to SEQ ID NO: 12, 10, 11 or 13” renders the claim indefinite because when the sequences are recited in alternative, there would not be any selections.
Regarding claim 2, the term “heterologous amino acids” renders the claim indefinite because it is unclear what such amino acids are heterologous to. In other words, it is unclear how to determine an amino acid in a given sequence meets the limitation of being “heterologous.”
Dependent claims 2, 8-12, 21, 24-27 and 29 are rejected for same reason because they depend on claim 1 and claim 2 and does not remedy the indefiniteness.
Response to Arguments
In response to the rejection, Applicant argues that a person of ordinary skilled in the art would recognize that the recitation of the first peptide and the second peptide in the alternative defines the metes and bounds of the claims because it requires the first and second peptide must have amino acid sequence with recited identity to any one of SEQ ID NO: 10, 11, 12 or 13.
The above argument is not persuasive because the claim recites “a first peptide selected from …SEQ ID NO: 10, 11, 12, or 13,” not a first peptide being anyone of SEQ ID NO: 10, 11, 12 or 13. In order to make a selection, the must be choices among a group of sequences, not just a single sequence. It would be remedial to delete the “selected from.”
In response to the term “heterologous,” Applicant argues that a person of ordinary skill would recognize that the recitation of “heterologous amino acids” defines metes and bounds of the claims even this term caused metes and bounds of the claims to not be readily recognizable. Applicant states that the specification defines heterologous amino acids as referring to amino acids that are not normally or naturally found flanking the sequence depicted at SEQ ID NO: 1-31 (paragraph 0052). The specification discloses an example of a CRM protein at paragraph 0037, and the skilled person can readily determine if a multimer of claim 1 incudes one or more heterologous amino acids at the amino terminal end, the carboxyl terminal end or both.
The above argument has been considered but not persuasive. Claim 1 recites a multimer without specifying whether it is derived from TT and/or CRM as described in paragraph [0037]. Paragraph [0052] states “heterologous amino acids” refers to amino acids that are not normally or naturally found flanking the sequences depicted at, for instance, SEQ ID NO: 1-31. However, this is not a limiting definition for “heterologous amino acids” because claim 1 claims an amino acid sequence having at least 80% identity to SEQ ID NO: 10, 11, 12 or 13. As such, it is unclear how to determine whether an amino acid is heterologous to claimed sequences because a natural occurring amino acid would have same structure with a synthetic or recombinantly made amino acid. As such, the metes and bounds of the claim cannot be established.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1, 2, 8, 11, 12, 27 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsybovsky (WO2020061564, IDS). This rejection is rewritten to address the amendment.
Claim 1 is drawn to a multimer comprising a first peptide selected from an animo acid sequence having 80% identity to SEQ ID NO: 10, 11, 12 or 13 and a second peptide selected an animo acid sequence having 80% identity to SEQ ID NO: 10, 11, 12 or 13. The specification teaches SEQ ID NO: 10-13 are fragments of CRM197 having sequence of SEQ ID NO: 2 (page 7, last paragraph-page 8). As such, the prior art known CRM197 anticipates the claimed multimer because it comprises SEQ ID NO: 10, 11, 12 and 13, and they are covalently joined by peptide bond, and meets the limitation of being adjacent to each other because adjacent encompasses both “next to” or “being near.”
Tsybovsky teaches self-assembling protein nanoparticle subunit that comprises fusion of an antigen and a heterologous carrier proteins (page 18, line 10-11). Tsybovsky teaches the heterologous carrier protein may be CRM197, or a sequence having 90% identical to said CRM197 sequence as set forth in SEQ ID NO: 66 (page 34, line 9-12, page 37, SEQ ID NO:66). Tsybovsky further teaches that the CRM197 protein may comprise amino acid substitutions to remove one or more N-linked glycosylation sites, such as the one disclosed in SEQ ID NO: 67, or an amino acid sequence having at least 90% homology to said SEQ ID NO: 67 (page 38, lines 1-10). Therefore, the teaching from Tsybovsky anticipates the multimer as claimed in claim 1.
Regarding claim 2, since SEQ ID NO: 10-13 are not consecutive CRM197 sequences, any sequence in between is considered to meet the limitation of a spacer. Since the specification does not give a limiting definition to what is considered “heterologous amino acids,” the variation of sequences 90% identical to SEQ ID NO: 66, and/or SEQ ID NO:67 meets the spacer limitation because it comprises at least two heterologous amino acids.
Regarding claim 8, since the claim does not recite which enzyme is cleaving the spacer sequence, the CRM197 sequence in between the fragments meets this limitation because they can be cleaved by proteases.
Regarding claim 11, Tsybovsky further teaches heterologous T cell helper epitope is included in the fusion at any location (page 44, lines 25-29).
Regarding claim 12, Tsybovsky teaches the T cell helper epitope is SEQ ID NO: 240 (which has C at N terminal end), and SEQ ID NO: 241 (which has V at C terminal end) (page 44, lines 19 and 20).
Regarding claim 27, Tsybovsky teaches the fusion protein comprising the carrier protein is formulated in pharmaceutically acceptable carrier (page 100, lines 20-27).
Regarding claim 29, Tsybovsky teaches the pharmaceutical composition may further comprise and adjuvant (page 101, lines 10-18).
Claim(s) 1, 21, 24 and 25 is/are rejected under 35 U.S.C. 102(a2)as being anticipated by Kamboji (The Journal of Infectious Disease, 2003, Vol.187, No.10, pages 1629-1638).
Kamboji teaches a vaccine conjugate that comprises capsular polysaccharide (CP) from S. pneumoniae serotypes 6B, 4, 9V, 14, 18, 19F and 23F covalently linked to CRM197. Since CRM197 meets the limitation of multimer claimed in claim 1 (see discussion above), the disclosure from Kamboji anticipates the invention of claims 1, 21, 24 and 25.
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, 2, 8, 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsybovsky, in view of Lucke (Biomaterials, 2018, Vol.172, pages 105-115).
The teaching from Tsybovsky has been discussed above. Tsybovsky further teaches various linkers that links the carrier protein including CRM197 (page 39, lines 13-26). Tsybovsky also teaches the self-assembled nanoparticles will include multiple copies of carrier protein, for example SEQ ID NO: 248 (page 53, last line), and SEQ ID NO: 253 (page 44, last line).
However, Tsybovsky does not teach a spacer comprises cathepsin-sensitive sequence.
Lucke teaches a conjugate vaccine that comprises antigenic peptide conjugated to silk spider protein particle through a cathepsin-sensitive sequence (page 112, bridging paragraph of 1st col. and 2nd col). Lucke teaches the particles with cathepsin-sensitive cleavable sequence induced strongest priming of antigen-specific T cells (page 112, 2nd col., 1st paragraph, last 4 lines).
It would have been obvious to an ordinary skilled in the art to use the cathepsin-sensitive cleavable sequence linker for the vaccine conjugate taught by Tsybovsky based on the teaching from Lucke. The ordinary skilled in the art would be motivated to use said cathepsin sensitive sequence as linker/spacer because Lucke teaches conjugates with said linker induced strong priming of antigen specific T cells. The ordinary skilled in the art would have reasonable expectation of success to introduce the linker between carrier protein taught by Tsbovsky following combined teaching from Tsybovsky and Lucke. Therefore, the claimed invention of claims 1, 2, 8 and 9 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 1, 2, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsybovsky, in view of Kwon (Molecular Pharmaceuticals, 2005, Vol.1, no.2, pages 83-91).
The teaching from Tsybovsky has been discussed above. However, Tsybovsky does not teach the linker/spacer being acid labile.
Kwon teach an acid labile linker, linker2, which is used in conjugated vaccine for controlled release in lysosome to cytoplasm (page 88, 2nd col., 3rd paragraph).
It would have been obvious to an ordinary skilled in the art that the use the acid labile linker for the vaccine conjugate taught by Tsybovsky based on the teaching from Kwon. The ordinary skilled in the art would be motivated to use said acid labile linker/spacer because Kwon teaches vaccine conjugates with said linker produce controlled release of the antigen in lysosome. The ordinary skilled in the art would have reasonable expectation of success to introduce the linker between carrier protein taught by Tsybovsky following combined teaching from Tsybovsky and Kwon. Therefore, the claimed invention of claims 1, 2 and 10 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 1, 21 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Passwell (Infection and Immunity, 2001, Vol.69, No.3, pages 1351-1357), in view of Tontini (Vaccine 2016, vol.34, pages 4235-4242).
Passwell teaches Shigella flexneri serotype 2a LPS is conjugated with corynebacterium diphtheriae toxin CRM9 and elicited high IgG, IgM and IgA in serum following injection (Table 2, page 1353).
Tontini teaches there are five carrier proteins in licensed in glycoconjugate vaccines, including CRM197, which has been extensively used as carrier for licensed conjugate vaccine for Hib, S. pneumoniae and Neisseria meningitidis and other vaccines in clinical development (page 4235, 1st col., 3rd paragraph).
It would have been obvious to an ordinary skilled in the art to make a conjugate vaccine against Shegella flexneri 2a LPS using CRM197 as carrier protein based on combined teaching from Passwell and Tontini. The ordinary skilled in the art would be motivated to replace the CRM9 from the conjugate vaccine taught by Passwell with CRM197 because it is extensively used and a licensed carrier for conjugate vaccine. There would have been reasonable expectation of success to conjugate CP from Shigella flexneri 2a with CRM197 following combined teaching of Passwell and Tontini. Therefore, the claimed invention of claims 1 and 21 and 26 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Response to Arguments
In response to the rejection, Applicant argues that Tsybovsky and Kamboji do not teach the peptides of SEQ ID NO: 10-13 are adjacent and covalently joined.
This argument is not persuasive for reason discussed in above rewritten rejection. Briefly, the peptide bond meets the limitation of covalent bond, so that the peptides of SEQ ID NO: 10-13 are covalently joined. The word “adjacent” is not limited to next to each other, but also encompasses near each other. This is further evidenced by claim 2, which claims there is linker between 1st and 2nd peptide. Since the specification does not set a limiting definition for how far the peptide needs to be next to each other, the CRM197 taught by both Tsybovsky and Kamboji meets the claim limitation. Therefore, the above rejections are still considered proper and thus maintained.
Allowable Subject Matter
Claim 45 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
THIS ACTION IS MADE FINAL. 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