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 .
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/IB2021/054106 filed 05/13/2021, which claims the benefit of the priority of US Provisional application 63/061,844 filed 08/06/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements submitted on 11/06/2025 has been considered by the examiner.
Election/Restrictions
Claims 16, 20-21, 23-24, 38, 63-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II- IV. Election was made with traverse in the reply filed on 07/15/2025. Applicant’s election without traverse of Group I drawn to a method of chemically producing a protein, in the reply filed on 07/15/2025 is acknowledged.
The traversal is on the grounds that Kent does not teach splitting and co-folding the segments. Examiner notes that the rejection contains a combination of references that render obvious the instant invention. Further, chemical ligation to produce larger proteins is known in the art as shown in the rejection below. The arguments are unpersuasive.
Claim Status
Claims 1, 6, 10, 13, 15-16, 20-21, 23-25, 29, 33, 38, 63-66 are pending. Claims 16, 20-21, 23-24, 38, 63-66 are withdrawn. Claims 1, 6, 10, 13, 15, 25, 29, and 33, are being examined on the merits in this office action.
Claim Rejections - Withdrawn
The rejection of claims 1, 6, 10, 13, 15, 25, 29, and 33 under 35 U.S.C. 103 as being unpatentable over Pech et al. (US20160304926A1 – hereinafter “Zhu”) in view of Kent et al. (US6184344B1 – hereinafter “Kent”) and Cistrone et al. (Curr. Protoc. Chem. Biol. 2019 Jan 15;11(1):e61) is withdrawn in view of the arguments.
Claim Rejections - 35 USC § 102 - New
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.
Claims 1, 6, 10, 13, 25, 29, and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weidmann et al. (Cell Chemical Biology 26, 645–651).
Regarding claim 1, Weidmann teaches utilizing enantiomeric L-nucleotides and D-amino acids rather than the natural components, for the synthesis of a functional DNA-ligase in the D-enantiomeric conformation, which is an exact mirror-image of the natural enzyme (Summary section). Weidmann teaches that homology modeling was performed to predict the structure of the LigA ligase in order to identify positions in the protein sequence that allow for cysteine mutagenesis without disturbing the structure significantly, which may cause a reduction or loss of the DNA-ligase functionality (Page 647, left col., “Results” section 1st paragraph). Weidmann teaches that all fragments were assembled applying the cysteine-based ligation strategy and that an additional desulfurization step was included, converting the cysteine residue to alanine because the native sequence contains an alanine at this position (Page 648, left col., whole paragraph). Examiner notes that this disclosure reads on parts (i) (iii). Weidmann teaches that six peptide fragments were produced and subsequently, the fragments were chemically ligated to yield the complete protein (Page 648, left col., whole paragraph). This reads on part (ii) and part a) and b). Weidmann teaches folding of both the D- and the natural L-form of the E. coli protein DapA (Page 649, left col., line 1-5; Page 652, 3rd paragraph, 7th paragraph). This reads on part c). Weidmann teaches all the steps of the claimed invention anticipating claim 1.
Regarding claim 6, Weidmann teaches that homology modeling was performed to predict the structure of the LigA ligase in order to identify positions in the protein sequence that allow for cysteine mutagenesis without disturbing the structure significantly, which may cause a reduction or loss of the DNA-ligase functionality (Page 647, left col., “Results” section 1st paragraph). Examiner notes that this disclosure reads on part (iii) of identifying structurally lose section-part (d). Weidmann teaches that six peptide fragments were produced and subsequently, the fragments were chemically ligated to yield the complete protein (Page 648, left col., whole paragraph). Examiner notes that this disclosure reads on obtaining a plurality of ligation conducive segments – part (e). Weidmann teaches that all fragments were assembled applying the cysteine-based ligation strategy and that an additional desulfurization step was included, converting the cysteine residue to alanine because the native sequence contains an alanine at this position (Page 648, left col., whole paragraph). Examiner notes that this disclosure reads on part (f). Weidmann teaches chemically synthesizing the peptide segments (page 648, whole left col.,; Page 649, left col., 2nd paragraph, line 1-5). Examiner notes that this disclosure reads on part (g).
Regarding claim 10, Weidmann teaches that the protein produced is 268 amino acids (Fig. 2; Page 647, left col., “Results” section, line 1-4) and further that a truncated version by removing the 16 amino acids from the synthetic enzyme, reducing the total length of the synthetic LigA to 252 amino acids (Page 647, right col., end of 1st paragraph).
Regarding claim 13, Weidmann teaches utilizing enantiomeric L-nucleotides and D-amino acids rather than the natural components, for the synthesis of a functional DNA-ligase in the D-enantiomeric conformation, which is an exact mirror-image of the natural enzyme (Summary section; Title; Fig 2). Examiner further notes that D-amino acids appear to be non-Gly (See Table on Page 652), which anticipates claim 13.
Regarding claim 25, Weidmann teaches utilizing enantiomeric L-nucleotides and D-amino acids rather than the natural components, for the synthesis of a functional DNA-ligase in the D-enantiomeric conformation, which is an exact mirror-image of the natural enzyme (Summary section). Weidmann teaches that homology modeling was performed to predict the structure of the LigA ligase in order to identify positions in the protein sequence that allow for cysteine mutagenesis without disturbing the structure significantly, which may cause a reduction or loss of the DNA-ligase functionality (Page 647, left col., “Results” section 1st paragraph). Examiner notes that this disclosure reads on part (iii) of identifying structurally lose section. Weidmann teaches that six peptide fragments were produced and subsequently, the fragments were chemically ligated to yield the complete protein (Page 648, left col., whole paragraph). Weidmann teaches that all fragments were assembled applying the cysteine-based ligation strategy and that an additional desulfurization step was included, converting the cysteine residue to alanine because the native sequence contains an alanine at this position (Page 648, left col., whole paragraph). Weidmann teaches folding of both the D- and the natural L-form of the E. coli protein DapA (Page 649, left col., line 1-5; Page 652, 3rd paragraph, 7th paragraph). Weidmann discloses on Fig. 2, the six peptide segments which comprises D-amino acids and the segments indicate that at least 90% are non-Gly (Fig. 2 A and B on Page 646). Weidmann teaches all the steps of the claimed invention anticipating claim 25.
Regarding claim 29, Weidmann teaches that homology modeling was performed to predict the structure of the LigA ligase in order to identify positions in the protein sequence that allow for cysteine mutagenesis without disturbing the structure significantly, which may cause a reduction or loss of the DNA-ligase functionality (Page 647, left col., “Results” section 1st paragraph). Examiner notes that this disclosure reads on part (iii) of identifying structurally lose section-part (d). Weidmann teaches that six peptide fragments were produced and subsequently, the fragments were chemically ligated to yield the complete protein (Page 648, left col., whole paragraph). Examiner notes that this disclosure reads on obtaining a plurality of ligation conducive segments – part (e). Weidmann teaches that all fragments were assembled applying the cysteine-based ligation strategy and that an additional desulfurization step was included, converting the cysteine residue to alanine because the native sequence contains an alanine at this position (Page 648, left col., whole paragraph). Examiner notes that this disclosure reads on part (f). Weidmann teaches chemically synthesizing the peptide segments (page 648, whole left col.,; Page 649, left col., 2nd paragraph, line 1-5). Examiner notes that this disclosure reads on part (g). Weidmann discloses on Fig. 2, the six peptide segments which comprises D-amino acids and the segments indicate that at least 90% are non-Gly (Fig. 2 A and B on Page 646).
Regarding claim 33, Weidmann teaches that the protein produced is 268 amino acids (Fig. 2; Page 647, left col., “Results” section, line 1-4) and further that a truncated version by removing the 16 amino acids from the synthetic enzyme, reducing the total length of the synthetic LigA to 252 amino acids (Page 647, right col., end of 1st paragraph).
Claim Rejections - 35 USC § 103 - New
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 15 is rejected under 35 U.S.C. 103 as being unpatentable over Weidmann et al. (Cell Chemical Biology 26, 645–651) as applied to claim 1 above, and further in view of Cistrone et al. (Curr. Protoc. Chem. Biol. 2019 Jan 15;11(1):e61).
The teachings of Weidmann are disclosed above and incorporated herein by reference.
Weidmann teaches amino acid substitutions with D- amino acids but does not teach substituting isoleucine with D-amino acids or with Glycine as recited in claim 15.
Cistrone teaches native chemical ligation of proteins and teaches selecting ligation sites in the target protein, and further teaches ligating from three or more peptide fragments (see paragraph 1-3 in page 2). Cistrone teaches that the target protein is split up into synthetically accessible fragments, and that as the choice of the ligation site defines the polypeptide fragments used in the ligation, a number of considerations must be made with regards to the amino acid sequence, as well as the primary, secondary and tertiary structure of the protein (Page 2, 5th paragraph). Cistrone teaches that amino acids such as isoleucine should be avoided as ligation sites (Page 26, 1st paragraph) and that peptides with glycine tend to react more rapidly (Page 15, part 7). Examiner notes that this reads on substituting isoleucine with other amino acids such as glycine. Cistrone teaches a folding step in the method (Page 3, 2nd paragraph; page 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Weidmann and substitute ile with D-amino acids since Cistrone teaches that amino acids such as isoleucine should be avoided as ligation sites (Page 26, 1st paragraph) and that peptides with glycine tend to react more rapidly (Page 15, part 7). Examiner notes that this reads on substituting isoleucine with other amino acids such as glycine. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in modifying Weidmann with Cistrone and substitute Ile with D-amino acids or an amino acid such as Glycine for efficient ligation. The disclosures render obvious claim 15.
Response to Arguments
Applicant’s arguments, see Applicant Arguments, filed 01/30/2026, with respect to the rejection(s) of claim(s) 1, 6, 10, 13, 15, 25, 29, and 33 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Weidmann et al.
Conclusion
No claims are allowed.
Due to new grounds of rejection, this action in Non-Final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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