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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/5/2025 has been entered.
Claim Status
Claims 1-9, 11-15, and 20 are pending.
Claims 10 and 16-19 is cancelled.
The elected species of L-glutamate N-carboxyanhydride dated 11/10/2021 is still valid. According to the previous office action dated 10/30/2024, claim 2 is interpreted as a linear homopolymer of L-glutamate in consistent with the species election. Any peptide sequences NOT homopolymer of L-glutamate will be withdrawn in compliance with RCE filing. Thus, claims 4, 6, and 8 are withdrawn as being directed to a non-elected species.
Claims 1 and 11-15 are withdrawn as being directed to a non-elected compound invention, the election having been made on 11/10/2021.
Claims 2-3, 5, 7, 9, and 20 have been examined.
Priority
This application is a 371 of PCT/KR2018/008328 filed on 07/24/2018, which claim foreign priority of REPUBLIC OF KOREA10-2017-0093530 filed on 07/24/2017.
Claim Objections
Claims 5 and 20 objected to because of the following informalities:. Appropriate correction is required.
Claims 5 and 20 are improper Markush group because the phrase “… selected from a group consisting of …” in claim 5 (line 2) and in claim 20 (line 3-4) should be “selected from the group consisting of”.
Furthermore, the examiner suggest applicant to amend claim 20 as follow.
The method of claim 2, wherein in Chemical Formula 2, a hydrogen atom of each of the alkyl group, the cycloalkyl group, the aryl group and the cycloalkenyl group and optionally substituted the group consisting of an ether group, a carbonyl group, an alkenyl group, an allyl group, a halogen atom, a hydroxy group, a phenyl group, and a cyano group.
Modified Rejection
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.
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.
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.
Claims 2-3, 5, 7, 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (J. Am. Chem. Soc. 2012, 134, 9163−9171, previously cited 1/10/2022) in view of Fevre et al. (Polym. Chem. 2013; (4):1995-2003, previously cited 1/10/2022), Cheng et al. (Top Curr Chem. 2012:310:1-26) and evidenced by (i) De Greef et al. (Chem. Rev. 2009; 109: 5687–5754) and (ii) Deming et al. (Chem. Rev. 2016, 116, 786−808).
Claim 2 is drawn to a method for producing a linear polypeptide comprising:
preparing a mixture of an α-amino acid N-carboxyanhydride and an organic solvent in an oxygen-removed and dried reaction vessel;
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adding an a hexylamine compound to the reaction vessel;
adding an anhydrous catalyst represented by a following Chemical Formula 2 to the reaction vessel;
reacting the α-amino acid N-carboxyanhydride with the anhydrous catalyst in an anhydrous reaction to produce a linear polypeptide; and
wherein the linear polypeptide produced using the method has a polydispersity index (PDI) of 1.5 or lower.
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Guo et al. teach a method for producing a compound of polymerizing α-amino acid N-carboxyanhydride using N-heterocyclic carbene of NHC 1 or a functional equivalent analogue as a catalyst for ring open polymerization of amino acids (reading on α-amino acid N-carboxyanhydride) in an anhydrous reaction shown as follows (p9164, scheme 1) to produce linear polymer by end-capping with electrophiles (e.g., acetyl chloride) (p9170, col 2, line 1-3). Guo et al. further show the method has a polydispersity index (PDI) of 1.5 or lower (pS4, Table S1; pS5, Table S2).
Guo et al. teach the polymerization reaction is performed under a nitrogen atmosphere before isolation of the polymer (p9165, col 1, last para; S2, Experimental details, para 1), but do not teach the use of N-heterocyclic carbene with a pharmaceutical sat of HCO3-.
Similarly, Fevre et al. teach NHCs are relative instable when exposed to air makes them difficult to handle. As a consequence, NHCs must often be stored and manipulated under dry and inert conditions. Fevre et al. teach a general strategy to circumvent this limitation is to convert the NHC into a masked form, the in situ generation of the free NHC being generally achieved by
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thermal activation (p1995, col 2, para 2). Fevre et al. teach [NHC(H)][HCO3-] pre-catalysts (p1998, Fig 1) are air-stable and easily accessible via a one-step undemanding process (p2002, col 1, Conclusion). Fevre et al. further teach all experiments were performed under an inert atmosphere using standard Schlenk techniques. Dry, oxygen-free solvents and reagents were employed (p1996, col 1, Materials). Because Fevre et al. teach beneficial use of a stable and easily accessible [NHC(H)][HCO3-] pre-catalyst to substitute Guo’s air-sensitive NHC catalysts for ring-opening polymerisations, one of ordinary skill in the art would have found it obvious to prepare the reactants of mixed α-amino acid N-carboxyanhydride and an organic solvent in an oxygen-removed and dried reaction vessel for conducting the polymerization reaction according to Guo’s scheme 1 shown above.
Guo et al. in view of Fevre et al. did not specify adding a hexylamine compound to the reaction of Ring-Opening Polymerization of α-Amino Acid N-Carboxyanhydrides.
Cheng et al. teach Synthesis of Polypeptides by Ring-Opening Polymerization of α-Amino Acid N-Carboxyanhydrides (Title). Cheng et al. teach beneficially adding n-hexylamine initiator to polymerization solvents for ring-open polymerization of γ-benzyl-L-glutamate NCA (p3, 2nd last para) shown as follows (p5, scheme 2).
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De Greef et al. is cited to show common knowledge of adding a small amount of initiator lowering the value of polydispersity index (p5694, Col 2, para 1) by preventing monomers from reacting with each other (p5716, col 2, para 1) known in the art. Consistently, Deming is further cited to show polymerization of side chain modified L-glutamate NCA in the presence of an initiator to generate a homopolymer with polydispersity index of 1.05 (p792, col 2, para 2) known in the art.
With respect to the limitation (i), Guo et al. teach the polymerization in a polar solvent of DMSO or DMF without water for synthesis a polymer of low molecular weight (p9170, col 2, line 8). Guo et al. show polymerization of an α-amino acid N-carboxyanhydride in an organic solvent with an N-Heterocyclic carbene (NHC) as a catalyst (p9164, scheme 1). Guo et al. teach the polymerization reaction is performed under a nitrogen atmosphere before isolation of the polymer (p9165, col 1, last para; S2, Experimental details, para 1). Similarly, Fevre et al. teach all experiments were performed under an inert atmosphere using standard Schlenk techniques. Dry, oxygen-free solvents and reagents were employed (p1996, col 1, Materials).
With respect to the limitation (ii), Cheng et al. teach adding n-hexylamine initiator to polymerization solvents for polymerization of γ-benzyl-L-glutamate NCA (p3, 2nd last para) shown in scheme 2 (p5). De Greef et al. teach the addition of a small amount of initiator lowering the value of polydispersity index to a value of 1.5 (p5694, Col 2, para 1) by preventing monomers from reacting with each other (p5716, col 2, para 1). Consistently, Deming et al. teach polymerization of side chain modified L-glutamate NCA in the presence of an initiator to generate a homopolymer with polydispersity index of 1.05 (p792, col 2, para 2).
With respect to the limitation (iii), Guo et al. show addition of N-heterocyclic carbene of NHC 1 or a functional equivalent analogue as a catalyst for ring open polymerization of amino
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acids to produce a linear peptide (p9164, scheme 1). Fevre et al. teach beneficial use of air-stable and easily accessible [NHC(H)][HCO3-] pre-catalysts (p1998, Fig 1) converted to active catalyst by the thermal activation (p1995, col 2, para 2; p2002, col 1, Conclusion).
With respect to the limitation (iv), Guo et al. in view of Fevre et al. teach addition of [NHC(H)][HCO3-] pre-catalysts for ring open polymerization of amino acids to produce a linear peptide (p9164, scheme 1) in organic solvent ,such as DMF, under a nitrogen atmosphere and anhydrous condition (See Guo et al. p9164, scheme 1; p9170, col 2, line 8).
With respect to the limitation (v), Guo et al. further show the method has a polydispersity index (PDI) of 1.5 or lower (pS4, Table S1; pS5, Table S2). De Greef et al. teach the addition of a small amount of initiator lowering the value of polydispersity index to a value of 1.5 (p5694, Col 2, para 1) by preventing monomers from reacting with each other (p5716, col 2, para 1). Consistently, Deming et al. teach polymerization of side chain modified L-glutamate NCA in the presence of an initiator to generate a homopolymer with polydispersity index of 1.05 (p792, col 2, para 2).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to modify Guo’s method for producing a compound of polymerizing α-amino acid N-carboxyanhydride with Fevre’s pre-catalysts for ring open polymerization of amino acids to produce a linear peptide because (a) Guo et al. teach polymerizing α-amino acid N-carboxyanhydride using N-heterocyclic carbene and (b) Fevre et al. teach beneficial use of a stable and easily accessible [NHC(H)][HCO3-] pre-catalyst to substitute Guo’s air-sensitive NHC catalysts for ring-opening polymerisations (p2002, col 1, Conclusion). The modification would have reasonable expectation of success because Fevre’s [NHC(H)][HCO3-] pre-catalyst can become the active catalyst by thermal activation (p1995, col 2, para 2).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Guo et al. in view of Fevre et al. with (ii) Cheng et al. because (a) Guo et al. in view of Fevre et al. teach ring-opening polymerization of α-amino acid N-carboxyanhydrides and (b) Cheng et al. teach beneficially adding n-hexylamine initiator to polymerization solvents for polymerization of γ-benzyl-L-glutamate NCA (p3, 2nd last para) shown by Scheme 2 (p5). The combination would have reasonable expectation of success because all references teach ring-opening polymerization of α-amino acid N-carboxyanhydrides. De Greef et al. is cited to show common knowledge of adding a small amount of initiator lowering the value of polydispersity index (p5694, Col 2, para 1) by preventing monomers from reacting with each other (p5716, col 2, para 1) known in the art. Consistently, Deming is further cited to show polymerization of side chain modified L-glutamate NCA in the presence of an initiator to generate a homopolymer with polydispersity index of 1.05 (p792, col 2, para 2) known in the art.
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With respect to claims 3 and 20, Fevre et al. show the air-stable and easily accessible [NHC(H)][HCO3-] pre-catalyst of compound 4a shown as follows, reading on the limitation and elected species of claim 3 (p1998, Fig 1) and a hydrogen atom of each of the alkyl group of claim 20.
With respect to claim 5, Guo et al. teach the synthesized product is poly(N-butyl glycine) (p9164, col 2, Results and Discussion, line 3), reading on L-glycine N-carboxyanhydride for polymerization of a liner peptide. Cheng et al. teach adding n-hexylamine initiator to polymerization solvents for polymerization of γ-benzyl-L-glutamate NCA (p3, 2nd last para) shown in scheme 2 (p5), reading on the elected species of L- glutamate N-carboxyanhydride.
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With respect to claim 7, Guo et al. teach the polymerization reaction is in an inert N2 atmosphere (pS12, Table S6).
With respect to claim 9, Guo et al. teach the reaction time of polymerization is within 100 minutes shown as follows (p9165, Fig 1).
Applicant’s Argument
None of the cited references teach adding hexylamine compound to the reaction (Remarks, p12. Obviousness Rejection to p15)
Response to Arguments
Applicant's arguments filed 9/5/2025 have been fully considered but they are not persuasive because the arguments do not apply to the modified rejection based on Guo et al. (J. Am. Chem. Soc. 2012, 134, 9163−9171, previously cited 1/10/2022) in view of Fevre et al. (Polym. Chem. 2013; (4):1995-2003), Cheng et al. (Top Curr Chem. 2012:310:1-26) and evidenced by (i) De Greef et al. (Chem. Rev. 2009; 109: 5687–5754) and (ii) Deming et al. (Chem. Rev. 2016, 116, 786−808). In particular, Cheng et al. teach beneficially adding n-hexylamine initiator to polymerization solvents for polymerization of γ-benzyl-L-glutamate NCA (p3, 2nd last para) shown in scheme 2 (p5). De Greef et al. is cited to show common knowledge of adding a small amount of initiator lowering the value of polydispersity index (p5694, Col 2, para 1) by preventing monomers from reacting with each other (p5716, col 2, para 1) known in the art. Consistently, Deming is further cited to show polymerization of side chain modified L-glutamate NCA in the presence of an initiator to generate a homopolymer with polydispersity index of 1.05 (p792, col 2, para 2) known in the art.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
03-January-2026
/LI N KOMATSU/Primary Examiner, Art Unit 1658