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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claim 1 and the following species: leucine as the P2’ amino acid in claim 36, leucine as the P2’’ amino acid in claim 37, nanobody as the antibody or functional fragment in claim 46 and therapeutic agent, specifically, MMAE for claims 47-50 in the reply filed on 03/20/2026 is acknowledged.
Claims 1 and 17-50 are pending. Claims 36-50 are new.
Claims 17-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 48-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/20/2026.
Claims 1, 36-47 and 50 (claims set filed 03/20/2026) are examined on the merits herein.
Priority
This application is a 371 of PCT/SG2023/050219 filed 03/31/2023. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on applications SINGAPORE 10202203286W filed 03/31/2022 and SINGAPORE 10202300549P filed 03/01/2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/11/2023 and 12/23/2025 comply with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 38 and 39 are rejected 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. 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.
Claim 38 is directed to PAL selected from the group reciting various PAL proteins with the corresponding SEQ ID NOs and includes functional fragments or variants thereof. Claim 38 depends upon claim 1 which recites PAL to cleave the first peptide or protein and ligate the first peptide or protein to the second peptide or protein. Claim 39 is directed to QC selected from the group reciting various PQC proteins with the corresponding SEQ ID NOs and includes functional fragments or variants thereof. Claim 39 depends upon claim 1 which recites QC to cyclize P1’ in the released P1’-P2’ dipeptide motif to pyroglutamyl. The specification defines “functional fragment” as a portion of a protein that retains some or all of the activity or function (p. 11, lines 10-11). The specification defines “variant” as an amino acid sequence that is altered by one or more amino acids of the non-variant reference sequence, but retains the ability to recognize its target and affect its function (p. 11, lines 29-31). Claim 38 is interpreted as directed to PAL polypeptides identified by the SEQ ID NOs and their fragments and to variants of those polypeptides with any possible substitutions. Claim 39 is interpreted as directed to QC polypeptides identified by the SEQ ID NOs and their fragments and to variants of those polypeptides with any possible substitutions.
Thus, claim 38 broadly encompasses a genus of PAL proteins, PAL protein fragments and PAL proteins variants and claim 39 broadly encompasses a genus of QC proteins, QC protein fragments and QC proteins variants. This would represent large pools of variant amino acid sequences encoding the PAL proteins which are functional and are required to cleave the first peptide or protein and ligate the first peptide or protein to the second peptide or protein and QC proteins which are functional and are required to cyclize P1’ in the released P1’-P2’ dipeptide motif to pyroglutamyl. The Specification does not provide structure function correlation for PAL proteins and QC proteins and does not describe domains and/or amino acid residues essential for PAL protein and QC proteins and domain and/or amino acid residues which can be modified without loss of PAL or QC activity. Further, applicants have not shown possession of a representative number of species for fragments and variants of PAL and QC proteins as Specification provides only examples involving full-length PAL proteins, i.e. butelase-1 and VyPAL2 and one variant, OaAEP1b-C247A in Examples 1-4 and mentions only human and mouse QC in Example 4. Other variants or variants and/or fragments of other PAL and QC proteins are not provided.
Therefore, one of ordinary skill in the art would not be able to identify which PAL fragments and variant polypeptide sequences encode for functional PAL protein and which QC fragments and variant polypeptide sequences encode for functional QC protein. One of ordinary skill in the art would conclude based on the lack of representative number of species and the lack of describing the domains or amino acid residues of PAL and QC critical for the function of PAL and QC proteins, respectively, that the Applicant was not in possession of the claimed genera and that the specification fails to satisfy the requirements of written description under 35 U.S.C. 112 (a). Therefore, claims 38 and 39 are rejected.
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 36-39, 45 and 46 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.
Claim 36 recites a group for P2’: “P2’ is selected from the group comprising Leu, Met, Phe, Tyr, Trp, Val, Ile and Thr”. It is unclear if Applicant is attempting to use Markush language. Although reciting alternatives is not governed by a particular format, an issue of lack of clarity arises when it is not clear if the list of alternatives is closed or open. “Group” points to closed language and “comprising” indicates open language. It is not clear if other alternatives are intended to be encompassed due to transitional phrase “comprising”. The scope and boundaries of claim 36 are not clear making claim 36 indefinite. Applicant is suggested to replace recitation with: “P2’ is selected from the group consisting of Leu, Met, Phe, Tyr, Trp, Val, Ile and Thr” if Applicant intended to make this a closed grouping.
Claims 37-38, 45 and 46 have the same issues as claim 36 and are rejected.
Claim 45 recites: ”an affibody such as ZEFGR or ZEFGR-Fc”. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The scope and boundaries of claim 45 are not certain making claim 45 indefinite. Claim 46 dependent on claim 45, does not resolve the issue mentioned above and is rejected.
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.
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.
Claims 1 and 36-42 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2018056899 A1 on record in IDS) in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS) and Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833 on record in IDS) as evidenced by Shilling (Shilling et al., Biochemistry, 2005, 44, 13415-13424).
Regarding claim 1, Wu teaches enzymatic peptide ligation. Wu describes a method of ligating a first peptide via its C-terminus to the N-terminus of a second peptide, wherein reaction is catalyzed by asparagine/aspartate peptide ligase OaAEP1 Cys247Ala (Abstract). The first peptide has formula: P1-Asx-Xaa3-Leu-COOH/CONH2 and the second peptide: H2N-Xaa1-Xaa2-P2, wherein P1and P2 are each independently any peptide, Asn is Asp pr Asn, Xaa1 is any amino acid, Xaa2 is any amino acid except Pro and preferably Leu (which is a hydrophobic amino acid) and Xaa3 is an amino acid selected from the group, which includes Gln and Glu (p. 2, lines 12-25). That corresponds to instant first peptide or protein having motif P1-P1’-P2’ wherein P1 is Asn or Asp, P1’ is Gln or Glu and P2’ is a hydrophobic amino acid and to instant second peptide having motif P1”-P2”, wherein P1” is any amino acid and P2” is a hydrophobic amino acid. Wu discloses that the peptide ligase cleaves the first peptide after Asn/Asp and ligates the fragment P1-Asx via its C-terminus to the N-terminus of the second peptide to form ligated peptide of formula: P1-Asx-Xaa1-Xaa2 (p. 2, lines 26-31).
Wu does not teach glutamyl cyclase that cyclizes Glu or Gln in the dipeptide motif of the first peptide to pyroglutamyl.
Rehm teaches that for asparaginyl endopeptidase such as OaAEP1 Cys247Ala reaction a substantial excess of the substrate is necessary to out-compete the leaving dipeptide group liberated from the substrate following cleaving after Asp/Asn since the reaction is reversible (p. 4004, right column, 2nd paragraph). Rehm described approach to shift the reaction equilibrium OaAEP1 Cys247Ala toward product formation (Abstract, Figure 1). Rehm mentions a need to quench the competing nucleophile to drive the reaction to completion (p. 4004, right column, 2nd paragraph).
Seifert teaches that glutamyl cyclase catalyzes intramolecular cyclization of N-terminal glutamyl or glutamate residues with formation of pyroglutamic acid (Abstract). Seifert discloses that the N-terminal formation of pyroglutamate represents an irreversible reaction. (p. 11831, left column, 1st paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow teaching of Rehm and Seifert and try adding glutamyl cyclase to the peptide ligation reaction taught by Wu. One would have been motivated to do so since Rehm teaches the leaving dipeptide group to compete the ligation reaction and points to necessity to shift the equilibrium of the peptide ligation reaction towards product formation and Seifert teaches enzyme, glutamyl cyclase, that can use the leaving dipeptide having Glu or Gln residue in the irreversible reaction of cyclization and thus will prevent the dipeptide from competing the peptide ligation and move the equilibrium of reaction towards product. A skilled artisan would have reasonably expected success in the combination because Wu and Rehm teach peptide ligation by peptidyl asparaginyl ligase, OaAEP1 Cys247Ala, and Seifert provides enzyme that can increase the efficiency of peptide ligation reaction. Thus, Wu, Rehm and Seifert teachings render claim 1 obvious.
Regarding claims 36 and 37, Wu teaches the preferable amino acid residue for the Xaa2 which corresponds to instant P2’ and P2”, to be Leu (elected species). Thus, Wu, Rehm and Seifert teachings render claims 36 and 37 obvious.
Regarding claim 38, Wu teaches Cys247Ala mutant of OaAEP1 peptidyl asparaginyl ligase from Ovaloparmena affinis with SEQ ID NO:1 (p. 23). The sequence of OaAEP1 of Wu has 100% identity to residues 86-537 of instant OaAEP1b with SEQ ID NO:11. Since claim 38 includes functional fragments and variants of the recited sequences, Wu sequence of OaAEP1 Cys247Ala reads on the claim 38 limitations. Thus, Wu, Rehm and Seifert teachings render claim 38 obvious.
Regarding claim 39, Seifert teaches human glutaminyl cyclase (QC) (Abstract) and for protein expression refers (S2, 1st paragraph) to previous publication of Shilling (p. 11833, left column, 1st paragraph). As evidenced by Shilling, the sequence of human QC of Seifert teaching (Shilling, Figure 7) comprises sequence of instant human QC with SEQ ID NO:12 without last 6 residues of His-tag. Since claim 39 includes functional fragments and variants of the recited sequences, Seifert and Shilling sequence of human QC reads on the claim limitations.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use human glutamyl cyclase from Seifert and Shilling teachings for the peptide ligation based on Wu teaching. One would have been motivated to do so with reasonably expected success because Seifert teaches human QC with the sequence described by Shilling that can catalyze cyclization of the dipeptide having Glu or Gln residue in the irreversible reaction and that will prevent the dipeptide formed during peptide ligation from competing with the substrate and will move the equilibrium of reaction towards the product. Thus, Wu, Rehm and Seifert teachings as evidenced by Shilling render claim 39 obvious.
Regarding claims 40 and 42, Wu teaches preparation of dimers, oligomers or multimers of peptides or proteins of interest using peptide ligation method (p. 3, lines 37-38). Figure 14b shows two-step heterodimerization strategy. The protein of interest having the first peptide motif is ligated to the second peptide during the first step. In the second ligation step another first peptide with the protein of interest is ligated to the second peptide already having the same protein of interest thus providing formation of the dimer of the same protein. The motif of two amino acids, GL, corresponding to instant P1”-P2” acyl acceptor, is connected to the second peptide via linker consisting of two glycine residues and can be considered a spacer. Thus, Wu, Rehm and Seifert teachings render claims 40 and 42 obvious.
Regarding claim 41, Wu teaches that during homodimerization step 50 µM of the first peptide (NGL-tagged protein)is reacted with 0.5 µM of peptidyl asparaginyl ligase (p. 35, lines 35-37), that provides ratio of PAL to first peptide of 1:100 which is in the range of claim limitation. Seinfert teaches cyclization of peptides in the range of 0.25 to 6 mM with 0.37 mg/ml of human QC (S2, 3rd paragraph). Since human QC has molecular mass of about 40 kDa as evidenced by Shilling (p. 13415, right column, 2nd paragraph), 0.37 mg/ml is equal to 0.0093 mM. Therefore, the ratio of QC to its substrate can reach 1:648 which is in the range of claim limitation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the ratio of enzymes to the first substrate during peptide ligation as taught by Wu for PAL and by Seinfert for QC and optimize, if necessary, the ratio for the combination of enzymes. One would have been motivated to do so since Seifert teaches human QC that can catalyze cyclization of the dipeptide having Glu or Gln residue in the irreversible reaction and that will prevent the dipeptide formed during peptide ligation taught by Wu from competing with the substrate and will move the equilibrium of the reaction towards the product. A skilled artisan would have reasonably expected success in that because selection of enzyme to substrate ratio is routine and conventional. Thus, teaching of Wu, Rehm and Seifert as evidenced by Shilling render claim 41 obvious.
Claims 43, 45 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2018056899 A1 on record in IDS) in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS) and Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833 on record in IDS) as applied to claim 1 above, and further in view of Tam (Tam et al. Sci. China Chem., 2020, 63, 296-307 on record in IDS).
The teachings of Wu, Rehm and Seifert have been set forth above.
Wu teaches that peptides can be functionalized to bind a variety of cargo molecules, such as affinity tags or therapeutic agents (p. 19, lines 28-31). However, Wu, Rehm and Seifert do not teach peptide to be an antigen-binding peptide or antibody.
Regarding claims 43, 45 and 47, Tam teaches peptide asparaginyl ligases and their application in engineering bioactive peptides and precision protein modifications, antibody-drug conjugates, and live-cell labeling (Abstract). Tam describes ligation of proteins of interest or protein as cargo (p. 302, Figure 3) and labeling of proteins of interest with different compounds (p. 297, Scheme 1) by peptide ligation reaction. Tam mentions antibody labeling with fluorescein (p. 301, Table 4). Tam concludes that peptide asparaginyl ligases enable precision manufacturing of complex biologics such as antibody-drug conjugates (p. 306, left column, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Tam teaching and apply enzymatic peptide ligation based on Wu, Rehm and Seifert teachings to generation of conjugate of antibody bound to one of the peptides with drug/therapeutic agent bound to the other peptide. One would have been motivated to do so since Tam describes modification of antibodies with peptide ligation and mentions generation of antibody-drug conjugate and Wu teaches different cargo molecules that can functionalize peptides including therapeutic agents and because it would provide efficient delivery of the therapeutic agent to specific cell recognized by the antibody. A skilled artisan would have reasonably expected success in that because Wu and Rehm teach peptide ligation by peptidyl asparaginyl ligase, Seifert provides enzyme that can increase the efficiency of peptide ligation reaction and Tam points to enzymatic peptide ligation application. Thus, Wu, Rehm, Seifert and Tam teachings render claims 43, 45 and 47 obvious.
Claims 44 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2018056899 A1 on record in IDS) in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS), Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833 on record in IDS) and Tam (Tam et al. Sci. China Chem., 2020, 63, 296-307 on record in IDS) as applied to claims 1, 43 and 47 above, and further in view Law (Law et al. Clin. Cancer Res., 2004, 10, 7842-7851).
The teachings of Wu, Rehm, Seifert and Tam have been set forth above.
Wu, Rehm, Seifert and Tam do not teach a payload-releasing linkage and MMAE as therapeutic agent (elected species).
Law teaches antibody-drug conjugate for treatment of B-lineage lymphomas. Law describes conjugate of anti-CD20 antibody and anti-mitotic agent, monomethyl auristatin E (MMAE) linked via lysosomally cleavable dipeptide, valine-citrulline (Abstract). Rituximab-vcMMAE was selectively cytotoxic against CD20+ B-lymphoma cell lines, was internalized within 4 hours after binding to CD20+ cells and induced rapid cell cycle arrest and apoptosis. Rituximab-vcMMAE showed antitumor efficacy in xenograft models of CD20-positive lymphoma. Law concludes that anti-CD20–based antibody-drug conjugates are effective antitumor agents when prepared with a stable, enzyme-cleavable peptide linkage to highly potent cytotoxic agents such as MMAE (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Law teaching of anti-cancer antibody-MMAE conjugate containing drug releasing linkage with method of preparation of antibody-drug/therapeutic agent by enzymatic peptide ligation based on Wu, Rehm, Seifert and Tam teachings. One would have been motivated to do so since Law describes specific binding of Rituximab-vcMMAE to B-lymphoma cells, rapid release of highly potent cytotoxic agent, MMAE due to lysosomally cleavable linker and effect on cancer cells in vitro and in vivo. A skilled artisan would have reasonably expected success in that because Wu and Rehm teach peptide ligation by peptidyl asparaginyl ligase, Seifert provides enzyme that can increase the efficiency of peptide ligation reaction, Tam points to application of enzymatic peptide ligation for antibody-drug conjugates and Law provides such antibody-drug conjugate. Thus, Wu, Rehm, Seifert, Tam and Law teachings render claims 44 and 50 obvious.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2018056899 A1 on record in IDS) in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS), Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833 on record in IDS) and Tam (Tam et al. Sci. China Chem., 2020, 63, 296-307 on record in IDS) as applied to claims 1, 43 and 45 above, and further in view Salvador (Salvador et al. Anal. Bioanal. Chem., 2019, 411, 1703-1713).
The teachings of Wu, Rehm, Seifert and Tam have been set forth above.
Wu, Rehm, Seifert and Tam do not teach nanobody as an antibody (elected species).
Salvador teaches nanobody features and diagnostic and therapeutic applications. Salvador discloses that nanobodies have unique properties like internalization, size, thermal and chemical stability, affinity and blood clearance (Abstract). Salvador mentions that nanobodies can improve physico-chemical properties of conventional monoclonal antibodies and maintain degree of recognition in nanomolar range (p. 1704, left column, 2nd paragraph). Salvador describes that nanobodies are used in therapeutic applications for treatment of cancer, neurogenerative and infectious diseases (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute antibody in the antibody-drug conjugates prepared by enzymatic peptide ligation based on Wu, Rehm, Seifert and Tam teachings with nanobodies described by Salvador. One would have been motivated to do so since Salvador teaches that nanobodies have improved properties over monoclonal antibodies and have unique properties like internalization, size, thermal and chemical stability and high affinity in nanomolar range. A skilled artisan would have reasonably expected success in that because Wu and Rehm teach peptide ligation by peptidyl asparaginyl ligase, Seifert provides enzyme that can increase the efficiency of peptide ligation reaction, Tam and Law teach antibody-drug conjugates and Salvador points to efficiency and advantages of nanobodies over antibodies. Thus, Wu, Rehm, Seifert, Tam and Salvador teachings render claim 46 obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9 and 10 of copending application 18/465,824 (reference application) in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS) and Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833 on record in IDS).
Claim 1 of instant application is directed to a method of enzymatic peptide ligation comprising contacting a peptidyl asparaginyl ligase (PAL) and a glutamyl cyclase (QC) with a first peptide or protein having P1-P1’-P2’ motif wherein P1 is Asn or Asp, P1’ is Gln or Glu and P2’ is a hydrophobic amino acid and a second peptide or protein having P1”-P2” motif wherein P1” is any amino acid and P2” is a hydrophobic amino acid and wherein PAL cleaves the first peptide after P1 and ligates it to the P1”-P2” motif of the second peptide and QC cyclizes the released P1’-P2’ to pyroglutamyl.
Reference claim 1 teaches a method of forming a peptide of formula P1-Asx-Xaa1-Xaa2-P2 comprising ligating a first peptide of formula: P1-Asx-Xaa3-Xaa4-COOH/CONH2 to a second peptide of formula H2N-Xaa1-Xaa2-P2, wherein P1and P2 are each independently any peptide, Asx is Asn or Asp, Xaa1, Xaa3 and Xaa4 are any amino acid and Xaa2 is any amino acid except Pro; cleaving the bond between Asx and Xaa3 of the first peptide and ligating P1-Asx of the first peptide via its C-terminus to the N-terminus of the second peptide, and wherein reaction is catalyzed by asparaginyl endopeptidase OaAEP1 Cys247Ala. Reference claim 2 teaches Xaa2 to be a Leu or Ile which are hydrophobic amino acids, Xaa3 to be selected from a group including Gln and Glu and Xaa4 to be selected from a group including hydrophobic amino acids. Reference claim 3 teaches two or more features of reference claim 2.
That corresponds to instant first peptide or protein having motif P1-P1’-P2’ wherein P1 is Asn or Asp. P1’ is Gln or Glu and P2’ is a hydrophobic amino acid and to instant second peptide having motif P1”-P2”, wherein P1” is any amino acid and P2” is a hydrophobic amino acid and asparaginyl endopeptidase OaAEP1 Cys247Ala of reference claim 1 is peptidyl asparaginyl ligase.
Reference claims do not teach glutamyl cyclase that cyclizes Glu or Gln in the dipeptide motif of the first peptide to pyroglutamyl.
Rehm teaches that for asparaginyl endopeptidase such as OaAEP1 Cys247Ala reaction a substantial excess of the substrate is necessary to out-compete the leaving dipeptide group liberated from the substrate following cleaving after Asp/Asn since the reaction is reversible (p. 4004, right column, 2nd paragraph). Rehm described approach to shift the reaction equilibrium OaAEP1 Cys247Ala toward product formation (Abstract, Figure 1). Rehm mentions a need to quench the competing nucleophile to drive the reaction to completion (p. 4004, right column, 2nd paragraph).
Seifert teaches that glutamyl cyclase catalyzes intramolecular cyclization of N-terminal glutamyl or glutamate residues with formation of pyroglutamic acid (Abstract). Seifert discloses that the N-terminal formation of pyroglutamate represents an irreversible reaction. (p. 11831, left column, 1st paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow teaching of Rehm and Seifert and try adding glutamyl cyclase to the peptide ligation reaction taught by reference claims. One would have been motivated to do so since Rehm teaches the leaving dipeptide group to compete the ligation reaction and points to necessity to shift the equilibrium of the peptide ligation reaction towards product formation and Seifert teaches enzyme, glutamyl cyclase, that can use the leaving dipeptide having Glu or Gln residue in the irreversible reaction of cyclization and thus will prevent the dipeptide from competing the peptide ligation and will move the equilibrium of reaction towards product. A skilled artisan would have reasonably expected success in the combination because reference claims and Rehm teach peptide ligation by peptidyl asparaginyl ligase, OaAEP1 Cys247Ala, and Seifert provides enzyme that can increase the efficiency of peptide ligation reaction. Thus, reference claims 1-3, Rehm and Seifert teachings render claim 1 obvious.
Claim 36 of instant application is drawn to P2’ being Leu (elected species). Reference claims 2 and 3 teach the corresponding amino acid Xaa2 to be Leu. Thus, reference claims 2 and 3, Rehm and Seifert teachings render claim 36 obvious.
Claim 37 of instant application is drawn to P2” being Leu (elected species). Reference claims 2 and 3 teach the corresponding amino acid Xaa4 to be selected from amino acids including Leu. Thus, reference claims 2 and 3, Rehm and Seifert teachings render claim 37 obvious.
Claim 38 of instant application is directed to PAL selected from the recited proteins, their functional fragments or variants. Reference claims 1, 9 and 10 teach OaAEP1 Cys247Ala with SEQ ID NO:1. The sequence of OaAEP1 of reference application has 100% identity to residues 86-537 of instant OaAEP1b with SEQ ID NO:11. Since claim 38 includes functional fragments and variants of the recited sequences, reference sequence of OaAEP1 Cys247Ala reads on the claim limitations. Thus, reference claims 1, 9 and 10, Rehm and Seifert teachings render claim 38 obvious.
Therefore, since instant claims 1 and 36-38 encompass the subject matter of the reference claims 1-3, 9 and 10, they are rejected under obviousness double patenting.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 36-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7 and 8 of U.S. Patent No. 11795488 in view of Rehm (Rehm et al. Angew. Chem. Int. Ed., 2021, 60, 4004-4008 or record in IDS) and Seifert (Seifert et al. Biochemistry, 2009, 48, 11831-11833).
Claim 1 of instant application is directed to a method of enzymatic peptide ligation comprising contacting a peptidyl asparaginyl ligase (PAL) and a glutamyl cyclase (QC) with a first peptide or protein having P1-P1’-P2’ motif wherein P1 is Asn or Asp, P1’ is Gln or Glu and P2’ is a hydrophobic amino acid and a second peptide or protein having P1”-P2” motif wherein P1” is any amino acid and P2” is a hydrophobic amino acid and wherein PAL cleaves the first peptide after P1 and ligates it to the P1”-P2” motif of the second peptide and QC cyclizes the released P1’-P2’ to pyroglutamyl.
Reference claim 1 teaches a method of forming a peptide of formula P1-Asx-Xaa1-Xaa2-P2 comprising ligating a first peptide has formula: P1-Asx-Xaa3-Leu-COOH/CONH2 to a second peptide of formula H2N-Xaa1-Xaa2-P2, wherein P1and P2 are each independently any peptide, Asx is Asn or Asp, Xaa1 and Xaa3 are any amino acid and Xaa2 is any amino acid except Pro; cleaving the bond between Asx and Xaa3 of the first peptide and ligating P1-Asx of the first peptide via its C-terminus to the N-terminus of the second peptide, and wherein reaction is catalyzed by asparaginyl endopeptidase OaAEP1 Cys247Ala. Reference claim 2 teaches Xaa2 to be a Leu or Ile which are hydrophobic amino acids and Xaa3 to be selected from a group including Gln and Glu. Reference claim 3 teaches two or more features of reference claim 2.
That corresponds to instant first peptide or protein having motif P1-P1’-P2’ wherein P1 is Asn or Asp. P1’ is Gln or Glu and P2’ is a hydrophobic amino acid and to instant second peptide having motif P1”-P2”, wherein P1” is any amino acid and P2” is a hydrophobic amino acid and asparaginyl endopeptidase OaAEP1 Cys247Ala of reference claim 1 is peptidyl asparaginyl ligase.
Reference claims do not teach glutamyl cyclase that cyclizes Glu or Gln in the dipeptide motif of the first peptide to pyroglutamyl.
Rehm teaches that for asparaginyl endopeptidase such as OaAEP1 Cys247Ala reaction a substantial excess of the substrate is necessary to out-compete the leaving dipeptide group liberated from the substrate following cleaving after Asp/Asn since the reaction is reversible (p. 4004, right column, 2nd paragraph). Rehm described approach to shift the reaction equilibrium OaAEP1 Cys247Ala toward product formation (Abstract, Figure 1). Rehm mentions a need to quench the competing nucleophile to drive the reaction to completion (p. 4004, right column, 2nd paragraph).
Seifert teaches that glutamyl cyclase catalyzes intramolecular cyclization of N-terminal glutamyl or glutamate residues with formation of pyroglutamic acid (Abstract). Seifert discloses that the N-terminal formation of pyroglutamate represents an irreversible reaction. (p. 11831, left column, 1st paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow teaching of Rehm and Seifert and try adding glutamyl cyclase to the peptide ligation reaction taught by reference claims. One would have been motivated to do so since Rehm teaches the leaving dipeptide group to compete the ligation reaction and points to necessity to shift the equilibrium of the peptide ligation reaction towards product formation and Seifert teaches enzyme, glutamyl cyclase, that can use the leaving dipeptide having Glu or Gln residue in the irreversible reaction of cyclization and thus will prevent the dipeptide from competing the peptide ligation and will move the equilibrium of reaction towards product. A skilled artisan would have reasonably expected success in the combination because reference claims and Rehm teach peptide ligation by peptidyl asparaginyl ligase, OaAEP1 Cys247Ala, and Seifert provides enzyme that can increase the efficiency of peptide ligation reaction. Thus, reference claims 1-3, Rehm and Seifert teachings render claim 1 obvious.
Claim 36 of instant application is drawn to P2’ being Leu (elected species). Reference claims 1 teaches the corresponding amino acid to be Leu. Thus, reference claim 1, Rehm and Seifert teachings render claim 36 obvious.
Claim 37 of instant application is drawn to P2” being Leu (elected species). Reference claims 2 and 3 teach the corresponding amino acid Xaa2 to be Leu. Thus, reference claim 2 and 3, Rehm and Seifert teachings render claim 37 obvious.
Claim 38 of instant application is directed to PAL selected from the recited proteins, their functional fragments or variants. Reference claims 1, 7 and 8 teach OaAEP1 Cys247Ala with SEQ ID NO:1. The sequence of OaAEP1 of reference application has 100% identity to residues 86-537 of instant OaAEP1b with SEQ ID NO:11. Since claim 38 includes functional fragments and variants of the recited sequences, reference sequence of OaAEP1 Cys247Ala reads on the claim limitations. Thus, reference claim 1, 7 and 8, Rehm and Seifert teachings render claim 38 obvious.
Therefore, since instant claims 1 and 36-38 encompass the subject matter of the reference claims 1-3, 7 and 8, they are rejected under obviousness double patenting.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
Prosecution Insights