DETAILED ACTION
Acknowledgment and entry of the Amendment submitted on 11/3/25.
Claims 1, 2, 4, 6, 10, 14, 21, 27, 29 and 32 are currently under examination.
Claims 34-44 remain withdrawn without traverse.
Applicants’ arguments are rendered moot due to the new grounds of rejection necessitated by the Amendments to the claims.
Allowable Subject Matter
Claims 6 and 14 are 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.
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.
Claim(s) 1, 2, 4, 10, 21, 27, 29 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schödel (Infection and Immunity, 57(4):1347–1350 (April 1989; provided by Applicants), Schodel (1990, Vaccine 8:569–572) and Schodel et al (1991, Gene 99:255–259) in view of Dallas et al (Nature. 1980. 288: 499-501; UnitProt Accession Nos. P32890; P01557; P13768), Leong et al (Infect. Immun. 48:73-77.1985), Tsuji et al (Microb. Pathog. 2:381-390(1987) and Florack (EP1685848-A1; 8/2/2006) in further view of Qingdao et al (CN 10522760 A; provided by Applicants).
Schodel et al (Infect. Immun) teach the construction of a plasmid for expression of foreign epitopes as fusion proteins with subunit B of Escherichia coli heat-labile enterotoxin. In that paper they describe a vector (pFS2.2) that expresses fusion polypeptides between LT-B and foreign epitopes, specifically parts of the human and woodchuck hepatitis B virus surface and nucleocapsid antigens, in E. coli and Salmonella—i.e., LT-B–viral antigen fusions. Schödel et al. (Vaccine 1990) showed recognition of an HBV nucleocapsid T-cell epitope expressed as an LT-B fusion in attenuated Salmonella (functional vaccine context). Schödel et al. (Gene) reported secretion of hepatitis B virus antigens fused to LT-B in Vibrio cholerae.
The concept of fusing LTB to viral peptides has long been known in the prior art. Although Schoedel et al does not specifically recite the amino acid sequence of the LTB it would inherently be part of the LTB, or an obvious choice. The variant LTB set forth in SEQ ID NO: 1 has also been long known in the art, e.g., as far back or longer than the Schoedel references, as shown in the following references.
Dallas et al (1980) teach an E. coli heat labile toxin with 100% identity to SEQ ID NO: 1 and also 124 in total length. The reference shows amino acid homology between cholera toxin and E. coli heat-labile toxin. Leong et al (1985) teach an E. coli heat labile toxin with 100% identity to SEQ ID NO: 1 and also 124 in total length. The reference is a nucleotide comparison between heat-labile toxin B-subunit cistrons from E. coli of porcine origin. Tsuji et al (1985) disclose a unique amino acid sequence of the B subunit of a heat-labile enterotoxin isolated from a human enterotoxigenic Escherichia coli. The E. coli heat labile toxin with 100% identity to SEQ ID NO: 1 and also 124 in total length. Note: See the sequence alignment under “Uniprot” in the supplemental content tab in Public Pair which shows the alignment data.
Additonally, Florack et al teach an E.coli LT-B comprising an amino acid sequence with 100% to Applicants’ SEQ ID NO: 1. Florack teaches the use of a protein complex comprising an antigen of interest fused to the B-subunit of Vibrio cholerae cholera toxin (CT-B) or Escherichia coli heat-labile enterotoxin (LT-B) for manufacturing oral fish vaccine. Protein complexes are useful for the delivery of antigens to and across mucosa, which can be easily formulated in fish feed for the induction of an immune response in fish and for the production of said complexes in a host cell, preferably plants. The antigen is derived from a virus or micro-organism pathogenic to fish selected from infectious pancreatic necrosis virus (IPNV), striped jack nervous necrosis virus (SJNNV), infectious hematopoietic necrosis virus (IHNV), viral hemorrhagic septicemia virus (VHSV), pancreas disease virus (SPDV), infectious salmon anemia virus (ISAV), Spring viremia of carp virus (SVCV), koi herpesvirus (KHV), Flexibacter columnaris, Edwardsiella ictaluri, E. tarda, Piscirickettsia salmonis, Vibrio spp. and Aeromonas spp., Yersinia ruckeri, Pasturella piscicida or Renibacterium salmoninarum. The present sequence is an Escherichia coli heat-labile enterotoxin (LT-B) protein.
It also has been known in the prior art that a plurality of viral antigens may be used in a fusion with heat-labile subunit B (LTB). For instance, Qingdao teaches mucosal immune vaccine composition comprising: a heat labile toxin subunit B (LTB) polypeptide comprising SEQ ID NO: 16 having more than 80% sequence identity to LTB encoded by SEQ ID NO: 1 claimed by the present application (see sequence alignment); and a plurality of immunogenic polypeptides from IBV; wherein said plurality of immunogenic polypeptides comprises at least two viral peptides that can be spike and nucleocapsid for treating for instance coronavirus. Qingdao teaches fusion protein for preventing avian infectious bronchitis, a preparation method of the fusion protein and an application of the fusion protein. The fusion protein contains epitopes of main structural proteins Si protein and N protein of the avian infectious bronchitis virus (IBV), a recombinant heat-labile toxin b subunit and a purification tag. The multiple antigenic epitopes of major structural protein S1 protein and N protein are used in vaccine framework structure, and is connected in series with Escherichia coli heat-labile toxin B subunit through flexible linker. After cloning into pRSETB vector, Escherichia coli is transformed into a mucosal immune vaccine for avian infectious bronchitis with ideal immunogenicity through fermentation, purification and emulsification. The vaccine prepared can effectively prevent infection of avian infectious bronchitis virus.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to make a composition comprising an LTB comprising SEQ ID NO: 1 and at least two viral peptides. The design choices of the arrangement of these peptides and LTB in fusion would have been known to those of ordinary skill in the art as evidenced by Qingdao.
Pertinent art, not presently relied upon:
CN107050443-A.Nov 16, 2017 100% SEQ ID NO: 1 LTB E.coli. fused to pneumoccoal congjugate
Handley et al (WO200127144-A2. October 5, 2000) E. coli 100% same size match to SEQ ID NO: 1. The rCTB or other B subunits of the invention can also be used to induce tolerance to infection, e.g. parasitic infection. The present sequence represents a variant of the E. coli heat labile toxin B (LTB) protein. In the present invention the heat-labile enterotoxin (LT) of Escherichia coli was used as an exotoxin. LT is a member of the ADP-ribosylating exotoxin (bARE) family. The protein variants are useful for selectively delivering nucleic acid to mucosal cells, for inducing an immune response when the
nucleic acid encodes an antigen to which the immune response is desired
Welter, LM WO200111960-A1. Feb. 2001 134 LENGTH but 100% SEQ IDENTITY
The present invention relates to recombinant exotoxin protein variants, which comprise an exotoxin mucosal cell binding motif and a nucleic acid affinity domain. The present sequence is one such protein variant. In the present invention the heat-labile enterotoxin (LT) of Escherichia coli was used as an exotoxin. LT is a member of the ADP-ribosylating exotoxin (bARE) family. The protein variants are useful for selectively delivering nucleic acid to mucosal cells, for inducing an immune response when the nucleic acid encodes an antigen to which the immune response is desired, for selectively delivering a gene to a mucosal cell, and for achieving expression of a protein in a subject, by administering a composition comprising the protein variant
Vermeij et al (US 2008/0107653)
Hybrid toxins comprising shiga or shiga-like toxin subunits fused to escherichia coli heat labile enterotoxin subunits and vaccines thereof. 100% to SEQ ID NO: 1; Identical length
Xie et al CN113480665-A. Oct 8, 2021 after priority
Fusion protein useful for preparing recombinant protein vaccine, subunit vaccines and oral vaccines for porcine epidemic diarrhea obtained by fusing receptor-binding domain region protein in S protein of porcine epidemic diarrhea virus with B subunit protein.
ALL OF THESE 100% identity to SEQ ID NO: 1 AND 124 IN TOTAL LENGTH:
Tsuji T., Iida T., Honda T., Miwatani T., Nagahama M., Sakurai J., Wada K.,
RA Matsubara H.;
RT "A unique amino acid sequence of the B subunit of a heat-labile enterotoxin
RT isolated from a human enterotoxigenic Escherichia coli.";
RL Microb. Pathog. 2:381-390(1987).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX PubMed=8478941; DOI=10.1006/jmbi.1993.1209;
RA Sixma T.K., van Zanten B.A.M., Dauter Z., Hol W.G.J.;
RT "Refined structure of Escherichia coli heat-labile enterotoxin, a close
RT relative of cholera toxin.";
RL J. Mol. Biol. 230:890-918(1993).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=2034287; DOI=10.1038/351371a0;
RA Sixma T.K., Pronk S.E., Kalk K.H., Wartna E.S., van Zanten B.A.M.,
RA Witholt B., Hol W.G.J.;
RT "Crystal structure of a cholera toxin-related heat-labile enterotoxin from
RT E. coli.";
RL Nature 351:371-377(1991).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.14 ANGSTROMS).
RX PubMed=11880036; DOI=10.1016/s1074-5521(02)00097-2;
RA Pickens J.C., Merritt E.A., Ahn M., Verlinde C.L.M.J., Hol W.G.J., Fan E.;
RT "Anchor-based design of improved cholera toxin and E. coli heat-labile
RT enterotoxin receptor binding antagonists that display multiple binding
RT modes.";
RL Chem. Biol. 9:215-224(2002).
"Amino acid sequence homology between cholera toxin and Escherichia coli
RT heat-labile toxin.";
RL Nature 288:499-501(1980).
RA Leong J., Vinal A.C., Dallas W.S.;
RT "Nucleotide sequence comparison between heat-labile toxin B-subunit
RT cistrons from Escherichia coli of human and porcine origin.";
RL Infect. Immun. 48:73-77(1985).
CN105002195-A. Dong et al. 10.28/2015 100% but larger. (609 comprising)
The present invention relates to a novel ORF3-ORF5 fusion gene, useful
CC for preparing a recombinant vaccine for preventing porcine reproductive
CC and respiratory syndrome virus infection (PRRSV, also known as blue ear
CC pig disease). The invention further provides: (1) an ORF3-ORF5 fusion
CC protein; (2) a plasmid pCB130NG-ORF3-ORF5 expression vector; and (3) a
CC recombinant vaccine for blue ear pig disease. The present sequence
CC represents a PRRSV GP3-GP5 (ORF3-ORF5) fusion protein, the DNA of which
CC is used in the plasmid vector for preparing the vaccine of the invention
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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Thursday from 8:00 AM-6:30 PM.
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/JENNIFER E GRASER/Primary Examiner, Art Unit 1645 11/17/25