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 .
DETAILED ACTION
Claim Status
Claims 47-66 are currently pending. Claim 1-46 are canceled claims. Claims 47-66 are new. Claims 47-66 will be examined on the merits.
Priority
Acknowledgement is made of applicant’s claim for foreign priority based on an application filed on August 16, 2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement (IDS)
The IDS submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claims 47-48, 51, 56-64, 66 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892).
As claims 47-48, Curtiss teaches “nucleic acids, vector systems, and vaccines for vaccinating fresh water and marine fish using Ichthyophthirius multifiliis (Ich) i-antigens. In particular, a recombinant attenuated Edwardsiella vaccine (RAEV) vector system is disclosed with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes Ich protective antigens to enable vaccination of fresh water and marine fish species susceptible to white spot disease”. See Abstract.
Curtiss teaches that “This vaccine construct is designed to exhibit the invasive properties of virulent Edwardsiella at the time of bath immunization and then is programmed to gradually lose virulence attributes and to synthesize protective antigens as a consequence of in vivo cell division as the RAEV colonizes internal effector lymphoid tissues. The ultimate lysis in vivo delivers a bolus of protective antigen along with immunostimulatory molecules to exhibit complete biological containment with no potential for survival in vivo or ex vivo”. See Abstract.
Curtiss teaches “the bacterium may be capable of the regulated expression of a nucleic acid encoding the antigen, regulated attenuation, and/or capable of regulated lysis”. See paragraph [0061].
Curtiss teaches “Construction of a Regulated Programmed Lysis System”. See paragraph [0178].
Curtiss teaches E. piscicida mutants; E. piscicida strains. See paragraph [0062; 0156]. See Tables 1-2.
Curtiss teaches that the fish-pathogenic Glade of Edwardsiella tarda, as Edwardsiella piscicida, which is a versatile pathogen causing disease in many species of both cultured and wild fish populations was reclassified. These findings were supported based on comparison of gyrB sequences of many Edwardsiella strains. The homology between E. piscicida and E. tarda was <87% whereas between E. piscicida and E. ictaluri was 95.9%. See paragraph [0153].
As claim 51, Curtiss teaches that “bacterium as described herein can elicit an immune response against a fish pathogen other than Edwardsiella piscicida in a host. The fish pathogen can be a bacterial, viral, fungal or parasitic pathogen of fish”. See paragraph [0009].
As claim 56, Curtiss teaches “a vector comprising at least one nucleic acid sequence encoding a protective antigen operably linked to a promoter regulated by the repressor, such that the expression of the nucleic acid sequence encoding the antigen is repressed during in vitro growth of the bacterium, but the bacterium is capable of high-level expression in vivo”. See paragraph [0013].
As claim 57, Curtiss teaches “This vaccine construct, as fully described below, is designed to exhibit the invasive properties of virulent Edwardsiella at the time of bath immunization and then is programmed to gradually lose virulence attributes and to synthesize protective antigens as a consequence of in vivo cell division as the RAEV colonizes internal effector lymphoid tissues. The ultimate lysis in vivo delivers a bolus of protective antigen along with immunostimulatory molecules to exhibit complete biological containment with no potential for survival in vivo or ex vivo. These RAEV vector systems thus have the same well-documented safety and efficacy attributes of systems using Salmonella vectors”. See paragraph [0042].
As claims 58-64, Curtiss teaches “The expression of these genes is dependent on arabinose provided during growth. Thus, following colonization of lymphoid tissues, the Fur and/or Crp proteins cease to be synthesized due to the absence of arabinose such that attenuation is gradually manifest in vivo to preclude induction of diseases symptoms”. See paragraph [0169].
Curtiss teaches that “Ferric uptake regulator (Fur) and cyclic AMP receptor protein (Crp) are global regulators for expression of genes encoding various virulence factors in Gram-negative bacteria (Choe et al., 2017)”. See paragraph [0170].
Curstiss teaches “the araC ParaBAD cassette is dependent both on the presence of arabinose and the binding of the catabolite repressor protein Crp, a ΔPcrp::TT araC ParaBAD crp deletion insertion mutation may be included as an additional means to reduce expression of any nucleic acid sequence under the control of the ParaBAD promoter. This means that when the bacterium is grown in a non-permissive environment (i.e. no arabinose) both the repressor itself and the Crp protein cease to be synthesized, consequently eliminating both regulating signals for the araC PBAD regulated nucleic acid sequence. This double shut off of araC ParaBAD may constitute an additional safety feature ensuring the genetic stability of the desired phenotypes. See paragraph [0119].
Curtiss teaches that “To achieve regulated delayed attenuation in vivo, a tightly regulated araC ParaBAD cassette was substituted for the promoters of the E. piscicida fur and crp genes”. See paragraph [0166].
Curtiss teaches “χ16022 construct that is ΔasdA, ΔPfur170:TT araC ParaBAD fur, and ΔPcrp68:TT araC ParaBAD crp. This strain displays the regulated delayed attenuation phenotype and can be used to deliver synthesized protective antigens encoded on AsdA.sup.+ plasmid vectors. See paragraph [0175].
Curtiss teaches “one or more bacteria, one or more vectors, and optionally a constituent required for permissive growth and/or expression, for example arabinose”. See for example, paragraph [0139].
Curtiss teaches “the bacterium is capable of the regulated expression of at least one heterologous nucleic acid encoding an antigen, wherein the bacterium comprises at least one chromosomally integrated nucleic acid sequence encoding a repressor”. See claim 7.
Curtiss teaches “methods of eliciting an immune response in a fish, the method comprising administering a bacterium as described herein or a vaccine to a fish.” “The fish can be a teleost fish; the fish can be a farmed teleost fish; the fish can be a catfish; the fish can be a channel catfish; the fish can be a zebrafish”. See paragraph [0017].
Curtiss teaches “An aspect of the present disclosure of significance is the fact that E. piscicida is able to infect not only catfish but also salmonid fish such as trout and salmon as well as tilapia, whereas E. ictaluri only infects catfish and therefore can only be used to develop vaccines for catfish”. See paragraph [0058].
Curtiss teaches “Vaccine compositions disclosed herein may be administered to a host capable of mounting an immune response. Preferably, the host is a fish. In embodiments, the host is a teleost fish, such as a catfish, trout, salmon, or tilapia. In an exemplary embodiment, the host is a fish used in aquaculture. The vaccine can be administered as a prophylactic or for treatment purposes”. See paragraph [0127].
As claim 66, Curtiss teaches “a vaccine composition” comprising “A genetically modified Edwardsiella piscicida bacterium displaying a regulated delayed manifestation of attenuation in vivo, able to synthesize and deliver protective antigens encoded by genes from heterologous pathogens and capable of infecting fresh water and marine fish to deliver such synthesized protective antigens”. “The immune response is a protective immune response.” “The method further comprises delivering a bolus of antigen to the fish, wherein delivering a bolus of antigen comprises lysing the Edwardsiella bacterium. “Administering is one or more of administering by bath immersion, oral administration, or intracoelomic administration”. See claims 1-7, 11-18.
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.
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.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892) as applied to claims 47-48, 51, 56-64, 66 above, in view of Swain et al. (Published January 25, 2022; hereafter Swain; PTO-892).
Curtiss teaches all the limitations of claims 47-48, 51, 56-64, 66 as fully disclosed and incorporated herein.
However, Curtiss does not teach expression of one or more host cytokine genes selected from an il-8 gene, an it-1# gene, a tnf-a gene, an il-6 gene, and an ifn-y gene, as claim 49.
Swain teaches “vaccine strain χ16022(pG8R8029) is attenuated and induces systemic and mucosal IgM titer against E. piscicida and Ich in zebrafish. This vaccine strain is a regulated-delayed attenuation in vivo phenotype that is based on the replacement of an arabinose-regulated araC ParaBAD cassette for the promoters of the fur and crp genes of E. piscicida such that the expression of these genes is dependent on arabinose provided during growth. Thus, following colonization, the Fur and Crp proteins stop being synthesized due to the lack of arabinose and attenuation is progressively achieved in vivo to prevent generation of diseases symptoms. which is pertinent to claim 42.
Swain teaches “Transcript levels of tnf-α, il-1β, il-6 and il-8 were significantly increased in different tissues of vaccinated zebrafish compared to unimmunized fish”. Zebrafish vaccinated with χ16022(pG8R8029) showed 60% survival upon intracoelomic (i.c.) challenge with a lethal dose of virulent E. piscicida strain J118, which is pertinent to claim 42. See For example, Figure 8.
Swain teaches “RAEV system could be used as a generalized vaccine-vector system to protect teleost fish against multiple bacterial, viral and parasitic infectious diseases, which is pertinent to claim 42. See for example, Abstract.
It would have been obvious to one of ordinary skill in the art to modify the teachings of Curtiss, thereby arriving at the invention of claim 49. Since Curtiss teaches the same recombinant attenuated Edwardsiella vaccine (RAEV) vector system with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes Ich protective antigens to enable vaccination of fresh water and marine fish, and Swain teaches the immune response via transcriptional levels of cytokines generated by the same sort of immunization system/vaccine in Zebrafish, it would been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892) as applied to claims 47-48, 51, 56-64, 66 above, in view of Liu et al. (Published 2017; hereafter Liu; PTO-892).
Curtiss teaches all the limitations of claims 47-48, 51, 56-64, 66 as fully disclosed and incorporated herein.
However, Curtiss does not teach expression of genes encoding CD4-1, CD4-2, CD8-a, CD8-p, MHC-II, or any combination thereof as claim 50.
Li teaches vaccine candidates from Outer Membrane Proteins (OMPs) of Edwardsiella tarda. A total of thirteen OMPs were selected from the E. tarda genome and analysed using bioinformatics software, and six of them were predicted to contain conserved surface antigens or play important roles in bacterial survival and infection and were selected to test their vaccine potential. The selected six OMPs were recombinantly expressed, and their immune protective effects against a E. tarda challenge in a flounder (Paralichthys olivaceus) model were evaluated. Meanwhile, the levels of specific serum antibodies and sIg+ lymphocytes and the expression of immune-related genes after vaccination were also measured. Finally, effective vaccine candidates were selected through comprehensive comparisons of the relative percent survivals (RPS) and the immune responses induced by the six recombinant OMPs, which is pertinent to claim 50. See for example, Abstract.
Li teaches “the immune response of flounder induced by rOMPs was investigated, and the results showed that: (1) The levels of specific antibodies against E. tarda induced by rOmpI and rOmpX were significantly higher at weeks 3 and 4 post-vaccination than those of the other rOMPs; (2) all six rOMPs could induce the proliferation of sIg+ lymphocytes, and the peaks of sIg+ lymphocytes in the blood and spleen of rOmpI-, rOmpX- and rOmpH-vaccinated fish were significantly higher than those of other rOMPs; (3) all six rOMPs could induce up-regulation of the MHC IIα, CD4-1, CD4-2, CD8α, CD8β, IL-1β, TNF-α and IFN-γ genes. Among them, the mRNA levels of the CD4-1 and CD4-2 genes induced by rOmpI and rOmpX were generally higher than those induced by the other rOMPs, while there was no significant difference in the expression of TLR2, TLR5M and MHC Iα between the rOMPs-vaccinated group and control group. These results demonstrate that rOmpI and rOmpX could produce a RPS of over 80% against the challenge of E. tarda and induce stronger immune responses in flounder, which indicates that OmpI and OmpX are promising vaccine candidates against E. tarda infection, which is pertinent to claim 50. See for example, abstract; Figure 6.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Curtiss and Liu, thereby arriving at the invention of claim 50. Since Curtiss teaches the recombinant attenuated Edwardsiella vaccine (RAEV) vector system with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes Ich protective antigens to enable vaccination of fresh water and marine fish because the recombinant attenuated Edwardsiella vaccine (RAEV) vector system carries the outer membrane proteins (OMPs) and Liu already has showed that OMPs induce up-regulation of the MHC IIα, CD4-1, CD4-2, CD8α, CD8β, IL-1β, TNF-α and IFN-γ genes, it would been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Claims 52, 54, 65 are rejected under 35 U.S.C. 103 as being unpatentable over Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892) as applied to claims 47-48, 51, 56-64, 66 above, in view of Wang et al. (Published 2017; hereafter Wang; PTO-892).
Curtiss teaches all the limitations of claims 47-48, 51, 56-64, 66 as fully disclosed and incorporated herein.
However, neither Curtiss does not teach the bacterial pathogen comprises Aeromonas hydrophila as claim 52.
Curtiss does not teach the antigen comprises outer membrane protein 00002501, AGM43135, AGM42919, AOKFG8, AOKGW8, A0KQ46, AOKQZ1, AOKIU8, AGH12866, a TonB domain of AOKFG8, an OMP domain of AOKFG8, a Plug domain of AOKFG8, or any combination thereof as claim 54.
Curtiss does not teach the pathogen comprises tilapia lake virus (TiLV) or Aeromonas hydrophila as claim 65.
Wang teaches quantitative proteomic analysis of iron-regulated outer membrane proteins in Aeromonas hydrophila as potential vaccine candidates, which is pertinent to claim 52.
Wang teaches that the iron-regulated outer membrane protein (OMP) of Aeromonas hydrophila is an effective vaccine candidate. The differentially expressed sarcosine-insoluble fractions of A. hydrophila in iron-limited and normal medium using tandem mass tag labeling-based quantitative proteomics, and identified 91 upregulated proteins including 21 OMPs and 83 downregulated proteins including 10 OMPs. Subsequent bioinformatics analysis showed that iron chelate transport-related proteins were enriched in increasing abundance, whereas oxidoreductase activity and translation-related proteins were significantly enriched in decreasing abundance. The proteomics results were further validated in selected altered proteins by Western blotting. Finally, the vaccine efficacy of five iron-related recombinant OMPs (A0KGW8, A0KFG8, A0KQ46, A0KIU8, and A0KQZ1) that were increased abundance in iron-limited medium, were evaluated when challenged with virulent A. hydrophila against zebrafish, suggesting that these proteins had highly efficient immunoprotectivity. Our results indicate that quantitative proteomics combined with evaluation of vaccine efficacy is an effective strategy for screening novel recombinant antigens for vaccine development, which is pertinent to claims 52, 54, 65. See for example, Abstract.; Figures 4, 7.
Wang also teaches that “for A. hydrophila, recombinant Omp48 (LamB), Omp38, OmpG, ompTS, OmpF, OmpC, Aha1 and OmpW were reported to induce protective immune responses as well”, which is pertinent to claims 52, 54, 65. See for example, introduction; paragraph [01].
Wang teaches that “several studies have reported that attenuated bacterial strains and OMP fractions cultured in iron-limited conditions enhance vaccine efficacy in Flavobacterium psychrophilum
and Aeromonas salmonicida”, which is pertinent to claims 52, 54, 65.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Curtiss and Wang, thereby arriving at the invention of claims 52, 54, 65. Since Curtiss teaches the recombinant attenuated Edwardsiella vaccine (RAEV) vector system with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes Ich protective antigens to enable vaccination of fresh water and marine fish and the OMPs antigens of Wang have shown to be effective vaccinal candidates against the pathogen, Aeromonas hydrophila, it would been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Claims 53, 55 are rejected under 35 U.S.C. 103 as being unpatentable over Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892) as applied to claims 47-48, 51, 56-64, 66 above, in view of Lipkin et al. (WO 2016100328 A1; hereafter Lipkin; PTO-892).
Curtiss teaches all the limitations of claims 47-48, 51, 56-64, 66 as fully disclosed and incorporated herein.
However, Curtiss does not explicitly teach the viral pathogen comprises tilapia lake virus (TiLV) as claim 53.
Curtiss also does not the TiLV gene encoding the at least one antigen and has at least 80% sequence identity with any one of SEQ ID NOs. 47-55 as claim 55.
Lipkin teaches a new virus found in tilapia, denoted Tilapia Lake Virus (TiLV) and immunogenic compositions for inducing an immune response against TiLV in an animal, which is pertinent to claims 53, 55.
Lipkin teaches Isolated nucleic acid used in immunogenic composition for preparing vaccine for preventing or treating Tilapia Lake Virus in animal, comprises nucleobases sequence, which is pertinent to claims 53, 55.
Lipkin teaches SEQ ID NO: 12, which is pertinent to claims 53, 55. See for example, claim 19; SEQ ID NO 12; 93pp.
The SEQ ID NO: 12 of Lipkin is 98.9% identical to SEQ ID NO: 48, which is pertinent to claim 55. See Figure below. See page 25;
Lipkin teaches that “TiLV polypeptides described here, natural variations can exist between individual TiLV strains. These variations may be demonstrated by (an) amino acid difference(s) in the overall sequence or by deletions, substitutions, insertions, inversions or additions of (an) amino acid(s) in said sequence. Amino acid substitutions which do not essentially alter biological and immunological activities, have been described, e.g. by Neurath et al in "The Proteins" Academic Press New York (1979)”, which is pertinent to claim 55. See for example, page 14; For more SEQ ID NO:12, see also lines 5-25; page 25; lines 11-33; page 26; lines1-10.
Lipkin teaches “the term "animal" refers to a vertebrate, including, but not limited to, fish, (e.g. tilapia)”, which is pertinent to claims 53, 55.
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It would have been obvious to one of ordinary skill in the art to combine the teachings of Curtiss and Lipkin, thereby arriving at the invention of claims 53, 55. Since Curtiss teaches the recombinant attenuated Edwardsiella vaccine (RAEV) vector system with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes Ich protective antigens to enable vaccination of fresh water and marine fish and SEQ ID NO:12 of Lipkin can be used as an immunogenic component for preparing vaccine for preventing or treating Tilapia Lake Virus in animal, it would been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be expected because Curtiss et al. (US 20210093704 A1; hereafter Curtiss; PTO-892) specifically suggests using a genetically modified Edwardsiella piscicida bacterium displaying a regulated delayed manifestation of attenuation in vivo, able to synthesize and deliver protective antigens encoded by genes from heterologous pathogens and capable of infecting fresh water and marine fish to deliver such synthesized protective antigens and does not specify any other protective antigen that should not be used.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., the recombinant attenuated Edwardsiella vaccine (RAEV) vector system with regulated delayed attenuation and regulated delayed lysis in vivo attributes that synthesizes protective antigens such as Ichthyophthirius multifiliis (Ich) i-antigens (Ich proteins) to enable vaccination of fresh water and marine fish and vaccinal antigens/immunogenic proteins from Aeromonas species, such as OMPs and Tilapia Virus Lake, such as SEQ ID NO: 48 and other sequence variations) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571)272-2784. The examiner can normally be reached M-F 6:15 AM-3:00 PM.
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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