DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/30/26 has been entered.
Claims 1, 6, 12, 14, 15, 19, 23, 24, 26, 27, 29 and 30 are currently under examination.
Claims 9 and 31 remain withdrawn for being drawn to a non-elected invention.
Claim Rejections - 35 USC § 112-2nd paragraph
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 1, 6, 12, 14, 15, 19, 23, 24, 26, 27, 29 and 30 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 1 is vague and confusing because it is unclear if both FliC and FimH are in the cell. Applicants’ summary of Claimed subject matter on page 5 of the 4/30/26 response recites:
The present application is directed to engineered bacterial cells, and particularly, to Lactobacillus acidophilus strains that express both an exogenous polypeptide (e.g., a viral antigen) and a specific pair of adjuvant polypeptides comprising flagellin (FliC) and type 1 fimbrin D- mannose specific adhesin protein (FimH), wherein the polypeptides are integrated into the bacterial S-layer protein (SLP) or S-layer associated proteins (SLAPs). The combination of FliC and FimH represents a novel dual-adjuvant strategy: FliC activates toll-like receptor 5 (TLR5) and NLRC4 to stimulate the innate and adaptive immune response, while FimH binds to glycoprotein 2 (GP2) expressed on intestinal microfold (M) cells to enhance uptake into Peyer's patches and mesenteric lymph node (MLN) trafficking. As demonstrated in working examples, the combined FliC and FimH adjuvant strategy results in a statistically significant increase in antigen-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) responses.
However, claim 1 recites:
(ii) at least one adjuvant polypeptide, wherein the at least one adjuvant polypeptide comprises flagellin (FliC) and type 1 fimbrin D-mannose specific adhesin protein (FimH)
Accordingly, this language is unclear because FliC and FimH are individual adjuvant polypeptides and the way the claim is written makes it appear to be an improper Markush grouping wherein the engineered cell many contain just one of them (at least one), e.g., FliC or FimH, and not both as Applicants’ summary states. Is this a fusion polypeptide? If both polypeptides are intended to be in the cell as Applicants recite, it would not be ‘at least one adjuvant polypeptide’ unless this was a fusion polypeptide comprising FliC and FimH or if the cell contained both FimH and FliC, e.g., it should be made clear both polypeptides are in the cell. Further, the use of the “is/are” in the second to last line of the claim implies just one of these polypeptides may be integrated into SLP or SLAP. Even more unclear is it appears that these adjuvant polypeptides may not be necessarily integrated into the SLP/SLAP because the claim is written with “and/or” allowing either the viral polypeptide or the adjuvant to be integrated. Appropriate clarification and/or correction is required.
Claims 15, 19, 23, 24 are vague and indefinite for the same reasons, e.g., it is unclear if the referenced “at least one adjuvant polypeptide comprises both FimH and FliC. Appropriate clarification and/or correction is required.
Claim 14 is vague and indefinite due to the term “derived from a spike protein (S) or a membrane protein (M) because the term “derived” does not provide the character or properties from the source that are to be retained in the final product, e.g., paper is derived from wood but is very different from wood. The claim should remove “derived from” and replace it with “is”. Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 112-Scope of Enablement
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 1, 6, 12, 14, 15, 19, 23, 24, 26, 27, 29 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
An engineered Lactobacillus acidophilus strain that expresses both an exogenous immunogenic polypeptide from a virus and a fusion polypeptide comprising flagellin (FliC) and type 1 fimbrin D- mannose specific adhesin protein (FimH), wherein the polypeptides are integrated into the bacterial S-layer protein (SLP) or S-layer associated proteins (SLAPs).
does not reasonably provide enablement for:
An engineered Lactobacillus bacterial cell comprising: (i) an exogenous immunogenic polypeptide from a virus; and (ii) at least one adjuvant polypeptide comprises flagellin (FliC) and type 1 fimbrin D-mannose specific adhesin protein (FimH); and wherein the exogenous immunogenic polypeptide and the at least one adjuvant polypeptide are expressed by the Lactobacillus bacterial cell, and wherein the exogenous immunogenic polypeptide and/or the at least one adjuvant polypeptide is/are integrated into an S- layer protein (SLP) or an S-layer associated protein (SLAP).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The present application is directed to engineered bacterial cells, and particularly, to Lactobacillus acidophilus strains that express both an exogenous polypeptide (e.g., a viral antigen) and a specific pair of adjuvant polypeptides comprising flagellin (FliC) and type 1 fimbrin D- mannose specific adhesin protein (FimH), wherein the polypeptides are integrated into the bacterial S-layer protein (SLP) or S-layer associated proteins (SLAPs). The combination of FliC and FimH represents a novel dual-adjuvant strategy: FliC activates toll-like receptor 5 (TLR5) and NLRC4 to stimulate the innate and adaptive immune response, while FimH binds to glycoprotein 2 (GP2) expressed on intestinal microfold (M) cells to enhance uptake into Peyer's patches and mesenteric lymph node (MLN) trafficking. As demonstrated in working examples, the combined FliC and FimH adjuvant strategy results in a statistically significant increase in antigen-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) responses. The instant specification provides examples of this vaccine platform in the context of multiple viral antigens, including SARS-CoV-2 antigens (e.g., S1/S2 and S2' cleavage site peptides; membrane protein) and rotavirus antigens (VP8pep, VP8-1, VP7pep, VP7, VP5).
The specification and Applicants recite that the invention is a “vaccine platform” comprising genetically engineered microorganisms for use in the production of pharmaceutical vaccine compositions for treating and/or preventing diseases and disorders associated with infections from pathogenic organisms. See paragraph [0033], Detailed Description. Figure 1 shows various L. acidophilus strains engineered to express the paragraph [0101] the immunogenic viral polypeptides and adjuvant polypeptides within the bacterial surface layer protein (SLP) after genomic insertion. The SlpA gene was cloned and the virus peptide was inserted into a region of the sequence known to preserve SlpA structure and provide surface exposure. The plasmid was transfected into L. acidophilus and selected for homologous recombination using nutrient selective pressure. Example 2 on page 32, teaches that induction of robust immune response is key to preventing infections by pathogens and evaluated the polypeptide adjuvants FliC and FimH.
Accordingly, the specification does not enable a “vaccine platform” that is
An engineered Lactobacillus bacterial cell comprising: (i) an exogenous immunogenic polypeptide from a virus; and (ii) at least one adjuvant polypeptide comprises flagellin (FliC) and type 1 fimbrin D-mannose specific adhesin protein (FimH); and wherein the exogenous immunogenic polypeptide and the at least one adjuvant polypeptide are expressed by the Lactobacillus bacterial cell, and wherein the exogenous immunogenic polypeptide and/or the at least one adjuvant polypeptide is/are integrated into an S- layer protein (SLP) or an S-layer associated protein (SLAP).
This claim does not require the adjuvant proteins and the exogenous protein to be integrated into the SLP or SLAP.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
Response to Applicants’ arguments:
Applicants argue:
As amended, claim 1 is limited to an engineered Lactobacillus cell expressing a viral antigen alongside full-length FliC (e.g., SEQ ID NO: 14) and FimH (e.g., SEQ ID NOs: 15-16) as adjuvant polypeptides, wherein the exogenous polypeptide and/or the adjuvant polypeptides are integrated into an S-layer protein (SLP) or an S-layer associated protein (SLAP). The amended claim scope is commensurate with the enabling disclosure in the specification because the new Lactobacillus host limitation aligns the claim with the genus of bacteria for which working examples are provided. All constructs in Table 1 are L. acidophilus-based, and all in vivo immunogenicity data is from L. acidophilus oral immunization studies. The SLP/SLAP integration limitation further narrows the claim to the specific antigen and adjuvant display mechanism demonstrated in all working examples (see, e.g., Application paragraph [0101]; FIG. 1). Third, with respect to the exogenous polypeptide limitation, the claim requires a "viral antigen" expressed by the bacterial cell. The specification provides enabling working examples for viral antigens from three distinct virus families (SARS-CoV-2, rotavirus, and feline coronavirus), demonstrating the generality of the platform for diverse viral antigens (see, e.g., Table 1; Table 3 (SEQ ID NOs: 1-13); FIGS. 5, 7, 8; Table 2). The enablement of expressing a structurally diverse set of viral antigens in Lactobacillus via the SlpA/SLAP integration system is demonstrated across multiple constructs.
These arguments have been fully and carefully considered but are not deemed persuasive because they are not commensurate in scope with the claimed invention. The bacterial cell may be any species of Lactobacillus and the claims do not require the engineered cell to express both FliC and FimH (as outlined in the 112, second paragraph rejections and the enablement rejection above). Additionally, the claims do not require the adjuvant polypeptide comprising both FliC and FimH and the exogenous immunogenic polypeptide from a virus to be integrated into an S-layer protein (SLP) or an S-layer associated protein (SLAP). The instant claims allow for just one of the adjuvants, e.g., FliC, and not FimH or the viral antigen, or just the viral antigen and not FimH or FliC, to be integrated in to the SLP or SLAP protein.
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, 6, 12, 14, 15, 19, 23, 24, 26, 27, 29 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kajikawa et al (PLoS One. 2015 Oct 28;10(10): 1-15) in view of Makvandi et al (Microbial Pathogenesis. May 2018. Vol 118: 87-90) and Paul-Ehrlich-Insititut (https://www.pei.de/EN/newsroom/press-releases/year/2017/12-mode-of-action-of-vaccine-adjuvant-flagellin-in-fusion-proteins-has-been-clarified.html#:~:text=The%20benefit%20of%20flagellin%20is%20that%20the,various%20different%20antigens%20using%20genetic%20engineering%20technologies December 2017).
Kajikawa teaches that surface layer proteins of probiotic lactobacilli are theoretically efficient epitope-displaying scaffolds for oral vaccine delivery due to their high expression levels and surface localization. In this study, Kajkawa constructed genetically modified Lactobacillus acidophilus strains expressing the membrane proximal external region (MPER) from human immunodeficiency virus type 1 (HIV-1) within the context of the major S-layer protein, SlpA. Intragastric immunization of mice with the recombinants induced MPER-specific and S-layer protein-specific antibodies in serum and mucosal secretions. Moreover, analysis of systemic SlpA-specific cytokines revealed that the responses appeared to be Th1 and Th17 dominant. These findings demonstrated the potential use of the Lactobacillus S-layer protein for development of oral vaccines targeting specific peptides. See abstract. The reference teaches that the probiotic strain Lactobacillus acidophilus NCFM is particularly promising as an oral vaccine vector because: (1) it is acid and bile tolerant; (2) it expresses mucus-binding proteins and associates with the intestinal mucosa; and (3) it binds to dendritic cells (DCs) through DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) and other pattern recognition receptors described above. The reference recites that proof of principle has been demonstrated by Mohamadzadeh et al., who constructed recombinant L. acidophilus producing the Bacillus anthracis protective antigen and succeeded in inducing protective immunity in a murine model.
For construction of recombinant L. acidophilus as a vaccine candidate, there are three strategies for the subcellular distribution of antigens: cytoplasmic accumulation, secretion, and cell surface display. In this study, Kajikawa inserted a linear epitope from the membrane proximal external region (MPER) of HIV-1 into the highly expressed bacterial surface layer protein (SlpA) of L. acidophilus, as a prototype oral mucosal vaccine platform, and assessed immunogenicity in a mouse model. n a preliminary experiment, L. acidophilus NCK2208 was only weakly immunogenic with no antibody response to MPER. To improve the mucosal immunogenicity of NCK2208, matured murine IL-1β was employed since IL-1 and IL-1 family proteins are known to act as mucosal adjuvants. We previously showed that biologically active IL-1β can be produced and secreted by another recombinant Lactobacillus strain. In the first round of i.g. immunization with the recombinant strain and reference strains, both MPER-specific Abs and the specific IgA-producing cells were detected exclusively in the group receiving the IL-1β-secreting strain. On the other hand, SlpA-specific responses did not rely on the cytokine. These results implied that the induction of MPER-specific but not SlpA-specific Abs was adjuvant-dependent. However, in the second trial where mice received four additional boosts, both L. acidophilus strains eventually elicited MPER-specific Ab responses regardless of IL-1β co-expression. This suggests that IL-1β was not essential for, but possibly expedited the specific immune responses. Additional studies are needed to confirm the adjuvant effect of IL-1β and better define the mechanism of action.
While Kajikawa teaches an engineered L. acidophilus cell comprising an exogenous polypeptide and at least one adjuvant polypeptide inserted into the S-layer protein, e.g., as a prototype oral mucosal vaccine platform, they do not particularly exemplify the use of FliC and/or FimH as the adjuvant polypeptide or the use of additional exogenous polypeptides.
Makvandi et al teach that flagellin is the major structural protein monomer of bacterial flagella. Flagellin through binding to its receptor and activation of antigen presenting cells stimulates the innate and adaptive immune responses. Flagellin is used as an effective systemic or mucosal adjuvant to stimulate the immune system. Recently, the therapeutic and protective role of flagellin in some infectious diseases and cancers has been investigated. In this study, we cloned the fliC genes from Salmonella typhimurium and Escherichia coli into pET-28a vector and investigated their expression in the prokaryotic system. Methods: The fliC genes of S. typhimurium and E. coli were amplified by PCR with a specific oligonucleotide primer set. thse were cloned into the pET-28a vector and the recombinant pET-28a-fliC plasmids were successfully transformed into the E. coli strain BL-21(DE3). The expression of flagellin proteins in the prokaryotic cells were evaluated. Finally, Transcription of TNF-α mRNA was confirmed using Real-time PCR. Results: The expression of proteins in the prokaryotic cells were approved by SDS-PAGE and western blotting method. Further, the functional characterization of flagellin proteins were evaluated using their ability to induce increased m-RNA expression of pro-inflammatory cytokine. Conclusions: The flagellin proteins were expressed in the prokaryotic system. These proteins can be used to link target antigens as an effective adjuvant for future DNA vaccine studies. Purified recombinant proteins in this study can also be used for therapeutic and prophylactic purposes.
The reference from the Paul-Ehrlich-Institut teaches the benefit of flagellin is that the gene sequence encoding for flagellin can be merged with gene sequences of various different antigens using genetic engineering technologies. This produces so-called fusion proteins, in which the antigen against which an immune response is to be induced and flagellin are closely connected with each other in a single molecule. Although multiple animal models and clinical studies have shown before that the administration of such fusion proteins efficiently induces immune responses against the fused antigen, it has up to now largely been unknown how such fusion proteins exactly induce these immune responses.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made that an appropriate adjuvant polypeptide to be co-expressed with a therapeutic/vaccine exogenous polypeptide in the successful vaccine platform taught by Kajikawa is flagellin polypeptide. Makvandi et al teaches that these adjuvant polypeptides can be expressed in prokaryotic host cell systems and the Paul-Ehrlich Insitut teaches they can be merged with various different antigens and expressed as fusion proteins. The use of second or additional exogenous polypeptides as recite din instant claims 26 and 27 would be an obvious design choice and one of ordinary skill in the art would be motivated to include additional antigens which reduce the number of immunizations and allow for a broader immunological response.
Claim(s) 12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kajikawa et al (PLoS one. October 2015. 10(10): 1-15) in view of Makvandi et al (Microbial Pathogenesis. May 2018. Vol 118: 87-90) and Paul-Ehrlich-Insititut (https://www.pei.de/EN/newsroom/press-releases/year/2017/12-mode-of-action-of-vaccine-adjuvant-flagellin-in-fusion-proteins-has-been-clarified.html#:~:text=The%20benefit%20of%20flagellin%20is%20that%20the,various%20different%20antigens%20using%20genetic%20engineering%20technologies December 2017), as applied to claims 1, 6, 12, 14, 15, 19, 23, 24, 26, 27, 29 and 30 above, and further in view of Dimitrov et al. 2006 (US 2006/0240515).
The teachings of Kajikawa, Makvandi and the Paul-Ehrlich-Institut are set forth above. Although they teach an engineered L. acidophilus cell comprising an viral polypeptide and at least one adjuvant polypeptide inserted into the S-layer protein, e.g., as a prototype oral mucosal vaccine platform, and FliC and/or FimH as adjuvant polypeptide, they do not particularly exemplify wherein the exogenous polypeptide is a SARS-CoV-2 antigen, and particularly one form a nucleocapsid protein, spike protein, envelope protein or membrane protein.
Dimitrov teaches whole-cell, microorganism-based vaccines, e.g., engineered bacterial cells, for the treatment of severe acute respiratory syndrome (SARS) comprising nucleic acid constructs encoding SARS-CoV spike proteins, including the use of operably linked prokaryotic promoters (e.g. [0011-19, 0079-87]; and Dimitrov claims 1, 20-21, and 32-33). Dimitrov provides an example of expression and secretion of the spike protein from E. coli cells (e.g. [0032, 0076]; Figure 2 and Example 7. Dimitrov teaches the microorganisms used for vaccines (i.e. necessarily adapted for administration to a subject) express the spike protein and include Listeria and Salmonella (e.g. [0024, 0099]; and Dimitrov claim 33; meeting limitations found in claims 1 and 17). Dimitrov teaches the spike proteins may be use alone or coupled to carrier proteins (i.e. peptide adjuvants), including formulated as a fusion protein (e.g. [0058, 0069, 0090, 0094]. [0090] An immune composition of the invention can include an adjuvant and a nucleic acid, polypeptide, peptide fragment, a peptidomimetic, a coupled protein, an immunopeptide of the invention, or any combination thereof. [0093] The invention also provides vaccines that include a nucleic acid, polypeptide, a peptide fragment, a peptidomimetic, a coupled protein, an immunopeptide of the invention, a nucleic or any combination thereof. Such vaccines can be formulated as described herein or as known in the vaccine arts. [0094] The invention also provides nucleic acid-based vaccines that express a polypeptide, a peptide fragment, or a coupled protein of the invention. [0099] The invention also provides microbe-based vaccines. Generally, these vaccines relate to microbes that have been transformed with a nucleic acid construct that provides for the expression of a polypeptide, a peptide fragment, or a coupled protein of the invention. For example, Listeria monocytogenes may be used as a vector to elicit T-cell immunity. This is because it infects antigen-presenting cells and also because infection originates at the mucosa. According, Listeria may be transformed with a nucleic acid construct that provides for the expression of a polypeptide, a peptide fragment, or a coupled protein that elicits an immune response against the spike protein from the coronavirus that causes severe acute respiratory syndrome. Highly attenuated forms of Listeria may be constructed according to methods reported in the art. Lieberman and Frankel, Vaccine, 20:2007 (2002). Salmonella may also be used as a vector to elicit a cytotoxic T lymphocyte (CTL) response against the coronavirus that causes severe acute respiratory syndrome. Accordingly, Dimitrov includes engineered bacterial cells wherein the adjuvant is expressed with the exogenous polypeptide antigen.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use any of the Covid viral proteins taught by Dimitrov in the Lactobacillus acidophilus vaccine platform taught by Kajikawa et al because Kajikawa teaches numerous advantages over E. coli. For example, the L.acidophilus: 1) it is acid and bile tolerant; (2) it expresses mucus-binding proteins and associates with the intestinal mucosa; and (3) it binds to dendritic cells (DCs) through DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) and other pattern recognition receptors. Additionally, Kajikawa teaches that the SLAP is a highly expressed bacterial surface layer protein (SlpA) which would be advantageous for expression of the exogenous peptides. The use of Kajikawa’s vaccine platform and the polypeptide adjuvants taught by Makvandi and Paul-Erlich institute to express the covid antigens taught by Dimitrov would have been prima facie obvious to one of ordinary skill in the art as it would be expected to be an improved vaccine platform as Kajikawa teaches L.acidophilus: 1) it is acid and bile tolerant; (2) it expresses mucus-binding proteins and associates with the intestinal mucosa; and (3) it binds to dendritic cells (DCs) through DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) and other pattern recognition receptors. Additionally, Kajikawa teaches that the SLAP is a highly expressed bacterial surface layer protein (SlpA) which would be advantageous for expression of the exogenous peptides. Both SARS-CoV-2 and SARS-CoV use the same host cell receptor. It also found that, for both viruses, the viral proteins used for host cell entry bind to the receptor with the same tightness (affinity). SARS-CoV and SARS-CoV-2 share many viral antigens, as both viruses are genetically similar and belong to the same family of coronaviruses. They are closely related, with genetic sequences indicating an 80% similarity between SARS-CoV-1 and SARS-CoV-2. This genetic similarity suggests that they may share some common antigens that are involved in their pathogenesis and transmission dynamics. Accordingly, the use of a SARS-CoV2 antigen, would have been an obvious design choice as well.
Response to Applicants’ arguments:
Applicants argue that:
The § 103 rejections are overcome by argument: the cited references collectively fail to teach or suggest FimH as an adjuvant polypeptide expressed by an engineered bacterial cell (Rejection 4 and 5); Paul-Ehrlich-Institut teaches FlaA from Listeria, not FliC, and is directed to allergy therapy rather than a live bacterial vaccine platform (Rejection 4 and 5); Makvandi's vaccine adjuvant application is explicitly characterized as future work and is limited to in vitro purified protein characterization (Rejection 4 and 5); and Dimitrov discloses SARS-CoV antigens from a virus that is distinct from SARS-CoV-2 (Rejection 5).
These arguments have been fully and carefully considered but are not deemed persuasive because they are not commensurate in scope with the claimed invention. As addressed above, the instant claims do not require that FimH be in the engineered cell given the ambiguity in the wording of the claims. See 112, first and second paragraph rejections above. Additionally, Makvandi teaches that the fliC genes of S. typhimurium and E. coli were amplified by PCR with a specific oligonucleotide primer set. thse were cloned into the pET-28a vector and the recombinant pET-28a-fliC plasmids were successfully transformed into the E. coli strain BL-21(DE3). The expression of flagellin proteins in the prokaryotic cells were evaluated. Finally, Transcription of TNF-α mRNA was confirmed using Real-time PCR. Results: The expression of proteins in the prokaryotic cells were approved by SDS-PAGE and western blotting method. Further, the functional characterization of flagellin proteins were evaluated using their ability to induce increased m-RNA expression of pro-inflammatory cytokine. Conclusions: The flagellin proteins were expressed in the prokaryotic system. These proteins can be used to link target antigens as an effective adjuvant for future DNA vaccine studies. Purified recombinant proteins in this study can also be used for therapeutic and prophylactic purposes. Makvandi’s teachings provide the motivation to combine the flagellin protein with a target antigen. They expressly state that the flagellin proteins can be used to link target antigens as an effective adjuvant. That is the motivation for using them. Paul-Erlich is used for its teaching of flagellin proteins in general, and the teaching that they can be merged with various different antigens and expressed as fusion proteins. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Lastly, both SARS-CoV-2 and SARS-CoV use the same host cell receptor. It also found that, for both viruses, the viral proteins used for host cell entry bind to the receptor with the same tightness (affinity). SARS-CoV and SARS-CoV-2 share many viral antigens, as both viruses are genetically similar and belong to the same family of coronaviruses. They are closely related, with genetic sequences indicating an 80% similarity between SARS-CoV-1 and SARS-CoV-2. This genetic similarity suggests that they may share some common antigens that are involved in their pathogenesis and transmission dynamics. Accordingly, the use of a SARS-CoV2 antigen, would have been an obvious design choice as well and claims 12 and 14 do not specify a specific antigen, but broadly allow for any “SARS-CoV2 antigen, spike proteins or membrane proteins.
Status of claims:
“An engineered Lactobacillus acidophilus strain that expresses both an exogenous immunogenic polypeptide from a virus and a fusion polypeptide comprising flagellin (FliC) and type 1 fimbrin D- mannose specific adhesin protein (FimH), wherein the polypeptides are integrated into the bacterial S-layer protein (SLP) or S-layer associated proteins (SLAPs)” is free of the prior art and 112, issues recited above.
Note: claim 9 is withdrawn and has not been amended for potential rejoinder. The claim is dependent on canceled claim 7 and includes the indefinite claim language “any derivatives or fragments thereof.” The claim may be “withdrawn amended.”
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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-Friday from 8:00 AM-4 PM.
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/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 5/7/26
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