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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/7/26 has been entered.
Claims 1, 3-5, 7-9, 14, 15 and 17-24 are currently pending.
Claims 14 and 15 remain withdrawn from consideration for being drawn to a non-elected invention.
Claims 1, 3-5, 7-9 and 17-24 are currently under examination.
Claim Objections
Claim 1 is objected to because of the following informalities: the word “microbiota” in line 6 of the claims is repeated twice. One of the “microbiota” should be deleted. Appropriate correction is required.
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, 3-5, 7-9 and 17-24 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 indefinite because use of “said antigen” in the claim is unclear. The amended claim now recites oral microbiota that comprise and antigen having “structural similarity to a spike protein, or a receptor binding domain (RBD) sequence of a spike protein of the coronavirus” and with the added functional ability of inducing production of a neutralizing antibody that binds the spike protein. This antigen is not adequately defined for one to understand the immunogen. The functional limitation provides no insight to the actual sequence of the antigen. The description of this antigen is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. The claim should provide any structural properties, such as the amino acid sequence of this individual antigen, which would allow for one to identify the antigen without ambiguity. The mere recitation of a name does not adequately define the claimed the antigen to be used as the active immunogen. This is different than administering a whole cell bacterium. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow one to identify what is being claimed.
Appropriate correction and/or clarification is required.
Claim Rejections - 35 USC § 112-Written Description
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, 3-5, 7-9 and 17-24 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.
Newly amended claim 1 recites:
(Currently amended) A method for inducing production of a neutralising antibody that binds a spike protein of a coronavirus and treating and/or reducing the risk of infection of a subject by the coronavirus, the method comprising:
administering to a subject an immunogenic composition, said composition comprising: one or more commensal bacteria of the human oral microbiota microbiota comprising an antigen having structural similarity to a spike protein, or to a receptor-binding domain (RBD) sequence of a spike protein, of the coronavirus, said structural similarity being sufficient to induce in the subject production of a neutralising antibody that binds the spike protein, wherein the commensal bacteria comprise one or more of Streptococcus salivarius, Veillonella parvula, Bacillus cereus and/or Bifidobacterium pseudocatenulatum, and/or
said antigen, wherein after administering the composition in the subject, the bacteria or antigen induces induce production of the neutralising antibody that binds the antigen and the spike protein, thereby inducing acquired immunity to the coronavirus infection in the subject.
The instant specification fails to provide written description for an “isolated antigen” which upon administration induces induce production of the neutralising antibody that binds the antigen and the spike protein, thereby inducing acquired immunity to the coronavirus infection in the subject.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of antigens such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed.
With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" inquiry, whatever is now claimed. See Vas-Cath, Inc. v. Mahurkar,935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).Furthermore, the written description provision of 35 USC § 112 is severable fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The [product] itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus'" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fires v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).
University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
In the instant case, there is no structure associated with function with regard to the members of the genus of described antigen. The specification does not describe the structure for a representative number of antigens from the Genus, with the required functionality in the claim.
Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1). C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Kwiatkowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
Because the art is unpredictable and the scope of the claim includes numerous structural variants and the genus is highly variant because a significant number of structural differences between genus members is permitted. The specification does not describe any members of the claimed genus by complete structure. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
There are no drawings or structural formulas disclosed of any of theseantigens. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of modified Corynebacterium.
"Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
Claim Rejections - 35 USC § 112-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, 3-5, 7-9 and 17-24 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Newly amended claim 1 recites:
(Currently amended) A method for inducing production of a neutralising antibody that binds a spike protein of a coronavirus and treating and/or reducing the risk of infection of a subject by the coronavirus, the method comprising:
administering to a subject an immunogenic composition, said composition comprising: one or more commensal bacteria of the human oral microbiota microbiota comprising an antigen having structural similarity to a spike protein, or to a receptor-binding domain (RBD) sequence of a spike protein, of the coronavirus, said structural similarity being sufficient to induce in the subject production of a neutralising antibody that binds the spike protein, wherein the commensal bacteria comprise one or more of Streptococcus salivarius, Veillonella parvula, Bacillus cereus and/or Bifidobacterium pseudocatenulatum, and/or
said antigen, wherein after administering the composition in the subject, the bacteria or antigen induces induce production of the neutralising antibody that binds the antigen and the spike protein, thereby inducing acquired immunity to the coronavirus infection in the subject.
The instant specification fails to provide enablement for an “isolated antigen” which upon administration induces induce production of the neutralising antibody that binds the antigen and the spike protein, thereby inducing acquired immunity to the coronavirus infection in the subject.
The instant specification provides no more than a simple verbal statement of the possible therapeutic use of Bacillus sanfensis, Bacillus pumilis, Bacillus mobilis, Baccilus cereus, Velionella parvulla, Staphylococcus epidermidis, Bifidobacterium pseudocatenulatum, Bifidobacterium longum or an Escherichia strain to treat or prevent conditions associated with SARS- COV-2. This also applies to treatment of SARS-Cov infections in general other than SARS-CoV-2, as only SARS-CoV-2 has been tested in the present application. 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.”
The instant specification discloses the administration of heat-killed (example 8) S. salivarius strains of the upper respiratory tract microbiome i.e. as a vaccine and does not encompass administration of individual antigens from S. salivarius, V. parvula, B.cereus and/or B. pseudocatenulatum. Kaci et al (Appl. Environ. Microbiol. Feb 2014, 80(3): 928-934), for instance, showed that oral administration of a live S. salivarius strain protects against inflammatory disorders in mice, while administration of dead bacteria does not. The reference states that S. salivarius has been used without any safety issues for many years as an oral probiotic against streptococcal pharyngitis and halitosis in New Zealand and that strain K12 received FDA generally regarded as safe (GRAS) status in the United States in 2011 might facilitate the use of other strains of this species as probiotics. In the instant specification, the unexpected effect linked to this difference is the generation of antibodies against this bacteria that cross-reacts with SARS- CoV-2 RGB region of the spike protein, with the use of killed/dead bacteria. These are anti-SARS- Cov2 neutralizing antibodies. The effect has been demonstrated in the specification for Streptococcus salivarius (K12) (examples 7,8 and 9) for heat-killed bacteria in the context of SARS- Cov-2. The same applies to SARS diseases other than SARS-Cov-2. It is further noted that the present claims are not clearly directed to the treatment of SARS-CoV-2 but to the prevention or the treatment of conditions associated with SARS-COV2. These conditions have not been tested.
Despite the identification of various bacteria that can induce cross-reactive immune responses against the RBD domain of the SARS-CoV-2 Spike protein, it remains to be determined whether induction of such antibodies in humans may protect from SARS-CoV-2 infection or severe course of COVID-19.
MacPherson et al Annual review of Immunology. Vol. 36:359-381 (Volume publication date April 2018) IgA antibodies at mucosal surfaces are mainly induced by commensal microbiota.
Applicants have found that RSSL-01370 of S. salivarius can induce both non-neutralizing and neutralizing Abs against S and subsequently promote viral clearance in vivo in an animal model. The instant specification teaches oral supplementation with S. salivarius and B. pseudocatenulatum induced such cross-reactive Abs in mice. SARS-CoV-2 vaccination induces an early increase in S. salivarius in the oral cavity.
Anti-Spike-SARS-CoV-2 antibodies bind to S. salivarius via molecular mimicry S. salivarius induces cross-reactive anti-Spike Abs in mice, aiding virus clearance. S. salivarius boosts salivary anti-Spike antibodies in the vaccinees. The specification shows that a specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals.
The prior art teaches that secretion of Abs at mucosal surfaces can be enhanced by antigens presented by the mucosal microbiota. It is estimated that the human microbiota contains several millions of genes, thus potentially providing a plethora of epitopes for Ab binding. Some of these epitopes may resemble host proteins, potentially inducing cross-reactive autoimmunity, whereas others may mimic proteins from different microorganisms and provide cross-protective immunity.12 Microbiota-induced immunity is known to provide protection against microbial infections by Citrobacter rodentium, Clostridiodes difficile, Pseudomonas aeruginosa and by viruses such as influenza, yet these studies do not directly correlate to any bacteria from any human microbiota treating or reducing o medical condition associated with coronavirus or SARS-CoV. The instant specification identified distinct bacterial mimics of RBD, and investigated whether the bacteria expressing these proteins could induce a cross-reactive anti-RBD Ab response in vivo. They focused on S. salivarius and B. pseudocatenulatum, taking into account that S. salivarius is increased in humans after the first month upon vaccination (Figure 2H) and on B. pseudocatenulatum abundance which inversely correlates with the development of the post-COVID-19 acute syndrome. Considering that these bacteria can be normal constituents of the microbiota, Applicants fed C57BL/6 mice by oral gavage with S. salivarius K12 or B. pseudocatenulatum to test whether a cross-reactive IgA response would be induced. Within 21 days, fecal IgA reactive to RBD was detectable in mice fed with both S. salivarius K12 and B. pseudocatenulatum (Figure 4A). At the same time, they failed to detect anti-RBD antibody responses upon immunization with Bifidobacterium pseudocatenulatum (Fig. 4B). Thus, isolated bacterial strains might induce anti- RBD responses. It is noted that the present claims are not clearly directed to the treatment of SARS-CoV-2 but to the treatment of conditions associated with SARS-COV2.
Response to Applicants’ arguments:
Applicants arguments as they pertain to the rejection of the newly amended claims:
Example 11 and Fig. 12A thus show that administration of live S. salivarius K12 and B. pseudocatenulatum leads to induction of an anti-RBD IgA antibody response in fecal supernatants of mice. It is further shown that such produced antibodies produced in that way can inhibit the interaction between the spike protein RBD and its receptor ACE2.
Figure 11B: Inhibition of RBD binding to ACE2 by sera from bacteria immunized animals. The data thus show that immunization with any one of S. salivarius, Veillonella parvula, Bacillus cereus or B. pseudocatenulatum leads to induction of neutralizing antibodies inhibiting binding of RBD to ACE2 (Fig. 11B, 12B).
Moreover, sera from immunized mice were able to inhibit infection of Vero6 cells by pseudovirus and Fig. 4D shows that sera from mice immunized with Streptococcus salivarius K12 also inhibited binding of RBD to ACE2 expressed in 293 T cells. Since 293 T cells are human cells, these data support the usability of the bacteria for treating and/or reducing the risk of infection of a subject by a coronavirus not only in mice, but also in humans. Additionally, for S. salivarius, anti-RBD antibody production could also be shown in humans (Fig. 15).
Together with the fact that several bacteria that were shown to produce neutralizing antibodies in mice were also found to bind to anti-RBD antibodies from COVID-19 patients (Fig. 3C: B. pseudocatenulatum, S. salivarius, V. parvula), these findings also support applicability to host species other than mice, such as humans. Of note, Veillonella and Streptococcus genera were significantly reduced during severe COVID (Fig. 5D; p. 28, 1. 36-38; p. 29, 1. 9-11), suggesting a cross-reactivity of anti-IgG antibodies against said genera also in humans. The effect of producing neutralizing antibodies is thus clearly demonstrated for killed and live bacteria, making it therefore also plausible for the respective attenuated bacteria and their respective antigens that they are capable of inducing the neutralizing antibodies. A limitation to killed bacteria and/or to S. salivarius would therefore represent an undue limitation of the claims as there are data showing that live bacteria and bacteria other than S. salivarius also provide the effect of producing neutralizing antibodies.
The Examples further demonstrate that antibodies produced in mice immunized with different bacteria, such as the claimed Veillonella parvula and S. salivarius, also bind the spike protein of human coronaviruses other than SARS-CoV-2, namely NL63, 229E, HKU1 and OC43 (see Example 12, Fig. 13). These data support generalizability to coronaviruses other than SARS- CoV-2. The data thus support a method for inducing production of a neutralizing antibody that binds a spike protein of a coronavirus and of treating and/or reducing the risk of infection of a subject by a coronavirus due to a reduced likelihood of coronavirus infection of cells via interaction with the receptor protein after treatment with the recited bacteria.
These arguments have been fully and carefully considered but are not commensurate in scope with the claimed invention. The instant claims allow for the administration of an “antigen”. The instant specification had not identified or shown any working examples with a single antigen. They have only shown whole cell bacteria.
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, 3-5, 7-9 and 17-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Di Pierro et al (Minerva Medica. June 1, 2020. 111(3): pages 1-3. “A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SAR S-CoV-2.”; provided by Applicants), D’Ettorre et al (Frontiers in Med. Vol 7. July 7, 2020. Pages 1-7; provided by Applicants) and Olaimat et al (Science of Food 4(1), pages 1-7, 12/1/2020; provided b y Applicants) and
Di Pierro et al. discloses that Covid-19 patients with pneumonia have a different lung microbiota composition compared to healthy individuals, particularly Streptococcus salivarius (K12) was found and correlated with an improved immune response against coronavirus SARS-Cov-2. The effect is attributed to the enhancement of production of salivary IFN-y upon administration of the Streptococcus salivarius (K12) (Fig.1). Figure 1 shows the detection of salivary IFN-γ after administration of Streptococcus salivarius K12. They teach that Streptococcus salivarius, known as K12, has been clinically demonstrated to play a role in creating a stable upper respiratory tract microbiota capable of protecting the host from pathogenic bacteria, fungi and viruses, thereby reducing the incidence of streptococcal pharyngo-tonsillitis, acute and secretory otitis media, halitosis, oral thrush and viral infections (rhinitis, influenza, pharyngitis, laryngitis, tracheitis and enteritis). The antibacterial role of strain K12 has been attributed to the release of bacteriocins (Salivaricin A2 and Salivaricin B) that can create instability in the membranes of susceptible, pathogenic bacteria. Streptococcus salivarius is a predominant commensal species in healthy oral and upper respiratory tract microbiotas, and some members of this species have been shown to actively interfere with the growth of potentially-pathogenic microbes. Along with other oral commensals, Streptococcus salivarius is a common member of the lung eubiotic microbiota, and its presence in the lung correlates with healthy or more stable conditions. COVID-19 patients have a significantly altered lung microbiota, particularly enriched by potentially pathogenic species of bacteria and markedly different to that of healthy subjects. Strain K12 is the most thoroughly studied strain of Streptococcus salivarius. Colonization of the upper respiratory tract with strain K12 leads to a significantly reduced occurrence of many viral upper respiratory tract infections, both in children and in adults, possibly due to its ability to stimulate IFN-γ release and to activate natural killer cells without triggering aggressive inflammatory responses. Although its efficacy has never been specifically evaluated with respect to SARS-CoV-2, the various observations of its clinical potential, together with its strong safety profile extending over more than 20 years of probiotic application, may prompt physicians to consider using it as an adjunct to help control viral lung infections and associated pneumonias and to improve host immune functions.
D'Ettore et al discloses the administration of live probiotics comprising Streptococcus thermophilus DSM 32345, L. acidophilus DSM 32241, L. helveticus DSM 32242, L. paracasei DSM 32243, L. plantarum DSM 32244, L. brevis DSM 27961, B. lactis DSM 32246, B. lactis DSM 32247 to treat COVID-19 in particular to prevent respiratory failure (Abstract).
Olaimat et al. discloses that probiotics supplementation (not inactivated or killed) would prevent or treat respiratory tract infection in the context of coronavirus and Covid-19 (abstract and page 3).
The instant claims are drawn to methods using improved probiotic compositions to treat or prevent conditions associated with coronavirus and SARS-CoV infection. The difference between D’Ettore and the present claims is the choice of a different bacteria of the microbiome that is administered to treat or prevent SARS-Cov-2. One of ordinary skill in the art would have been motivated to administer S.salivarius K12 to covid patients as suggested in the Di Pierro et al reference. The composition of Di Pierro is configured for oral administration. It is noted that the administration of the bacteria itself is inherently linked to the production of cross-reactive antibody with RBD of the spike of SARS-Cov-2, in their present formulation (instant claims 4-5). It could reasonably have been expected that live bacteria will also raise cross-reactive antibodies to SARS- Cov-2 as seen in example 1 and 2 of the instant specification. With regard to the other strains mentioned, in absence of any demonstrated special technical effect, they are seen as obvious alternative probiotics of the normal microbiome of the oral or gastrointestinal respiratory tract that are seen as equally suitable as the probiotics, to prevent or treat conditions associated with SARS-CoV infection.
Response to Applicants’ arguments:
Applicant argue:
Even if the technical effect of producing a neutralizing antibody that binds a bacterial antigen and the spike protein of a coronavirus, thereby inducing acquired immunity to a coronavirus infection may be inherent to the bacteria, the effect, and hence the purpose of the claimed method, is not obviously derivable from the cited prior art documents. The method of the present invention is performed in order to produce a neutralizing antibody that binds a spike protein of a coronavirus and for treating and/or reducing the risk of infection of a subject by the coronavirus. This purpose is distinct from, and thus not obviously derivable from, any of the cited prior art documents.
Based on the above amendments and remarks, Applicant respectfully submits that the combination of Di Pierro, D'Ettore, and Olaimat et al. wholly fails to teach or motivate all elements required by the instantly claimed invention. The above-described differences between the instantly claimed invention and the prior art of record represent novel departures that are respectfully submitted to be entitled to patentable weight. As such, currently amended independent claim 1 and all claims dependent therefrom, are believed to be novel and in allowable form. Additionally, Applicant respectfully submits that all currently pending dependent claims include subject matter allowable separate from dependency from independent claim 1. Applicant reserves the right to make such arguments in due course of prosecution in the event that any of these rejections are maintained.
These arguments have been fully and carefully considered but are not deemed persuasive. The objective of the claimed methods and the method steps of the claimed method are the same as those taught by DiPierro. Although DiPierro does not specifically test for neutralizing antibody that binds spike protein, it would inherently occur given the same compositions being used for the same purposes. It is noted that the administration of the bacteria itself is inherently linked to the production of cross-reactivity with RBD of the spike of SARS-Cov-2 in the present formulation so such live bacteria would also be expected to raise cross-reactive/neutralizing antibodies to SARs-CoV-2.
Prior art not presently relied upon:
Marchisio et al (EUr. J. Clin. Microbio. & Infect. Dis. 34(12). Sept. 2015, pp. 2377-2383; provided by Applicants) discloses the administration of S. salivarius K12 (not inactivated or killed) by nasal spray to prevent otitis media in children.
Di Pierro Francesco (Clinical Effects of Streptococcus salivarius K12 in Hospitalized COVID-19 Patients: Results of a Preliminary Stdy. Microorganisms, (2022 Sep 28. Vol. 10, No. 10; post-filing date)
Di Pierro Francesco (The administration of S. salivarius K12 to children may reduce the rate of SARS-CoV-2 infection; Minerva medica, (20210800) Vol. 112, No. 4, pp. 514-516; post-filing date).
Bondareva et al Cell Host & Microbe Volume 31, Issue 11, 8 November 2023, Pages 1866-1881.e10 interestingly, introduction of K12 into mice induced anti-S responses, whereas K12 administration in humans, who harbor S. salivarius as commensal, did not significantly increase S-specific IgA in the saliva. By contrast, vaccinated persons supplemented with S. salivarius showed the enhanced presence of salivary anti-S1 IgG Abs. Whether these IgG Abs are produced by sort-or long-lived plasma cells, and whether in this case trans-epithelial transport is affected, remains to be shown. Considering that such an increase has been observed not only for wild-type (WT) S but also for omicron RBD and sequence-related RBD of human coronavirus HKU1, but not for sequence-unrelated NL63 RBD (Figure 6; data not shown), it is conceivable that the induction of such Abs may happen locally at the mucosal surfaces via low-affinity interactions. Thus, it would be interesting to evaluate in the future the secreted and systemic Ab repertoire that can be shaped via molecular mimicry.
TITLE: Disruption of nasal bacteria enhances protective
immune responses to influenza A virus and
SARS-CoV-2 infection in mice
AUTHOR(S): Nagai, Minami; Moriyama, Miyu; Ichinohe, Takeshi
CORPORATE SOURCE: Division of Viral Infection, Department of Infectious
Disease Control, International Research Center for
Infectious Diseases, Institute of Medical Science, The
University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan
SOURCE: bioRxiv (2020) 1-42, 2020
CODEN: BIORFP
URL: https://www.biorxiv.org/
DIGITAL OBJECT ID: 10.1101/2020.12.25.424300
PUBLISHER: Cold Spring Harbor Laboratory Press
DOCUMENT TYPE: Preprint
LANGUAGE: English
ED Entered STN: 05 Jan 2021
AB Gut microbiota plays a crit. role in the induction of adaptive immune
responses to influenza virus infection. However, the role of nasal
bacteria in the induction of the virus-specific adaptive immunity is less
clear. Here we demonstrate that while intranasal administration of
influenza virus hemagglutinin vaccine alone was insufficient to induce
the vaccine-specific antibody responses, disruption of nasal bacteria by
lysozyme or addn. of culturable oral bacteria from a healthy human
volunteer rescued inability of the nasal bacteria to generate antibody
responses to intranasally administered the split-virus vaccine.
Myd88-depdnent signaling in the hematopoietic compartment was required for
adjuvant activity of intranasally administered oral bacteria. In addn.,
we found that the oral bacteria-combined intranasal vaccine induced
protective antibody response to influenza virus and SARS-CoV-2
infection. Our findings here have identified a previously unappreciated
role for nasal bacteria in the induction of the virus-specific adaptive
immune responses.
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