DETAILED ACTION
Acknowledgment and entry of the Amendment submitted on 3/3/26 and the Supplemental response of 3/4/26 is made.
Claims 1-5, 7-9 and 14-23 are currently pending.
Claims 14 and 15 remain withdrawn for being drawn to a non-elected invention.
Claims 1-5, 7-9 and 16-23 are currently under examination.
Applicants have satisfied the sequence compliance requirements.
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 1-5, 7-9 and 16-23 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 it is unclear what “medical conditions associated with coronavirus” encompass. This is vague and indefinite. 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 for one to identify what is being claimed. The diseases meant by "conditions associated with coronavirus infection" should be clearly recited in the claims in order to be considered clear. Appropriate correction and/or clarification is required.
Claim 1 is also vague and indefinite due to the recitation of a composition comprising “one or more bacteria of the human microbiota and/or immunogenic parts thereof”. The human microbiota is vast and it is unclear what bacteria this composition comprises. The composition is not adequately defined. Gut microbiota may comprise Firmicutes (e.g., Clostridium, Lactobacillus, Ruminococcus, Faecalibacterium prausnitzii), Bacteroidetes (e.g., Bacteroides, Prevotella),Actinobacteria (e.g., Bifidobacterium), Proteobacteria (e.g., Escherichia coli in small numbers), Skin microbiota as vast as Staphylococcus epidermidis, Propionibacterium acnes (now Cutibacterium acnes), Corynebacterium spp.,Staphylococcus aureus, Oral microbiota: Streptococcus mutans, Streptococcus salivarius, Porphyromonas gingivalis, Vaginal microbiota: Lactobacillus species (e.g., L. crispatus, L. jensenii), and Nasal/respiratory microbiota, etc. Then, the claim also recites any “immunogenic parts thereof” which is incredibly vague. It is unclear what actual ‘parts’ are being referenced and from such a vast number of bacteria. Accordingly, the composition to be used in the method is not adequately define and the metes and bounds of the invention is not readily understood. 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 for one to identify what is being claimed.
Applicants have amended the claim 1 to recite “coronavirus” instead of SARS-CoV and added the phrase “wherein after administration of said bacteria in the subject, the bacteria induce production of a neutralising antibody that binds said bacteria and the spike protein of a coronavirus.” First, it is unclear if the ‘immunogenic parts thereof’ also induce production of a neutralising antibody that binds said bacteria and the spike protein of a coronavirus since the claim just recites production of such antibodies occur after administration of ‘said bacteria” and does not include “and/or immunogenic parts thereof”. Second, this functional language provides no incite to the structure being claimed.
Appropriate correction and/or clarification is required.
Response to Applicants’ arguments:
Applicants argue:
Applicant respectfully submits that the recitation "medical condition associated with a coronavirus infection" is sufficiently definite as a PHOSITA readily understands what medical conditions are associated with a coronavirus infection. Applicant also submits that the recitations "human microbiota" and "immunogenic parts thereof" are also sufficiently definite to a PHOSITA, in at least because claim 1 has been amended to recite in relevant part, "wherein after administration of said bacteria in the subject, the bacteria induce production of a neutralising antibody that binds said bacteria and the spike protein of a coronavirus." This amendment is respectfully submitted to provide adequate structural properties to be sufficiently clear and definite.
These arguments have been fully and carefully considered but are not deemed persuasive. There are many different “parts” of bacteria with vastly different structures and properties. A “part” is not an art-recognized term to define a structure. Applicants have argued that a person of ordinary skill in the art would know what is “human microbiota” and any “immunogenic parts thereof”, but this argument is not persuasive. The claim is drawn to a method which requires administration of said ‘human microbiota’ or any ‘immunogenic parts thereof.’ Human microbiota consists of the fully array of microorganisms that live on and in humans, e.g,, bacteria, archaea, fungi, viruses, and some protozoans that inhabit various parts of the body, including the gut, skin, mouth, respiratory tract, and urogenital system. The microbiota collectively contributes to the human microbiome, which is the total genetic material of these microorganisms. The genomes that constitute the human microbiome represent a remarkably diverse array of microorganisms that includes bacteria, archaea (primitive single-celled organisms), fungi, and even some protozoans and nonliving viruses. Bacteria are by far the most numerous members of the human microbiome: the bacterial population alone is estimated at between 75 trillion and 200 trillion individual organisms, while the entire human body consists of about 50 trillion to 100 trillion somatic (body) cells. The sheer microbial abundance suggests that the human body is in fact a “superorganism,” a collection of human and microbial cells and genes and thus a blend of human and microbial traits.
Accordingly, the bacteria of the human microbiota vary among individuals and the components are vast. The claim does not clearly or adequately describe the composition to be administered. The use of the functional language “wherein the bacteria induce production of neutralizing antibody” does not help to define the structure of the composition being administered. 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 for one to identify what is being claimed.
Appropriate clarification and/or correction is required.
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) 1-5, 7-9 and 16-23 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 (however, it is noted that claims 1, 2, 4, 5, 7-9 and 16-23 do not recite any genus or species of bacteria, e.g., they recite of the human microbiota), especially the medical conditions associated with SARS- Cov2, recited in instant claim 7. 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 4-6). 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 claim 3, 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 that generation of coronavirus spike protein-cross-reactive antibodies by human microbiota is a technical effect clearly distinct from the mechanism disclosed in Di Pierro et al., in which the attribute of S. salivarius K12 to modulate an immune response is through enhancing the levels of IFN-γ, as well as K12 suppressing bronchial inflammatory responses by inhibiting NF-kB pathways (see Di Pierro, p. 281, right column). Moreover, IFN-γ was detected in Di Pierro within 24 hours after K12 supplementation, suggesting amplification of non-specific innate immune responses, but not adaptive immunity. Adaptive immunity takes much longer to develop. In stark contrast, in the context of the present invention, the immune modulation relates to antibody production. Neither Di Pierro et al nor D'Ettorre et al disclose this technical effect. The technical effect achieved by the invention is thus not obvious over the cited prior art documents.
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 neutralzing 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 antibodes to SARs-CoV-2.
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 1-5, 7-9 and 16-23 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.
Instant claim 1 encompasses for example:
A method for treating and/or reducing the risk of any medical condition associated with a SARS-CoV infection, the method comprising administering to a subject an immunogenic composition, said composition comprising one or more of any bacteria of the human microbiota and/or immunogenic parts thereof, wherein said composition is capable of inducing acquired immunity to said infection.
The instant specification does not enable this invention. 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. The specification also only teaches the administration of killed/dead S.salivarius 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 live or attenuated probiotics, any immunogenic parts of any bacteria or any probiotic other than killed S. salivarius. This is seen as an essential technical feature and should be incorporated into the claims. Alternatively, evidence that killed and live bacteria attain the claimed technical effect should be provided. 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. There is no evidence on file that the bacteria of claim 3 other than S. salivarius have this unexpected property, nor that live bacteria would provide the same technical effect. 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 (as in claims 7) 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 prevention or the treatment of conditions associated with SARS-COV2. These conditions (as in claims 7) have not been tested.
Response to Applicants’ arguments:
Applicants argue:
Amended claim 1 recites a medical condition associated with a coronavirus infection. The Examples of the present invention demonstrate that neutralising antibodies from mice immunized with different bacteria, e.g. Veillonella, Bifidobacterium pseudocatenulatum and S. salivarius, also bind the spike protein of a coronavirus, wherein different coronaviruses were tested, including SARS-CoV-2, NL63, 229E, HKU1 and OC43 (see Examples 10-12, p. 29ff., Figs. 11-13). This indicates that the immunogenic composition according to the present invention is applicable not only to SARS-CoV-2, but also to other coronaviruses. Considering the technical effect of the invention and the generation of a neutralizing antibody response against a coronavirus, and when considering Example 8, which shows that sera from mice immunized with bacteria prevented infection of target Vero6 cells by a pseudovirus expressing spike protein, it is certainly plausible that any disease condition associated with a coronavirus infection can be treated or prevented, as the activity and infectivity of the virus itself is known to be attenuated by the antibody response, which has been shown in detail and in multiple models. See also Fig. 4B, 4D, 11B and 12B. The present invention is based on the novel technical effect of commensal bacteria inducing a neutralising antibody which recognises a spike protein of a coronavirus. The instantly claimed invention is respectfully submitted to be sufficiently disclosed and enabled in at least due to the evidence shown in the Examples, in addition to demonstration of the cross-reactivity between various commensal bacteria and the RBD of various coronavirus spike proteins (e.g. Examples 2- 3, 7, 10-12) as well as demonstration of the relevant technical effect including inhibition of the interaction of the RBD of the spike protein of a virus with ACE2, thus inhibiting infection and therefore plausibly treating and/or reducing the risk of a medical condition associated with a coronavirus infection (see Examples 1, 4, 8 and 10-12; Fig. 1E; p. 25, 1. 12-21; p. 18, 1. 1-5; p. 15, 1. 37-39; and p. 7, 1. 33-38). Live or attenuated bacteria: The experiments of Examples 1-3 demonstrate that the IgA from living fecal microbiota recognised the RBD of coronavirus and that neutralising anti-RBD antibodies recognised commensal bacteria isolated from humans. Furthermore, Example 11 and Fig. 12A show that administration of live (see also p. 35, 1. 10) K12 and B. pseudo leads to induction of the desired antibody response in fecal supernatants of mice. Therefore, it is certainly plausible that living bacteria enable the technical effect of inducing a neutralising antibody that recognises a spike protein of a coronavirus. Similarly, since the effect is plausible for living and killed bacteria, the effect is also plausible for attenuated bacteria. "Any" bacteria of the human microbiota and/or immunogenic parts thereof: Experimental data can be found for different bacteria, e.g., several Bacilli species, Streptococci, Staphylococcus epidermidis, Bifidobacteria, several Enterococci species, Veillonella and Acidaminococcus were identified as bacterial strains bound by anti-RBD antibodies (Fig. 3B- C; Fig. 8 and 10; p. 27, 1. 27-30). Example 4, Fig. 11A and Fig. 12A show that microbiota species can induce anti-RBD antibody production. Inhibition of ACE2-RBD binding via neutralizing antibodies is demonstrated upon use of different bacterial strains, e.g., in Fig. 11B and Fig. 12B. Hence, sufficient evidence is provided in the application as filed for various commensal bacteria supporting a generalization to human microbiota. As such, it is also plausible that immunogenic parts of the bacteria (e.g. antigens, see also Example 3 and p. 31, 1. 10-12) of the human microbiota also provide the technical effect of inducing production of a neutralising antibody that binds said bacteria and the spike protein of a coronavirus. Applicant respectfully submits that the extensive data on file sufficiently enables a PHOSITA to be able to reproduce the instantly claimed invention without undue effort.
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 any ‘one or more bacteria’ of the human microbiota and/or any immunogenic part thereof. Human microbiota consists of the fully array of microorganisms that live on and in humans, e.g,, bacteria, archaea, fungi, viruses, and some protozoans that inhabit various parts of the body, including the gut, skin, mouth, respiratory tract, and urogenital system. The microbiota collectively contributes to the human microbiome, which is the total genetic material of these microorganisms. The genomes that constitute the human microbiome represent a remarkably diverse array of microorganisms that includes bacteria, archaea (primitive single-celled organisms), fungi, and even some protozoans and nonliving viruses. Bacteria are by far the most numerous members of the human microbiome: the bacterial population alone is estimated at between 75 trillion and 200 trillion individual organisms, while the entire human body consists of about 50 trillion to 100 trillion somatic (body) cells. The sheer microbial abundance suggests that the human body is in fact a “superorganism,” a collection of human and microbial cells and genes and thus a blend of human and microbial traits.
Accordingly, the bacteria of the human microbiota vary among individuals and the components are vast. The claim does not clearly or adequately describe the composition to be administered. The use of the functional language “wherein the bacteria induce production of neutralizing antibody” does not help to define the structure of the composition being administered.
With respect to the argument that “it is certainly plausible that living bacteria enable the technical effect of inducing a neutralising antibody that recognises a spike protein of a coronavirus. Similarly, since the effect is plausible for living and killed bacteria, the effect is also plausible for attenuated bacteria,” 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.”
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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