DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-6, 10-12, 22-25, 28, 30-31, and 33 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I (a method for debulking viral load from the oral cavity in a subject) in the reply filed on 12/10/2025 is acknowledged.
Claims 22-23, 30-31 and 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2022/028801 filed on 05/11/2022. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 63/187,924, filed on 05/12/2021. The present application and all claims are being examined with an effective filing date of 05/12/2021. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/11/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement have been considered by the examiner.
Claim Objections
Claim 12 is objected to because of the following informalities:
The claim recites “said carrier being selected from selected from a chewing gum…”. Please amend the claim to recite “said carrier being .
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 4, 24-25, and 28 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 4 is indefinite due to the recitation of “said trapping molecule is selected from…”. It is unclear whether “said trapping molecule” is one that has an affinity for the surface of a virus, one that has affinity for the surface of bacteria/fungus, or one that has affinity for a virus and bacteria/fungus.
Claim 24 (claims 25 and 28 dependent on) is indefinite due to the recitation of “wherein binding of said microorganism … traps said microorganism within said carrier…”, as it is unclear whether this clause recites an additional method step, a structural/functional limitation describing the relationship between the trapping molecule and carrier, or merely a statement of intended result. For examination purposes, the wherein clause is treated as not imposing a further structural or process limitation beyond those already recited and is therefore not afforded patentable weight.
Claim 25 is indefinite due to the recitations of “the microorganism is a bacteria and, or a fungus” and “the administering takes places before or after the subject is exposed to bacteria” while subsequently reciting that the administering reduces recovery time for bacteria and, or fungal infection.. As currently written, the claim links the exposure limitation solely to bacteria, while reciting therapeutic reduction of both bacterial and fungal infection, thereby creating ambiguity as to whether the exposure requirement applies to fungal embodiments.
Claim Rejections - 35 USC § 112(a)
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, 10-12, 24-25, and 28 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.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow. Claim 1 has been broadly interpreted as encompassing a genus of methods of debulking viral load from the oral cavity in a subject, comprising administering a genus of compositions comprising a genus of carriers including a genus of trapping molecules having affinity for a protein or glycan on the surface of a genus of viruses. Claim 2 has been broadly interpreted as encompassing a genus of methods, according to claim 1, wherein administering…reduces recovery time, eliminates, or minimizes at least one complication from any viral infection. Claim 24 has been broadly interpreted as encompassing a genus of methods for debulking pathogenic microorganism load and, or virus load from the oral cavity in a subject, comprising orally administering a genus of compositions comprising a genus of carriers including a genus of trapping molecules having affinity for said microorganisms and, or said viruses. Claim 25 has been broadly interpreted as encompassing the genus of methods according to claim 24, wherein the administering…reduces recovery time, eliminates, or minimizes at least one complication from any bacterial and, or any fungal infection.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. 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…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
In the instant case, the specification primarily describes embodiments directed to specific viral pathogens, namely certain SARS-CoV strains and certain influenza strains (e.g., H1N1 and H3N2), using specific trapping molecules including ACE2, CTB-ACE2, and FRIL including chewing gum as the carrier. The disclosure is heavily focused on chewing gum formulations, including detailed preparation of chewing gum and chewing gum tablets for local oral retention, however, the term “tablet,” under its broadest reasonable interpretation, encompasses swallowed systemic tablets and other non-chewing forms. The specification does not describe systemic tablet embodiments or otherwise demonstrate possession of such delivery formats. Therefore, the breadth of the carrier limitation exceeds the scope of the embodiments described in the specification. Additionally, claim 1 is not limited to the specific viruses or specific trapping molecules listed above. Rather, the claim encompasses any trapping molecule having affinity for any viral surface protein or glycan in any carrier.
The specification does not provide representative species or working examples demonstrating the use of trapping molecules across the full scope of the claimed genus. There is no demonstration of IVA blocking peptides, antimicrobial peptides, and lipases – all of which contain numerous species within their own class. For example, the specification defines antimicrobial peptides as “host defense peptides which comprise a part of the innate immune response found among all classes of life”, and then lists examples of such – protegrin, retrocyclin defensins, PGLA, etc., while none from this vast genus are actually exemplified. In other words, while ACE2, CTB-ACE2, and FRIL are described, the claim encompasses structurally and functionally diverse classes of viral-binding molecules without corresponding representative disclosure. Accordingly, the specification does not reasonably convey possession of the full scope of the claimed genus of trapping molecules and viral targets.
With respect to claims 2 and 25, while the specification describes in vitro assays demonstrating viral binding and reduction in viral titers for certain SARS-CoV and influenza strains, the disclosure does not provide representative species, working examples, or data demonstrating reduction in recovery time, elimination of any complication, or minimization of complications across the full scope of the viral infections encompassed by claim 2, and bacterial/fungal infections encompassed by claim 25. The specification defines “complication” broadly as “any deviation from a normal state in a subject”. Under the broadest reasonable interpretation, this definition encompasses essentially any pathological manifestation associated with any viral infection. However, the disclosure does not describe how the claimed compositions eliminate such deviations across the full genus of viruses, bacteria and fungi, nor does it provide evidence that viral, bacterial, and fungal load reduction necessarily results in elimination of their corresponding complications.
Moreover, claims 3 and 25 further expand the scope of the claimed genus by extending the method to include reduction of bacterial and/or fungal load in the oral cavity and by reciting trapping molecules having affinity for the surface of bacteria and/or fungi. This expands the claimed genus beyond viral surface-binding molecules to encompass distinct classes of microorganisms and corresponding binding agents, also not adequately described, as the specification does not disclose any representative species demonstrating reduction of bacterial or fungal load in the oral cavity using the claimed trapping molecules.
Claims 4, 10, and 12 further recite trapping molecules selected from ACE2, CTB-ACE2, IVA blocking peptides, FRIL, antimicrobial peptides, and lipase. While ACE2, CTB-ACE2, and FRIL are specifically described in the specification, the recited categories of IVA blocking peptides, antimicrobial peptides, and lipases represent functional genera encompassing numerous structurally distinct species. The specification does not provide working examples or representative species demonstrating the use of IVA blocking peptides, antimicrobial peptides, or lipases as trapping molecules within the claimed oral formulations. Nor does it demonstrate possession of the full scope of such genera in the context of reducing viral, bacterial, or fungal load in the oral cavity.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the full scope of the claimed invention. Accordingly, claims 1-6, 10-12, 24-25, and 28 fail to comply with the written description requirement of 35 U.S.C. §112(a) because the specification does not reasonably convey possession of the full breadth of the claimed genera.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 24-25 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Quindos et al. (Therapeutic tools for oral candidiasis: Current and new antifungal drugs, Med Oral Patol Oral Cir Bucal. 2019 Mar 1;24 (2):e172-80, cited in the IDS).
Quindos et al. teaches that the antifungal nystatin binds to ergosterol in the fungal plasma membrane and forms pores, resulting in fungicidal activity, corresponding to a trapping molecule having affinity for a microorganism (fungus). It is noted that the binding and resulting fungicidal effect reduces Candida burden in the oral cavity, thereby reducing microorganism load in the oral cavity of the subject. It is further noted that nystatin is considered as “very active” against several Candida species, including Candida albicans (pg. e175, Table 1). Quindos et al. further teaches antifungal formulations are “marketed as oral suspensions, tablets, pastilles, gels, mucoadhesive tablets, toothpastes, etc. for facilitating their therapeutic action…” (pg. e176). Specifically, Quindos et al. teaches the treatment of oral candidiasis, according to the Infectious Diseases Society of America, using nystatin (oral) suspension (100,000 U/ mL, 4-6 ml, four times daily), or nystatin pastilles (1-2 pastilles, 200,000 U each, four times daily for 7-14 days) - corresponding to a method for reducing Candida in the oral cavity, comprising administering a composition, comprising a carrier including a trapping molecule. With respect to the limitation “wherein the microorganism is a bacteria and, or a fungus and the administering takes place before or after the subject is exposed to the bacteria wherein the administering reduces recovery time for, eliminates, or minimizes at least one complication from bacterial and, or fungal infection” in claim 25, Quindos et al. teaches administering the nystatin suspension and pastilles for treatment of oral candidiasis, which necessarily occurs after exposure to the fungus. Additionally, the method of Quindos et al. explicitly teaches the fungicidal effect of nystatin which corresponds to reduction in fungal burden. A person or ordinary skill in the art would understand that reducing fungal burden at the site of infection would reasonably be expected to lessen severity and duration of illness, thereby reducing recovery time and minimizing complications associated with said fungal infection.
Therefore, claims 24-25 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Quindos et al. (Therapeutic tools for oral candidiasis: Current and new antifungal drugs, Med Oral Patol Oral Cir Bucal. 2019 Mar 1;24 (2):e172-80, cited in the IDS).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-6, 10, 24-25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al. (“Engineered ACE2 receptor traps potently neutralize SARS-CoV-2,” PNAS, Vol 117, no. 45, 2020, pg. 28046-28055, cited in the IDS), Shephard et al. (Virucidal action of sore throat lozenges against respiratory viruses parainfluenza type 3 and cytomegalovirus, Antiviral Research 123 (2015), pg. 158–162, cited in PTO-892), and Quindos et al. (Therapeutic tools for oral candidiasis: Current and new antifungal drugs, Med Oral Patol Oral Cir Bucal. 2019 Mar 1;24 (2):e172-80, cited in the IDS).
Glasgow et al. discloses engineered angiotensin-converting enzyme 2 (ACE2) receptor “traps” that bind to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and neutralize viral infection, because SARS-CoV-2 infection begins with viral spike protein binding to the human ACE2 receptor (Abstract). It is noted that SARS-CoV-2 is from the coronavirus and the RBD of the spike protein is on the surface of the virus (pg. 28046, left column). Specifically, Glasgow et al. describe engineering soluble variants of the extracellular domain of ACE2 to generate “receptor traps” that bind the spike RBD and “potently block SARS CoV-2 infection of cells”, teaching that these engineered ACE2 receptor traps are affinity-optimized soluble extracellular ACE2 proteins that block viral spike protein binding to cellular ACE2, thereby inhibiting infection (Abstract; pg. 28046, right column and pg. 28053, left column). Furthermore, Glasgow et al. teaches that these ACE2 receptor traps exhibit measurable binding affinity (KD values in the nanomolar range) for the SARS-CoV-2 spike RBD, including KD values of approximately 10.8 nM and 2.8 nM for the variants ACE2(614) and ACE2(740), respectively, thereby demonstrating specific and strong binding affinity for a viral surface protein. Additionally, Glasgow et al. teaches that ACE2 neutralizes SARS-CoV-2 infection, significantly reducing viral RNA levels, with reported IC50 values in the nanogram per milliliter range, thereby demonstrating reduction of viral load at low concentrations (pg. 28050, right column and Fig. 4D–F). However, Glasgow et al. does not teach orally administering the ACE2 (i.e., trapping molecule) to a subject via a carrier.
Shepherd et al. discloses locally/orally delivered lozenge formulations for treatment of viral respiratory tract infections. Shepherd teaches that “locally delivered formats such as lozenges and sprays are useful as they enable active ingredients to reach the site of infection directly,” and that such localized delivery allows treatment at the throat/oral cavity while minimizing systemic side effects (Abstract and pg. 159, left column). Shepherd et al. evaluated virucidal activity in vitro by dissolving the lozenge formulations in artificial saliva, incubating the resulting solution with parainfluenza virus type 3 (PIV3) or cytomegalovirus (CMV) for contact times of 1-10 minutes, neutralizing the mixture, and quantifying remaining infectious virus using a TCID50 assay in host cells (pg. 159–160). Shepherd et al. discloses multi-log reductions in infectious viral titer under these artificial saliva conditions (pg. 160-161; Figs. 1–3), supporting oral administration of a lozenge formulation to a subject infected with a viral respiratory tract infection. Shepherd et al. concludes that such lozenges have the potential to provide local antiviral effects in patients with sore throat due to viral respiratory tract infections and support their use as a first-line treatment for sore throat caused by viral RTIs (pg. 161, Conclusions). Although Shepherd et al. does not expressly teach administering the lozenge to a subject confirmed to be suffering from a viral respiratory tract infection and measuring viral titer in vivo, the artificial saliva contact model simulates the dissolution of a lozenge within the oral cavity and short-term exposure of virus to the active agents in saliva. Thus, the reported reductions in infectious viral titer in artificial saliva represent the antiviral activity expected when the lozenge is orally administered and dissolved in the oral cavity.
With respect to the limitation reciting “wherein the administering takes place before or after the subject is exposed to the virus and reduces recovery time for, eliminates, or minimizes at least one complication from viral infection” in claim 2, Shephard et al. teaches administering lozenges for treatment of viral respiratory tract infections, which necessarily occurs after exposure to the virus. Additionally, the method of Shephard et al. explicitly teaches a reduction in viral titer which corresponds to reduction in infectious viral burden. A person or ordinary skill in the art would understand that reducing viral burden at the site of infection would reasonably be expected to lessen severity and duration of viral illness, thereby reducing recovery time and minimizing complications associated with viral infection.
Quindos et al. teaches that the antifungal nystatin binds to ergosterol in the fungal plasma membrane and forms pores, resulting in fungicidal activity, corresponding to a trapping molecule having affinity for a microorganism (fungus). It is noted that the binding and resulting fungicidal effect reduces Candida burden in the oral cavity, thereby reducing microorganism load in the oral cavity of the subject. Quindos et al. further teaches antifungal formulations are “marketed as oral suspensions, tablets, pastilles, gels, mucoadhesive tablets, toothpastes, etc. for facilitating their therapeutic action…” (pg. e176). Specifically, Quindos et al. teaches the treatment of oral candidiasis, according to the Infectious Diseases Society of America, using nystatin (oral) suspension (100,000 U/ mL, 4-6 ml, four times daily), or nystatin pastilles (1-2 pastilles, 200,000 U each, four times daily for 7-14 days) - corresponding to a method for reducing Candida in the oral cavity, comprising administering a composition, comprising a carrier including a trapping molecule.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Glasgow et al. that engineered soluble ACE2 receptor traps bind the SARS-CoV-2 spike protein and neutralize viral infection, thereby reducing viral load, combined with the teachings of Shepherd et al. that antiviral agents can be administered orally via lozenge formulations to locally reduce infectious viral titer in the oral cavity, would have motivated a person of ordinary skill in the art to administer Glasgow’s ACE2 receptor traps in a locally delivered oral carrier such as a lozenge for the purpose of reducing viral burden in the oral cavity. Given that Glasgow et al. demonstrates a successful viral neutralization strategy using soluble ACE2 receptor traps and Shepherd demonstrates that oral lozenge formulations effectively deliver antiviral agents locally and reduce viral titer under saliva-like conditions, a person of ordinary skill in the art would have reasonably expected that formulating the ACE2 receptor traps in an oral lozenge carrier would successfully result in a method for debulking viral load in the oral cavity, with a reasonable expectation of success. Moreover, the teachings of Quindos et al., that oral administration of the antifungal nystatin, delivered in the form of pastilles and suspensions, is effective for reducing fungal load in the oral cavity, further establishes a reasonable expectation of success that locally delivered pathogen binding agents administered in oral carriers can successfully reduce infectious burden in the oral cavity. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claims 1-2, 5-6, 10, 24-25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al., Shephard et al. and Quindos et al.
Claims 3-4, 25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al., Shephard et al. and Quindos et al., as applied to claims 1 and 24 above, and further in view of Sancho-Vaello et al. (The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics. Sci Rep 10, 17356, herein “Sancho”, cited in the IDS).
The combined teachings of Glasgow et al., Shepherd et al., and Quindos et al. as they apply to claims 1 and 24, have been discussed above. Briefly, Glasgow et al. discloses engineered angiotensin-converting enzyme 2 (ACE2) receptor traps that bind to the receptor-binding domain of SARS-CoV-2 and neutralize viral infection, reducing viral load. Shepherd et al. teaches locally delivered oral lozenge formulations capable of reducing viral titer in a saliva-based model representative of the oral cavity. Together, these teachings render obvious administering ACE2 in a locally delivered oral formulation to a subject suffering from, or at risk of, viral respiratory infection. Quindos et al. teaches the oral delivery of antifungal agents via carriers such as oral suspension and pastilles, for the treatment of oral candidiasis. Neither Glasgow, Shepherd nor Quindos discloses teachings relating to reducing bacterial and/or fungal load in the oral cavity.
Sancho discloses the human antimicrobial peptide LL-37, an antimicrobial peptide (AMP), which are part of the innate immune response and exhibit broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria (pg. 1). Sancho teaches that AMPs typically carry a surplus of positively charged residues and initially interact with negatively charged bacterial surface components, including lipopolysaccharides (LPS) and lipoteichoic acid (LTA) molecules on bacterial cell walls (pg. 1-2), thereby binding to the bacterial surface. Sancho further teaches that LL-37 forms membrane-disruptive structures that destabilize bacterial membranes (pg. 3) and reports antimicrobial activity of LL-37 against clinically relevant bacterial strains, including Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, and Pseudomonas syringae, with minimal inhibitory concentration (MIC) values in the range of approximately 3.25–25 µg/mL (PG 5), thus demonstrating bactericidal activity. With respect to the limitation reciting “wherein…the administering takes place before or after the subject is exposed to the bacteria wherein the administering reduces recovery time for, eliminates, or minimizes at least one complication from bacterial and, or fungal infection”, a person of ordinary skill in the art would have understood that reducing bacterial load through bactericidal activity necessarily reduces the severity and duration of bacterial infection and would therefore be expected to reduce recovery time and minimize complications associated with such infection. Additionally, administration of an antimicrobial agent either prior to or after bacterial exposure represents predictable prophylactic or therapeutic use of a known antibacterial compound.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Glasgow et al., which disclose engineered viral trapping molecules that bind viral surface proteins and neutralize infection by reducing viral load, combined with the teachings of Shepherd et al., which disclose local oral administration of antiviral lozenge formulations for reducing viral titer in the oral cavity, made obvious the administration of an oral delivery lozenge formulation of ACE2 to reduce SARS-CoV-2 viral load in the oral cavity. Combined with the teachings of Sancho, that antimicrobial peptides such as LL-37 bind to bacterial surface components and exhibit bactericidal activity against clinically relevant bacterial strains, including S. pyogenes (claim 28), a person of ordinary skill in the art would have been motivated to incorporate a known antimicrobial peptide, such as LL-37, into the orally delivered formulation, made obvious by Shepherd and Glasgow, in order to additionally reduce bacterial (S. pyogenes) load in the oral cavity. The inclusion of an antimicrobial peptide would have been a predictable use of a known antibacterial agent for its known purpose of binding to bacterial surfaces and reducing bacterial infection. Given that Sancho demonstrates successful bacterial surface binding and killing activity of LL-37, a person of ordinary skill in the art would have reasonably expected that incorporating such an antimicrobial peptide into the process rendered obvious by Glasgow and Shepherd would further result in reduction of bacterial load and associated complications. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claims 3-4, 25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al., Shephard et al. and Quindos et al., as applied to claims 1 and 24 above, and further in view of Sancho.
Claims 11-12 rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al., Shephard et al. and Quindos et al., as applied to claims 1 and 5 above, and further in view of Liu et al. (Carbohydrate-Binding Protein from the Edible Lablab Beans Effectively Blocks the Infections of Influenza Viruses and SARS-CoV-2. Sci Rep 10, 17356, Cell Reports 32, 108016, cited in the IDS).
The combined teachings of Glasgow et al., Shepherd et al. and Quindos et al., as they apply to claims 1 and 24, have been discussed above. Briefly, Glasgow et al. discloses engineered angiotensin-converting enzyme 2 (ACE2) receptor traps that bind to the receptor-binding domain of SARS-CoV-2 and neutralize viral infection, reducing viral load. Shepherd et al. teaches locally delivered oral lozenge formulations capable of reducing viral titer in a saliva-based model representative of the oral cavity, including cytomegalovirus. Together, these teachings render obvious administering ACE2 in a locally delivered oral formulation to a subject suffering from, or at risk of, viral respiratory infection. Quindos et al. teaches the oral delivery of antifungal agents via carriers such as oral suspension and pastilles, for the treatment of oral candidiasis. Neither Glasgow, Shepherd nor Quindos teach wherein the virus is an Alpha influenza virus and comprises at least one of Influenza A virus, Influenza B virus, and Influenza C virus; wherein said trapping molecule is an influenza virus A (IVA) blocking peptide comprising virus binding portions of HA and, or neuraminidase proteins and, or a FRIL molecule from lablab bean powder that binds a glucan on a virus surface, and traps influenza viral particles.
Liu et al. discloses that the lectin FRIL, isolated from Lablab purpureus (lablab bean), exhibits potent anti-influenza activity and neutralizes multiple representative human and avian influenza strains, including influenza A (H1N1, H3N2, H5N1, H7N9) and influenza B strains, at low nanomolar concentrations (pg. 1-3 and Fig. 2). Liu et al. further teaches that influenza hemagglutinin (HA) is heavily glycosylated and contains complex-type N-glycans on the viral surface (pg. 1-2) and that FRIL binds preferentially to complex-type N-glycans present on influenza viral envelope glycoproteins via FRIL’s carbohydrate-binding domain (pg. 4-5; pg. 7; and Fig. 3). Liu et al. teaches that FRIL aggregates influenza virions through multivalent binding, forming large three-dimensional aggregates of viral particles and that FRIL first binds and extracellularly cross-links virus particles, creating aggregates that prevent viral entry and nuclear import. This aggregation effectively “traps” influenza viral particles and halts infection at the late endosomal stage (pg. 7-8 and Fig. 4-5). Furthermore, Liu et al. discloses in vivo administration of FRIL in a mouse influenza infection model wherein FRIL was administered intranasally to BALB/c mice prior to viral challenge and repeatedly following infection. The treated mice exhibited increased survival and delayed mortality compared to controls, demonstrating in vivo antiviral efficacy against influenza virus (pg. 3-4 and Fig. 2D-F). Liu et al. explicitly suggests the potential therapeutic applications of FRIL for prevention and/or treatment of influenza and COVID-19 and proposes oral delivery formats such as aerosol mists or inhalers (pg. 12).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Glasgow et al., which disclose engineered viral trapping molecules that bind viral surface proteins and neutralize infection by reducing viral load, combined with the teachings of Shepherd et al., which disclose local oral administration of antiviral lozenge formulations for reducing viral titer in the oral cavity, made obvious the administration of an oral delivery lozenge formulation of ACE2 to reduce SARS-CoV-2 viral load in the oral cavity. In further view of Liu et al., which discloses that the lectin FRIL binds complex-type N-glycans on influenza viral surface glycoproteins, aggregates influenza virions, neutralizes influenza virus, and demonstrates antiviral efficacy in vivo following intranasal administration, it would have been obvious to a person of ordinary skill in the art to substitute FRIL for the ACE2 trapping molecule in the orally administered formulation made obvious by Glasgow and Shepherd, for the purpose of targeting Influenza A and B viruses. Given that Liu et al. demonstrates that FRIL functions as a viral trapping molecule that binds influenza A and B viral surface glycans, and reduces infection in vivo, a person of ordinary skill in the art would have reasonably expected that incorporating FRIL into a known locally administered oral antiviral formulation, such as the lozenge platform taught by Shepherd et al., would likewise reduce influenza A/B viral load in the oral cavity with a reasonable expectation of success. Thus, substitution of one known viral-binding protein for another in a known delivery format constitutes the use of a known element according to its established function. Therefore, it would be obvious for a person of ordinary skill in the art, to make these substitutions and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claims 11-12 rejected under 35 U.S.C. 103 as being unpatentable over Glasgow et al., Shephard et al. and Quindos et al., as applied to claims 1 and 5 above, and further in view of Liu et al.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/ Examiner, Art Unit 1652
/RICHARD G HUTSON/ Primary Examiner, Art Unit 1652