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 the Claims
Claims 1-14 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/KR2023/001159, filed on 01/26/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/18/2024 and 12/02/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 and 4-12 are anticipated by von Andrian.
Claims 1-2 and 4-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by von Andrian (U.S. PG Pub 2013/0287857 A1).
Claim 1 is drawn to a composition of matter that is mucoadhesive nanoparticles wherein the particles are comprised of poly(D,L-lactide-co-glycolide) (PLGA), in which a mucoadhesive polymer is bound to a surface of the nanoparticles. According to the instant disclosure, polyethylene glycol (PEG) is an exemplary mucoadhesive polymer (page 6, lines 1-5). Von Andrian discloses vaccine nanocarriers (Abstract), including nanocarriers that have a mean geometric diameter of less than 500 nm [paragraph [0018]) and are composed of one or more polymers, including embodiments wherein the nanocarrier is composed of PEG-PLGA polymers (paragraph [0014]). In Example 3, illustrated in Figure 24, von Andrian discloses exemplary PEG-PLGA nanoparticles that bind to lymph node macrophages, including both surface un-modified nanoparticles and surface modified nanoparticles wherein the surface is bound with Fc-domain proteins of immunoglobulins (Figure 24 and paragraphs [0150] and [0598]-[0600]).
Thus, claim 1 is anticipated by the disclosure of von Andrian.
Claim 2 further limits claim 1 to wherein the mucoadhesive polymer is selected from a Markush group that includes PEG, and is met by the disclosure of von Andrian, as discussed above.
Claim 4 further limits claim 1 to wherein the nanoparticles contain an antigen therein.
Claim 5 further limits claim 4 to wherein the antigen is selected from a Markush group that includes peptide. According to the instant disclosure, “peptide” includes polypeptides and proteins (page 8, lines 12-14).
Von Andrian discloses that one aspect of the invention is the provision of vaccines. A vaccine according to the invention typically contains an antigen. In one embodiment, the antigen is physically 'bound' to the nanocarrier by covalent or noncovalent means. Noncovalently bound includes, for example, ionic bonding, hydrophobic bonding and physical entrapment. Von Andrian further discloses that such vaccine nanocarriers can further comprise an immunostimulatory agent for enhancing, suppressing, directing, or redirecting an immune response, preferably to an antigen. (paragraph [0008]). Von Andrian discloses that in some embodiments the nanocarrier comprises a B cell antigen. In some embodiments, the B cell antigen is a degenerative disease antigen, an infectious disease antigen, a cancer antigen, an atopic disease antigen, an autoimmune disease antigen, an alloantigen, a xenoantigen, an allergen, an addictive substance, or a metabolic disease enzyme or enzymatic product (paragraph [0021]). Von Andrian also discloses that in some embodiments, the nanocarrier comprises a T cell antigen. In some embodiments, the T cell antigen is on the surface of the nanocarrier, encapsulated within the nanocarrier, or both. In some embodiments, the antigen is a degenerative disease antigen, an infectious disease antigen, a cancer antigen, an atopic disease antigen, an autoimmune disease antigen, an alloantigen, a xenoantigen, an allergen, an addictive substance, or a metabolic disease enzyme or enzymatic product. In some embodiments the T cell antigen is a 'universal' T cell antigen (i.e., one which can be used with an unrelated B cell antigen, including a carbohydrate, to stimulate T cell help) (paragraph [0022]).
In Figure 24, that depicts von Andrian’s “Example 3”, von Andrian discloses PEG-PLGA nanoparticles that bear Fc-domain immunoglobulin fragments as antigens that target subscapular sinus macrophages (SCS-Mphs) and follicular dendritic cells (paragraph [0150]). Von Andrian discloses that these targeted nanoparticles colocalize with CD169+ subscapular macrophages (SCS-Mphs) adjacent to B cell follicles (middle, FIG. 24A), and at 24 hours after injection, discrete cell sized accumulations of targeted nanoparticles are seen in the cortical region between the SCS and the medulla, suggesting uptake and transport by migratory dendritic cells (paragraph [0599]).
Thus, claims 4-5 are anticipated by the disclosure of von Andrian.
Claim 6 further limits claim 4 to wherein the nanoparticles further contain an adjuvant therein. Von Andrian discloses that, in some embodiments, the vaccine nanocarriers are formulated with one or more adjuvants such as gel-type adjuvants (e.g., aluminum hydroxide, aluminum phosphate, calcium phosphate), microbial adjuvants (e.g., immunomodulatory DNA sequences that include CpG motifs; endotoxins such as monophosphoryl lipid A; exotoxins such as cholera toxin, E. coli heat labile toxin, and pertussis toxin; muramyl dipeptide); oil-emulsion and emulsifier-based adjuvants (e.g., Freund's Adjuvant, MF59 [Novartis], SAF); particulate adjuvants (e.g., liposomes, biodegradable microspheres, saponins); synthetic adjuvants (e.g., nonionic block copolymers, muramyl peptide analogues, polyphosphazene, synthetic polynucleotides), and/or combinations thereof (paragraph [0298]).
Claim 7 further limits claim 1 to a composition comprising the nanoparticles of claim 1 as an active ingredient for the intended use of inducing maturation of antigen-presenting cells (APCs). According to the instant disclosure, "antigen-presenting cells (APCs)" used herein refer to cells that present an antigen-derived peptide fragment to T cells along with a major histocompatibility complex (MHC) molecule to activate the T cells after endocytosis of a protein antigen. Representative APCs include dendritic cells (DCs), B cells, and macrophages, and correspond to main immune cells that are responsible for cellular immunity in vivo. These cells serve as antigen expressing cells, which present an antigen, which has entered the cells, on the surface after endocytosis and thus allow other cells (T cells, etc.) of the immune system to recognize the antigen (page 9, lines 13-20).
Claim 8 further limits claim 7 to wherein the APCs are dendritic cells.
Von Andrian discloses that the invention disclosed therein can include nanocarriers that target follicular dendritic cells (FDCs) as well as B cells, and can stimulate humoral immunity by combining multiple features, including (a) antigenic material for CD4 T cells that is targeted to and presented by dendritic cells (DCs); (b) high density surface antigens that can be presented in their native form by SCS-Mph to antigen specific follicular B cells; ( c) the capacity to be acquired and processed by follicular B cells for presentation to follicular helper (TFH) cells; (d) the ability to reach FDC and be retained on FDC in intact form and for long periods of time; and ( e) adjuvant activity to render APC fully immunogenic and to avoid or overcome tolerance (paragraph [0340]).
Claim 9 further limits claim 1 to a pharmaceutical composition comprising the nanoparticles of claim 1 as an active ingredient, wherein the composition has an intended use of preventing or treating an infectious disease. Von Andrian discloses that, in one aspect of the invention, a method for the prophylaxis and/or treatment of a disease, disorder, or condition (e.g., a microbial infection) is provided. In some embodiments, the prophylaxis and/or treatment of the disease, disorder, or condition comprises administering a therapeutically effective amount of inventive vaccine nanocarriers to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. In certain embodiments of the present invention a "therapeutically effective amount" of an inventive vaccine nanocarrier is that amount effective for treating, alleviating, ameliorating, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of microbial infection. In some embodiments, a "therapeutically effective amount" is an amount effective to modulate the immune system. Such an amount may be an immunogenic amount, i.e., an amount sufficient to elicit a detectable immune response in a subject, e.g., a detectable antibody response and/or detectable T cell response (paragraph [0467]). Von Andrian further discloses pharmaceutical compositions comprising a therapeutically effective amount of one or more vaccine nanocarriers and one or more pharmaceutically acceptable excipients (paragraph [0476]).
Claim 11 further limits claim 1 to a pharmaceutical composition comprising the nanoparticles of claim 1 as an active ingredient, wherein the composition has an intended use of preventing or treating cancer. Von Andrian discloses that the compositions disclosed therein can be used for the prophylaxis and/or treatment of any cancer (paragraph [0465]) and further discloses that by combining selected immunomodulatory agents with targeting moieties and immunostimulatory agents for different antigen-presenting cells (APCs), immune responses (e.g. effector responses) can be tailored to preferentially elicit the most desirable type of immune response for a given indication, e.g., humoral response, type 1 T cell response, type 2 T cell response, cytotoxic T cell, response, and/or a combination of these responses, for a broad range of applications that includes immunotherapy of existing diseases, including cancer, and provides a list of exemplary cancers suitable to such immunotherapy (paragraphs [0470]-[0471]). Additionally, as discussed above, von Andrian discloses pharmaceutical compositions comprising the nanocarriers disclosed therein along with pharmaceutically acceptable excipient(s) (paragraph [0476]).
Claims 10 and 12 further limit claims 9 and 11, respectively, to wherein each claim is limited to the intended administration route of spraying into an oral cavity. Von Andrian discloses liquid dosage forms for oral administration (paragraph [0492]), and further discloses formulations for buccal administration, including aerosolized and/or atomized solutions and suspensions comprising the active ingredient (i.e., nanocarrier) (paragraph [0507]), and further discloses that pharmaceutical compositions of the invention disclosed therein may be administered by any route, and specifically discloses “an oral spray” (paragraph [0513]).
Thus, claims 6-12 are anticipated by the disclosure of von Andrian.
Claims 1 and 4-8 are anticipated by Krishnakumar.
Claims 1 and 4-8 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Krishnakumar (Krishnakumar, D., et al.; Journal of Pharmaceutical Investigation, v42, pp315-326; 2012).
The limitations of claims 1 and 4-8 are discussed in the rejection above and hereby incorporated into the instant rejection.
Krishnakumar teaches a study in the comparative efficacy of nanoparticles, prepared alternatively from poly(lactic-co-glycolic acid) (PLGA), trimethyl chitosan (TMC), or TMC-coated PLGA, when the particles of each material are loaded with Hepatitis B surface antigen (HBsAg) and employed as a nasal vaccine (Abstract). Krishnakumar teaches that TMC has been shown by many researchers to have a mucoadhesive nature, and Krishnakumar shows that nanoparticles made from TMC and TMC-coated PLGA show superior mucin retention ability compared to PLGA nanoparticles that are uncoated (page 321).
Thus, claim 1 is anticipated by the teaching of Krishnakumar.
Regarding claims 4-5, as discussed above, the TMC-coated PLGA mucoadhesive nanoparticles of Krishnamkumar are loaded with Hepatitis B surface antigen (HBsAg), a peptide antigen.
Regarding claim 6, wherein the nanoparticles must include an adjuvant therein, the instant disclosure defines “adjuvant” as “a material that positively affects the action of another material pharmacologically or immunologically”. Krishnakumar compares the “immune-adjuvant effect” of antigen-loaded nanoparticles to the effect of HBsAg alone, by intranasally administering the differing nanoparticles or HBsAg alone to female BALB/c mice and measuring the titers of Anti-Hepatitis serum IgG and surface IgA, and found that the HBsAg-loaded, TMC-coated PLGA nanoparticles provided significantly higher titer of each, compared to HBsAg administered alone (pages 323-324, including Figures 9-10), thus the TMC-coated PLGA nanoparticles constitute an adjuvant material for the antigen HBsAg. The Examiner notes that claim 6 does not require that the “adjuvant” be a separate material from either the PLGA base polymer or the mucoadhesive polymer.
Regarding claims 7-8, Krishnakumar teaches that the HBsAg-loaded, TMC-coated PLGA nanoparticles were able to induce the maturation of dendritic cells (DCs), with up-regulation of all maturation markers, and most significant up-regulation of MHCII (page 322 and Figure 7, page 323).
Thus, claims 4-8 are anticipated by the teaching of Krishnakumar.
Claims 1-2, 4-9 and 11 are anticipated by Satchi-Fainaro.
Claims 1-2, 4-9 and 11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Satchi-Fainaro (U.S. PG Pub 2022/0111029 A1).
The limitations of claims 1-2, 4-9 and 11 are discussed in the rejection above and hereby incorporated into the instant rejection.
Satchi-Fainaro discloses an invention of a polymeric nanoparticle which comprises:
at least one disease-associated antigen, encapsulated in the nanoparticle;
at least one adjuvant; and
a dendritic cell targeting moiety attached to the outer surface of the nanoparticle (Abstract).
Regarding the polymeric nanoparticle, Satchi-Fainaro discloses that the nanoparticle can be fabricated from a polymer selected from the group consisting of PLGA, PEG-PLGA, and PEG-poly(lactic acid) (PEG-PLA) (paragraph [0032]). Satchi-Fainaro discloses that the PEG-PLGA combination may be used to improve the hydrophilicity of the nanoparticle and to promote DC targeted delivery (paragraph [0258]). Satchi-Fainaro discloses specific exemplary formulations in Table 1A (paragraph [0261]), including the specific formulation below1:
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88
758
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300
790
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As shown in the excerpt above, Satchi-Fainaro’s exemplary formulation includes PLGA-bonded to PEG, and thereby meets the limitations of instant claims 1-2.
Thus, claims 1-2 are anticipated by the disclosure of Satchi-Fainaro.
Regarding claims 4-5, Satchi-Fainaro’s exemplary nanoparticle formulation includes one or both of “Adpgk MC38” antigen types (Major Histocompatibility Complex I (MHCI) and Major Histocompatibility Complex II (MHCII) version), which are disclosed by Satchi-Fainaro as antigens of colorectal cancer (paragraph [0134]), with peptide sequences provided therein.
Regarding claim 6, Satchi-Fainaro’s exemplary nanoparticle formulation includes Toll-like Receptor (TLR) Ligands “CpG ODN 1826”, a CpG oligodeoxynucleotide, and “Poly(I:C)”, which is polyinosinic-polycytidylic acid (paragraph [0039]). Satchi-Fainaro discloses that the TLR ligands serve in the role of adjuvant in the nanoparticle formulation (paragraph [0037]).
Regarding claims 7-8, Satchi-Fainaro’s exemplary nanoparticle formulation includes a dendritic cell (DC) targeting moiety, which comprises mannose, a carbohydrate, conjugated to the PLGA polymer (Man-PLGA). Satchi-Fainaro discloses that DC targeting moieties ensure that the nanoparticles are preferentially endocytosed by dendritic cells as compared to macrophages (paragraph [0124]), and discloses that mannose is a DC targeting moiety (paragraph [0126]) and also discloses that nanoparticles bearing mannose are preferentially taken up in vivo by circulating DCs compared to macrophages and resident DCs, and that the “nano-vaccine” comprised of the such nanoparticles is able to significantly increase the expression of activation/maturation markers at dendritic cell surface (paragraph [0400] and Figure 1H).
Regarding claims 9 and 11, Satchi-Fainaro discloses that the polymeric nanoparticle invention is for use in treating a disease associated with abnormal growth or an infection, and in some embodiments the disease associated with abnormal growth is cancer. In the exemplary formulation above, the nanoparticle includes, as discussed above, an antigen for colorectal cancer. Satchi-Fainaro also discusses the incorporation of antigens for bacterial infections, viral antigens, and fungal antigens (paragraphs [0154]-[0156]). Satchi-Fainaro discloses that the nanoparticles are used as a vaccine, and that “vaccine” refers to a pharmaceutical composition (paragraphs [0262]-[0263]).
Thus, claims 3-9 and 11 are anticipated by the disclosure of Satchi-Fainaro.
Claims Free of the Prior Art
Claims 13-14 are allowed. Prior art does not teach or reasonably suggest, alone or in combination, a method of preparing mucoadhesive-PLGA nanoparticles in which a mucoadhesive
polymer is bound to a surface of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles, comprising:
a) mixing an aqueous solution including an antigen and an adjuvant with an organic
solution including PLGA; and
b) mixing the mixture with a compound in which PVA-NH2 in which an amino group
is introduced into polyvinyl alcohol (PVA), and a mucoadhesive polymer in which a carboxyl group is introduced are chemically bonded to each other;
including wherein the mucoadhesive-PLGA nanoparticles are CAT-PLGA nanoparticles, and the mucoadhesive polymer to be mixed with PVA in step (b) is 3,4-dihydroxyhydrocinnamic acid.
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Excerpted formulation from Col. 16; column titles from top of Table 1A.
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