DETAILED ACTION
Status of the Claims
Claims 1, 3, 5-13 are pending in the instant application. Claims 9-13 have been withdrawn based upon Restriction/Election as discussed below. Claims 1, 3 and 5-8 are being examined on the merits in the instant application.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/25/2026 has been entered.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 03/30/2020, the filing date of the U.S. Provisional Application No. 63/001,893.
Information Disclosure Statement
The information disclosure statement submitted on 09/04/2025 was filed after the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3 and 5-8 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Claimed Invention:
Applicant claims a mesoporous silica nanoparticle comprising: a plurality of pores and an outer surface; a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells; and an immunomodulatory moiety comprising a pathogen-associated molecular pattern (PAMP), a danger-associated molecular molecule (DAMP), a cytokine, an antibody, or other immunomodulatory moiety, the immunomodulatory moiety either disposed in at least a portion of the pores; or bound to at least a portion of the outer surface. (instant claim 1).
The limitation “a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells” is considered new matter not supported in the as filed Application, and is considered new matter. Additionally, the examiner finds only written description support for PEI 25,000 Dalton (molecular weight) as supporting “a cationic layer disposed to at least a part of the outer surface […] effective to kill cancer cells.”
Disclosure of the Prior Art:
Xia et al. (“Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs,” 2009, ACS; ACSNano, Vol. 3, No. 6, pp. 3273-3286) is cited as teaching the cytotoxicity of PEI. Xia et al. particularly teaches that: “It is documented that, while low MW PEI is not cytotoxic, these polymers are ineffective at transfecting nucleotides in contrast to the high MW PEI. In this regard, it has been demonstrated that the size (MW), compactness, and chemical modification of PEI affect the efficacy and toxicity of this polymer. Therefore, we experimented with several PEI polymer sizes ranging from MW of 0.6 to 25 kD in order to balance the efficiency of nucleic acid delivery and cellular toxicity. PEI cytotoxicity occurs via a proton sponge effect, which involves proton sequestration by the polymer surface that leads to heightened proton pump activity inside the cell, osmotic swelling of the endocytic compartment, endosomal rupture, and ultimately cell death by a mitochondrial mediated mechanism.” (p. 3274, col. 1, line 18 through p. 3275, col. 1, line 7). And that: “To screen for particle hazard, we used the MTS assay, which reflects dehydrogenase activity in healthy cells. While most of the MSNP did not interfere in MTS activity in the PANC-1 and BxPC3 pancreatic cancer cell lines, particles coated with the 25 kD PEI polymer showed decreased cellular viability (Figure 1B). The particles coated with the 25 kD polymer also induced toxicity in macrophage (RAW 264.7) and bronchial epithelial (BEAS-2B) cell line staining (Supporting Information Figure 2).” (p. 3275, col. 2, lines 2-11). And further that: “A potential downside of cationic functionalization for drug or nucleic delivery is the possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” (p. 3280, col. 2, lines 3-5).
Salis et al. (“Mesoporous Silica Nanoparticles Functionalized with Hyaluronic Acid and Chitosan Biopolymers. Effect of Functionalization on Cell Internalization,” 2016, ACS Biomaterials Science and Engineering, Vol. 2, pp. 741-751) teaches that: “This work focuses on MSNs based on MCM-41 matrices functionalized either with hyaluronic acid (HA) or chitosan (CHIT) and on the evaluation of their cytotoxicity toward 3T3 mouse fibroblast cell lines. As reported in recent works, the functionalization with HA and CHIT should produce MSNs characterized by negative and positive charged interfaces respectively, at physiological pHs.” (p. 742, col. 2, lines 1-7), and specifically teaches: “Cytotoxicity of MSNs was determined by the MTS assay.” (p. 743, §2.4). And that: “The high level of the viability of 3T3 cells, determined through the MTS assay after a contact with the MSNs for 24 h, was confirmed by the cell growth curve obtained through Coulter counter. The whole results clearly assess the high biocompatibility of all types of functionalized MSNs, without any significant effect because of the different functionalizations.” (p. 749, col. 1, last two lines through col. 2, line 5).
Hartono et al. (“Poly-L-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery,” 2012, ACSNano, Vol. 6, No. 3, pp. 2104-2117) teaches that: “In this work, we develop a novel and facile method to attach PLL onto LP-MSNs to produce LP-MSN-P (poly-L-lysine functionalized large pore mesoporous silica nanoparticles) and use it as a carrier to deliver siRNA into cancer cells.” (p. 2105, Col. 2, 2nd paragraph, lines 1-5). And that: “Moreover, the PLL-modified silica nanoparticles also exhibit a high biocompatibility, with low cytotoxicity observed up to 100 µg/mL.” (Abstract, last two lines). Also see “Cytotoxicity Study” (pp. 2112-2113, § Cytotoxicity Study).
Disclosure of the Instant Application:
“FIG. 7. Cancer cell proliferation (left) and bone marrow-derived dendritic cell (BMDC, right) proliferation in the presence of increasing amounts of mesoporous silica nanoparticles (MSNs). Relative BR5-Akt ovarian cancer cell (left) or BMDC (right) proliferation in the presence of increasing concentrations of control or TLR ligand-bound MSN at 24 hours.” (p. 3, lines 8-11).
“FIG. 7 is data from a proliferation assay that shows that while MSN-PEI-MPL (cationic nanoparticles containing MPL) display concentration dependent toxicity towards (BR5-Akt) cancer cells, all mesoporous silica nanoparticles with PEI in their formulation are highly toxic to dendritic cells. Thus, while direct cancer cells killing may be involved in the therapeutic effect of MSN particles, the main mechanism of action appears to be on immune cells.” (p. 7, lines 9-13).
The Specification discloses that: “and linear PEI (MW 25,000) was purchased from Polysciences, Inc. (Warrington, PA).” (p. 12, §Materials, lines 25-26).
The examiner finds no disclosure in the as-filed Application of any amount of “a cationic layer disposed on at least a portion of the outer surface”, and particularly no “amount effective to kill cancer cells”. Applicant arguments state that: “Claim 1 is amended to incorporate subject matter previously recited in claim 2 and claim 4. The amendments to claim 1 are further supported in Applicant's specification at, for example, page 6, lines 17-28.” (p. 6, lines 2-4). Previously presented claim 2 recited “The mesoporous silica nanoparticle of claim 1, wherein the mesoporous silica nanoparticle comprises a cationic disposed on at least a part of the outer surface and the immunomodulatory moiety is bound to at least a portion of the cationic layer.” which claim fails to recite any amount of “a cationic layer disposed on at least a portion of the outer surface”.
Discussion:
The as-filed Application does not provide any support for “an amount” of “a cationic layer disposed on at least a part of the outer surface”, let alone, “an amount effective to kill cancer cells” which is considered new matter.
Additionally, claim 1 is generic to any “cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells”. However, the as-filed Application only discloses MSN-PEI with “PEI (MW 25,000)” which is suggested by the prior art to be cytotoxic, whereas both chitosan, and poly(L-lysine) are suggested by the prior art to not be cytotoxic. Thus, the limitation is considered to lack proper written description as only one example is disclosed, and not considered supportive of the claimed genus.
Xia et al. teaching that: “A potential downside of cationic functionalization for drug or nucleic delivery is the possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” [emphasis added](p. 3280, col. 2, lines 3-5).
Salis et al. teaching that: “This work focuses on MSNs based on MCM-41 matrices functionalized either with hyaluronic acid (HA) or chitosan (CHIT) and on the evaluation of their cytotoxicity toward 3T3 mouse fibroblast cell lines. As reported in recent works, the functionalization with HA and CHIT should produce MSNs characterized by negative and positive charged interfaces respectively, at physiological pHs.” (p. 742, col. 2, lines 1-7), and specifically teaches: “Cytotoxicity of MSNs was determined by the MTS assay.” (p. 743, §2.4). And that: “The high level of the viability of 3T3 cells, determined through the MTS assay after a contact with the MSNs for 24 h, was confirmed by the cell growth curve obtained through Coulter counter. The whole results clearly assess the high biocompatibility of all types of functionalized MSNs, without any significant effect because of the different functionalizations.” [emphasis added](p. 749, col. 1, last two lines through col. 2, line 5).
Hartono et al. teaching that: “In this work, we develop a novel and facile method to attach PLL onto LP-MSNs to produce LP-MSN-P (poly-L-lysine functionalized large pore mesoporous silica nanoparticles) and use it as a carrier to deliver siRNA into cancer cells.” (p. 2105, Col. 2, 2nd paragraph, lines 1-5). And that: “Moreover, the PLL-modified silica nanoparticles also exhibit a high biocompatibility, with low cytotoxicity observed up to 100 µg/mL.” [emphasis added](Abstract, last two lines). Also see “Cytotoxicity Study” (pp. 2112-2113, § Cytotoxicity Study).
Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111, (Fed. Cir. 1991), states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claim indicates that these claims are drawn to a genus, i.e., any “cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells”.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1); and Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336 (Fed. Cir. 2010), especially Slip Op. at pp. 21-23 and 27-28).
In the instant case the as-filed Application does not provide any support for “an amount” of “a cationic layer disposed on at least a part of the outer surface”, let alone, “an amount effective to kill cancer cells” which is considered new matter. Therefore, the claims are properly rejected as containing 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, at the time the application was filed, had possession of the claimed invention for introduction of New Matter.
Additionally, claim 1 is generic to any “cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells”. However, the as-filed Application only discloses MSN-PEI with “PEI (MW 25,000)” which is suggested by the prior art to be cytotoxic, whereas both chitosan, and poly(L-lysine) are suggested by the prior art to not be cytotoxic. Thus, the limitation is considered to lack proper written description as only one example is disclosed, and not considered supportive of the claimed genus. Therefore, the claims are properly rejected as containing 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, at the time the application was filed, had possession of the claimed invention for Lack of Written Description.
Response to Arguments:
Applicant's arguments filed 02/25/2026 have been fully considered but they are persuasive. However, Applicants amendment introduces new issues under 112(a) both new matter and written description, as detailed above.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (“Hyaluronic acid and carbon dots-gated hollow mesoporous silica for redox and enzyme-triggered targeted drug delivery and bioimaging,” 2017; ELSEVIER; Materials Science and Engineering C, Vol. 78, pp. 475-484) in view of LAWMAN (US 2017/0042993; published February, 2017); MOONEY (US 2018/0117171; published May, 2018); Shin et al. (“Hyaluronic acid-supported combination of water insoluble immunostimulatory compounds for anti-cancer immunotherapy,” 2017, ELSEVIER, Carbohydrate Polymers, Vol. 155, pp. 1-10), and Xia et al. (“Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs,” 2009, ACS; ACSNano, Vol. 3, No. 6, pp. 3273-3286).
Applicants Claims
Applicant claims a mesoporous silica nanoparticle comprising: a plurality of pores and an outer surface; a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells; and an immunomodulatory moiety comprising a pathogen-associated molecular pattern (PAMP), a danger-associated molecular molecule (DAMP), a cytokine, an antibody, or other immunomodulatory moiety, the immunomodulatory moiety either disposed in at least a portion of the pores; or bound to at least a portion of the outer surface. (instant claim 1).
Elected Species: Applicants have elected the following species in the reply filed 05/13/2025: (a) A species of a mesoporous nanoparticle with specificity to: (i) a bioactive agent is a bioactive agent that alters the tumor microenvironment, (ii) an immunomodulatory moiety is pathogen-associated molecular pattern (PAMP), (iii) a cationic layer is polyethyleneimine (PEI), and (iv) an anionic layer is hyaluronic acid. A species of administering is intraperitoneally administering.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Zhao et al. teaches hollow mesoporous silica nanoparticles (HMSN) coated with polyethyleneimine (PEI) and subsequently coated with hyaluronic acid HA (see whole document). Zhao et al. particularly teaches that: “In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethyleneimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as “gatekeepers” to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SSCDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44-receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy.” (abstract).
Zhao et al. teaches that: “In our research, the redox and enzyme dual-stimuli responsive DDS (HMSN-SS-CDPEI@HA) based on HMSN was developed as shown in Scheme 1.” (p. 476, col. 1, 2nd paragraph; Scheme 1)(instant claims 2-3, 6-7 and 14, the cationic layer is PEI and the anionic layer is HA).
Zhao et al. further teaches that: “And the cumulative release of DOX under dual stimuli was about 2.5-fold higher than that in pH 7.4 PBS and pH 5.0 PBS alone. Clearly, DOX/HMSN-SS-CDPEI@HA had the ability to achieve redox and enzyme dual-responsive drug release (Scheme 2).” (p. 481, col. 2, 1st paragraph; Scheme 2).
Zhao et al. teaches that: “Moreover, the IC50 values (the concentration at which 50% of cells were killed) were calculated by SPSS Statistics software and the results were given in Table 2. The IC50 value of the DOX/HMSN-SS-CDPEI@HA was much lower than that of the free DOX and DOX/HMSN-SH for A549 cells, demonstrating the excellent anticancer activity of the DOX/HMSN-SSCDPEI@HA against A549 cells.” (p. 483, col. 1, lines 19-25). Zhao et al. teaches that: “polyethylenimine (PEI, Mw=25,000)” was used in their compositions, which is consistent with Applicant’s own disclosure (instant Specification p. 12, line 26), and therefore would have had the same result (instant claim 1, “a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells”).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Zhao et al. is that Zhao et al. does not expressly teach: (i) the immunomodulatory moiety is pathogen-associated molecular pattern (PAMP), or (ii) “a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells”.
LAWMAN et al. teaches multi-indication mRNA cancer immunotherapy (title, see whole document). LAWMAN teaches that: “The vaccine can be used not only in conjunction with checkpoint inhibitor therapy but also chemotherapy, radiation therapy, whole cell vaccines, other nucleic acid therapy, natural killer cell therapy or chimeric antigen receptor therapy prior to or concurrently with administration of the RNA vaccine.” ([0053]). And that: “In other cases, a cancer patient is treated with regimens that alter the tumor microenvironment, including but not limited to, cytokines, anti-fugetaxis agents, chemotactic agents and metronomic doses of chemicals prior to or concurrently with administration of the vaccine.” ([0054])(instant claim 1, a bioactive agent that alters the tumor microenvironment).
MOONEY teaches immunoconjugates for programming or reprogramming of cells (title, see whole document). MOONEY teaches that: “The invention provides a solution to the long standing clinical problems of aberrant immune responses such as those involved in cancer immunity, autoimmunity, allergy/asthma, and chronic or inappropriate inflammation in the body, e.g., inflammation that leads to tissue/organ damage and destruction. In the context of cancer therapy, the challenge is how to treat cancer in view of a tumor's immune evasive phenotype.” ([0010]).
MOONEY teaches that: “Accordingly, an exemplary composition comprises an immunomodulatory agent covalently linked to an antigen and a delivery vehicle, wherein said antigen comprises a tumor antigen.” ([0012]). And that the adjuvant comprises a toll-like receptor (TLR) ligand such as a cytokine etc., and “In various embodiments, the TLR ligand comprises a CpG oligonucleotide or a poly I:C poly nucleotide. […] Optionally, CpG or poly I:C are condensed. For example, the adjuvant is condensed and then linked to an antigen; alternatively the adjuvant is linked to the antigen and then the conjugate is condensed. Exemplary condensing agents include poly-L-lysine (PLL), polyethyleneimine (PEI), […]” ([0012] and [0013])(instant claim 2, a cationic layer disposed on at least a portion of the outer surface and the immunomodulatory moiety is bound to at least a portion of the cationic layer.).
MOONEY teaches that: “The invention provides a device comprising a porous polymeric structure composition, e.g., delivery scaffold or device, that includes a conjugate comprising a tumor antigen, and a toll-like receptor (TLR) agonist (as an immunomodulatory agent, e.g., adjuvant). For example, the device
comprises a polymeric structure composition, a tumor antigen, and a combination of toll-like receptor (TLR) agonists, wherein the TLR agonist is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. For example, the polymeric structure comprises poly (D,L-lactide-co-glycolide)(PLG). Exemplary TLR agonists include pathogen associated molecular patterns (PAMPs), e.g., an infection-mimicking composition such as a bacterially-derived immunomodulator. TLR agonists include nucleic acid or lipid compositions [e.g., monophosphoryl lipid A (MPLA)].” ([0017])(instant claims 4-5, wherein the PAMP comprises MPL).
MOONEY teaches that: “Also provided is a delivery device comprising a composition described herein and a dendritic cell (DC) recruitment composition. For example, a delivery device is provided that comprises a dendritic cell (DC) recruitment composition and a composition comprising an antigen covalently linked to a tolerogen, where the antigen comprises a) a peptide associated with an immune activation disorder or b) a lysate of a cell associated with an immune activation disorder.” ([0039]). And that: “Exemplary DC recruitment compositions include granulocyte-macrophage colony stimulating factor (GM CSF), PMS-like tyrosine kinase 3 ligand, N-formyl peptides, fractalkine, monocyte chemotactic protein-I, or macrophage inflammatory protein-3 (MIP-3a).” ([0040]). And further that: “In some cases, the delivery device further comprises a Th1 promoting agent. For example, the Th1 promoting agent comprises a toll-like receptor (TLR) agonist. For example, the TLR agonist comprises a CpG oligonucleotide. In some examples, the Th1 promoting agent comprises a pathogen-associated molecular pattern (PAMP) composition or an alarmin. In some cases, the Th1 promoting agent comprises a TLR 3, 4, or 7 agonist.” ([0041])(instant claim 1, “myeloid immune cell activating activity”).
MOONEY teaches that: “In some embodiments, an immunomodulatory agent comprises a mesoporous silica particle (e.g., a sphere or a rod), or structural material. Mesoporous silica has proinflammatory, e.g., adjuvant properties.” ([0028]). And that: “In some embodiments, the delivery vehicle comprises mesoporous silica (MPS). With respect to promoting an immune response, delivery of an immunoconjugate comprising an adjuvant conjugated to an antigen ( e.g., a peptide antigen conjugated to a carrier protein), from a MPS vaccine scaffold increases the immunogenicity and humoral responses against the antigen or peptide as compared to delivering the antigen and adjuvant as separate entities.” ([0326]).
MOONEY teaches that: “Also within the invention are vaccines comprising
the loaded delivery device scaffold(s) described above and a pharmaceutically-acceptable excipient for injection or implantation into a subject for the to elicit antigen specific immune tolerance to reduce the severity of disease.” ([0062])(instant claim 8).
Regarding instant claim 3 reciting, in part, “the immunomodulatory moiety is bound to at least a portion of the anionic layer.” the examiner cites Shin et al. teaching hyaluronic acid-supported combination of water insoluble immunostimulatory compounds for anti-cancer immunotherapy (title, see whole document), and particularly that: “With the help of hyaluronic acid (HA), water insoluble monophosphoryl lipid A (MPL), QS21 and imiquimod (R837),could be easily dispersed in aqueous solution and lyophilized as powder-form, which have an advantage in room-temperature storage stability compared with those conventional liquid formulation that requires cold storage.” (abstract). Given that Zhao et al. teaches a hyaluronic acid coated mesoporous silica nanoparticle, and MOONEY teaches immunoconjugates for cancer therapy, and Shin et al. teaches hyaluronic acid as supporting monophosphoryl lipid A, it would have been prima facie obvious to combine the hyaluronic acid an the monophosphoryl lipid A as a suitable means of supporting the same in an aqueous environment.
Additionally, regarding the limitation: “myeloid immune cell activating activity” Shin et al. teaches that: “The major progress for cancer immunotherapy has involved the development of dendritic cells (DCs)-based therapy […]” (p. 1, col. 1, lines 5-7). And that: “MPL have shown excellent properties in the activation of immune cells such as dendritic cells and macrophages, also induced effective humoral and cellular immunity.” And further that: “Both MPL and R837 stimulated immune system by the recognition of common pathogen-associated molecular-patterns (PAMPs) and induced a cellular immune response.” (p. 1, col. 2, lines 12-14 & 19-21). The described “activation of immune cells such as dendritic cells and macrophages” reads on “myeloid immune cell activating activity” as dendritic cells and macrophages are myeloid immune cells.
Further regarding the limitation “a cationic layer disposed on at least a part of the outer surface in an amount effective to kill cancer cells” (instant claim 1, lines 3-4), Xia et al. teaches the cytotoxicity of PEI, particularly that: “It is documented that, while low MW PEI is not cytotoxic, these polymers are ineffective at transfecting nucleotides in contrast to the high MW PEI. In this regard, it has been demonstrated that the size (MW), compactness, and chemical modification of PEI affect the efficacy and toxicity of this polymer. Therefore, we experimented with several PEI polymer sizes ranging from MW of 0.6 to 25 kD in order to balance the efficiency of nucleic acid delivery and cellular toxicity. PEI cytotoxicity occurs via a proton sponge effect, which involves proton sequestration by the polymer surface that leads to heightened proton pump activity inside the cell, osmotic swelling of the endocytic compartment, endosomal rupture, and ultimately cell death by a mitochondrial mediated mechanism.” (p. 3274, col. 1, line 18 through p. 3275, col. 1, line 7). And that: “To screen for particle hazard, we used the MTS assay, which reflects dehydrogenase activity in healthy cells. While most of the MSNP did not interfere in MTS activity in the PANC-1 and BxPC3 pancreatic cancer cell lines, particles coated with the 25 kD PEI polymer showed decreased cellular viability (Figure 1B). The particles coated with the 25 kD polymer also induced toxicity in macrophage (RAW 264.7) and bronchial epithelial (BEAS-2B) cell line staining (Supporting Information Figure 2).” (p. 3275, col. 2, lines 2-11). And further that: “A potential downside of cationic functionalization for drug or nucleic delivery is the possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” (p. 3280, col. 2, lines 3-5). Therefore, the prior art clearly establishes that MSNP-PEI 25 kD, would have been expected to be cytotoxic to cells in vitro, as per the teaching of Xia et al. and Applicants disclosure.
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a mesoporous silica nanoparticle coated with PEI and HA for cancer therapy, as suggested by Zhao et al., and to combine cancer immunotherapy agents, as suggested by LAWMAN, MOONEY, and Shin et al. in order to produce a cancer immunotherapy mesoporous silica nanoparticle agent, and further that MSNP-PEI 25 kD, as suggested by Xia et al., would have been expected to be cytotoxic to cells in vitro.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill to produce a mesoporous silica nanoparticle coated with PEI and HA and bonded to an adjuvant such as MPL-A, and including a bioactive agent that alters the tumor microenvironment as per the cited prior art. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 02/25/2026 have been fully considered but they are not persuasive.
Applicant argues that: “Applicant submits that the combination of Zhao, Lawman, Mooney, and Shin fails to establish that all of the features recited in claim 1 were established in the prior art. Further, Applicant submits, as explained by Dr. Serda during the interview, that the combination of components as recited in claim 1 provided a surprising result that was not predictable from the cited documents.” (p. 8, 2nd paragraph). And that: “Zhao provides no teaching that PEI, or any other cationic layer material is present in an amount effective to kill cancer cells. The Office Action acknowledges that Zhao teaches the use of doxorubicin as an anti-cancer drug released via redox-responsive and/or enzyme-responsive drug release from the HSMNs. Id. No cancer cell killing activity in Zhao is attributed to anything other than doxorubicin.” (p. 8, 4th paragraph).
In response the examiner argues that Zhao et al. clearly teaches that: “Moreover, the IC50 values (the concentration at which 50% of cells were killed) were calculated by SPSS Statistics software and the results were given in Table 2. The IC50 value of the DOX/HMSN-SS-CDPEI@HA was much lower than that of the free DOX and DOX/HMSN-SH for A549 cells, demonstrating the excellent anticancer activity of the DOX/HMSN-SS-CDPEI@HA against A549 cells.” p. 483, col. 1, lines 19-25). Which clearly suggest cancer cell killing activity. Furthermore, Zhao et al. utilizes “polyethylenimine (PEI, Mw=25,000)” which is the same as the instant Specification (p. 12, line 26), which Xia et al. suggest as: “possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” (p. 3280, col. 2, lines 3-5). Therefore, the prior art clearly establishes that MSNP-PEI 25 kD, would have been expected to be cytotoxic to cells in vitro, as per the teaching of Xia et al. and Applicants disclosure. Therefore, it is not considered unexpected relative to the prior art.
Applicant further argues that: “Without acquiescing to the position stated in the Office Action, Applicant submits that the teaching of Mooney fails to cure the deficiencies of Zhao with respect to the mesoporous silica nanoparticle of claim 1 as amended herein. Mooney provides no teaching that the condensing agent is provided in an amount effective to kill cancer cells. In fact, Mooney teaches indirect anti-tumor activity that is the result of delivering a tumor antigen and an adjuvant to immune cells to stimulate an immune response against tumor cells. Mooney, paragraphs [0010][0016]. Mooney provides no teaching that the delivery vehicle, itself, includes any component that kills cancer cells without eliciting an immune response against the cancer cell. Consequently, Mooney fails to cure the deficiency of Zhao with respect to a mesoporous silica nanoparticle having a cationic layer provided in an amount effective to kill cancer cells, as recited in claim 1 as amended herein.” (paragraph bridging pp. 9-10). Applicant further argues that: “In sum, none of Lawman, Mooney, or Shin provides teaching that cures the deficiencies of Zhao with respect to the mesoporous silica nanoparticle (MSN) recited in claim 1 as amended herein. None of Zhao, Lawman, Mooney, or Shin provides any teaching of a mesoporous silica nanoparticle that has cancer cell killing activity in the absence of either (a) delivering an antitumor drug or (b) eliciting an immune response against the target cancer cell. In contrast, the MSN recited in claim 1 possesses both direct cancer cell killing activity (via the cationic layer present in an amount effective to kill cancer cells) and immunostimulatory activity (via the immunomodulatory moiety disposed in at least a portion of the pores of the MSN or bound to at least a portion of the outer surface of the MSN). For at least these reasons, Applicant submits that claim 1 is nonobvious over the combination of Zhao, Lawman, Mooney, and Shin.” (p. 10, 3rd paragraph).
In response the examiner argues that the instantly rejected claims are open-ended - “A mesoporous nanoparticle comprising:” – MPEP §2111.03 makes clear that: “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” And, as discussed above, Zhao et al. clearly teaches mesoporous nanoparticles that utilizes “polyethylenimine (PEI, Mw=25,000)” which is the same as the instant Specification (p. 12, line 26), which Xia et al. suggest as: “possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” (p. 3280, col. 2, lines 3-5).
Applicant further argues that: “Further, however, Applicant submits that the mesoporous silica nanoparticle recited in claim 1 as amended herein provides a surprising result that was not predictable. In the Examiner Interview, Dr. Serda explained that the composition as recited in claim 1 was first prepared to be a negative control in experiments intended to gauge the efficacy of similar mesoporous silica nanoparticle that further included an antigen. Dr. Serda' s expectation was that in the absence of antigen (or anti-tumor drug), the mesoporous silica nanoparticle would not have any cancer cell killing activity and, therefore, provide a baseline against which the antigen-delivering mesoporous silica nanoparticle could be compared. To her surprise, she found that the mesoporous silica nanoparticle as recited in claim 1 actually possessed the ability to directly kill cancer cells-i.e., the mesoporous silica nanoparticles killed cancer cells without eliciting an immune response, without presenting an antigen against which an immune response is mounted, and without delivering an anti-tumor drug. Dr. Serda explained that upon further investigation confirming the surprising and unexpected result, the cancer cell killing activity can be attributed to the cationic layer disposed on at least a portion of the outer surface of the mesoporous silica nanoparticle.” (paragraph bridging pp. 10-11). And that: “This unexpected activity differentiates the mesoporous silica nanoparticle recited in claim 1 from the approaches described in Zhao, Mooney, Lawman, and Shin.” (p. 11, 2nd paragraph).
In response the examiner argues that instant claim 1 is open-ended, as discussed above, therefore it is unclear what exactly what “composition as recited in claim 1 was first prepared to be a negative control in experiments”. The prior art clearly shows that 25,000 MW PEI would have been expected to be cytotoxic in a MSN-PEI composition (Xia et al. suggest as: “possibility of cytotoxicity, best demonstrated by the use of MSNP-PEI 25 kD.” (p. 3280, col. 2, lines 3-5)). Therefore, the results showing cytotoxicity of MSN-PEI (Figure 7) are not considered unexpected relative to the prior art. Additionally, claims are not limited to MSN-PEI which Applicant has apparently regarding as a negative control.
Conclusion
Claims 1, 3 and 5-8 are pending and have been examined on the merits. Claims 1, 3 and 5-8 are rejected under 35 U.S.C. 112(a)(New matter, and written description); and claims 1, 3 and 5-8 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights