DETAILED ACTION
Status of the Claims
Claims 1-3, 5, 7-9, 11, 15, 16, 21-23 and 26-33 are pending in the instant application. Claims 21-23 and 31 have been withdrawn based upon Restriction/Election. Claims 1-3, 5, 7-9, 11, 15, 16, 26-30, 32 and 33 are being examined on the merits in the instant application.
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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 instant Application is the national stage (371) of PCT/GB2021/050960 filed 04/21/2021which claims priority to GB2005957.2 filed 04/23/2020.
The U.S. effective filing date has been determined to be 04/23/2020, the filing date of GB2005957.2.
Information Disclosure Statement
The information disclosure statement submitted on 11/18/2025 was filed after the mailing date of the first office action on the merits, however Applicant has indicated the appropriate fee has been paid. 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 Objections
Claim 21 is objected to because of the following informalities: The status identifier (previously presented) however the claim has been withdraw based on Election/Restriction and should have the status identifier (withdrawn). Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 has been amended to depend from claim 32 and is therefore rejected under 112(d), as depending from a subsequent claim. MPEP 608.01(n)(III) requires a claim in dependent form to “reference a claim previously set forth”. When examining a dependent claim, the examiner should determine whether the claim complies with 35 U.S.C. 112(d), which requires that dependent claims contain a reference to a previous claim in the same application, specify a further limitation of the subject matter claimed, and include all the limitations of the previous claim. If the dependent claim does not comply with the requirements of 35 U.S.C. 112(d), the examiner should reject the dependent claim under 35 U.S.C. 112(d) as unpatentable rather than objecting to the claim. See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92, 79 USPQ2d 1583, 1589-90 (Fed. Cir. 2006).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 5, 7-9, 11, 26-30, 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over YANTASEE (US 2017/0173169; published June, 2017) in view of YU (US 2018/0105422; published April, 2018); Xia et al. (“Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs,” 2009; ACSNano, Vol. 3, No. 10, pp. 3273-3286); Kuroda et al. (“Simplified lentivirus vector production in protein-free media using polyethylenimine-mediated transfection,” 2009; ELSEVIER, Journal of Virological Methods, Vol. 157, pp. 113-121) and Song et al. (“Plasmid DNA Delivery: Nanotopography Matters,” 2017; ACS; Journal of the American Chemical Society, Vol. 139, pp. 18247-18254; and supporting info. – p S1-S27).
Applicants Claims
Applicant claims a composition comprising an inorganic mesoporous nanoparticle comprising silica; and at least one delivery component; wherein the nanoparticle comprises projections on its external surface; wherein the nanoparticle has a diameter in the range of 50 nm to 3000 nm; wherein the at least one delivery component comprises a viral vector; and wherein the external surface of the nanoparticle is at least partially coated with the at least one delivery component (instant claim 1). Applicant further claims the inorganic mesoporous nanoparticle comprises a shell comprising silica, a hollow core with a volume defined by the inner surface of the core, and a plurality of projections comprising silica deposited on the exterior of the shell (instant claim 3). Applicant further claims the transfection agent is polyethyleneimine (PEI)(instant claims 9 & 30).
Determination of the scope
and content of the prior art (MPEP 2141.01)
YANTASEE teaches cross-linked polymer modified nanoparticles (title, see whole document), and particularly “nanoconstructs comprising a nanoparticle, coated with additional agents such as cationic polymers, stabilizers, targeting molecules, labels, oligonucleotides and small molecules. These constructs may be used to deliver compounds to treat solid tumors and to diagnose cancer and other diseases. Further disclosed are methods of making such compounds and use of such compounds to treat or diagnose human disease.” (abstract). YANTASEE teaches that: “The nanoconstruct may further include a stabilizer bound to the cationic polymer or nanoparticle, for instance, to prevents aggregation of the nanoconstruct in solution. In some embodiments, the nanoparticle is mesoporous, such as a mesoporous silica nanoparticle.” ([0007])(instant claim 1, “an inorganic mesoporous nanoparticle comprising silica”). YANTASEE teaches that: “The nanoconstruct may have a hydrodynamic diameter of from about 10 to about 200 nm.” ([0008])(instant claim 1, “wherein the nanoparticle has a diameter in the range of 50 nm to 3000 nm.” – MPEP §2144.05(I)). YANTASEE teaches that: “The cationic polymer may be polyethylenimine (PEI), […]. The cationic polymer may be cross-linked by reacting cationic polymer on the surface of the nanoparticle with a cross-linker in the presence of cationic polymer in solution, e.g., to prevent or reduce aggregation of nanoconstructs.” ([0009])(instant claim 1, “wherein the inorganic nanoparticle in at least partially coated with a transfection agent”; instant claims 8-9; instant claim 30, “wherein the transfection agent is […] polyethyleneimine (PEI).”).
YANTASEE teaches that: “In some embodiments, the nanoconstruct includes
at least one type of oligonucleotide, e.g., siRNA, miRNA, miRNA mimic, or antisense oligomer, electrostatically bound to the cationic polymer. In some embodiments, the at least one type of oligonucleotide is siRNA, e.g., that targets one or more genes selected from the group consisting of HER2, AKT1, AKT2, AKT3, EPS8L1, GRB7, AR, Myc, VEGF, VEGF-R1, RTP801, proNGF, Keratin K6A, Bc1-2, PLK1, LMP2, LMP7, MECL1, RRM2, PKN3, Survivin, HIF1α, Furin, KSP, eiF-4E, p53, β-catenin, ApoB, PCSK9, HSP47, CFTR, CTGF, SNALP, RSV nucleocapsids, CD47, PD-L1, and CTLA-4. […] The at least one type of oligonucleotide may include two or more different siRNAs loaded onto the nanoconstruct.” ([0011])(instant claim 1 “at least one delivery component”; instant claim 11). YANTASEE teaches that: “The nanoconstruct may include a small molecule. In some embodiments, the small molecule is attached on an inside of a pore. The small molecule may be attached to the exterior surface of the mesoporous silica nanoparticle. […] In some embodiments, the small molecule is about 0.5% to about 30% by weight of the mesoporous silica nanoparticle. In some embodiments, the small molecule is a chemotherapeutic agent, such as doxorubicin, paclitaxel, docetaxel, cisplatin, carboplatin, rapamycin, or camptothecin.” ([0038])(instant claim 1, “wherein the external surface of the nanoparticle is at least partially coated with the at least one delivery component.”).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of YANTASEE is that YANTASEE does not expressly teach their mesoporous silica nanoparticles include a hollow core and a shell with projections disposed on the exterior of the shell or integral with the shell (instant claims 3, 27-29); or an adeno-viral vector or a lenti-viral vector (instant claims 2, 26).
YU teaches “Particulate material comprising rough mesoporous hollow nanoparticles. The rough mesoporous hollow nanoparticles may comprise a mesoporous shell, the external surface of which has projections thereon, the projections having smaller sizes than the particle size. The particulate material may be used to deliver active agents […].” (title, abstract, see whole document).
YU teaches “Rough mesoporous hollow nanoparticles are defined as hollow particles or spheres with a mesoporous the projections having smaller sizes than the particle size. The particle size may range from 100 nm to 3000 nm, the size of projections may range from 5 nm to 1000 nm, preferably from 100 nm to 500 nm. In one embodiment, the projections may comprise nanospheres on the shell.” ([0014]) And that: “In one embodiment, the mesoporous shell may comprise, silica, […].” ([0017]) And further that: “The rough mesoporous hollow nanoparticles will typically have a hollow core that is surrounded by a shell having a mesoporous structure. As the shell that surrounds and defines the hollow core is porous, compounds may pass through the pores and enter into the hollow core.” And further that: “As the shell that surrounds and defines the hollow core is porous, compounds may pass through the pores and enter into the hollow core. The shell that surrounds the hollow core may have a thickness of from 10 nm to 100 nm.” ([0020])(instant claims 3, 5, 7, 27-29).
YU teaches that: “The present inventors have also found that the particles of the present invention can function as an effective delivery system for nucleic acids such as plasmid DNA (p-DNA) and messenger RNA (mRNA) that are used in emerging vaccination strategies. […] In formulating a DNA or mRNA-based vaccine, the particles of the present invention may be coated with substances that increase the affinity of the particles to these nucleic acids. This may involve covalently grafting chemical functional groups onto the particles, or applying a coating that interacts with the particle surface via hydrogen bonding, electrostatic attraction or some other means known to those skilled in the art. For example, polyethylenimine (PEI) may be coated onto the particles.” ([0038]).
Song et al. teaches Plasmid DNA delivery including nanotopography (title, see whole document), and particularly that: “For silica nanoparticles with rambutan-, raspberry-, and flower like morphologies composed of spike-, hemisphere-, and bowl-type subunit nano topographies, respectively, the rambutan-like nanoparticles with spiky surfaces demonstrate the highest plasmid DNA binding capability and transfection efficacy of 88%, higher than those reported for silica-based nanovectors.” [emphasis added](abstract)(instant claim 1, “wherein the nanoparticle comprises projections on its externa surface”).
Xia et al. teaches polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs (title, see whole document).
Xia et ale teaches that: “Surface-functionalized mesoporous silica nanoparticles (MSNP) can be used as an efficient and safe carrier for bioactive molecules. In order to make the MSNP a more efficient delivery system, we modified the surface of the particles by a functional group that enhances cellular uptake and allows nucleic acid delivery in addition to traditional drug delivery. Noncovalent attachment of polyethyleneimine (PEI) polymers to the surface not only increases MSNP cellular uptake but also generates a cationic surface to which DNA and siRNA constructs could be attached. While efficient for intracellular delivery of these nucleic acids, the 25 kD PEI polymer unfortunately changes the safety profile of the MSNP that is otherwise very safe. By experimenting with several different polymer molecular weights, it was possible to retain high cellular uptake and transfection efficiency while reducing or even eliminating cationic MSNP cytotoxicity. The particles coated with the 10 kD PEI polymer were particularly efficient for transducing HEPA-1 cells with a siRNA construct that was capable of knocking down GFP expression. Similarly, transfection of a GFP plasmid induced effective expression of the fluorescent protein in > 70% cells in the population. These outcomes were quantitatively assessed by confocal microscopy and flocytometry. We also demonstrated that the enhanced cellular uptake of the nontoxic cationic MSNP enhances the delivery of the hydrophobic anticancer drug, paclitaxel, to pancreatic cancer cells. In summary, we demonstrate that, by a careful selection of PEI size, it is possible to construct cationic MSNP that are capable of nucleotide and enhanced drug delivery with minimal or no cytotoxicity. This novel use of a cationic MSNP extends its therapeutic use potential.” (abstract).
The Xia et al. online article features the following visual abstract:
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Clearly indicating the surface of the mesoporous silica nanoparticles coated with plasmid DNA, which is GFP plasmid (i.e. green fluorescent protein (GFP)).
Kuroda et al. teaches simplified lentivirus vector production in protein-free media using polyethyleneimine-mediated transfection (title, see whole document). Kuroda et al. teaches that: “During the past 12 years, lentiviral vectors have emerged as valuable tools for transgene delivery because of their ability to transduce nondividing cells and their capacity to sustain long-term transgene expression. Despite significant progress, the production of high-titer high-quality lentiviral vectors is cumbersome and costly. The most commonly used method to produce lentiviral vectors involves transient transfection using calcium phosphate (CaP)-mediated precipitation of plasmid DNAs. However, inconsistencies in pH can cause significant batch-to-batch variations in lentiviral vector titers, making this method unreliable. This study describes optimized protocols for lentiviral vector production based on polyethylenimine (PEI)-mediated transfection, resulting in more consistent lentiviral vector stocks. To achieve this goal, simple production methods for high-titer lentiviral vector production involving transfection of HEK 293T cells immediately after plating were developed. Importantly, high titers were obtained with cell culture media lacking serum or other protein additives altogether. As a consequence, large-scale lentiviral vector stocks can now be generated with fewer batch-to-batch variations and at reduced costs and with less labor compared to the standard protocols.” (abstract)(instant claim 1, viral vector, instant claims 2 & 26, retroviral vector – lentiviral vector).
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 composition comprising a rough hollow mesoporous silica nanoparticle (MSN) for gene delivery having the cationic polymer PEI on the surface along with anionic nucleic acids such as one or more siRNA and/or mRNA, as suggested by YANTASEE and YU, the rough hollow mesoporous silica nanoparticles having a rambutan shape as per Song et al, and further to surface functionalize the MSN with a plasmid DNA, as suggested by Xia et al., the plasmid DNA being a lentiviral vector, as suggested by Kuroda et al., in order to produce an improved mesoporous silica nanoparticle for gene delivery
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 rough hollow mesoporous silica nanoparticles for gene delivery were known including the common PEI coating thereon. 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).
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over YANTASEE in view of YU; Xia et al.; Kuroda et al. and Song et al. as applied to claims 1-3, 5, 7-9, 11, 26-30, 32 and 33 above, and further in view of LEE (US 2019/0010288 A1; published January, 2019) and Moffett et al. (“Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers,” 2017, NPG; Nature Communications, Vol. 8, No. 389, pp. 1-13).
Applicants Claims
Applicant claims a composition comprising an inorganic mesoporous nanoparticle comprising silica; and one or more delivery components; wherein the nanoparticle comprises projections thereon; wherein the nanoparticle has a diameter in the range of 50 nm to 3000 nm; wherein the inorganic nanoparticle is at least partially coated with a transfection agent; and wherein the one or more delivery components comprises a viral vector (instant claim 1). Applicant further claims the composition further includes a cell (instant claim 15), and wherein the cell is a CAR-T cell or TCR-T cell (instant claim 16).
Determination of the scope
and content of the prior art (MPEP 2141.01)
YANTASEE teaches cross-linked polymer modified nanoparticles, as discussed above and incorporated herein by reference.
YU teaches compositions comprising rough mesoporous hollow nanoparticles, as discussed above and incorporated herein by reference.
Song et al. teaches Plasmid DNA delivery including nanotopography by rambutan-like hollow mesoporous silica nanoparticles, as discussed above and incorporated herein by reference.
Xia et al. teaches MSN surface functionalized with plasmid DNA, as discussed above and incorporated by reference.
Kuroda et al. teaches simplified lentivirus vector production in protein-free media using polyethyleneimine-mediated transfection, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of YANTASEE et al. is that YANTASEE et al. do not expressly teach the inclusion of a cell such as a CAR-T cell (claims 15-16).
LEE teaches nanocomposite compositions that include poly(ethyleneimine) coated silica nanoparticles (P-NP)(title, abstract, [0010], see whole document). LEE teaches that: “The nanocomposite composition of the present technology may further include cells, tissue, or combinations thereof. Suitable cells include mammalian cells, including […] human cells […].” ([0043])(instant claim 15).
Moffett et al. teaches that: “Therapies based on immune cells have been applied for diseases ranging from cancer to diabetes. However, the viral and electroporation methods used to create cytoreagents are complex and expensive. Consequently, we develop targeted mRNA nanocarriers that are simply mixed with cells to reprogram them via transient expression. Here, we describe three examples to establish that the approach is simple and generalizable. First, we demonstrate that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knockout selected genes in anti-cancer T-cells. Second, we imprint a long-lived phenotype exhibiting improved antitumor activities into T-cells by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, we show how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties. The simplicity of the approach contrasts with the complex protocols currently used to program therapeutic cells, so our methods will likely facilitate manufacturing of cytoreagents.” [emphasis added](abstract, see whole document). MOFFET et al. teaches that: “It has become possible to focus immune responses towards these diseases by genetically engineering T-cells to express targeted chimeric antigen receptors (CARs) or T cell receptors (TCRs), and this approach has presented positive clinical responses in cancer patients who have no other curative options.” (p. 2, col. 1, lines 13-18)(instant claim 16).
Moffett et al. teaches that: “Here, we describe a nanoreagent that, via a comparatively simple process, produces transient gene expression in cultured cells. We demonstrate that an appropriately designed messenger RNA (mRNA) nanocarrier can accomplish dose-controlled delivery of functional macromolecules to lymphocytes or HSCs simply by mixing the reagent with the cells in vitro (Fig. 1a). These nanoparticles (NPs) can be designed to target particular cell subtypes and, upon binding to them, stimulate receptor-mediated endocytosis, thereby introducing the synthetic mRNA they carry which the cells can now express. Because nuclear transport and transcription of the transgene are not required, this process is fast and efficient. Here, we illustrate in three examples how this new platform can be implemented to manufacture effective cell products for clinical use.” (p. 2, col. 2, 3rd paragraph, Figure 1).
Moffett et al. teaches that: “Here, we demonstrate using two therapeutic cell-based products–CAR-programmed T-cells and stem cells–that appropriately designed mRNA nanocarriers can transiently program gene expression to improve their therapeutic potential. We show how cell function and/or differentiation can be permanently reprogrammed by the simple addition of bioengineered NPs to cultures of cells used for therapy. This nanotechnology platform does not require special cell handling, so it can be easily integrated into established protocols for the manufacture of therapeutic cells without changing the workflow, or the equipment used in the process.” (p. 10, col. 1, §Discussion, 2nd paragraph, lines 1-11).
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 composition comprising a rough hollow mesoporous silica nanoparticle for gene delivery having the cationic polymer PEI on the surface along with anionic nucleic acids such as one or more siRNA and/or mRNA, as discussed above, and further to include a cell as suggested by LEE, the cell being a CAR-T or TCR-T cell reprogrammed by the rough hollow mesoporous silica nanoparticle suggested by YANTASEE et al., by the method of Moffett et al. as a simple means of programming said cells for cell therapy (CAR-T or TCR-T cell therapy).
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 rough hollow mesoporous silica nanoparticles for gene delivery were known including the common PEI coating thereon. 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 11/18/2025 have been fully considered but they are not persuasive.
Applicant’s argument that “That is, Sapre teaches encapsulating a viral vector within a cocoon of silica to reduce its immunogenicity while preserving its capability. This is NOT what the claimed nanoparticles do; the claimed nanoparticles operate by physically entrapping payload species on or between the protrusions present on the external surface of the nanoparticle. This feature is neither taught nor suggested by any of the cited references or by their asserted combination.” (p. 8, 1st paragraph).
In response, initially Sapre is no longer relied upon, and it would have been prima facie obvious to coat mesoporous silica nanoparticles including those such as taught by Yu with PEI and a plasmid DNA such as a lentiviral vector as per Xia et al. and Kuroda et al. (newly cited references).
Conclusion
Claims 1-3, 5, 7-9, 11, 15, 16, 26-30, 32 and 33 are pending and have been examined on the merits. Claim 21 is objected to; claim 8 is rejected under 35 U.S.C. 112(d) and claims 1-3, 5, 7-9, 11, 15, 16, 26-30, 32 and 33 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/IVAN A GREENE/Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619