DETAILED ACTION
Status of the Claims
Claims 1-20 are pending in the instant application. Claims 14-20 have been withdrawn based upon Restriction/Election as discussed below. Claims 1-13 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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 U.S. effective filing date has been determined to be 03/06/2023, the filing date of the instant application.
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 1-4, 6-11 and 13 remain rejected under 35 U.S.C. 103 as being unpatentable over Croissant et al. (“Biodegradable Ethylene-Bis(Propyl)Disulfide-Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for Efficient In-Vitro Drug Delivery,” 2014; Advanced Materials, Vol. 26, pp. 6174-6180) in view of He et al. (“Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel,” 2017, ELSEVIER; Materials Science and Engineering C,” Vol. 78, pp. 12-17); Tamanoi et al. (“Biodegradable Periodic Mesoporous Organosilica (BPMO) Loaded with Daunorubicin: A Promising Nanoparticle-Based Anticancer Drug,” 2020, ChemMedChem, Vol. 15, pp. 593-599) and Wu et al. (“Synthesis and characterization of mesoporous magnetic nanocomposites wrapped with chitosan gatekeepers for pH-sensitive controlled release of doxorubicin,” 2017, ELSEVIER; Materials Science and Engineering C, Vol. 70, pp. 132-140).
Applicants Claims
Applicant claims a nano device, comprising: (a) a spherical a biodegradable periodic mesoporous organsilicas (BPMO) framework comprising by Si-O-Si covalent bonds and disulfide covalent bonds, wherein said BPMO framework comprises a plurality of 2.5 nm diameter mesopores formed on an entire surface area of said BPMO framework derived from a silane precursor selected from akyl alkoxy silane, aryl alkoxy silane, and bis[3(triethoxysilyl)propyl] disulfide and (b) an independent and separate protective layer consisting of a chitosan layer, deposited directly on said BPMO framework, operable to wrap around said entire surface area and protect said BPMO framework and said plurality of mesopores (c) a plurality of paclitaxel (PTX) drugs cargos situated in said plurality of 2.5 nm diameter mesopores by said disulfide covalent bonds; wherein when exposed to a first condition, said chitosan layer degrades to expose said plurality of PTX drug cargos; and wherein when exposed to a second condition, said disulfide covalent bonds release said plurality of said PTX drug cargos.(instant claim 1). Applicant further claims the nanodevice of claim 6 wherein in said second condition said BPMO framework releases said drug cargos from said plurality of mesoporous by allowing a predetermined concentration of glutathione to break said disulfide (S-S) covalent bonds (instant claim 7).
Claim interpretation: The instant claims are directed at compositions of matter and include certain process steps, particularly instant claim 1 recites “wherein said BPMO framework is synthesized by adjusting an exact amount of 250 mg of 0.69 mM hexadecyltrimethylammonium bromide (CTAB) width 800 uL of 1M alkaline hydroxide and then by adding dropwise 300 uL of 0.88 mmol of a Silane precursor selected from alkyl alkoxy silane and ary] alkoxy silane and then 100 uL 0.2 mmol bis[3(triethoxysilyl)propyl] disulfide in that exact order” (instant claim 9). Composition of matter claims (or Product claims) that include process steps are considered Product-by-Process claims which are not limited by the process steps but rather the structure implied by those steps (MPEP §2113 stating in part that: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process."”). The examiner is interpreting the pore size (2.50 nm) and the genus/species alkyl] alkoxy silane, aryl alkoxy silane and bis[3(triethoxysilyl)propyl] disulfide as structural limitations.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Croissant et al. teaches biodegradable ethylene-bis(propyl) disulfide-Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for efficient In-Vitro drug delivery (title, see whole document). Croissant et al. teaches that “In our study we report the syntheses of biodegradable PMO 200 nm nanospheres and 450 to 130 nm nanorods based on bis(triethoxysilyl)ethylene (E) and bis(3-triethoxysilylpropyl) disulfide (DIS) bridging groups in various weight ratios. The control of the NPs shape and size was found to be directly correlated to the ethylene over bis(propyl)disulfide ratio (RE/DIS). […] Depending on the RE/DIS , ethylene-disulfide (EDIS) mixed PMO (MPMO) nanorods and nanospheres of various sizes were elaborated and used as biodegradable nanocarriers of drugs in breast cancer cells. The EDIS MPMO nano-objects were very efficient in inducing cancer cell death when loaded with doxorubicin (DOX).” [emphasis added](p. 6174, col. 2, 1st paragraph). The examiner notes that bis(triethoxysilyl)ethylene (E) is being regarded as an alkyl alkoxy silane (instant claim 1, line 11) and 1,2-bis(triethoxysilyl)ethylene (instant claim 10).
Croissant et al. teaches that: “Furthermore, the materials were found to have high surface areas and pores size from 2.5 to 2 nm (Figure S7). The specific surface areas were lowered when the RE/DIS decreased, from 1087 (RE/DIS = 90/10), 923 (RE/DIS = 75/25), and 890 m2⸱g-1 (RE/DIS = 50/50). […] Accurate nanomaterial pore sizes of 3.1 (E PMO), 2.7 (EDIS 90/10), 2.3 (EDIS 75/25), and 2.2 nm (EDIS 50/50) were determined via the Gurvich method (ESI), which are consistent (though higher) with those obtained by the BJH method (2.0 to 2.5 nm).” (p. 6175, col. 1, lines 18-22 & 28-30, col. 2, lines 1-2)(instant claim 1, “wherein each of said plurality of pores has a diameter of 2.50 nm”).
Croissant et al. teaches that: “The degradability of EDIS nanorods and nanospheres was then studied in solution. EDIS 50/50 nanospheres were dispersed in PBS (pH 7.4) at 37 °C with 6 μM or 2 mM of mercaptoethanol (ME) ( Figure 3), so as to respectively mimic the extracellular and intracellular equivalents of glutathione. The idea was to induce the disulfide bond cleavage in order to progressively degrade the NPs in a simulated extracellular or intracellular environment.” (p. 6176, col. 1, 2nd paragraph, lines 1-8).
Croissant et al. teaches that: “Dried nanomaterial powders were placed at the bottom of a plastic cuvette then filled gently with water. The absence of premature release was monitored by UV-visible spectroscopy and plotted as a function of time (see pH 7 in Figure 4 ). However, as soon as the pH was lowered to 5.5 (as in the lysosomal compartment), instantaneous DOX release occurred for all porous nanocarriers. […] the trend of the release efficiencies correlated the nanomaterials surface areas and pore size: E > EDIS 90/10 > EDIS 75/25 > EDIS 50/50 (see Figure S7). Zink et al. have shown the primary importance of the surface area in the loading capacities of mesoporous silica NPs, though other parameters may be involved in such PMO NPs (particle size, shape, composition, etc.).” (p. 6176, col. 2, last three lines through p. 6177, col. 1, line 13; Figures 3-4).
Croissant et al. teaches that: “The synthesis was performed in water with a cetyltrimethylammonium bromide micellar template and sodium hydroxide catalysis […].” (p. 6174, col. 2, 2nd paragraph, lines 1-4)(instant claim 11).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Croissant et al. is that Croissant et al. does not expressly teach a chitosan coating on the nanoparticles (instant claim 1).
He et al. teaches mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel (title, see whole document). He et al. teaches that: “Mesoporous silica nanoparticles (MSN) were great promising drug carriers because of their good biocompatibility, feasibility of surface modification, tunable pore size, high pore volume and large surface area. MSN had been shown to overcome the poor water solubility of many hydrophobic drugs and enhance their bioavailability. It had been reported that drug dissolution rate reduced as the pore size of MSN decreased.” And that: “Paclitaxel (PTX), a broad-spectrum anticancer drug, was effective in treating various types of solid tumors. However, the hydrophobic nature of PTX confined its use as a suitable anticancer drug. In this study, to overcome the poor water solubility of PTX and improve its bioavailability, MSN were synthesized as hydrophobic drug vehicles for PTX.” (p. 12, col. 2, lines 3-15)(instant claim 1, “(c) paclitaxel (PTX) drugs cargos situated in said plurality of 2.5 nm diameter mesopores”). He et al. teaches the porous characteristics of the MSN before and after loading with PTX, including a surface area of 956.22 and 701.70 m2/g and pore size of 3.05 and 2.42 nm, respectively (p. 15, col. 1, Table 1)(instant claim 8).
He et al. concludes that: “In this study, MSN were examined as potential drug delivery vehicles for the poor water-solubility PTX. Several variables including solvent, drug loading period and drug/carrier mass ratio had been verified to affect the drug loading capacity of MSN. Either the decrease of the solvent polarity parameter or the increase of drug/carrier mass ratio could increase the drug loading content. The in vitro release study showed that the solubility of PTX was remarkably improved after loading into MSN. The MTT assay revealed that MSN did not exhibit obvious cytotoxicity on HepG2 cells under the test condition, while the MSN@PTXdic showed a dose-dependent cytotoxic effect, and the cytotoxicity increased with the increase of PTX concentration. These results demonstrated MSN were promising carriers for hydrophobic drugs.” (p. 16, §4-Conclusion).
Tamanoi et al. teaches that: “While MSN are synthesized by classical sol-gel
reaction of tetraethyl orthosilicate (TEOS), BPMO use bridged organosilane precursors that enable homogeneous and covalent incorporation of organic moieties. In particular, this approach results in the uniform distribution of biodegradable bonds into the silylated framework. These bonds include disulfide and tetrasulfide bonds that are sensitive to reducing conditions. […] BPMO possess all the advantageous features of pure inorganic MSN such as high surface area, large pore volume and fine control of the pore diameter. On the other hands, the organic groups confer degradability under biorelevant conditions thus contributing to the issue of safety of nanomaterials during clinical use. Uptake of BPMO into cancer cells and delivery of anticancer drugs such as camptothecin and doxorubicin have been reported.” (p. 593, col. 1, lines 6-9, col. 2, lines 1-12). Tamanoi et al. teaches that: “Cetyltrimethylammonium bromide (CTAB) was used as a structure directing agent to promote pore network formation in the nanostructure.” (p. 594, 3rd paragraph, lines 5-7).
Wu et al. teaches that: “Synthesis and characterization of mesoporous magnetic nanocomposites wrapped with chitosan gatekeepers for pH-sensitive controlled release of doxorubicin,” (title, see whole document), and particularly that: “The chitosan (CS) was employed to wrap the Fe3O4@mSiO2-DOX as the blocking agent to inhibit premature drug release […].” (abstract, lines 5-6). Wu et al. teaches that: “Meanwhile, 0.5 g CS was dissolved in 20 mL of acetic acid aqueous solution (10% v/v) under stirring and ultrasound for 15 min and the pH was adjusted to 6.0 with saturated NaOH solution. Then the freshly prepared Fe3O4@mSiO2-DOX was added under ultrasound for 10 min and the reaction went on for 40 h at room temperature.” (p. 134, col. 1, §2.4, lines 5-9).
Regarding the drug loading capacity (instant claims 9 and 13) the cited prior art suggest the same constituent ingredients, including the pore size and high surface area. The cited prior art also suggests encapsulating paclitaxel in the pore structure, therefore the drug loading capacity would have also been the same as now claimed.
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 biodegradable periodic mesoporous organosilica (BPMO) nanoparticle composition for drug delivery, as suggested by, Croissant et al. and Tamanoi et al., and further to coat the BPMO nanoparticle with chitosan in order to prevent premature release of drug, as suggested by Wu et al., the, the BPMO being capable of delivering paclitaxel, as suggested by He et al., for improved delivery of the hydrophobic drug species paclitaxel.
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 Croissant et al. teaches producing spherical mesoporous silica nanoparticles using bis(triethoxysilyl)ethylene, and bis[3-(triethoxysilyl) propyl] disulfide, and it would have required no more than an ordinary skill to coat the same with chitosan as suggested by Wu et al., and within the ordinary level of skill in the art to which the invention pertains. 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).
Claim 5 remains rejected under 35 U.S.C. 103 as being unpatentable over Croissant et al. in view of He et al.; Tamanoi et al. and Wu et al. as applied to claims 1-4, 6-11 and 13 above, and further in view of Senthilkumar et al. (“Targeted delivery of a novel anticancer compound anisomelic acid using chitosan-coated porous silica nanorods for enhancing the apoptic effect,” 2015, RSC; Biomaterials Science, Vol. 3, pp. 103-111); and as evidenced by Sigma-Aldrich product information for Chitosan - low molecular weight (448869), retrieved from <www.sigmaaldrich.com/US/en/product/aldrich/448869> on 11/23/2023, pp. 1-8).
Applicants Claims
Applicant claims a nano device, as discussed above. Applicant further claims the chitosan [in the chitosan] layer has a molecular weight between 50 kDa to 300 kDa (instant claim 5).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Croissant et al. teaches biodegradable ethylene-bis(propyl) disulfide-Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for efficient In-Vitro drug delivery, as discussed above and incorporated herein by reference.
He et al. teaches mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel, as discussed above and incorporated herein by reference.
Tamanoi et al. suggest BPMO’s for drug delivery as a better alternative to MSN’s, as discussed above and incorporated herein by reference.
Wu et al. synthesis and characterization of mesoporous magnetic nanocomposites wrapped with chitosan gatekeepers for pH-sensitive controlled release of doxorubicin, 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 Croissant et al. is that Croissant et al. does not expressly teach a chitosan coating on the nanoparticles has a molecular weight in the range of between 50 kDa to 300kDa (instant claim 5).
Senthilkumar et al. teaches targeted delivery of a novel anticancer compound anisomelic acid using chitosan-coated porous silica nanorods for enhancing apoptic effect (title, see whole document). Senthilkumar et al. teaches that: "In the past decade, mesoporous silica particles (MSPs) have attracted considerable attention in related biomedical applications. Meanwhile, rod-shaped nanoparticles have also gained less but significant attention in the last few years. In line with previous studies regarding rod-shaped particles, our recent investigation on the morphology effect of spherical and rod-shaped MSPs on cellular internalization showed that the rod shaped MSPs displayed increased cellular uptake as compared to the spherical particles. Thus, such studies could have important implications for the further development of MSP-based drug delivery systems." (p. 103, col. 2, lines 10-20).
Senthilkumar et al. teaches that: "Polymers used for coating aiming at drug delivery applications must be biocompatible and biodegradable. Among natural polymers, polysaccharides tend to be internalized and degraded rapidly, thus enabling a moderate intracellular release of the drug. Chitosan is a natural cationic polysaccharide, obtained by alkaline deacetylation of chitin, which is derived from shrimp and other crustacean shells. In the literature, from a drug delivery point of view, chitosan is one of the few natural cationic biopolymers available and has been increasingly employed as drug carriers in the form of chitosan nanoparticles generated by employing different preparation techniques. In addition to this, chitosan has been implied to provide slow/controlled drug release with the advantage of pH-responsiveness. This inherent property of chitosan can lead to prolonged retention time of drugs and continuous drug release in vivo as well as improving the drug bioavailability. Chitosan has also been utilized in improving the solubility, stability and efficacy of drugs. These accumulated literature data consequently endow chitosan with advantages that could be beneficial for different biomedical and drug delivery applications." (p. 104, col. 1, lines 9-29). And further that: "In light of the considerations above, we envisioned that elongated nanoparticles would be more favourable for therapeutic applications based on targeting-specificity, biodistribution, as well as cellular internalization profiles. In addition to the morphological advantages of NR-MSP, the prepared particle design also comprises the advantages of chitosan, which was electrostatically adsorbed on the NR-MSPs after drug loading. [ ... ] Furthermore, we also aimed at uptake enhancement by means of active cellular targeting for the delivery of AA to folate receptor (FR)-enriched cancer cell surfaces by conjugating folic acid (FA) to chitosan, with subsequent coating of the NR-MSP surfaces with the folic acid-chitosan conjugate." (p. 104, col. 1, lines 35-52).
Senthilkumar et al. teaches that: "Chitosan adsorption was preferred for modification of NR-MSP and NR-MSP/AA samples in order to enhance the dispersibility and stability of particles in suspension while capping the pores of NRMSPs after drug loading." (p. 105, col. 1, lines 2-5).
Senthilkumar et al. discloses the chitosan used was low molecular weight chitosan (p. 104, col. 2, §Experimental - Materials, line 3) which is evidenced by Sigma-Aldrich product No. 448869 (Chitosan - low molecular weight) as having a molecular weight in the range of 50,000 to 190,000 Da (based on viscosity)(p. 1, bottom, §PROPERTIES - mol wt), which is 50 to 190 kDa (instant claim 5).
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 biodegradable periodic mesoporous organosilica (BPMO) nanoparticle composition for drug delivery, as suggested by, Croissant et al. and Tamanoi et al., and further to coat the BPMO nanoparticle with chitosan in order to prevent premature release of drug, as suggested by Wu et al., the, the BPMO being capable of delivering paclitaxel, as suggested by He et al., for improved delivery of the hydrophobic drug species paclitaxel; the chitosan having a molecular weight in the range of 50,000 to 190,000 Da, as suggested, by Senthilkumar et al. as evidenced by Sigma-Aldrich product No. 448869.
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 Croissant et al. teaches producing spherical mesoporous silica nanoparticles using bis(triethoxysilyl)ethylene, and bis[3-(triethoxysilyl) propyl] disulfide, and it would have required no more than an ordinary skill to coat the same with chitosan as suggested by Wu et al., and Senthilkumar et al., and within the ordinary level of skill in the art to which the invention pertains. 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).
Claim 12 remains rejected under 35 U.S.C. 103 as being unpatentable over Croissant et al. in view of He et al.; Tamanoi et al. and Wu et al. as applied to claims 1-4, 6-11 and 13 above, and further in view of Chen et al. (“Colloidal HPMO Nanoparticles: Silica-Etching Chemistry Tailoring, Topological Transformation, and Nano-Biomedical Applications,” 2013, Advanced Materials, Vol. 25, pp. 3100-3105).
Applicants Claims
Applicant claims a nano device, as discussed above. Applicant further claims the aryl alkoxy silane is selected from 1,4-Bis(triethoxysilyl)benzene and 4,4’-Bis(triethoxysilyl)biphenyl (instant claim 12).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Croissant et al. teaches biodegradable ethylene-bis(propyl) disulfide-Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for efficient In-Vitro drug delivery, as discussed above and incorporated herein by reference.
He et al. teaches mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel, as discussed above and incorporated herein by reference.
Tamanoi et al. suggest BPMO’s for drug delivery as a better alternative to MSN’s, as discussed above and incorporated herein by reference.
Wu et al. synthesis and characterization of mesoporous magnetic nanocomposites wrapped with chitosan gatekeepers for pH-sensitive controlled release of doxorubicin, 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 Croissant et al. is that Croissant et al. does not expressly teach an aryl alkoxy silane (instant claim 12).
Chen et al. teaches periodic mesoporous organosilicas (PMOs), including for drug delivery (see whole document, particularly, p. 3100, col. 2, 2nd paragraph). Chen et al. teaches that: “In addition, it has been demonstrated that some families of PMOs exhibit the far higher chemical stability than mesoporous silica NPs with pure Si-O-Si frameworks under hydrothermal conditions, implying that the Si-C-Si bond in these PMOs is much more stable than Si-O-Si bond in the presence of etchant. Thus, it is anticipated that such a difference in chemical stability under etching can most probably be used for the selective removal of silica core to produce HPMOs.” (p. 3101, col. 1, lines 5-13). And that: “To verify this assumption, we chose three representative bissilylated precursors with varied organic R moieties: = 1,4-bis(triethoxysilyl)benzene (BTEB) with R1 = phenyl (aromatic) group, 1,2-bis(triethoxysilyl)ethane (BTEE) with R2 = ethyl (aliphatic) group and bis(triethoxysilyl)ethylene (BTEEE) with R3 = vinyl (alkene) group.” (p. 3101, col. 1, 2nd paragraph; Figure 1).
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 biodegradable periodic mesoporous organosilica (BPMO) nanoparticle composition for drug delivery, as suggested by, Croissant et al. and Tamanoi et al., and further to coat the BPMO nanoparticle with chitosan in order to prevent premature release of drug, as suggested by Wu et al., the BPMO being capable of delivering paclitaxel, as suggested by He et al., for improved delivery of the hydrophobic drug species paclitaxel; the organic R groups of the BPMO nanoparticles being substitutable among bis(triethoxysilyl)benzene (BTEB) with R1 = phenyl (aromatic) group, 1,2-bis(triethoxysilyl)ethane (BTEE) with R2 = ethyl (aliphatic) group and bis(triethoxysilyl)ethylene (BTEEE) with R3 = vinyl (alkene) group, as suggested by Chen et al. for the production of BPMO nanoparticles (MPEP 2144.06-II).
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 Croissant et al. teaches producing spherical mesoporous silica nanoparticles using bis(triethoxysilyl)ethylene, (or bis(triethoxysilyl)ethane or bis(triethoxysilyl)benzene, as suggested by Chen et al.) and bis[3-(triethoxysilyl) propyl] disulfide, and it would have required no more than an ordinary skill to coat the same with chitosan as suggested by Wu et al., and within the ordinary level of skill in the art to which the invention pertains. 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 03/13/2025 have been fully considered but they are not persuasive.
Applicant argues that: “First, Croissant teaches away a chitosan layer or any additional protective layers that cover the nanocarriers, e.g., EDIS NP and EDIS. Croissant used different types of nanocarriers such as EDIS 50/50, EDIS 75/25, etc. to control the concentration and the release of DOX. Croissant stated that this is the efficient way to control drug adsorption (to avoid premature drug release).” (p. 10, 3rd paragraph). And that: “In the meantime, Wu teaches a Chitosan layer on the Fe3O4@mSiO2-DOX carrier. Therefore, in order to combine Croissant and Wu, a PHOSITA needs to rebuild Croissant's nanocarriers from scratch to obtain Fe3O4@mSiO carrier, thus destroying the researches and results presented by Croissant.” (p. 10, 5th paragraph). And that: “In fact, in order to combine Croissant, He, Tamanoi, and Wu, a PHOSITA must rebuild a new nanocarrier from scratch. This is equivalent to use claim 1 as a template to piece together the prior-art references to achieve the claimed invention.” (p. 11, 1st paragraph).
In response the examiner argues that a person having ordinary skill in the art would have recognized the separate and severable function of the chitosan layer in WU. Indeed WU clearly teaches that: “Presently, the interesting concept of stimulus-responsive gatekeeping has been introduced to optimize the application of mSiO2 in drug delivery. And nanoparticles, organic molecules and supramolecular nanovalves have been employed as “gatekeepers” for mSiO2 to show its well-controlled drug release performance. The controlled drug release process can be regulated either by external stimuli such as thermal and light, or by internal stimuli such as enzymes and pH. Prominently, chitosan (CS), one of the high performance biomass materials, has been widely used in intelligent drug delivery system due to its unique properties like non-toxicity, biocompatibility, biodegradability and so on. In addition, unlike any other polymers coating, most of which need to add poisonous solvent and the preparation processes are complex. Using CS to coat the mSiO2 does not need those poisonous solvent and its preparation process of hydrogen bonding is very simple and facile. Moreover, the ionization of great amount of amino groups on chains of CS provides it as a pH-sensitive “gatekeeper”. In view of the above one of ordinary skill would have clearly recognized that chitosan could be used as a pH-sensitive gatekeeper on the nanocarriers taught by Croissant et al. in order to produce an intelligent drug delivery system.
Applicant further argues that: “In other words, in order to combine, Wu must change the operating principle of Croissant. The operating principle of Croissant is to use different type of nanocarriers such as EDIS 50/50, EDIS 75125, EDIS 90/1 0 etc. to cope with efficiency and the delivery amount. Equivalently, Croissant teaches away from using a blocking agent to prevent premature drug release.” (p. 11, 3rd paragraph).
In response the examiner argues that both Croissant et al. and Wu et al. are directed to intracellular delivery nanocarriers for cancer therapy therefore operating principle is the same for both Croissant et al. and Wu et al. And while Wu et al. teaches chitosan (CS) as a gatekeeper (the CS employed to wrap the nanocarriers as a pore blocking agent to inhibit premature drug release (abstract, lines 5-7)), and Croissant et al. teaching that release based on disulfide bond cleavage induced by glutathione (p. 6176, col. 1, 2nd paragraph; p. 6177, Figure 3). Both Croissant et al. and Wu et al. are directed at cancer drug delivery using nanocarriers for cancer therapy and CS gatekeeper of Wu et al. is clearly a surface coating, whereas the biodegradation in glutathione is related to the organosilica framework. One of ordinary skill in the art would have recognized that CS coating of Wu et al. employed in the nanocarriers of Croissant et al. would have provided additional protection to prevent premature drug release, as suggested by Wu et al.
Applicant further argues that: “(b) Croissant He et al., Tamanoi and Wu, individually or in combinations thereof still fail to teach the claimed limitations "an independent and separate protective layer consisting of a chitosan layer, deposited directly on said BPMO framework." (p. 12, item b). And that: “all of the above prior-art references (even if combined) fail to teach the claimed element (a) the PTX drug is conjugated by the disulfide covalent bonds and (b) when exposed to the second condition (glutathione) these disulfide covalent bonds are broken to release the PTX drugs to the target areas.” (p. 13).
In response the examiner argues that Wu et al. clearly teaches an independent and separate protective layer consisting of a chitosan layer, deposited directly on a silica-based framework, and Croissant et al. teaches a organosilica framework (periodic mesoporous organosilica – PMO), and one of ordinary skill would have recognized that CS was know as a coating useful for facilitating pH sensitive gatekeeper (the CS employed to wrap the nanocarriers as a pore blocking agent to inhibit premature drug release (abstract, lines 5-7)), it would have therefore been prima facie obvious to utilize the CS coating for the same function described by Wu et al. in the organosilica framework nanocarriers of Croissant et al., both references being directed to nanocarriers for cancer drug delivery to cancer cells for cancer therapy.
Applicant argues that: “Senthilkumar teaches a FA-Chitosan-NR-MSP that is only pH responsive. Thus, Senthilkumar fails to cure the deficiencies of Croissant, He, Tamanoi, and Wu.” And “Thus, claim 5 of the present invention is now patentable under 35 U.S.C. §103 over the teachings of Croissant, He, Tamanoi, Wu, and Senthilkumar. (p. 14, paragraph 3-4). Applicant further argues that: “As to claim 12, the amended claim 12 is now recited "said aryl alkoxy silane is selected from 1,4-Bis(triethoxysilyl)benzene and 4,4'-Bis(triethoxysilyl)biphenyl." Since, the Examiner agrees that aryl alkoxy silane is a structural limitations of the claimed BPMO, not a process limitations.” (p. 15, paragraphs 1-2).
In response the examiner argues that Applicants arguments over the combination of Croissant, He, Tamanoi, and Wu have not been convincing as discussed above. An claims 5 and 12, are not considered allowable for the same reasons as the parent claim(s), as discussed above.
Conclusion
Claims 1-13 are pending and have been examined on the merits. Claims1-13 remain rejected under 35 U.S.C. 103. No claims allowed at this time.
THIS ACTION IS MADE FINAL. 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
/TIGABU KASSA/Primary Examiner, Art Unit 1619