DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-14 and 20-25 are pending and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-4, 6-9, 12-14 and 20-24 are rejected under 35 U.S.C. 103 as being unpatentable over Chakravarty et al. (US 2022/0048788) in view of Hwan et al. (KR 20130114346).
Chakravarty teaches tantalum oxide nanoparticle contrast agents. In various aspects, the current technology provides a nanoparticle composition including a plurality of nanoparticles, each nanoparticle of the plurality having a core including tantalum oxide, and a covalent coating covalently bound to the core, the covalent coating including a surface modifier selected from the group consisting of (3-aminopropyl)trimethoxy silane (APTMS), (3-aminopropyl)triethoxy silane (APTES), APTMS-methoxy-poly(ethylene-glycol)-succinimidyl glutarate (APTMS-m-PEG-glutarate), APTES-methoxy-poly(ethylene-glycol)-succinimidyl glutarate (APTES-m-PEG-glutarate), 2-[methoxy (polyethyleneoxy)-9-12-propyl]trimethoxysilane (PEG-Silane), fluorescein isothiocyanate (FITC)-APTMS, FITC-APTES, hexadecyltriethoxy silane, and combinations thereof (paragraph 0012).
In one aspect, the surface modifier includes the PEG-Silane, the APTMS, and the APTMS-m-PEG-glutarate and the plurality of nanoparticles are hydrophilic. In one aspect, the surface modifier includes the PEG-Silane and the plurality of nanoparticles are hydrophilic. In one aspect, the surface modifier includes the PEG-Silane, and the APTMS and the plurality of nanoparticles are hydrophobic. In one aspect, the surface modifier includes the PEG-Silane and the FITC-APTMS and the plurality of nanoparticles are hydrophilic. In one aspect, the surface modifier includes the PEG-Silane, the APTMS, and the FITC-APTMS and the plurality of nanoparticles are hydrophobic (paragraph 0014).
In various aspects, the current technology yet further provides a method of synthesizing a nanoparticle composition, the method including combining an organic solvent with an aqueous solution to form a water-in-oil micro-emulsion; adding a compound including tantalum to the micro-emulsion to form uncoated tantalum nanoparticles; and covalently binding a surface modifier to the uncoated tantalum nanoparticles, the surface modifier being selected from the group consisting of an emulsifier, (3-aminopropyl)triethoxy silane (APTMS), APTMS-methoxy-poly(ethylene-glycol)-succinimidyl glutarate (APTMS-m-PEG-glutarate), 2-[methoxy (polyethyleneoxy)-9-12-propyl]trimethoxysilane (PEG-Silane), fluorescein isothiocyanate-APTMS (FITC-APTMS), hexadecyltriethoxy silane, and combinations thereof to form the nanoparticle composition, wherein the nanoparticle composition includes a plurality of nanoparticles, each nanoparticle of the plurality having a core including tantalum oxide, and a covalent coating, the covalent coating including the surface modifier covalently bound to the core. In one aspect, the method further includes embedding the plurality of nanoparticles within a polymer. In one aspect, the method further includes dialyzing the plurality of nanoparticles in water and lyophilizing the plurality of nanoparticles to generate a lyophilized powder including the plurality of nanoparticles (paragraph 0019).
In vivo micro-CT demonstrations with this diverse set of NPs establishes the versatility and utility of TaOx-based NPs, and in vitro and in vivo toxicology assays demonstrate the acute non-toxic nature of these materials, showing that the TaOx-based NPs are useful for clinical CT molecular imaging (paragraph 0132).
Synthesis of TaOx NCs: The general synthetic approach for the various TaOx NCs is shown in FIG. 4A. In particular, refer to the pathways leading to TaOx NC1, TaOx NC2, and TaOx NC3 of FIGS. 4B, 4C, and 4D, respectively. In the first step, a surfactant promoted micro-emulsion is formed that acts as the reaction chamber for the generation of preliminary TaOx NCs (NCO). On addition of tantalum (V) ethoxide to this micro-emulsion, a base catalyzed sol-gel reaction ensues that results in rapid formation of NCO. The acidic (pH=5) surface of these preliminary TaOx NCs in the reaction micro-emulsion has pendant hydroxyl groups that have a high propensity to undergo condensation reaction with silanes, and, henceforth, the addition of a poly(ethylene glycol) moiety with a silane end cap (PEG-Silane) results in formation of well-dispersed hydrophilic TaOx NCs. At this point of the synthesis, a mixture of different commercially available silanes could be potentially employed to engineer the hydrophilicity/hydrophobicity of the NCs (paragraph 0150).
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See in particular TaOx NC1, shown above.
By controlling the surface modifier, its concentration and/or the ratio of at least two surface modifiers, the hydrophobicity or hydrophilicity of the resulting nanoparticles can be manipulated. For example, contacting the uncoated NCs with a combination of PEG-Silane and APTMS and/or APTES and then further contacting the now partially-coated NC with methoxy polyethylene glycol-succinimidyl glutamate ester (mPEG-SG) results in the nanoparticles having the covalent coating comprising the surface modifiers of PEG-Silane and APTMS-m-PEG-glutarate and/or APTES-m-PEG-glutarate, which after the dialysis, is highly hydrophilic (paragraph 0125).
Altering the ratio of PEG-Silane and APTMS in favor of a higher concentration of the latter (1:6 ratio, v/v) followed by subsequent work up leads to the hydrophobic TaOx NC3 (paragraph 0137).
Varying ratios of APTMS and PEG-Silane are incorporated to synthesize three different TaOx NC variants—a highly water soluble TaOx (NC1), a partially hydrophilic TaOx (NC2), and a hydrophobic TaOx (NC3) are taught (paragraph 0151).
The nanoparticle including the core and the covalent coating, has a diameter DNP of greater than or equal to about 1 nm to less than or equal to about 50 nm (paragraph 0110).
The bio-ink comprises a liquid carrier and optionally an initiator and/or cross-linker to facilitate solidification into a printed shaped object or scaffold. In some aspects, the liquid carrier is a hydrogel comprising at least one of the above polymers. Non-limiting examples of cross-linkers include CaCl2… glycerin (glycerol), alginate, amino acids, etc. (paragraph 0118).
Accordingly, Chakravarty teaches a nanoparticle having a first poly(ethylene glycol) (PEG)-silanization coating covalently attached to the magnetic core, wherein the first PEG-silanization coating comprises a mixture of PEG silane and aminosilane; and a second PEG coating covering at least a part of the first PEG-silanization coating, wherein the second PEG coating comprises a PEG group having at least one amine reactive group, the second PEG coating is attached to the first PEG-silanization coating via an amino group on the aminosilane and the amine reactive group on the second PEG coating, but does not teach wherein the nanoparticle comprises a magnetic core.
Hwan teaches a transition metal oxide/tantalum oxide core/shell nanoparticle is provided to be used as an X-ray CT contrast agent and an MRI T2 contrast agent by combining a biocompatible molecule or ligand on the surface of a tantalum oxide shell. A core/shell nanoparticle comprises a transition metal oxide core and a tantalum oxide shell. The transition metal oxide is selected from ferric oxide, manganese oxide, ceria, titanium oxide, nickel oxide, cobalt oxide, and zinc oxide. The size of the transition metal oxide is 1-100 nm, and the thickness of the tantalum oxide shell is 1-50 nm. A silane group or a phosphine group is combined to the surface of the tantalum oxide shell, and a functional material is combined to the silane group or the phosphine group. The functional material is selected from a biocompatible material, organic dye, a bioactive material, a functional group, an organic molecule, organic metal, a nanoparticle, a shell structure, or a combination thereof (abstract).
The inventors have invented multifunctional Fe3O4 / TaOx core / shell nanoparticles, their synthesis and a bimodal CT-MR imaging method using the same. MRI provides high sensitivity images of the tumor microenvironment, and CT images show tumor-associated vessels (translation page 2).
The particles may further comprise a PEG-silane coating. To prepare RITC-fucntionalized silane, 110 μl of aminopropyltriethoxysilane (APTES, Aldrich) and 50 mg of rhodamine-B-isothiocyanate in 3.75 ml of ethanol (RITC) was reacted at room temperature for 24 hours. Thus obtained 1.5 ml and 5 ml of 2-methoxy (polyethyleneoxy) propyl trimethoxysilane (PEG-silane, Gelest, 597-725 Da) were synthesized with Fe3O4 / TaOx core / shell nano to 1 L of the mixture containing the particles was added (translation page 3).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a magnetic core in the tantalum oxide nanoparticles comprising first and second PEG coatings when the teaching of Chakravarty is taken in view of Hwan. One would have been motivated to do so, with a reasonable expectation of success, because Hwan teaches that a nanoparticle comprising core containing magnetic iron oxide/tantalum oxide provides the advantage of a bimodal CT-MR imaging, and that MRI provides high sensitivity images of the tumor microenvironment, and CT images show tumor-associated vessels. With regard to claim 3, it would have been further obvious to vary the ratio of PEG-silane and aminosilane in the PEG coatings as a matter of routine optimization of a result effective variable in providing coated nanoparticles because Charkaarty teaches varying ratios of APTMS and PEG-Silane to synthesize TaOx NC variants and that doing so alters hydrophobicity/hydrophilicity.
Claim(s) 1-9, 12-14 and 20-24 are rejected under 35 U.S.C. 103 as being unpatentable over Chakravarty et al. (US 2022/0048788) in view of Hwan et al. (KR 20130114346), in further view of Uvdal (WO 08/096279).
The rejection over Chakravarty in view of Hwan is applied as above.
With regard to claim 5, Chakravarty and Hwan do not specifically teach wherein the PEG group on the second coating includes a PEG moiety attached to the end opposite of the PEG group as the reactive amine reactive group, wherein the secondary PEG moiety is selected from a targeting agent.
Uvdal teaches coated metal oxide nanoparticles, including in one alternative, one or more structures for coating. Typically a coating may be a polyethylene glycol silane (PEG-silane), a ligand- silane, a label silane such as a fluorophore silane, etc.
In certain variants of imaging of tissue material of a patient by MR, PET, fluoresence etc and in neutron capturing therapy there is often a desire to target the innovative particles to a certain part or organ of the material or patient. In analogy with targeting as commonly used in therapy, the coating of the nanoparticles may exhibit a covalently attached targeting group/ compound (= ligand) that is capable of specifically binding (e.g. by affinity binding) to a target structure specific for the part or the organ to be imaged or treated. The target structure may be specific for a disease such as a diseased organ including specific cancer cells or other types of malignant or disease-related cells. The term "specific" in this context typically means that the target structure is abnormally expressed in a malignancy, on a diseased organ, on malignant cells etc including over-expression, structurally changed, abnormally distributed etc. The targeting group/compound typically exhibits one or more structures selected among (i) peptide structure such as mono and polypeptide structures, (ii) carbohydrate structure such as mono- and polysaccharide structure, (iii) nucleotide structure such as polynucleotide structure, (iv) steroid structure, (v) lipid structure, (vi) vitamin structure, (vii) hormone structure, and (viii) and synthetic mimetics of structures (i)-(vii). Antibodies and antigen/hapten binding fragments of antibodies are commonly used as targeting groups/compounds and exhibit peptide structures (page 14-15).
In one embodiment, a Gd2O3-DEG nanoparticle suspension, filtered and dialyzed for 72 h, is added followed by vortexing and sonication for 2 h. The tube is then placed on a mixer table overnight to give a total incubation time of at least 20 h. To remove excess of MaI- PEG-NHS and MPTES, dialysis is performed against Milli-Q for 48 h using a 10 000 MWCO membrane. The same procedure is done using 5 mg of MaI-PEG-NHS with 0.05 μL MPTES and 10 mg of MaI-PEG-NHS with 0.1 μL MPTES. The NHS group of the thus NHS functionalized nanoparticles can then be further functionalised with targeting groups, labels such as fluorophors and the like, etc exhibiting an amino group. c) Silanization by the use of PEG silanes, such as PEG-triethoxy silane (one-step PEG- ylation procedure). This kind of silanes (MWPEG = 4000 and 5000 daltons) is reacted as outlined for other silanes, for instance with the PEG moiety in mono methoxylated form (page 28-29).
It would have been obvious to provide a targeting ligand on the end of the PEG moiety opposite the reactive group when the teachings of Chakravarty and Hwan are taken in view of Uvdal. One would have been motivated to do, with a reasonable expectation of success, because Uvdal teaches that provision of a targeting ligand on a coated metal oxide nanoparticle for use as a contrast agent provides the advantage of directing the nanoparticles to a site specific location, such as diseased organ including specific cancer cells. One would have had a reasonable expectation of success in doing so because Uvdal teaches that bifunctional NHS-PEG functionalized nanoparticles can then be further functionalised with targeting groups, labels such as fluorophors and the like, etc exhibiting an amino group.
Claim(s) 1-4, 6-14 and 20-25 are rejected under 35 U.S.C. 103 as being unpatentable over Chakravarty et al. (US 20220048788) in view of Hwan et al. (KR 20130114346), in further view of Khoee et al. (J Nanostruct Chem, 2014, 4, 111).
The rejection over Chakravarty in view of Hwan is applied as above.
With regard to claims 10, 11 and 25, Chakravarty and Hwan do not specifically teach wherein the PEG-silane has the claimed structure.
Khoee teaches that magnetic iron oxide nanoparticles (MNPs) have been widely explored for use in biomedical applications. In the present study, iron oxide nanoparticles were connected to methoxy poly(ethylene glycol) (mPEG) via a new method. The mPEG was acrylated at first and Michael reaction was carried out between acrylated mPEG and 3-aminopropyl triethoxysilane as a coupling agent. The chemical structures of modified mPEG were characterized by Fourier transform-infrared spectroscopy (FT-IR) and nuclear magnetic resonance. In the next step, iron oxide nanoparticle was coupled with the above-mentioned adduct. Preparation of magnetic nanoparticles with average particle size of 20–30 nm was proved by scanning electron microscopy. The structure of mPEG grafted on the surface of MNPs was confirmed by FT-IR spectroscopy and thermal gravimetric analysis. The synthesized nanoparticles have the potential to be used in different biomedical applications (abstract). See Scheme 1.
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It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute mPEG silane as taught by Khoee as functionally equivalent to mPEG silane employed by Chakravarty for preparation of PEG-silane / aminosilane coated metal oxide nanoparticles when the teachings of Chakravarty and Hwan are taken in view of Khoee. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known mPEG silane for another, and the results of the substitution would have been predictable, that is preparation of a PEG silane coated metal oxide nanoparticle for use as a contrast agent.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618