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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/3/2025 has been entered.
Status of Claims
Claim 1 has been amended. Claim 27 is newly added. Claims 1, 3, 7, 10, 11, 13-18, 20-25 and 27 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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.
Claims 1, 3, 10-11, 13-18, 20 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Tilley et al. (EP 2387787) in view of Lee et al. (US 2010/0081130).
Tilley teaches nanoparticles comprising metal, metal carbide, metal nitride, metal sulfide, metal phosphide, metal oxide or a mixture thereof. The invention also relates to methods for preparing nanoparticles having a core comprising metal, metal carbide, metal nitride, metal sulfide, metal phosphide, or a mixture thereof and a metal oxide shell (abstract).
Iron nitride exists in many different phases. Those most frequently reported in the literature are γ'-Fe4N, ε-Fe3N and α"-Fe16N2 (paragraph 0010). See also paragraph 0154 directed to Fe16N2.
A method of preparing the nanoparticles is set forth on paragraph 0016.
The present invention enables a method of magnetic bioseparation using magnetic nanoparticles prepared by the method of the invention. The present invention also enables a method of MRI imaging using magnetic nanoparticles prepared by the method of the invention (page paragraph 0017).
In other embodiments a magnetic nanoparticle of the invention comprises a "core" of metal, metal carbide, metal nitride, metal sulfide, metal phosphide, or a mixture thereof surrounded by a "shell" of metal oxide (page 0028).
Ligand coated particles in solvent are taught (paragraph 0137).
See various iron oxide shells in the Examples.
Therefore, superparamagnetic nanoparticles are ideal for use in applications such as bioseparation and as MRI imaging or contrast agents. In MRI applications, superparamagnetic nanoparticles can affect the magnetic environment around tissue but, because they do not have a remnant magnetisation, they are not attracted to one another and do not aggregate together. Aggregation is undesirable because it adversely affects the MRI signal. Superparamagnetic nanoparticles are useful for bioseparation applications because they do not aggregate and can be readily resuspended (page 0150).
Tilley does not specifically recite a fluorescent moiety of the surface of the nanoparticles.
Lee teaches particles which can comprise a magnetic core and a surrounding shell of inorganic glass which comprises covalently bound fluorescent dye for confocal laser scanning microscopy and which further comprises a covalently bound surface agent which enhances the cellular uptake for the particles (paragraph 0012).
One embodiment provides a composition comprising: a plurality of particles having an average particle size of about 100 nm or less, wherein the particles comprise: a core comprising magnetic material, and a glassy inorganic oxide shell disposed around the core which is covalently bound to at least one luminescent organic dye which is distributed through the glassy inorganic oxide shell, wherein the shell further comprises a surface agent which is covalently bound to the shell and provides the surface with an anionic or cationic charge (paragraph 0016).
In summary, the MNP@SiO2(OD), which can be detected by fluorescence and MRI imaging, can be fabricated using silicon compounds having dual functionality (-PEG/NH2) (paragraph 0162-77).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide iron nitride particles comprising Fe16N2 and an iron oxide shell as contrast agents. One would have been motivated to do so, with a reasonable expectation of success, because Tilley teaches nanoparticles which comprises a "core" of metal, metal carbide, metal nitride, metal sulfide, metal phosphide, or a mixture thereof surrounded by a "shell" of metal oxide, for use as MRI contrast agents. Metal oxide shells are exemplified. One of ordinary skill in the art would have been capable of selection of Fe16N2 as one of a few phases of iron nitride set forth in Tilley. With regard to claim 9, iron oxide comprises iron.
It would have been further obvious to one of ordinary skill in the art at the time of the invention to provide a fluorescent surface functionality to the nanoparticles taught by Tilley when the teaching of Tilley is taken in view of Lee. One would have been motivated to do so, with a reasonable expectation of success, because Tilley teaches the use of the iron nitride particles having iron oxide shell for use as MRI contrast agents, and it is known from Lee that particles having a magnetic core can be used for MRI as well as florescent imaging, as the multifunctional particles and nanomaterials having a useful combination of magnetic and optical properties and biocompatibility. The particle surfaces can be derivatized with, for example, DNA or antibodies. The system is stable, versatile, and well-controlled. In addition novel gene delivery can be achieved using nanoparticles as a carrier, as taught by Lee (abstract).
Response to arguments
Applicant argues that a person of ordinary skill in the art would not be motivated to modify the nanoparticles of primary reference Tilley to modify a nanoparticle shell comprising Fe, FeO, or a combination thereof according to the teachings of Lee. Applicant asserts that Lee teaches the presence of a glassy inorganic oxide shell surrounding a metal core. For instance, Lee teaches that “the shell can comprise an inorganic oxide material such as, for example, silica or alumina, and in particular silica.” Lee at [0014]. Further, Lee teaches that “organic fluorescent dyes have been incorporated into a silica shell for more extensive applications” and also “that organic fluorescent dye embedded in silica nanobeads showed long-term fluorescent stability and significantly reduced photobleaching phenomena....”. Id. at [0007]. Applicant argues that a skilled artisan would not be motivated to modify a nanoparticle shell comprising Fe and/or FeO, as Lee teaches that the silica-containing shell is an important feature for incorporation of fluorescent dyes.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the rejection does not require modification of the iron and/or iron oxide shell. It is respectfully submitted that Lee teaches disposition of a silica shell around a magnetic core. However, doing so does not necessitate modification of the iron oxide shell around a “core" of metal, e.g. metal nitride. It is respectfully submitted that one of ordinary skill in the art would have recognized that disposition of silica as taught in Lee on the magnetic nanoparticle as a whole, e.g. MNP@SiO2 as taught by Lee.
Claim(s) 1, 3, 10-11, 13,14, 20 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US 2014/0085023) in view of Armijo et al. (US 2014/0079621), in further view of Lee et al. (US 2010/0081130).
Takahashi discloses ferromagnetic particles capable of exhibiting a high purity and excellent magnetic properties from the industrial viewpoints and a process for producing the ferromagnetic particles, and also provides an anisotropic magnet, a bonded magnet and a compacted magnet which are obtained by using the ferromagnetic particles. The ferromagnetic particles comprising an Fe16N2 compound phase in an amount of not less than 80% as measured by Mossbauer spectrum and each having an outer shell in which FeO is present in the form of a layer having a thickness of not more than 5 nm (abstract and paragraph 0032). With regard to claim 10 it is noted that FeO comprises iron.
Takahashi does not specifically recite the nanoparticles in solution for use as MRI contrast agents and comprising a fluorescent moiety.
Armijo teaches magnetic iron nitride nanoparticles, such as Fe16N2 nanoparticles, are made by subjecting iron nanoparticles synthesized from iron oxide or iron carbonyl precursor to a solid-gas reaction with a nitrogen-containing gas (abstract). These iron nitride nanoparticles can find applications in magnetic memory devices, medical hyperthermia, magnetic drug carriers, and the like. For example, colloidal suspensions of magnetic nanoparticles (MNPs) called ferrofluids have been proposed for a range of biomedical applications such as magnetic gradient-guided drug carriers for targeted drug delivery, cancer thermotherapy, and MRI contrast agents (paragraph 0006). Sample 2 consisted of a ferrofluid; colloidal suspension of martensite (Fe16N2) particles with a mean radius of 11 nm in deionized water solvent with succinylated PEG as a capping agent (paragraph 0050).
Lee teaches particles which can comprise a magnetic core and a surrounding shell of inorganic glass which comprises covalently bound fluorescent dye for confocal laser scanning microscopy and which further comprises a covalently bound surface agent which enhances the cellular uptake for the particles (paragraph 0012).
One embodiment provides a composition comprising: a plurality of particles having an average particle size of about 100 nm or less, wherein the particles comprise: a core comprising magnetic material, and a glassy inorganic oxide shell disposed around the core which is covalently bound to at least one luminescent organic dye which is distributed through the glassy inorganic oxide shell, wherein the shell further comprises a surface agent which is covalently bound to the shell and provides the surface with an anionic or cationic charge (paragraph 0016).
In summary, the MNP@SiO2(OD), which can be detected by fluorescence and MRI imaging, can be fabricated using silicon compounds having dual functionality (-PEG/NH2) (paragraph 0162-77).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the nanoparticles taught by Takahashi comprising Fe16N2 nanoparticles having an FeO coating in solution for use as MRI contrast agents when the teaching of Takahashi is taken in view of Armijo. Each of Takahashi and Armijo are directed to Fe16N2 magnetic nanoparticles. While Takahashi does not specifically recite the nanoparticles in solution for use as MRI contrast agents, one would have been motivated to provide a solution as such, with a reasonable expectation of success, because Armijo teaches that in addition to use in magnetic memory devices, Fe16N2 nanoparticles have use in biomedical applications such as magnetic gradient-guided drug carriers for targeted drug delivery, cancer thermotherapy, and MRI contrast agents. Further, Sample 2 consisted of a ferrofluid; colloidal suspension of martensite (Fe16N2) particles with a mean radius of 11 nm in deionized water solvent with succinylated PEG as a capping agent.
It would have been further obvious to provide a fluorescent surface functionality to the nanoparticles taught by Takahashi and Armijo in view of Lee. It is known from Armijo that iron nitride nanoparticles are used for drug delivery, cancer thermotherapy, and MRI contrast agents. One would have been motivated to incorporation a fluorescent coating on a magnetic core, as it is known from Lee that particles can be used for MRI as well as florescent imaging, as the multifunctional particles and nanomaterials having a useful combination of magnetic and optical properties and biocompatibility. The particle surfaces can be derivatized with, for example, DNA or antibodies. The system is stable, versatile, and well-controlled. In addition novel gene delivery can be achieved using nanoparticles as a carrier, as taught by Lee (abstract).
Response to arguments
Applicant argues that one of ordinary skill in the art would not be motivated to modify the nanoparticles of Takahashi/Armijo to modify a nanoparticle shell comprising Fe, FeO, or a combination thereof according to the teachings of Lee. Applicant asserts that Takahashi/Armijo does not teach the presence of a fluorescent moiety on the surface of the nanoparticles. Applicant notes that Lee teaches the presence of a glassy inorganic oxide shell surrounding a metal core. For instance, Lee teaches that “the shell can comprise an inorganic oxide material such as, for example, silica or alumina, and in particular silica.” Lee at [0014]. Further, Lee teaches that “organic fluorescent dyes have been incorporated into a silica shell for more extensive applications” and also “that organic fluorescent dye embedded in silica nanobeads showed long-term fluorescent stability and significantly reduced photobleaching phenomena....”. Id. at [0007]. Applicant argues that a skilled artisan would not be motivated to modify a nanoparticle shell comprising Fe and/or FeO, as Lee teaches that the silica-containing shell is an important feature for incorporation of fluorescent dyes.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the rejection does not require modification of the iron and/or iron oxide shell. It is respectfully submitted that Lee teaches disposition of a silica shell around a magnetic core. However, doing so does not necessitate modification of the iron oxide shell around a “core" of metal, e.g. metal nitride. It is respectfully submitted that one of ordinary skill in the art would have recognized that disposition of silica as taught in Lee on the magnetic nanoparticle as a whole, e.g. MNP@SiO2 as taught by Lee.
Claims 1, 3, 10-11, 13-18 and 20-25 are rejected under 35 U.S.C. 103 as being unpatentable over Tilley et al. (EP 2387787) in view of Lee et al. (US 2010/0081130), in further view of Feldmann et al. (US 2007/0258888).
The rejection over Tilly in view of Lee is applied as above.
With regard to claims 21 and 22, saline solution or sterile solution as the pharmaceutical carrier for the MRI contrast agents are not specifically taught by Armijo and Lee.
Feldmann teaches a contrast agent for medical imaging techniques is described, comprising particles consisting of at least a core, the core comprising at least an oxide, mixed oxide, or hydroxide of specific elements. The particles optionally comprise shells containing or consisting of precious metal, radioactive isotopes, bio-compatibility agents, and/or antibodies. The applied imaging techniques comprise in particular magnetic resonance tomography (MRI), magnetic particle imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), and ultrasound (US) (abstract). The cores consisting of oxides and hydroxides according to the preferred embodiment, may be employed as contrast agent for magnetic resonance tomography (MRI) and/or computed tomography (CT) themselves (paragraph 0014). According to another preferred embodiment of the present invention, at least one further shell is present, providing biocompatibility. This ensures, that after administering the contrast agent to a living organism, no immune reaction against this agent takes place, which allows the application in vivo. This shell particularly consists of SiO2, a polyphosphate (e.g. calcium polyphosphate), an amino acid (e.g. asparagin acid), an organic polymer (e.g. polyethylene glycol/PEG, polyvinyl alcohol/PVA, polyamide, polyacrylate, polyurea), a biopolymer (e.g. polysaccharide, such as dextrane, xylane, glycogene, pectine, cellulose, or polypeptide, such as collagene, globuline), cysteine, or a peptide with a high amount of asparagine, or a phospholipide (paragraph 0035).
According to a further preferred embodiment of the present invention, at least one further shell is present, containing at least one antibody. By immobilizing antibodies on the surface of the nanoscale particles, a specific antibody-antigene reaction can be established. This leads to specific adsorption/concentration of the contrast agent in infected tissue (e.g. cancer cells, coronar plaques). As a result, the contrast agent and the imaging process are highly specific to the respective case. Moreover, medical imaging is possible on a cellular or even molecular level. Dependent on the desired purpose, one or more antibodies may be employed (paragraph 0037).
Preferably, the core has a diameter of 1 to 500 nm, preferably 5 to 50 nm (paragraph 0056).
In one aspect, the composition for administration comprises a contrast agent of the invention in a pharmaceutically acceptable carrier, e.g., an aqueous carrier. A variety of carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration and imaging modality selected.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the iron nitride nanoparticles of Tilley and Lee in sterile solution, including aqueous or saline solution, when the teachings of Tilley and Lee are taken in view of Feldmann. One would have been motivated to do so, with a reasonable expectation of success, because Tilley’s nanoparticles are intended for use as MRI contrast agents, and Feldmann teaches that a variety of carriers can be used formulation of core/shell MRI contrast agents including, e.g., buffered and that the solutions should be sterile and generally free of undesirable matter. It would have been further obvious to substitute a silica coating as functionally equivalent to the polyethylene glycol coating because Feldmann teaches that a variety of shells can be provided, including silica, PEG, etc. for the purpose of providing biocompatibility. It would have been further obvious to provide a targeting ligand such as an antibody because Feldmann teaches that doing so provides for highly specific imaging at a targeted site, including imaging possible on a cellular or even molecular level.
Claims 1, 3, 7, 10-11, 13-18, 20 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Tilley et al. (EP 2387787) in view of Lee et al. (US 2010/0081130), in further view of Wang et al. (US 2022/0354973).
The rejection over Tilley in view of Lee is applied as above.
With regard to claim 7, Tilley does not specifically teach wherein the nanoparticle further comprises Fe4N.
Wang teaches synthesis methods for γ′-Fe4N nanoparticles through a gas nitriding approach. These γ′-Fe4N nanoparticles are then surface functionalized using wet ball milling and a surface-active media such as a commercially available nanoparticle surfactant, oleic acid (OA), or tetramethylammonium hydroxide solution (TMAOH). The surface-active nanoparticles then may be separated using a centrifugation process to collect the uniformly sized, sub-100-nm γ′-Fe4N nanoparticles from the supernatants (paragraph 0031). FIG. 1 is a flow diagram illustrating an example technique for forming magnetic nanoparticles that include iron nitride (e.g., γ′-Fe4N, α′-Fe8N, α″-Fe16NxZ2-x, or α′-Fe8NxZ1-x, wherein Z comprises at least one of C, B, or O).
The nitriding may form nanoparticles including iron nitride. The iron nitride may include at least one of γ′-Fe4N, γ′-Fe4NZ1-x, α′-Fe8N, α″-Fe16NZ2-x, or α′-Fe8NZ.sub.1-x, wherein Z comprises at least one of C, B, P, Si, or O. In some examples, the nanoparticles may include a mixture of iron nitride phases, may include iron nitride and one or more iron phases, or the like (paragraph 0037).
Regardless of whether the iron nitride is formed or purchase, the technique of FIG. 1 then includes wet ball milling a plurality of iron nitride nanoparticles in the presence of a surface active agent to modify a surface of the plurality of iron nitride nanoparticles and form a plurality of surface-modified iron nitride nanoparticles. The iron nitride nanoparticles may include any of those described above, including at least one of γ′-Fe4N, α′-Fe8N, α″-Fe16NxZ2-x, or α′-Fe8NxZ1-x, wherein Z comprises at least one of C, B, or O. The surface-modifying agent may include any agent that reacts with a surface of the iron nitride nanoparticles to form a surface layer on the iron nitride nanoparticles. For example, the surface-modifying agent include at least one hydroxyl group that reacts with a surface of the iron nitride nanoparticles to form a surface layer on the iron nitride nanoparticles. Example surface-modifying agents include sources of at least one of polyvinylpyrrolidone, a polyoxyalkylene amine derivative, polyethylene glycol, ethylene glycol monobutyl ether, nonylphenol, or tetramethylammonium hydroxide (paragraph 0038).
Iron nitride nanoparticles produced using the techniques described herein may be used in a variety of applications in which high uniformity, high magnetic saturation, and/or low coercivity may be desired. In some examples, iron nitride nanoparticles may be used in biomedical applications including, but not limited to, magnetic resonance imaging (MRI), magnetic particle imaging (MPI) (paragraph 0043). The particles are dispersed in aqueous solution (paragraph 0048 and 50).
Accordingly, Wang teaches nanoparticles may include a mixture of iron nitride phases Fe4N, Fe16NxZ2-x, etc. but does not specifically teach wherein x = 2.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide nanoparticles comprising Fe4N and Fe16N2 when the teachings of Tilley and Lee are taken in view of Wang. One would have been motivated to do so, with a reasonable expectation of success, because Wang teaches that nanoparticles may comprise a mixture of iron nitride phases Fe4N including Fe16NxZ2-x for use as functionally equivalent MRI contrast agents, and Tilley teaches that Fe16N2 nanoparticles (such that x = 2 according to Wang) are suitable for use as MRI contrast agents.
Claim(s) 1, 3, 10-11, 13, 14, 20-25 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US 2014/0085023) in view of Armijo et al. (US 2014/0079621), in further view of Lee et al. (US 2010/0081130) and Feldmann et al. (US 2007/0258888).
The rejection over Takahashi and Armijo in view of Lee is applied as above.
With regard to claims 21 and 22, saline solution or sterile solution as the pharmaceutical carrier for the MRI contrast agents are not specifically taught by Takahashi, Armijo and Lee.
Feldmann teaches a contrast agent for medical imaging techniques is described, comprising particles consisting of at least a core, the core comprising at least an oxide, mixed oxide, or hydroxide of specific elements. The particles optionally comprise shells containing or consisting of precious metal, radioactive isotopes, bio-compatibility agents, and/or antibodies. The applied imaging techniques comprise in particular magnetic resonance tomography (MRI), magnetic particle imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), and ultrasound (US) (abstract). The cores consisting of oxides and hydroxides according to the preferred embodiment, may be employed as contrast agent for magnetic resonance tomography (MRI) and/or computed tomography (CT) themselves (paragraph 0014). According to another preferred embodiment of the present invention, at least one further shell is present, providing biocompatibility. This ensures, that after administering the contrast agent to a living organism, no immune reaction against this agent takes place, which allows the application in vivo. This shell particularly consists of SiO2, a polyphosphate (e.g. calcium polyphosphate), an amino acid (e.g. asparagin acid), an organic polymer (e.g. polyethylene glycol/PEG, polyvinyl alcohol/PVA, polyamide, polyacrylate, polyurea), a biopolymer (e.g. polysaccharide, such as dextrane, xylane, glycogene, pectine, cellulose, or polypeptide, such as collagene, globuline), cysteine, or a peptide with a high amount of asparagine, or a phospholipide (paragraph 0035).
According to a further preferred embodiment of the present invention, at least one further shell is present, containing at least one antibody. By immobilizing antibodies on the surface of the nanoscale particles, a specific antibody-antigene reaction can be established. This leads to specific adsorption/concentration of the contrast agent in infected tissue (e.g. cancer cells, coronar plaques). As a result, the contrast agent and the imaging process are highly specific to the respective case. Moreover, medical imaging is possible on a cellular or even molecular level. Dependent on the desired purpose, one or more antibodies may be employed (paragraph 0037).
Preferably, the core has a diameter of 1 to 500 nm, preferably 5 to 50 nm (paragraph 0056).
In one aspect, the composition for administration comprises a contrast agent of the invention in a pharmaceutically acceptable carrier, e.g., an aqueous carrier. A variety of carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration and imaging modality selected.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the iron nitride nanoparticles of Takahashi and Lee in sterile solution, including aqueous or saline solution, when the teachings of Takahashi and Lee are taken in view of Feldmann. One would have been motivated to do so, with a reasonable expectation of success, because Takahashi’s nanoparticles are intended for use as MRI contrast agents, and Feldmann teaches that a variety of carriers can be used formulation of core/shell MRI contrast agents including, e.g., buffered and that the solutions should be sterile and generally free of undesirable matter. It would have been further obvious to substitute a silica coating as functionally equivalent to the polyethylene glycol coating because Feldmann teaches that a variety of shells can be provided, including silica, PEG, etc. for the purpose of providing biocompatibility. It would have been further obvious to provide a targeting ligand such as an antibody because Feldmann teaches that doing so provides for highly specific imaging at a targeted site, including imaging possible on a cellular or even molecular level.
Claim(s) 1, 3, 7, 10-11, 13,14, 20 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US 2014/0085023) in view of Armijo et al. (US 2014/0079621), in further view of Lee et al. (US 2010/0081130) and Wang et al. (US 2022/0354973).
The rejection over Takahashi in view of Armijo and Lee is applied as above.
With regard to claim 7, Takahashi does not specifically teach wherein the nanoparticle further comprises Fe4N.
Wang teaches synthesis methods for γ′-Fe4N nanoparticles through a gas nitriding approach. These γ′-Fe4N nanoparticles are then surface functionalized using wet ball milling and a surface-active media such as a commercially available nanoparticle surfactant, oleic acid (OA), or tetramethylammonium hydroxide solution (TMAOH). The surface-active nanoparticles then may be separated using a centrifugation process to collect the uniformly sized, sub-100-nm γ′-Fe4N nanoparticles from the supernatants (paragraph 0031). FIG. 1 is a flow diagram illustrating an example technique for forming magnetic nanoparticles that include iron nitride (e.g., γ′-Fe4N, α′-Fe8N, α″-Fe16NxZ2-x, or α′-Fe8NxZ1-x, wherein Z comprises at least one of C, B, or O).
The nitriding may form nanoparticles including iron nitride. The iron nitride may include at least one of γ′-Fe4N, γ′-Fe4NZ1-x, α′-Fe8N, α″-Fe16NZ2-x, or α′-Fe8NZ.sub.1-x, wherein Z comprises at least one of C, B, P, Si, or O. In some examples, the nanoparticles may include a mixture of iron nitride phases, may include iron nitride and one or more iron phases, or the like (paragraph 0037).
Regardless of whether the iron nitride is formed or purchase, the technique of FIG. 1 then includes wet ball milling a plurality of iron nitride nanoparticles in the presence of a surface active agent to modify a surface of the plurality of iron nitride nanoparticles and form a plurality of surface-modified iron nitride nanoparticles. The iron nitride nanoparticles may include any of those described above, including at least one of γ′-Fe4N, α′-Fe8N, α″-Fe16NxZ2-x, or α′-Fe8NxZ1-x, wherein Z comprises at least one of C, B, or O. The surface-modifying agent may include any agent that reacts with a surface of the iron nitride nanoparticles to form a surface layer on the iron nitride nanoparticles. For example, the surface-modifying agent include at least one hydroxyl group that reacts with a surface of the iron nitride nanoparticles to form a surface layer on the iron nitride nanoparticles. Example surface-modifying agents include sources of at least one of polyvinylpyrrolidone, a polyoxyalkylene amine derivative, polyethylene glycol, ethylene glycol monobutyl ether, nonylphenol, or tetramethylammonium hydroxide (paragraph 0038).
Iron nitride nanoparticles produced using the techniques described herein may be used in a variety of applications in which high uniformity, high magnetic saturation, and/or low coercivity may be desired. In some examples, iron nitride nanoparticles may be used in biomedical applications including, but not limited to, magnetic resonance imaging (MRI), magnetic particle imaging (MPI) (paragraph 0043). The particles are dispersed in aqueous solution (paragraph 0048 and 50).
Accordingly, Wang teaches nanoparticles may include a mixture of iron nitride phases Fe4N, Fe16NxZ2-x, etc. but does not specifically teach wherein x = 2.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide nanoparticles comprising Fe4N and Fe16N2 when the teachings of Takahashi/Armijo and Lee are taken in view of Wang. One would have been motivated to do so, with a reasonable expectation of success, because Wang teaches that nanoparticles may comprise a mixture of iron nitride phases Fe4N including Fe16NxZ2-x for use as functionally equivalent MRI contrast agents, and Takahashi teaches that Fe16N2 nanoparticles (such that x = 2 according to Wang) are suitable for use as MRI contrast agents.
Claims 1, 3, 10-11, 13-18, 20, 23-25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Tilley et al. (EP 2387787) in view of Lee et al. (US 2010/0081130) in further view of Aizawa (US 2009/0068639).
The rejection over Tilly in view of Lee is applied as above.
With regard to claim 27, Tilley and Lee do not specifically teach EDC/sulfo-NHS crosslinking of substituents on the nanoparticle. For example, Lee teaches smart magnetic core-silica shell nanoparticles are capable of qualitative and specific immobilization through maleimide moieties on the silica shell. To establish a general protocol for the immobilization of any type of antibody in the absence of sequence information, sulfhydryl residues were introduced into the antibody molecules for conjugation with maleimide-modified MNP@SiO2(FITC)-PEG/NH2 by reducing indigenous disulfide linkages in the antibody hinge region.
Aizawa teaches fluorescent silica particles for labeling the target biomolecule has a fluorochrome compound bonded or adsorbed chemically with a silica component.
Antibody modification of fluorescent silica particles is taught such that fluorescent silica particle and a mixture of 3-sulfo-N-hydroxysuccinimide (Sulfo-NHS) and 1-ethyl-3 (3-dimethylaminopropyl) -carbodiimide (EDC) (0.05 M Sulfo-NHS, 0. 450 μl of 2M EDC, dissolved in phosphate buffered saline (PBS) was added and mixed for 10 minutes, 50 μl of anti-mouse IL-2 antibody was added, and the mixture was further mixed for 1 hour (page 14).
After silica particles were precipitated by centrifugation and the supernatant was removed, dialysis was performed twice against PBS to remove unreacted reagents. As a result, fluorescent silica particles having anti-mouse IL-2 antibody introduced on the surface of the silica particles were obtained.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide EDC/sulfo-NHS for coupling a substitent to the nanoparticles taught by Tilley and Lee when the teachings of Tilley and Lee are taken in view of Aizawa. While Lee teaches sulfhydryl/maleimide coupling of substituents to the silica surface, one of ordinary skill could have readily substituted EDC/sulfo-NHS coupling as a functionally equivalent means by which to couple a substituent to silica surface as shown by Aizawa. 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 coupling moiety for another, and the results of the substitution would have been predictable, that is conjugation or crosslinking a substituent to the silica surface of a nanoparticle.
Claim(s) 1, 3, 10-11, 13,14, 20, 23-25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US 2014/0085023) in view of Armijo et al. (US 2014/0079621), in further view of Lee et al. (US 2010/0081130) and Aizawa (US 2009/0068639).
The rejection over Takahashi and Armijo in view of Lee is applied as above.
With regard to claim 27, Takahashi and Lee do not specifically teach EDC/sulfo-NHS crosslinking of substituents on the nanoparticle. For example, Lee teaches smart magnetic core-silica shell nanoparticles are capable of qualitative and specific immobilization through maleimide moieties on the silica shell. To establish a general protocol for the immobilization of any type of antibody in the absence of sequence information, sulfhydryl residues were introduced into the antibody molecules for conjugation with maleimide-modified MNP@SiO2(FITC)-PEG/NH2 by reducing indigenous disulfide linkages in the antibody hinge region.
Aizawa teaches fluorescent silica particles for labeling the target biomolecule has a fluorochrome compound bonded or adsorbed chemically with a silica component.
Antibody modification of fluorescent silica particles is taught such that fluorescent silica particle and a mixture of 3-sulfo-N-hydroxysuccinimide (Sulfo-NHS) and 1-ethyl-3 (3-dimethylaminopropyl) -carbodiimide (EDC) (0.05 M Sulfo-NHS, 0. 450 μl of 2M EDC, dissolved in phosphate buffered saline (PBS) was added and mixed for 10 minutes, 50 μl of anti-mouse IL-2 antibody was added, and the mixture was further mixed for 1 hour (page 14).
After silica particles were precipitated by centrifugation and the supernatant was removed, dialysis was performed twice against PBS to remove unreacted reagents. As a result, fluorescent silica particles having anti-mouse IL-2 antibody introduced on the surface of the silica particles were obtained.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide EDC/sulfo-NHS for coupling a substitent to the nanoparticles taught by Takahashi/Armijo and Lee when the teachings of Takahashi, Armijo and Lee are taken in view of Aizawa. While Lee teaches sulfhydryl/maleimide coupling of substituents to the silica surface, one of ordinary skill could have readily substituted EDC/sulfo-NHS coupling as a functionally equivalent means by which to couple a substituent to silica surface as shown by Aizawa. 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 coupling moiety for another, and the results of the substitution would have been predictable, that is conjugation or crosslinking a substituent to the silica surface of a nanoparticle.
Conclusion
No claims are allowed at this time.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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