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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 11/2/2025 is acknowledged. Claims 13-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II and III, and there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/2/2025.
Status of Claims
Withdrawn: 13-20
Cancelled: 9
Examined Herein: 1-8, 10-12
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in KR10-2021-0192357 on 12/30/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/9/2022 and 9/6/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings received on 6/9/2022 are accepted.
Withdrawn Rejections
All rejections of claim 9 are hereby withdrawn. Its cancellation moots the rejection.
The rejection of claims 1, 2, 3, and 5 under 35 U.S.C. 103 over Kang and Lei is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
The rejection of claims 1, 2, 3, 4, and 5 under 35 U.S.C. 103 over Kang, Lei, and Sun is hereby withdrawn in view of Applicant’s substantive amendments to claims 1 and 4.
The rejection of claims 1, 2, 3, 5, and 8 under 35 U.S.C. 103 over Kang, Lei, and Yang is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
The rejection of claims 1, 2, 3, 5, and 12 under 35 U.S.C. 103 over Kang, Lei, and Lu is hereby withdrawn in view of Applicant’s substantive amendments to claims 1 and 12.
The rejection of claims 1, 2, 3, 5, and 6 under 35 U.S.C. 103 over Kang, Lei, and Pearce is hereby withdrawn in view of Applicant’s substantive amendments to claims 1 and 6.
The rejection of claim 10 under 35 U.S.C. 103 over Kang, Lei, and Wong is hereby withdrawn in view of Applicant’s substantive amendments to claims 1 and 10.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 10 and 11 rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 10 and 11 recite the limitation “The nanosatellite-substrate complex of claim 1… wherein a magnetic field is applied….” This limitation renders the claim indefinite because it claims both a product and method steps of using the product. As a result, it is unclear when direct infringement occurs. MPEP 2173.05(p).
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, 2, 3, 5, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang (Magnetic Manipulation of Reversible Nanocaging Controls In Vivo Adhesion and Polarization of Macrophages, 5/16/2018, ACS Nano, 12, 5978−5994), in view of Lei (US 2020/0129640 A1, Published 4/30/2020), and Wong (Magnetically Tuning Tether Mobility of Integrin Ligand Regulates Adhesion, Spreading, and Differentiation of Stem Cells, 2/24/2017, Nano Letters, 17:1685-1695).
With respect to claim 1, Kang discloses a nanosatellite-substrate complex for regulating stem cell adhesion and differentiation comprising:
a substrate;
a magnetic particle (magnetic nanocage) spaced apart from at least one side of the substrate;
a gold nanoparticle connected to one side of the magnetic particle;
a first linker (MPTMS) connecting the substrate and the gold nanoparticle;
a second bond (Au-S bond) connecting the gold nanoparticle and a ligand (RGD); and
the ligand connected to the gold nanoparticle via the second bond;
wherein:
the gold nanoparticle is connected to the ligand via the second bond to form a nanoassembly;
the magnetic particle is conjugated to the nanoassembly to form a nanosatellite structure;
the nanoassembly comprises one gold nanoparticle;
one second bond connected to the one gold nanoparticle;
the ligand connected to the second bond;
one or more nanoassemblies are comprised in the nanosatellite structure; and
a surface of the nanosatellite structure, which faces the substrate, is spaced apart from the substrate with the first linker interposed therebetween. [Kang, Page 5980, Scheme 1; Page 5981, Scheme 2; Page 5982, Figure 1]
With respect to claim 3, Kang discloses that the gold nanoparticle has an average diameter of 12 nm. [Kang, Page 5979, Col. 2, Paragraph 3]
With respect to claim 11, Kang discloses that the nanosatellite structure is spaced apart from one side of the substrate. [Kang, Page 5981, Scheme 2; Page 5982, Figure 1]
Kang further discloses that a PEG molecule at a high molecular weight (e.g., thiol-PEG-NH2, MW = 5 kDa) exhibits a highly flexible nature such that it can be stretched into a longer chain similar to a spring or coiled back into a shorter chain reversibly, based on entropic elasticity, which allows reversible tuning of the proximity of the MNC tethered to it and the RGD-bearing GNP by the magnetic field. [Kang, Page 5979, Col. 2, Paragraph 4; Page 5980, Col. 2, Paragraph 2] Kang discloses that the magnetic nanoparticle is functionalized with a linker comprising thiol-PEG5K-NH2 to graft it to the RGD-GNP. [Kang, Page 5979, Col. 2, Paragraph 4; Page 5981, Scheme 2]
Kang does not disclose that the magnetic particle is a core-shell type, that the complex comprises a second linker connected to the GNP and ligand, or that the first linker is elastic and its length thereof is reversibly changed by application of a magnetic field.
However, with respect to claim 1, Lei discloses a nanosatellite structure comprising:
a gold nanoparticle connected to one side of a core-shell type magnetic particle (IONP);
a second linker (acetylthio-PEG5K-maleimide) connecting the gold nanoparticle and a ligand (peptide);
the ligand connected to the gold nanoparticle via the second linker;
wherein:
the gold nanoparticle is connected to the ligand via a second linker to form a nanoassembly;
the magnetic particle is conjugated to the nanoassembly to form a nanosatellite structure;
the nanoassembly comprises one or more gold nanoparticles;
one or more second linkers are connected to the one or more gold nanoparticles;
the ligand is connected to the one or more second linkers;
one or more nanoassemblies are comprised in the nanosatellite structure. [Lei, Figure 10; 0017, 0031, 0077]
With respect to claim 2, Lei discloses that the magnetic particle is composed of:
a core composed of iron oxide; and
a shell covering an outer surface of the core and comprising a diblock copolymer (PEO-b-yMPS). [Lei, Figure 10; 0017, 0031, 0077] Lei further discloses the shell may alternatively comprise silica. [Lei, 0019]
With respect to claim 3, Lei discloses that the gold nanoparticles have a diameter of 2 nm. [Lei, Figure 10; 0077] Lei further discloses that the gold nanoparticles (or satellite particles) may have an average diameter of 2-7 nm. [Lei, 0017, 0019]
With respect to claim 5, Lei discloses that the nanoassemblies completely cover the outer surface of the magnetic particle. [Lei, Figure 10]
With respect to claim 7, Lei discloses that the second linker has a structure of Formula 1, wherein:
R1 is a thiol group (-SH)
R2 is a succinimidyl ester group
n is ~113. [Lei, 0077]
Kang nor Lei disclose that the first linker is elastic and that its length can be is reversibly changed by applying a magnetic field.
However, with respect to claim 1, Wong discloses a complex comprising an RGD-bearing magnetic nanoparticle conjugated to a substrate via a PEG (MW: 2000) linker. Wong discloses that the RGD-bearing magnetic nanoparticle is spaced apart from one side of the substrate, with a PEG linker interposed between them. [Wong, Page 1686, Figure 1] Wong discloses that the length (or tether mobility) of the PEG linker is reversibly changed by applying a magnetic field. [Wong, Page 1686, Figure 1, Page 1693, Col. 2, Paragraph 1; See also, Page 1691, Col. 1, Paragraph 1; Page 1692, Col. 2, Paragraph 2]
With respect to claim 11, Wong discloses that the RGD-bearing magnetic nanoparticle is spaced apart from one side of the substrate via a PEG linker interposed therebetween. Wong discloses that the PEG linker stretches. [Wong, Page 1690, Col. 2, Paragraph 2] Wong discloses that when the PEG linker has a long tether length, a high degree of freedom, and high tether mobility, the RGD-bearing magnetic nanoparticle moves in a direction away from the substrate. [Wong, Page 1686, Figure 1]
Wong further discloses that high-molecular weight PEG molecules have highly flexible and coiled chains that affords the inherent mobility and compliance to the tethered RGD-bearing MNPs. [Wong, Page 1690, Col. 2, Paragraph 1] Moreover, Wong discloses that the PEG linker affects the tether mobility of RGD on the substrate, and the application of a magnetic field enables dynamic tuning of the RGD tether mobility. [Wong, Page 1693, Col. 1, Paragraph 2; Figure 9]
Modifying the nanosatellite-substrate complex disclosed by Kang by (1) replacing the magnetic particle (nanocage) with a magnetic core-shell type particle (i.e., with a core composed of iron oxide and a silica shell covering the outer surface), (2) replacing the first linker, MPTMS, with MPTMS-PEG5K-NH2, and (3) replacing the second bond with a second linker, acetylthio-PEG5K-maleimide) results in the complex of claim 1, 2, 3, 7, and 11, wherein the nanosatellite-substrate complex comprises:
a substrate;
a core-shell type magnetic particle (composed of an iron oxide core and a silica shell) spaced apart from at least one side of the substrate;
a gold nanoparticle (having an average diameter of 12 nm) connected to one side of the magnetic particle;
a first linker (MPTMS-PEG5K-NH2) connecting between the substrate and the gold nanoparticle;
a second linker (acetylthio-PEG5K-maleimide) connecting between the gold nanoparticle and a ligand (RGD);
the ligand connecting to the gold nanoparticle via the second linker;
wherein:
the gold nanoparticle is connected to the ligand via the second linker to form a nanoassembly;
the magnetic particle is conjugated to the nanoassembly to form a nanosatellite structure;
the nanoassembly comprises one or more gold nanoparticles;
one or more second linkers are connected to the one or more gold nanoparticles;
the ligand is connected to the one or more second linkers; and
one or more nanoassemblies are comprised in the nanosatellite structure.
Moreover, the first linker, MPTMS-PEG-NH2, is elastic, and its length can be reversibly changed. MPTMS-PEG5K-NH2 comprises PEG (MW = 5 kDa), which Kang characterizes as a long flexible polymer. [Kang, Page 5979, Col. 2, Paragraph 4;] Recall that Kang discloses that high-MW PEG is highly flexible and can be stretched into a longer chain like a spring, or reversibly coiled back into a shorter chain based on entropic elasticity. [Kang. Page 5980, Col. 2, Paragraph 2] Since PEG5K is the same flexible, high-MW PEG described by Kang, the PEG5K-NH2 portion of the first linker is elastic and its length can be reversibly changed.
With respect to claim 7, Kang and Lei disclose that the first linker, MPTMS-PEG5K-NH2, has a structure of Formula 1, wherein:
R1 is a thiol group (-SH)
R2 is an amine group (-NH2)
n is ~113. [Kang, Page 5979, Col. 2, Paragraph 4; Page 5981, Scheme 2]
With respect to claim 11, Kang discloses that the nanosatellite structure is spaced apart from one side of the substrate. [Kang, Page 5981, Scheme 2; Page 5982, Figure 1] Kang and Wong disclose that the first linker stretches and that the nanosatellite structure moves in a direction away from the substrate. Recall that Kang discloses that the first linker, MPTMS-PEG-NH2, comprises PEG (MW = 5 kDa), which Kang characterizes as a long, flexible polymer. Kang further discloses that high-MW PEG is highly flexible and can be stretched into a longer chain. [Kang. Page 5980, Col. 2, Paragraph 2] Because PEG (MW = 5 kDa) is the same flexible, high-MW PEG described by Kang, the first linker can stretch. Wong discloses that when the PEG linker has a long tether length, a high degree of freedom, and high tether mobility, the cargo it is tethered to moves in a direction away from the substrate. [Wong, Page 1686, Figure 1] In the modified nanosatellite complex, the PEG linker is tethered to the nanosatellite structure. Therefore, when the PEG linker has a long tether length, a high degree of freedom, and a high tether mobility, the nanosatellite structure tethered to the PEG linker moves in a direction away from the substrate.
Further modifying the nanosatellite-substrate complex disclosed by Kang so that more than one nanoassembly completely covers the outer surface of the magnetic particle results in the complex of claims 1 and 5.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang by replacing the magnetic nanocage with a magnetic core-shell particle and have a reasonable expectation of success. Kang discloses a nanosatellite-substrate complex comprising a nanosatellite structure conjugated to a substrate. The nanosatellite structure comprises a magnetic particle (nanocage) that is functionalized with a linker to enable conjugation to a nanoassembly. Lei discloses an alternative nanosatellite structure, which is the same nanosatellite architecture disclosed by Kang, comprising a magnetic particle (a core-shell type nanoparticle) conjugated to a nanoassembly. Lei discloses that the core-shell type magnetic particle comprises a biocompatible coating that may be functionalized with thiol or amine groups. Accordingly, the combined teachings of Kang and Lei reasonably suggest that the nanosatellite structure disclosed by Kang may alternatively comprise a core-shell type magnetic nanoparticle conjugated to the nanoassembly. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Kang discloses that the magnetic nanocage is functionalized with a linker to conjugate it within the complex. [Kang, Page 5979, Col. 2, Paragraph 4] Lei discloses that the core-shell-type magnetic particle comprises a biocompatible coating, such as silica, functionalized with thiol or amine groups produced using siloxane molecules such as MPTMS or APTES, respectively. [Lei, 0019] Therefore, one would have been motivated by the expectation that replacing the nanocage with a core-shell type particle would enable the surface chemistry of the particle to be tailored through functionalization of the biocompatible coating material with thiol groups or amine groups, thereby providing the surface functional groups needed to attach the linker interposed between the magnetic particle and the nanoassembly within the complex disclosed by Kang.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang by adding a PEG segment to the first linker and have a reasonable expectation of success. Kang discloses a nanosatellite-substrate complex comprising a functionalized glass substrate conjugated to an RGD-bearing gold nanoparticle via a MPTMS linker. Kang further discloses that the complex comprises a magnetic nanoparticle that is functionalized with a linker comprising PEG-NH2 to graft it to the RGD-gold nanoparticle. Wong discloses a complex comprising a functionalized glass substrate conjugated to an RGD-bearing magnetic nanoparticle via an MPTMS-PEG linker. Accordingly, the combined teachings of Kang and Wong suggest that the MPTMS linker used to conjugate the RGD-bearing gold nanoparticle to the substrate in the complex disclosed by Kang may further include a PEG segment, PEG-NH2, as Kang already employs PEG-NH2 to graft the gold nanoparticle to another component within the same complex and because Wong establishes that such a linker is also suitable for grafting the gold nanoparticle to a glass substrate. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Wong discloses that altering the tethering mobility of RGD peptides on a substrate via a magnetic field by introducing a lengthy, flexible PEG linker between a glass substrate and RGD-bearing nanoparticles regulates cell adhesion, spreading, mechanosensing, and differentiation. [Wong, Page 1686, Col. 2, Paragraph 1] Therefore, one would have been motivated by the expectation that adding a PEG segment to the first linker would enable regulation of cell-substrate interactions, including cell adhesion, spreading, and differentiation, in the nanosatellite-substrate complex disclosed by Kang via a noncontact physical mechanism of cell adhesion.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang by replacing the second bond with a second linker, acetylthio-PEG5k-maleimide, and have a reasonable expectation of success. Kang discloses a nanosatellite-substrate complex comprising a nanosatellite structure conjugated to a substrate. The nanosatellite structure comprises a magnetic nanoparticle conjugated to a nanoassembly, wherein the nanoassembly comprises a gold nanoparticle coupled to a ligand via a bond (Au-S bond). Lei discloses an alternative nanosatellite structure comprising a core-shell type magnetic nanoparticle conjugated to a nanoassembly, wherein the nanoassembly comprises a gold nanoparticle conjugated to a ligand via an acetylthio-PEG5k-maleimide linker. Lei further discloses that the gold nanoparticle may be coupled to the ligand via conjugation or absorption. Accordingly, the combined teachings of Kang and Lei reasonably suggest that the gold nanoparticle and ligand of the nanoassembly disclosed by Kang may alternatively be coupled via an acetylthio-PEG5k-maleimide linker. The selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07. Lei demonstrates that acetylthio-PEG5k-Maleimide is suitable for conjugating a peptide ligand to the gold satellite nanoparticle of a nanosatellite structure. [Lei, 0017, 0077, Figure 10] Therefore, the selection of acetylthio-PEG5k-maleimide as the second linker conjugating the gold nanoparticle to RGD in the complex disclosed by Kang, based on its known suitability for coupling a peptide ligand to a gold nanoparticle in a nanosatellite structure, is prima facie obvious.
It would be obvious to one of ordinary skill in the art to further modify the nanosatellite-substrate complex disclosed by Kang by adding more than one nanoassembly that completely covers an outer surface of the magnetic particle and have a reasonable expectation of success. Kang discloses a nanosatellite-substrate complex comprising a nanosatellite structure conjugated to a substrate. The nanosatellite structure comprises a magnetic nanoparticle conjugated to a nanoassembly. Lei discloses an alternative nanosatellite structure, which is the same nanosatellite architecture disclosed by Kang, comprising a magnetic particle (a core-shell type nanoparticle) conjugated to one or more nanoassemblies that completely cover the outer surface of the magnetic particle. Accordingly, the combined teachings of Kang and Lei reasonably suggest that the magnetic particle of the nanosatellite disclosed by Kang may be conjugated to more than one nanoassembly that completely cover the outer surface of the magnetic particle. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Kang discloses that varying the nanospacing and density of RGD-coated gold nanoparticles modulates cellular adhesion. [Kang, Page 5979, Col. 1, Paragraph 3] Therefore, one would have been motivated by the expectation that employing more than one nanoassembly in the nanosatellite-substrate complex disclosed by Kang would increase the density of RGD-coated gold nanoparticles per nanosatellite structure, which would provide the RGD-coated gold nanoparticles with the spacing and density necessary to modulate cellular adhesion.
Claims 1, 2, 3, 5, 6, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang, Lei, and Wong, as applied to claims 1, 2, 3, 5, 7, and 11 above, and further in view of Bhatia (US 2008/0213377 A1, Published 9/4/2008).
With respect to claim 1, Kang, Lei, and Wong disclose the teachings above.
With respect to claim 6, Lei discloses that the biocompatible coating of the core-shell type magnetic particle is functionalized with thiol groups or amine groups, produced using MPTMS or APTES, respectively. [Lei, 0019]
Moreover, Kang discloses that the nanosatellite-substrate complex is used to temporally manipulate macrophage adhesion and polarization both in vitro and in vivo. [Kang, Page 5980, Scheme 1]
Kang, Lei, and Wong do not disclose that the magnetic particle has an average diameter of greater than 200 nm to 250 nm.
However, with respect to claim 6, Bhatia discloses magnetically detectable nanoparticles for delivery to tissues, cells, and/or subcellular locales, including core-shell magnetic nanoparticles having an iron oxide core and an organic outer shell or coating, such as silica. Such particles typically react to magnetic force resulting from a magnetic field. The field can attract or repel the particle towards or away from the source of the magnetic field, respectively, optionally causing acceleration or movement in a desired direction in space. A magnetically detectable nanoparticle is a magnetic particle that can be detected within a living cell as a consequence of its magnetic properties. [Bhatia, 0009, 0136, 0144, 0150-0151] Bhatia further discloses that physicochemical features of particles, including particle size, can be selected to allow a particle to circulate longer in plasma by decreasing renal excretion and/or liver clearance. Nanoparticles with a diameter of approximately 200 nm, 225 nm, or 250 nm (which are less than 1000 nm) are small enough to avoid clearance of particles from the bloodstream by the liver. [Bhatia, 0116, 0117]
Modifying the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the magnetic particle has an average diameter of 200 nm to 250 nm results in the complex of claim 6.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the magnetic particle has an average diameter of 200 nm to 250 nm and have a reasonable expectation of success. Kang, Lei, and Wong disclose a nanosatellite-substrate complex comprising a core-shell magnetic particle functionalized with thiol or amine groups on its surface. Kang discloses that the nanosatellite-substrate complex is used to temporally manipulate macrophage adhesion and polarization both in vitro and in vivo. Bhatia discloses core-shell magnetic nanoparticles with a diameter of approximately 200 nm, approximately 225 nm, or approximately 250 nm, which are used for delivery to tissues, cells, and/or subcellular locales. Bhatia further discloses that physicochemical features of particles, including particle size, can be selected to allow a particle to circulate longer in plasma by decreasing renal excretion and/or liver clearance. Accordingly, the combined teachings of Kang, Lei, Wong, and Bhatia reasonably suggest that the core-shell type magnetic particle of the complex disclosed by Kang, Lei, and Wong, which is used in vivo, may have an average diameter of 200 nm to 250 nm. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Bhatia further discloses that physiochemical features of particles, including particle size, can be selected to allow a particle to circulate longer in plasma by decreasing renal excretion and/or liver clearance. Nanoparticles with a diameter of approximately 200 nm, 225 nm, or 250 nm (which are less than 1000 nm) are small enough to avoid clearance of particles from the bloodstream by the liver. [Bhatia, 0117] Therefore, one would have been motivated by the expectation that modifying the size of the magnetic particle of the complex disclosed by Kang, Lei, and Wong to an average diameter of 200 nm to 250 nm would avoid clearance of particles from the bloodstream by the liver when used in vivo.
Claims 1, 2, 3, 4, 5, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang, Lei, and Wong, as applied to claims 1, 2, 3, 5, 7, and 11 above, and further in view of Sun (US 2021/0346478 A1, Published 11/11/2021).
With respect to claim 1, Kang, Lei, and Wong disclose the teachings above.
With respect to claim 4, Kang, Lei, and Wong disclose that the nanoassemblies are disposed adjacent to each other. [Lei, Figure 10; 0017, 0031, 0077]
Kang, Lei, and Wong do not disclose that the distance between the gold nanoparticles in each nanoassembly is 3-4 nm.
However, with respect to claim 4, Sun discloses a nanosatellite structure comprising a core-shell magnetic particle (ION-polymer) conjugated to a nanoassembly comprising a gold nanoparticle connected to a ligand (peptide) via a second linker. Sun further discloses that the nanoassemblies are disposed adjacent to each other, and the distance between the gold nanoparticles in each nanoassembly is 4-7 nm. [Sun, Figure 1, 0009-0011]
Modifying the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the distance between the gold nanoparticles in each nanoassembly is 4 nm results in the complex of claim 4.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the distance between the gold nanoparticles in each nanoassembly is 4 nm and have a reasonable expectation of success. Kang, Lei, and Wong disclose a nanosatellite-substrate complex, wherein the nanosatellite comprises a plurality of nanoassemblies (or gold nanoparticles connected to a ligand via a second linker) disposed adjacent to each other. Sun discloses a nanosatellite comprising a plurality of nanoassemblies disposed adjacent to each other at a distance of 4-7 nm. Accordingly, the combined teachings of Kang/Lei/Wong and Sun reasonably suggest that the plurality of nanoassemblies disposed adjacent to each other in the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong may be disposed adjacent to each other at a distance of 4 nm. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Kang discloses that varying the nanospacing of RGD-coated gold nanoparticles designed on biomaterial surfaces is a technique used in the art to modulate cellular adhesion. [Kang, Page 5979, Col. 1, Paragraph 3 and Page 5980, Col. 1, Paragraph 2] Therefore, one would have been motivated to modify the distance between the gold nanoparticles in each of the nanoassemblies of the complex disclosed by Kang/Lei/Wong to modulate cellular adhesion of the complex as desired.
Claims 1, 2, 3, 5, 7, 8, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang, Lei, and Wong, as applied to claims 1, 2, 3, 5, 7, and 11 above, and further in view of Yang (Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation
coordination, 2019, Nature Communications, 10:1696).
With respect to claim 1, Kang, Lei, and Wong disclose the teachings above.
With respect to claim 8, Kang, Lei, and Wong disclose that the ligand is an RGD ligand. [Kang, Page 5981, Scheme 2]
Kang, Lei, and Wong do not disclose that the ligand is a cyclic RGD ligand.
However, with respect to claim 8, Yang discloses that RGD is a cell-adhesive ligand. [Yang, Page 5, Col. 1, Paragraph 2] Yang further discloses that both cyclic and linear RGD peptides promote macrophage adhesion. [Yang, Page 5, Col. 2, Paragraph 1].
Modifying the nanosatellite-complex disclosed by Kang, Lei, and Wong by replacing the ligand, linear RGD, with cyclic RGD results in the complex of claim 8.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-complex disclosed by Kang, Lei, and Wong by replacing the ligand with cyclic RGD and have a reasonable expectation of success. Kang, Lei, and Wong disclose a nanosatellite-substrate complex comprising a cell-adhesive ligand, a linear RGD peptide. Yang discloses a complex comprising a cell-adhesive ligand and a linear or cyclic RGD peptide. Yang further discloses that both ligands stimulate integrin and subsequent macrophage attachment. Thus, Yang establishes that a cyclic RGD peptide is a cell-adhesive ligand used in an applicable complex to stimulate integrin and subsequent macrophage attachment. Accordingly, the combined teachings of Kang/Lei/Wong and Yang reasonably suggest that cyclic RGD peptide may function as the cell-adhesive ligand in the complex disclosed by Kang, Lei, and Wong. One would have been motivated to do so because it is prima facie obvious to substitute equivalents known for the same purpose when the equivalency is recognized in the prior art. MPEP 2144.06(II). In the present case, Yang discloses that both cyclic and linear RGD peptides promote macrophage adhesion. [Yang, Page 5, Col. 2, Paragraph 1]. Therefore, it is prima facie obvious to substitute one RGD ligand that promotes macrophage adhesion (linear RGD) for another (cyclic RGD).
Claims 1, 2, 3, 5, 7, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kang, Lei, and Wong, as applied to claims 1, 2, 3, 5, 7, and 11 above, and further in view of Lu (Monolayer surface chemistry enables 2-colour single molecule localisation microscopy of adhesive ligands and adhesion proteins, 8/20/2018, Nature Communications, 9:3320).
With respect to claim 1, Kang, Lei, and Wong disclose the teachings above.
Recall, with respect to claim 12, Kang, Lei, and Wong disclose that the nanosatellite structure may comprise one RGD ligand. [Kang, Page 5980, Scheme 1 & Page 5981, Scheme 2; Lei, 0017]
Kang, Lei, and Wong do not disclose that the density of the nanosatellite structure disposed on the substrate is 1.0 nanosatellite structure/µm2 to 4 nanosatellite structures/µm2.
However, with respect to claim 12, Lu discloses that a minimum of 4-7 RGD peptides/um2 are needed for cell spreading and adhesion formation on nanofabricated surfaces. [Lu, Page 7, Col. 1, Paragraph 3]
Modifying the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the density of the nanosatellite structure (comprising a single gold nanoparticle conjugated to a single RGD ligand) disposed on the substrate is 4 nanosatellites/µm2 results in the complex of claim 12.
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong so that the density of the nanosatellite structure disposed on the substrate is 4 nanosatellites/µm2 and have a reasonable expectation of success. Kang, Lei, and Wong disclose a nanosatellite-substrate complex comprising one or more nanosatellites disposed on a
fabricated substrate wherein each nanosatellite comprises one RGD ligand. Lu discloses that 4-7 RGD peptides/um2 are needed for cell spreading and adhesion formation on nanofabricated surfaces. Thus, Lu establishes that a minimum surface density of 4-7 RGD peptides/µm2 effectively promotes cell spreading and adhesion. Accordingly, the combined teachings of Kang/Lei/Wong and Lu reasonably suggest that the nanosatellite-substrate complex disclosed by Kang, Lei, and Wong may have a density of 4 RGD peptides/µm2, equivalent to 4 nanosatellites/µm2, since each nanosatellite comprises a single RGD ligand. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Kang discloses that varying the density of RGD-coated gold nanoparticles designed on biomaterial surfaces is a technique used in the art to modulate cellular adhesion. [Kang, Page 5979, Col. 1, Paragraph 3 and Page 5980, Col. 1, Paragraph 2] Therefore, one would have been motivated to modify the density of the nanosatellite structures disclosed by Kang, Lei, and Wong to modulate cellular adhesion of the complex as desired.
Claims 1, 2, 3, 5, 7, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang, Lei, and Wong, as applied to claims 1, 2, 3, 5, 7, and 11 above, and further in view of Topolanick (US 2023/0273199 A1, Filed 7/8/2021).
With respect to claim 1, Kang, Lei, and Wong disclose the teachings above.
With respect to claim 10, Kang discloses that the nanosatellite structure is spaced apart from one side of the substrate. [Kang, Page 5981, Scheme 2; Page 5982, Figure 1]
Kang and Wong disclose that the nanosatellite structure moves in a direction toward the substrate. Recall that Kang discloses that the first linker, MPTMS-PEG-NH2, comprises PEG (MW = 5 kDa), which Kang characterizes as a long flexible polymer. Kang discloses that high-MW PEG is highly flexible and can be stretched into a longer chain like a spring, or reversibly coiled back into a shorter chain, based on entropic elasticity. [Kang. Page 5980, Col. 2, Paragraph 2] Wong discloses that when the PEG linker has a short tether length, a low degree of freedom, and low tether mobility, the cargo it is tethered to moves in a direction toward the substrate. [Wong, Page 1686, Figure 1] In the modified nanosatellite complex, the PEG linker is tethered to the nanosatellite structure. Therefore, when the PEG linker has a short tether length, a low degree of freedom, and a low tether mobility, the nanosatellite structure to which it is tethered moves in a direction toward the substrate.
Kang, Lei, and Wong do not explicitly state that the first linker can be compressed.
However, with respect to claim 10, Topolancik discloses that polymers (e.g., PEG3300 or PEG 6260) are entropic; that is, stretching or compressing the coil away from its equilibrium size decreases the number of possible conformations and, thus, exhibits entropy. [Topolancik, 0096]
The combination of Kang, Lei, Wong, and Topolancik results in the complex of claim 10 wherein the first linker can be compressed.
It would be obvious to one of ordinary skill in the art to combine the teachings of Kang, Lei, Wong, and Topolancik and conclude that the first linker of the modified complex can be compressed such that the nanosatellite structure moves in a direction toward the substrate, and have a reasonable expectation of success. Kang, Lei, and Wong disclose a nanosatellite substrate complex comprising a first linker, MPTMS-PEG5K-NH2, spaced apart from one side of the substrate. The linker can move the nanosatellite structure tethered to it in a direction toward or away from the substrate. MPTMS-PEG-NH2 comprises PEG (MW = 5 kDa), which Kang characterizes as a long flexible polymer. Kang discloses that high-MW PEG is highly flexible and can be stretched into a longer chain, like a spring, or reversibly coiled back into a shorter chain, based on entropic elasticity. Topolancik discloses that entropic polymers (e.g., PEG3300 or PEG 6260) stretch or compress the coil away from its equilibrium size, decreasing the number of possible conformations. Accordingly, the combined teachings of Kang, Lei, and Wong, and Lei reasonably suggest that the first linker compresses because PEG (MW = 5 kDa) is the same flexible, high-MW PEG described by Kang; therefore, it exhibits the entropy described by Topolancik by stretching or compressing. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Wong discloses that low RGD tether mobility facilitates mechanical feedback in cells via RGD-integrin ligation and the subsequent activation of mechanotransduction pathways involving nuclear translocation of the mechanosensitive transcriptional regulator YAP, thereby enhancing the osteogenic differentiation of hMSCs. [Wong, Page 1693, Col. 1, Paragraph 1] Therefore, one would have been motivated by the expectation that a first linker capable of compressing would shorten the tether length/mobility between the nanosatellite structure and the substrate, thereby enhancing cell differentiation.
Response to Arguments
Applicant's arguments filed 7/27/2026 have been fully considered but they are not persuasive.
Applicant asserts, “First, Kang and Lei are directed to different fields of endeavor and different technical purposes… Absent a more specific articulated rationale tied to Applicant's claimed purpose of regulating stem cell adhesion and differentiation via a magnetically tunable linker, the Office's stated motivation (flexibility in selecting a biocompatible coating) does not, without more, establish a sufficient reason for a person of ordinary skill in the art to combine the specific structural teachings of Kang and Lei in the manner claimed.” [Remarks 7/27/2026, Page 8, Paragraph 6]
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. MPEP 2144(IV). Accordingly, the Office's stated motivation need not be tied to Applicant's claimed purpose of regulating stem cell adhesion and differentiation via a magnetically tunable linker.
Applicant asserts, “claim 1 as amended now additionally recites that "a surface of the nanosatellite structure, which faces the substrate, is spaced apart from the substrate with the first linker interposed therebetween, and the first linker is elastic and a length thereof is reversibly changed by application of a magnetic field." Neither Kang nor Lei, alone or in combination, discloses or suggests a first linker that is elastic and whose length reversibly changes upon application of a magnetic field.” [Remarks 7/27/2026, Page 9, Paragraph 1]
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. MPEP 2145(IV). The rejection of claim 1 relies on the combined teachings of Kang, Lei, and Wong, not Kang and Lei alone.
Kang and Wong both disclose that high-MW PEG linkers are inherently elastic and that their length is reversibly changed. Accordingly, the first linker of the modified complex, MPTMS-PEG5K-NH2, is elastic, and a length thereof is reversibly changed by application of a magnetic field.
Applicant asserts, “Furthermore, claim 4, as amended, recites that the distance between the gold nanoparticles in each of the nanoassemblies disposed adjacent to each other is 3 nm to 4 nm. Sun is cited for disclosing a distance of 5 nm to 20 nm. Sun's disclosed range does not overlap with, and does not render obvious, the presently claimed 3 nm to 4 nm range. The Office Action has not identified, and Applicant is not aware of, any teaching in Sun, Kang, or Lei that would have led a person of ordinary skill in the art to reduce the inter-nanoparticle distance below Sun's disclosed lower bound of 5 nm.” [Remarks 7/27/2026, Page 9, Paragraph 1]
Sun is cited for disclosing distances of 5 nm to 20 nm and 4 nm to 7 nm. Sun discloses the latter teaching in paragraph 0009, and it was cited in the CTNF of 7/6/2026. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP 2144.05(I). The claimed range of 4 nm overlaps with the range of 4 nm to 7 nm range disclosed by Sun. Therefore, the prima facie case of obviousness of record is properly supported.
Applicant asserts, “Applicant respectfully submits that claim 1 is allowable over Kang and Lei, and Pearce fails to cure the deficiencies of Kang and Lei noted above with regard to claim 1.” [Remarks 7/27/2026, Page 10, Paragraph 2-5]
Applicant’s arguments with respect to Pearch have been considered but are moot because the new ground of rejection does not rely on Pearce for any teaching or matter specifically challenged in the argument.
Applicant asserts, “With respect to claim 7, Wong is relied upon for disclosing a single specific embodiment of a linker (MPTMS-Mal-PEG-SH) in which n = 113, which corresponds only to the lower boundary of the range recited in claim 7 (n =113 to 450). The disclosure of a single data point does not, by itself, render obvious the full scope of a numerical range absent some showing that the variable in question is recognized in the art as a result-effective variable for which routine optimization would have led a person of ordinary skill to arrive at the full claimed range. See MPEP § 2144.05(11). No such showing has been made here.” [Remarks 7/27/2026, Page 11, Paragraph 1]
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP 2144.05(I). Kang discloses the first linker, MPTMS-PEG5K-NH2, wherein n=113 and Lei discloses the second linker, acetylthio-PEG5K-malemide, wherein n=113, lies within the claimed range. The value n=113 lies within the claimed range of n=113-450. Therefore, the prima facie case of obviousness of record is properly supported.
Furthermore, none of the rejections of record rely on routine optimization to establish the prima facie case of obviousness. Therefore, MPEP 2144.05(II) is immaterial.
Applicant asserts, “Furthermore, Yang is cited for disclosing that both linear and cyclic RGD peptides promote macrophage adhesion in the context of a dynamic ligand-cation coordination system, which is structurally and mechanistically distinct from Applicant's magnetically-actuated nanosatellite-substrate complex. Applicant respectfully submits that Yang's general teaching regarding ligand equivalency in a different system does not establish, without further evidence, a reasonable expectation that a cyclic RGD ligand would perform equivalently to a linear RGD ligand within the specific structural and functional context of the presently claimed complex.” [Remarks 7/27/2026, Page 11, Paragraph 5]
Conclusive proof of efficacy is not required to show a reasonable expectation of success. MPEP 2143.02(I). Substituting equivalents known for the same purpose is prima facie obvious where their equivalency is recognized in the art. MPEP 2144.06(II). As started in the CTNF of 7/6/2026, Yang discloses that both cyclic and linear RGD peptides promote macrophage adhesion, thereby establishing their art-recognized equivalency for the same purpose. [Yang, Page 5, Col. 2, Paragraph 1] The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. MPEP 2143.02(I). The expectation of success need not be demonstrated within the identical structural context of the claimed complex. Moreover, Applicant provides no evidence that a cyclic RGD ligand would fail to perform in the claimed complex, and arguments presented by applicant cannot take the place of evidence in the record. MPEP 2145(I).
Applicant asserts, “Furthermore, claim 12, as amended, recites that the density of the nanosatellite structure disposed on the substrate is 1.0 to 4.0 nanosatellite structures/μm2. Lu is cited for disclosing that a minimum of 4 to 7 RGD peptides per μm2 are needed for cell spreading and adhesion formation on nanofabricated surfaces generally. By its own terms, Lu teaches that densities below 4 per μm2 are insufficient to achieve the desired cell-adhesion effect. Lu therefore does not suggest, and indeed teaches away from, the presently claimed density range of 1.0 to 4.0 nanosatellite structures/μm2. Applicant's specification demonstrates that within Applicant's specific nanosatellite-substrate architecture, the claimed lower density range in fact achieves effective, magnetically-tunable regulation of stem cell adhesion and differentiation notwithstanding Lu's general teaching regarding minimum density requirements in an unrelated system.” [Remarks 7/27/2026, Page 12, Paragraph 3]
Where the claimed ranges "overlap or lie inside ranges disclosed by the prior art," a prima facie case of obviousness exists. MPEP 2144.05(I). Lu discloses a density of 4 to 7 RGD peptides per µm2 (which equals 4 nanosatellites/µm2 since each nanosatellite comprises a single RGD ligand in the complex disclosed by Kang, Lei, and Wong), which overlaps with the claimed range of 1.0 to 4.0 nanosatellite structures/µm2. Accordingly, the prima facie case of obviousness of record is properly supported. Moreover, Lu does not teach away from the claimed range. A reference teaches away only when it criticizes, discredits, or otherwise discourages the claimed solution. MPEP 2145(X)(D)(1). Lu discloses that a density of 4 RGD peptides/µm2 is sufficient for cell spreading and adhesion formation, and that density falls within the claimed range of 1.0 to 4.0 nanosatellite structures/µm2. [Lu, Page 7, Col. 1, Paragraph 3] Lu therefore does not teach away from the claimed range.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/K.A.C./Examiner, Art Unit 1618 /Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights