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.
Claim 13-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II and III, and there being no allowable generic or linking claim.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Withdrawn: 13-20
Examined Herein: 1-12
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Withdrawn Rejections
The rejection of claims 1, 5, 10 and 11 under 35 U.S.C. 112(b) is hereby withdrawn in view of Applicant’s amendments to claims 1, 5, 10, and 11, which remove the term “provided to,” thereby rendering the rejection moot.
The rejection of claim 6 under 35 U.S.C. 112(b) is hereby withdrawn in view of Applicant’s amendments to claim 6, which removes the parenthetical limitations, thereby rendering the rejection moot.
The rejection of claims 1-3, 5, 6 and 8 under 35 U.S.C. 103 over Kim and Kang is hereby withdrawn in view of Applicant’s persuasive arguments that Kim is disqualified as a prior art reference in accordance with 35 U.S.C. §102(b)(1)(A) and 35 U.S.C. § 102(b)(2)(c) and Kang alone is insufficient to establish a prima facie case of obviousness.
The rejection of claims 1-3 and 5-11 under 35 U.S.C. 103 over Kim, Kang, Lundgren, and Albutt is hereby withdrawn in view of Applicant’s persuasive arguments that Kim is disqualified as a prior art reference in accordance with 35 U.S.C. §102(b)(1)(A) and 35 U.S.C. § 102(b)(2)(c) and the combination of Kang, Lundgren, and Albutt is insufficient to establish a prima facie case of obviousness.
The rejection of claims 1-6, and 8 under 35 U.S.C. 103 over Kim, Kang, and Sun is hereby withdrawn in view of Applicant’s persuasive arguments that Kim is disqualified as a prior art reference in accordance with 35 U.S.C. §102(b)(1)(A) and 35 U.S.C. § 102(b)(2)(c) and the combination of Kang and Sun is insufficient to establish a prima facie case of obviousness.
The provisional rejection of claims 1-12 on the ground of nonstatutory double patenting over claim 1-12 of copending Application No. 17/834,314 (reference application) is hereby withdrawn as Applicant has filed an e-Terminal Disclaimer.
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, and 5 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).
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 between the substrate and the gold nanoparticle;
a second bond (Au-S bond) connecting between 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 gold nanoparticle; and
the ligand connected to the second bond; and
one nanoassembly is comprised in the nanosatellite structure. [Kang, Page 5980, Scheme 1; Page 5981, Scheme 2]
With respect to claim 3, Kang discloses the gold nanoparticle has an average diameter of 12 nm. [Kang, Page 5979, Col. 2, Paragraph 3]
Kang does not disclose that the magnetic particle is a core-shell type or that the complex comprises a second linker.
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 (SH-PEG5K-maleimide) connecting between 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 is connected to the gold nanoparticle; and
the ligand is connected to the second linkers; and
one or more nanoassemblies are comprised in the nanosatellite structure. [Lei, Figure 10; 0017, 0031, 0077]
With respect to claim 2, Lei discloses 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] Sun further discloses the shell may alternatively comprise silica. [Lei, 0019]
With respect to claim 3, Lei discloses the gold nanoparticles have a diameter of 2 nm. [Lei, Figure 10; 0077] Lei further discloses 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 an outer surface of the magnetic particle. [Lei, Figure 10]
Modifying the nanosatellite-substrate complex disclosed by Kang by 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) and by replacing the second bond with a second linker (i.e., SH-PEG5K-maleimide) results in the compound of claim 1, 2, and 3, 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) connecting between the substrate and the gold nanoparticle;
a second linker (SH-PEG5K-maleimide) connecting between the gold nanoparticle and a ligand (RGD);
the ligand connected 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 gold nanoparticle;
one second linker is connected to the gold nanoparticle;
the ligand is connected to the second linker; and
one nanoassembly is comprised in the nanosatellite structure.
Further modifying the nanosatellite-substrate complex disclosed by Kang so that it comprises more than one nanoassemblies that completely cover an outer surface of the magnetic particle results in the compound of claim 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 type 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) conjugated to a nanoassembly. Lei discloses an alternative nanosatellite structure comprising magnetic particle (a core-shell type nanoparticle) conjugated to a nanoassembly. Thus, Lei establishes that a core-shell type magnetic nanoparticle may be employed as the magnetic particle in a nanosatellite comprising a magnetic particle conjugated to a nanoassembly (which is the same nanosatellite architecture disclosed by Kang). Accordingly, the combined teachings of Kang and Lei suggest that the nanosatellite structure disclosed by Kang may alternatively comprise a core-shell type magnetic nanoparticle conjugated to the nanoassembly. Therefore, it is reasonable to expect the nanosatellite-substrate complex disclosed by Kang may be modified by replacing the magnetic nanocage with a magnetic core-shell type 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, Lei discloses that the core-shell-type magnetic particle comprises a biocompatible coating selected from HSA, PEG, triblock copolymer, PEO-b-PPO-b-PEO (F121), PEO-b-PVP, glucosylated poly(pentafluorostyrene), chitosan, silica, and gum Arabic, gluconic acid, lactobionic acid, polyacrylic acid, apatite, and Casein, and is functionalized with thiol groups or amine groups. [Lei, 0017-0019] 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 the selection of the biocompatible coating material and functionalization with thiol groups or amine groups.
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 (i.e., SH-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 a linker (SH-PEG5K-maleimide). Lei further discloses the gold nanoparticle may be coupled to the ligand via conjugation or absorption. Thus, Lei establishes that a linker may be employed in a nanoassembly to couple a gold nanoparticle to a ligand. Accordingly, the combined teachings of Kang and Lei suggest that the gold nanoparticle and ligand of the nanoassembly disclosed by Kang may be coupled via a linker. Therefore, it is reasonable to expect the nanosatellite-substrate complex disclosed by Kang may be modified by replacing the second bond with a second linker (SH-PEG5K-maleimide). 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 PEG molecules at a high molecular weight exhibit 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 an entropic elasticity. The flexible nature of PEG allows reversible tuning of the tether by a magnetic field. [Kang, Page 5980, Col. 2, Paragraph 2] Lei demonstrates that SH-PEG5K-maleimide is a suitable linker for coupling a gold nanoparticle and a ligand in a nanoassembly. Therefore, one would have been motivated by the expectation that replacing the second bond with a second linker comprising a PEG molecule, SH-PEG5K-maleimide, could enable the linker to be tuned by a magnetic field.
It would be obvious to one of ordinary skill in the art to further modify the nanosatellite-substrate complex disclosed by Kang so that it comprises more than one nanoassemblies that completely cover 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 comprising a core-shell type magnetic nanoparticle conjugated to one or more nanoassemblies that completely cover the outer surface of the magnetic particle. Thus, Lei establishes that a nanosatellite comprising a magnetic particle conjugated to a nanoassembly (which is the same nanosatellite architecture disclosed by Kang) may be conjugated to one or more nanoassemblies that completely cover the outer surface of the magnetic particle. Accordingly, the combined teachings of Kang and Lei suggest that the magnetic particle of the nanosatellite disclosed by Kang may be conjugated to one or more nanoassemblies that completely cover the outer surface of the magnetic particle. Therefore, it is reasonable to expect that the nanosatellite-substrate complex disclosed by Kang may be modified so that it comprises more than one nanoassemblies that completely cover an 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 is used to modulate cellular adhesion. [Kang, Page 5979, Col. 1, Paragraph 3] Therefore, one would have been motivated by the expectation that employing more than one nanoassemblies in the nanosatellite-substrate complex disclosed by Kang could provide an arrangement of RGD-coated gold nanoparticles having spacing and density necessary to modulate cellular adhesion.
Claims 1, 2, 3, 4, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Kang and Lei, as applied to claims 1, 2, 3, and 5 above, and further in view of Sun (US 2021/0346478 A1, Published 11/11/2021).
With respect to claim 1, Kang and Lei disclose the teachings above.
With respect to claim 4, Kang and Lei disclose that the nanoassemblies are disposed adjacent to each other. [Lei, Figure 10; 0017, 0031, 0077]
Kang and Lei do not disclose that the distance between the gold nanoparticles in each of the nanoassemblies is 3-4 nm, 15-20 nm, or 18-22 nm.
However, with respect to claim 4, Sun discloses a nanosatellite structure comprising a core-shell type magnetic particle (IONP-polymer) conjugated to a nanoassembly comprising a gold nanoparticle that is connected to a ligand (peptide) via a second linker. Sun further discloses the nanoassemblies are disposed adjacent to each other, and the distance between the gold nanoparticles in each of the nanoassemblies is 5-20 nm. [Sun, Figure 1, 0007-0011]
Modifying the nanosatellite-substrate complex disclosed by Kang and Lei so that the distance between the gold nanoparticles in each of the nanoassmeblies is 5-20 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 and Lei so that the distance between the gold nanoparticles in each of the nanoassemblies is 5-20 nm and have a reasonable expectation of success. Kang and Lei 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 5-20 nm. Thus, Sun establishes that in a nanosatellite comprising a plurality of nanoassemblies disposed adjacent to each other, the nanoassemblies may be disposed at a distance of 5-20 nm. Accordingly, the combined teachings of Kang/Lei and Sun suggest that the plurality of nanoassemblies disposed adjacent to each other in the nanosatellite-substrate complex disclosed by Kang and Lei may be disposed adjacent to each other at a distance of 5-20 nm. Therefore, it is reasonable to expect the nanosatellite-substrate complex disclosed by Kang and Lei may be modified so that the distance between the gold nanoparticles in each of the nanoassemblies is 5-20 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 to modulate cellular adhesion of the complex as desired.
Claims 1, 2, 3, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Kang and Lei, as applied to claim 1, 2, 3, and 5 above, and further in view of Pearce (Insights into Active Targeting of Nanoparticles in Drug Delivery: Advances in Clinical Studies and Design Considerations for Cancer Nanomedicine, 8/23/2019, Bioconjugate Chemistry, 30: 2300-2311).
With respect to claim 1, Kang and Lei disclose the teachings above.
With respect to claim 6, Kang and Lei disclose that the magnetic nanoparticle has a thiol group on a surface thereof. [Lei, Figure 10]
Moreover, Kang discloses the nanosatellite-substrate complex is used to temporally manipulate the adhesion and polarization of macrophages both in vitro and in vivo. [Kang, Page 5980, Scheme 1]
Kang and Lei do not disclose that the magnetic particle has an average diameter of 150 nm to 250 nm.
However, with respect to claim 6, Pearce discloses that the size, shape, and surface charge of nanoparticles dictate the biodistribution among the different organs, including the lungs, liver, spleen, and kidneys. Particularly, the size of the drug delivery particles will dictate the in vivo fate and avoidance of clearance mechanisms following administration. For example, studies show a lower limit of 5 nm nanoparticles to avoid renal filtration, and an upper limit of 200 nm nanoparticles to avoid excessive liver and spleen accumulation. [Pearce, Page 2302, Figure 2 and Col. 1, Paragraph 2]
Modifying the nanosatellite-substrate complex disclosed by Kang and Lei so that the magnetic nanoparticle has an average diameter of greater than 150 nm (i.e., 150 nm-200 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 and Lei so that the magnetic nanoparticle has an average diameter of greater than 150 nm and have a reasonable expectation of success. Kang and Lei disclose a nanosatellite-substrate complex that is administered in vivo, comprising a core-shell type magnetic nanoparticle. Pearce discloses that nanoparticles are drug delivery vehicles and the size, shape, and surface charge of the nanoparticles govern their biodistribution among different organs. For example, nanoparticles that have an average diameter of greater than 150 nm distribute well in the lungs, liver, and spleen, but not the kidneys. Thus, Pearce establishes that nanoparticles intended for in vivo administration are selected according to their size, including nanoparticles having an average diameter of greater than 150 nm. Accordingly, the combined teachings of Kang/Lei and Pearce suggest that the core-shell type magnetic nanoparticles comprised in the nanosatellite-substrate complex, which is administered in vivo, disclosed by Kang and Lei, may have an average diameter of greater than 150 nm. Therefore, it is reasonable to expect that the complex disclosed by Kang and Lei may be modified so that the magnetic nanoparticle has an average diameter of greater than 150 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 a nanosatellite-substrate complex that is administered in vivo, comprising a core-shell type magnetic nanoparticle. Pearce discloses that the size of the drug delivery particles will dictate the in vivo fate and avoidance of clearance mechanisms following administration. Particularly, Pearce discloses that nanoparticles having an average diameter of greater than 150 nm exhibit notable biodistribution in the lungs, liver, and spleen. [Pearce, Page 2302, Figure 2 and Col. 1, Paragraph 2] Therefore, one would have been motivated by the expectation that a magnetic nanoparticle having an average diameter of greater than 150 nm would enable the complex disclosed by Kang and Lei to exhibit notable biodistribution in the lungs, liver, and spleen when administered in vivo.
Claims 1, 2, 3, 5, 7, 9, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Kang and Lei, as applied to claim 1, 2, 3, and 5 above, and further in view of 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 and Lei disclose the teachings above.
With respect to claim 7, Kang discloses 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. [Kang, Page 5981, Scheme 2]
With respect to claim 9, Kang discloses a surface of the nanosatellite structure, which faces the substrate, is spaced apart from the substrate with the first linker interposed therebetween. [Kang, Page 5981, Scheme 2]
With respect to claims 10 and 11, Kang discloses the nanosatellite structure is spaced apart from one side of the substrate. [Kang, Page 5981, Scheme 2]
Kang further discloses that a PEG molecule at a high molecular weight 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 an entropic elasticity. [Kang, Page 5980, Col. 2, Paragraph 2]
Kang and Lei do not disclose that the first linker has a structure of Formula 1. (Claim 7) Kang and Lei do not disclose that the first linker is elastic and a length thereof is reversibly changed by application of a magnetic field. (Claim 9) Kang and Lei do not disclose that the first linker is compressed by applying a magnetic field to the other side of the substrate and the nanosatellite structure moves in a direction toward the substrate (Claim 10) or the first linker is stretched by applying a magnetic field to an upper side of the nanosatellite structure, and the nanosatellite structure moves in a direction away from the substrate. (Claim 11).
However, with respect to claims 7, 9, 10, and 11, Wong discloses a complex comprising an RGD-bearing magnetic nanoparticle conjugate to a substrate via a PEG (MW: 20000) linker. [Wong, Page 1686, Figure 1; Page 1687, Table 1] Wong further 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] For example, Wong discloses that the tether of RGD to the glass consists of ∼17.8 nm initial PEG spacer between MNP and substrate, the intermediate MNP of ∼36.6 nm in diameter, and the ∼17.8 nm PEG spacer between MNP and RGD. Therefore, the total tether length is ∼72.2 nm (including the diameter of MNP). In the absence of magnetic attraction, the longer RGD tether length entails extra time and effort by the cells to develop the critical traction force required for efficient cell adhesion and spreading. On the other hand, the magnetic attraction instantly decreases the tether length from ∼72.2 nm to ∼17.8 nm, and this represents an almost 4-fold reduction in the RGD tether length. [Wong, Page 1691, Col. 1, Paragraph 1; Page 1692, Col. 2, Paragraph 2]
Modifying the nanosatellite-substrate complex disclosed by Kang and Lei by adding a PEG segment to the first linker results in the complex of claim 7, 9, 10, and 11, wherein:
With respect to claim 7, the modified first linker, in one embodiment, is MPTMS-Mal-PEG-SH and has a structure of Formula 1, wherein:
R1 is a thiol group (-SH)
R2 is a succinimidyl ester group
n is 113.
With respect to claim 9, the modified first linker comprises PEG. Therefore, the linker is elastic, and a length thereof is reversibly changed by application of a magnetic field. [Wong, Page 1686, Figure 1; Page 1693, Figure 9]
With respect to claim 10, the modified first linker comprises PEG. Therefore, the linker is compressed by applying a magnetic field to the other side of the substrate, and the nanosatellite structure (to which the first linker is attached via the gold nanoparticle) moves in a direction toward the substrate. [Wong, Page 1686, Figure 1; Page 1693, Figure 9]
With respect to claim 11, the modified first linker comprises PEG. Therefore, the linker is stretched by applying a magnetic field to an upper side of the nanosatellite structure, and the nanosatellite structure (to which the first linker is attached via the gold nanoparticle) moves in a direction away from the substrate. [Wong, Page 1686, Figure 1; Page 1693, Figure 9]
It would be obvious to one of ordinary skill in the art to modify the nanosatellite-substrate complex disclosed by Kang and Lei by adding a PEG segment to the first linker and have a reasonable expectation of success. Kang and Lei disclose a nanosatellite-substrate complex for macrophage polarization comprising a functionalized glass substrate conjugated to a gold nanoparticle via a MPTMS linker. Wong discloses a complex for macrophage polarization comprising a functionalized glass substrate conjugated to a magnetic nanoparticle via an MPTMS-PEG linker. Thus, Wong establishes that PEG moieties may be incorporated into macrophage polarization complexes comprising MPTMS-based linkers used to conjugate nanoparticles to functionalized substrates. Accordingly, the combined teachings of Kang/Lei and Wong suggest that the MPTMS linker used to conjugate the gold nanoparticle to the substrate in the complex disclosed by Kang and Lei may include a PEG spacer segment. Therefore, it is reasonable to expect the nanosatellite-substrate complex disclosed by Kang and Lei may be modified by adding a PEG segment to the first linker. 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 tethering mobility of RGD peptides on substrate via magnetic field by introducing lengthy and flexible PEG linker between glass substrate and RGD bearing nanoparticles regulates the adhesion, spreading, mechanosensing, and differentiation of cells. [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 the ability to regulate cell–substrate interactions, including cell adhesion, spreading, and differentiation, in the nanosatellite-substrate complex disclosed by Kang and Lei via a noncontact physical mechanism of cell adhesion.
Claims 1, 2, 3, 5, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Kang and Lei, as applied to claims 1, 2, 3, and 5 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 and Lei disclose the teachings above.
With respect to claim 8, Kang and Lei disclose that the ligand is an RGD ligand. [Kang, Page 5981, Scheme 2]
Kang and Lei do not disclose the ligand is a cyclic RGD ligand.
However, with respect to claim 8, Yang discloses 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 and Lei 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 and Lei by replacing the ligand with cyclic RGD and have a reasonable expectation of success. Kang and Lei disclose a nanosatellite-substrate complex comprising a cell-adhesive ligand, a linear RGD peptide. Yang discloses a complex comprising a cell-adhesive ligand, linear or cyclic RGD peptide. Yang further discloses that both ligands stimulate integrin and subsequent macrophage attachment. Thus, Yang establishes that 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 and Yang suggest that cyclic RGD peptide may function as the cell-adhesive ligand in the complex disclosed by Kang and Lei. Therefore, it is reasonable to expect the nanosatellite-complex disclosed by Kang and Lei may be modified by replacing the ligand with cyclic RGD. 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 2144.07. 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, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kang and Lei, as applied to claims 1, 2, 3, and 5 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 and Lei disclose the teachings above.
Recall, Kang and Lei disclose the nanosatellite structure may comprise one RGD ligand. [Cite].
Kang and Lei do not disclose that the density of the nanosatellite structure disposed on the substrate is 1.0 nanosatellite structure/μm2 to 6 nanosatellite structures/μm2.
However, with respect to claim 12, Lu discloses that a minimum of 4−7 RGD peptides per µm2 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 and Lei 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 to 7 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 and Lei so that the density of the nanosatellite structure disposed on the substrate is 4 to 7 nanosatellites /μm2 and have a reasonable expectation of success. Kang and Lei 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 per µm2 are needed for cell spreading and adhesion formation on nanofabricated surfaces. Thus, Lu establishes that a minimum surface density of 4−7 RGD peptides per µm2 is effective for promoting cell spreading and adhesion. Accordingly, the combined teachings of Kang/Lei and Lu suggest that the nanosatellite-substrate complex disclosed by Kang and Lei may require a minimum of 4−7 RGD peptides per µm2. Therefore, it is reasonable to expect the nanosatellite-substrate complex disclosed by Kang and Lei may be modified so that the density of the nanosatellite structure disposed on the substrate is 4 -7 nanosatellites/μm2 (which is equivalent to 4−7 RGD peptides per 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 to modulate cellular adhesion of the complex as desired.
Response to Arguments
Applicant’s arguments, filed 4/2/2026, with respect to the rejection of all claims under 35 U.S.C. 103 over Kim and Kang have been fully considered and are persuasive.
Applicant submits that Kim is disqualified as a prior art reference in accordance with 35 U.S.C. §102(b)(1 )(A) and 35 U.S.C. § 102(b)(2)(c) and Kang alone is insufficient to establish a prima facie case of obviousness of claim 1 at least because Kang alone and/or in combination with Lundgren, Albutt, Sun, or Khatua fails to disclose or suggest every claimed feature. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the references cited above.
Oath/Declaration
The declaration under 37 CFR 1.132 filed 4/2/2026 is sufficient to overcome the rejection of all examined claims based upon Applicant’s statement that the disclosure of Kim was obtained directly or indirectly from the instant inventor (Young-Keun KIM) and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A).
Conclusion
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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