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 .
Response to Amendment
The Amendment filed 02/17/2026 has been entered. Claims 1-5, 8-10, and 13-21 remain pending in the application. Claims 13-21 are withdrawn Applicant’s amendments to the claims have overcome each and every objection and 112(b) rejections previously set forth in the Non-Final Office Action mailed 12/09/2025. New grounds of rejections necessitated by amendments are discussed 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Yasuda et al. (US 20150299758 A1; cited in the IDS filed 01/23/2023) in view of Stahler et al. (US 20110092380 A1), Benn et al. (US 20050277125 A1), and Ueno et al. (JP 2015031596 A; see machine translation).
Regarding claim 1, Yasuda teaches a hemispherical shell-shaped hollow-multilayered microstructure (Fig. 1) for use in the detection of a target molecule (interpreted as an intended use, MPEP 2114; paragraphs [0028],[0145],[0183]), comprising:
a first thin film layer in the form of a substantially micro-hemispherical shell (Fig. 1, teaches thin film layer 3, which is a substantially micro-hemispherical shell; paragraphs [0132]-[0133],[0156] teaches the microscopic object is hemispherical) composed of a first material comprising a magnetic material (paragraph [0046] teaches the layer structure is formed of a substance exhibiting ferromagnetic property), and
a second thin film layer disposed on the inner surface of the micro-hemispherical shell (Fig. 1, thin film layer 1 disposed on an inner surface of the thin film layer 3; paragraphs [0133],[0156]) and composed of a second material (paragraphs [0142], [0146] teaches the innermost thin film layer comprises a substance, i.e. gold, which is easily chemically modified), wherein said second material is capable of removably fixing a fluorochrome-labeled probe and causing fluorescence resonance energy transfer between the fluorochrome and the second material (interpreted as a functional limitation, see MPEP 2114; paragraphs [0142],[0146] teach the inner most thin film layer comprises gold, which is capable of performing the claimed functional limitations; the instant application, paragraph [0023] discloses the second material comprises gold; therefore, since Yasuda’s second material is identical to the claimed second material, Yasuda’s second material is capable of performing the functional limitations, MPEP 2112.01),
wherein a hollow space defined by the second thin film layer (Figs. 1-2 shows a hollow space defined by thin film 1) has a size that is capable of capturing at least one cell of the target molecule or a portion thereof in said hollow space (Figs. 1-2 and 11 and paragraph [0184] teaches a hollow space capable of capturing biological molecules; paragraph [0188] teaches a cell having a size smaller than a hemispherical microscopic object are recovered), and
wherein the fluorochrome-labeled probe is a molecule capable of specific binding to the target molecule, and said binding to the target molecule can alter the structure of the fluorochrome-labeled probe, thereby causing a change from quenching to emission of the fluorochrome (note that “the probe” is not positively recited structurally and is interpreted as a functional limitation of the second thin film layer, see MPEP 2114; paragraph [0142] teaches the innermost layer is capable of binding to a macromolecule; paragraph [0031] teaches a cell-bindable substance, i.e. a probe capable of binding to a target molecule, attached to an inner surface of the innermost layer; therefore, the claimed probe is capable of being removably fixed to the innermost layer to function to bind a target molecule to alter the structure of the probe to cause a change from quenching to emission of the fluorochrome at a later time).
While Yasuda teaches a cell-bindable substance attached to an inner surface of an innermost layer of the hollow structure (paragraph [0031]), fluorescence-emitting substances (paragraphs [0138], [0140],[0144]), and an embodiment of a probe (Fig. 11, chain-line biological molecule 14 and capturing biological molecules 13) fixed to the innermost surface of the hollow structure (Fig. 11), Yasuda fails to teach: wherein the hemispherical shell-shaped hollow multilayer microstructure comprises said fluorochrome-labeled probe removably fixed to a surface of said second thin film layer, and wherein the fluorochrome-labeled probe is a nucleic acid molecule modified with the fluorochrome at one end and a pyrene molecule at the other end, and wherein the fluorochrome-labeled probe is removably fixed to the surface of the second thin film layer via a spacer molecule and/or wherein the fluorochrome is bound to the fluorochrome-labeled probe via the spacer molecule.
Stahler teaches improved molecular-biological processing equipment and an improved method of processing biological samples (abstract), wherein the invention involves detect and isolate nucleic acids (abstract). Stahler teaches a DNA probe, where a labeling sequence is located at one end of the DNA probe, and the other end is immobilized on the support surface (paragraph [0093]). Stahler teaches receptors that bind to an analyte and are immobilized on a support, wherein the receptor can include nucleic acid molecules, which can carry dyes (paragraph [0104]), i.e. fluorochrome-labeled probe. Stahler teaches nucleic acids with attached fluorescent dyes, i.e. fluorochrome-labeled probe, can be synthesized on a reaction support (paragraph [0179]). Stahler teaches a hairpin probe which is quenched in a closed state and emits fluorescence in an open state based hybridization events (paragraphs [0270],[0296]), which allows for marker-free detection of DNA (paragraph [0302]). Stahler teaches receptors can be immobilized on a surface, such as noncovalent self-assembly on a gold surface by means of thiol groups, preferably via a spacer or linker (paragraph [0284]). Stahler teaches an embodiment of a FRET reaction for analysis or information gathering, where a probe comprises a free 3' end that can represent the fluorescence acceptor (paragraph [0313]). Stahler teaches receptors are synthesized on a surface of a support via linkage via a linker (paragraph [0332]). Stahler teaches probes comprising a fluorophore or quencher, where structural changes can be detected (paragraphs [0085],[0087]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the hemispherical shell-shaped hollow multilayer microstructure of modified Yasuda to incorporate Stahler’s teachings of a nucleic acid probes with labeled on one end with fluorescent dyes and the other end immobilized on a support, and immobilizing receptors on a gold surface by a spacer or linker (paragraphs [0093],[0104],[0179],[0284],[0313],[0332]) and teachings of FRET reactions for analysis and fluorescent probes that change shape based on hybridization events that can be optically detected (paragraphs [0085],[0087][0270],[0296],[0313]) and Yasuda’s teachings of fluorescent emitting substances and cell-binding substances fixed to the innermost gold layer of the hollow structure (Fig. 11; paragraphs [0031],[0138], [0140],[0144]) and binding of organic molecules, such as DNA and RNA having a thiol group at a terminus for immobilization (paragraph [0167]) to provide: wherein the hemispherical shell-shaped hollow multilayer microstructure comprises said fluorochrome-labeled probe fixed to a surface of said second thin film layer, and wherein the fluorochrome-labeled probe is a nucleic acid molecule modified with the fluorochrome at one end, and wherein the fluorochrome-labeled probe is fixed to the surface of the second thin film layer via a spacer molecule. Doing so would have a reasonable expectation of successfully improving arrangement and attachment of the fluorochrome to the probe and the probe to the gold innermost layer of Yasuda, and therefore improving detection of specific target analytes.
Modified Yasuda fails to teach: said fluorochrome-labeled probe removably fixed to a surface of said second thin film layer; the nucleic acid molecule modified with a pyrene molecule at the other end; and wherein the fluorochrome-labeled probe is removably fixed to the surface of the second thin film layer.
Benn teaches a device for performing reactions on a reaction surface for interrogating samples with diagnostic reagents (abstract). Benn teaches a detection reactant may be labeled with a fluorescent label (paragraph [0077]). Benn teaches an array comprising a fluorescently-labeled complimentary DNA, i.e. fluorochrome-labeled probe, (paragraph [0295]). Benn teaches once a hybridization assay is completed, probes can be removed from the sample DNA by strong washing of the reaction surface to allow for reuse of membranes (paragraph [0299]). Benn teaches labels include fluorophores (paragraph [0103]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second thin film layer of modified Yasuda to incorporate the teachings of detection reactants labeled with fluorescent labels and removing the probes after completing an assay of Benn (paragraphs [0077],[0295],[0299]) and the teachings of fluorescent emitting substances and cell-binding substances fixed to the innermost layer of the hollow structure of Yasuda (Fig. 11; paragraphs [0031],[0138], [0140],[0144]) to provide: said fluorochrome-labeled probe removably fixed to a surface of said second thin film layer; and wherein the fluorochrome-labeled probe is removably fixed to the surface of the second thin film layer. Doing so would have a reasonable expectation of successfully improving detection of specific target analytes while allowing for reuse of the microstructure (Benn, paragraph [0299]).
Modified Yasuda fails to teach: the nucleic acid molecule modified with a pyrene molecule at the other end.
Stahler teaches receptors can be immobilized on a surface, such as noncovalent self-assembly on a gold surface by means of thiol groups, preferably via a spacer or linker. (paragraph [0284]).
Ueno teaches a biomolecular detection chip for detecting biomolecules (paragraph [0001]). Ueno teaches pyrene functions as a linker molecule to firmly fix a graphene oxide to the aptamer (paragraph [0038]). Ueno teaches molecules for detecting dye-bound biomolecules are immobilized on a surface by bonding a five-terminated amino group to a linker molecule pyrene (paragraph [0042]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid molecule of modified Yasuda to incorporate the Stahler’s teachings of receptors immobilized to a gold surface by a linker (paragraph [0284]) and Ueno’s teachings of pyrene functioning as a linker molecule to attach an aptamer or biomolecule to a surface (paragraphs [0038],[0042]) to provide: the nucleic acid molecule modified with a pyrene molecule at the other end. Doing so would have a reasonable expectation of successfully improving arrangement and attachment of the probe to the gold innermost layer of Yasuda.
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. the nucleic acid molecule modified with a pyrene molecule at the other end) by known methods with no change in their respective functions (i.e. attachment of the probe to a surface), and the combinations yielded nothing more than predictable results (i.e. providing the nucleic acid molecule modified with a pyrene molecule at the other end would yield nothing more than the obvious and predictable result of enabling attachment of the probe to the gold surface of Yasuda via the use of a pyrene linker). See MPEP 2143(A).
Regarding claim 2, Yasuda further teaches wherein the first material comprises a magnetic material selected from the group consisting of nickel, iron, cobalt, gadolinium, ruthenium, iron oxide, chromium oxide, ferrite and neodymium (paragraph [0046] teaches the layer structure is formed of a substance exhibiting ferromagnetic property; paragraphs [0032] and [0050]-[0052] teaches the substance that exhibits ferromagnetic property includes nickel, iron, cobalt, gadolinium, ferrites, iron oxide).
Regarding claim 3, Yasuda further teaches wherein the second material comprises an element having an SP2 hybrid orbital, an element in which an SP2 bonded region and an SP3 bonded region are mixed, or a metal (paragraphs [0142], [0146] teaches the inner most thin film layer comprises a substance, i.e. gold).
Regarding claim 4, Yasuda further teaches wherein the second material comprises nanocarbon, nanographene or gold (paragraphs [0142], [0146] teaches the inner most thin film layer comprises a substance, i.e. gold).
Regarding claim 5, while Yasuda teaches introducing an amino group for immobilizing DNA (paragraph [0181]), modified Yasuda fails to teach: wherein the second thin film layer has an amino group on its surface.
Stahler teaches improved molecular-biological processing equipment and an improved method of processing biological samples (abstract), wherein the invention involves detect and isolate nucleic acids (abstract). Stahler teaches a DNA probe, where a labeling sequence is located at one end of the DNA probe, and the other end is immobilized on the support surface (paragraph [0093]). Stahler teaches receptors that bind to an analyte and are immobilized on a support, wherein the receptor can include nucleic acid molecules, which can carry dyes (paragraph [0104]). Stahler teaches receptors can be immobilized on a surface, such as noncovalent self-assembly on a gold surface by means of thiol groups (paragraph [0284]). Stahler teaches an embodiment of a FRET reaction for analysis or information gathering, where a probe comprises a free 3' end that can represent the fluorescence acceptor (paragraph [0313]). Stahler teaches reaction supports where surfaces can be prepared with one of numerous configurations known by a person skilled in the art for binding of molecules, for example with amino groups (paragraph [0171]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second thin film layer of modified Yasuda to incorporate the teachings of reaction supports where surfaces can be prepared with one of numerous configurations known by a person skilled in the art for binding of molecules, for example with amino groups of Stahler (paragraph [0171]) and Yasuda’s teachings an amino group for immobilizing DNA (paragraph [0181]) and the innermost layer is gold and can be easily chemically modified (paragraph [0144]) to provide: wherein the second thin film layer has an amino group on its surface. Doing so would have a reasonable expectation of successfully improve attachment the probe to the gold innermost layer of Yasuda.
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. the claimed second thin film layer has an amino group on its surface) by known methods with no change in their respective functions (i.e. attachment of the probe on the second thin film layer), and the combinations yielded nothing more than predictable results (i.e. providing the second thin film layer has an amino group on its surface would yield nothing more than the obvious and predictable result of enabling and improving attachment of the probe to the gold surface of Yasuda). See MPEP 2143(A).
Regarding claim 8, Yasuda further teaches wherein the target molecule comprises a protein, peptide, nucleic acid, cell surface molecule or cell secretory vesicle (paragraph [0183] teaches target biological molecules include antigen and protein; note that “target molecule” is not positively recited structurally are is interpreted as an intended use of the claimed hemispherical shell-shaped hollow-multilayered microstructure, see MPEP 2114).
Regarding claim 9, Yasuda further teaches wherein the film thickness of each thin film layer is in the range of 0.1nm to 1mm (paragraph [0117] teaches the first layer of 10 nm and second layer of 2nm; paragraph [0133] teaches each of the layers is 1nm - 1um; paragraph [0187] teaches the gold inner layer has a thickness of 10 nm and the nickel outer layer has a thickness of 2 nm).
Regarding claim 10, modified Yasuda further teaches an array of hemispherical shell-shaped hollow multilayer microstructures (Yasuda, Fig. 11 and paragraph [0183] teaches an array of the hemispherical shell-shaped hollow-multilayered microstructure) comprising a hemispherical shell-shaped hollow multilayer microstructure according to claim 1 (see above claim 1).
Response to Arguments
Applicant’s arguments, see page 6, filed 02/17/2026, with respect to the claim objections and rejections under 35 U.S.C. 112 have been fully considered and are persuasive. The claim objections and rejections under 35 U.S.C. 112 of 12/09/2025 have been withdrawn.
Applicant’s arguments, see pages 7-8, filed 02/17/2026, with respect to the rejection(s) of claims 1-5, 8-10, and 12 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yasuda et al. (US 20150299758 A1; cited in the IDS filed 01/23/2023) in view of Stahler et al. (US 20110092380 A1), Benn et al. (US 20050277125 A1), and Ueno et al. (JP 2015031596 A; see machine translation).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Oberhaus et al. (Oberhaus et al., “Immobilization Techniques for Aptamers on Gold Electrodes for the Electrochemical Detection of Proteins: A Review”, Biosensors, April 27, 2020, 10(5), 45) teaches immobilization techniques for aptamers on gold electrodes for electrochemical detection (abstract). Oberhaus teaches pyrene aptamer immobilization strategies (Fig. 24).
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 HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758