DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-2, 4-5, 8-11, 22, 26-28, 30-31, 40-42, and 47 are pending and are under examination.
Claims 49 and 53 are withdrawn.
Applicant’s election without traverse of Group I, which includes Claims 1-2, 4-5, 8-11, 22, 26-28, 30-31, 40-42, and 47 in the reply filed on 04/21/2026 is acknowledged.
Claims 49 and 53 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method for tuning brightness by altering nucleic acid linker, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/21/2026.
Claim Interpretation
The recited “ a fluorescently labeled nucleic acid nanostructure” of claim 1 is interpreted as broad enough to cover two distinct alternatives:
The feature is interpreted as encompassing broader definition provided in Applicant’s specification paragraph 0058, which defines “nucleic acid nanostructure” as “an oligonucleotide construction of any size” compose of one or more strands and further states that such nanostructures may include “fluorescent moieties of any type”. Under this interpretation, the claim read on an oligonucleotide that is attached/linked/associated with fluorophores, without requiring the nucleic acid to function as fluorophore trapping scaffold.
The feature is interpreted as encompassing a nanostructure scaffold that is DNA- or RNA-based architecture (like origami) engineered to carry organic fluorophores for signal tunning and enhancing brightness, consistent with Applicant’s Fig. 4B.
Interpretation #1 - Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 5, 8-11, 22, 26-28, 31, 40-42, and 47 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Nakamoto et al. (US11834715B2; EFD: May 5th 2019)
Regarding claim 1, Nakamoto discloses a method for combining cell enrichment, cell sorting, and/or immunofluorescent cell labeling with genomic analysis comprising (a) performing cell enrichment, cell sorting, and/or immunofluorescent cell labeling on a cell and/or sample of cells and (b) performing genomic analysis on the same cell and/or sample of cells, using the fluorescent-labeled sequence-tagged specificity determining molecule conjugate; (e.g. method for analysis of cellular component targets of cells of interest; wherein cells are labeled with binding moiety conjugated to detectable moieties and oligonucleotide that comprise index barcode. The binding construct enables the binding reagent to be employed for both fluorescence analysis (e.g., cell sorting) and sequence analysis (e.g., protein expression profiling) [abstract])
wherein the fluorescent label component is a fluorescently labeled nucleic acid nanostructure; (e.g. Fig. 12 shows fluorescent label 1212 comprise nucleic acid structure linked to fluorophore)
wherein the specificity determining molecule component is sequence-tagged; (e.g. binding moiety conjugated to oligonucleotide that comprise index barcode [abstract])
wherein the method first comprises contacting the cell and/or sample of cells with the fluorescent-labeled sequence-tagged specificity determining molecule conjugate; (e.g. contacting binding agents with cells sample; wherein each of cellular component-binding reagents is associated with a specific oligonucleotide comprising a detectable moiety and an identifier sequence [Column 1, lines 40-55])
wherein the genomic analysis occurs after the cell enrichment, cell sorting, and/or immunofluorescent cell labeling; (e.g. method includes labeling cells from biological samples and obtaining cells before subjecting cells to downstream analysis to obtain sequence information [column 1, lines 40-column 2 line 19])
wherein the specificity determining molecule is an antibody or an antigen-binding fragment, variant, or derivative thereof. (e.g. cellular component-binding reagent (e.g., an antibody) [Abstract])
Regarding claims 2, 28, and 41, Nakamoto further discloses the fluorescent label component is attached to the specificity determining molecule component via a nucleic acid linker; wherein the nucleic acid linker comprises a double-stranded segment; (Fig. 12 shows binding moiety attached to unique barcode label, which comprises a unique barcode sequence. The unique barcode sequence hybridizes to label nucleic acid sequence that can comprise fluorophore(s), hence forming double-stranded nucleic acid [column 57, lines 23-57]. The linkage between binding moiety and unique barcode label is covalent [column 56, lines 52-column 57, line10])
Regarding claims 5 and 31, Nakamoto further discloses the specificity determining molecule component comprises a PCR primer region, a barcode region and a capture sequence. (e.g. Fig. 12 shows cellular component-binding reagent specific oligonucleotide comprises PCR handle, unique barcode, and capture sequence (polyA))
Regarding claim 8, Nakamoto further discloses wherein the choice of genomic analysis method is based on the results of the cell enrichment, cell sorting, and/or immunofluorescent cell labeling. (e.g. method can comprise performing an analysis of the number of copies of each of the cellular component targets of the cells associated with the cellular component-binding reagents based on the experiment result of the cells.[column 3, lines 18-26])
Regarding claim 9, Nakamoto further discloses cell enrichment and/or cell sorting comprises flow cytometry [column 70, lines 42].
Regarding claim 10, Nakamoto further discloses the genomic analysis comprises next generation sequencing (NGS) [column 74, lines 48-67]
Regarding claim 11, Nakamoto further discloses the method is applied to a single-cell suspension [column 74, lines 28-29].
Regarding claim 22, Nakamoto further discloses the degree of labeling (DoL) of the specificity determining molecule component is used to increase the signal detection; and/or the fluorescent label is a fluorescently labeled nucleic acid nanostructure and the number of fluorescent molecules incorporated into the fluorescently labeled nucleic acid nanostructure is used to increase the signal detection.(e.g. the disclosed detectable moieties include polymers such as polyfluorene conjugated polymeric dye having multiple fluorescent/chromophores repeat units (e.g. 2-100,000 units) and fluorene/aryl structures where n and m may each be up to 10,000. [columns 83-84]. The reference further discloses polymeric detectable moieties function as light harvesting multichromophores and emission amplification occurs when the number of repeated individual chromophores is large.[column 81, lines 1-30])
Regarding claim 26, Nakamoto further discloses the use of a sequence-tagged fluorescent-label specificity determining molecule conjugate allows data from cell enrichment, cell sorting, and/or immunofluorescent cell labeling to be linked to data from genomic analysis. (e.g. cells are selected based on detectable moieties (flow cytometry) and the same reagent specific oligonucleotide then barcoded, extended, and sequence to determine cellular component target information [column 87, lines 13-column88, line 15])
Regarding claim 27, Nakamoto discloses a sequence-tagged fluorescent-label specificity determining molecule conjugate comprising a specificity determining molecule component conjugated to a fluorescent label component, wherein said conjugate is suitable for use in the method of claim 1; wherein the fluorescent label component is a fluorescently labeled nucleic acid nanostructure; (e.g. Fig. 12 shows fluorescent label 1212 comprise nucleic acid structure linked to fluorophore)
wherein the specificity determining molecule component is sequence-tagged; wherein the specificity determining molecule is an antibody or an antigen-binding fragment, variant, or derivative thereof.(e.g. binding moiety (e.g. antibody) conjugated to detectable moieties and oligonucleotide that comprise index barcode.[abstract]).
Regarding claim 40, Nakamoto further discloses the conjugate comprises one or more unique identifying sequence.[e.g. element 1220 of Fig 12]
Regarding claims 42, Nakamoto further discloses the nucleic acid linker is a hybridized entirely double-stranded nucleic acid, the specificity determining molecule component is covalently attached to one strand of the linker, the fluorescent label component is covalently attached to the opposite strand of the linker, and wherein the specificity determining molecule component and the fluorescent label component are not covalently attached but instead linked via the hybridization of their respective linker strands. (Fig. 12 shows binding moiety attached to unique barcode label, which comprises a unique barcode sequence. The unique barcode sequence hybridizes to label nucleic acid sequence that can comprise fluorophore(s), hence forming double-stranded nucleic acid [column 57, lines 23-57]. The linkage between binding moiety and unique barcode label is covalent [column 56, lines 52-column 57, line10])
Regarding claim 47, Nakamoto discloses a kit comprising, the sequence-tagged fluorescent-label specificity determining molecule conjugate of claim 27, or a component thereof; one or more reagents for performing cell enrichment, cell sorting, or immunofluorescent cell labeling, and genomic analysis; instructions either printed and/or on an electronic storage medium, buffers and/or additional reagents, and/or packaging materials. [column 121 line 1-column 125 line 2].
Interpretation #1 - Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claim(s) 4 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nakamoto et al. (US11834715B2; EFD: May 5th 2019) in view of Nazor et al. (WO2017190020A1; EFD: April 28th 2017, disclosed in IDS)
Regarding claims 4 and 30, Nakamoto further discloses label nucleic acid that hybridizes to the binding reagent oligonucleotide may vary in length, ranging in some instances from 5 to 100 nt [column 57, lines 16-22]. As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to select their linker length between 10 and 70 nucleotides through routine optimization of recognized variable. For example, Nazor et al. provide working example of hybridizing oligonucleotide segment sequences to connect binding moiety with detectable moiety with length of ranging from about 12 to about 60 nucleotides [¶00138], showing the claimed range is known and used in the art for the same purpose. See MPEP § 2144.05 (I) “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 (II) A "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
Interpretation #2 - Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Nakamoto et al. and Lebeck et al.
Claim(s) 1-2, 5, 8-11, 22, 26-28, 31, 40-42, and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nakamoto et al. (US11834715B2; EFD: May 5th 2019) in view of Lebeck et al. (WO2018231805A2, EFD: June 6th 2018, disclosed in IDS)
Regarding claim 1, Nakamoto discloses a method for combining cell enrichment, cell sorting, and/or immunofluorescent cell labeling with genomic analysis comprising (a) performing cell enrichment, cell sorting, and/or immunofluorescent cell labeling on a cell and/or sample of cells and (b) performing genomic analysis on the same cell and/or sample of cells, using the fluorescent-labeled sequence-tagged specificity determining molecule conjugate; (e.g. method for analysis of cellular component targets of cells of interest; wherein cells are labeled with binding moiety conjugated to detectable moieties and oligonucleotide that comprise index barcode. The binding construct enables the binding reagent to be employed for both fluorescence analysis (e.g., cell sorting) and sequence analysis (e.g., protein expression profiling) [abstract])
wherein the specificity determining molecule component is sequence-tagged; (e.g. binding moiety conjugated to oligonucleotide that comprise index barcode [abstract])
wherein the method first comprises contacting the cell and/or sample of cells with the fluorescent-labeled sequence-tagged specificity determining molecule conjugate; (e.g. contacting binding agents with cells sample; wherein each of cellular component-binding reagents is associated with a specific oligonucleotide comprising a detectable moiety and an identifier sequence [Column 1, lines 40-55])
wherein the genomic analysis occurs after the cell enrichment, cell sorting, and/or immunofluorescent cell labeling; (e.g. method includes labeling cells from biological samples and obtaining cells before subjecting cells to downstream analysis to obtain sequence information [column 1, lines 40-column 2 line 19])
wherein the specificity determining molecule is an antibody or an antigen-binding fragment, variant, or derivative thereof. (e.g. cellular component-binding reagent (e.g., an antibody) [Abstract])
However, Nakamoto does not disclose the fluorescent label component is a fluorescently labeled nucleic acid nanostructure.
Lebeck discloses optical resonators network label form from DNA nanostructures, wherein fluorophores or other optical resonators are positioned on DNA strands through self-assembly to create optically distinguishable labels. [abstract]
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to substitute resonator DNA nanostructures in place of detectable signal molecules discloses in Nakamoto’s ¶0080 because Lebeck expressly teaches that 1) these structures can be coupled to an antibody, aptamer, or other analyte-specific receptor to be used in similar purpose as Nakamoto’s such as cell imaging, flow cytometry, or multiplexed detection of analytes [Abstract and ¶0055] and 2) the structures offer additional advantages such as large library of distinguishable labels can allow for the simultaneous detection of a large number of different analytes [¶0056], enhanced and tunable brightness relative to existing labels [¶0058], and avoid crowding-induced self-quenching issue of chromophores [¶00111]. Accordingly, the substitution would have predictably provided Nakamoto’s sequence tagged antibody conjugate with a fluorescent nucleic acid nanostructure label suitable for “fluorescence base detection while maintaining the sequence barcode functionality.
Regarding claims 2, 28, and 41, Nakamoto further discloses the fluorescent label component is attached to the specificity determining molecule component via a nucleic acid linker; wherein the nucleic acid linker comprises a double-stranded segment; (Fig. 12 shows binding moiety attached to unique barcode label, which comprises a unique barcode sequence. The unique barcode sequence hybridizes to label nucleic acid sequence that can comprise fluorophore(s), hence forming double-stranded nucleic acid [column 57, lines 23-57]. The linkage between binding moiety and unique barcode label is covalent [column 56, lines 52-column 57, line10])
Regarding claims 5 and 31, Nakamoto further discloses the specificity determining molecule component comprises a PCR primer region, a barcode region and a capture sequence. (e.g. Fig. 12 shows cellular component-binding reagent specific oligonucleotide comprises PCR handle, unique barcode, and capture sequence (polyA))
Regarding claim 8, Nakamoto further discloses wherein the choice of genomic analysis method is based on the results of the cell enrichment, cell sorting, and/or immunofluorescent cell labeling. (e.g. method can comprise performing an analysis of the number of copies of each of the cellular component targets of the cells associated with the cellular component-binding reagents based on the experiment result of the cells.[column 3, lines 18-26])
Regarding claim 9, Nakamoto further discloses cell enrichment and/or cell sorting comprises flow cytometry [column 70, lines 42].
Regarding claim 10, Nakamoto further discloses the genomic analysis comprises next generation sequencing (NGS) [column 74, lines 48-67]
Regarding claim 11, Nakamoto further discloses the method is applied to a single-cell suspension [column 74, lines 28-29].
Regarding claim 22, Lebeck further discloses the fluorescent label is a fluorescently labeled nucleic acid nanostructure and the number of fluorescent molecules incorporated into the fluorescently labeled nucleic acid nanostructure is used to increase the signal detection.(e.g. a resonator label could include multiple distinct or inter-connected resonator networks to increase and/or control the effective brightness of the label [¶0089])
Regarding claim 26, Nakamoto further discloses the use of a sequence-tagged fluorescent-label specificity determining molecule conjugate allows data from cell enrichment, cell sorting, and/or immunofluorescent cell labeling to be linked to data from genomic analysis. (e.g. cells are selected based on detectable moieties (flow cytometry) and the same reagent specific oligonucleotide then barcoded, extended, and sequence to determine cellular component target information [column 87, lines 13-column88, line 15])
Regarding claim 27, Nakamoto discloses a sequence-tagged fluorescent-label specificity determining molecule conjugate comprising a specificity determining molecule component conjugated to a fluorescent label component, wherein said conjugate is suitable for use in the method of claim 1; wherein the specificity determining molecule component is sequence-tagged; wherein the specificity determining molecule is an antibody or an antigen-binding fragment, variant, or derivative thereof.(e.g. binding moiety (e.g. antibody) conjugated to detectable moieties and oligonucleotide that comprise index barcode.[abstract]).
However, Nakamoto does not disclose the fluorescent label component is a fluorescently labeled nucleic acid nanostructure.
Lebeck discloses optical resonators network label form from DNA nanostructures, wherein fluorophores or other optical resonators are positioned on DNA strands through self-assembly to create optically distinguishable labels [abstract].
The rationale for combining the Nakamoto and Lebeck references with respect to claim 27 is the same as set forth above for claim 1 and is incorporated herein by reference, as claim 27 does not introduce a limitation that would alter the motivation to combine or the predictable resulted achieved by the combination.
Regarding claim 40, Nakamoto further discloses the conjugate comprises one or more unique identifying sequence.[e.g. element 1220 of Fig 12]
Regarding claims 42, Nakamoto further discloses the nucleic acid linker is a hybridized entirely double-stranded nucleic acid, the specificity determining molecule component is covalently attached to one strand of the linker, the fluorescent label component is covalently attached to the opposite strand of the linker, and wherein the specificity determining molecule component and the fluorescent label component are not covalently attached but instead linked via the hybridization of their respective linker strands. (Fig. 12 shows binding moiety attached to unique barcode label, which comprises a unique barcode sequence. The unique barcode sequence hybridizes to label nucleic acid sequence that can comprise fluorophore(s), hence forming double-stranded nucleic acid [column 57, lines 23-57]. The linkage between binding moiety and unique barcode label is covalent [column 56, lines 52-column 57, line10])
Regarding claim 47, Nakamoto discloses a kit comprising, the sequence-tagged fluorescent-label specificity determining molecule conjugate of claim 27, or a component thereof; one or more reagents for performing cell enrichment, cell sorting, or immunofluorescent cell labeling, and genomic analysis; instructions either printed and/or on an electronic storage medium, buffers and/or additional reagents, and/or packaging materials. [column 121 line 1-column 125 line 2].
Nakamoto et al., Lebeck et al., and Nazor et al.
Claim(s) 4 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nakamoto et al. (US11834715B2; EFD: May 5th 2019) in view of Lebeck et al. (WO2018231805A2, EFD: June 6th 2018, disclosed in IDS) and Nazor et al. (WO2017190020A1; EFD: April 28th 2017, disclosed in IDS)
Regarding claims 4 and 30, Nakamoto further discloses label nucleic acid that hybridizes to the binding reagent oligonucleotide may vary in length, ranging in some instances from 5 to 100 nt [column 57, lines 16-22]. As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to select their linker length between 10 and 70 nucleotides through routine optimization of recognized variable. For example, Nazor et al. provide working example of hybridizing oligonucleotide segment sequences to connect binding moiety with detectable moiety with length of ranging from about 12 to about 60 nucleotides [¶00138], showing the claimed range is known and used in the art for the same purpose. See MPEP § 2144.05 (I) “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 (II) A "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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