DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on November 26, 2025 has been entered. The claims pending in this application are claims 10-15. The objection not reiterated from the previous office action is hereby withdrawn in view of applicant’s amendment filed on November 26, 2025. Claims 10-15 will be examined.
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.
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 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al., (US 2015/0267251 A1, priority date: April 30, 2013) in view of 1988 Stratagene catalog (page 39).
Note that this rejection is modified from the rejection under 35 U.S.C. 103 mailed on
August 27, 2025.
Regarding claims 10-13, Cai et al., teach a) a plurality of pre-decoding oligonucleotides (ie., the intermediate oligonucleotides), wherein the pre-decoding oligonucleotides are unlabeled (eg., the intermediate oligonucleotides which do not have a detectable moiety), and wherein each of the plurality of pre-decoding oligonucleotides comprises: (1) a targeting sequence that specifically hybridizes to one target transcript or genomic locus, and (ii) two or more binding sites that specifically hybridize to one of a plurality of decoding oligonucleotides; and b) a first plurality of decoding oligonucleotides (ie., hybridization complexes comprising bridge oligonucleotides and different initiator sequences of different hairpin sets), wherein each of the first plurality of decoding oligonucleotides comprises: (i) a different cleavable detectable moiety capable of generating a different signal (ie., a new hybridization complex comprising a bridge oligonucleotide and a different initiator sequence of a different hairpin set with a different fluorescent dye which is cleavable, see paragraphs [0076] to [0078]), (ii) a binding site that specifically hybridizes to one of the plurality of pre-decoding oligonucleotides, (iii) two or more binding sites that specifically hybridize to one of a second plurality of decoding oligonucleotides (ie., an initiator sequence of a hairpin set has two or more binding site for its complementary sequence of the hairpin set); and (iv) a cleavable linker positioned between (i) and (ii) (ie., a region of the different initiator sequence of the different hairpin set adjacent to the location of the fluorescent dye on the different initiator sequence), wherein the first plurality of decoding oligonucleotides are configured to be cleaved at the cleavable linker while allowing the binding site that specifically hybridizes to one of the plurality of pre-decoding oligonucleotides to remain hybridized; and c) the second plurality of decoding oligonucleotides (ie., complementary sequences of initiator sequences of hairpin sets, see paragraphs [0076] to [0078]), wherein each of the second plurality of decoding oligonucleotides comprises: (i) a different cleavable detectable moiety capable of generating a different signal (ie., a complementary sequence of a different initiator sequence of a different hairpin set with a different fluorescent dye which is cleavable, see paragraphs [0076] to [0078]); (ii) a binding site that specifically hybridizes to one of the first plurality of decoding oligonucleotides; and (iii) a cleavable linker positioned between (i) and (ii) (ie., a region of the complementary sequence of the different initiator sequence of the different hairpin set adjacent to the location of the fluorescent dye on the complementary sequence of the different initiator sequence), wherein the second plurality of decoding oligonucleotides are configured to be cleaved at the cleavable linker while allowing the binding site that specifically hybridizes to one of the first plurality of decoding oligonucleotides to remain hybridized as recited in claim 10 wherein the detectable moiety is selected from the group consisting of a fluorophore, radioactive isotope, and metal isotope as recited in claim 11, the plurality of pre-decoding oligonucleotides, the first plurality of decoding oligonucleotides, and the second plurality of decoding oligonucleotides are selected from the group consisting of DNA oligonucleotides, RNA oligonucleotides, peptide nucleic acid (PNA) oligonucleotides, locked nucleic acid (LNA) oligonucleotides, peptide nucleic acids (PNAs), and modified oligonucleotides as recited in claim 12, and written instructions for using the plurality of pre-decoding oligonucleotides and the first plurality of decoding oligonucleotides, and the second plurality of decoding oligonucleotides to detect target transcripts or genomic loci as recited in claim 13 (see paragraphs [0006] to [0038], [0061], [0076] to [0078], [0083] to [0093], [0096] to [0099], [0104] to [0111], [0122], [0147] to [0155], [0174], [0206], [0209], [0235], [0238], [0240], [0255], [0258], [0260], [0266], [0286], [0292], [0310], and [0311], claims 1-81, and Figures 1, 15, and 21-23).
Cai et al., do not disclose the kits recited in claims 10-13. However, Cai et al., teach a kit comprising a plurality of detectably labeled oligonucleotides (see claims 1-19, 58, and 59).
1988 Stratagene catalog teaches a motivation to combine reagents into a kit format (page 39).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have made the kits recited in claims 10-13 by putting the plurality of pre-decoding oligonucleotides, the first plurality of decoding oligonucleotides, the second plurality of decoding oligonucleotides, and the written instructions for using the plurality of pre-decoding oligonucleotides and the first plurality of decoding oligonucleotides, and the second plurality of decoding oligonucleotides to detect target transcripts or genomic loci taught by Cai et al., into a kit format in view of the prior arts of Cai et al., and 1988 Stratagene. One having ordinary skill in the art would have been motivated to do so because the Stratagene catalog teaches a motivation for combining reagents of use in an assay into a kit, “[E]ach kit provides two services: 1) a variety of different reagents have been assembled and pre-mixed specifically for a defined set of experiments. 2) The other service provided in a kit is quality control” (page 39, column 1).
Response to Arguments
In page 4, third paragraph bridging to page 5, second paragraph of applicant’s remarks, applicant argues that “[W]ithout acquiescing to the rejection, and solely to facilitate prosecution, claim 10 is amended to recite that the first and second pluralities of decoding oligos comprise a cleavable linker positioned between the cleavable detectable moiety and the binding site that hybridizes to the other set of decoding oligos, wherein the decoding oligos are configured to be cleaved at the cleavable linker while allowing the binding site to remain hybridized. Neither Cai nor Stratagene disclose a kit comprising decoding oligos having these features. In Cai, the oligos do not comprise cleavable linkers that can be cleaved to remove the signal. Rather the entire oligos (‘bridging strands’) are digested and removed from the target strand to eliminate the signal. See, e.g. Cai at FIG. 21 and paragraph [0076]. As described in the present application, since the claimed system provides visualization of genomic loci or transcripts as single detectable signals that remain in place during consecutive hybridization, it allows for varied signal profiles that increase exponentially with each hybridization cycle, enabling rapid, high-throughput genome or transcriptome-wide analysis. See, e.g. Specification at paragraph [0005]. Stratagene merely discloses combining reagents for ‘gene characterization’ in a kit, and also does not disclose a kit with oligos having the claimed features. Therefore, Applicant submits that claims 10-13 are not unpatentable over Cai and Stratagene”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection because Cai et al., teach a cleavable linker positioned between (i) and (ii) (ie., a region of the different initiator sequence of the different hairpin set adjacent to the location of the fluorescent dye on the different initiator sequence) wherein the first plurality of decoding oligonucleotides are configured to be cleaved at the cleavable linker while allowing the binding site that specifically hybridizes to one of the plurality of pre-decoding oligonucleotides to remain hybridized as recited in b) of claim 10 and a cleavable linker positioned between (i) and (ii) (ie., a region of the complementary sequence of the different initiator sequence of the different hairpin set adjacent to the location of the fluorescent dye on the complementary sequence of the different initiator sequence) wherein the second plurality of decoding oligonucleotides are configured to be cleaved at the cleavable linker while allowing the binding site that specifically hybridizes to one of the first plurality of decoding oligonucleotides to remain hybridized as recited in c) of claim 10 (see above rejection under 35 U.S.C 103).
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al., in view of 1988 Stratagene catalog as applied to claims 10-13 above, and further in view of Davies et al., (US 2003/0143591 A1, published on July 31, 2003) and Samusik et al., (US 2015/0368697 A1, priority date: June 23, 2014).
The teachings of Cai et al., and 1988 Stratagene catalog have been summarized previously, supra.
Cai et al., and 1988 Stratagene catalog do not disclose that the detectable moiety is attached to the first plurality of decoding oligonucleotides and the second plurality of decoding oligonucleotides through a chemically cleavable linker as recited in claim 14 and the cleavable linker and the detectable moiety comprises an NHS ester functionalized cleavable tetramethylrhodamine and the kit further comprises TCEP as recited in claim 15.
Davies et al., teach to covalently attach a dye, TAMRA, to a nucleic acid probe by a chemical linker wherein TAMRA is a NHS ester carboxytetramethylrhodamine dye (see paragraphs [0080], [0188] and [0255]).
Samusik et al., teach to use TCEP as a cleaving reagent for cleaving fluorophore linking to a nucleotide through a cleavage linker (see paragraphs [0083] and [0094]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have made the kits recited in claims 14 and 15 comprising TCEP wherein the detectable moiety is attached to the first plurality of decoding oligonucleotides and the second plurality of decoding oligonucleotides through a chemically cleavable linker and the cleavable linker and the detectable moiety is an NHS ester functionalized cleavable tetramethylrhodamine in view of the prior arts of Cai et al., 1988 Stratagene, Davies et al., and Samusik et al.. One having ordinary skill in the art would have been motivated to do so because Cai et al., teach that labels of the present invention is or comprise one or more fluorescent dyes, including but not limited to fluorescein, rhodamine, Alexa Fluors, DyLight fluors, ATTO Dyes, or any analogs or derivatives thereof (see paragraph [0096]), Davies et al., teach to covalently attach a dye, TAMRA, to a nucleic acid probe by a chemical linker wherein TAMRA is a NHS ester carboxytetramethylrhodamine dye (see paragraphs [0080], [0188] and [0255]), and Samusik et al., teach to use TCEP as a cleaving reagent for cleaving fluorophore linking to a nucleotide through a cleavage linker (see paragraphs [0083] and [0094]). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to make the kits recited in claims 14 and 15 by attaching both the first plurality of decoding oligonucleotides and the second plurality of decoding oligonucleotides with a TAMRA dye through a chemically cleavable linker and putting labeled first plurality of decoding oligonucleotides, labeled second plurality of decoding oligonucleotides and TECP to the kit recited in claim 10 in view of the prior arts of Cai et al., 1988 Stratagene, Davies et al., and Samusik et al., such that one having ordinary skill in the art at the time the invention is able to use the first plurality of decoding oligonucleotides labeled with a TAMRA, the second plurality of decoding oligonucleotides labeled with a TAMRA dye and TECP when he or she performs an assay.
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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
February 5, 2026