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 Application
The Response filed October 13, 2025 is acknowledged.
Claims 1-19 and 21-27 were pending. Claims 1-11, 13, 17-19, 21-26 and new claims 98-100 are being examined on the merits. Claims 12, 14-16 and 27 remain withdrawn.
Response to Arguments
Applicant’s arguments filed October 13, 2025 has been fully considered.
The following rejections are WITHDRAWN in view of the instant claim amendments:
Rejection of claim 21 under 35 USC § 112(b), indefiniteness
Prior Art rejections
Response to arguments regarding prior art rejections
The prior art rejections of record are withdrawn in view of the instant amendments to the claims. The Examiner agrees with Applicant’s position that the primary reference, Zhu, does not teach or suggest all of the limitations of, in particular, independent claim 1, as amended, and that the secondary references do not remedy those deficiencies (Remarks, pp. 7-8).
Information Disclosure Statements
The Information Disclosure Statements submitted August 1, 2025 and October 13, 2025 have been considered.
Claim Objections
Claim 98 is objected to because of the following informalities:
In claim 98, the limitation “the bound from …” in the last line should be “the bound
probe from …” .
Appropriate correction is required.
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 1-11, 13, 17-19, 21-23, 26 and 98-100 are rejected under 35 U.S.C. 103 as being unpatentable over Aksel (US Patent App. Pub. No. 2022/0162684 A1) in view of Zhu1 (US Patent App. Pub. No. 2016/0060687).
Regarding independent claim 1, Aksel teaches …
A method of detecting a first reaction, comprising: (a) providing immobilized on a solid support containing a plurality of sites: (i) a plurality of analytes, each site of the plurality of sites containing only one immobilized analyte of the plurality of analytes, and each site of the plurality of sites is an optically resolvable distance from any other site of the plurality of sites (Fig. 8: 830 – one analyte, indirectly immobilized to the solid support, 870, via an anchoring group, 840; para. 548 also teaches an embodiment where the analyte is directly attached to the solid support; paras. 21, 25, 32, 264, 369, 404, 538, 542);
and (ii) a plurality of first reactants, each site of the plurality of sites containing a first reactant of the plurality of first reactants, and each first reactant of the plurality of first reactants being immobilized on the solid support within a first distance from an analyte of the plurality of analytes (Fig. 8: 850 – one first reactant, which, optionally, may be directly attached to an immobilized to the solid support, 870; paras. 21, 25, 32, 264, 369, 404, 538, 542);
(b) contacting the solid support comprising the immobilized analytes with a plurality of probes, each probe individually comprising an affinity reagent attached to a detectable label and a second reactant, the affinity reagent having binding specificity for an analyte of the plurality of analytes, and the second reactant being capable of a second reaction with the first reactant when within a second distance from the first reactant (Fig. 8: a probe which comprises an affinity reagent and a detectable label, 810, and a second reactant, 820; paras. 21, 25, 32, 264, 369, 404, 538, 542);
(c) forming a first reaction between the analyte of the plurality of analytes and an affinity reagent of a probe of the plurality of probes at a site of the plurality of sites, thereby bringing the second reactant within the second distance of the first reactant; (d) forming the second reaction between the first reactant and the second reactant (Fig. 8: forming a first reaction between 810 and 830, forming a second reaction, 860, between 820 and 850; paras. 21, 25, 32, 264, 369, 404, 538, 542);
and (e) detecting at single-analyte resolution an optical signal emitted from the detectable label of the probe at the site of the plurality of sites, thereby detecting a presence of a bound probe comprising the affinity reagent attached to the detectable label at the site of the plurality of sites (Fig. 8; paras. 21, 25, 32, 264, 369, 404, 405, 535, 538, 542, 559).
Aksel does not teach that the second reaction is formed after the first reaction. Rather, Aksel is silent as to which reaction is formed first. However, Zhu teaches this limitation (Example 3; Figs. 4A-B; Fig. 1A).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Aksel method to form the second reaction after the first reaction is formed, as taught by Zhu. The ordinary artisan would understand that there are only two options for the timing of the first reaction and the second reaction (i.e., either the first reaction occurs first in time, or the second reaction occurs first in time). It would have been obvious to try the two timing options and arrive at the former option to customize the assay as needed through routine optimization, and because Zhu teaches that such a method can be designed so that the first reaction is formed first. Further, MPEP 2144.04 (IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”. The ordinary artisan would have had an expectation of success as the design and modification of analyte detection assays is known in the art, and because Aksel and Zhu teach that the assay components can be arranged in a variety of different ways.
Regarding dependent claims 2-4, Aksel additionally teaches that the first distance is an optically non-resolvable distance between the analyte and the first reactant (para. 21: “two or more label components of a detectable probe or affinity reagent can provide overlapping indistinguishable signals”), as recited in claim 2. In addition, as recited in claims 3-4, Aksel teaches or suggests that the first distance is less than 300 nm, or optionally, less than 50 nm, respectively. Specifically, Aksel teaches the ranges of 500 nm or less, 50 nm or less, etc. (para. 235). When a claimed range lies inside a range disclosed by the prior art, a prima facie case of obviousness exists. MPEP 2144.05(I).
Regarding dependent claims 5-6 and 8-9, as noted above, Aksel teaches the distance between some components. Aksel additionally provides guidance on the spacing of various components (paras. 19, 21, 22, 192, 231, 235, 239, 282, 296-298, 300-302, 412-413). Zhu also provides various guidelines on how to prepare such arrays, including the density of features (e.g., paras. 423-430). The references do not specifically teach the length of the second distance or the length of the linker. However, the ordinary artisan can derive appropriate lengths through routine optimization for the second distance and the linker based on the physical constraints imposed by the distance between the analyte and first reaction.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Aksel method and array, discussed above, with the distances and lengths of various array features and components, according to the additional teachings of Aksel combined with Zhu. The ordinary artisan would have been motivated to customize the arrangement of the array through routine optimization with the expectation that doing so would result in the advantage of an efficient and cost-effective array. The ordinary artisan would have had an expectation of success as ordering elements on an array is well-known in the art.
Regarding dependent claim 7, Aksel additionally teaches that the probe comprises a linker which couples the affinity reagent to the second reactant (paras. 317, 417, 443).
Regarding dependent claims 10-11, Aksel additionally teaches that the second reaction comprises a non-covalent binding reaction (Figs. 8 and 9A-B; paras. 35, 369, 370), as recited in claim 10, that the first and second reactants comprise first and second oligonucleotides, respectively (Figs. 8 and 9A-B; paras. 35, 369, 370), as recited in claim 11.
Regarding dependent claims 13, 22-23 and 26, Zhu additionally teaches that the non-covalent binding interaction comprises hybridizing the first and second oligonucleotides to a third oligonucleotide (Example 3; Figs. 4A-B; Fig. 1A), as recited in claim 13, and binding a bridging molecule to the first reactant and the second reactant (Example 3; Figs. 4A-B; Fig. 1A), as recited in claim 22, that the bridging molecule brings the second reactant with the second distance of the first reactant (Example 3; Figs. 4A-B; Fig. 1A), as recited in claim 23, and that the bridging molecule non-covalently binds to the first and second reactants (Example 3; Figs. 4A-B; Fig. 1A), as recited in claim 26.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Aksel method and array, discussed above, to incorporate a bridging molecule as taught by Zhu. The ordinary artisan would have been motivated to do so with the expectation of achieving the advantage of a method with more flexibility than the modified Aksel method. For example, addition of a bridging molecule would allow for additional flexibility in detecting the first and second oligonucleotides (i.e., the bridging molecule itself could be detectably labeled), or it would permit brining the first and second oligonucleotides into proximity with one another such that the ends could be ligated and PCR could be performed across the ligation junction. The ordinary artisan would have had an expectation of success since Zhu teaches the use of such bridging molecules (i.e., splints) in assays with similar components.
Regarding dependent claims 17-19, Aksel additionally teaches that forming the second reaction comprises forming a photon transfer reaction (paras. 80-81, 192, 270, 398, 400), as recited in claim 17, that detecting the presence of the bound probe comprises detecting a photon from the photon transfer reaction (paras. 80-81, 192, 270, 398, 400), as recited in claim 18, and that the first and second reactants comprise first and second fluorescent labels, respectively, and that that the first and second fluorescent labels form a FRET interaction (paras. 80-81, 192, 270, 398, 400), as recited in claim 19.
Regarding dependent claim 21, Aksel additionally teaches that detecting the presence of the bound probe comprises detecting a signal from the detectable label (Fig. 8; para. 21).
Regarding dependent claim 98, Aksel additionally teaches that after detecting the optical signal, the bound probe is dissociated from the analyte (paras. 305, 369, 370, 570).
Regarding dependent claims 99-100, Aksel additionally teaches that a plurality of particles is immobilized on the plurality of sites, wherein each site of the plurality of sites is attached to a single particle of the plurality of particles, and wherein the only one immobilized analyte attached to each site of the plurality of sites is attached to the single particle (Fig. 8, anchoring group (840); paras. 369, 407, 417: anchoring group is, e.g., a nucleic acid, a chemical linker), as recited in claim 99, and that a particle of the plurality of particles comprises a nucleic acid particle, an organic particle or an inorganic particle (Fig. 8, anchoring group (840); paras. 369, 407, 417: anchoring group is, e.g., a nucleic acid, a chemical linker), as recited in claim 100.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Aksel (US Patent App. Pub. No. 2022/0162684 A1) in view of Zhu (US Patent App. Pub. No. 2016/0060687), as applied to claims 1 and 22 above, and further in view of Costa2 (US Patent App. Pub. No. 2024/0026448; effective filing date: June 1, 2022).
Regarding dependent claims 24-25, Zhu teaches a bridging molecule (Example 3; Figs. 4A-B; Fig. 1A). Costa teaches that the bridging molecule comprises a detectable label, and also teaches detecting the signal from the detectable label (paras. 50-54, 146, 301).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the bridging molecule in the modified Aksel method and array, discussed above, with a detectable label, according to Costa. The ordinary artisan would have been motivated to customize the detection mechanism and the corresponding detectable labels on the array through routine optimization with the expectation that doing so would result in the advantage of an efficient and cost-effective array. The ordinary artisan would have had an expectation of success as substituting detection mechanisms on an array is well-known in the art.
Conclusion
Claims 1-11, 13, 17-19, 21-26 and 98-100 are being examined, and are rejected. Claim 98 is objected to. No claims are allowed.
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.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681
1 Zhu was cited in the PTO-892 Notice of References Cited mailed January 3, 2025.
2 Costa was cited in the PTO-892 Notice of References Cited mailed January 3, 2025.