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 .
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.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2021/038463, filed 06/22/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application Nos. 63/076,833, filed 09/10/202 and 63/042,596, filed 06/23/2020.
Status of the Claims
Claims 1, 2 and 4-21 are pending; claims 1 and 4 are amended; claims 17-21 are newly recited, no claims are withdrawn. Claims 1, 2, and 4-21 are examined below.
Information Disclosure Statement
The information disclosure statement (IDS) filed 02/13/2026 is considered, initialed and is attached hereto.
Withdrawn Objections/Rejections
The previous rejection of claims under 35 U.S.C. 103 is withdrawn in response to Applicant’s amendments to the claims; see new grounds set forth in detail below in response to the amendments.
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.
Claim(s) 1, 3-6, 8-10 and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kingsmore et al., US PG Pub No. 2006/0166227A1 in view of Fischer et al., Emerging technologies to increase ligand binding assay sensitivity, The AAPS Journal, 17(1), (2015), pages 93-101 and Rissin et al., Single molecule enzyme linked immunosorbent assay detects serum proteins at subfemtomolar concentrations, Nature Biotechnology, 28(6), (2010), p. 595-600 (IDS entered 05/08/2023).
Kingsmore et al. teach for example, methods comprising solid support that is a magnetic bead modified with a capture antibody, further capture target (IgE) (providing sample, contacting beads with capture moiety with the sample containing the biomolecule analyte (IgE) for time sufficient to bind), and detecting using an immunoRCA conjugate (para [0430] (anti-IgE-DNA conjugate contacted with the captured analyte), see also para [438], describing a format comprising biotinylated anti-human-IgE antibody and anti-biotin antibody conjugated to an oligonucleotide containing an RCA-priming sequence, thereby also addressing methods comprising contacting with solution with a binding moiety (the second detection antibody), then contacting with signal amplification moiety (the anti-biotin antibody conjugated to an oligonucleotide containing RCA priming sequence to allow for generation of an on bead non-diffusible detectable signal for detection of each bead.
Kingsmore et al. teaches a method substantially as claimed however fails to teach immobilizing the beads prior to detecting the signal.
Fischer et al. teach introduction of bead-based methods, coupled with single molecule detection standardization and the ability to amplify assay signals, has improved the sensitivity of many immunoassays, in some cases by several logs of magnitude (abstract). Fischer review, for example, single molecule array technology (Simoa™-based digital ELISA, see page 96, end of col. 1), a technique that involves capture in a sandwich binding format (similar to above), followed by immobilization (for example in an array of microwells) for detection. See specifically Fischer indicating this as a technique capable of femtogram per milliliter level detection, the assay using paramagnetic bead based immunoassay coupled with unique signal detection and data acquisition system, Fischer describe the technique as comprising antigen capture using microscopic beads coupled with capture reagent, followed by addition of detection antibody, the beads in solution then loaded into femtoliter sized microwells. Fischer teach (page 96, col. 2), that the Simoa™ detection system allows the detection of a single binding event, which can be acquired digitally at low concentration (improved sensitivity; digital ELISA) or in analog mode at high concentration (improved assay dynamic range).
Referring to single molecule array technology, Fischer cites Rissin et al., the more details provided at Rissin et al. teach a method with the ability to detect single protein molecules, teaching such detection could accelerate the discovery and use of more sensitive biomarkers (abstract). Rissin teach their method uses arrays of femtoliter sized reaction chambers (SiMoAs) to isolate and detect (page 595, col. 2, para 2), their method comprising a sandwich binding format (similar to Kingsmore above), followed by immobilization (for example in an array of microwells) for detection (see col. 2, para 2). Rissin teach their single molecule technique allows detection at extremely low concentration (also col. 2, para 2).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kingsmore et al. in order to further introduce an immobilization step (for example, immobilized the bead captured, amplified product at individual wells as in Fischer’s description of Simoa™-based digital assays) in order to achieve single-molecule detection, the art recognized bead based methods coupled with single molecule standardization and ability to amplify signals as recognized improvements to detection in the assay art. Further one having ordinary skill in the art would have been motivated to modify as indicated above because Rissin et al. teach such single molecule capture and detection as allowing the ability to detect even at extremely low concentrations, the ability to detect at the single molecule level having the potential to accelerate the discovery and use of more sensitive biomarkers.
One having ordinary skill in the art would have a reasonable expectation of success because similar to that technique described in Fischer, Kingsmore et al. is also teaching a bead based capture technique which operates on the principal of capture in a sandwich binding format. Kingsmore’s method is a relative detection method, and given the teaching of Fischer, modifying it in order to detect at the single molecule level would be considered an advantage, particular considering Kingsmore also teaches amplification of signal using RCA.
Regarding claim 4 and 9, the method of Kingsmore et al. comprises contacting with a signal amplification moiety (antibody conjugate having rolling circle amplification primer corresponding to template containing the DNA enzyme complementary sequence).
Regarding claim 5, Kingsmore teach fluorescent signal (see paras [0011], [0058], [0059], [0107], [0108], [0109], [0114]).
Regarding claim 6, Kingsmore et al. as modified by Fischer comprises detecting individual (the number of) beads.
Regarding claim 8, Kingsmore et al. is teaching detectable signal by RCE followed by hybridization with a complementary fluorescently labeled DNA.
Regarding claim 10, the claim recites “wherein the pre-amplified signal is a labeled polymer or nanoparticle”, see the combination of the cited art teaches magnetic nanoparticle, and conjugate comprises a polymer (polymeric sequence).
Regarding claim 16, Kingsmore et al. teach hybridization with fluorescently labeled DNA probe (cited above, including para [0011], [0031], [0052], [0059]).
Regarding claims 17 and 20, see as cited above, Kingsmore and the cited art address RCA and hybridization with complementary fluorescently labeled DNA probe.
Regarding claim 18, although Kingsmore (cited above) teaching biotin and anti-biotin antibody, see also para [0113], Kingsmore also teach other molecules for using detecting any of the TS-DNA products, including ligand binding molecules such as avidin. See also para [0098], the prior art recognized avidin-biotin as a known attachment agent combination (see also para [0110], biotin-streptavidin is an art recognized binding pair). It would have been further obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the example of Kingsmore (the example relying on biotin-anti-biotin binding) to instead rely on biotin-avidin binding (also taught by Kingsmore) as a simple substitution of one known biotin binding partner for another, both recognized in the prior art for the purpose of linking detection antibody to signal producing labeling system. Specifically, the prior art recognized both anti-biotin and avidin as suitable binding partner for biotin (biotinylated antibody reagent). One having ordinary skill would have a reasonable expectation using avidin in place of anti-biotin since both are known to bind biotin.
Regarding claim 19, see as cited above, detecting biomolecule that is IgE (a protein).
Regarding claim 21, the combination of the cited art addresses claim 21 for the same reasons as discussed above (detecting at the single molecule level addressing “allowing detection of each bead carrying the protein”).
Claim(s) 2, 12, 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Kingsmore et al., in view of Fischer et al. and Rissin et al., ad applied to claim 1 above, and further in view of Wassie et al., Expansion microscopy: principles and uses in biological research, Nature Methods, 16, (2019), p. 33-41 and Gao, et al. US PG Pub No. 2019/0256633A1.
Kingsmore et al. and the cited prior art teach a method substantially as claimed, but fails to teach the immobilizing comprising catalyzing gelation of the solution (claim 2); fails to teach the solution applied to or in contact with a surface and gelation catalyzed before signal is detected (claim 12).
Wassie et al. teach embedding specimens in hydrogel material for optical microscopy (e.g., page 33, col. 1, para 1). See further page 35, col. 1, para 2, the technique of Wassie enables nanoscale imaging with commonly available microscopes, the technique compatible with a variety of biomolecules, including proteins and RNA with existing labels or stains. Wassie also teach their method compatible with amplification chemistries (page 38, col. 2, para 2, including RCA, see col. 2, para 3). Wassie teach specimens are immersed in monomer solution (containing sodium acrylate) that reacts with free radical polymerization for form a densely cross-linked (gelation) hydrogel (sodium polyacyrylate, page 33, col. 2, para 2), the material then swelled. Wassie et al. teach additional advantages to the use of their hydrogel material include that the final product is mostly water, and as such transparent, with nearly 100% light transmission through even thick specimens, that it accommodates very fast imaging modalities, and since it is compatible with many biomolecules including proteins and RNA with existing labels/stains, it can push many already existing techniques into the super-resolution realm.
Regarding expansion microscopy comprising embedding targeted analytes (para [0003],biomolecules, including proteins, nucleic acids, etc. para [0080]) in hydrogel, as in Wassie, see also Gao et al., teach detail regarding the process, immersing specimens, placed on glass slide in solution, initiating polymerization, imaging/detecting signal (e.g., paras [0015]- [0019], [0148]).
It would have been further prima facie obvious to one having ordinary skill in the art to have modified the method as taught by Kingsmore et al. in view of Fischer and Rissin, detecting captured amplified analyte at the single molecule level, to have applied the technique as taught by Wassie and Gao et al., namely the method of encasing the targeted analyte in a hydrogel (a solution that undergoes catalyzing gelation), because this technique is a known technique that affords nanoscale imaging, and is compatible with targets including those of Li et al. (Wassie). The modification would be an obvious matter of substituting one art recognized technique for visualizing individual captured molecules for another, both recognized in the prior art as suitable techniques for single molecule analysis (nanoscale microscopy), one of ordinary skill further motivated to rely on this manner of immobilization because it affords super-resolution detection (Wassie).
One having ordinary skill in the art would have a reasonable expectation of success because Wassie and Gao recognize it as a technique not only applicable to specimens that are tissue, but also proteins and RNA (Wassie, Gao).
Claim(s) 2, 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kingsmore et al. in view of Fischer et al. and Rissin et al., as applied to claim 1 above, and further in view of Schweitzer et al., Immunoassays with rolling circle DNA amplification: A versatile platform for ultrasensitive antigen detection, 97(18), (2000), p. 10113-10119 and Li et al., An ultrasensitive flow cytometric immunoassay based on bead surface-initiated template free DNA extension, Chem. Sci, 9, (2018), p. 6605-6613.
Regarding claim 2, Kingsmore et al. and the combination of the cited art teach a method substantially as claimed, however, fails to teach regarding immobilizing RCA based microparticle assays, immobilizing on a solid support by dropcasting the solution comprising the beads onto a slide (claim 3); and fails to teach the dropcast solution allowed to dry (claim 11) before signal is detected; and further fails to teach the surface is for example, a slide (claim 13).
Schweitzer et al. teach applying RCA for the purpose of ultrasensitive detection (RCA as in Li et al. above). Like Li et al. (CN107236795A), Schweitzer et al. similarly review magnetic bead based immunoassay, using binding partner coated magnetic beads to bind and capture analyte, using an immunoRCA conjugate for detection (page 10114, col. 2, para 2). Distinct from magnetic bead immunoassay, Schweizer teach alternatively using microspots (glass slides having hand spotted arrays for capturing target, page 10114, last paragraph to page 10115) and microarrays on glass slides for capture (performing immunoRCA directly on the slides, page 10115, col. 1, para 4 to col. 2), both techniques comprising dried slides prior to signal detection (prior to imaging), see also page 10115, col. 2, para 4 and Figure 5.
Schweitzer et al. teach (abstract) that immunoRCA enables microspot/microarray formats (detection, dried on glass slides as summarized above) with exquisite sensitivity.
See also Li et al., (2018), Li (2018) is an example in the art of demonstrating how to obtain magnetic bead captured analyte for imaging/detection, at page 6607, col. 1, para 4, Li refer to dropping (i.e., dropcasting) the solution on a glass slide substrate in order to collect images.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified Kingsmore et al. and the cited prior art (comprising microwell detection), to have instead immobilized solution containing RCA conjugate captured analyte on a glass slide (as in Schweitzer et al.), by way dropcasting and drying the solution (as in Li (2018)), one of ordinary skill motivated to rely on a slide for individual detection by imaging because Schweitzer specifically teach the RCA amplification technique as specifically enables slide based visualization capture assays (e.g., microspots/microarray, having captured conjugate immobilized at the surface of a glass slide) to be performed with exquisite sensitivity (i.e., imaging the amplified product on a slide). The modification additionally considered an obvious matter of one known substrate suitable for detection of the amplified signal for another (i.e., glass slide in place of microwell of a disc, i.e., assay chip), specifically the prior art teaching RCA technique applicable for detection at either substrate (thereby also attributing to a reasonable expectation of success).
Even further, one would have been motivated to have provided the bead based captured and amplified target to the glass slide by way of dropcasting and drying prior to signal detection (imaging), because the prior art specifically demonstrate that by dropping solution and drying magnetic bead captured target on a glass slide surface, one is able to visualize the dispersed captured target via imaging (Li (2018). The modification would have been an obvious matter of applying a known technique to a known method, as the prior art contained the base method (as taught by Kingsmore et al., primary reference cited above, comprising bead based RCA capture and detection, this further supported as being a method known to those skilled in the art, as acknowledged in the teaching of Schweitzer et al., teaching magnetic bead capture utilizing amplification by RCA). The prior art further contained the known technique for immobilizing magnetic particle captured target on a glass slide (namely, by dropcasting bead captured analyte, i.e., dropcasting, as supported by Li (2018), the prior art also teaching captured target analyte on a glass slide is known to be dried prior to imaging, (see Schweitzer et al.). One having ordinary skill would have been motivated to apply these modifications in order to achieve ultra-sensitive detection for the reasons as discussed previously above.
One having ordinary skill in the art would have a reasonable expectation of success modifying to detect on a slide rather than the microwells as in the original combination of cited references, because one would still expect to detect on the single molecule/nanoscale level, so the benefit of detecting at this level rather than relative amounts would be maintained, one merely substituting the substrate on which the captured analytes are separated for imaging.
Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kingsmore et al. in view of Fischer et al., and Rissin et al., as applied to claim 1, and further in view of Maldonado-Camargo et al., Magnetic characterization of iron oxide nanoparticles for biomedical applications, Methods Mol. Biol., 1570, (2017), 27 pages.
Kingsmore et al. and the cited art teach a method substantially as claimed (see as cited above).
Although Kingsmore et al. (primary reference) teach magnetic nanoparticles, the reference fails to teach the material of the magnetic particles, and as such fails to teach comprising polymer, metal, metal-oxide, semiconductor and/or semiconductor oxide (claim 7).
Maldonado-Camargo et al. teach iron oxide nanoparticles are of interest in a wide range of biomedical applications due to their response to applied magnetic fields and their unique magnetic properties (abstract). See for example, page 1, paragraph 1, iron oxide magnetic nanoparticles have been widely used, for example due to the capability of manipulating particle motion.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have relied on iron oxide (metal oxide) nanoparticles as the magnetic nanoparticles of Kingsmore et al., one motivated to rely on iron oxide as an obvious matter of applying a known material for its intended purpose (it was known that iron oxide particles are favorable magnetic particles, e.g., see Maldonado-Camargo cited above). One having ordinary skill in the art would have had a reasonable expectation of success using a known material for its intended purpose (it was known that iron oxide nanoparticles are magnetic nanoparticles), and further one would reasonably expect success because Kingsmore et al. (primary reference) does not particularly limit their magnetic nanoparticles to any particular composition species.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-2, 4-6, 8, 9 and 16-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/618,019 (reference application) in view of Li et al. (2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Regarding claim 1, see ‘019 similarly recites a method of detecting a biomolecule in a sample (see for example ‘019 at claim 7), the method comprising: providing a solution comprising the sample; contacting the sample with a plurality of beads comprising a capture moiety that binds to the biomolecule, under conditions and for a time sufficient for biomolecules in the sample to bind to the capture moiety (claim 1 of ‘019); contacting the solution with a binding moiety that binds to the biomolecule, followed by contacting with signal amplification moiety that binds to the binding moiety and allows for generation of an on-bead non-diffusible detectable signal sufficient to allow detection of each bead carrying a target molecule (claims 1 and 2 of ‘019), and then generating the amplified signal (also claims 1 and 2 of ‘019).
‘019 differs from that which is claimed in that ‘019 recites detecting the detectable signal by flow cytometry rather than the claimed step of immobilizing and then detecting the signal.
However, see the cited art in detail previously above, namely Li et al. (2018), who recognize rolling circle amplification as a prominent art recognized technique to increase sensitivity of an immunoassay (page 6606, col. 1, para 3). Li et al. demonstrate the ability to sensitively detect nucleic acid amplified signal using flow cytometry; however, see also by imaging (e.g., Figure 2, corresponding fluorescence image). See page 6607, col. 1, para 4, fluorescence images performed on glass slides.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified ‘019 in order to image the captured conjugate having amplified signal on glass slides (immobilized on a glass slide, thereby also addressing present claim 2, followed by detecting signal) alternative to flow cytometry for detection as a simple substitution of one known detection technique for another, both recognized in the art as suitable for detecting a detectable label, particularly applicable to systems comprising amplification (amplification by nucleic acid extension techniques). One having ordinary skill in the art would have a reasonable expectation of success because Li (2018) demonstrate achieving detection of conjugate both ways (via cytometry and imaging).
Regarding claim 2, the combination of the cited art teaches dropcasting, see Li (2018) is an example in the art of demonstrating how to obtain magnetic bead captured analyte for imaging/detection, at page 6607, col. 1, para 4, Li refer to dropping (i.e., dropcasting) the solution on a glass slide substrate in order to collect images.
Regarding claim 4, see ‘019 at claim 2 (further addresses amplification comprising enzyme).
Regarding claims 5-6, the combination of the cited art above addresses the claim (contacting with signal amplification solution, imaging to detect signal, determining the individual captured target conjugates).
Regarding claim 8, see ‘019 at claim 2.
Regarding claims 9 and 10, see ‘019 similarly teach binding nanoparticle.
Regarding claim 16, based on the citation of Li et al. (2018) (which show immobilized particle/bead-analyte conjugate), dropcasting solution of bead captured analyte on a slide results in monolayer level thickness of particle (see individual particles, Figure 2). Further, given that the combination of the cited art is teaching dropcasting to deposit and provide the immobilized bead captured target (technique that is not distinguishable from the claims), it would be expected that the technique achieve the same result (i.e., monolayer deposition).
Regarding claim 17, see copending claim 2 RCA followed by hybridization with complementary fluorescently labeled DNA.
Regarding claim 18, see copending claims 3 and 4 (reciting biotin-streptavidin).
Regarding claim 19, see copending claim 7 (protein as the biomolecule).
Regarding claim 20, see as cited above (including copending claims 1-2).
Regarding claim 21, see copending claim 1 cited above.
Claim 7 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/618,019 (reference application) in view of Li et al. (2018), as applied to claim 1, and further in view of Maldonado-Camargo.
Regarding claim 7, ‘019, although ‘019 recites bead that is magnetic bead, ‘019 fails to teach the species of bead, and as such fails to teach polymer, metal, metal-oxide, semiconductor, and/or semiconductor oxide
Maldonado-Camargo et al. teach iron oxide nanoparticles are of interest in a wide range of biomedical applications due to their response to applied magnetic fields and their unique magnetic properties (abstract). See for example, page 1, paragraph 1, iron oxide magnetic nanoparticles have been widely used, for example due to the capability of manipulating particle motion.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have relied on iron oxide (metal oxide) nanoparticles as the magnetic nanoparticles of Li et al., one motivated to rely on iron oxide as an obvious matter of applying a known material for its intended purpose (it was known that iron oxide particles are favorable magnetic particles, e.g., see Maldonado-Camargo cited above). One having ordinary skill in the art would have had a reasonable expectation of success using a known material for its intended purpose (it was known that iron oxide nanoparticles are magnetic nanoparticles), and further one would reasonably expect success because Li et al. (primary reference) does not particularly limit their magnetic nanoparticles to any particular composition species.
Claims 11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/618,019 (reference application) in view of Li et al. (2018), as applied to claim 1, and further in view of Schweitzer et al.
Regarding claim 2, ‘019 and Li et al. (2018) teach a method substantially as claimed, further see also Li et al., (2018) is an example in the art of demonstrating how to obtain magnetic bead captured analyte for imaging/detection, at page 6607, col. 1, para 4, Li refer to dropping (i.e., dropcasting) the solution on a glass slide substrate in order to collect images.
However, the combination of the cited art fails to teach the dropcast solution allowed to dry (claim 11) before signal is detected.
Schweitzer et al. teach applying RCA for the purpose of ultrasensitive detection (RCA as in Li et al. above). Like Li et al., Schweitzer et al. similarly review magnetic bead based immunoassay, using binding partner coated magnetic beads to bind and capture analyte, using an immunoRCA conjugate for detection (page 10114, col. 2, para 2). Distinct from magnetic bead immunoassay, Schweizer teach alternatively using microspots (glass slides having handspotted arrays for capturing target, page 10114, last paragraph to page 10115) and microarrays on glass slides for capture (performing immunoRCA directly on the slides, page 10115, col. 1, para 4 to col. 2), both techniques comprising dried slides prior to signal detection (prior to imaging), see also page 10115, col. 2, para 4 and Figure 5.
Schweitzer et al. teach (abstract) that immunoRCA enables microspot/microarray formats (detection, dried on glass slides as summarized above) with exquisite sensitivity.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified ‘019 in view of Li et al., to have dried the solution (the dropcast solution, as in Li (2018)), one would have been motivated to have provided the bead based captured and amplified target to the glass slide by way of dropcasting and drying prior to signal detection (imaging), because the prior art specifically demonstrate that by dropping solution and drying magnetic bead captured target on a glass slide surface, one is able to visualize the dispersed captured target via imaging (Li (2018)). The prior art further contained the known technique for immobilizing magnetic particle captured target on a glass slide (namely by dropcasting bead captured analyte, i.e., dropcasting, as supported by Li (2018), the prior art also teaching captured target analyte on a glass slide is known to be dried prior to imaging, (see Schweitzer et al.). One having ordinary skill would have been motivated to have applied this modification in order to achieve successful ultra-sensitive detection for the reasons as discussed previously above.
Claims 2, 12, 14 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/618,019 (reference application) in view of Li et al. (2018), as applied to claim 1, and further in view of Wassie et al., Expansion microscopy: principles and uses in biological research, Nature Methods, 16, (2019), p. 33-41 and Gao, et al. US PG Pub No. 2019/0256633A1.
‘019 in view of Li et al. (2018) teach a method substantially as claimed, but fail to teach the immobilizing comprising catalyzing gelation of the solution (claim 2); fails to teach the solution applied to or in contact with a surface and gelation catalyzed before signal is detected (claim 12).
Wassie et al. teach embedding specimens in hydrogel material for optical microscopy (e.g., page 33, col. 1, para 1). See further page 35, col. 1, para 2, the technique of Wassie enables nanoscale imaging with commonly available microscopes, the technique compatible with a variety of biomolecules, including proteins and RNA with existing labels or stains. Wassie also teach their method compatible with amplification chemistries (page 38, col. 2, para 2, including RCA, see col. 2, para 3). Wassie teach specimens are immersed in monomer solution (containing sodium acrylate) that reacts with free radical polymerization for form a densely cross-linked (gelation) hydrogel (sodium polyacyrylate, page 33, col. 2, para 2), the material then swelled. Wassie et al. teach additional advantages to the use of their hydrogel material include that the final product is mostly water, and as such transparent, with nearly 100% light transmission through even thick specimens, that it accommodates very fast imaging modalities, and since it is compatible with many biomolecules including proteins and RNA with existing labels/stains, it can push many already existing techniques into the super-resolution realm.
Regarding expansion microscopy comprising embedding targeted analytes (para [0003],biomolecules, including proteins, nucleic acids, etc. para [0080]) in hydrogel, as in Wassie, see also Gao et al., teach detail regarding the process, immersing specimens, placed on glass slide in solution, initiating polymerization, imaging/detecting signal (e.g., paras [0015]- [0019], [0148]).
It would have been further prima facie obvious to one having ordinary skill in the art to have modified the method as taught by ‘019 and Li et al. (2018), detecting captured amplified analyte at the single molecule level on a slide, to have instead applied the technique as taught by Wassie and Gao et al. for immobilizing for imaging, namely to have modified to instead use the method of encasing the targeted analyte in a hydrogel (a solution that undergoes catalyzing gelation), because this technique is a known technique that affords nanoscale imaging, and is compatible with targets including those of ‘019 in view of Li (Wassie). The modification would be considered substituting one art recognized technique for visualizing individual captured molecules for another, both recognized in the prior art as suitable techniques for single molecule analysis (nanoscale microscopy), one of ordinary skill further motivated to rely on this manner of immobilization because it affords super-resolution detection (Wassie).
One having ordinary skill in the art would have a reasonable expectation of success because Wassie and Gao recognize it is a technique not only applicable to specimens that are tissue, but also proteins and RNA (Wassie, Gao).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 06/02/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues (remarks page 6) that as amended, the claims require a two part binding architecture, (1) contacting with binding moiety that binds the biomolecule and (2) contacting the solution with a signal amplification moiety that binds the binding moiety. Applicant argues this is different than Li et al. (CN107236795A) because Li et al. is not a two part protocol, arguing that in Li et al. the signal probe directly hybridizes to the target DNA, the signal probe contains the RCA primer such that it is a single entity, not two separate binding moieties. Applicant argues the citations of Fischer and Rissin (as well as art cited addressing the dependent claims, see remarks pages 7-8) fail to cure the Applicant asserted deficiencies argued above.
Regarding Applicant’s remarks, see new grounds of rejection set forth in response to amendments to the claims, Li et al. is no longer relied upon. The combination of Kingsmore et al. and the cited art addresses the claims.
Regarding the rejection of claims on the grounds of nonstatutory double patenting (remarks page 8-9), Applicant argues the current application has an earlier patent term filing date. However, the claims are now allowable at this time, as such the rejection is maintained.
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.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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