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 .
Response to Arguments
Applicant's arguments, filed July 1, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Drawings
Applicants amended the drawings filed July 1, 2026, the issues identified in the April 1, 2026 Office Action have been fully resolved. Therefore, the drawings received on July 1, 2026 are acceptable.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Weidemaier et al. (US 2011 0275061; cited on IDS filed December 15, 2022) in view of Mir (US 2014 0162892; cited on IDS filed December 15, 2022) and Tsien et al. (US 2010 0233726; cited on IDS filed December 15, 2022).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 1, 2026 and those set forth herein.
Weidemaier discloses a method for detecting the presence or amount of one or more analytes in a biological sample, the method comprising contacting the sample with a reagent comprising surface enhanced Raman spectroscopy (SERS)-active nanoparticles (NPs) (reads on donor material) and magnetic capture particles associated with at least one reference label capable of generating a detectable signal (reporter molecule, reads on probe); illuminating the localized area; and comparing the detectable signals (claim 1). Weidemaier discloses that the donor materials can be associated with the probe having label (¶ 121; FIG. 2) and the probe can be any molecule that provides a Raman signal upon exposure to appropriate irradiation (¶ 77). Weidemaier discloses that the method can be used for monitoring specific markers or diagnosing abnormal pathology in vivo by introducing the donor materials targeted to a molecule (¶ 282; ¶ 300). Weidemaier discloses that the components can be reversibly bound to a target molecule and the components can be selectively removed by one or more washing steps (¶ 100; ¶ 103). The washing steps would require delivering a solution to dislodge the molecules from the coupling site. Weidemaier discloses that functionalization of the donor material can provide a specific interaction with a target analyte and the probe can be functionalized to be conjugated with the donor material (¶¶ 81-82; ¶ 121; FIG. 2). Weidemaier discloses that the target analyte can be a cancerous cell (¶ 174). Weidemaier discloses that the donor material can comprise gold (¶ 56). Weidemaier discloses that the donor material can comprise the encapsulated NP with a diameter between about 20 nm and about 200 nm (¶ 68).
Weidemaier does not disclose the new limitation of amended claim 1, determining the optical change in the probe comprises detecting destruction of the dye molecules. Weidemaier does not disclose the step of extracting the probe from the target in a living organism and extracting the probe comprises a blood draw.
Mir discloses a method of sequencing a target polynucleotide using a fluorescence tag such as a dye (abstract; ¶ 37). Mir discloses that the detection of signal change can comprise chemically inactivating or photobleaching the fluorescence tag (claim 6; ¶ 44), which reads on the destruction of the dye molecules.
Tsien discloses a recombinant tandem fluorescent protein construct comprising a donor fluorescent protein moiety, an acceptor fluorescent protein moiety, and a peptide linker moiety that couples the donor and acceptor moieties (claim 1). Tsien discloses that the construct can be used for enzymatic assays on living cells or organisms in vivo (¶ 102). Tsien discloses that blood samples containing the construct or cleaved moieties can be extracted from the organism and tested (¶ 107). The blood sample would require drawing the blood from the organism.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Weidemaier to determine the optical change in the probe by detecting destruction of the dye molecules, and add a step of extracting the probe from the target in a living organism by a blood draw. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Mir teaches that determining the optical change can comprise detecting destruction of the dye molecule, and Tsien teaches that a blood sample including cleaved moieties such as probe molecule can be extracted from a living organism by a blood draw. Further, a person of ordinary skill in the art would have been motivated to destruct the dye molecule when determine the optical change in order to improve sensitivity, and extract the probe from the target in a living organism in order to minimize its residence time in vivo and perform additional analysis. Accordingly, applying the teachings of Mir and Tsien to the method of Weidemaier constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering instant claims obvious.
Applicant argues that the cited combination of Weidemaier, Tsien, and Mir fails to teach or suggest each and every element of amended claim 1, at least because it fails to teach or suggest the determination of an optical change by detecting the destruction of a dye molecule. Applicant argues that the proposed combination is technically inoperable, teaches away from the claimed proximity requirements, and lacks proper motivation. Applicant argues that Weidemaier requires an intact reporter, and Tsien similarly requires intact surviving protein moieties. Applicant argues that a POSITA would not be motivated to utilize the distant, reset-oriented labels of Mir in a system designed to confirm a targeting location via proximity- dependent energy transfer.
This argument is unpersuasive. A reference teaches away only if a POSITA upon reading the references, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. The destruction of a reporter molecule does not negate or destroy the function of the assay systems. In SERS analysis of Weidemaier, photobleaching and photochemical degradation are well-known and inherent phenomena associated with SERS due to intense localized plasmonic fields. Utilizing controlled irradiation to induce photobleaching of background fluorescence or monitoring single-molecule SERS intensity decay is a standard technique used for single-molecule detection and signal specificity, Similarly, in FRET (fluorescence resonance energy transfer) system of Tsien (¶ 37), acceptor photobleaching is a standard quantitative method where the acceptor dye is selectively destroyed to measure the corresponding optical change (de-quenching/increase) in donor signal intensity. Therefore, applying Mir’s teaching of detecting optical changes via dye destruction/photobleaching to the SERS/FRET system of Weidemaier and Tsien does not render them inoperable. Rather, it merely utilize an established analytical phenomenon in both SERS and FRET spectroscopy to confirm target interaction. Further, Applicant’s assertion of inoperability is unsupported by objective evidence. The arguments or conclusory statements in the remarks section of a response do not take the place of evidence in the record. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Examiner does not rely on Mir for its specific linker length or broad spatial isolation. The rejection relies on Mir for its explicit technical disclosure that detecting an optical signal change can comprise destroying/photobleaching a dye molecule. A POSITA is not limited to combining references only for their specific preferred embodiments or exact physical configurations. A POSITA seeking to enhance optical signal, evaluate probe interaction, or confirm molecular proximity in the systems of Weidemaier and Tsien would be motivated to combine Mir’s photobleaching detection method, yielding a predictable result regardless of the physical linker length chosen for the specific assay design.
Applicant argues that Mir utilizes photobleaching as a post-detection step to reset an array for the next sequencing cycle, not as a primary signal to confirm a targeting operation. Applicant argues that the dye molecules in Mir are designed for the generic reporting of a sequencing cycle rather than to provide confirmation of a donor material and/or probe at a specific targeted location.
This argument is unpersuasive. Obviousness does not require that the prior art references be combined for the exact same application purpose intended by the original authors. The test for obviousness is not whether the prior art references can be physically combined in the exact same manner or for the exact same purpose as proposed by the applicant. Rather, the test is whether a POSITA, seeking to solve the problem at hand (improving signal sensitivity or analyzing optical changes), would have been motivated to look to Mir’s teaching of dye destruction and apply it to the system of Weidemaier and Tsien. Because Mir explicitly discloses that dye destruction yields a detectable optical signal change, applying this mechanism to Weidemaier and Tsien constitutes nothing more than the predictable use of prior art elements according to their established functions. Under the broadest reasonable interpretation in light of the specification, “determining the optical change” of the claim 1 encompasses detecting the destruction/photobleaching of dye molecules taught by Mir. Whether photobleaching is performed as a sequence reset or as a target confirmation step, the underlying physical event, irradiating the dye, destroying the molecule, and measuring the optical change, is identical, and results in an optical change that can be determined as required by the claims. The physical mechanism taught by Mir operates in the same manner regardless of the broader functional objective of the assay. Accordingly, applying this known optical detection mechanism to confirm target location is an obvious combination of prior art elements according to their established functions.
Applicant argues that all other rejected claims depend from claim 1 and are therefore allowable by virtue of their dependence on an allowable base claim.
This argument is unpersuasive. As discussed above, amended claim 1 is rendered obvious by Weidemaier in view of Mir and Tsien. Because Applicant has not presented separate arguments regarding the patentability of the dependent claims, the rejection of all other dependent claims are maintained for the reasons of record set forth herein.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Weidemaier, Mir, and Tsien as applied to claims 1-3, 6, 7, and 10 above, and further in view of Baker et al. (US 2008 0261202; cited on IDS filed December 15, 2022).
Weidemaier, Mir, and Tsien are discussed above.
None of Weidemaier, Mir, and Tsien disclose a solution having a pH within a range of 8.0-8.5.
Baker discloses tagged polyfunctional reagents capable of reversibly binding to target substances in a pH-dependent manner (title). Baker discloses that the binding can be severed at a pH of 8.5 (¶ 51).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Weidemaier, Mir, and Tsien to include a solution with a pH of 8.5 to sever the coupling between the probe and the donor material. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Baker teaches that a solution with an elevated pH, such as pH 8.5 can be used to sever the coupling between molecules. Further, a person of ordinary skill in the art would have been motivated to use pH-based probe dislodging for specific and efficient extraction of the probe. Accordingly, applying the teachings of Baker to the method of Weidemaier, Mir, and Tsien constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claim 4 obvious.
Applicant argues that Baker fails to cure the deficiencies of Weidemaier, Tsien, and Mir regarding independent claim 1.
This argument is unpersuasive. As discussed above, amended claim 1 is rendered obvious by Weidemaier in view of Mir and Tsien without reliance on Baker. Baker is cited not for claim 1, but to address dependent claim 4. Baker teaches a solution having a pH within the claimed range to sever the coupling. Thus, claim 4 is rendered obvious by Weidemaier, Mir, and Tsien, further in view of Baker.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Weidemaier, Mir, and Tsien as applied to claims 1-3, 6, 7, and 10 above, and further in view of Schmidt and Ostafin (Advanced Materials, 2002; cited on IDS filed December 15, 2022).
Weidemaier, Mir, and Tsien are discussed above.
None of Weidemaier, Mir, and Tsien disclose that the probe comprises CaP and the probe is characterized by a diameter of between about 5 nm and about 100 nm.
Schmidt discloses nanoscale shells composed of CaP (page 533, col. 1, ¶ 1). Schmidt discloses that the diameter of the shells can be 30-50 nm (page 533, col. 2, ¶ 2). Schmidt discloses that calcium phosphate enclosed liposomes (CaPELs) can be used as sustained delivery vehicles for drugs or fluorescent dyes (page 532, col. 2, ¶3; page 534, col. 2, ¶ 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Weidemaier, Mir, and Tsien to use CaPELs with a diameter of 30-50 nm for the probe. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Schmidt teaches that the CaPELs with a diameter of 30-50 nm can be used as delivery vehicles encapsulating fluorescent dyes. Further, a person of ordinary skill in the art would have been motivated to use CaPELs in order to improve biocompatibility and controlled release. Accordingly, applying the teachings of Schmidt to the method of Weidemaier, Mir, and Tsien constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims 8 and 11 obvious.
Applicant argues that Schmidt fails to cure the deficiencies of Weidemaier, Tsien, and Mir regarding independent claim 1.
This argument is unpersuasive. As discussed above, amended claim 1 is rendered obvious by Weidemaier in view of Mir and Tsien without reliance on Schmidt. Schmidt is cited not for claim 1, but to address dependent claims 8 and 11. Baker teaches a CaP probe having a diameter within the claimed range. Thus, claims 8 and 11 are rendered obvious by Weidemaier, Mir, and Tsien, further in view of Schmidt.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Weidemaier, Mir, and Tsien as applied to claims 1-3, 6, 7, and 10 above, and further in view of Vérant et al. (Journal of Biomedical Optics, 2008).
Weidemaier, Mir, and Tsien are discussed above.
None of Weidemaier, Mir, and Tsien disclose that the probe comprises SRB.
Vérant discloses the use of SRB for in vivo staining and imaging (abstract). Vérant discloses that SRB is an amphiphilic fluorescent dye with notable benefits such as low toxicity, high water solubility, and rapid clearance (page 064028-2, col 1, ¶ 1; page 064028-4, col. 1, ¶ 1)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Weidemaier, Mir, and Tsien to use SRB for the probe. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Vérant teaches that the SRB can be an effective dye molecule for in vivo imaging. Further, a person of ordinary skill in the art would have been motivated to use SRB as a highly sensitive, non-destructive, and cost-effective dye. Accordingly, applying the teachings of Vérant to the method of Weidemaier, Mir, and Tsien constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claim 9 obvious.
Applicant argues that Vérant fails to cure the deficiencies of Weidemaier, Tsien, and Mir regarding independent claim 1.
This argument is unpersuasive. As discussed above, amended claim 1 is rendered obvious by Weidemaier in view of Mir and Tsien without reliance on Vérant. Vérant is cited not for claim 1, but to address dependent claim 9. Vérant teaches a SRB probe as recited in the claim. Thus, claim 9 is rendered obvious by Weidemaier, Mir, and Tsien, further in view of Vérant.
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.
Claims 1-4 and 6-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 11 of U.S. Patent No. US 11,531,025. Although the claims at issue are not identical, they are not patentably distinct from each other.
Applicant requests that the Office hold this rejection in abeyance until this application is otherwise in condition for allowance. This rejection is MAINTAINED for the reasons of record set forth herein.
Regarding claim 1, claim 1 of the ‘025 recites a method of confirming a targeting operation, the method comprising: delivering a donor material to a target; delivering a probe to the target, wherein the probe couples with the donor material; irradiating the target; determining an optical change in the probe to confirm the donor material and probe reached the target; delivering a solution to dislodge the probe from the donor material; and extracting the probe from the target, wherein the target is in a living organism. Regarding new limitation of amended claim 1, claim 5 of the ‘025 recites the probe comprises dye molecules, and wherein determining an optical change in the probe comprises detecting destruction of the dye molecules.
Regarding claim 2, claim 2 of the ‘025 recites further comprising: functionalizing the donor material to seek the target; and functionalizing the probe to conjugate with the donor material.
Regarding claim 3, claim 3 of the ‘025 recites the target comprises cancerous tissue in the living organism, and wherein extracting the probe comprises a blood draw.
Regarding claim 4, claim 4 of the ‘025 recites the solution comprises a pH of within a range of 8.0-8.5, and wherein the solution severs the coupling between the probe and the donor material.
Regarding claims 6 and 10, claim 6 of the ‘025 recites the donor material comprises at least one material selected from the group consisting of lanthanide oxide, hafnium oxide, tungsten oxide, platinum, gold, bismuth, and uranium-238.
Regarding claim 7, claim 7 of the ‘025 recites the donor material comprises a nanomaterial having a diameter between about 25 nm and about 1,000 nm.
Regarding claim 8, claim 8 of the ‘025 recites the probe comprises at least one material selected from the group consisting of TiO2, ZnO, Al2O3, SiO2, CaP, polystyrene, and poly N-isopropylacrylamide.
Regarding claim 9, claim 9 of the ‘025 recites the probe further comprises at least one material selected from the group consisting of coumarin-3-carboxylic acid, 3′-(p aminophenyl) fluorescein, 2-[6-(4V-amino)phenoxy-3H-xanthen-3-on-9-yl] benzoic acid (APF), dihydroethidine (DHE), dihydrorhodamine, 4′,5′-diaminofluorescein, sulforhodamine B, calcein, and fluorescein.
Regarding claim 11, claim 11 of the ‘025 recites the probe is characterized by a diameter of between about 5 nm and about 100 nm.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael G Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Nissa M Westerberg/Primary Examiner, Art Unit 1618
Prosecution Insights