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 Amendment
The Amendment filed 12/10/2025 has been entered. Claims 1 and 3-20 remain pending in the application. Claims 11-17 are withdrawn. New grounds of rejections necessitated by amendments are discussed below.
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, 3-10, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tadenuma et al. (US 20150065377 A1; cited in the IDS filed 08/13/2021) in view of Beechem et al. (US 20110281740 A1; cited in the IDS filed 08/13/2021) and Oldham et al. (US 20060252079 A1).
Regarding claim 1, Tadenuma teaches a nucleic acid sequence measurement device (abstract; Figs. 1-4 and 10A) that measures a target having a specific nucleic acid sequence included in a sample by means of hybridization (abstract), the nucleic acid sequence measurement device comprising:
a donor fluorescent probe (Fig. 10A, fluorescent probe 10B) having a first binding part (Fig. 10A, sequence of fluorescent probe 10B) and a first base end (bottom end of probe 10B; note that Fig. 2 shows a detailed labeled view of probe 10, where the first base end is the bottom end of probe 10 towards linker 14) and having a donor fluorescent molecule added at a tip or middle position of the donor fluorescent probe (fluorescent molecule 11 at 3’ is at a tip of fluorescent probe 10B);
a quenching probe (Fig. 10A, quenching probe 20B) having a second binding part (sequence of quenching probe 20B) and a second base end (bottom end of probe 20B; note that Fig. 2 shows a detailed labeled view of probe 20B, where the second base end is the bottom end towards linker 24) and having an acceptor molecule (quenching substance 21 at 5’) added at a position adjacent to the donor fluorescent molecule of the donor fluorescent probe when the quenching probe is bound to the donor fluorescent probe (Fig. 10A shows quenching substance 21 at a position adjacent to the fluorescent molecule 11 when quenching probe 20B is bound to fluorescent probe 10A); and
a substrate having a solid phase surface (Fig. 2, solid surface 100; note that Fig. 10A does not depict the solid surface, however, Fig. 2 shows the detailed elements of the probes 10B and 20B; paragraph [0058], “solid surface 100”) to which the first base end of the donor fluorescent probe and the second base end of the quenching probe are fixed (Fig. 2; paragraph [0058]),
wherein the first binding part of the donor fluorescent probe and the second binding part of the quenching probe have sequences complementary to each other (Figs. 2 and 10A and paragraph [0011], teach the fluorescent probe 10B and quenching probe 20B are complementary with each other),
wherein at least one of the donor fluorescent probe and the quenching probe has a detection part having a sequence complementary to a nucleic acid sequence of the target (Fig. 3 shows probe 10 having a sequence complementary with target 30; paragraphs [0085]-[0087] teach the target 30 is designed to be coupled with fluorescent probe 10 or quenching probe 10, therefore the fluorescent probe 10B or the quenching probe 20B have a sequence complementary to the sequence of the target), and
wherein the donor fluorescent probe and the quenching probe have a positional relationship in which fluorescence of the donor fluorescent molecule is quenched with the acceptor molecule that approaches the donor fluorescent molecule (Figs. 3 and 10A and paragraph [0058] teaches fluorescent molecule 11 and quenching substance 21 have a positional relationship and fluorescent molecule 11 is quenched with the quenching substance 21 that approaches the fluorescent molecule 11), and the first base end and the second base end are fixed to the solid phase surface (Fig. 2),
wherein, when hybridization between the target and the detection part has not occurred (Fig. 10A), a binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is maintained (Fig. 10A), and thus the fluorescence of the donor fluorescent molecule is quenched with the acceptor molecule that approaches the donor fluorescent molecule (Fig. 10A; paragraphs [0058],[0061]),
wherein, when hybridization between the target and the detection part occurs (Fig. 3, right image; paragraphs [0085]-[0087]; note that Fig. 10A depicts an embodiment of a plurality of fluorescent and quenching molecules, which would perform in the same way as shown in Fig. 3), the binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is released (Fig. 3, right image), the donor fluorescent molecule separated from the acceptor molecule exhibits fluorescence (Fig. 3, right image; paragraph [0063]), and
wherein a plurality of donor fluorescent molecules (Fig. 10A, fluorescent molecules 11) are added to the donor fluorescent probe (Fig. 10A, fluorescent probe 10B) and a plurality of acceptor molecules (Fig. 10A, quenching substances 21) are added to the quenching probe (Fig. 10A, quenching probe 20B).
Tadenuma fails to teach: the quenching probe having an acceptor fluorescent molecule added at the position adjacent to the donor fluorescent molecule of the donor fluorescent probe when the quenching probe is bound to the donor fluorescent probe; wherein the donor fluorescent probe and the quenching probe have a positional relationship in which fluorescence of the donor fluorescent molecule is quenched with the acceptor fluorescent molecule that approaches the donor fluorescent molecule; wherein, when hybridization between the target and the detection part has not occurred, a binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is maintained, and thus the fluorescence of the donor fluorescent molecule is quenched with the acceptor fluorescent molecule that approaches the donor fluorescent molecule, and the acceptor fluorescent molecule exhibits fluorescence, wherein, when hybridization between the target and the detection part occurs, the binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is released, the donor fluorescent molecule separated from the acceptor fluorescent molecule exhibits fluorescence; wherein a plurality of acceptor fluorescent molecules are added to the quenching probe; and wherein molecules that absorb light in a detection wavelength of fluorescence of the acceptor fluorescent molecules which is in a wavelength range not covering an absorption wavelength spectrum of the acceptor fluorescent molecules within a fluorescence wavelength spectrum of the donor fluorescent molecules are added as the donor fluorescent molecules to the donor fluorescent probe.
Tadenuma teaches employing quenching by fluorescence resonance energy transfer, i.e. FRET, (paragraph [0055]). Tadenuma teaches a plurality of kinds of fluorescent molecules and quenching substances may be added to a plurality of positions in the fluorescent probe and the quenching probe (paragraph [0085]). Tadenuma teaches a known problem of quenching of fluorescence with probes, since offset fluorescence intensity increases to deteriorate detection sensitivity (paragraph [0028]).
Beechem teaches methods and compositions for single molecule sequencing (abstract). Beechem teaches detecting and monitoring progress of a sequencing reaction based on detection of signals resulting from fluorescence resonance energy transfer (FRET), where FRET uses a FRET donor and FRET acceptor (paragraph [0061]). Beechem teaches the process of FRET results in a quenching of fluorescence intensity and excited state lifetime of the FRET donor, and can produce an increase in the emission intensity of the FRET acceptor; wherein FRET occurs only when two appropriately labeled molecules are sufficiently proximal to each other to transfer energy (paragraph [0061]). Beechem teaches any detectable label is suitable for attachment to a polymerase or nucleotide is used, where the label comprises a FRET donor and/or acceptor and the FRET donor and/or acceptor is typically a fluorophore or fluorescent label (paragraph [0071]). Beechem teaches the FRET donor and/or acceptor can also be a quencher that can participate the in the reaction (paragraph [0071]). Beechem teaches a method of using quenchers in conjunction with fluorescent labels, where discrimination of the nucleotide bases is based on the wavelength and/or intensity of light emitted from the FRET acceptor, as well as the intensity of light emitted from the FRET donor (paragraph [0098]). Beechem teaches modulating FRET efficiency by varying the distance between the nanoparticle donor and the fluorescent label or quencher acceptor, where modulation of FRET efficiency results in a detectable modulation of emission intensity or quenching (paragraph [0099]).
Since Beechem teaches detecting a sequencing reaction and FRET, similar to Tadenuma, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the quenching probe of Tadenuma to incorporate the teachings of the use of fluorescent donor and fluorescent acceptors for monitoring sequencing reactions of Beechem (paragraphs [0061],[0071]) and the teachings of FRET and a plurality of fluorescent molecules of Tadenuma (paragraphs [0055],[0085]) to provide: the quenching probe having an acceptor fluorescent molecule added at the position adjacent to the donor fluorescent molecule of the donor fluorescent probe when the quenching probe is bound to the donor fluorescent probe; wherein the donor fluorescent probe and the quenching probe have a positional relationship in which fluorescence of the donor fluorescent molecule is quenched with the acceptor fluorescent molecule that approaches the donor fluorescent molecule, and wherein a plurality of acceptor fluorescent molecules are added to the quenching probe. Doing so would have a reasonable expectation of successfully allowing for detection of modulation of emission intensity or quenching as discussed by Beechem (paragraph [0099]), and improving discrimination of the nucleotide bases is based on the wavelength and/or intensity of light of the donor and acceptor as discussed by Beechem (paragraph [0098]).
Additionally, since Beechem teaches it is known for an acceptor marker to be either a fluorescent label or a quencher molecule when detecting sequencing reactions on the basis of a change (paragraphs [0061],[0071],[0099]), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modified the quenching probe of Tadenuma to incorporate the teachings of the use of fluorescent donor and acceptors for monitoring sequencing reactions of Beechem (paragraphs [0061],[0071]) to provide: the quenching probe having an acceptor fluorescent molecule added at the position adjacent to the donor fluorescent molecule of the donor fluorescent probe when the quenching probe is bound to the donor fluorescent probe; wherein the donor fluorescent probe and the quenching probe have a positional relationship in which fluorescence of the donor fluorescent molecule is quenched with the acceptor fluorescent molecule that approaches the donor fluorescent molecule, and wherein a plurality of acceptor fluorescent molecules are added to the quenching probe. I.e. It would have been obvious to have substituted one known element (Tadenuma’s quenching substance) for another (Beechem’s fluorescent label), and the results of the substitution would have been predictable (detectable modulation of emission intensity or quenching as taught by Beechem, paragraph [0099], via a quenching effect from FRET). See MPEP 2143(I)(B).
Since Beechem teaches detecting a sequencing reaction and FRET, similar to Tadenuma, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the quenching probe of Tadenuma to incorporate the teachings of the use of fluorescent donor and fluorescent acceptors for monitoring sequencing reactions of Beechem (paragraphs [0061],[0071], [0098]) to provide: wherein, when hybridization between the target and the detection part has not occurred, a binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is maintained, and thus the fluorescence of the donor fluorescent molecule is quenched with the acceptor fluorescent molecule that approaches the donor fluorescent molecule, and the acceptor fluorescent molecule exhibits fluorescence, wherein, when hybridization between the target and the detection part occurs, the binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is released, the donor fluorescent molecule separated from the acceptor fluorescent molecule exhibits fluorescence. Doing so would have a reasonable expectation of successfully allowing for detection of modulation of emission intensity or quenching as discussed by Beechem (paragraph [0099]) and improve discrimination of the nucleotide bases is based on the wavelength and/or intensity of light of the donor and acceptor as discussed by Beechem (paragraph [0098]).
Modified Tadenuma fails to teach: wherein molecules that absorb light in a detection wavelength of fluorescence of the acceptor fluorescent molecules which is in a wavelength range not covering an absorption wavelength spectrum of the acceptor fluorescent molecules within a fluorescence wavelength spectrum of the donor fluorescent molecules are added as the donor fluorescent molecules to the donor fluorescent probe.
Tadenuma teaches a known problem of quenching of fluorescence with probes, since offset fluorescence intensity increases to deteriorate detection sensitivity (paragraph [0028]). Tadenuma teaches: in the case of adding the plurality of fluorescent molecules and quenching substances to each probe, the kinds of fluorescent molecules and quenching substances may vary; and in the case where the plurality of fluorescent molecules and quenching substances is added to each probe, the fluorescence quantity when the detection target molecules are coupled increases, thereby enabling more sensitive detection (paragraph [0085]).
Oldham teaches a system comprising excitation sources, at least one detector, and dyes, wherein the dyes can include FRET dye moieties (abstract). Oldham teaches energy transfer dyes generally can provide a larger effective Stokes shift than non-energy transfer fluorescent dyes because the Stokes shift of an energy transfer dye is determined by the difference between the wavelength at which the donor dye maximally absorbs light and the wavelength at which the acceptor dye maximally emits excitation energy (paragraph [0035]). Oldham teaches in some embodiments, the excitation energy emitted by the donor dye moiety can be absorbed by the acceptor dye moiety that can in-turn fluoresce (paragraphs [0007],[0033]). Oldham teaches a donor dye moiety can be capable of absorbing radiation at a first wavelength or within a first wavelength range, and emitting excitation energy, at a second, different wavelength or within a second wavelength range, while the acceptor dye moiety can be capable of absorbing the excitation energy that is emitted from the donor dye moiety and fluorescing in response to the excitation (paragraph [0038]). Oldham teaches each donor dye moiety of a plurality of energy transfer dyes absorbs maximum radiation at a different wavelength than the other energy transfer dyes used in the system (paragraph [0054]). Oldham teaches dyes of a set have different absorption wavelength ranges (paragraph [0006]), wherein the non-energy transfer dyes and donor dye moieties have sufficiently distinct absorbances such that the absorption spectra of the respective dyes can be resolved using ordinary detection means (paragraph [0021]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the donor fluorescent molecules of modified Tadenuma to incorporate Tadenuma’s teachings of using different kinds of fluorescent molecules (paragraph [0085]) and known issue of offset fluorescence intensity (paragraph [0028]) and Oldham’s teachings of an acceptor dye moiety absorbing excitation energy emitted from a donor dye (paragraphs [0007], [0033],[0038],[0054]) and dyes having different absorption wavelength ranges (paragraphs [0006],[0021],[0038],[0054]) to provide: wherein molecules that absorb light in a detection wavelength of fluorescence of the acceptor fluorescent molecules which is in a wavelength range not covering an absorption wavelength spectrum of the acceptor fluorescent molecules within a fluorescence wavelength spectrum of the donor fluorescent molecules are added as the donor fluorescent molecules to the donor fluorescent probe. Doing so would have a reasonable expectation of successfully providing FRET dyes with sufficiently distinct absorbances to improve sensitivity of detection (Oldham, paragraph [0028],[0035]; Tadenuma, paragraph [0021],[0085]).
Regarding claim 3, Tadenuma further teaches wherein the donor fluorescent probe has the detection part (Fig. 3 shows probe 10 having a sequence complementary with target 30, i.e. detection part; paragraphs [0087] teaches the target 30 is designed to couple with fluorescent probe 10, i.e. probe 10B of Fig. 10A).
Regarding claim 4, modified Tadenuma fails to teach wherein the quenching probe has the detection part.
Tadenuma teaches an embodiment wherein the quenching probe has the detection part (Fig. 10B and paragraph [0088] teaches a target is coupled to the quenching probe, thus the quenching probe has a sequence complementary with target 30, i.e. detection part). Tadenuma teaches the probe may be designed so that the target is coupled with the quenching probe; wherein in this case, the change in characteristic of the fluorescent molecule due to the proximity of the target can be avoided (paragraph [0087]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the device of modified Tadenuma to incorporate the teachings of an embodiment of a quenching probe with a detection part of Tadenuma (paragraphs [0087]-[0088]; Fig. 10B) to provide wherein the quenching probe has the detection part. Doing so would have a reasonable expectation of successfully detecting a target and avoid change in characteristic of the fluorescent molecule due to the proximity of the target as taught by Tadenuma (paragraph [0087]).
Regarding claim 5, Tadenuma further teaches wherein the substrate is a flat plate (Fig. 1, solid surface 100; paragraph [0036], “flat plate”), and the solid phase surface is a flat surface of the flat plate (Fig. 1, solid surface 100 is a flat surface of a flat plate).
Regarding claim 6, Tadenuma further teaches wherein at least a part of the first binding part of the donor fluorescent probe functions as the detection part (Fig. 3 shows at least part of the sequence of probe 10 having a sequence complementary with target 30, i.e. functions as the detection part; paragraphs [0087] teaches the target 30 is designed to couple with fluorescent probe 10, therefore probe 10B of Fig. 10A functions as the detection part as claimed).
Regarding claim 7, modified Tadenuma fails to teach wherein at least a part of the second binding part of the quenching probe functions as the detection part.
Tadenuma teaches an embodiment at least a part of the second binding part of the quenching probe functions as the detection part (Fig. 10B and paragraph [0088] teaches a target is coupled to the quenching probe, thus the quenching probe has a sequence complementary with target 30, i.e. detection part). Tadenuma teaches the probe may be designed so that the target is coupled with the quenching probe; wherein in this case, the change in characteristic of the fluorescent molecule due to the proximity of the target can be avoided (paragraph [0087]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the device of modified Tadenuma to incorporate the teachings of an embodiment of a quenching probe with a detection part of Tadenuma (paragraphs [0087]-[0088]; Fig. 10B) to provide wherein at least a part of the second binding part of the quenching probe functions as the detection part. Doing so would have a reasonable expectation of successfully detecting a target and avoid change in characteristic of the fluorescent molecule due to the proximity of the target as taught by Tadenuma (paragraph [0087]).
Regarding claim 8, modified Tadenuma fails to teach wherein the position to which the donor fluorescent molecule is added is in the middle of the donor fluorescent probe.
Tadenuma teaches the fluorescent molecule or the quenching substance may not adhere to the end of the probe (paragraph [0084]). Tadenuma teaches an embodiment where the predetermined position to which the donor fluorescent molecule is added is in the middle of the donor fluorescent probe (Fig. 9B; paragraph [0084]). Tadenuma teaches in the case of adding the fluorescent molecule or the quenching substance to the position other than the end of the probe, the end of the probe can be modified differently, which is advantageous (paragraph [0084]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the position of the donor fluorescent molecule of modified Tadenuma to incorporate the teachings of positioning a fluorescent molecule in the middle of a probe of Tadenuma (Fig. 9B; paragraph [0084]) to provide wherein the predetermined position to which the donor fluorescent molecule is added is in the middle of the donor fluorescent probe. Doing so would have a reasonable expectation of successfully improving modification of the probe as taught by Tadenuma (paragraph [0084]).
Regarding claim 9, modified Tadenuma fails to teach wherein the position to which the acceptor fluorescent molecule is added is in the middle of the quenching probe.
Tadenuma teaches the fluorescent molecule or the quenching substance may not adhere to the end of the probe (paragraph [0084]). Tadenuma teaches an embodiment where the predetermined position to which the quencher substance is added is in the middle of the quenching probe (Fig. 9B; paragraph [0084]). Tadenuma teaches in the case of adding the fluorescent molecule or the quenching substance to the position other than the end of the probe, the end of the probe can be modified differently, which is advantageous (paragraph [0084]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the position of the donor fluorescent molecule of modified Tadenuma to incorporate the teachings of positioning a fluorescent molecule in the middle of a probe of Tadenuma (Fig. 9B; paragraph [0084]) to provide wherein the predetermined position to which the acceptor fluorescent molecule is added is in the middle of the quenching probe. Doing so would have a reasonable expectation of successfully improving modification of the probe as taught by Tadenuma (paragraph [0084]).
Regarding claim 10, modified Tadenuma fails to teach wherein both the donor fluorescent probe and the quenching probe have the detection part.
Tadenuma teaches an embodiment where both the fluorescent probe and the quenching probe may have the detection part (paragraph [0043]). Tadenuma teaches when the both probes have the detection sequence, the coupling frequency of the target can be increased (paragraph [0086]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the quenching probe of modified Tadenuma to incorporate the teachings of both probes having a detection sequence of Tadenuma (paragraph [0086]) to provide wherein both the donor fluorescent probe and the quenching probe have the detection part. Doing so would have a reasonable expectation of successfully improving coupling frequency of the target (Tadenuma, paragraph [0086]).
Regarding claim 18, modified Tadenuma further teaches wherein, when hybridization between the target and the detection part occurs (Tadenuma, Fig. 3, right image; paragraphs [0085]-[0087]; note that Fig. 10A depicts an embodiment of a plurality of fluorescent and quenching molecules, which would perform in the same way as shown in Fig. 3), the binding between the first binding part of the donor fluorescent probe and the second binding part of the quenching probe is released (Fig. 3, right image), and thus the donor fluorescent molecule separated from the acceptor fluorescent molecule exhibits fluorescence (see above claim 1; Tadenuma in view of Beechem teaches the claimed limitation in claim 1).
Modified Tadenuma fails to explicitly teach: when hybridization between the target and the detection part occurs, the fluorescence of the acceptor fluorescent molecule is quenched.
Beechem teaches detecting and monitoring progress of a sequencing reaction based on detection of signals resulting from fluorescence resonance energy transfer (FRET), where FRET uses a FRET donor and FRET acceptor (paragraph [0061]). Beechem teaches the process of FRET results in a quenching of fluorescence intensity and excited state lifetime of the FRET donor, and can produce an increase in the emission intensity of the FRET acceptor; wherein FRET occurs only when two appropriately labeled molecules are sufficiently proximal to each other to transfer energy (paragraph [0061]). Beechem teaches any detectable label is suitable for attachment to a polymerase or nucleotide is used, where the label comprises a FRET donor and/or acceptor and the FRET donor and/or acceptor is typically a fluorophore or fluorescent label (paragraph [0071]). Beechem teaches the FRET donor and/or acceptor can also be a quencher that can participate the in the reaction (paragraph [0071]). Beechem teaches a method of using quenchers in conjunction with fluorescent labels, where discrimination of the nucleotide bases is based on the wavelength and/or intensity of light emitted from the FRET acceptor, as well as the intensity of light emitted from the FRET donor (paragraph [0098]). Beechem teaches modulating FRET efficiency by varying the distance between the nanoparticle donor and the fluorescent label or quencher acceptor, where modulation of FRET efficiency results in a detectable modulation of emission intensity or quenching (paragraph [0099]).
Since Beechem teaches detecting a sequencing reaction, similar to Tadenuma, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the quenching probe of Tadenuma to incorporate the teachings of the use of FRET and fluorescent donor and fluorescent acceptors for monitoring sequencing reactions of Beechem (paragraphs [0061],[0071], [0098]) to provide: when hybridization between the target and the detection part occurs, the fluorescence of the acceptor fluorescent molecule is quenched. Doing so would have a reasonable expectation of successfully allowing for detection of modulation of emission intensity or quenching as discussed by Beechem (paragraph [0099]) and improve discrimination of the nucleotide bases is based on the wavelength and/or intensity of light of the donor and acceptor as discussed by Beechem (paragraph [0098]).
Regarding claim 19, modified Tadenuma fails to teach: wherein, types of the plurality of donor fluorescent molecules are different from each other, or types of the plurality of acceptor fluorescent molecules are different from each other.
Tadenuma teaches a plurality of kinds, i.e. types, of fluorescent molecules and quenching substances may be added to a plurality of positions in the fluorescent probe and the quenching probe; wherein in the case of adding the plurality of fluorescent molecules and quenching substances to each probe, the kinds of fluorescent molecules and quenching substances may vary (paragraph [0085]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the plurality of donor fluorescent molecules or the plurality of acceptor fluorescent molecules of modified Tadenuma to incorporate the teachings of the kinds of fluorescent molecule substances may vary of Tadenuma (paragraph [0085]) to provide: wherein, types of the plurality of donor fluorescent molecules are different from each other, or types of the plurality of acceptor fluorescent molecules are different from each other. Doing so would have a reasonable expectation of successfully providing desired kinds or types of fluorescent molecules at specific positions of the probes to improve sensitivity of detection as taught by Tadenuma (paragraph [0085]).
Regarding claim 20, Tadenuma further teaches wherein, one of the plurality of donor fluorescent molecules (Fig. 10A and paragraph [0085], one of fluorescent molecules 11) absorbs light in a detection wavelength of fluorescence of one of the plurality acceptor fluorescent molecules (interpreted as a functional limitation of the claimed fluorescent molecule, see MPEP 2114; since Tadenuma’s fluorescent molecule 11 is identical to that of the claim, the fluorescent molecule 11 is structurally capable of performing the function of “absorbs light…”, see MPEP 2112.01(I); note that the specific fluorescent molecules or wavelengths are not claimed).
In an alternative interpretation of claim 20, if it is determined that Tadenuma fails to teach wherein, one of the plurality of donor fluorescent molecules (Fig. 10A and paragraph [0085], one of fluorescent molecules 11) absorbs light in a detection wavelength of fluorescence of one of the plurality acceptor fluorescent molecules, Tadenuma teaches: in the case of adding the plurality of fluorescent molecules and quenching substances to each probe, the kinds of fluorescent molecules and quenching substances may vary; and in the case where the plurality of fluorescent molecules and quenching substances is added to each probe, the fluorescence quantity when the detection target molecules are coupled increases, thereby enabling more sensitive detection (paragraph [0085]).
Oldham teaches a system comprising excitation sources, at least one detector, and dyes, wherein the dyes can include FRET dye moieties (abstract). Oldham teaches energy transfer dyes generally can provide a larger effective Stokes shift than non-energy transfer fluorescent dyes because the Stokes shift of an energy transfer dye is determined by the difference between the wavelength at which the donor dye maximally absorbs light and the wavelength at which the acceptor dye maximally emits excitation energy (paragraph [0035]). Oldham teaches in some embodiments, the excitation energy emitted by the donor dye moiety can be absorbed by the acceptor dye moiety that can in-turn fluoresce (paragraphs [0007],[0033]). Oldham teaches a donor dye moiety can be capable of absorbing radiation at a first wavelength or within a first wavelength range, and emitting excitation energy, at a second, different wavelength or within a second wavelength range, while the acceptor dye moiety can be capable of absorbing the excitation energy that is emitted from the donor dye moiety and fluorescing in response to the excitation (paragraph [0038]). Oldham teaches each donor dye moiety of a plurality of energy transfer dyes absorbs maximum radiation at a different wavelength than the other energy transfer dyes used in the system (paragraph [0054]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified one of the plurality of the plurality of donor fluorescent molecules of modified Tadenuma to incorporate the teachings of using different kinds of fluorescent molecules of Tadenuma (paragraph [0085]) and the teachings of an acceptor dye moiety absorbing excitation energy emitted from a donor dye of Oldham (paragraphs [0007], [0033],[0038],[0054]) to provide: one of the plurality of donor fluorescent absorbs light in a detection wavelength of fluorescence of one of the plurality acceptor fluorescent molecules. Doing so would have a reasonable expectation of successfully providing FRET dyes to improving sensitivity of detection (Oldham, paragraph [0035]; Tadenuma, paragraph [0085]).
Response to Arguments
Applicant’s arguments, see pages 8-15, filed 12/10/2025, with respect to the rejection(s) of claims 1, 3-10, and 18-20 under 35 U.S.C. 103, specifically regarding the amendments to claim1, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Tadenuma et al. (US 20150065377 A1; cited in the IDS filed 08/13/2021) in view of Beechem et al. (US 20110281740 A1; cited in the IDS filed 08/13/2021) and Oldham et al. (US 20060252079 A1).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lee et al. (US 20070154926 A1) teaches donor dyes and acceptor dyes (abstract). Lee teaches the energy transfer dyes of the present invention include a donor dye which absorbs light at a first wavelength and emits excitation energy in response, an acceptor dye which is capable of absorbing the excitation energy emitted by the donor dye and fluorescing at a second wavelength in response, and a linker which attaches the donor dye to the acceptor dye (paragraph [0066]).
Bauer et al. (US 20070212746 A1) teaches a biosensor (abstract), which monitors changes that occur in FRET between a donor and acceptor fluorophore (paragraph [0014]). Bauer teaches one of the requirements for the acceptor fluorophore is that the acceptor fluorophore whose absorption wavelength does not overlap the absorption wavelength of the donor fluorophore be able to absorb emission of the donor fluorophore land thus emit its own emission (paragraph [0029]).
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 HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758