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 .
Election/Restrictions
Applicant’s election of Group I, claims 1-37 in the reply filed on June 23, 2025 is acknowledged. Applicant’s election of Species A1, B1, C10, D2, E1, F10, and G1 in the reply filed on July 30, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). As a result, the claims to be examined are claims 1-2, 4-21, and 23-34.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because reference character “16” has been used to designate both endogenous solutes and aptamer in Figure 3. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim(s) 25 is/are objected to because of the following informalities:
Claim 25, line 1: “where” is suggested to be “wherein”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 1-2, 4-21, and 23-34 is/are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 recites the limitation "any analyte" in line 10. It is unclear what “any analyte” is or whether it is the same as the “at least one analyte” recited in lines 1-2. It is suggested to be “the at least one analyte.”
Dependent claim(s) 2, 4-21, and 23-34 is/are rejected based on rejected claim 1.
Claim 9 recites the limitation “the aptamers” in line 3. There is insufficient antecedent basis for the limitation in the claim. It is suggested to be “the plurality of aptamers.”
Dependent claim(s) 10-11 is/are rejected based on rejected claim 9.
Claim 14 recites the limitations "the " in line. There are insufficient antecedent bases for these limitations in the claim. It is suggested to be “the plurality of signaling aptamers” and “the plurality of anchor aptamers.”
Dependent claim(s) 15-16 is/are rejected based on rejected claim 14.
Claim 15 recites the limitations "the anchor aptamers" in line 3. There is insufficient antecedent basis for the limitation in the claim. It is suggested to be “the plurality of anchor aptamers.”
Claim 16 recites the limitations "the " and "the anchor aptamers" in line 2. There are insufficient antecedent bases for these limitations in the claim. It is suggested to be “the plurality of signaling aptamers” and “the plurality of anchor aptamers.”
Claim 16 recites the limitations "a subset of signaling aptamers" in line 2. There is insufficient antecedent basis for the limitation in the claim. It is suggested to be “a subset of the plurality of signaling aptamers.”
Claim 16 recites the limitations "at least a subset of anchor aptamers" in line 3. There is insufficient antecedent basis for the limitation in the claim. It is suggested to be “at least a subset of the plurality of anchor aptamers.”
Claim 16 recites the limitation "any analyte" in line . It is unclear what “any analyte” is or whether it is the same as the “at least one analyte” recited in claim 1, lines 1-2. It is suggested to be “the at least one analyte.”
Claim 17 recites the limitations "signaling aptamer" in line 1 and "anchor aptamer" in line 2. There are insufficient antecedent bases for these limitations in the claim. It is suggested to be “the plurality of signaling aptamers” and “the plurality of anchor aptamers.”
Claim 23 recites the limitation "the " in line. There is insufficient antecedent basis for this limitation in the claim. It is suggested to be “the at least one electrode.”
Claim Rejections - 35 USC § 103
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 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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim(s) 1-2, 9-10, 12, 23, 25-31, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bertrand (WO 2017/189122) in view of Lin (US 2020/0196925).
Regarding claim 1, Bertrand teaches a device (¶6: an EAB sweat sensing device) for detecting the presence of, or measuring the concentration or amount of, at least one analyte in a sample fluid (¶6: to detect target analytes in a sweater sample), the device comprising:
at least one electrode (Fig. 3; ¶37: at least one EAB sensor 322 and an optional secondary sensor 324);
a sensor fluid (Fig. 3; ¶37: the sweat sample 14 enters the device and flows into the concentration channel 380; here the fluid inside the concentration channel 380 is deemed to be sensor fluid);
a plurality of aptamers (Fig. 1; ¶33: aptamer 140; ¶55: a plurality of aptamers may be chosen to cover the concentration range);
a plurality of redox tags (Fig. 1; ¶33: a redox moiety 150) associated with at least a subset of aptamers of the plurality of aptamers (Fig. 1: the redox moiety 150 attached on the end of the aptamer 140);
wherein the sensor fluid is capable of fluidic connection with a sample fluid introduced thereinto (Fig. 3; ¶37: the sweat sample 14 enters the device and flows into the concentration channel 380); and
wherein the detection or measurement of any analyte may occur through a change in electron transfer from at least one redox tag of the plurality of redox tags (Fig. 4; ¶11: an EAB response curve for varying sensor current output as a function of analyte concentration; ¶48: the reactive potential of the redox moiety that produces the electrical signal indicating analyte capture).
Bertrand does not disclose the plurality of aptamers freely diffuse in the sensor fluid.
However, Lin teaches a microdevice for monitoring a target analyte, including a field effect transistor and a microfluidic channel including graphene ([Abstract]). The aptameric graphene nanosensing integrates aptamer-based selective analyte enrichment, and then the sample target was released into a free aptamer solution for binding of the free aptamer to the standard target on graphene via competitive binding, thus changing the graphene conductance (Fig. 38; ¶109).
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 Bertrand by employing free aptamers in the sensor fluid for sensing as taught by Lin because it is a suitable detection method based on aptameric nanosensing due to specific binding between the aptamer and the analyte (Fig. 38; ¶109). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 2, Bertrand teaches wherein the device is a continuous sensing device (¶4: permit continuous use on a wearer’s skin).
Regarding claim 9, Bertrand teaches the device further comprising at least one membrane (Fig. 3; ¶37: pre-sensor membrane 394), wherein the membrane separates the sample fluid and the sensor fluid (Fig. 3: indicating the sample 14 and the fluid inside the concentration channel 380 separated by the pre-sensor membrane 394). Further, the combined Betrand and Lin would necessarily result in the membrane retaining the freely diffusive aptamers inside the sensor fluid (Bertrand, Fig. 3) for aptamer-based measurement in the sensor fluid (Lin, Fig. 38; ¶109).
Regarding claim 10, Bertrand and Lin discloses all limitations of claim 9, but fail to teach wherein the at least one membrane has a molecular weight cutoff that is chosen from less than 300 Da, less than 1000 Da, less than 3 kDa, less than 10 kDa, less than 30 kDa, less than 100 kDa, and less than 300 kDa.
However, Bertrand teaches a pre-sensor membrane 394, a concentrating membrane 390, and an optional post-sensor membrane 392 (Fig. 3; ¶¶37-39). For example, the concentrating membrane is a dialysis membrane, with a 12 kDa molecular mass cutoff that retain solutes that are above 12 kDa (¶38). The membranes could all be dialysis membranes with different mass cutoffs (¶60).
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 Bertrand and Lin by using a dialysis membrane for the pre-sensor membrane and adjusting the molecular weight cutoff of the membrane within the claimed range because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I). Further, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05(II)(A).
Regarding claim 12, Bertrand teaches wherein the measurement of change in electron transfer is performed using voltammetry (¶33: square wave voltammetry SWB).
Regarding claim 23, Bertrand and Lin disclose all limitations of claim 1 but fail to teach wherein the electrode is coated with at least one membrane.
However, Lin teaches the entire nanosensor can be coated with a glucose-permeable hydrogel (¶329). The hydrogel can be directly immobilized onto the surface of the transducer via in situ polymerization and can be stable over time, thereby reducing the use of a semipermeable membrane, or other mechanical barriers and moving parts (¶468).
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 Bertrand by incorporating a in situ polymerization hydrogel as a membrane coated on the electrodes as taught by Lin because the hydrogel membrane would be selectively permeable to the analyte and stable over time, thereby reducing the use of a semipermeable membrane, or other mechanical barriers and moving parts (¶¶329, 468). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 25, Bertrand and Lin disclose all limitations of claim 1. Bertrand fails to teach where each aptamer of the plurality of aptamers has a molecular weight chosen from at least 1 kDa, at least 10 kDa, and at least 100 kDa.
However, Lin teaches a microdevice and techniques for monitoring a target analyte in a sample using a receptor (e.g., ¶45: an aptamer) capable of binding to the target analyte (¶23). The design parameters include, for example, the number and dimensions of atomic layers and substrate platform layers, shape and dimensions of the graphene, and molecular weight of the aptamers, linkers, and polymers (¶372), rendering it a result-effective parameter.
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 Bertrand and Lin by adjusting the molecular weight of the plurality of aptamers within the claimed range because the molecular weight of the plurality of aptamers is a result-effective variable and can be optimized through routine experimentation. MPEP 2144.05 (II)(B).
Regarding claim 26, Bertrand and Lin disclose all limitations of claim 1. Bertrand fails to teach wherein the change in electron transfer is associated with a condition of a change in electron transfer rate.
However, Lin teaches the electrical conductance through the change in conductance caused by the target analyte binding to the aptamer immobilized on the graphene can be measured by measuring the drain current at a fixed drain voltage (¶52). For example, the polymer-glucose binding can change the transconductance, i.e., the drain-source current change rate with respect to the gate voltage (¶316).
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 Bertrand by using electron transfer rate for measuring the binding event as taught by Lin because the electron transfer rate is characteristic to the change of the transconductance due to target analyte binding. Applying a known technique to a known method ready for improvement to yield predictable results is prima facie obvious. MPEP 2141(III)(D).
Regarding claims 27-28, the designations “wherein the device is factory-calibrated” in claim 27 and “wherein the device is calibration-free” in claim 28 do not further limit the method as claimed because they do not require steps to be performed in the recited method. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. In method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. MPEP 2111.04.
Regarding claims 29-30, Bertrand and Lin disclose all limitations of claim 1. Bertrand fails to teach wherein the device contains two or more types of aptamers for measurement of two or more analytes (claim 29) or wherein distinguishing between measurement of two or more analytes is accomplished via use of potential (claim 30).
However, Lin teaches the aptamer can bind specifically to the target analyte, and the functionalized aptamers may be two or more types of aptamers specific for either the same or different analyte (¶374). The transfer characteristics of graphene can be measured in buffer by sweeping the gate voltage (¶380). When the target analyte in a sample can be captured by the aptamer, the charged target analyte can alter the carrier concentration of the graphene, and thus induce a shift of the Dirac point (VDirac), the voltage at which the Ids reaches its minimum (Fig. 32A; ¶380).
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 Bertrand by incorporating two or more types of aptamers as taught by Lin because the different types of aptamers specific would provide the capability of detecting the same or different analyte (¶374) based on the different characteristic electron transfer at the minimum voltage (¶380). Applying a known technique to a known method ready for improvement to yield predictable results is prima facie obvious. MPEP 2141(III)(D).
Regarding claim 31, Bertrand teaches wherein the at least one electrode further comprises a plurality of electrodes (Fig. 3; ¶37: at least one EAB sensor 322 and an optional secondary sensor 324), wherein each electrode of the plurality of electrodes is are used at a different time than each of the other electrodes of the plurality of electrodes (Fig. 3: since the sweat sample 14 flows from the left to right inside of concentration channel 380 and thus the electrodes are used at different times).
Regarding claim 33, the designation “wherein the in electron transfer is due to a change in diffusion coefficient for the aptamers” does not further limit the method as claimed because it does not require steps to be performed in the recited method. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. In method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. MPEP 2111.04.
Claim(s) 4-8, 11, 13-19, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bertrand in view of Lin, and further in view of Vallee-Belisle (WO 2019/232618).
Regarding claims 4-5, Bertrand and Lin discloses all limitations of claim 1. Bertrand fails to teach the device further comprising a passivating layer on the at least one electrode (claim 4) or wherein the passivating layer includes exogenous molecules (claim 5).
However, Vallee-Belisle teaches functionalized gold electrode for electrochemical measurement (p. 26, l. 5). After functionalization of anchoring DNAs, 2 mM MCH solution was used for removing physically adsorbed anchoring DNA and passivating the rest surface of gold electrode (p. 26, ll. 11-13). Here, Examiner notes that the mercaptohexanol (MCH) is an exogenous molecule.
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 Bertrand and Lin by incorporating a passivating layer including exogenous molecules, e.g., MCH, on the electrode as taught by Vallee-Belisle because MCH would remove physically adsorbed anchoring DNA and passivating the rest surface of gold electrode (p. 26, ll. 11-13) for aptamer-based electrochemical sensors. Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claims 6-8, Bertrand teaches wherein the passivating layer includes molecules that are endogenous to the sample fluid (¶36: potential target analyte are cortisol, hormones, or proteins; e.g., ¶55: luteinizing hormone (LH) or follicle stimulating hormone (FSH); here, Examiner notes that hormones are endogenous molecules, which are diffusive to close to the electrode surface forming a thin layer on the electrode that is deemed to be the passivating layer); wherein a source of the endogenous molecules is the sample fluid (Fig. 3: the analyte solutes are from the sweat sample 14); and wherein a source of the endogenous molecules is the sensor fluid (Fig. 3: the source of the solutes are in the fluid inside of the concentration channel 380 after the sweat sample 14 flowing through the pre-sensor membrane 394).
Regarding claim 11, Bertrand and Lin disclose all limitations of claim 9. Bertrand and Lin fail to teach wherein the change in electron transfer is chosen from greater than 5%, greater than 10%, greater than 20%, greater than 50%, greater than 100%, and greater than 200%.
However, Vallee-Belisle teaches DNA-based reaction by employing a selective DNA-based signaling mechanism using a redox-labeled “signaling” DNA and a complementary “anchoring” DNA strand attached to a gold electrode (p. 28, ll. 11-14). The tested reaction produced a 100% increase in electrochemical current in the presence of 100 µM of quinine in the first 5 minutes of the reaction, as shown in Figures 3B-D (p. 29, ll. 7-8). Upon adding 100 nM of aptamer and signaling DNA, the electrochemical current was found 40% higher after only 30 seconds and kept increasing up to 175% after 30 min of reaction, as shown in Figure 3D (p. 29, ll. 12-14).
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 Bertrand and Lin by employing the current increase (i.e., the change in electron transfer) within the claimed range because it would provide electrochemical signal for the quantitative measurement of the analyte (p. 29). Applying a known technique to a known method ready for improvement to yield predictable results is prima facie obvious. MPEP 2141(III)(D).
Regarding claims 13-14, Bertrand and Lin disclose all limitations of claim 1 but fail to teach wherein the plurality of aptamers comprise a plurality of signaling aptamers and a plurality of anchor aptamers (claim 13) or wherein the plurality of redox tags are bound to the signaling aptamers, but are not bound to the anchor aptamers (claim 34).
However, Vasllee-Belisle teaches detection of a target using oligonucleotides (p. 1, ll. 7-8). The device includes a receptor aptamer (SEQ ID NO: 1), a signaling DNA (SEQ ID NO: 4), and an anchoring DNA (SEQ ID NO: 8) (Fig. 3; p. 5, ll. 33-35). The redox tag is bound to the signaling DNA, but not the anchor aptamer (Fig. 3(a), p. 28, ll. 13-14: redox-labeled signaling DNA).
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 Bertrand and Lin by incorporating a plurality of signaling aptamers labeled with redox tags for electrochemical detection upon hybridization of the signaling aptamers with the anchoring aptamers because it would provide kinetically controlled detection (p. 2, ll. 5-6). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claims 15-16, the designations “wherein the plurality of anchor aptamers are adapted to bind the analyte, and wherein each signaling aptamer of a majority of the plurality of signaling aptamers is bound to a respective anchor aptamer when a majority of anchor aptamers are not bound to any analyte” in claim 15 and “wherein the plurality of anchor aptamers are adapted to bind the analyte, and wherein a subset of signaling aptamers dissociates from the anchor aptamers when at least a subset of anchor aptamers bind to any analyte” in claim 16 do not further limit the method as claimed because they do not require steps to be performed in the recited method. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. In method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. MPEP 2111.04. Further, Vallee-Belisle teaches a DNA-based reaction employing a robust and selective DNA-based signaling mechanism, including a redox-labeled signaling DNA and a complementary anchoring DNA strand attached to a gold electrode (p. 28, ll. 11-14). For example, if unbound to its ligand, the receptor aptamer acts like an inhibitor of the signaling mechanism by sequestrating the signaling strand thus preventing it to hybridize to the anchoring DNA on the electrode (Fig. 3A: see k2; p. 28, ll. 20-23). When the specific aptamer-binding target is present, this latter acts as an aptamer inhibitor by sequestrating it and preventing it to bind to the signaling DNA (Fig. 3A: see k1; p. 28, ll. 23-25). Thus, Vallee-Belisle teaches the anchor aptamers are adapted to bind the analyte, and it would naturally occur that a majority of the plurality of signaling aptamers would be bound to a respective anchor aptamer when a majority of anchor aptamers are not bound to any analyte and wherein a subset of signaling aptamers dissociates from the anchor aptamers when at least a subset of anchor aptamers bind to any analyte as recited.
Regarding claim 17, Bertrand, Lin, and Vallee-Belisle disclose all limitations of claim 13. Bertrand and Lin do not disclose wherein the concentration of signaling aptamer is less than the concentration of anchor aptamer.
However, Vallee-Belisle teaches the signaling DNA was designed so that it is complementary to a specific receptor DNA aptamer (e.g., a quinine binding aptamer) (p. 28, ll. 17-19). The reactions were triggered by adding 100 nM of signaling DNA to solution containing quinine (p. 29, ll. 8-11). To optimize the gain, the concentration of the aptamer was increased from 50 nM to 200 nM, showing the reaction rates were increased by increasing the substrate concentration (Fig. 5A: the gain increases with the increasing concentration of aptamer; p. 6, ll. 14-18).
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 Bertrand and Lin by adjusting the concentrations of the signaling aptamers and the anchor aptamers (e.g.; 100 nM of signaling DNA and 200 nM anchoring aptamer) as taught by Vallee-Basile because the increase in the concentration of the anchor aptamers would increase the gain of the signal (Fig. 5; p. 6). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claims 18-19, Bertrand, Lin, and Vallee-Belisle disclose all limitations of claim 13. Bertrand and Vallee-Belisle fail to teach wherein the plurality of anchor aptamers are immobilized to a first material (claim 18) or wherein the first material is not freely diffusing in fluid (claim 19).
However, Lin teaches the aptamer can be functionalized along with a polymer 1105c, which can reduce the nonspecific adsorption of background molecules 1110 (Fig. 32B; ¶379). Thus, Lin teaches the anchor aptamers (e.g., the aptamer for binding the analyte) are immobilized to a first material (¶379: a polymer 1105c) which is fixed on the sensing surface and thus not freely diffusing in fluid (Fig. 32B).
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 Bertrand and Vallee-Belisle by incorporating a material fixed on the sensing surface so that the aptamers can be immobilized on the first material as taught by Lin because it reduce the nonspecific adsorption of background molecules 1110 (Fig. 32B; ¶379). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 24, Bertrand and Lin disclose all limitations of claim 1. Bertrand and Lin do not disclose wherein the concentration of signaling aptamer is less than the concentration of anchor aptamer.
However, Vallee-Belisle teaches the signaling DNA was designed so that it is complementary to a specific receptor DNA aptamer (e.g., a quinine binding aptamer) (p. 28, ll. 17-19). To optimize the gain, the concentration of the aptamer was increased from 50 nM to 200 nM, showing the reaction rates were increased by increasing the substrate concentration (Fig. 5A: the gain increases with the increasing concentration of aptamer; p. 6, ll. 14-18).
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 Bertrand and Lin by adjusting the concentrations of the aptamers (e.g.; 50 nM to 200 nM anchoring aptamer) as taught by Vallee-Basile because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Claim(s) 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bertrand in view of Lin, and further in view of Schneider (US 2011/0136099).
Regarding claims 20-21, Bertrand and Lin disclose all limitations of claim 1. Bertrand and Lin fail to teach wherein the plurality of redox tags comprises two or more redox tags per each aptamer of the plurality of aptamers, wherein the distance between the two or more redox tags alters depending on the presence of analyte (claim 20) or wherein the two or more redox tags are comprised of identical molecules (claim 21).
However, Schneider teaches the detection and/or quantification of one or more target molecules (¶9), using an aptamer that includes a releasable first tag and has a specific affinity for a target molecule (¶11), and a second tag (which may be the same as the releasable first tag) is attached to the target molecule of the aptamer affinity complex (¶11). The second tag is designed such that it can be attached to the target in a manner that does not disrupt the aptamer affinity complex (¶11). The target may be reacted with the second tag while the aptamer affinity complex is still immobilized to the first solid support, and adding the second tag after the partitioning step eliminates the labeling of target molecules that are not part of an aptamer affinity complex (¶11).
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 Bertrand and Lin by incorporating a second redox tag attached to the aptamer affinity complex as taught by Schneider because adding the second tag after the partitioning step eliminates the labeling of target molecules that are not part of an aptamer affinity complex (¶11). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Claim(s) 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bertrand in view of Lin, and further in view of Plaxco (US 2019/0209063).
Regarding claim 32, Bertrand and Lin disclose all limitations of claim 1 but fail to teach wherein the measurement of change in electron transfer is amperometry.
However, Plaxco teaches electrochemical, aptamer-based sensors to analyze complex samples ([Abstract]). Measurement methods can be cyclic voltammetry, differential pulse voltammetry, alternating current voltammetry, square wave voltammetry, potentiometry or amperometry as known in the art (¶42).
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 Bertrand and Lin by using amperometry for the electrochemical measurement on aptamer-based sensors as taught by Plaxco because amperometry is well-known in the art as an alternative technique to square wave voltammetry (¶42). Applying a known technique to a known method ready for improvement to yield predictable results is prima facie obvious. MPEP 2141(III)(D).
Claim(s) 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bertrand in view of Lin, and further in view of Buse (US 2008/0027302).
Regarding claim 34, Bertrand and Lin disclose all limitations of claim 1 but fail to teach wherein the at least one electrode is paired with at least a second electrode and the distance between the electrodes is chosen from less than 50 µm, less than 10 µm, less than 2 µm, and less than 0.4 µm.
However, Buse teaches sensors capable of electrochemically measuring an analyte, including at least two electrodes (¶6). The sensor includes an electrode pair having a working electrode, a counter electrode, and a measurement zone between the two electrodes, the measurement zone being sized to hold no more than about 1 µL of sample (¶12). The electrodes are preferably separated by a distance of no more than 200 µm, preferably no more than 100 µm, and most preferably no more than 50 µm (¶171), which overlaps the claimed range.
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 Bertrand and Lin by adjusting the distance between electrodes of the pair of electrodes within the claimed range because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAITLYN M SUN whose telephone number is (571)272-6788. The examiner can normally be reached M-F: 8:30am - 5:30pm.
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/C. SUN/Primary Examiner, Art Unit 1795