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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/18/2026 has been considered by the examiner.
Although a concise explanation of the relevance of the information is not required for English language information, applicants are encouraged to provide a concise explanation of why the English-language information is being submitted and how it is understood to be relevant. Concise explanations (especially those which point out the relevant pages and lines) are helpful to the Office, particularly where documents are lengthy and complex and applicant is aware of a section that is highly relevant to patentability or where a large number of documents are submitted and applicant is aware that one or more are highly relevant to patentability (see MPEP 609.04.a.III.)
Claim Objections
Claims 11, 20 and 26 are objected to because of the following informalities:
Claim 11, line 1: please amend “monitoring three or more analytes,” to monitoring of three or more analytes --.
Claim 20, line 1: please amend “monitoring three or more analytes,” to monitoring of three or more analytes, --.
Claim 26, line 1: please amend “monitoring three or more analytes,” to monitoring of three or more analytes, --.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claim 27 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 27, claim 27 recites “to sense the third analyte by a competitive immunosensing detection”. However, claim 26 previously recited “the third analyte includes one of cortisol, ketone body, lactate, or C-peptide”. The specification and the figures do not support detecting a ketone body, lactate, or C-peptide by competitive immunosensing. For example, the specification recites “the electrochemical chip can be expanded for additional disease biomarkers, particularly using electrochemical assay of ketone bodies (through enzymatic detection of hydroxybutyrate)” [see Para. 0049 of the instant specification]. Therefore, claim 27 is new matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 26 and 28-30 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Shah et al. (US20060076236A1).
Regarding claim 26, a sensor device (Shah teaches an analyte sensing device 100 adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]), the limitation “for simultaneous monitoring three or more analytes” is an intended use limitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the above analyte sensing device 100 as shown in Fig. 2 and 4 that is specifically configured to perform the functional limitations above (Shah teaches an analyte sensing device 100 adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]), comprising:
a substrate (Shah teaches base layer 102 [Fig. 2; Para. 0055]);
three or more detecting electrodes disposed on the substrate (Shah teaches an array of working electrodes where the sensor has two, three, or four or more working electrodes on the base layer 102 [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4]),
the three or more detecting electrodes including a first electrode, a second electrode, and a third electrode (Shah teaches the array of working electrodes which has two, three, or four or more working electrodes [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4] and thus includes a first, second and third electrode), the limitations “a first electrode to sense a first analyte, a second electrode to sense a second analyte, and a third electrode to sense a third analyte is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the three or more working electrodes as shown in Fig. 2 and 4 that are specifically configured to perform the functional limitations above (Shah teaches the array of working electrodes which has three or more working electrodes [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4], with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]. Shah further teaches the analyte sensing device is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon and is made so that at least two of the analyte sensor elements “electrodes” in the analyte sensing device sense different analytes [claim 22 and Para. 0133]. Therefore, the first, second and third electrode are specifically configured and capable to sense a first, second, and third analyte, respectively.)
wherein the first analyte includes glucose, the second analyte includes insulin, and the third analyte includes one of cortisol, ketone body, lactate, or C-peptide (The limitation further limits the sample but fail to further limit the apparatus. A claim is only limited by positively recited elements. Thus, "inclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims." See MPEP 2115. Since the claims further limit the analyte [material worked upon] but fails to limit the sensor device [by a structure being claimed], the limitation has no patentable weight. Examiner notes, however, that Shah expressly teaches the first analyte is glucose and the analytes include lactate [see e.g., Para. 0011, claim 5]), and
the limitation “wherein the first analyte, the second analyte, and the third analyte are detectable in a microliter (μL) sample of a biological fluid when deposited on the first electrode, the second electrode, and the third electrode, respectively” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the three or more working electrodes as shown in Fig. 2 and 4 that are specifically configured to perform the functional limitations above (Shah teaches the array of working electrodes which has three or more working electrodes [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4], with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]. Shah further teaches the sensor can be in contact with blood as typically occurs for example with intravenous sensors and can be used to sense analytes of interest in one or more physiological environment, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient [Para. 0087, 0008, 0015]. The analyte sensors are typically designed to be implantable within a mammal and the analyte sensor elements “electrodes” are adapted to contact and sense analytes, the electrochemical sensor including at least one electrode for contacting an analyte to be assayed [see, e.g. element 104 in FIG. 2] [Para. 0086, 0009, 0092, 0065]. Therefore, the first, second and third working electrodes are specifically configured and capable to detect the first, second and third analytes in a microliter sample of a biological fluid [whole-blood] when deposited on the electrodes.);
three or more functionalization layers disposed on the three or more detecting electrodes, respectively, wherein the three or more functionalization layers includes a first functionalization layer disposed on the first electrode, a second functionalization layer disposed on the second electrode, and a third functionalization layer disposed on the third electrode (Shah teaches analyte sensing constituent 110 “functionalization layer” disposed on the electrodes of the sensor [the sensor having three or more working electrodes] and the analyte sensing constituent can coat all of the various electrodes of the sensor [Para. 0068 and Fig. 2]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon [Para. 0133; Fig. 2 and 4]. Thus, there are three or more analyte sensing constituents/membranes disposed on the three or more working electrodes including a first analyte sensing constituent on the first working electrode, a second analyte sensing constituent on the second working electrode, and a third analyte sensing constituent on the third working electrode.); and
one or both of a reference electrode and a counter electrode disposed on the substrate (Shah teaches the analyte sensor 100 includes a reference electrode and a counter electrode or a combined reference and counter electrode where the counter and reference electrodes necessary for electrochemical sensor function may be common to the entire array, or located within each well. The conductive layer is disposed upon the base layer “substrate” where the conductive layer includes a working electrode, a reference electrode and a counter electrode [corresponding to disposed on the substrate] [Para. 0066, 0056, 0040, 0015]).
Regarding claim 28, the sensor device of claim 26, wherein the ketone body includes hydroxybutyrate (This claim further limits the sample but fails to further limit the apparatus. A claim is only limited by positively recited elements. Thus, "inclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims." See MPEP 2115. Since the claim further limits the ketone body analyte [material worked upon] but fails to limit the sensor device [by a structure being claimed], the limitation has no patentable weight).
Regarding claim 29, the sensor device of claim 26, wherein the biological fluid is a non-pretreated biological fluid including at least one of whole blood, saliva, tears, sweat, or interstitial fluid (ISF) (This claim further limits the sample but fails to further limit the apparatus. A claim is only limited by positively recited elements. Thus, "inclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims." See MPEP 2115. Since the claim further limits the biological fluid [material worked upon] but fails to limit the sensor device [by a structure being claimed], the limitation has no patentable weight. Examiner notes, however, that Shah expressly teaches the biological fluid is non-pretreated [designed for use as subcutaneous or transcutaneous glucose sensors for monitoring blood glucose levels in a diabetic patient] including whole-blood, saliva, tears, or interstitial fluid [see e.g., Para. 0086-0087, 0116]).
Regarding claim 30, the sensor device of claim 26, wherein the substrate is one or more of flexible, bendable, or stretchable (Shah teaches the base layer 102 can be a flexible film [Para. 0118]).
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. (US20060076236A1) in view of Niroula et al. (Combined covalent and noncovalent carboxylation of carbon nanotubes for sensitivity enhancement of clinical immunosensors, 2016, ChemComm, 52, Pages 13039-13042), Bertin et al. (US 20130112572 A1), and Munje et al. (Lancet-free and label-free diagnostics of glucose in sweat using Zinc Oxide based flexible bioelectronics, 2017, Sensors and Actuators B, 238, Pages 482-490).
Regarding claim 20, a multi-biomarker sensor device (Shah teaches an analyte sensing device 100 adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]), the limitation “for simultaneous monitoring three or more analytes” is an intended use limitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the above analyte sensing device 100 as shown in Fig. 2 and 4 that is specifically configured to perform the functional limitations above (Shah teaches an analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]), the device comprising:
a substrate (Shah teaches base layer 102 [Fig. 2; Para. 0055]);
three or more detecting electrodes disposed on the substrate (Shah teaches an array of working electrodes where the sensor has two, three, or four or more working electrodes on the base layer 102 [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4]), the limitation “operable to simultaneously detect three distinct analytes from a microliter (μL) sample of whole blood” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the three or more working electrodes as shown in Fig. 2 and 4 that are specifically configured to perform the functional limitations above (Shah teaches the array of working electrodes which has three or more working electrodes [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4], with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]. Shah further teaches the sensor can be in direct contact with blood as typically occurs for example with intravenous sensors and can be used to sense analytes of interest in one or more physiological environment, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient [Para. 0087, 0008, 0015, 0067]. The analyte sensors are typically designed to be implantable within a mammal and the analyte sensor elements “electrodes” are adapted to contact and sense analytes in a liquid sample of biological fluid including whole-blood [Para. 0086, 0009, 0092, 0065]. Therefore, the first, second and third working electrodes are specifically configured and capable to detect three distinct analytes from a microliter sample of whole blood.)
the three or more detecting electrodes including a first electrode, a second electrode, and a third electrode (Shah teaches the array of working electrodes which has two, three, or four or more working electrodes [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4] and thus includes a first, second and third electrode), the limitation “a first electrode to sense a first analyte by an enzymatic or direct electrochemical detection” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the first working electrode in the working electrode array that is specifically configured to perform the functional limitations above (Shah teaches the first electrode 104 of the array of working electrodes has a first analyte sensing constituent which includes an enzyme, glucose oxidase, which catalyzes the conversion of glucose “first analyte” to hydrogen peroxide and gluconolactone. The hydrogen peroxide diffuses to the electrode where it can be reacted to form oxygen and a proton to produce a current that is proportional to the glucose concentration and the change in concentration can be measured by measuring the change in the current at the electrode of the conductive constituent for detection of glucose at the first working electrode by enzymatic electrochemical detection [Para. 0082, 0068, 0073, 0098; Fig. 2 and 4])
wherein the first analyte includes glucose, the second analyte includes insulin, and the third analyte includes cortisol (The limitation further limits the sample but fail to further limit the apparatus. A claim is only limited by positively recited elements. Thus, "inclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims." See MPEP 2115. Since the claims further limit the analyte [material worked upon] but fails to limit the sensor device [by a structure being claimed], the limitation has no patentable weight. Examiner notes, however, that Shah expressly teaches the first analyte is glucose [see e.g., Para. 0011, claim 5]);
a first functionalization layer disposed on the first electrode (Shah teaches analyte sensing constituent 110 “functionalization layer” disposed on the electrodes of the sensor [the sensor having three or more working electrodes] and the analyte sensing constituent can coat all of the various electrodes of the sensor [Para. 0068 and Fig. 2]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon [Para. 0133; Fig. 2 and 4]. Thus, there are three or more analyte sensing constituents/membranes disposed on the three or more working electrodes including a first analyte sensing constituent disposed on the first working electrode), the first functionalization layer including a catalyst to facilitate an electrochemical reaction to detect the first analyte at the first electrode (Shah teaches the first analyte sensing constituent includes an enzyme, glucose oxidase, which catalyzes the conversion of glucose to hydrogen peroxide and gluconolactone. The hydrogen peroxide diffuses to the electrode where it can be reacted to form oxygen and a proton to produce a current that is proportional to the glucose concentration and the change in concentration can be measured by measuring the change in the current at the electrode of the conductive constituent for detection of glucose at the first working electrode [Para. 0082, 0068, 0073, 0098]);
a second functionalization layer disposed on the second electrode (Shah teaches analyte sensing constituent 110 “functionalization layer” disposed on the electrodes of the sensor [the sensor having three or more working electrodes] and the analyte sensing constituent can coat all of the various electrodes of the sensor [Para. 0068 and Fig. 2]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon [Para. 0133; Fig. 2 and 4]. Thus, there are three or more analyte sensing constituents/membranes disposed on the three or more working electrodes including a second analyte sensing constituent disposed on the second working electrode),
a third functionalization layer disposed on the third electrode (Shah teaches analyte sensing constituent 110 “functionalization layer” disposed on the electrodes of the sensor [the sensor having three or more working electrodes] and the analyte sensing constituent can coat all of the various electrodes of the sensor [Para. 0068 and Fig. 2]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon [Para. 0133; Fig. 2 and 4]. Thus, there are three or more analyte sensing constituents/membranes disposed on the three or more working electrodes including a third analyte sensing constituent disposed on the third working electrode); and
a counter electrode (Shah teaches the analyte sensor 100 includes a counter electrode or a combined reference and counter electrode where the counter electrode necessary for electrochemical sensor function may be common to the entire array, or located within each well [Para. 0066, 0056, 0040, 0015]), the limitation “to detect a signal with respect to that detected by the one or both of the first electrode and the second electrode” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the counter electrode that is specifically configured to perform the functional limitations above (he analyte sensor 100 includes a counter electrode or a combined reference and counter electrode where the counter electrode necessary for electrochemical sensor function may be common to the entire array, or located within each well and thus is specifically configured to detect a signal with respect to that detected by the electrodes in the array [Para. 0066, 0056, 0040, 0015]).
Shah does not explicitly disclose the second functionalization layer including a capture antibody to facilitate an electrochemical immunoassay reaction to detect the second analyte at the second electrode, wherein the capture antibody of the second functionalization layer is attached to the second electrode via a self-assembled monolayer (SAM);
However, Shah teaches an analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4] for the management of diabetes and the monitoring of fluids of the human body of diabetics [Para. 0005 and 0122]. Shah further teaches the analyte sensing device is made so that at least two of the analyte sensor elements in the analyte sensing device sense different analytes [claim 22 and Para. 0133] and the working electrode may be made from gold [Para. 0065]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon [Para. 0133]. Furthermore, Shah expressly teaches other useful analyte sensing constituents can be formed to include antibodies whose interaction with a target analyte is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of an analyte in a sample [Para. 0074].
Niroula teaches an electrochemical insulin immunosensor for measuring insulin levels [the analyte] in human serum for type 1 and type 2 diabetes (Scheme 1 and Page 13039, Col. 2, Para. 2; Page 13042, Col. 1, Para. 2). Niroula discloses a gold electrode with a capture antibody which is a monoclonal insulin antibody [corresponding to an anti-insulin antibody] attached to the electrode via chemically carboxylated multiwalled carbon nanotubes, and EDC, NHS for covalent attachment with the lysine resides of the antibody surface [corresponding to attaching the anti-insulin antibody via a self-assembled monolayer SAM] (Scheme 1 and Page 13039, Col. 2, Para. 3). Niroula further teaches a detection antibody comprising horseradish peroxidase (HRP) attachable to the anti-insulin monoclonal antibody to provide an enzyme label and a molecular complex comprising hydroquinone and hydrogen peroxide (H2O2) [Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2]. Niroula teaches this configuration is beneficial since the HRP-labeled antibody catalyzed oxidation of hydroquinone to quinone in the presence of hydrogen peroxide, monitored as current signals, which are proportional to the concentration of bound serum insulin on the gold sensor surface [Scheme 1 and Page 13040, Col. 1, Para. 1-2]. Furthermore, this surface chemistry is beneficial for measuring serum insulin concentrations with direct type 1 and type 2 diabetes relevant picomolar detection levels [Page 13042, Col. 1, Para. 2]
Given the teachings of Shah regarding the analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon and the analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [electrodes] adapted to sense different analytes simultaneously for the management of diabetes and the monitoring of fluids of the human body of diabetics, it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the antibody in the second analyte sensing constituent attached to the second gold electrode of Shah with an anti-insulin capture antibody, as taught by Niroula, and to modify the sensor device of Shah to provide the anti-insulin antibody attached to the second electrode via a self-assembled monolayer, and to provide a HRP-labeled detection antibody attachable to the anti-insulin antibody to provide an enzyme label, and to provide a molecular complex comprising hydroquinone and hydrogen peroxide to provide an enzymatic substrate/mediator, as taught by Niroula, since Niroula teaches this configuration is beneficial since the HRP-labeled antibody catalyzed oxidation of hydroquinone to quinone in the presence of hydrogen peroxide, monitored as current signals, which are proportional to the concentration of bound serum insulin on the gold sensor surface [Scheme 1 and Page 13040, Col. 1, Para. 1-2 of Niroula] and this surface chemistry is beneficial for measuring serum insulin concentrations with direct type 1 and type 2 diabetes relevant picomolar detection levels [Page 13042, Col. 1, Para. 2 of Niroula]. Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]). Furthermore, 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].
While the examiner takes the position that the chemically carboxylated multiwalled carbon nanotubes, and EDC, NHS for covalent attachment with the lysine resides of the antibody surface in modified Shah meet the limitation of “wherein the capture antibody of the second functionalization layer is attached to the second electrode via a self-assembled monolayer SAM”, in the alternative, Bertin discloses methods and compositions relating to biosensors for use in the detection of target analytes (Para. 0014). Further, Bertin teaches gold electrodes that each comprise a self-assembled monolayer (SAM) with a capture ligand attached to the SAM (Para. 0191 and 0212, Figure 1 and Figure 11A). The capture ligand can be an antibody (Para. 0321). Bertin teaches this configuration is beneficial because the use of a monolayer reduces the amount of non-specific binding of biomolecules to the surface and serves as a physical barrier to block solvent accessibility (and charged species within the solvent) to the electrode (Para. 0212).
Modified Shah and Bertin are considered analogous art to the claimed invention because they are both in the same field of biosensors for the determination of analyte concentrations (Shah, Abstract and Para. 0005; Bertin, Para. 0014). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sensor device in modified Shah by attaching the anti-insulin capture antibody of the second analyte sensing constituent to the second working gold electrode via a SAM, as taught by Bertin, since Bertin teaches the use of a SAM reduces the amount of non-specific binding of biomolecules to the surface and serves as a physical barrier to block solvent accessibility (and charged species within the solvent) to the electrode (Para. 0212). Furthermore, 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(A)).
The limitation “to facilitate an electrochemical immunoassay reaction to detect the second analyte at the second electrode” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Shah as outlined in the rejection above yields an anti-insulin capture antibody in the second functionalization layer on the second working electrode which would be capable of and specifically configured for facilitating an electrochemical immunoassay reaction for detecting the second analyte at the second working electrode as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample [Para. 0074 of Shah; Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2 of Niroula])
The limitation “a second electrode to sense a second analyte by an immunosensing detection” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Shah as outlined in the rejection above yields an anti-insulin capture antibody in the second functionalization layer on the second working electrode, the second working electrode being capable of and specifically configured for sensing a second analyte by an immunosensing detection as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements “electrode” after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample [Para. 0074 of Shah; Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2 of Niroula])
Modified Shah does not explicitly disclose the third functionalization layer including a capture antibody to facilitate an electrochemical immunoassay reaction to detect the third analyte at the third electrode, wherein the capture antibody of the third functionalization layer is attached to the third electrode via a self-assembled monolayer (SAM).
However, Shah teaches an analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4] for the management of diabetes and the monitoring of fluids of the human body of diabetics [Para. 0005 and 0122]. Shah further teaches the analyte sensing device is made so that at least two of the analyte sensor elements in the analyte sensing device sense different analytes [claim 22 and Para. 0133] and the working electrode may be made from gold [Para. 0065]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon [Para. 0133]. Furthermore, Shah expressly teaches other useful analyte sensing constituents can be formed to include antibodies whose interaction with a target analyte is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of an analyte in a sample [Para. 0074].
Munje discloses a wearable, flexible electrochemical biosensor for the label-free, low-volume and ultrasensitive detection of glucose and cortisol [Abstract]. Munje teaches the electrochemical immunoassay for cortisol detection includes a cortisol capture antibody that binds to cortisol antigen, and the cortisol capture antibody is immobilized to the electrode surface via DSP linker molecule “self-assembled monolayer” [Fig. 1 and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3]. This configuration is beneficial for an electrochemical immunoassay for cortisol detection [Fig. 1 and Abstract] and this would be beneficial because glucose and cortisol are two valuable molecules that have physiological interconnection [Page 482, Col. 2, Para. 1]. Cortisol is a glucocorticoid hormone that plays an important role in regulation of glucose metabolism, and it enhances the expression of enzymes involved in glucogenesis, to maintain the glucose levels in plasma. The direct correlation between glucose and cortisol levels in case of Type 2 diabetes patients has been well established. Recent studies have shown that the disturbance in circadian rhythm (influenced by cortisol) may increase both fasting and postprandial plasma glucose concentrations through inadequate pancreatic insulin secretion. Therefore, simultaneous monitoring of these molecules can be used to better predict the onset of diabetes and/or stress related symptoms as well as monitoring the diabetic conditions [Page 482, Col. 2, Para. 1].
Given the teachings of Shah regarding the analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon and the analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [electrodes] adapted to sense different analytes simultaneously for the management of diabetes and the monitoring of fluids of the human body of diabetics, it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the antibody in the third analyte sensing constituent attached to the third gold electrode of Modified Shah with a cortisol capture antibody, as taught by Munje, and to modify the sensor device of Modified Shah to provide the cortisol capture antibody attached to the third electrode via a self-assembled monolayer, as taught by Munje, since Munje teaches this configuration would be beneficial for an electrochemical immunoassay for cortisol detection [Fig. 1 and Abstract of Munje] and would be beneficial because glucose and cortisol are two valuable molecules that have physiological interconnection [Page 482, Col. 2, Para. 1 of Munje] and simultaneous monitoring of these molecules can be used to better predict the onset of diabetes and/or stress related symptoms as well as monitoring the diabetic conditions [Page 482, Col. 2, Para. 1 of Munje]. Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]). Furthermore, 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].
While the examiner takes the position that the DSP linker molecule in modified Shah meet the limitation of “wherein the capture antibody of the third functionalization layer is attached to the third electrode via a self-assembled monolayer SAM”, in the alternative, Bertin discloses methods and compositions relating to biosensors for use in the detection of target analytes (Para. 0014). Further, Bertin teaches gold electrodes that each comprise a self-assembled monolayer (SAM) with a capture ligand attached to the SAM (Para. 0191 and 0212, Figure 1 and Figure 11A). The capture ligand can be an antibody (Para. 0321). Bertin teaches this configuration is beneficial because the use of a monolayer reduces the amount of non-specific binding of biomolecules to the surface and serves as a physical barrier to block solvent accessibility (and charged species within the solvent) to the electrode (Para. 0212).
Modified Shah and Bertin are considered analogous art to the claimed invention because they are both in the same field of biosensors for the determination of analyte concentrations (Shah, Abstract and Para. 0005; Bertin, Para. 0014). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sensor device in modified Shah by attaching the cortisol capture antibody of the third analyte sensing constituent to the third working gold electrode via a SAM, as taught by Bertin, since Bertin teaches the use of a SAM reduces the amount of non-specific binding of biomolecules to the surface and serves as a physical barrier to block solvent accessibility (and charged species within the solvent) to the electrode (Para. 0212). Furthermore, 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(A)).
The limitation “to facilitate an electrochemical immunoassay reaction to detect the third analyte at the third electrode” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Shah as outlined in the rejection above yields a cortisol capture antibody in the third functionalization layer on the third working electrode which would be capable of and specifically configured for facilitating an electrochemical immunoassay reaction for detecting the third analyte at the third working electrode as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample [Para. 0074 of Shah; Fig. 1, Abstract and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3 of Munje).
The limitation “a third electrode to sense a third analyte by a immunosensing detection” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Shah as outlined in the rejection above yields a cortisol capture antibody in the third functionalization layer on the third working electrode, the third working electrode being capable of and specifically configured for sensing a third analyte by an immunosensing detection as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements “electrode” after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample [Para. 0074 of Shah; Fig. 1, Abstract and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3 of Munje)
Claim(s) 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shah in view of Niroula, Bertin, and Munje as applied to claim 20 above, and further in view of Wang et al. (US 20170325724 A1).
Regarding claim 21, the sensor device of claim 20, Shah is silent to wherein the catalyst is immobilized inside a permeable polymer film, and wherein the permeable polymer film comprises a tetrathiafulvalene (TTF) mediator layer formed on the first electrode and a layer comprising at least one of the catalyst, chitosan, or a sulfonated tetrafluoroethylene polymer.
Wang discloses an electrochemical sensor device with electrodes disposed over a substrate for glucose testing (Abstract and Para. 0004, 0009). Further, Wang discloses an electrochemical transducer layer including functionalizing the working electrode surface with tetrathiafulvalene (TTF) electroactive redox mediator layer and depositing a layer of chitosan, a biocompatible polymer on the electrode (Para. 0313). An enzyme catalyst [such as lactate oxidase] is immobilized inside the permeable polymer film/electrochemical transducer layer by tethering the active site of the enzyme catalyst (Para. 0313) Additionally, Wang discloses that chitosan can also be utilized as a polymeric matrix for immobilizing the enzyme glucose oxidase on an electrode surface (Para. 0017 and 0130). The disclosed electrochemical transducer layer is beneficial because: TTF enhances transduction (Para. 0333) and lowers the oxidation potential and has more stable performance (Para. 0354) and chitosan impedes the efflux of the biocatalytic backbone from the enzyme-electrode to the aqueous environment (Para. 0313).
Modified Shah and Wang are considered analogous art to the claimed invention because they are both in the same field of biosensors for glucose sensing (Abstract of Shah and Para. 0004 of Wang). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sensor device in modified Shah by providing a permeable polymer film comprising a TTF mediator layer attached to the first electrode and a layer comprising chitosan with the glucose oxidase catalyst immobilized inside the permeable polymer film, as taught by Wang, since Wang teaches this is beneficial because TTF enhances transduction (Para. 0333 of Wang), lowers the oxidation potential and has more stable performance (Para. 0354 of Wang), and tethers the active site of enzyme catalysts such as oxidases on the electrode surface of the working electrode (Para. 0313 of Wang) and chitosan impedes the efflux of the biocatalytic backbone from the enzyme-electrode to the aqueous environment (Para. 0313 of Wang). Furthermore, 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 22, the sensor device of claim 20, comprising: Modified Shah is silent to an electronics unit including an electric circuit coupled to a data processing unit, wherein, when the sensor device is electrically coupled to the electronics unit,
Wang teaches a processing and communications unit 600 including a data processing unit 608 coupled to a processor 614 “electric circuit” and connected to a power source 602, an analog to digital converter 612, and a potentiostat (sensor signal acquirer) 606, where the noninvasive electrochemical sensor is electrically coupled to the processing and communications unit 600 (Para. 0142, Fig. 6A and 6B). This configuration is beneficial for signal processing and communications to external devices and perform various operations, e.g., such as receiving information, commands, and/or data, processing information and data, and transmitting or providing information/data to another entity or to a user (Para. 0142).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sensor device of modified Shah by providing a processing and communications unit including an electric circuit coupled to the data processing unit and to provide the sensor to be electrically coupled to the processing and communications unit, as taught by Wang, since Wang teaches this configuration would be beneficial for signal processing and communications to external devices and perform various operations, e.g., such as receiving information, commands, and/or data, processing information and data, and transmitting or providing information/data to another entity or to a user (Para. 0142 of Wang). Furthermore, 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(A)).
The limitation “wherein, when the sensor device is electrically coupled to the electronics unit, the sensor device is operable to detect the first analyte, the second analyte, and the third analyte and determine a concentration of the first analyte, of the second analyte, and of the third analyte” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Shah teaches the sensor device that functions as a multi-analyte sensor for determining the concentration of various analytes [Para. 0006, 0033, 0058, 0074, 0093 of Shah] and the added processing and communications unit including an electric circuit coupled to a data processing unit, where the sensor device is electrically coupled to the sensor device and can produce data on the analytes such as the chemical concentration (Para. 0142 and 0116 of Wang), and thus, the prior art device of modified Shah is specifically configured for performing the claimed functions.
Regarding claim 23, the sensor device of claim 20, Shah is silent to wherein the catalyst includes glucose oxidase (GOx) immobilized inside a permeable polymer film comprising tetrathiafulvalene (TTF) mediator layer attached to the first electrode.
However, Shah teaches the enzyme catalyst is glucose oxidase [Para. 0050 and 0060].
Wang discloses an electrochemical sensor device with electrodes disposed over a substrate for glucose testing (Abstract and Para. 0004, 0009). Further, Wang discloses an electrochemical transducer layer including functionalizing the working electrode surface with tetrathiafulvalene (TTF) electroactive redox mediator layer and depositing a layer of chitosan, a biocompatible polymer on the electrode (Para. 0313). An enzyme catalyst [such as lactate oxidase] is immobilized inside the permeable polymer film/electrochemical transducer layer by tethering the active site of the enzyme catalyst (Para. 0313) Additionally, Wang discloses that chitosan can also be utilized as a polymeric matrix for immobilizing the enzyme glucose oxidase on an electrode surface (Para. 0017 and 0130). The disclosed electrochemical transducer layer is beneficial because: TTF enhances transduction (Para. 0333) and lowers the oxidation potential and has more stable performance (Para. 0354) and chitosan impedes the efflux of the biocatalytic backbone from the enzyme-electrode to the aqueous environment (Para. 0313).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sensor device in modified Shah, which includes a glucose oxidase catalyst, by providing a permeable polymer film comprising a TTF mediator layer attached to the first electrode and a layer comprising chitosan with the glucose oxidase catalyst immobilized inside the permeable polymer film, as taught by Wang, since Wang teaches this is beneficial because TTF enhances transduction (Para. 0333 of Wang), lowers the oxidation potential and has more stable performance (Para. 0354 of Wang), and tethers the active site of enzyme catalysts such as oxidases on the electrode surface of the working electrode (Para. 0313 of Wang) and chitosan impedes the efflux of the biocatalytic backbone from the enzyme-electrode to the aqueous environment (Para. 0313 of Wang). Furthermore, 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].
The limitation “wherein the glucose is detectable at a millimolar (mM) concentration via a reaction involving a reoxidation of a reduced form of TTF to yield a current response detectable at the first electrode that is proportional to a concentration of the glucose in the μL sample of the whole blood” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, modified Shah teaches the above sensor device that is specifically configured to perform the functional limitations above (Modified Shah as outlined in the rejection above yields a first functionalization layer on the first electrode, wherein the glucose oxidase catalyst is immobilized inside a permeable polymer film comprising TTF mediator layer attached to the first electrode, and a glucose analyte [see rejection above, Para. 0058 – 0060 of Shah and Para. 0313 of Wang]. Furthermore, Shah teaches the sensor can be in contact with blood as typically occurs for example with intravenous sensors and can be used to sense analytes of interest in one or more physiological environment, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient [Para. 0087, 0008, 0015]. The analyte sensors are typically designed to be implantable within a mammal and the analyte sensor elements “electrodes” are adapted to contact and sense analytes, the electrochemical sensor including at least one electrode for contacting an analyte to be assayed [Para. 0086, 0009, 0092, 0065 of Shah]. Since the prior art does disclose a sensing device comprising substantially the same elements or components as that of the applicant, it is contended that the sensing device of the prior art is capable of detecting glucose at a millimolar concentration via a reaction involving a reoxidation of a reduced form of TTF to yield a current response detectable at the first electrode that is proportional to a concentration of the glucose in the μL sample of the biological fluid. Accordingly, products of identical chemical composition cannot have mutually exclusive properties, and thus, the claimed property (i.e. wherein the glucose is detectable at a millimolar (mM) concentration via a reaction involving a reoxidation of a reduced form of TTF to yield a current response detectable at the first electrode that is proportional to a concentration of the glucose in the μL sample of the biological fluid), is necessarily present in the prior art material. [See MPEP 2112.01 (II)])
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shah in view of Niroula, Bertin, and Munje as applied to claim 20 above, and further in view of Moerman et al. (US-20150031053-A1).
Regarding claim 24, the sensor device of claim 20, wherein the capture antibody of the second functionalization layer includes an anti-insulin antibody that is attached to the second electrode via the SAM, and with a detection antibody comprising horseradish peroxidase (HRP) attachable to the anti-insulin antibody to provide an enzyme label and a molecular complex comprising 2O2) to provide an enzymatic substrate/mediator (Modified Shah as outlined in the rejection of claim 20 above yields an anti-insulin capture antibody in the second analyte sensing constituent layer attached to the second working electrode via a SAM and a HRP-labeled detection antibody attachable to the anti-insulin antibody to provide an enzyme label, and a molecular complex comprising hydroquinone and hydrogen peroxide to provide an enzymatic substrate/mediator [see rejection of claim 20 above; Scheme 1 and Page 13040, Col. 1, Para. 1-2, Page 13039, Col. 2, Para. 2-3 of Niroula; Para. 0191, 0212, 0321, Figure 1 and Figure 11A of Bertin; Para. 0074 and Fig. 2 of Shah).
Modified Shah is silent to a molecular complex comprising 3,3',5,5'-tetramethylbenzidine (TMB).
However, Modified Shah as outlined in the rejection of claim 20 above yields a molecular complex comprising hydroquinone and hydrogen peroxide (see rejection of claim 20 above, Scheme 1 and Page 13040, Col. 1, Para. 1-2 of Niroula).
Moerman teaches a home test or point of care test device that can both detect blood glucose and insulin levels for diabetic patients (Abstract). Moerman further teaches an electron transfer mediator corresponding to a molecular complex to provide an enzymatic substrate/mediator which can be hydroquinone or 3,3,5,5-tetramethylbenzidine [Para. 0157].
Modifed Shah and Moerman are considered analogous art to the claimed invention because they are in the same field of electrochemical sensors [Abstract of Shah and Moerman]. It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the hydroquinone mediator of modified Shah with 3,3,5,5-tetramethylbenzidine as taught by Moerman, since Moerman teaches either hydroquinone or 3,3,5,5-tetramethylbenzidine can function as electron transfer mediators [Para. 0157 of Moerman]. Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]). Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
The limitation “wherein the insulin is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a reaction ” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, modified Shah teaches the above sensor device that is specifically configured to perform the functional limitations above (Modified Shah as outlined in the rejection above yields a second functionalization layer on the second electrode, including a anti-insulin capture antibody that is attached to the second electrode via a SAM, a HRP-linked detection antibody attachable to the anti-insulin antibody as an enzyme label and a molecular complex comprising TMB/hydrogen peroxide as an enzymatic substrate/mediator [see rejection above, Para. 0074 and Fig. 2 of Shah; Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2 of Niroula and Para. 0212 of Bertin]. Furthermore, Shah teaches the sensor can be in contact with blood as typically occurs for example with intravenous sensors and can be used to sense analytes of interest in one or more physiological environment, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient [Para. 0087, 0008, 0015]. The analyte sensors are typically designed to be implantable within a mammal and the analyte sensor elements “electrodes” are adapted to contact and sense analytes, the electrochemical sensor including at least one electrode for contacting an analyte to be assayed [Para. 0086, 0009, 0092, 0065 of Shah]. Additionally, Niroula teaches their surface chemistry is beneficial for measuring serum insulin concentrations with picomolar detection levels [Page 13042, Col. 1, Para. 2 of Niroula]. Since the prior art does disclose a sensing device comprising substantially the same elements or components as that of the applicant, it is contended that the sensing device of the prior art is capable of detecting insulin at a picomolar concentration in the μL sample of the biological fluid via a reaction with the detection antibody and a molecular complex. Accordingly, products of identical chemical composition cannot have mutually exclusive properties, and thus, the claimed property (i.e. wherein the insulin is detectable at a picomolar (pM) concentration in the μL sample of the biological fluid via a reaction with a detection antibody comprising horseradish peroxidase (HRP) attachable to the anti-insulin antibody to provide an enzyme label and a molecular complex comprising 3,3',5,5'-tetramethylbenzidine (TMB)/hydrogen peroxide (H2O2) to provide an enzymatic substrate/mediator), is necessarily present in the prior art material. [See MPEP 2112.01 (II)]).
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shah as applied to claim 26 above, in view of Niroula et al. (Combined covalent and noncovalent carboxylation of carbon nanotubes for sensitivity enhancement of clinical immunosensors, 2016, ChemComm, 52, Pages 13039-13042) and Munje et al. (Lancet-free and label-free diagnostics of glucose in sweat using Zinc Oxide based flexible bioelectronics, 2017, Sensors and Actuators B, 238, Pages 482-490).
Regarding claim 27, the sensor device of claim 26, the limitation “wherein the first electrode is configured to sense the first analyte by an enzymatic or direct electrochemical detection” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Shah teaches the first working electrode in the working electrode array that is specifically configured to perform the functional limitations above (Shah teaches the first electrode 104 of the array of working electrodes has a first analyte sensing constituent which includes an enzyme, glucose oxidase, which catalyzes the conversion of glucose “first analyte” to hydrogen peroxide and gluconolactone. The hydrogen peroxide diffuses to the electrode where it can be reacted to form oxygen and a proton to produce a current that is proportional to the glucose concentration and the change in concentration can be measured by measuring the change in the current at the electrode of the conductive constituent for detection of glucose at the first working electrode by enzymatic electrochemical detection [Para. 0082, 0068, 0073, 0098; Fig. 2 and 4]).
Regarding the limitation “the second electrode is configured to sense the second analyte by an immunosensing detection” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114.
Shah teaches an analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4] for the management of diabetes and the monitoring of fluids of the human body of diabetics [Para. 0005 and 0122]. Shah further teaches the analyte sensing device is made so that at least two of the analyte sensor elements in the analyte sensing device sense different analytes [claim 22 and Para. 0133] and the working electrode may be made from gold [Para. 0065]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon [Para. 0133]. Furthermore, Shah expressly teaches other useful analyte sensing constituents can be formed to include antibodies whose interaction with a target analyte is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of an analyte in a sample [Para. 0074].
Niroula teaches an electrochemical insulin immunosensor for measuring insulin levels [the analyte] in human serum for type 1 and type 2 diabetes (Scheme 1 and Page 13039, Col. 2, Para. 2; Page 13042, Col. 1, Para. 2). Niroula discloses a gold electrode with a capture antibody which is a monoclonal insulin antibody [corresponding to an anti-insulin antibody] attached to the electrode via chemically carboxylated multiwalled carbon nanotubes, and EDC, NHS for covalent attachment with the lysine resides of the antibody surface (Scheme 1 and Page 13039, Col. 2, Para. 3). Niroula teaches this configuration is beneficial for monitoring current signals, which are proportional to the concentration of bound serum insulin on the gold sensor surface [Scheme 1 and Page 13040, Col. 1, Para. 1-2]. Furthermore, this surface chemistry is beneficial for measuring serum insulin concentrations with direct type 1 and type 2 diabetes relevant picomolar detection levels [Page 13042, Col. 1, Para. 2]
Given the teachings of Shah regarding the analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon and the analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [electrodes] adapted to sense different analytes simultaneously for the management of diabetes and the monitoring of fluids of the human body of diabetics, it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the antibody in the second analyte sensing constituent attached to the second gold electrode of Shah with an anti-insulin capture antibody, as taught by Niroula, since Niroula teaches this configuration is beneficial for monitoring current signals, which are proportional to the concentration of bound serum insulin on the gold sensor surface [Scheme 1 and Page 13040, Col. 1, Para. 1-2 of Niroula] and this surface chemistry is beneficial for measuring serum insulin concentrations with direct type 1 and type 2 diabetes relevant picomolar detection levels [Page 13042, Col. 1, Para. 2 of Niroula]. Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]).
In the instant case, Modified Shah as outlined in the rejection above yields an anti-insulin capture antibody in the second functionalization layer on the second working electrode, the second working electrode being capable of and specifically configured for performing the functional limitations above of sensing the second analyte by an immunosensing detection as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements “electrode” after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample [Para. 0074 of Shah; Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2 of Niroula].
Regarding the limitation “the third electrode is configured to sense the third analyte by a competitive immunosensing detection is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114.
Shah teaches an analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4] for the management of diabetes and the monitoring of fluids of the human body of diabetics [Para. 0005 and 0122]. Shah further teaches the analyte sensing device is made so that at least two of the analyte sensor elements in the analyte sensing device sense different analytes [claim 22 and Para. 0133] and the working electrode may be made from gold [Para. 0065]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon [Para. 0133]. Furthermore, Shah expressly teaches other useful analyte sensing constituents can be formed to include antibodies whose interaction with a target analyte is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of an analyte in a sample [Para. 0074].
Munje discloses a wearable, flexible electrochemical biosensor for the label-free, low-volume and ultrasensitive detection of glucose and cortisol [Abstract]. Munje teaches the electrochemical immunoassay for cortisol detection includes a cortisol capture antibody that binds to cortisol antigen, and the cortisol capture antibody is immobilized to the electrode surface via DSP linker molecule “self-assembled monolayer” [Fig. 1 and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3]. This configuration is beneficial for an electrochemical immunoassay for cortisol detection [Fig. 1 and Abstract] and this would be beneficial because glucose and cortisol are two valuable molecules that have physiological interconnection [Page 482, Col. 2, Para. 1]. Cortisol is a glucocorticoid hormone that plays an important role in regulation of glucose metabolism, and it enhances the expression of enzymes involved in glucogenesis, to maintain the glucose levels in plasma. The direct correlation between glucose and cortisol levels in case of Type 2 diabetes patients has been well established. Recent studies have shown that the disturbance in circadian rhythm (influenced by cortisol) may increase both fasting and postprandial plasma glucose concentrations through inadequate pancreatic insulin secretion. Therefore, simultaneous monitoring of these molecules can be used to better predict the onset of diabetes and/or stress related symptoms as well as monitoring the diabetic conditions [Page 482, Col. 2, Para. 1].
Given the teachings of Shah regarding the analyte sensor apparatus is made so that the plurality of analyte sensor elements have a plurality of different analyte sensor membranes disposed thereon and the analyte sensing device adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements [electrodes] adapted to sense different analytes simultaneously for the management of diabetes and the monitoring of fluids of the human body of diabetics, it would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the antibody in the third analyte sensing constituent attached to the third gold electrode of Modified Shah with a cortisol capture antibody, as taught by Munje, since Munje teaches this configuration would be beneficial for an electrochemical immunoassay for cortisol detection [Fig. 1 and Abstract of Munje] and would be beneficial because glucose and cortisol are two valuable molecules that have physiological interconnection [Page 482, Col. 2, Para. 1 of Munje] and simultaneous monitoring of these molecules can be used to better predict the onset of diabetes and/or stress related symptoms as well as monitoring the diabetic conditions [Page 482, Col. 2, Para. 1 of Munje]. Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]).
In the instant case, Modified Shah as outlined in the rejection above yields a cortisol capture antibody in the third functionalization layer on the third working electrode, the third working electrode being capable of and specifically configured for performing the functional limitations above of sensing the third analyte by competitive immunosensing detection as the antibody whose interaction with the target analyte produces a detectable signal that can be sensed by the electrically conductive elements “electrode” after interacting with the target analyte whose presence is to be detected for electrochemically determining the concentration of the analyte in the sample and the cortisol capture antibody is capable of binding cortisol antigen to perform competitive immunosensing detection [Para. 0074 of Shah; Fig. 1, Abstract and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3 of Munje].
Allowable Subject Matter
Claims 11-19 are allowed.
Claim 25 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art of record does not teach or suggest the claimed invention as a whole, with particular attention to the following limitations of the independent claim 11: “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction”.
Claim 25 would be allowable for disclosing the following limitations: “wherein the capture antibody of the third functionalization layer includes a cortisol capture antibody that is attached to the third electrode via the SAM, and wherein the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction”.
The closest prior art to the present application is Shah et al. (US20060076236A1), Wang et al. (US 20170325724 A1), Niroula et al. (Combined covalent and noncovalent carboxylation of carbon nanotubes for sensitivity enhancement of clinical immunosensors, 2016, ChemComm, 52, Pages 13039-13042), Moerman et al. (US-20150031053-A1), and Munje et al. (Lancet-free and label-free diagnostics of glucose in sweat using Zinc Oxide based flexible bioelectronics, 2017, Sensors and Actuators B, 238, Pages 482-490).
As outlined in the non-final rejection above, Shah teaches an analyte sensing device 100 adapted to function as multi-analyte sensor on a single chip, with multiple individual sensor elements adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]), comprising: a base layer 102 [Fig. 2; Para. 0055]); an array of working electrodes where the sensor has two, three, or four or more working electrodes on the base layer 102 [Para. 0066, 0021, 0040, 0055; Fig. 2 and 4]), with multiple individual sensor elements [24 electrodes as shown in Fig. 4] adapted to sense different analytes simultaneously [Para. 0093, Fig. 2; Fig. 4]. Shah further teaches the analyte sensing device is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon and is made so that at least two of the analyte sensor elements “electrodes” in the analyte sensing device sense different analytes [claim 22 and Para. 0133]. Shah expressly teaches the first analyte is glucose and the analytes include lactate [see e.g., Para. 0011, claim 5]). Shah further teaches the sensor can be in contact with blood as typically occurs for example with intravenous sensors and can be used to sense analytes of interest in one or more physiological environment, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient [Para. 0087, 0008, 0015]. The analyte sensors are typically designed to be implantable within a mammal and the analyte sensor elements “electrodes” are adapted to contact and sense analytes, the electrochemical sensor including at least one electrode for contacting an analyte to be assayed [see, e.g. element 104 in FIG. 2] [Para. 0086, 0009, 0092, 0065]. Shah teaches analyte sensing constituent 110 “functionalization layer” disposed on the electrodes of the sensor [the sensor having three or more working electrodes] and the analyte sensing constituent can coat all of the various electrodes of the sensor [Para. 0068 and Fig. 2]. The analyte sensor apparatus is made so that the plurality of analyte sensor elements “electrodes” have a plurality of different analyte sensor membranes “functionalization layers” disposed thereon [Para. 0133; Fig. 2 and 4]. The analyte sensor 100 includes a reference electrode and a counter electrode or a combined reference and counter electrode where the counter and reference electrodes necessary for electrochemical sensor function may be common to the entire array, or located within each well. The conductive layer is disposed upon the base layer “substrate” where the conductive layer includes a working electrode, a reference electrode and a counter electrode [corresponding to disposed on the substrate] [Para. 0066, 0056, 0040, 0015]). However, Shah is silent to the particulars of claimed the third functionalization layer including a cortisol capture antibody that is attached to the third electrode via a self-assembled monolayer (SAM) and a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP). Therefore, Shah does not teach or suggest “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction” as required by claim 11 and claim 25.
Wang discloses an electrochemical sensor device with electrodes disposed over a substrate for glucose testing (Abstract and Para. 0004, 0009). Further, Wang discloses an electrochemical transducer layer including functionalizing the working electrode surface with tetrathiafulvalene (TTF) electroactive redox mediator layer and depositing a layer of chitosan, a biocompatible polymer on the electrode (Para. 0313). An enzyme catalyst [such as lactate oxidase] is immobilized inside the permeable polymer film/electrochemical transducer layer by tethering the active site of the enzyme catalyst (Para. 0313) Additionally, Wang discloses that chitosan can also be utilized as a polymeric matrix for immobilizing the enzyme glucose oxidase on an electrode surface, (Para. 0017 and 0130). The disclosed electrochemical transducer layer is beneficial because: TTF enhances transduction (Para. 0333) and lowers the oxidation potential and has more stable performance (Para. 0354) and chitosan impedes the efflux of the biocatalytic backbone from the enzyme-electrode to the aqueous environment (Para. 0313). Wang discloses an electrochemical transducer layer where the last layer, Nafion solution [corresponding to a sulfonated tetrafluoroethylene polymer] is applied to the electrode to act as a protective layer (Para. 0345). The disclosed electrochemical transducer layer is beneficial because Nafion serves as a protective layer for the electrode (Para. 0345). Wang teaches a pseudo counter/reference electrode that can be made of a Ag/AgCl ink (Para. 0126). However, Wang is silent to detection of cortisol and the particulars of the claimed third functionalization layer including a cortisol capture antibody that is attached to the third electrode via a self-assembled monolayer (SAM) and a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP). Therefore, Wang does not teach or suggest “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction” as required by claim 11 and claim 25.
Niroula teaches an electrochemical insulin immunosensor for measuring insulin levels [the analyte] in human serum (Scheme 1 and Page 13039, Col. 2, Para. 2). Niroula discloses a gold electrode with a capture antibody which is a monoclonal insulin antibody [corresponding to an anti-insulin antibody] attached to the electrode via chemically carboxylated multiwalled carbon nanotubes, and EDC, NHS for covalent attachment with the lysine resides of the antibody surface [corresponding to attaching the anti-insulin antibody via a self-assembled monolayer SAM] (Scheme 1 and Page 13039, Col. 2, Para. 3). Niroula further teaches a detection antibody comprising horseradish peroxidase (HRP) attachable to the anti-insulin monoclonal antibody to provide an enzyme label and a molecular complex comprising hydroquinone and hydrogen peroxide (H2O2) [Scheme 1 and Page 13039, Col. 2, Para. 3 and Page 13040, Col. 1, Para. 1-2]. Niroula teaches this configuration is beneficial since the HRP-labeled antibody catalyzed oxidation of hydroquinone to quinone in the presence of hydrogen peroxide, monitored as current signals, which are proportional to the concentration of bound serum insulin on the gold sensor surface [Scheme 1 and Page 13040, Col. 1, Para. 1-2]. Furthermore, this surface chemistry is beneficial for measuring serum insulin concentrations with direct type 1 and type 2 diabetes relevant picomolar detection levels [Page 13042, Col. 1, Para. 2]. However, Niroula is silent to detection of cortisol and the particulars of the claimed third functionalization layer including a cortisol capture antibody that is attached to the third electrode via a self-assembled monolayer (SAM) and a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP). Therefore, Niroula does not teach or suggest “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction” as required by claim 11 and claim 25.
Moerman teaches a home test or point of care test device that can detect both blood glucose and insulin levels for diabetic patients, the device being based on the simultaneous detection of insulin and glucose levels in a whole blood sample of the subject (Abstract and Para. 0001). The device includes an analyte reaction zone b) comprising at least two tracts, one for detecting blood glucose, and one for detecting blood insulin, the glucose and insulin measured using a single sensor system [Para. 0019-0020, 0030]. The insulin is bound by two antibodies: a first antibody, complexed with an enzyme label (701), and a second antibody, complexed with a magnetic particle (702), both present in the reaction zone. Outside the detection zone (513), e.g. in the reaction zone (512), a magnet (514) can be placed, which upon activation (514*), will draw away all magnetic bead-second antibody complexes from the detection zone. When insulin is present, it will be bound to the second antibody-magnetic bead and will be attracted to the magnet, together with the first antibody-enzyme complex. This reduces the amount of electrons produced at the site of the working electrode (508) and detection zone (513) [Para. 0108]. Moerman further teaches an electron transfer mediator corresponding to a molecular complex to provide an enzymatic substrate/mediator which can be hydroquinone or 3,3,5,5-tetramethylbenzidine [Para. 0157]. However, Moerman is silent to detection of cortisol and the particulars of the claimed third functionalization layer including a cortisol capture antibody that is attached to the third electrode via a self-assembled monolayer (SAM) and a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP). Therefore, Moerman does not teach or suggest “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction” as required by claim 11 and claim 25.
Munje discloses a wearable, flexible electrochemical biosensor for the label-free, low-volume and ultrasensitive detection of glucose and cortisol [Abstract]. Munje teaches the electrochemical immunoassay for cortisol detection includes a cortisol capture antibody that binds to cortisol antigen, and the cortisol capture antibody is immobilized to the electrode surface via DSP linker molecule “self-assembled monolayer” [Fig. 1 and Page 484, Col. 1, Para. 1-2 and Col. 2, Para. 3]. This configuration is beneficial for an electrochemical immunoassay for cortisol detection [Fig. 1 and Abstract] and this would be beneficial because glucose and cortisol are two valuable molecules that have physiological interconnection [Page 482, Col. 2, Para. 1]. Cortisol is a glucocorticoid hormone that plays an important role in regulation of glucose metabolism, and it enhances the expression of enzymes involved in glucogenesis, to maintain the glucose levels in plasma. The direct correlation between glucose and cortisol levels in case of Type 2 diabetes patients has been well established. Recent studies have shown that the disturbance in circadian rhythm (influenced by cortisol) may increase both fasting and postprandial plasma glucose concentrations through inadequate pancreatic insulin secretion. Therefore, simultaneous monitoring of these molecules can be used to better predict the onset of diabetes and/or stress related symptoms as well as monitoring the diabetic conditions [Page 482, Col. 2, Para. 1]. However, Munje is silent to the particulars of the claimed detection reaction including a a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP). Therefore, Munje does not teach or suggest “the cortisol is detectable at a picomolar (pM) concentration in the μL sample of the whole blood via a detection reaction with a cortisol detection antibody comprising cortisol-3-alkaline phosphatase (C-ALP) and 1-naphthyl phosphate (1-NPP) to provide an enzymatic label to catalyze or initiate the detection reaction” as required by claim 11 and claim 25.
The prior art whether taken individually or in combination would not disclose all of the cumulative limitations of claims 11 and 25. Claims 12-19 depend from claim 11 and are allowed for the same reasons above.
Conclusion
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/S.Y.O./Examiner, Art Unit 1794
/JAMES LIN/Supervisory Patent Examiner, Art Unit 1794
