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 1/17/2023 has been considered by the examiner.
Election/Restrictions
Applicant's election of Group I, Claims 1-10, without traverse in the reply filed on 01/07/2026 is acknowledged.
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 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
Regarding claim 2, claim 2 recites “the surface of a substrate”, which lacks antecedent basis, and it is unclear which surface (e.g., top surface, bottom surface, or all surfaces of the substrate) of the substrate does it refer to. Therefore, the scope of claim 2 is indefinite.
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 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.
Claims 1, 4-5 and 9-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dong et al. (An enzyme-free ultrasensitive electrochemical immunosensor for calprotectin detection based on PtNi nanoparticles functionalized 2D Cu-metal organic framework nanosheets, Sensors and Actuators B: Chemical, 2020, 308, 127687).
Regarding claim 1, Dong teaches an electrochemical biosensor for detection of a calprotectin antigen in a sample solution (an enzyme-free ultrasensitive electrochemical immunosensor for calprotectin detection in human serum [title, abstract, scheme 1, and the first paragraph in Col. 2 on page 2]), the electrochemical biosensor comprising:
a reference electrode (Ag/AgCl electrode as reference electrode [section 2.2]);
a counter electrode (platinum wire as auxiliary electrode [section 2.2]); and
a working electrode (modified GCE as the working electrode [section 2.2]) comprising a surface coated with an anti-calprotectin antibody (scheme 1B shows Au@MWCNTs of the GCE is coated with CALP monoclonal antibody Ab1 [sections 2.1 and 2.8]) configured to bind to the calprotectin antigen in the sample solution (scheme 1 shows the Ab1 is configured to bind to the calprotectin antigen [CALP] in the sample solution); and
“wherein the biosensor is configured to detect a concentration of the calprotectin antigen in the sample solution based on a resistance change at the surface of the working 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, Dong teaches the claimed biosensor, as outlined in the rejection above. Dong further teaches the current response increases along with the increasing CALP concentrations, as shown in Figs. 5A and 5B (section 3.6). Since current is inversely proportional to the resistance based on the Ohm’s law. Thus, the disclosed biosensor in Dong is configured to detect a concentration of the calprotectin antigen in the sample solution based on a resistance change at the surface of the working electrode (see Fig.5).
Regarding claim 4, Dong teaches the electrochemical biosensor of claim 1, and the limitation “wherein the surface of the working electrode is coated with an antibody solution of the anti-calprotectin antibody” is considered as a product-by-process limitation. The determination of patentability is based upon the product or apparatus structure itself. Patentability does not depend on its method of production or formation. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. See In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP § 2113). In the instant case, Dong teaches the surface of the working electrode is coated with the anti-calprotectin antibody, as outlined in the rejection of claim 1 above. Thus, the final product in the product-by-process claim is the same as or obvious from the product of Dong with the top surface of the working electrode coated with anti-CALP. Furthermore, Examiner notes that Dong does teach wherein the surface of the working electrode is coated with an antibody solution of the anti-calprotectin antibody (the modified GCE was incubated with 6µL Ab1 of 10 µg/mL at 4 oC [section 2.8]).
Regarding claim 5, Dong teaches the electrochemical biosensor of claim 4, wherein the concentration of the anti-calprotectin antibody in the antibody solution is 1 µg/mL to 20 µg/mL (the modified GCE was incubated with 6µL Ab1 of 10 µg/mL at 4 oC [section 2.8]; the disclosed 10 µg/mL falls within the claimed concentration range).
Regarding claim 9, Dong teaches the electrochemical biosensor of claim 4, wherein the antibody solution consists of the anti-calprotectin antibody and a bovine serum (the modified GCE was incubated with Ab1, then 5 µL BSA solution was dropped onto the surface of the modified electrode and reacted for 10 min to block the nonspecific adsorption sites [section 2.8]; Thus, the antibody solution consists of anti-calprotectin antibody and a bovine serum [BSA]. Note that the disclosed coating method is the same as that adopted in this instant application: “The thiolated calprotectin antibodies are then coated onto the outer surface 26 of working electrode 20 by drop casting the anti-calprotectin antibody solution on the working electrode 20 and incubating the working electrode 20. …The blocking agent 30, such as bovine serum albumin (BSA), is added to the outer surface 26 of the working electrode 20 to block non-site specific binding of the calprotectin biomarker 32 with the anti-calprotectin antibody” [para. 0033] in PG-Pub of this instant specification).
Regarding claim 10, Dong teaches the electrochemical biosensor of claim 1, and “wherein the biosensor detects the concentration of the calprotectin antigen in the sample solution from 4 ng/mL to 240 ng/mL” 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, Dong teaches the claimed biosensor, as outlined in the rejection of claim 1 above. Dong further teaches the CALP immunosensor has a low detection limit of 137.7 fg/mL (abstract and section 3.6). Thus the disclosed biosensor is capable of performing the claimed function of detecting the concentration of the calprotectin antigen in the sample solution from 4 ng/mL to 240 ng/mL since the claimed concentration of CALP is above the low detection limit of 137.7 fg/mL of the disclosed biosensor.
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 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 2 is rejected under 35 U.S.C. 103 as being unpatentable over Dong, as applied to claim 1 above, and in view of Wang et al. (US20140106441A1).
Regarding claim 2, Dong teaches the electrochemical biosensor of claim 1, and is silent to wherein the reference electrode, the counter electrode, and the working electrode are formed on an electrode layer on the surface of a substrate.
Wang teaches bioaffinity sensors for detection of a target molecule (title and abstract), and further teaches a three-electrode system comprising a gold disk-shaped working electrode, an Ag pseudo-reference electrode, and a gold counter electrode, all of them screen-printed on a ceramic substrate. An insulating layer was printed over the exemplary electrode system, e.g., leaving the electric contacts and a working area uncovered [para. 0133].
Dong and Wang are considered analogous art to the claimed invention because they are in the same field of affinity based electrochemical biosensor comprising a three-electrode setup. 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 three electrodes in Dong to have the reference electrode, the counter electrode, and the working electrode are formed on an electrode layer on a top surface of a substrate, as taught by Wang, since Wang teaches suitable alternative three-electrode configuration of having the three electrodes integrated on the same substrate [para. 0133]. Furthermore, the use of a one-piece, integrated construction instead of the structure disclosed or taught in the prior art would have been within the ambit of a person of ordinary skill in the art. See In re Larson, 340 F.2d 965, 968, 144 USPQ 347, 349 (CCPA 1965) (see MPEP § 2144.04).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Dong, as applied to claim 1 above, and in view of Khammanivong et al. (S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma, Plos one, 2013, https://doi.org/10.1371/journal.pone.0069395) and Chatrathi et al. (Sandwich electrochemical immunoassay for the detection of Staphylococcal enterotoxin B based on immobilized thiolated antibodies, Biosensors and Bioelectronics, 2007, 22, 2932-2938).
Regarding claim 3, Dong teaches the electrochemical biosensor of claim 1, wherein the anti-calprotectin antibody comprises a monoclonal anti-calprotectin antibody (CALP monoclonal antibody [section 2.1]).
Dong is silent to wherein the monoclonal anti-calprotectin antibody is a thiolated mouse monoclonal anti-calprotectin antibody.
Khammanivong teaches the use of mouse anti-S100A8/A9 antibody 27E10 to immunoprecipitated S100A8/A9 (section of Co- immunoprecipitated on page 11). Using 27E10 antibody (specific for S100A8/A9 complex) for capture, PP2A co-immunoprecipitated with S100A8/A9 (Fig.5) (section of S100A8/A9 interacts with PP2A phosphatase and increases activity on page 4). S100A8/A9 (calprotectin) is a calcium-binding heterodimeric protein complex implicated in cell cycle regulation (abstract). Thus, Khammanivong teaches mouse anti-S100A8/A9 antibody 27E10 specific for S100A8/A9 (calprotectin).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the CALP monoclonal antibody in Dong with mouse anti-S100A8/A9 antibody 27E10, as taught by Khammanivong, since Khammanivong teaches mouse anti-S100A8/A9 antibody 27E10 as suitable alternative antibody specific for calprotectin (section of Co- immunoprecipitated on page 11 and section of S100A8/A9 interacts with PP2A phosphatase and increases activity on page 4). Thus, modified Dong teaches wherein the anti-calprotectin antibody comprises a mouse monoclonal anti-calprotectin antibody.
Modified Dong is silent to wherein the mouse monoclonal anti-calprotectin antibody is thiolated.
Dong further teaches the anti-calprotectin antibody is coated on the surface of Au@MWCNTs of the GCE (section 2.8) .
Chatrathi teaches electrochemical immunoassay based on immobilized thiolated antibodies on a gold surface (abstract), and further teaches the thiol-gold chemistry is very well established and can be used to efficiently control the antibody immobilization (the 2nd paragraph in Col. 1 on page 2933). Fig.1 shows thiolated antibodies immobilized on the gold electrode.
Given the teachings of Dong regarding the anti-CALP antibody is immobilized on the surface of Au@MWCNT, and the teachings of Chatrathi regarding the use of the well established thiol-gold chemistry to efficiently control the antibody immobilization, 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 mouse monoclonal anti-calprotectin antibody in modified Dong to thiolated mouse monoclonal anti-calprotectin antibody, since the well-established thiol-gold chemistry would efficiently control the antibody immobilization (the 2nd paragraph in Col. 1 on page 2933 in Chatrathi).
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Dong, as applied to claim 4 above, and in view of Zorea et al. (Probing antibody surface density and analyte antigen incubation time as dominant parameters influencing the antibody-antigen recognition events of a non-faradaic and diffusion-restricted electrochemical immunosensor, Anal. Bioanal. Chem., 2020, 412, 1709-1717).
Regarding claims 6-8, Dong teaches the electrochemical biosensor of claim 4, and is silent to wherein the concentration of the anti-calprotectin antibody in the antibody solution is 4 µg/mL to 6 µg/mL (of claim 6); wherein the concentration of the anti-calprotectin antibody in the antibody solution is 4.5 µg/mL to 5.5 µg/mL (of claim 7); and wherein the concertation of the anti-calprotectin antibody in the antibody solution is 5 µg/mL (of claim 8).
Zorea teaches electrochemical sensors based on antibody-antigen recognition events are commonly used for the rapid, label-free, and sensitive detection of various analytes (abstract). Fig.1 shows antibody immobilized on the surface of a working electrode for detecting antigen. The working electrodes are incubated with two antibody concentrations, 1 µg/ µL (high density) and 100 pg/ µL (low density) for detecting 5 different antigen concentrations (section of Antibody incubation characterization and antigen detection measurements using non-faradaic electrochemical impedance spectroscopy in Col. 2 on page 1711). The antibody probe’s density on the surface of the electrode can affect the probe’s conformation and the measured electrochemical signal. The high-density antibody-modified electrode resulted in increased RMS roughness (2.2 ±0.2 nm) than the low-density antibody-modified electrode (1.28 ± 0.04 nm). Taken together, our results indicate that antibodies under low-density conditions are arranged differently on the electrode than under high-density conditions (the 1st paragraph in Col. 2 on page 1713). For high-density-antibody-modified electrode, the solution resistance element increased as antigen accumulated, whereas in the low-density-antibody-modified electrode, it decreased. The limit of detection (LOD) for each antibody density (Fig.6b) was, 2.2 µM and 0.26 µM for the high- and low-density antibody-modified electrode, respectively (the first paragraph in Col. 1 on page 1715). For high antibody density, the antibodies rearrange in a vertical conformation, whereas for low antibody density the antibodies are in a horizontal conformation (Conclusions). Thus, Zorea teaches the concertation of the antibody in the antibody solution used to immobilize/coat the antibody on the working electrode for the detection of antigen in electrochemical immunosensors affects the conformation of the antibody prior to the antigen-antibody binding, the root-mean-square (RMS) roughness of the antibody coating, and limit of detection of the antigen. Therefore, the concentration of the antibody in the antibody solution is a result effective variable in electrochemical immunosensors based on antibody-antigen binding.
Since Dong also teaches coating anti-calprotectin antibody on the surface of the working electrode with the antibody solution for the detection of the CALP antigen, as outlined in the rejection of claim 4 above, and Zorea teaches the concentration of the antibody in the antibody solution is a result effective variable in electrochemical immunosensors based on the antibody-antigen binding, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the concertation of the anti-calprotectin antibody in the antibody solution in Dong is also a result effective variable, and would affect the conformation of the antibody prior to the antigen-antibody binding, the RMS roughness of the antibody coating, and limit of detection of the antigen.
As the conformation of the antibody prior to the antigen-antibody binding, the RMS roughness of the antibody coating, and the limit of detection of the antigen are variables that can be modified, among others, by adjusting the antibody concentration in the antibody solution for coating the antibody on the working electrode, the precise concertation of the anti-calprotectin antibody would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed concertation of the anti-calprotectin antibody in instant claims 6-8 cannot be considered critical. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the concertation of the anti-calprotectin antibody in modified Dong to obtain the desired concertation of the anti-calprotectin antibody in the antibody solution in order to obtain the desired detection performance for detecting CALP. “[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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
Conclusion
The prior arts made of record and not relied upon are considered pertinent to applicant's disclosure: Dulay et al. (Electrochemical detection of celiac disease-related anti-tissue transglutaminase antibodies using thiol-based surface chemistry, Biosensors and Bioelectronics, 2011, 26, 3852-3856) teaches immobilize antibodies on electrode surface with the thiol-based surface chemistry. Perez-Fernandez et al. (Electrochemical (Bio)Sensors for Pesticides Detection Using Screen-Printed Electrodes, Biosensors, 2020, 10, 32) teaches SPE on a substrate for electrochemical biosensors. Deng et al. (CN102507688A) teaches three electrode system printed on a substrate for an electrochemical biosensor.
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/SHIZHI QIAN/Examiner, Art Unit 1795