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 .
Status of Claims
Claims 1-20 are pending and examined herein.
Drawings
The drawings are objected to because insufficient quality of spectra and grey spectra lines in black-and-white drawings in Fig. 5, 7A and 9A prevent examination of the drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 2, 4, 12, and 14 are objected to because:
Claims 2, 4, 12, and 14 contain abbreviations AuNP. It should be completely spelled out in its first occurrence.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “antigen”, “captured antigens”, and “captured antigen”. It is unclear if the recited antigens are the same or different. Terminology should be consistent.
Claims 1 and 11 recite “pre-immobilizing an antibody/antigen”. It is unclear if the paper is provided with an antibody that was done during manufacturing or is it an active method step.
Claims 2 and 12 recite “the plasmonic paper is AuNP-loaded”. It is unclear if the claim is intending to recite a characteristic of the plasmonic paper as being AuNP-loaded or alternatively if the claim is intending to recite an active method step of loading the paper with AuNP.
Claims 3 and 13 contain the trademark/trade name Whatman. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a filter paper and, accordingly, the identification/description is indefinite.
Additionally, the claims recite grade 4 or 40 of this paper. The grade properties are not defined by the specification and therefore render the claims indefinite.
Claims 3-6 and 13-16 recite “about”. The term “about” is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For examination purposes, the term “about” is not given any patentable weight.
Claims 4 and 14 recite “the plasmonic paper is immersed in an AuNP suspension”. It is unclear if the claim is intending to recite a characteristic of the plasmonic paper as being immersed in an AuNP suspension or alternatively if the claim is intending to recite an active method step of immersing the paper in an AuNP suspension.
Claims 6 and 16 recite “the plasmonic paper treated with about 100 ng/mL antigens”. It is unclear at what step of the methods of claims 1 and 11 the recited antigen treatment step occurs because claim 1 does not recite antigen treatment and thus, the limitation lacks antecedent basis. It is also unclear if the diagnostic methods recited in parent claims 1 and 11 are getting limited to detection of antigens present at about 100 ng/mL concentration.
Claims 6 and 16 recite “Extrinsic Raman Labels”. Parent claims 1 and 11 already recite “Extrinsic Raman Labels”. It is unclear if claims 6 and 16 are referring to additional “Extrinsic Raman Labels” or the “Extrinsic Raman Labels” already recited in claims 1 and 11.
Claims 7 and 17 recite “the detecting step utilizes visual images”. It is unclear how the detection is performed: visually, by eye, or by taking images. The term “visual” usually means something related to seeing or sight. Images are taken by technical means. The combination of “visual” and “images” is confusing. The specification fails to disclose details of the detection step consistent with the claims and disclosed point-of-need ("PON') applications. This limitation will be interpreted in light of Fig. 5, 7A, and 9A disclosing signal intensity vs Raman shift.
Claims 8 and 18 recite “adding an additional layer of structurally diverse plasmonic nanoparticles”. It is unclear at which step of the methods of claims 1 and 11 the additional layers are added/introduced. Claims 1 and 11 do not recite preparation steps of the plasmonic paper or any layers of plasmonic nanoparticles.
Claims 9 and 19 are rejected because they depend from rejected claims 1 and 11.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5, and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Penn et al. (Anal Chem. 2013 Sep 17;85(18):8609-17) in view of Lopez et al. (Talanta. 2016; 146:388-93) and Singamaneni et al. (PGPub 2016/0257830), and as evidenced by Mekonnen et al. (Sensors and Actuators B Chemical, 2021, 345:130401).
Regarding claim 1, Penn teaches an immunoassay method using antibody-modified membrane as a flowthrough capture substrate for a nanoparticle-enabled SERS (Abstract). SERS is surface-enhanced Raman spectroscopy.
Specifically, Penn teaches:
providing plasmonic substrate prepared by immobilizing antibody on a gold-plated membrane filter (p. 8610, col. 1, par. 2);
introducing a sample solution to the plasmonic substrate to extract and concentrate antigen in the sample on the plasmonic substrate – “use of a syringe to flow the antigen” (id.);
passing Extrinsic Raman Labels through the plasmonic substrate to label captured antigens – flow “SERS labels through the capture membrane as a means to enhance binding kinetics and accelerate the SERS immunoassay (id. and Fig. 1); and
detecting captured antigen – Fig. 1 in step 3 teaches laser used for detection of the captured analyte. Since the immobilized antibody is goat anti-mouse IgG polyclonal antibody, then the mouse IgG it binds from the sample solution is an antigen for the goat anti-mouse IgG polyclonal antibody.
Although Penn does not specifically teach a diagnostic method, such limitation is drawn to intended use of the method and therefore the prior art only needs to be capable of performing the recited intended use. So long as the method of Penn is capable of detection for diagnostic purposes, it reads on the claims. Penn teaches detection of mouse IgG in serum (Abstract); therefore, it is considered capable of performing the intended use as diagnostic method.
Penn does not specifically teach plasmonic paper, an absorbing pad positioned under the plasmonic paper, and absorbing the remainder of the sample solution with the absorbing pad.
Regarding claim 1, Lopez teaches “SERS immunoassay based on the capture and concentration of antigen-assembled gold nanoparticles” (Title). Lopez also teaches an absorbing pad positioned under the plasmonic support for absorbing the remainder of the sample solution.
Specifically, Lopez teaches a filtration setup comprising a polycarbonate track etched membrane filter placed on top of four sheets of blot paper (pg. 389, col. 2, par. 1). The stack of the four sheets of blot paper is the absorbing pad of instant invention.
Penn and Lopez do not specifically teach plasmonic paper.
Regarding claim 1, Singamaneni teaches a method for multiplexed detection using bioplasmonic calligraphy ([0003]). The calligraphy approach allows creation of test domains on paper substrates using biofunctionalized plasmonic nanostructures as ink ([0033]). Singamaneni also teaches plasmonic paper.
Specifically, Singamaneni teaches that bioplasmonic paper is fabricated by immersing a paper substrate into a biofunctionalized AuNRs solution ([0042]) and a plasmonic ink comprising biofunctionalized nanostructures is deposited with a ballpoint pen ([0054] and [0056]) on Whatman #1 filter paper ([0067]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn of a SERS-based immunoassay method using a syringe to flow fluids (Fig. 1) with the absorbent pad as taught by Lopez, in order to provide a method for vertical flow SERS-based immunoassay, as an obvious matter of simple substitution of one known element (absorbent pad) for another (syringe-driven fluid flow) to obtain predictable results. One having ordinary skill in the art would have been motivated to use absorbent paper instead of a syringe because it allows running multiple samples at the same time or multiplexing (pg. 389, col. 2, par. 2) with minimal hands-on efforts. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above. Introducing a sample solution is inherent to all filter-based assays, regardless of the way the fluid is moved through the filter: pushed with a syringe or pulled through using an absorbent pad.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both absorbent pad and a syringe are widely known for driving a fluid through a capture membrane and can be used interchangeably.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn and Lopez of a SERS-based immunoassay method with the filter paper to prepare the plasmonic paper as taught by Singamaneni, in order to provide a method for vertical flow SERS-based immunoassay, as an obvious matter of simple substitution of one known element (paper filter of Singamaneni) for another (polycarbonate filter of Penn) to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because vertical flow assays are known for using different filters depending on the specific assay needs. For example, throughout the entire publication Mekonnen provides extensive evidence for using plasmonic paper in SERS assay applications (Abstract).
Regarding claim 2, Penn in view of Lopez, Singamaneni, and Mekonnen teaches the plasmonic paper is AuNP-loaded. Specifically, Singamaneni teaches preparation of plasmonic ink comprising AuNP-IgG conjugates ([0064] and [0065]).
Regarding claim 3, Penn in view of Lopez, Singamaneni, and Mekonnen teaches plasmonic paper is Whatman #1 filter paper (Singamaneni [0067]). Since Applicant has not disclosed that the specific pore sizes of 25 µm and 8 µm recited in the claim are for any particular purpose or solve any stated problem and the prior art teaches that the filter paper with the pore size 11 µm has been successfully used in a SERS-based assay it would have been obvious to one of ordinary skill in the art to consider additional grades of Whatman filter paper such as grade 4 or 40 during the course of routine optimization to obtain better results. The pore size of Whatman #1 filter paper is 11 µm falling between the pore sizes of Whatman filter paper grade 4 and 40 recited in claim 3.
Regarding claim 5, Penn teaches that 1.5 µg of goat anti-mouse IgG polyclonal antibody (150 μL, 10 μg/mL concentration) was immobilized on the gold-plated filter (pg. 8611, col. 1, par. 2). Since Applicant has not disclosed that 2 µg of antibody recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum amount of antibody for immobilization of the filter. Such optimizations are routine and the amount of antibody depends on specific properties of the filter paper, required binding capacity, and specific properties of an antibody.
Regarding claim 7, Penn teaches the detecting step utilizes visual images of the plasmonic paper. This limitation is interpreted in light of Fig. 5, 7A, and 9A disclosing signal intensity vs Raman shift. Specifically, Penn teaches measuring signal intensity vs Raman shift (Fig. 3A) and plotting SERS intensity at selected Raman shift value vs an experimental parameter (e.g., in Fig. 3B vs flow rate, or in Fig. 6 vs IgG concentration). Penn teaches the detecting step consistent with that of the specification (Fig. 5, 7A, and 9A).
Regarding claims 8-10, Penn in view of Lopez, Singamaneni, and Mekonnen teaches structurally diverse plasmonic nanoparticles, gold-based nanoparticles having a sphere gold.
Specifically, Singamaneni teaches that biofunctionalized nanostructures used in SERS assays include “biofunctionalized metal nanorods, biofunctionalized metal nanospheres, biofunctionalized metal nanoshells, biofunctionalized metal nanocubes, biofunctionalized metal nanobipyramids, biofunctionalized metal nanostars, biofunctionalized metal hollow nano structures, and combinations thereof. Suitable metals include gold, silver, and combinations thereof.” ([0035]). Metal nanospheres and gold metal meet the limitation of claim 9 reciting gold-based nanoparticles having a sphere gold.
Regarding the limitation of adding an additional layer of plasmonic nanoparticles and introducing an additional layer with plasmonic nanoparticles onto the plasmonic paper. Applicant claims adding an additional layer of plasmonic nanoparticles and introducing an additional layer with plasmonic nanoparticles onto the plasmonic paper, which is a duplication of parts previously known in the art. The duplication of parts has no patentable significance unless a new and unexpected result is produced (MPEP 2144.04). In the instant case Applicant fails to disclose any particular purpose or any known problem for which an additional layer of plasmonic nanoparticles should be used and fails to demonstrate the criticality of this specific limitation. Therefore, the duplication of layer is obvious in view of MPEP 2144.04:
In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a "web" which lies in the joint, and a plurality of "ribs" projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Penn in view of Lopez and Singamaneni, and as evidenced by Mekonnen, as applied to claim 1 above, and further in view of Lee et al. (Anal Chem. 2011 Dec 1;83(23):8953-8).
The teachings of Penn, Lopez, Singamaneni, and Mekonnen have been set forth above.
Regarding claim 4, Singamaneni teaches that bioplasmonic paper is fabricated by immersing a paper substrate into a biofunctionalized AuNRs solution ([0042]), but Penn, Lopez, Singamaneni, and Mekonnen fail to teach the plasmonic paper is immersed in an AuNP suspension for about 24 hours.
Regarding claim 4, Lee teaches “Highly Sensitive Surface Enhanced Raman Scattering Substrates Based on Filter Paper Loaded with Plasmonic Nanostructures” (Title). Lee also teaches the plasmonic paper is immersed in an AuNP suspension for about 24 hours.
Specifically, Lee teaches that laboratory filter paper was immersed in solution of gold nanorods for 2 days (Supplement, pg. 2, par. 1). Additionally, the reference teaches that incubation times of 12, 24, and 48 hours result in maximum binding of the gold nanorods (Fig. S3).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn, Lopez, Singamaneni, and Mekonnen for a SERS-based assay method with immersing the filter paper in a solution of gold nanoparticles as taught by Lee, in order to provide a method for vertical flow SERS-based immunoassay with incubation time that allows for maximum binding of nanoparticles. One having ordinary skill in the art would have been motivated to immerse the filter paper in a solution of gold nanoparticles to get maximum signal from the assay (Lee, Supplement, pg. 2, par. 1). This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.,
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references are similarly drawn to SERS-based assay methods, and Lee teaches that immersion of paper in gold nanoparticles results in a working SERS assay.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Penn in view of Lopez and Singamaneni and as evidenced by Mekonnen, as applied to claim 1 above, and further in view of Porter et al. (PGPub 2018/0031584).
The teachings of Penn, Lopez, Singamaneni, and Mekonnen have been set forth above.
Regarding claim 6, Penn teaches effects of different volumes (1, 3, and 9 mL) and concentrations of ERL on SERS intensity (pg. 8613, col. 2, last par. – pg. 8614, col. 1, par. 1-2, and Fig. 5). Specifically, Penn teaches that “the amount of antibody−antigen complexes formed is based on the absolute number of antigens or ERLs, rather than the antigen or ERL concentrations” (id.). However, Penn, Lopez, Singamaneni, and Mekonnen fail to teach 200 µl of Extrinsic Raman Labels (ERL) and 100 ng/mL concentration of antigens.
Regarding claim 6, Porter teaches methods for diagnosing tuberculosis using SERS-based immunoassay of LAM - a lipoglycan unique to mycobacteria ([0004] and [0005]).
Specifically, Porter teaches that the plasmonic substrate was exposed to 20.0 µl of a LAM-containing sample, rinsed, and then exposed to 20 µl of Extrinsic Raman Labels suspension ([0059]). Additionally, the reference teaches a calibration curve obtained using LAM-spiked buffer - LAM was spiked up to 10 ng/mL ([0069] and Fig. 5B).
Porter does not specifically teach 200 µl of Extrinsic Raman Labels. However, since Applicant has not disclosed that 200 µl of Extrinsic Raman Labels recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum volume of ERL to load in the assay. Such optimizations are routine and necessary because required ERL volume depends on the plasmonic filter surface area, and nanoparticles size and concentration.
Porter does not specifically teach 100 ng/mL concentration of antigens. However, since Applicant has not disclosed that 100 ng/mL concentration of antigens recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum antigen concentration. This concentration depends on a target analyte present in a sample and the surface density of the capture molecules immobilized on the plasmonic paper. Such optimizations are routine and necessary to achieve optimal assay performance.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn, Lopez, Singamaneni, and Mekonnen of a SERS-based assay method using plasmonic paper by employing volume of Extrinsic Raman Labels and concentration of antigens passed through the plasmonic paper as taught by Porter, in order to optimize the assay conditions. One having ordinary skill in the art would have been motivated to use already published starting conditions for this optimization to save time and resources. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because assay optimization is a routine and necessary step in assay development.
Claims 11-13, 15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Penn in view of Lopez, Singamaneni, Mink et al. (WO 2005/069,002), and as evidenced by Mekonnen.
Regarding claim 11, Penn teaches an immunoassay method using antibody-modified membrane as a flowthrough capture substrate for a nanoparticle-enabled SERS (Abstract). SERS is surface-enhanced Raman spectroscopy.
Specifically, Penn teaches:
providing plasmonic substrate prepared by immobilizing antibody on a gold-plated membrane filter (p. 8610, col. 1, par. 2);
introducing a sample solution to the plasmonic substrate to extract and concentrate antigen in the sample on the plasmonic substrate – “use of a syringe to flow the antigen” (id.);
passing Extrinsic Raman Labels through the plasmonic substrate to label captured antigens – flow “SERS labels through the capture membrane as a means to enhance binding kinetics and accelerate the SERS immunoassay (id. and Fig. 1); and
detecting captured analyte – Fig. 1 in step 3 teaches laser used for detection of the captured analyte.
Although Penn does not specifically teach a diagnostic method, such limitation is drawn to intended use of the method and therefore the prior art only needs to be capable of performing the recited intended use. So long as the method of Penn is capable of detection for diagnostic purposes, it reads on the claims. Penn teaches detection of mouse IgG in serum (Abstract); therefore, it is considered capable of performing the intended use as diagnostic method.
Penn does not specifically teach plasmonic paper, an antigen immobilized onto the plasmonic paper, an absorbing pad positioned under the plasmonic paper, and absorbing the remainder of the sample solution with the absorbing pad.
Regarding claim 11, Lopez teaches “SERS immunoassay based on the capture and concentration of antigen-assembled gold nanoparticles” (Title). Lopez also teaches an absorbing pad positioned under the plasmonic support for absorbing the remainder of the sample solution.
Specifically, Lopez teaches a filtration setup comprising a polycarbonate track etched membrane filter placed on top of four sheets of blot paper (pg. 389, col. 2, par. 1). The stack of the four sheets of blot paper is the absorbing pad of instant invention.
Penn and Lopez do not specifically teach plasmonic paper and an antigen immobilized onto the plasmonic paper.
Regarding claim 11, Singamaneni teaches a method for multiplexed detection using bioplasmonic calligraphy ([0003]). The calligraphy approach allows creation of test domains on paper substrates using biofunctionalized plasmonic nanostructures as ink ([0033]). Singamaneni also teaches plasmonic paper.
Specifically, Singamaneni teaches that bioplasmonic paper is fabricated by immersing a paper substrate into a biofunctionalized AuNRs solution ([0042]) and a plasmonic ink comprising biofunctionalized nanostructures is deposited with a ballpoint pen ([0054] and [0056]) on Whatman #1 filter paper ([0067]).
Penn, Lopez, and Singamaneni do not specifically teach an antigen immobilized onto the plasmonic paper and detecting captured antibodies.
Regarding claim 11, Mink teaches a rapid test for antibodies against HIV in urine (Abstract). Mink also teaches an antigen immobilized onto the plasmonic paper and detecting captured antibodies.
Specifically, Mink teaches methods suitable for rapid detection of endogenous urine antibodies directed against HIV viral coat proteins (Abstract and [0034]). The HIV proteins are antigens immobilized on a lateral flow assay device ([0007] and [0008]). The antigens capture anti-HIV antibodies present in urine samples. The captured anti-HIV antibodies are detected using colloidal gold conjugated to protein A or protein G ([0009]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn of a SERS-based immunoassay method using a syringe to flow fluids (Fig. 1) with the absorbent pad as taught by Lopez, in order to provide a method for vertical flow SERS-based immunoassay. One having ordinary skill in the art would have been motivated to use absorbent paper instead of a syringe because it allows running multiple samples at the same time or multiplexing (pg. 389, col. 2, par. 2) with minimal hands-on efforts. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above. Introducing a sample solution is inherent to all filter-based assays, regardless of the way the fluid is moved through the filter: pushed with a syringe or pulled through using an absorbent pad.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both absorbent pad and a syringe are widely known for driving a fluid through a capture membrane and can be used interchangeably.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn and Lopez for a SERS-based immunoassay method with the filter paper to prepare the plasmonic paper as taught by Singamaneni, in order to provide a method for vertical flow SERS-based immunoassay, as an obvious matter of simple substitution of one known element (paper filter of Singamaneni) for another (polycarbonate filter of Penn) to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because vertical flow assays are known for using different filters depending on the specific assay needs. For example, throughout the entire publication Mekonnen provides extensive evidence for using plasmonic paper in SERS assay applications (Abstract).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Penn, Lopez, Singamaneni, and Mekonnen for detection of an antigen using an immobilized antibody by employing detection of an antibody using an immobilized antigen as taught by Mink, in order to detect anti-HIV antibodies. One having ordinary skill in the art would have been motivated to make such a change to provide people with indication of their HIV status. Such combination would have been desirable to those of ordinary skill in the art, because the success of HIV treatment and prevention depends on HIV detection.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both sandwich formats: antibody-antigen-antibody-ERL (of Penn, Lopez, Singamaneni, and Mekonnen) and antigen-antibody-protein A-label (of Mink) are well-known in the art and can be used interchangeably with different labeling/detection methods.
Regarding claim 12, Penn in view of Lopez, Singamaneni, Mekonnen, and Mink teaches the plasmonic paper is AuNP-loaded. Specifically, Singamaneni teaches preparation of plasmonic ink comprising AuNP-IgG conjugates ([0064] and [0065]).
Regarding claim 13, Penn in view of Lopez, Singamaneni, Mekonnen, and Mink teaches plasmonic paper is Whatman #1 filter paper (Singamaneni [0067]). Since Applicant has not disclosed that the specific pore sizes of 25 µm and 8 µm recited in the claim are for any particular purpose or solve any stated problem and the prior art teaches that the filter paper with the pore size 11 µm has been successfully used in a SERS-based assay it would have been obvious to one of ordinary skill in the art to consider additional grades of Whatman filter paper such as grade 4 or 40 during the course of routine optimization to obtain better results. The pore size of Whatman #1 filter paper is 11 µm falling between the pore sizes of Whatman filter paper grade 4 and 40 recited in claim 3.
Regarding claim 15, Penn teaches that 1.5 µg of goat anti-mouse IgG polyclonal antibody (150 μL, 10 μg/mL concentration) was immobilized on the gold-plated filter (pg. 8611, col. 1, par. 2). Since Applicant has not disclosed that 2 µg of antibody recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum amount of antibody for immobilization of the filter. Such optimizations are routine and the amount of antibody depends on specific properties of the filter paper, required binding capacity, and specific properties of an antibody.
Regarding claim 17, Penn teaches the detecting step utilizes visual images of the plasmonic paper. This limitation is interpreted in light of Fig. 5, 7A, and 9A disclosing signal intensity vs Raman shift. Specifically, Penn teaches measuring signal intensity vs Raman shift (Fig. 3A) and plotting SERS intensity at selected Raman shift value vs an experimental parameter (e.g., in Fig. 3B vs flow rate, or in Fig. 6 vs IgG concentration). Penn teaches the detecting step consistent with that of the specification (Fig. 5, 7A, and 9A).
Regarding claims 18-20, Penn in view of Lopez, Singamaneni, Mekonnen, and Mink teaches structurally diverse plasmonic nanoparticles, gold-based nanoparticles having a sphere gold.
Specifically, Singamaneni teaches that biofunctionalized nanostructures used in SERS assays include “biofunctionalized metal nanorods, biofunctionalized metal nanospheres, biofunctionalized metal nanoshells, biofunctionalized metal nanocubes, biofunctionalized metal nanobipyramids, biofunctionalized metal nanostars, biofunctionalized metal hollow nano structures, and combinations thereof. Suitable metals include gold, silver, and combinations thereof.” ([0035]). Metal nanospheres and gold metal meet the limitation of claim 19 reciting gold-based nanoparticles having a sphere gold.
Regarding the limitation of adding an additional layer of plasmonic nanoparticles and introducing an additional layer with plasmonic nanoparticles onto the plasmonic paper. Applicant claims adding an additional layer of plasmonic nanoparticles and introducing an additional layer with plasmonic nanoparticles onto the plasmonic paper, which is a duplication of parts previously known in the art. The duplication of parts has no patentable significance unless a new and unexpected result is produced (MPEP 2144.04). In the instant case Applicant fails to disclose any particular purpose or any known problem for which an additional layer of plasmonic nanoparticles should be used and fails to demonstrate the criticality of this specific limitation. Therefore, the duplication of layer is obvious in view of MPEP 2144.04:
In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a "web" which lies in the joint, and a plurality of "ribs" projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Penn in view of Lopez, Singamaneni, Mekonnen, and Mink, as applied to claim 11 above, and further in view of Lee et al. (Anal Chem. 2011 Dec 1;83(23):8953-8).
The teachings of Lopez, Singamaneni, Mekonnen, and Mink have been set forth above.
Regarding claim 14, Singamaneni teaches that bioplasmonic paper is fabricated by immersing a paper substrate into a biofunctionalized AuNRs solution ([0042]), but Penn, Lopez, Singamaneni, Mekonnen, and Mink fail to teach the plasmonic paper is immersed in an AuNP suspension for about 24 hours.
Regarding claim 14, Lee teaches “Highly Sensitive Surface Enhanced Raman Scattering Substrates Based on Filter Paper Loaded with Plasmonic Nanostructures” (Title). Lee also teaches the plasmonic paper is immersed in an AuNP suspension for about 24 hours.
Specifically, Lee teaches that laboratory filter paper was immersed in solution of gold nanorods for 2 days (Supplement, pg. 2, par. 1). Additionally, the reference teaches that incubation times of 12, 24, and 48 hours result in maximum binding of the gold nanorods (Fig. S3).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn, Lopez, Singamaneni, Mekonnen, and Mink for a SERS-based assay method with immersing the filter paper in a solution of gold nanoparticles as taught by Lee, in order to provide a method for vertical flow SERS-based immunoassay with incubation time that allows for maximum binding of nanoparticles. One having ordinary skill in the art would have been motivated to immerse the filter paper in a solution of gold nanoparticles to get maximum signal from the assay (Lee, Supplement, pg. 2, par. 1). This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references are similarly drawn to SERS-based assay methods, and Lee teaches that immersion of paper in gold nanoparticles results in a working SERS assay.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Penn in view of Lopez, Singamaneni, Mekonnen, and Mink, as applied to claim 11 above, and further in view of Porter et al. (PGPub 2018/0031584).
The teachings of Penn, Lopez, Singamaneni, Mekonnen, and Mink have been set forth above.
Regarding claim 16, Penn teaches effects of different volumes (1, 3, and 9 mL) and concentrations of ERL on SERS intensity (pg. 8613, col. 2, last par. – pg. 8614, col. 1, par. 1-2, and Fig. 5). Specifically, Penn teaches that “the amount of antibody−antigen complexes formed is based on the absolute number of antigens or ERLs, rather than the antigen or ERL concentrations” (id.). However, Penn, Lopez, Singamaneni, Mekonnen, and Mink fail to teach 200 µl of Extrinsic Raman Labels (ERL) and 100 ng/mL concentration of antigens.
Regarding claim 16, Porter teaches methods for diagnosing tuberculosis using SERS-based immunoassay of LAM - a lipoglycan unique to mycobacteria ([0004] and [0005]).
Specifically, Porter teaches that the plasmonic substrate was exposed to 20.0 µl of a LAM-containing sample, rinsed, and then exposed to 20 µl of Extrinsic Raman Labels suspension ([0059]). Additionally, the reference teaches a calibration curve obtained using LAM-spiked buffer - LAM was spiked up to 10 ng/mL ([0069] and Fig. 5B).
Porter does not specifically teach 200 µl of Extrinsic Raman Labels. However, since Applicant has not disclosed that 200 µl of Extrinsic Raman Labels recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum volume of ERL to load in the assay. Such optimizations are routine and necessary because required ERL volume depends on the plasmonic filter surface area, and nanoparticles size and concentration.
Porter does not specifically teach 100 ng/mL concentration of antigens. However, since Applicant has not disclosed that 100 ng/mL concentration of antigens recited in instant claim is for any particular purpose or solves any stated problem, it would have been obvious for one of ordinary skill to discover the optimum antigen concentration. This concentration depends on a target analyte present in a sample and the surface density of the capture molecules immobilized on the plasmonic paper. Such optimizations are routine and necessary to achieve optimal assay performance.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Penn, Lopez, Singamaneni, Mekonnen, and Mink for a SERS-based assay method using plasmonic paper by employing volume of Extrinsic Raman Labels and concentration of antigens passed through the plasmonic paper as taught by Porter, in order to optimize the assay conditions. One having ordinary skill in the art would have been motivated to use already published starting conditions for this optimization to save time and resources. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because assay optimization is a routine and necessary step in assay development.
Conclusion
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/ALEXANDER ALEXANDROVIC VOLKOV/
Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677