DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of Group I (claims 1-5, 7-12, and 14-21) in the reply filed on10/31/2025 is acknowledged.
Applicant elected species (ii) Herpes Simplex Virus (HSV).
Group I claims 7-12 reads on elected species HSV and are under examination in this office action.
Group I claims 1-5, and 14-21 are withdrawn from consideration and examination because these claims read on un-elected species SARS-CoV-2 virus.
Group II (unelected group of invention) claims 6, 13, and 22 drawn to a method are withdrawn from consideration and examination.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Status of Claims
3. Claims 1-22 are pending.
4. Claims 1-6, and 13-22 are withdrawn from consideration due to restriction/species election.
5. Claims 7-12 that read on elected species HSV are being considered for examination.
Priority
6. This application is the U.S. national stage and is also a continuation- in-part of PCT/US2021/071789, filed October 8, 2021, which claims priority to U.S. Provisional Application No. 63/089,905, filed October 9, 2020, U.S. Provisional Application No. 63/134,690, filed January 7, 2021, and U.S. Provisional Application No. 63/155,963, filed March 3, 2021. The present application also claims priority to U.S. Provisional Application No. 63/489,494, filed March 10, 2023.
The instant claims 7-12 reciting HSV glycoprotein D (gD2) biosensor has subject matter support in CIP PCT/US2021/071789 and the application number 18/296,613 with a filing date of 10/08/2021 and in a provisional application 63/489494 filed on 03/10/2023 with the subject matter indicating incorporated in instant application number 18/296,613. Therefore, the instant claims 7-12 has priority date of 10/08/2021.
Information Disclosure Statement
7. Three information disclosure statements (IDSs) submitted on 06/08/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
8. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Applicant has listed many references in the specification on pages 76-89. References I listed 49 references (pages 76-80). References II listed 57 references (pages 80-86). Para [00234] listed additional references on pages 86-89.
9. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See Specification para [00232].
https://www.who.int/emergencies/diseases/novel-coronavirus-2019
48. https://www.ld.ru/w/multiplex/HSV-Kit-Brochure.pdf
49. https://handicare.blob.core.windows.net/media/254942/brosjyre-hsv.pdf
Claim Interpretation
10. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The instant claims 7 is interpreted to be directed to a device for assessing the presence of herpes simplex virus (HSV) in a biological sample comprising:
a substrate that includes a top surface and a back surface; and,
an electrode on the top surface of the substrate, wherein the electrode is functionalized with a detection moiety that binds HSV glycoprotein gD2.
According to the instant specification a substrate that includes a top surface and a back surface is comprised of bacterial cellulose membrane.
The instant claims 7-11 are directed to a device comprising a graphene electrode to which a binding or capturing or detecting moiety, Nectin-1 receptor or a HSV gD2 specific antibody is immobilized to detect and quantify presence of HSV in a biological sample. Based on the specification, the biosensor is impedimetric biosensors enabled for electrochemical diagnostic comprising detector moiety or binding moiety Nectin-1 receptor or a HSV gD2 specific antibody.
Claim 12 is directed to a device of claim 7 with an added limitation, further comprising a permselective membrane on the electrode. In light of the specification a preferred permselective membrane includes Nafion membrane that allows selective permeability based on size, and charge to enhance analyte (e.g. HSV gD2) detection sensitivity of the electrode.
Claim Rejections - 35 USC § 103
11. 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.
12. Claims 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Afsahi et al 2018 (Biosensors and Bioelectronics 100 (2018) 85–88), and further in view of Peña‑Bahamonde et al 2018 (J Nanobiotechnol (2018) 16:75), Gomes et al 2020 (Electrochimica Acta 349 (2020) 136341), Torres et al 2020 (Med Devices Sens. 2020;3:e10102), Bertucci et al 2003 (Journal of Pharmaceutical and Biomedical Analysis 32 (2003) 697-706), Giovine et al 2011 (PLoS Pathog. 2011 Sep;7(9): e1002277), Bhattarakosol et al 1990 (Arch Virol (1990) 115:89-100), and Young-Sook et al 2001 (J. Microbiol. Biotechnol, 20021, 11(2), 173-178).
Claims 7-11: Afsahi et al 2018 is in the viral antigen detection biosensor device art and teaches a novel portable graphene-based biosensor device enabled with a highly specific immobilized monoclonal antibody (detection moiety) for early detection of Zika virus NS1 antigen in a clinical sample from an infected human subject (See, abstract, entire article and Figures, supplementary data). Afsahi et al 2018 teaches graphene biosensor chip and antibody is immobilized on graphene chip along the PEG block, the antibody forms the dielectric in a liquid gated transistor with a graphene channel (See figure 1 and associated legend). The biosensor chips were then functionalized with the target sensing antibody, anti-Zika NS1 mouse mAb 6B1 (See, page 86 col 2 section 2.3.). The biosensor candidate graphene is a single layer, two-dimensional sheet of hexagonally arranged carbon atoms. The two-dimensional graphene material sheets every atom in a graphene is in direct contact with its environment and responds to electrostatic fluctuations, making it an ideal candidate for sensing applications and thus teaches instant claim 7 limitation a substrate that includes a top surface and a back surface (See, page 85 col 2). Graphene biosensor chips are read using the commercial Agile R100 system, the graphene biosensor chips are inserted into an electronic reader that applies a source-drain voltage across the graphene channel and a gate voltage between the applied liquid and the drain electrode of the graphene. There are 2 read-out channels available: the I-Response (current through the channel) and the C-Response (capacitance of biosensor to the liquid). In this study, the C-Response channel is used. Control of the system, as well as data readout is performed via the Agile Plus software, which is run on a PC attached to the system via USB (See page 86 col 1-2, page 87 Fig 1b). NHS amino or amine surface chemistry was used to build sensor chips ready for protein attachment (See, page 86, col 2). Afsahi et al 2018 teaches use of polyethylene glycol (PEG) as an effective blocker against non-specific interactions in general and specifically when covalently attached to graphene devices. Residual active NHS groups were first quenched using 3 mM amino-PEG5-alcohol (amino-PEG) pH 7.4 before a final quench with 1 M Ethanolamine pH 8.5 (See, page 86-87, section 2.3 Protein Immobilization). Biosensor chips are fabricated photolithography and plasma enhanced CVD is used to pattern and passivate graphene with Ti/Pt leads on 6” silicon wafers (See, page 86, section 2.1 Graphene biosensor fabrication) and the drain electrode of the graphene (See, page 86, col 2 para 1).
Afsahi et al 2018, as recited supra teaches a device (a biosensor comprising device) to detect Zika virus antigen sensed by a specific binding moiety, a monoclonal antibody, however, does not teach the claimed device comprising a substrate on which the electrode is mounted, and does not teach an electrode coated with binding moiety or antibody specifically to detect instant claim 7 HSV viral glycoprotein D (gD).
Peña‑Bahamonde et al 2018 teaches recent advances in graphene‑based biosensor technology comprising Graphene–Nafion composite film with applications in life sciences including pathogen detection such as viruses (Zika virus, Dengue virus, Rotavirus) and bacterial pathogen (E. coli) detection using specific antibody. Peña‑Bahamonde et al 2018 teaches Graphene cellulose nanopaper immunosensor design (See, Table 1) or Graphene cellulose microfiber immobilization platform for the electrode (See, Table 4) (See, abstract, page 2 Fig 1, page 4 col 2 para 2, Table 2, entire article).
The instant claim 7 limitation, a substrate that includes a top surface and a back surface is taught by disclosures of Gomes et al 2020, Torres et al 2020, and Peña‑Bahamonde et al 2018 that teaches bacterial cellulose membrane comprising nanofibers and small pore size mesh comprised in a biosensor design (See, entire articles by Gomes et al 2020 and, Torres et al 2020, and Peña‑Bahamonde et al 2018 - table 1, table 4).
Bertucci et al 2003 is in the art and teaches optical biosensor in studying herpes simplex virus glycoprotein D binding to target binding moiety nectin-1 receptor immobilized on the surface of the biosensor cuvette, bearing a carboxymethyl dextran layer. The immobilized receptor cuvette was then used for the binding experiments of the two glycoproteins. Bertucci et al 2003 teaches the binding of two recombinant forms of HSV glycoprotein D, gD(Δ290-299t) and gD(305t), and a recombinant form of the human cellular receptor for HSV, nectin1-Fc, by using an optical biosensor. The binding studies between soluble gD and members of the nectin family of cellular receptors. Comparative binding studies showed that despite the high level of conservation, human and murine nectin-1 receptors differ with respect to the binding properties to HSV virions and gD. HSV cellular receptors, i.e. human and murine nectin1, have been immobilized on the surface of the biosensor (See, abstract, entire article).
Giovine et al 2011 teaches the structure of Herpes Simplex virus glycoprotein D bound to the Human Receptor Nectin-1, the cell adhesion molecule nectin-1 (HveC, CD111) is the primary receptor for HSV-1 and HSV-2 on neurons, keratinocytes and epithelial cells (See, abstract, page 1).
Bhattarakosol et al 1990 teaches two monoclonal antibodies that specifically bind to HSV-2 glycoprotein gD2 (See, abstract, Fig 1, lands 5-6, table 2 Mabs gF-105 and gD106, see entire article).
Young-Sook et al 2001 teaches a monoclonal antibody SKS2v that recognizes or bind to glycoprotein D antigen of HSV-2 in western blot and sandwich ELISA, and immunofluorescence assay (See, abstract, page 176 Fig. 3 lane C, page 177 Fig. 4).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings of Afsahi et al 2018 on a device comprising a biosensor enabled to detect zika virus antigen bound to a specific monoclonal antibody coated on an electrode with the additional teachings of Peña‑Bahamonde et al 2018, Gomes et al 2020, and Torres et al 2020 on bacterial cellulose membrane use in biosensor, and further teachings of Bertucci et al 2003 and, Giovine et al 2011 on Nectin-1 (Nectin-1 receptor) that can bind both HSV-1 and HSV-2 gD that can provide a binding moiety (Nectin-1) to replace anti-Zika virus NS1 antigen Mab to arrive at a biosensor device that can detect both HSV 1 and HSV-2 glycoprotein D antigens (gD1 and gD2) in a sample from a subject or a laboratory cell culture grown HSV-1 and HSV-2 viruses. Alternatively, the teachings of Bhattarakosol et al 1990, and Young-Sook et al 2001 on HSV-2 gD (gD2) specific Mabs can be used to replace the Nectin-1 from the electrode to specifically detect HSV-2 glycoprotein D (gD2) to arrive at the invention of claims 7-11. One of ordinary skills in the art would have been motivated to modify the electrode coated with anti-Zika virus antibody comprised in device comprised a biosensor device of Afsahi et al 2018 with additional prior art teachings on Nectin-1 or HSV-2 glycoprotein D specific Mabs to develop a biosensor comprising device directed to detect HSV2 (anti-gD 2 Mab as a binding moiety) or both HSV-1 and HSV-2 (anti-gD Nectin-1 as a binding moiety for both gD1 and gD2) for rapid and sensitive diagnosis and for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 7-11 in view of the combined prior art teachings as recited supra and the availability of prior art teachings on graphene electrode-based biosensor devices in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions of claims 7-11. The instant claims 7-11 are prima facie obvious over the combined prior art teachings as recited supra. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
13. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Afsahi et al 2018 (Biosensors and Bioelectronics 100 (2018) 85–88), Peña‑Bahamonde et al 2018 (J Nanobiotechnol (2018) 16:75), Gomes et al 2020 (Electrochimica Acta 349 (2020) 136341), Torres et al 2020 (Med Devices Sens. 2020;3:e10102), Bertucci et al 2003 (Journal of Pharmaceutical and Biomedical Analysis 32 (2003) 697-706), Giovine et al 2011 (PLoS Pathog. 2011 Sep;7(9): e1002277), Bhattarakosol et al 1990 (Arch Virol (1990) 115:89-100), Young-Sook et al 2001 (J. Microbiol. Biotechnol, 20021, 11(2), 173-178), as applied to claim 7-11 above, and further as evidenced by Liu et al 1997 (J. Am. Chem. Soc. 1997, 119, 8720-8721), Fissell et al 2009 (Journal of Membrane Science 326 (2009) 58–63), and further in view of Monosik et al 2012 (Journal of Clinical Laboratory Analysis 26: 22–34 (2012)).
Claim 12: The combined teachings of Afsahi et al 2018, Peña‑Bahamonde et al 2018, Gomes et al 2020, Torres et al 2020, Bertucci et al 2003, Giovine et al 2011, Bhattarakosol et al 1990, and Young-Sook et al 2001 render obvious the device of claim 7 as recited supra. The applied teachings however do not expressively teach that silicon wafer used in coating of electrode is permselective.
Both Lit et al 1997 and Fissell et al 2009 provide the evidence that silicon wafers are known in the art as a permselective membrane (See, Liu et al 1997, page 8720, article title, col 1 para 1, col 2 para 2, Fig 1); silicon membrane as permselective (See, Fissell et al 2009, title, page 59 Fig 1, col 1 para 2). Thus, the device of claim 7 as rendered obvious by the combined prior art teachings is permselective as it comprises silicon wafers.
Based on instant specification, the permselective membrane comprises Nafion.
Monosik et al 2012 teaches Nafion membrane used for coating electrochemical biosensors in clinical diagnosis and the biosensor electrodes that have been constructed with a permselective nafion membrane functionalized graphene nanoplatelets (See, Monosik et al 2012, page 27, col 1 para 3, page 26, para 2).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Afsahi et al 2018, Peña‑Bahamonde et al 2018, Gomes et al 2020, Torres et al 2020, Bertucci et al 2003, Giovine et al 2011, Bhattarakosol et al 1990, and Young-Sook et al 2001 on a device of claim 7 with additional teachings of Monosik et al 2012 to comprise Nafion membrane on the electrode as permselective to arrive at device of claim 12 to detect HSV gD2 in a sample from a subject or cell culture grown HSV viruses (HSV-2 gD2) in a laboratory. One of ordinary skills in the art would have been motivated to modify the electrode with Nafion membrane to enhance robustness and sensitivity of the electrode for rapid and sensitive detection of HSV gD2 and for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 12 in view of the combined prior art teachings as recited supra and the availability of prior art teachings on graphene electrode-based biosensor devices in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions of claim 12. The instant claims 12 was prima facie obvious over the combined prior art teachings as recited supra. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
14. Relevant Prior Arts:
Nicola et al 1998. Monoclonal antibodies to distinct sites on herpes simplex virus (HSV) glycoprotein D block HSV binding to HVEM. J Virol. 1998 May;72(5):3595-601. Monoclonal antibody to gD of HSV-1 is disclosed.
Vermisoglou et al 2020. Human virus detection with graphene-based materials. Biosens Bioelectron. 2020 Oct 15; 166:112436. Different types of graphene-based sensors available for virus detection, including, e.g., photoluminescence and colorimetric sensors, and surface plasmon resonance biosensors. Various strategies of electrochemical detection of viruses based on antigen-antibody interactions are reviewed.
Garcia et al 2020. Impedimetric Biosensor for Bovine Herpesvirus Type 1-Antigen Detection. Electroanalysis 2020, 32, 1100 – 1106.
Siuzdak et al 2019. Biomolecular influenza virus detection based on the electrochemical impedance spectroscopy using the nanocrystalline boron-doped diamond electrodes with covalently bound antibodies. Sensors & Actuators: B. Chemical 280 (2019) 263–271. (Year: 2019).
Nguyen et al 2012. Electrochemical impedance spectroscopy characterization of nanoporous alumina dengue virus biosensor. Bioelectrochemistry 88 (2012) 15–21. (Year: 2012)
Conclusion
15. No claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600