CTNF 18/691,615 CTNF 82054 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Applicant’s preliminary amendment filed on March 13, 2024 is acknowledged. Claims 1-18 and 21-22 are pending and under examination in this Office action. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA Claim s 1-2, 5-6, 8 and 10-22 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Karakus et al. (Analytica Chimika Acta, August 2021, Vol. 1182, p. 1-10 in IDS on 3/13/2024) . Regarding claim 1. Karakus et al. discloses a method of detecting severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Abstract "the colorimetric and electrochemical detection of SARS-CoV-2 spike antigen with gold nanoparticle-based biosensors may be one such method") in a sample (p4, left col 2nd para "Saliva samples were collected from six healthy individuals and half of the samples were spiked with 500 ng/mL and 10 pg/mL of the SARS-CoV-2 spike antigen for optical and electrochemical measurements, respectively"), the method comprising: contacting the sample with a plurality of gold nanoparticles (AuNPs) that are conjugated with at least two sets of antibodies (p4, left col 2nd para "Then, all of the samples were transferred into the AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20", p2, right col 3rd para "SARS-CoV-2 spike monoclonal antibody (mAb)"), wherein at least a first set of antibodies binds to a first epitope of a SARS-CoV-2 protein and wherein at least a second set of antibodies binds to a second epitope of a SARS- CoV-2 protein (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS- CoV-2 spike antigen surface") under conditions sufficient for the first and second set of antibodies to bind to the first and second epitopes of the SARS-CoV-2 proteins in the sample to produce bound SARS-CoV-2 proteins (p3, right col 3rd para "The SARS-CoV-2 spike antigen was diluted serially at 250, 500, 750, 1000, and 2000 ng mL-1, and the proper amount was added to one-fold-concentrated AuNPsemAb conjugate solution, followed by incubation at room temperature for 10 min"): and, detecting the SARS-CoV-2 proteins when one or more aggregations of the bound SARS-CoV-2 proteins form with one another, thereby detecting the SARS-CoV-2 in the sample (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"). Regarding claim 2, Karakus discloses the method of claim 1, wherein the antibodies comprise monocional antibodies (p2, right col 3rd para "SARS-CoV-2 spike monoclonal antibody (mAb)"). Regarding claim 5, Karakus discloses the method of claim 1, wherein the detection step comprises determining a change in absorbance at a resonance wavelength of the AuNPs (p3, right col 3rd para "The colour of the mixtures changed from red to purple, and the SARS-CoV- 2 spike antigen could be detected with the naked eye and based on LSPR with redshifting (~25 nm)", p2, right coll 4th para "A UV-1900i spectrophotometer (Shimadzu) and quartz micro cuvettes (700 mL, Hellma) were used for all local surface plasmon resonance (LSPR) analyses"). Regarding claim 6, Karakus discloses the method of claim 1, comprising quantifying an amount of the SARS-CoV-2 proteins and/or the SARS-CoV-2 in the sample (p7, right col 2nd para "The proposed method is able to detect 1 pg/mL of the SARS-CoV-2 spike antigen and has a linear response to the antigen between 1 pg/mL and 10 ng/mL in 10mMof PB solution (pH 7.4) containing 0.2 mg/mL of Tween 20", p5, right coll 2nd para p6, left col 1st para "The linear relationship was observed between Imax and the SARS-CoV-2 spike antigen concentration, for a correlation coefficient of 0.99 that shows the method's applicability in quantitative analysis"). Regarding claim 10, Karakus discloses the method of claim 1, comprising obtaining the sample from a subject (p4, left col 2nd para "Saliva samples were collected from six healthy individuals and half of the samples were spiked with 500 ng/mL and 10 pg/mL of the SARS-CoV-2 spike antigen for optical and electrochemical measurements, respectively"). Regarding claim 14, Karakus discloses the method of claim 10, wherein the sample comprises saliva (p4, left col 2nd para "Saliva samples were collected from six healthy individuals and half of the samples were spiked with 500 ng/mL and 10 pg/mL of the SARS-CoV- 2 spike antigen for optical and electrochemical measurements, respectively"). Regarding claim 15, Karakus discloses the method of claim 1, wherein the detecting step comprises measuring a colorimetric change when the one or more aggregations of the bound SARS-CoV-2 proteins form with one another (p6, Scheme 2. "UV-vis detection of SARS- CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"). Regarding claim 16, Karakus discloses the method of claim 15, comprising visually detecting the colorimetric change when the one or more aggregations of the bound SARS-CoV-2 proteins form with one another (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"). Regarding claim 17, Karakus discloses the method of claim 15, comprising detecting the colorimetric change when the one or more aggregations of the bound SARS-CoV-2 proteins form with one another using a spectrometer (p6, Scheme 2. "UV-vis detection of SARS- CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"). Regarding claim 19, Karakus discloses a reaction mixture (p3, right col 4th para "50 mL of AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20 and with a proper amount of the SARS-CoV-2 spike antigen"), comprising: a sample comprising severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) protein (p4, left coll 2nd para "Saliva samples were collected from six healthy individuals and half of the samples were spiked with 500 ng/mL and 10 pg/mL of the SARS-CoV-2 spike antigen for optical and electrochemical measurements, respectively"); and, a plurality of gold nanoparticles (AuNPs) that are (i) conjugated with at least two sets of antibodies (p4, left col 2nd para "Then, all of the samples were transferred into the AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20", p2, right col 3rd para "SARS-CoV-2 spike monoclonal antibody (mAb)") wherein at least a first set of antibodies binds to a first epitope of a SARS-CoV-2 protein and wherein at least a second set of antibodies binds to a second epitope of a SARS-CoV-2 protein in the sample (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs- mAb on the SARS-CoV-2 spike antigen surface"). Regarding claim 20, Karakus discloses a composition (p3, right coll 4th para "50 mL of AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20 and with a proper amount of the SARS-CoV-2 spike antigen"), comprising: a plurality of gold nanoparticles (AuNPs) that are (i) conjugated with at least two sets of antibodies (p4, left coll 2nd para "Then, all of the samples were transferred into the AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20", p2, right col 3rd para "SARS-CoV-2 spike monoclonal antibody (mAb)") wherein at least a first set of antibodies binds to a first epitope of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) protein and wherein at least a second set of antibodies binds to a second epitope of a SARS-CoV-2 protein in the sample (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV -2 spike antigen surface"). Thus, by this disclosure Karakus anticipates the present claims . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-21-aia AIA Claim s 3-4, 7, 9, 11-13, 18, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Karakus et al. (Analytica Chimika Acta, August 2021, Vol. 1182, p. 1-10 in IDS on 3/13/2024) in view of Lima et al, (PNAS, July 2021, Vol. 118, p. 1-9 in IDS on 3/13/2024) and Frieman (US Application Publication 2017/0027975 A1) . Regarding claim 9, Karakus teaches the method of claim 1, but does not teach comprising drop casting the aggregations of the bound SARS-CoV-2 proteins prior to the detecting step. However, Lima teaches the drop-casting method is used to detect SARS-CoV-2 (p2, right col 1st para "The WE, where the (electro)chemical reaction/interaction takes place and is subsequently converted to a detectable analytical signal, was functionalized by the drop-casting method", p2, left col 1st para "The electrochemical device was designed to explore the remarkable binding affinity between SARS-CoV-2 spike protein (SP) and human ACE2, its receptor in the human body"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to apply the drop-casting method to the method by routine experimentation, in order to find the most effective method detecting SARS-CoV-2. Karakus teaches the method of claim 1, but does not teach freezing the aggregations of the bound SARS-CoV-2 proteins prior to the detecting step. However, it would have been obvious to one of ordinary skill in the art to be motivated to freeze the sample collected by routine experimentation, in order to prevent the degradation of the sample. Regarding claim 11, Karakus teaches the method of claim 10, but does not teach comprising administering one or more therapies to the subject when the SARS-CoV-2 is detected in the sample. However, it would have been obvious to one of ordinary skill in the art to be motivated to apply the method to detect the SARS-CoV-2 in the subject receiving one or more therapies by routine experimentation, in order to examine the efficacy of the method detecting SARS-CoV-2 in various situations. Regarding claim 12, Karakus teaches the method of claim 10, but does not teach comprising detecting the SARS-CoV-2 within about 20 minutes or less of obtaining the sample from the subject. However, it would have been obvious to one of ordinary skill in the art to be motivated to use the sample collected within about 20 minutes or less by routine experimentation, in order to prevent the degradation of the sample. Regarding claim 13, Karakus teaches the method of claim 10, but does not teach comprising repeating the method using one or more longitudinal samples obtained from the subject. However, it would have been obvious to one of ordinary skill in the art to be motivated to repeat the method using one or more longitudinal samples by routine experimentation, in order to verify the performance of the method. Regarding claim 18, Karakus teaches a plurality of gold nanoparticles (AuNPs) that are (i) conjugated with at least two sets of antibodies (p4, left coll 2nd para "Then, all of the samples were transferred into the AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20", p2, right col 3rd para "SARS-CoV-2 spike monocional antibody (mAb)"), wherein at least a first set of antibodies binds to a first epitope of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) protein and wherein at least a second set of antibodies binds to a second epitope of a SARS-CoV-2 protein (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"); a sample that comprises the SARS-CoV-2 under conditions sufficient for the first and second set of antibodies to bind to the first and second epitopes of the SARS-CoV-2 proteins in the sample to produce bound SARS-CoV-2 proteins (p3, right col 3rd para "The SARS-CoV-2 spike antigen was diluted serially at 250, 500, 750, 1000, and 2000 ng mL-1, and the proper amount was added to one-fold-concentrated AuNPsemAb conjugate solution, followed by incubation at room temperature for 10 min") and one or more aggregations of the bound SARS-CoV-2 proteins to produce a colorimetric change (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"), but does not teach a device, comprising reaction chamber comprising the plurality of gold nanoparticles (AuNPs); and the reaction chamber receives the sample; and the colorimetric change occurs in the reaction chamber. However, Karakus further teaches the detecting system can be formulated in commercial kit (p8, left col 3rd para "Therefore, the biosensing platform can be easily integrated into a ready-to-use commercial kit and adapted for the diagnosis of other emerging viral diseases"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to formulate the device comprising reaction chamber by routine experimentation, in order to provide the convenience to the users. Regarding claim 21, Karakus teaches a system, comprising: a plurality of gold nanoparticles (AuNPs) that are (i) conjugated with at least two sets of antibodies (p4, left col 2nd para "Then, all of the samples were transferred into the AuNPs-mAb in PB solution (10 mM, pH 7.4) containing 0.2 mg/mL of Tween 20", p2, right col 3rd para "SARS-CoV-2 spike monoclonal antibody (mAb)"), wherein at least a first set of antibodies, binds to a first epitope of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) protein and wherein at least a second set of antibodies binds to a second epitope of a SARS-CoV-2 protein (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"); a sample that comprises the SARS-CoV-2 under conditions sufficient for the first and second set of antibodies to bind to the first and second epitopes of the SARS-CoV-2 proteins in the sample to produce bound SARS-CoV-2 proteins (p3, right col 3rd para "The SARS-CoV-2 spike antigen was diluted serially at 250, 500, 750, 1000, and 2000 ng mL-1, and the proper amount was added to one-fold-concentrated AuNPsemAb conjugate solution, followed by incubation at room temperature for 10 min"); and, an electromagnetic radiation detection apparatus to detect one or more colorimetric changes produced when one or more aggregations of the bound SARS-CoV-2 proteins form with one another (p6, Scheme 2. "UV-vis detection of SARS-CoV-2 spike antigen based on the aggregation of AuNPs-mAb on the SARS-CoV-2 spike antigen surface"), but does not teach a device, comprising at least one reaction chamber or substrate comprising the plurality of gold nanoparticles (AuNPs); and the reaction chamber receives the sample; wherein the electromagnetic radiation detection apparatus is positioned, or positionable, within sufficient proximity to the device. Karakus further teaches the detecting system can be formulated in commercial kit (p8, left col 3rd para "Therefore, the biosensing platform can be easily integrated into a ready-to-use commercial kit and adapted for the diagnosis of other emerging viral diseases"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to formulate the device comprising reaction chamber by routine experimentation, in order to provide the convenience to the users. In addition, it would have been obvious to one of ordinary skill in the art to be motivated to position the apparatus within sufficient proximity to the device by routine experimentation, in order to obtain the most accurate results. Regarding claim 22, Karakus teaches the system of claim 21, wherein the electromagnetic radiation detection apparatus comprises a spectrometer (Abstract "In the presence of the SARS-CoV-2 spike antigen, gold nanoparticles aggregated rapidly and irreversibly due to antibody eantigen interaction and consequently changed in colour from red to purple, as easily observable with the naked eye or UVeVis spectrometry by way of spectral redshifting with a detection limit of 48 ng/mL"); but does not teach wherein the electromagnetic radiation detection apparatus comprises a microscope. Karakus further teaches the system utilizes transmission electron microscopy (p5, Fig. 3. "(b) TEM images of AuNPs-mAb after incubation with the SARS-CoV-2 spike antigen", p3, left col 1st para "High-resolution transmission electron microscopy (TEM) was performed with a JEOL JEM 2100 HRTEM at 200 kV to characterise the morphologies of monodispersed AuNPs and AuNPs bioconjugates before and after incubation with the SARS-CoV-2 spike antigen"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to apply the electromagnetic radiation detection apparatus comprising a microscope by routine experimentation, in order to detect thoroughly. Claims 3-4 lack inventive step under PCT Article 33(3) as being obvious over Karakus, in view of CN 112094343 A to University of Science and Technology of China USTC (hereinafter 'China'). Regarding claim 3, Karakus teaches the method of claim 1, but does not teach wherein the first and second set of antibodies comprise nanobodies. However, China teaches certain nanobodies can be used as diagnosis of SARS-CoV-2 infection (Abstract "The present disclosure relates to alpaca-derived antibodies or antigen-binding fragments thereof that bind to SARS-CoV-2RBD, and in particular, to alpaca-derived nanobodies or dual epitope-specific antibodies or antigen-binding fragments thereof consisting of the same that can bind to the receptor-binding Region (RBD) of the novel coronavirus (SARS-CoV-2) with high affinity, which can be used for the prevention, treatment and/or diagnosis of SARS-CoV-2 infection"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to apply the nanobodies disclosed by China to the method by routine experimentation, in order to find the most effective antibodies detecting SARS-CoV-2. Regarding claim 4, Karakus teaches the method of claim 1, but does not teach wherein the SARS-CoV-2 protein comprises a receptor- binding domain (RBD). However, China teaches the receptor-binding domain (RBD) of the SARS-CoV-2 protein binds to antibodies to detect SARS-CoV-2 infection (Abstract "The present disclosure relates to alpaca-derived antibodies or antigen-binding fragments thereof that bind to SARS-CoV-2RBD, and in particular, to alpaca-derived nanobodies or dual epitope-specific antibodies or antigen-binding fragments thereof consisting of the same that can bind to the receptor-binding Region (RBD) of the novel coronavirus (SARS-CoV-2) with high affinity, which can be used for the prevention, treatment and/or diagnosis of SARS-CoV-2 infection"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to identify whether the SARS-CoV-2 protein comprises a receptor-binding domain (RBD) by routine experimentation, in order to elucidate the mechanism of the detecting process. Regarding claim 7, Karakus teaches the method of claim 1, but does not teach further comprising centrifuging the aggregations of the bound SARS-CoV-2 proteins prior to and/or during the detecting step. Frieman teaches the centrifugation of SARS-CoV containing composition can clarify the composition (para[0038] "SARS-CoV containing supernatants were collected and clarified by centrifugation"). Thus, it would have been obvious to one of ordinary skill in the art to be motivated to centrifuge the aggregations of the bound SARS-CoV-2 proteins prior to and/or during the detecting step by routine experimentation, in order to clarify the aggregations. Thus, the present invention would have been prima facie obvious at the time the invention was made. Contact Information Any inquiry concerning this communication or earlier communications from the examiner should be directed to AGNIESZKA BOESEN whose telephone number is (571)272-8035. The examiner can normally be reached on 8:30 - 5:00 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /AGNIESZKA BOESEN/Primary Examiner, Art Unit 1648 Application/Control Number: 18/691,615 Page 2 Art Unit: 1672
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