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. Claims 5, 7, 12-15, 17, 20-21, 25, 28-29, 31-42 and 44-48 have been canceled. Claims 1-4, 6, 8-11, 16, 18-19, 22-24, 26-27, 30, 43 and 49 are pending and under examination. Claim Objections Claim 49 is objected to because of the following informalities: please provide full name of TSH, 4-ATP and SERS. 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 appl icant regards as his invention. Claims 1-4, 6, 8-11, 14-16, 18-19, 22-24, 26-27, 30, 43 and 49 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. As to claim 1, line 5, the term of “ average maximum and substantially uniform plasmonic field greater than 10 8 “ lacks unit. It is noted that applicants do not provide such unit in the whole specification. As to claim 43, step (b), the term “the … device’ lacks antecedent basis in relation to claim 1. As to claim 49, line 3, the volume of “at least about 50 µl or less” on a chip is not clear about the term “less”. Since “less’ than 50 µl could also encompass zero. Please clarify. As to claim 49, line 4, the incubation time, i.e. “for at least about 15 minutes or less” and generating a report time about 20 min or less” share the same problem . Please clarify. 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 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. Claim(s) 1- 2, 4, 6, 8 - 1 1 , 16, 18 -19 , 2 3 - 24, 26-27, 30 and 43 are rejected under 35 U.S.C. 103 (a) as being unpatentable over Owens (Biosensors 2015 5:664-677 ) in view of Fournier (US20220128477). The inventive concept in this application is a method of detecting a target by using a substrate having metallic anisotropic nanoparticles thereon having a linker coupled with a capture molecule wherein the capture molecule is capable of binding to the target, and wherein the shift of a Raman peak or feature is proportional or inversely to the concentration of the target molecule. Figure 5 illustrates the current invention. The “ATP” (4-aminothiopheol) is a linker on the substrate. The binding of TSH analytes causes the shift of Raman peak. Owens teaches a method of detecting a target molecule in a sample. Owens teaches using a substrate having a plurality of nano Au/Ag nanopillar array having anisotropic characters when in nanoscale , and the nano Au/Ag array coupled with a Raman active linker and the linker also conjugated with an antibody specific for target molecule for detection ( see Figure 2 ). The shift of Raman peak (red color) on the SERS spectrum to the right shows an increase concentration of the target (See Figure 2 below ). As to the nanostructures induc ing an average maximum and substantially uniform plasmonic field greater than plasmonic field greater than 10 8 , Owens does not explicitly disclose this feature. However, applicants discuss the nanostructure substrate in section 0043, “[t]he substrate described herein can have a variety of features including roughness ”. The roughness refers to the geometric shapes of the nanostructure as shown in Figure 1 of current invention where 102 is the pyramid shape of nanostructure on the substrate 100 (see below) . It is noted that claim 11 in current application recites the geometric shape of the nanostructures including trigonal pyramids, square pyramids or hexagonal pyramids. Moreover, in Example 2, applicants also use gold nanopyramid arrays for the experiments (section 0087-0090). It appears that the geometric shapes of the nanostructure contribute to the plasmonic field. Fournier teaches using pyramid shapes of nanostructure for Raman spectrometry (section 0036; Figure 3 below). Fournier teaches the multiple sharp edges that produce areas of surface plasmon resonance (SPR) upon excitation would facilitate enhancement of the Raman signal (section 0036, bottom). Therefore it would have been prima facie obvious to one ordinary skilled person to adapt the pyramid shape of the nanostructure on the substrate of Owens by using the sharp edges nanostructures as taught by Fournier for increasing signal detection for the assay. Since with the same pyramid shape and similar gold nanostructure, absence evidence to the contrary, the average maximum and substantially uniform plasmonic field would have been greater than 10 8 . As to claim 2, the capture molecule used by Owens is an antibody (see Figure 2). As to claim 4 and 6, silicon layer is used for the base layer (see Figure 2 see section “2. Experimental Section”, page 667 ). As to claim 8-9, the height of the height of the nanopillar array is about 600 nm ( see section “2. Experimental Section”, page 667 ). As to use the similar Au/Ag and height of nanostructure, it would have been prima facie periodicity from 200-5000 nm. As to claim 10, the pyramid shape is taught by Fournier (see Figure 3 above ). As to claim 16, Owens uses the same 4-aminothiophenol (4-ATP) as active linker (see abstract). Current invention also teaches uses the 4-ATP as Raman active linker (see Figure 1; section 0079, 0087, Example 2). Since Owens and the current invention use the same Raman active linker 4-aminothiophenol, the linker would have inherent length along the largest axis less than 40 nm. As to claim 18, the binding of target shows at higher wavenumber (red shift) and a lower wavenumber (blue shift) (see “Raman shifts” in Raman Spectroscopy in Figure 2 ). As to claim 19, the claim directs to a shift of Raman peak in a lower wavenumber direction when a capture molecule binds an analyte. It is noted that applicants use TSH and TSH-antibody for illustration in Figure 1 and shows a higher wavenumber shift (toward to the right) when TSH antibody binds TSH (see below). However, applicants also found out detecting the TSH in higher concentration s would ca use Raman shift slightly towards to a lower wavenumber (See Figure 7A and 7B, section 0057 where concentration is from 0 to 7.5 µIU/mL or 0 to 50 µIU/mL) (see below) . Therefore, it would have been prima facie obvious to one ordinary skilled person in the art to have observed similar Raman shift towards to a lower wavenumber when higher concentrations of target proteins are detected by Raman spectroscopy. As to claim 23, Owens uses silicon layer substrate (see section “2. Experimental Section”, page 667). As to claim s 24, and 26-27, Owens teaches using same divalent EDC ( 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ) and NHS ( N- hydroxysuccinimide ) solution for coupling Raman active linker to the substrate (see Owens section “2.1”, page 667 bottom ) (also see current specification Example 2 using same EDC ( 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ) and NHS ( N- hydroxysuccinimide ) ) . EDC/NHS is widely used for chemical coupling solution for linking -COOH groups on nanostructure to primary amine (-NH2) to form amide bonds , ideal for functionalizing nanostructures (see current specification section 0053 where divalent linker can be of an amide, also current claim 27) . As to claim 30 , it directs to a system for quantifying a biomarker in a sample. Owend teaches using a light source (excitation) illuminating on the substrate having nanostructure with Raman active linker followed by detection (see Figure 1 and Figure 2; page 666 and 668). The detection inherently is carried out by a detector detecting and computing signals for the Raman shift peak wavelength for the Raman active linker (see Figure 3, Raman shift, page 669). As to claim 43, similarly as described in claim 30, the samples of different concentrations of analytes are administered to the substrate and illuminating followed by measuring the Raman shift in different concentration of analytes (see Owens Figure 1, Figure 2, Figure 6, page 666, 668 and 671). However, step (a) directs to an unknown concentration of the analyte to the substrate. Nevertheless it would have been prima facie obvious to one ordinary skilled person in the art to do so in using the existing data from the known concentrations to estimate (i.e. mapping) the unknown concentration. Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Owens and Fournier as applied to claim s 1-2, 4, 6, 8-11, 16, 18-19, 23-24, 26-27, 30 and 43 above, and further in view of Hazen (US 20100330082) or Beidler (US 20080274114). Claim 3 directs to a binding affinity ( Kd )( at least 1 pM ) for the antibody. Owens teach using anti EGFR antibody for the assay, but does not disclose its Kd . Nevertheless anti EGFR antibody is well-known and commonly used in the field. For instance, Hazen teaches using EGFR antibody having Kd between 100nM to 1pM (section 0137). In addition, Beidler teaches anti EGFR antibody having Kd between 0.01 pM to 10 pM (section 0006). Therefore it would have been prima facie obvious to one ordinary skilled person like Owens to adapt anti EGFR antibody having at least 1pM Kd as taught by Hazen or Beidler for the detecting EGFR biomarkers in a sample for the assay and would have reasonable expectation of success. Under KSR case law, it is now apparent "obvious to try" may be an appropriate test in more situations. “When there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense”. In that instance the fact that a combination was obvious to try might show that it was obvious under 35 USC 103. See KSR Int'l Co v. Teleflex Inc ., 127 S. Ct. 1727; 82 USPQ 1385, 1397 (2007). The problem is to choose an antibody having Kd value at least 1 pM , and there were a number of sources (such as disclosed by Beidler or Hazen) available to do so. The skilled artisan would have reason to try these methodologies with reasonable expectation that at least one would be successful. Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Owens and Fournier as applied to claim s 1- 2, 4, 6, 8-11, 16, 18, 23-24, 26-27, 30 and 43 above, and further in view of Corona (US 2020003771) . Both Owens and Fournier references have been discussed but none teaches incorporating Raman-active chromophore to the linker. Corona teaches using Raman active chromophore for enhanc ing Raman spectroscopy detection (section 0071). Therefore it would have been prima facie obvious to one ordinary skilled in the field to have motivated Owens to incorporate the Raman active chromophore to the linker enhancing Raman spectroscopy for a better detection. Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Owens as applied to claim s 1- 2, 4, 6, 8-1 1 , 16, 18, 2 3 -24, 26-27, 30 and 43 above, and further in view of Fujimoto (EP 2042872) , Walavalkar (US 20150223739) . C laim 49 directs to a practical application of using the current invention to detect thyroid stimulating hormone (TSH), including placing samples in a chip, incubating at about 37 degree (+/- 3C) for about 15 min or less, and generating results . The detection is based upon the binding of TSH antigen in the sample to a plurality of nanostructure on the chip where the nanostructures having 4-ATP as SERS active linker coupling to TSH antibody . Owen s teaches using the nanostructures having 4-ATP active linker coupled to antibodies for p53and EGFR. Owens does not explicitly apply his invention to measure TSH using TSH antibody. However application of the known invention for medical diagnosis or research is common and a motivation to one ordinary skilled person. Fujimoto teaches an immunoassay for detection of TSH in a sample (see Example 1,page 6-7 ). TSH is known associated with Grave’s disease (section 0009-0010). Fujimoto teach using TSH specific antibody for capturing TSH in a sample (see Example 1, page 6-7). Note, the antigen TSH concentration in the assay is 2µIU/mL and can be detected (within recited range 0.01-50µIU/mL; see section 0052, 0053). In addition, it is noted that the TSH assaying time is about 1 2 min not including washing, including incubating labeled anti-TSH antibody with TSH antigen ( 30 µL total volume) for about 2 min at 42C°; 2) adding streptavidin magnetic particles for another 2.5 min ; 3) adding a secondary antibody binding to the TSH antibody for about 2.5 min , 4)washing 4 time; 4) dispersing and adding luminescent substrate for another 5 min for detection ( 2+2.5+2.5+5 = 12 min ; see Example 1; section 0052-0053). It would have been prima facie obvious to one ordinary skilled person in the art to have incubation time about 15 min or less for detecting TSH in a sample using a similar functional TSH antibody as taught by Fujimoto for detecting the same TSH antigen in the same pyramid shape nanostructure substrate having the same 4-ATP Raman active linker thereo n and one ordinary skilled person would have reasonable expectation of success. Walavalkar teaches a chip having nanostructures coupled with antibodies thereon for detecting analytes in a sample using SERS (section 0053-0055; Figure 1). It is known that the use of chip provides large-scale analysis and time-saving benefits. Walavalkar teaches incubating protein samples at about 37 degree. The measuring and showing results are a little bit over 10 min (section 0121 and 0129). Therefore, it would have been prima facie obvious to one ordinary skilled in the field before the filing of the invention to use assay chip s as taught by Walavalkar placing the nanostructure having coupled with Raman active linker wherein the linker also coupled with a TSH specific antibody as taught by Fujimoto for a large-scale and fast analysis with reasonable expectation of success. This is based on the availability of the similar functional TSH antibody and its clinical importance such as for diagnosis of Graves’ disease , and one clinician would have been motivated to apply the nanostructure to detect TSH related diseases in a large-scale and fast fashion and would have reasonable anticipation of success. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT CHANGHWA J CHEU whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0814 . 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Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. FILLIN "Examiner Stamp" \* MERGEFORMAT CHANGHWA J. CHEU Primary Examiner Art Unit 1678 /CHANGHWA J CHEU/ Primary Examiner, Art Unit 1678