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 .
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 Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 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.
The volume of “at least about 50 µl or less” on a chip is not clear since it both indicates that about 50 µl is the bottom of the range [via the limitation “at least about 50 ul] as well as the top of the range [via the limitation “or less”], which therefore presents a contradiction that does not make sense, or at least is vague. Clarification of the claims is required.
Similarly, claim 49, line 4, also recites the incubation time being “for at least about 15 minutes or less” and generating a report time “in about 20 min or less”, both of which share the same problem as mentioned above. Clarification of the claim is required.
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, 8-11, 16, 18-19, 23-24, 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.
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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).
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As to the nanostructures inducing an average maximum and substantially uniform plasmonic field greater than plasmonic field greater than 108, 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).
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It is noted that claim 11 in the 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).
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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 of nanostructures as taught by Fournier for increasing signal detection for the assay. 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 108.
As to claim 2, the capture molecule used by Owens is an antibody (see Figure 2).
As to claim 4 and6, 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 nanopillar array is about 600 nm (see section “2. Experimental Section”, page 667). As the micro- or nanostructures having a periodicity from 200-5000 nm, this falls within a workable or optimum range, and discovery of a workable or optimum range requires routine skills in the art where the general conditions of the claims are taught, such as here.
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 an active Raman 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 axisof 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 which shows a higher wavenumber shift (toward to the right) when TSH antibody binds TSH (see below).
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However, applicants also found that detecting the TSH in higher concentrations would cause 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).
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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 claims 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. Owen teaches using a light source (excitation) illuminating on the substrate having nanostructures with Raman active linker followed by detection (see Figure 1 and Figure 2; page 666 and 668). The detection 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, illuminated, 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. map) the unknown concentration.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Owens and Fournier as applied to claims 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 teaches 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 detecting EGFR biomarkers in a sample for the assay, with reasonable expectation of success.
Under KSR case law, "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.
Moreover, the antibody having a Kd of at least 1pM falls within a workable or optimum range of the modified Owen invention, and such discovery requires routine skills in the art where the genera
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Owens and Fournier as applied to claims 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 have been discussed but none teaches incorporating Raman-active chromophore to the linker.
Corona teaches using Raman active chromophore for enhancing Raman spectroscopy detection (section 0071).
Therefore it would have been prima facie obvious to one ordinary skilled in the field to have modified Owens to incorporate the Raman active chromophore to the linker to enhance Raman spectroscopy for a better detection, as taught by Corona.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Owens in view of Fournier as applied to claims 1-2, 4, 6, 8-11, 16, 18, 23-24, 26-27, 30 and 43 above, and further in view of Fujimoto (EP 2042872), Walavalkar (US 20150223739).
Claim 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 have 4-ATP as SERS active linker coupling to TSH antibody.
Owens 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 of one of ordinary skills in the art.
Moreover, Fujimoto teaches an immunoassay for detection of TSH in a sample (see Example 1,page 6-7). TSH is known to be 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 12 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 of ordinary skills in the art to provide incubation time of 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 thereon with reasonable expectation of success.
Furthermore 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 a 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). Walavalkar teaches that different types of nanostructures can be fabricated on a chip, with different spacing between pillars and/or metal structures, to achieve different degrees of surface plasmon enhancement (para. 0055)
Therefore, it would have been prima facie obvious to one ordinary skilled in the field before the filing of the invention to provide the modified Owen invention in a chip form for the benefits of large-scale analysis and time-saving, as taught by Walavalkar, wherein the nanostructure is coupled with Raman active linker and wherein the linker is also coupled with a TSH specific antibody as taught by Fujimoto with reasonable expectation of su,ccess. This is based on the availability of the similar functional TSH antibody and its clinical importance such as for diagnosis of Graves’ disease. One skilled in the art 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.
Response to Arguments
Applicant's arguments have been fully considered but they are not persuasive regarding these remaining issues.
Applicant argues that regarding claim 49, one skilled in the art would understand that the sample volume cannot be zero, because there would be no sample to analyze, and thus the rejection under 35 USC 112(b) should be withdrawn.
Applicant’s argument is not persuasive. The volume of “at least about 50 µl or less” on a chip is not clear since it both indicates that about 50 µl is the bottom of the range [via the limitation “at least about 50 ul] as well as the top of the range [via the limitation “or less”], which therefore presents a contradiction that does not make sense, or at least is vague.
Similarly, claim 49, line 4, also recites the incubation time being “for at least about 15 minutes or less” and generating a report time “in about 20 min or less”, both of which share the same problem as mentioned above.
Regarding the rejections under 35 USC 103, Applicant argues that the reference Fournier is not available as art under 35 USC 102(b)(2) since it claims priority to US Provisional Application 63/106.534, filed on October 28, 2020, which falls within the 1 year grace period for the instant application, which claims priority to US Provisional Application No. 63/132,248, filed on December 30, 2020, the one year grace period of which extends back to December 30, 2019. Applicant asserts that Fournier was filed within this 1 year grace period and therefore cannot be used in forming the basis of a rejection under 35 USC 103.
This is not persuasive since the 1 year grace period does not apply to preclude Fournier as prior art because 35 USC 102(b)(2) does not apply to Fournier.
35 USC 102(b)(2) is reproduced below:
“CLOSURES APPEARING IN APPLICATIONS AND PATENTS.—A disclosure shall not be prior art to a claimed invention under subsection (a)(2) if—
(A) the subject matter disclosed was obtained directly or indirectly from the inventor or a joint inventor;
(B) the subject matter disclosed had, before such subject matter was effectively filed under subsection (a)(2), been publicly disclosed by the inventor or a joint inventor or another who obtained the subject matter disclosed directly or indirectly from the inventor or a joint inventor; or
(C) the subject matter disclosed and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person.”
There is no inventor or assignee of the present application that is the same as that
listed for the Fournier reference (US 20220128477). Also, Applicant has not provided any evidence that the subject matter of Fournier meets (A), (B), or (C) (see above). Therefore, there is no evidence that the exception under 35 USC 102(b)(2) applies to preclude Fournier as prior art.
Applicant further argues that Owen fails to teach the structural features of claim 1; moreover, that Fujmoto teaches a sandwich assay method for detecting TSH levels and therefore fails to cure the deficiencies of Owens. This is not persuasive, as Owens in view of Fourner teaches the structural features of claim 1.
Applicant also argues that Walavakar fails to teach anisotropic nanostructures thereby failing to teach the structural features of the substrate of claim 1.
This is not persuasive since Owen in view of Fournier is cited for teaching recited nanostructures. Walavalkar is cited for teaching a chip form in which nanostructures coupled with antibodies thereon for detecting analytes in a sample using SERS can be provided(section 0053-0055; Figure 1). It is known that the use of a chip provides large-scale analysis and time-saving benefits. It would have been prima facie obvious to one ordinary skilled in the field before the filing of the invention to provide the modified .Owen invention in a chip form for the benefits of large-scale analysis and time-saving, as taught by Walavalkar
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ann Montgomery/Primary Examiner, Art Unit 1678
