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 .
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.
Election/Restrictions
Applicant’s election of Group I, claims 1-10 and 17-19, in the reply filed on 3/19/2025 is acknowledged. 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)).
Claims 11-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/19/2025.
Priority
The present application claims benefit under 35 U.S.C. 119(e) to provisional application 63/107,117 filed on 10/29/2020.
Information Disclosure Statement
The information disclosure statement filed 4/18/2023 is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10 and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for detecting two or more analytes using surface-enhanced Raman Spectroscopy, does not reasonably provide enablement for detecting two or more analytes using Raman Spectroscopy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not reasonably provide enablement for determining the presence of at least two analytes, i.e. the identifying peaks associated with each analyte, based on the Raman spectra of a linear polymer affinity agent and metal substrate.
The specification does not provide sufficient evidence that the claimed method of using/calibrating the sensor via generic Raman Spectroscopy is effective for determining the presence of at least two analytes, i.e. the identifying peaks associated with each analyte. The evidence provided relies on a specialized technique known as surface-enhanced Raman spectroscopy (SERS) (see Examples in the specification) but the use of generalized Raman Spectroscopy appears to be prospective. Therefore, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The nature of the invention is a bio-photonics/bio-optics case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed method(s), with a reasonable expectation of success, because it would not have been predictable from the disclosure that the claimed Raman Spectroscopy technique would function as claimed with respect to detecting two or more analytes (see MPEP § 2164.03).
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a).
Accordingly, Kerr et. al. Anal. Methods, 2015, 7, 5041 DOI: 10.1039/c5ay00327j (“Kerr”) teaches that “[t]he weak Raman signals associated with biological samples are often obscured by a broad slowly-varying background signal caused by fluorescent signals or stray light due to Mie scattering. These signals can originate from a number of sources including the sample itself, the sample substrate and the optical elements in the system that are common to both the delivery path and the collection path, especially the microscope objective. The presence of this background can compromise the ability to extract reliable and reproducible compositional information from biological Raman spectra” (page 5041 col. 1 para. 2 and col. 2 para. 1). Therefore, Kerr teaches that Raman signals are inherently weak and that various sources of noise impact the signal.
Furthermore, the level of skill in the art suggests that SERS is required for detecting mycotoxins, i.e. two or more analytes, in a sample solution. For example, Szlag, "Linear Polymer Affinity Agents for the Intrinsic SERS Detection of Food Safety Targets", A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA, July 2018 (“Szlag”) teaches that “recent research has focused on more accurate chemical analysis for the direct detection of proteins of interest, including Raman spectroscopy. By performing Raman spectroscopy in the presence of plasmonic nanoscale metal features (SERS), one can achieve the molecular “finger print” provided by Raman, circumvent the innately poor Raman scattering cross-section, and access ultra-low concentration sensitivity even in complex aqueous matrices” (page 39 paragraph 1). Therefore, Szlag also suggests that Raman signals are inherently weak and further provides the technique of SERS as a way to achieve high detection sensitivity in complex aqueous matrices. Note that the claims as presently recited are limited to a “sample solution”, which is reasonably interpreted as an aqueous matrix.
Additionally, Yuan et al. Food Chem 221, 797-802 (2017) (Cited on sheet 4 of IDS 4/18/2023) (“Yuan”) suggests that Raman spectroscopy for detecting DON has scattering efficiency limitations, and further suggests using surface enhanced Raman scattering (SERS) (“since the limitations of scattering efficiency for conventional Raman spectroscopy, more sensitive surface enhanced Raman scattering (SERS) could be investigated first time to meet requirement of regulatory standards for DON in cereals at several ∼μg/kg level” page 798 col. 2 paragraph 1). Given that the instant specification also relies on SERS for detecting DON, it is expected that a person having ordinary skill in the art would require undue experimentation to detect any two or more analytes (e.g. DON and OTA) using conventional Raman Spectroscopy.
Wu et al. Analyst, 2012,137, 4226-4234 DOI https://doi.org/10.1039/C2AN35378D (“Wu”) further teaches that “[a]mong the spectroscopic techniques, Raman scattering is considered a powerful platform with the potential for rapid detection of chemical and biological substances. Traditional Raman spectroscopy relies on the inelastic scattering interaction of the excitation light and the vibrational modes of the molecular bonds. These molecular vibrational modes possess identifiable functional groups; plotting the scattered intensities against the energies of these transitions generates a spectrum that can be used to identify the particular molecule(s) being probed. Surface-enhanced Raman spectroscopy (SERS) is a highly sensitive
Raman detection technique based on metallic nanostructured substrates. The nanostructure-induced enhancement factor can achieve 14–15 orders of magnitude, which allows the technique
to be sensitive enough to detect trace amounts of molecules, where even single molecule detection is possible. Such a tool could be very beneficial for mycotoxin detection, yet research in this area has been limited” (page 4227 col. 1 para. 1). Therefore, Wu also suggests that mycotoxin detection requires SERS.
Given the cited teachings of the prior art that Raman Signals are inherently weak and noisy, the cited references demonstrate that the use of generalized Raman Spectroscopy is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding how to use the claimed Raman Spectroscopy technique in the claimed methods is scant. The specification fails to provide enough description support for the determining the presence of at least two analytes, i.e. the identifying peaks associated with each analyte, based on the Raman spectra of a linear polymer affinity agent and metal substrate. Accordingly, the amount of experimentation required to determine how to use generic Raman Spectroscopy to detect two or more analytes is quite extensive.
Due to the large quantity of experimentation necessary to determine how to use the recited Raman Spectroscopy to detect two or more analytes, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules on optical detection techniques, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. §112 first paragraph.
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 7-8 and 17 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.
Regarding claim 7, the claim recites “determining whether two or more analytes are present comprises identifying a peak in the spectral data not associated with the linear polymer affinity agent or the two or more analytes”. However, it is not clear how identifying a peak in the spectral data not associated with the linear polymer affinity agent or the two or more analytes would permit determining whether two or more analytes are present. The specification seems to contradict the claim when disclosing that “[w]hile there was significant overlap between the two spectra of DON and OTA, as predicted by the computational spectra in FIG. 2, there were still stand-alone vibrational modes that corresponded to each toxin individually, implying that each toxin can be distinguished from the other” (page 24 lines 2-5). In other words, it seems that the method requires identifying peaks that correspond to either analyte in order to identify the analyte.
Claim 8 recites the limitation "different functional group of each toxin" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is not clear what other functional group of each toxin is being referred to because a first functional group of a toxin is not recited in claim 1.
Similarly, claim 17 recites the limitation "each toxin" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is not clear what toxin is being referred to because toxin is not recited before in the claim.
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.
Claims 1-3 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Szlag, "Linear Polymer Affinity Agents for the Intrinsic SERS Detection of Food Safety Targets", A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA, July 2018 (“Szlag”).
Regarding claim 1, Szlag suggests a method of using a sensor (“[t]his dissertation explores the use of polymer affinity agents for the surface-enhanced Raman spectroscopy (SERS) detection of food safety targets” Abstract), the method comprising: mixing a linear polymer affinity agent in a sample solution (“Reversible addition fragmentation chain transfer (RAFT) polymerization of pAEMA and pHEMA were conducted similar to previous syntheses published” page 55 last paragraph, see Table 3-1 showing the reaction specifics). Note that although Szlag fails to use the language “mixing…in a sample solution”, the teachings of the polymerization reaction of pAEMA inherently provides a step of mixing the linear polymer affinity agent in a sample solution (see Table 3-1 page 56). Szlag further suggests subjecting a metal substrate to the sample solution to attach the linear polymer affinity agent to the metal substrate (“FONs were fabricated as previously reported” page 58 paragraph 2, “A gold film of 95.4 nm thickness was deposited under vacuum using high purity gold” page 58 paragraph 5, “FONS used for SERS experiments were functionalized with polymer by incubation in a 1.0 mM polymer solution (40:60 MeOH/water) for 18 hrs. For AFB1 and control experiments, polymer-functionalized FONs were incubated in the desired condition for 6 hours” page 59 paragraph 3); generating, via Raman Spectroscopy, spectral data representing the linear polymer affinity agent attached to the metal substrate (“SERS spectra of five spots per FON were measured to later be averaged” page 59 paragraph 3); determining whether two or more analytes are present in the sample solution at respective minimum threshold concentrations based on the spectral data (“pAEMA29 FONS exposed to AFB1 resulted in spectra with increased intensity at 260, 340, 490, 855, 1008, 1240, 1390, 1453, 1575, and 1590 cm-1 shift” page 75 paragraph 1, see Figure 3-8, “potential of polymer affinity agent…for multiplexing” Abstract, “SERS as a label-free technique, inherently capable of multiplex detection based on specific vibrational modes of AFB1 and other analytes” Chapter 4, page 80 paragraph 2, “Affinity agents can… enabling sensor multiplexing” Introduction, page 3 paragraph 2, “Multiplex detection and target capture reversibility, and thus sensor regeneration, are all features expected from the moderate affinity of the polymer capture agent” Conclusion page 110 paragraph 3). Note that although Szlag fails to use the language “at respective minimum threshold concentrations”, this limitation is inherently provided by the determination of the presence of the analyte, i.e. determining the presence of the analyte would necessarily occur at the threshold of detection. Szlag further teaches that “[t]he utility and versatility of SERS is recognized broadly and has promoted its extensive use in many research communities (e.g. biomedical and food safety)” (page 3 paragraph 2). Szlag further teaches that “[t]he work in this thesis represents a novel effort to design linear polymer affinity agents for intrinsic detection of analytes by SERS. Previous linear polymer affinity agents functioned primarily through nonspecific interactions, much like small molecule partition layers” (page 109 paragraph 1).
Szlag fails to teach the method of using a sensor in a manner consistent with anticipation, i.e., because Szlag suggests determining whether two or more analytes are present in the sample solution in a separate embodiment (suggested in the Abstract, Introduction, Chapter 4 and Conclusion). Szlag teaches the remaining limitations of claim 1 in Chapter 3.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Szlag from separate embodiments, i.e. combining the determining whether two or more analytes are present in the sample from the Abstract, Introduction, Chapter 4 and Conclusion with the rest of the teachings of a method of using a sensor of Chapter 3 because Szlag teaches that SERS (a species of Raman Spectroscopy) is applicable in many fields such as biomedical and food safety, thereby motivating a person having ordinary skill in the art to determine whether two or more analytes are present in a sample for its application on many fields. A person having ordinary skill in the art would have had a reasonable expectation of success because Slag teaches that the sensing method is based on intrinsic Raman signals and the polymer affinity matrix functions via non-specific interactions with analytes. Therefore, a person having ordinary skill in the art would recognize that the method of using a sensor taught by Szlag would be applicable for determining whether two or more analytes were present in the sample solution.
Regarding claim 2, Szlag teaches wherein the polymer affinity matrix comprises methacrylamide (“nitrogen-inclusive poly(N-(2-aminoethyl) methacrylamide) (pAEMA)” Abstract).
Regarding claim 3, Szlag teaches wherein the linear polymer affinity agent is synthesized via polymerization of N-2(2-aminoethyl) methacrylamide hydrochloride (“Polymerization reaction, … N-(2-aminoethyl) methacrylamide hydrochloride (AEMAּ·HCl)” Table 3-1, page 56).
Regarding claim 6, Szlag suggests wherein determining whether two or more analytes are present comprises detecting one or more hydrogen bonds between the linear polymer affinity agent and at least one of the analytes (“Seven homopolymers of nitrogen-inclusive poly(N-(2-aminoethyl) methacrylamide) (pAEMA) and their oxygen analogs, poly(2-yydroxyethyl methacrylate) (pHEMA) were synthesized to be evaluated as AFB1 affinity agents based on hypothetical hydrogen bonding interactions and optimal polymer length” Abstract, “In comparison, the pAEMA, pHEMA, and pNAGA were hypothesized to hydrogen bond AFB1 carbonyl and/or furan oxygens by their amine, alcohol, and amide protons, respectively. At most, this system would have just two H-bonds/analyte and a higher LOD (~32 nM) correlates with this weaker bonding” page 109 paragraph 2). Although Szlag fails to use the language “detecting one or more hydrogen bonds”, the teaching of the correlation between the expected weaker bonding due to hydrogen bonds and the resulting higher detection limit, inherently suggests that the spectral data is detecting the one or more hydrogen bonds.
Regarding claim 7, although the claim is indefinite (see rejection above), in the interest of compact prosecution, the peaks in the spectral data not associated with the linear polymer affinity agent or the two or more analytes are interpreted to be drawn to peaks associated with the linear polymer affinity agent or the two or more analytes, individually. In other words, the peaks associated with the linear polymer affinity agent-analyte complex are interpreted to not be associated with the linear polymer affinity agent or the two or more analytes.
Szlag further suggests wherein determining whether two or more analytes are present comprises identifying a peak in the spectral data not associated with the linear polymer affinity agent or the two or more analytes (“One goal of this work is to detect the intrinsic vibrational bands attributable to the AFB1 target upon interacting with a substrate-bound affinity agent; this goal requires an affinity agent with SERS bands that do not obscure the AFB1 bands” page 68 paragraph 3). Note that although Szlag fails to use the language “two or more analytes”, Szlag inherently suggests this limitation when teaching that “SERS as a label-free technique, inherently capable of multiplex detection based on specific vibrational modes of AFB1 and other analytes” (Chapter 4, page 80 paragraph 2), and teaching that “Affinity agents can… enabling sensor multiplexing” (Introduction, page 3 paragraph 2) and then teaching the detection of the intrinsic SERS peaks associated with the analyte-polymer complex. In other words, it would inherently follow that the identification of the peaks associated with the analyte-polymer complex taught by Szlag would also apply to each of the analytes when multiplexing.
Regarding claim 8, although the claim is indefinite (see rejection above), in the interest of compact prosecution, “a different functional group” is interpreted to be drawn to a different functional group other than hydrogen bonding-related functional groups, and “of each toxin” is interpreted as “of each analyte”.
Slag further suggests wherein determining whether two or more analytes are present comprises identifying bonds with a different functional group of each toxin bonding with the linear polymer affinity agent (“Based on the conjugated character of AFB1, SERS is an attractive and widely used analytical technique due to its high enhancement factors, lack of interference from water in aqueous systems, and its ability to assign specific vibrational modes to certain molecules at low concentrations” page 54 paragraph 3, “Table 3-4 presents the vibrational mode assignments for AEMA, HEMA, and dipropyl carbonotrithioate (DPCTT) between 500-1800 cm-1” page 68 paragraph 3, Table 3-4 page 70 see the bonds with a different functional group assigned to each peak). Note that although Szlag fails to use the language “of each toxin” (interpreted as each analyte), Szlag inherently suggests this limitation when teaching that “Multiplex detection and target capture reversibility, and thus sensor regeneration, are all features expected from the moderate affinity of the polymer capture agent” (Conclusion page 110 paragraph 3) and then teaching the bonds associated with the SERS detection of the analyte. In other words, it would inherently follow that the identification of the different functional groups of the analyte taught by Szlag would also apply to each of the analytes when/for multiplexing given that this is a feature expected from the moderate affinity of the polymer capture agent as taught by Szlag.
Claims 4-5 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Szlag as applied to claim 1 above, and further in view of Li et al. Anal. Chem. 2019, 91, 3885−3892 DOI: 10.1021/acs.analchem.8b04622 (Cited on sheet 2 of IDS 4/18/2023) (“Li”).
Regarding claim 4, Szlag teaches the method of claim 1 as discussed above.
Szlag further teaches that “[b]esides pesticides, other small molecule contaminants in food require monitoring. Mycotoxins, such as ochratoxin A (OTA), are toxic small molecules released from fungi that can infect food and feedstocks” (page 15 paragraph 4).
Slag fails to explicitly teach determining whether two or more mycotoxins are present.
Li et al. teaches “Cauliflower-Inspired 3D SERS Substrate for Multiple Mycotoxins Detection” (Title). Li further teaches “a cauliflower-inspired 3D SERS substrate with intense hot spots was prepared through sputtering Au nanoparticles (Au NPs) on the surface of polydimethylsiloxane coated anodic aluminum oxide (PDMS@AAO) complex substrate…the results of Raman showed that the 3D-Nanocauliflower SERS substrates could realize the simultaneous label-free detection for three mycotoxins (aflatoxin B1, deoxynivalenol, and zearalenone) in maize for the first time. It behaved good linear relationship between the concentrations and Raman intensities of aflatoxin B1, zearalenone, and deoxynivalenol. For the three mycotoxins, this method exhibited the limit of detection (LOD) of 1.8, 47.7, and 24.8 ng/mL (S/N = 3), respectively. The 3D-Nanocauliflower SERS substrates with dense hot spots presented remarkable SERS effect and activity, which could be act as a potential candidate for SERS substrate applied in the rapid and label-free detection” (Abstract). Li further suggests that mycotoxin contamination of human food is a common and serious worldwide problem that threatens human health (“[o]wing to the risk such as varied toxicity and stable existence in many food processing, mycotoxins have been a worldwide problem that causes the loss of the maize consumption and threaten the human health. Hence, it is essential to develop facile and sensitive method to monitor the mycotoxins in food matrices” page 3886 col. 1 para. 1, see Introduction section). Li further suggests that SERS is “facile and sensitive method to monitor the mycotoxins in food matrices” (page 3886 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Szlag to rely on the determining whether two or more mycotoxins are present taught by Li because Li suggests that detecting mycotoxins in human food is essential for protecting human health. A person having ordinary skill in the art would have had a reasonable expectation of success because Szlag teaches that SERS is a label-free technique inherently capable of multiplex detection of analytes and Li teaches that the mycotoxins were detected and their concentration were quantitated with high sensitivity using SERS. Furthermore, both Szlag and Li use a gold substrate and detect AFB1 mycotoxin.
Regarding claims 5 and 10, Szlag teaches the method of claim 1 as discussed above.
Szlag fails to teach wherein determining whether two or more analytes are present comprises determining whether deoxynivalenol, ochratoxin A, or both are present; and comprises identifying a peak in a range from 300 to 1800 cm-1 as corresponding to deoxynivalenol.
Li teaches wherein determining whether two or more analytes are present comprises determining whether deoxynivalenol is present (Abstract). Li further teaches that “the most common mycotoxins in maize are aflatoxin B1 (AFB1), deoxynivalenol (DON), and zearalenone (ZON). …DON could result in emesis, anorexia, hemorrhage, diarrhea, and digestive disorders” (page 3885 col. 2 para. 2). Li further teaches that “the 3D-Nanocauliflower substrate was used to detect three kinds of mycotoxins (AFB1, ZON, and DON) simultaneously. The characteristic bands of … DON (659 and 1365 cm−1) could be markedly distinguished through the spectrum (Figure 7), revealing that the 3D-Nanocauliflower substrate could rapid and efficient discriminate the three mycotoxins in real samples” (page 3891 col. 1 para. 3).
Note that claim 5 recites the optional limitations of “ochratoxin A, or both” (ochratoxin A and deoxynivalenol), therefore these are not specifically required of the claim as presented.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Szlag to include the determining whether deoxynivalenol is present by identifying a peak in a range from 300 to 1800 cm-1 taught by Li because Li teaches that deoxynivalenol (DON) is a highly toxin mycotoxin and suggests that it is commonly found in contaminated food. A person having ordinary skill in the art would have had a reasonable expectation of success because Szlag teaches that SERS is a label-free technique inherently capable of multiplex detection of analytes and Li teaches that DON was detected by its characteristic band on SERS. Furthermore, both Szlag and Li use a gold substrate and further detect AFB1 mycotoxin.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Szlag as applied to claim 1 above, and further in view of Wang et al. Small 2018, 1801623 DOI: 10.1002/smll.201801623 (“Wang”).
Regarding claim 9, Szlag teaches the method of claim 1 as discussed above.
Szlag further teaches that “[b]esides pesticides, other small molecule contaminants in food require monitoring. Mycotoxins, such as ochratoxin A (OTA), are toxic small molecules released from fungi that can infect food and feedstocks” (page 15 paragraph 4).
Szlag fails to teach wherein determining whether two or more analytes are present comprises identifying a peak in a range from 300 to 1700 cm-1 as corresponding to ochratoxin A.
Wang teaches that “[a] surface-enhanced Raman scattering-based mapping technique is reported for the highly sensitive and reproducible analysis of multiple mycotoxins. Raman images of three mycotoxins, ochratoxin A (OTA), fumonisin B (FUMB), and aflatoxin B1 (AFB1) are obtained by rapidly scanning the surface-enhanced Raman scattering (SERS) nanotags-anchoring mycotoxins captured on a nanopillar plasmonic substrate” (Abstract). Wang further suggests that Ochratoxin A is “a key cause of various diseases, such as cancers, mutagenic and teratogenic effects, liver and kidney damage, and birth defects for a wide range of susceptible animal species including humans” (page 1 col. 2 para. 1). Wang further suggests that ochratoxin A poisoning is caused by the consumption of contaminated food therefore it important to monitor trace amount of ochratoxin A (“In many cases, these diseases are occurred after consumption of grains containing mycotoxins or products made from such grains…Therefore, it is important to develop a rapid and sensitive detection methods for monitoring trace amount of multiple mycotoxins” (page 1 col. 2 para. 1). Wang further teaches wherein determining whether two or more analytes are present comprises identifying a peak in a range from 300 to 1700 cm-1 as corresponding to ochratoxin A (“Figure 8. Average SERS spectra of 1368 pixel points for a) OTA” page 8, see Figure 8a showing peaks in a range from 300 to 1700 cm-1 as corresponding to ochratoxin A).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Szlag to include the determining whether ochratoxin A is present by identifying a peak in a range from 300 to 1700 cm-1 taught by Wang because Wang suggests that ochratoxin A is a key cause of various diseases, such as cancers, mutagenic and teratogenic effects, liver and kidney damage, and birth defects for a wide range of susceptible animal species including humans. A person having ordinary skill in the art would have had a reasonable expectation of success because both Szlag and Wang teach mycotoxin SERS detection, including AFB1. Furthermore, both Szlag and Wang teach that ochratoxin A is a mycotoxin found in food and therefore requires monitoring.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Li and Szlag.
Regarding claim 17, although the claim is indefinite (see 112b rejection above) in the interest of compact prosecution, “each toxin” is interpreted as “each analyte”.
Regarding claims 17-19, Li suggests a method of calibrating a sensor (“Cauliflower-Inspired 3D SERS Substrate for Multiple Mycotoxins Detection” Title, “the results of Raman showed that the 3D-Nanocauliflower SERS substrates could realize the simultaneous label-free detection for three mycotoxins (aflatoxin B1, deoxynivalenol, and zearalenone) in maize for the first time. It behaved good linear relationship between the concentrations and Raman intensities of aflatoxin B1, zearalenone, and deoxynivalenol” Abstract) the method comprising: subjecting a metal substrate to a calibrating solution comprising at least one agent and at least two analytes at respective known concentrations, wherein the at least two analytes comprise two mycotoxins and wherein the at least two analytes comprise deoxynivalenol (“The 3D-Nanocauliflower substrate was fabricated using the method described in previous work. Briefly, the surface of PDMS@AAO complex substrate was sputtered with Au at a ratio of 3.6 nm/min in a protective atmosphere of Ar2 with an ETD-3000 Ion sputtering” page 3887 col. 1 para. 4, “Real Food Sample Detection…The obtained samples were used as real samples for detection with the above-mentioned method. For multiple components detection, AFB1, ZON, and DON were added in supernatant with a final concentration of 0.05, 5, and 5 μg/mL, respectively” page 3887 col. 1 para. 6 and col. 2 para. 1, see graphical abstract showing the subjecting step) ; generating, via Raman Spectroscopy, spectral data representing the at least one agent being bound to the at least two analytes and being attached to the metal substrate (“The obtained 3D-Nanocauliflower SERS substrate had tremendous contact area and noticeable SERS hot spots, which contributed to the strong enhancement of Raman signals. As a result, the simultaneous detection of multimycotoxins (including AFB1, DON, and ZON) in maize are successfully realized using the developed 3D-Nanocauliflower SERS substrate, which made it a promising candidate in rapid and label-free detection” page 3886 col. 2 para. 1, “SERS is widely used to detect several substances due to exhibiting molecularly narrow band spectra. In this work, the 3D-Nanocauliflower substrate was used to detect three kinds of mycotoxins (AFB1, ZON, and DON) simultaneously” page 3891 col. 1 para. 3). Note that although Li fails to use the language “bound to the at least two analytes and being attached to the metal substrate”, the teaching of the 3D-Nanocauliflower SERS substrate having “tremendous contact area” inherently suggests that the analytes are bound to the agent in the substrate attached to the metal in the substrate. Li further suggests generating calibration data based on the spectral data to detect the at least two analytes at respective minimum threshold concentrations, wherein the calibration data includes identification of different peaks associated with each toxin (“The characteristic bands of AFB1 (1271, 1344, and 1499 cm−1), ZON (456 and 1036 cm−1), and DON (659 and 1365 cm−1) could be markedly distinguished through the spectrum (Figure 7), revealing that the 3D-Nanocauliflower substrate could rapid and efficient discriminate the three mycotoxins in real samples” page 3891 col. 1 para. 3, see Fig. 7). Note that both the spectral data and calibration data are provided in Figure 7 because it contains the Raman spectra of the at least two analytes and it further contains identification of the different peaks associated with each analyte.
Note that claim 19 recites the optional limitations of “ochratoxin A, or both” (ochratoxin A and deoxynivalenol), therefore these are not specifically required of the claim as presented.
Li fails to teach at least one linear polymer affinity agent.
Szlag teaches “linear polymer affinity agents for the intrinsic SERS detection of food safety targets” (Title). Szlag further teaches that “[t]he concept of linear polymer affinity agents grafted to a SERS substrate is a versatile one (Figure 1-13) that can be applied to any target class which can enable the detection of targets that have not been previously detected with SERS in a potentially inexpensive way” (page 32 para. 4 and page 33 para. 1). Szlag further teaches that linear polymer affinity agents enable SERS detection of analytes at low concentrations (“through repeat unit/analyte noncovalent interactions which would concentrate the analyte at the surface, enabling SERS detection at low concentrations” page 109 para. 1). Szlag further teaches that “the major advantage of a linear polymer affinity agent is its tunablity” (page 110 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Li to rely on the linear polymer affinity agent taught by Szlag because Szlag teaches that it is versatile, tunable, enables analyte detection at low concentrations and is potentially inexpensive. A person having ordinary skill in the art would have had a reasonable expectation of success because both Li and Szlag teach intrinsic SERS detection of food safety targets.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678