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 .
Claim Rejections - 35 USC § 112
Note that dependent claims will have the deficiencies of base and intervening claims.
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 6 and 18-20 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
a) claim 6 requires “. . . , where the nucleic acid detection is devoid of amplification.” It is not clear how this additional limitation modifies the device of underlying claim 1 as it only expresses a negative use (devoid of implication) of the device; and
b) independent claim 18 requires the step of “. . . ., and relating a change in a charge neutrality point to an identity of the nucleic acid; where a change in the charge neutrality point is proportional to a change in the drain current. [italicizing by the Examiner]” It is not clear from Applicant’s specification what is the scope of the phrase “charge neutrality point”. For claim examination purposes the Examiner assumes that it is as described in Fu et al., Sci. Adv. 2017;3: e1701247 25 October 2017 (hereafter “Fu”):
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See Fu page 2 of 7.
If Applicant is being his own lexicographer, please heed MPEP 2173.05(a).
Claim Rejections - 35 USC § 102
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 –
(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.
Claims 1, 2, 6, 8, 10, 12, 13, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wangyang et al. CN 114150089A, based on an EPO machine-generated English language translation (hereafter ‘Wangyang”).
Addressing claim 1, Wangyang discloses a device for detecting nucleic acids (see the title), the device comprising:
a CRISPR-Cas13a-mediated graphene field-effect transistor (see technical field on page 1 and Figure 1 (left embodiment) ) comprising:
a source electrode (as a first matter note the following in the Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection.);
a drain electrode (as a first matter note the following in the Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection. );
a gate electrode (not shown, but clearly implied by the VG axis in Figure 3, which one of ordinary skill in the art would understand to stand for gate voltage (and Ids to stand for drain-source current);
a detection channel (see annotated Figure 1 at the end of this claim rejection); where the channel comprises a CRISPR-Cas13a-mediated graphene layer; where Cas13a is operative to function as an effector protein that targets a specific RNA sequence for cleavage based on a recognition of the RNA sequence by crRNA1 (see annotated Figure 1 (left embodiment) at the end of this claim rejection and the first paragraph of Summary of the Invention, page 1, noting especially, “Cas13a/Cas12a are either free in solution, or fixed on graphite through PEG chains of different lengths. [italicizing by the Examiner] “2).
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Addressing claim 2, for the additional limitation of this note that one of ordinary skill in the art would understand from the following in Wnagyang that the R-PolyN shown in Figure 1 (left embodiment) functions as a reporter molecule
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(see page 2),
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(see page 3), and
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(see page 4).
Addressing claim 6, as a first matter, the Examiner notes that the additional limitation of this claim only expresses a negative intended use (devoid of amplification) of the device. In any event, there is no indication that amplification is performed when the device of Wangyang is used as intended. Indeed, Wangyang can be said to teach away from amplification as Wangyang states, “
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(see Wangyang page 1).
Addressing claim 8, as a first matter, the Examiner notes that the additional limitation of this claim only expresses an intended use of the device. In any event, although Wangyang is silent as to the detection limit for the device, since the device of Wangyang is structurally and compositionally the same as that claimed, inherent properties and capabilities may be assumed. See MPEP 2112.01(I) and 2112.01(II).
Addressing claim 10, Wangyang discloses a device for detecting nucleic acids (see the title), the device comprising:
a CRISPR-Cas12a-mediated graphene field-effect transistor (see technical field on page 1 and Figure 1 (right embodiment) ) comprising:
a source electrode (as a first matter note the following in the Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection.);
a drain electrode (as a first matter note the following in the Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection. );
a gate electrode (not shown, but clearly implied by the VG axis in Figure 3, which one of ordinary skill in the art would understand to stand for gate voltage (and Ids to stand for drain-source current);
a detection channel (see annotated Figure 1 at the end of this claim rejection); where the channel comprises a CRISPR-Cas12a-mediated graphene layer; where Cas12a is operative to function as an effector protein that targets a specific DNA sequence for cleavage based on a recognition of the DNA sequence by crRNA3 (see annotated Figure 1 (right embodiment) at the end of this claim rejection and the first paragraph of Summary of the Invention, page 1, noting especially, “Cas13a/Cas12a are either free in solution, or fixed on graphite through PEG chains of different lengths. [italicizing by the Examiner] “4).
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Addressing claim 12, as a first matter, the Examiner notes that the additional limitation of this claim only expresses a negative intended use (devoid of amplification) of the device. In any event, there is no indication that amplification is performed when the device of Wangyang is used as intended. Indeed, Wangyang can be said to teach away from amplification as Wangyang states, “
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(see Wangyang page 1).
Addressing claim 13, for the additional limitation of this claim note the following in Wangyang
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(see Wangyang page 5).
Addressing claim 16, as a first matter, the Examiner notes that the additional limitation of this claim only expresses an intended use of the device. In any event, although Wangyang is silent as to the detection limit for the device, since the device of Wangyang is structurally and compositionally the same as that claimed, inherent properties and capabilities may be assumed. See MPEP 2112.01(I) and 2112.01(II).
Claim 5 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wangyang as evidenced by Liu et al., 2017, Cell 170, 714–726 August 10, 2017 (hereafter “Liu”).
Addressing claim 5, as a first matter, Wangyang meets all of the limitations of underlying claim 1. See the rejection of claim 1 above under 35 U.S.C 102(a)(1) based on Waangyang. Also, the additional limitation of this claim expresses an intended use of the Cas13a protein, which, as evidenced by Liu, it is inherently capable of performing. See Liu Figure 7. In any event, it is clear from the following that this is how Cas13a protein will function when the device of Wangyang is used as intended
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(see Wangyang page 1) along with
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(se Wangyang page 2).
Claims 1, 2, 6, 8, 10, 12, 13, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gao et al. CN 113355397 A, bases on an EPO machine-generated English language translation (hereafter “Gao”).
Addressing claim 1, Gao discloses a device for detecting nucleic acids (see the title), the device comprising:
a CRISPR-Cas13a-mediated graphene field-effect transistor (see Figure 1. Also, on page 2, note the following
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. . . .
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. . . .
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Also see the second through fourth full paragraphs on page 4) comprising:
a source electrode (122 in Figure 1; see the last paragraph on page 2);
a drain electrode (121 in Figure 1; see the last paragraph on page 2);
a gate electrode (123 in Figure 1; see the last paragraph on page 2);
a detection channel (130) ; where the channel comprises a CRISPR-Cas13a-mediated graphene layer (note Cas protein 200, which may be CAs13a (see the fifth sentence on page 2), and which is fixed on the graphene layer. Also, see the second (“in this embodiment, . . . .”) through seventh full paragraphs on page 4.); where Cas13a is operative to function as an effector protein that targets a specific RNA sequence for cleavage based on a recognition of the RNA sequence by crRNA5 (see the second full paragraph on page 5 (“When the above . . . .”) ).
Addressing claim 2, for the additional limitation of this note that one of ordinary skill in the art would understand from the following in Gao that nucleic acid strand 140 shown in Figure 1 (left embodiment) functions as a reporter molecule
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(see Gao page 5).
Addressing claim 6, as a first matter, the Examiner notes that the additional limitation of this claim only expresses a negative intended use (devoid of amplification) of the device. In any event, there is no indication that amplification is performed when the device of Gao is used as intended. Indeed, Gao can be said to teach away from amplification as Gao states, “
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(See Gao page 1).
Addressing claim 8, as a first matter, the Examiner notes that the additional limitation of this claim only expresses an intended use of the device. In any event, although Gao is silent as to the detection limit for the device6, since the device of Gao is structurally and compositionally the same as that claimed, inherent properties and capabilities may be assumed. See MPEP 2112.01(I) and 2112.01(II).
Addressing claim 10, Gao discloses a device for detecting nucleic acids (see the title), the device comprising:
a CRISPR-Cas12a-mediated graphene field-effect transistor (see Figure 1. Also, on page 2, note the following
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. . . .
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. . . .
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Also see the second through fourth full paragraphs on page 4) comprising:
a source electrode (122 in Figure 1; see the last paragraph on page 2);
a drain electrode (121 in Figure 1; see the last paragraph on page 2);
a gate electrode (123 in Figure 1; see the last paragraph on page 2);
a detection channel (130) ; where the channel comprises a CRISPR-Cas12a-mediated graphene layer (note Cas protein 200, which may be CAs12a (see the fifth sentence on page 2), and which is fixed on the graphene layer. Also, see the second (“in this embodiment, . . . .”) through seventh full paragraphs on page 4.); where Cas12a is operative to function as an effector protein that targets a specific DNA sequence for cleavage based on a recognition of the DNA sequence by crRNA7 (see the second full paragraph on page 5 (“When the above . . . .”). Also see Example 1, which is discussed on pages 8-9, in which Cas12a (step f) is used to defect a certain DNA. ).
Addressing claim 12, as a first matter, the Examiner notes that the additional limitation of this claim only expresses a negative intended use (devoid of amplification) of the device. In any event, there is no indication that amplification is performed when the device of Gao is used as intended. Indeed, Gao can be said to teach away from amplification as Gao states, “
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(See Gao page 1).
Addressing claim 13, for the additional limitation of this claim note the following in Gao
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(See Gao page 7).
Addressing claim 16, as a first matter, the Examiner notes that the additional limitation of this claim only expresses an intended use of the device. In any event, although Gao is silent as to the detection limit for the device8, since the device of Gao is structurally and compositionally the same as that claimed, inherent properties and capabilities may be assumed. See MPEP 2112.01(I) and 2112.01(II).
Claim 5 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gao as evidenced by Liu.
Addressing claim 5, as a first matter, Gao meets all of the limitations of underlying claim 1. See the rejection of claim 1 above under 35 U.S.C 102(a)(1) based on Gao. Also, the additional limitation of this claim expresses an intended use of the Cas13a protein, which, as evidenced by Liu, it is inherently capable of performing. See Liu Figure 7. In any event, it is clear from the following that this is how Cas13a protein will function when the device of Gao is used as intended
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(see Gao page ) along with
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(see Gao page 4).
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.
Claims 1-4, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Sun et al., “High-intensity vector signals for detecting SARS-CoV-2 RNA using CRISPR/Cas13a couple with stabilized graphene field-effect transistor,” Biosensors and Bioelectronics 222 (2023)9 114979 with Supplemental information (hereafter “Sun”) or, in the alternative, under 35 U.S.C. 103 as obvious over Sun in view of Wangyang or Gao.
Addressing claim 1, Sun discloses a device for detecting nucleic acids (see the title), the device comprising:
a CRISPR-Cas13a-mediated graphene field-effect transistor (see the title) comprising:
a source electrode (one of ordinary skill in the art would recognize the source electrode in Figure 2. See annotated Figure 2(D) at the end of this claim rejection. );
a drain electrode (one of ordinary skill in the art would recognize the drain electrode in Figure 2. See annotated Figure 2(D) at the end of this claim rejection. );
a gate electrode (not shown, but clearly implied by the Vgate axis in Figures 1(A) and 1(B));
a detection channel (see annotated Figure 2(D) at the end of this claim rejection.); where the channel comprises a CRISPR-Cas13a-mediated graphene layer; where Cas13a is operative to function as an effector protein that targets a specific RNA sequence for cleavage based on a recognition of the RNA sequence by crRNA10 (see Figure 2 and the full paragraph on Sun page 4, bridging to page 5).
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Although Sun can be said to anticipate claim 1, as just discussed, it is not clear whether the claim 1 phrase “where the channel comprises a CRISPR-Cas13a-mediated graphene layer; . . . “ is meant to imply that CRISPR-Cas13a is part of a layer on graphene or more broadly interacts (mediates) with a graphene layer. If the former is meant, then in Sun as best understood by the Examiner the cas13a will be in solution above the graphene layer, mixed with sample. See Sun Figure 1 and the first sentence of 2.4. The collaborative system for detecting SARS-COV-2 RNA, which is on page 114979.
Wangyang discloses a device for detecting nucleic acids that meets all of the limitation of Applicant’s claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) above, which is based on Wang yang. Moreover, Wangyang states, in the first paragraph of Summary of the Invention, page 1, “Cas13a/Cas12a are either free in solution, or fixed on graphite through PEG chains of different lengths. [italicizing by the Examiner] “11).
Gao also discloses a device for detecting nucleic acids that meets all of the limitation of Applicant’s claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) above, which is based on Gao. Gao further discloses that CRISPR-cas13a may be either in solution or part of a layer on graphene. See Figures 1 and 2, the sixth paragraph on page 4 (“In this embodiment, the Cas protein 200 is immobilized on the functionalized graphene layer.”), and the penultimate paragraph on page 5 (“Please refer to Figure 2. An embodiment of the present invention also provides another nucleic acid detection kit. The composition of the kit is roughly the same as the above nucleic acid detection kit. The difference is that in this embodiment, the Cas protein does not It is fixed on the field effect transistor chip 20. When the kit is used, Cas protein is introduced into the reaction system in an external manner, and the Cas protein is free in the system.”).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the CRISPR-cas13a in Sun be part of a layer on the graphene as taught by Wangyang and Gao because in light of Wangyang and Gao it is prima facie “obvious to try”, that is, to choose from a finite number of identified, predictable solutions (here two solutions, CSPIR-cas13a in a sample mixture or as part of a layer on graphene), with a reasonable expectation of success (there is no apparent reason why the CSPIR-cas13 would function differently if part of a graphene layer as in Wangyang or Gao, rather than free in solution). See MPEP 2143(I)(E).
Addressing claim 2, for the additional limitation of this note that RP in Sun
Figure 2(E) stands for reporter probe. See Sun page 2, last paragraph in left column (“In this collaborative system, the reporter probes (RP) . . . .”).
Addressing claim 3, for the additional limitation of this claim see Sun Figure 2(E) and note that the RP (reporter probe) comprises 6U + 12 T, that is, a combination of polyUn and polyTn.
Addressing claim 4, as a first matter this claim does not positively require the reporter molecule to comprise polyUn, as polyUn is optional in underlying claim 3, only that if the reporter molecule is (or in combination is) polyUn than n is 5 to 50. So, clam 4 can be rejected on the same basis that claim 3 has been rejected. In any event, recall the following from the rejection of claim 3 “. . . . see Sun Figure 2(E) and note that the RP (reporter probe) comprises 6U + 12 T, that is, a combination of polyUn and polyTn. [italicizing by the Examiner]”
Addressing claim 6, as a first matter, the Examiner notes that the additional limitation of this claim only expresses a negative intended use (devoid of amplification) of the device. In any event, there is no indication that amplification is performed when the device of Sun is used as intended.
Addressing claim 8, as a first matter, the Examiner notes that the additional limitation of this claim only expresses an intended use of the device. In any event, since the device Of Sun is structurally and compositionally the same as that claimed, inherent properties and capabilities may be assumed. See MPEP 2112.01(I) and 2112.01(II). Also, the claimed detection limit appears implied by the following in Sun, “Here, thanks to the CRISPR-Cas13a system’s strong cleavage properties to RP, the coupling of multiple CRISPRs, the optimized structure of RP and the highly sensitive electrical properties of GFETs,. . . ., and exhibits a lower detection limit of 0.15 copies/ μL, compared with the pure CRISPR/Cas13a technology (100 copies/ μL) (Fozouni et al., 2021), in detecting SARS-CoV-2 RNA.” See 4. Discussion, which is on Sun page 4.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Wangyang or Gao as applied to claims 1-4, 6, and 8 above, and further in view of Liu.
Addressing claim 5, as a first matter the additional limitation of this claim expresses an intended use of the Cas13a protein, which, as evidenced by Liu, it is inherently capable of performing. See Liu Figure 7. In any event, it is clear from Sun Figure 2 the following that this is how Cas13a protein will function when the device of Sun is used as intended.
Claims 3, 4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Wangyang.
Addressing claim 3, as a first matter note that Wangyang meets all of the limitations of underlying claim 2. See the rejection of claim 2 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not explicitly disclose “. . . ., where the reporter molecule is polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, where n is the number of repeat units in the reporter molecule.” However, Wangyang does disclose that the reporter molecule may be a random combination of nucleotides U, A, T, G, and/or C:
“Further, the length of the ssRNA or ssDNA is a random sequence of 10-30 nt.” See Wangyang page 2. Also see the sequences listed in Table 1. To have the reporter molecule in Wangyang to be polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, rather than a random sequence of the relevant nucleotides is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II).
Addressing claim 4, as a first matter this claim does not positively require the reporter molecule to comprise polyUn, as polyUn is optional in underlying claim 3, only that if the reporter molecule is (or in combination is) polyUn than n is 5 to 50. So, clam 4 can be rejected on the same basis that claim 3 has been rejected. In any event, recall the following from the rejection of claim 3
To have the reporter molecule in Wangyang to be polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, rather than a random sequence of the relevant nucleotides is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II). [underlining added]
As for n being 5 to 50, also recall form the rejection of claim 3, ‘ “Further, the length of the ssRNA or ssDNA is a random sequence of 10-30 nt.” See Wangyang page 2. [underlining added]‘
Addressing claim 11, as a first matter note that Wangyang meets all of the limitations of underlying claim 10. See the rejection of claim 10 under 35 U.S.C. 102(a)(1) based on Wangyang above.
As for the claim 11 limitation “. . . .,where the graphene layer is functionalized with a reporter molecule; . . . .”, one of ordinary skill in the art would understand from the following in Wangyang that the D-PolyN shown in Figure 1 (right embodiment) functions as a reporter molecule
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(see page 2),
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(see page 5).
Wangyang, though, does not explicitly disclose “. . . ., where the reporter molecule is polyAn, polyCn, or a combination thereof, where n is the number of repeat units in the reporter molecule.” However, Wangyang does disclose that the reporter molecule may be a random combination of nucleotides U, A, T, G, and/or C:
“Further, the length of the ssRNA or ssDNA is a random sequence of 10-30 nt.” See Wangyang page 2. Also see the sequences listed in Table 1. To have the reporter molecule in Wangyang to be polyAn, polyCn, or a combination thereof, rather than a random sequence of the relevant nucleotides is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II).
Claims 3, 4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Gao.
Addressing claim 3, as a first matter note that Gao meets all of the limitations of underlying claim 2. See the rejection of claim 2 under 35 U.S.C. 102(a)(1) based on Gao above.
Gao does not explicitly disclose “. . . ., where the reporter molecule is polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, where n is the number of repeat units in the reporter molecule.” However, Gao does disclose as an example reporter molecule, “The structure of the field-effect transistor chip is shown in Figure 1. As shown, the nucleotide sequence of the guide RNA is shown in SEQ ID No. 1 (that is, 5'-UAAUUUCUACUCUUGUAGAUGAUUUUUUCUCCUUUUGUUCA-3'), . . . .” See the first paragraph of Example 1 on Gao page 8. As this molecule is made up of a combination of nucleotides U, A, T, G, and/or C, and, in fact, comprises polyUn, to have the reporter molecule in Gao to be polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, rather than the specific sequence of the relevant nucleotides in Gao Example 1, is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II).
Addressing claim 4, as a first matter this claim does not positively require the reporter molecule to comprise polyUn, as polyUn is optional in underlying claim 3, only that if the reporter molecule is (or in combination is) polyUn than n is 5 to 50. So, clam 4 can be rejected on the same basis that claim 3 has been rejected. In any event, recall the following from the rejection of claim 3
As this molecule is made up of a combination of nucleotides U, A, T, G, and/or C, and, in fact, comprises polyUn, to have the reporter molecule in Gao to be polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, rather than the specific sequence of the relevant nucleotides in Gao Example 1, is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II). [underlining added]
As for n being 5 to 50, also recall form the rejection of claim 3, “As shown, the nucleotide sequence of the guide RNA is shown in SEQ ID No. 1 (that is, 5'-UAAUUUCUACUCUUGUAGAUGAUUUUUUCUCCUUUUGUUCA-3'), . . . .” See the first paragraph of Example 1 on Gao page 8.” This sequence has fort-one nucleotides.
Addressing claim 11, as for the claim limitation “. . . ., where the graphene layer is functionalized with a reporter molecule; . . . ., one of ordinary skill in the art would understand from the following in Gao that nucleic acid strand 140 shown in Figure 1 (left embodiment) functions as a reporter molecule
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(see Gao page 5).
Gao, though, does not explicitly disclose “. . . ., where the reporter molecule is polyAn, polyCn, or a combination thereof, where n is the number of repeat units in the reporter molecule.” However, Gao does disclose as an example reporter molecule, “The structure of the field-effect transistor chip is shown in Figure 1. As shown, the nucleotide sequence of the guide RNA is shown in SEQ ID No. 1 (that is, 5'-UAAUUUCUACUCUUGUAGAUGAUUUUUUCUCCUUUUGUUCA-3'), . . . .” See the first paragraph of Example 1 on Gao page 8. As this molecule is made up of a combination of nucleotides U, A, T, G, and/or C, and, in fact, comprises A and C, to have the reporter molecule in Gao to be polyAn, polyCn, or a combination thereof, rather than the specific sequence of the relevant nucleotides in Gao Example 1, is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II).
Claims 7, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Wangyang in view of Aran et al. US 2019/0112643 A1 (hereafter “Aran”).
Addressing claim 7, as a first matter note that Wangyang meets all of the limitations of underlying claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not disclose “. . . ., where the device is one of a plurality of devices in an array.”
Aran discloses a CRISPR-functionalized field-effect biosensor (device). See the title, Abstract, and Figures 1A and 2A. The Figure 12 embodiment depicts a plurality of such biosensors (devices) in an array. See paragraph [0039]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Wangyang be one of a plurality of devices in an array as taught by Aran because this is prima facie obvious as largely duplication of parts for a multiplied effect, namely allowing multiple different targets (e.g., disease markers) maybe assayed in a single device simultaneously. See MPEP 2144.04(VI)(B).
Addressing claim 14, as a first matter note that Wangyang meets all of the limitations of underlying claim 11. See the rejection of claim 11 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not disclose “. . . ., where the graphene is blocked with at least one of ethanolamine hydrochloride, amino-polyethylene glycol alcohol, or a combination thereof.”
Aran discloses a CRISP-functionalized graphene field-effect biosensor. See Figure 1A. Preparing this biosensor involves graphene blocking by “using amino-PEGS-alcohol and ethanolamine hydrochloride”. See paragraph [0073].
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the graphene in the device of Wangyang blocked with amino-PEGS-alcohol and ethanolamine hydrochloride as taught by Aran because it is prima facie obvious simple substitution of one known element (graphene blocking agent) for another to obtain predictable results (see MPEP 2143(I)(B)), especially as Wangyang already discloses using ethanolamine as a blocking agent:
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(see Wangyang page 5).
Addressing claim 15, as a first matter note that Wangyang meets all of the limitations of underlying claim 10. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not disclose “. . . ., where the device is one of a plurality of devices in an array.”
Aran discloses a CRISPR-functionalized field-effect biosensor (device). See the title, Abstract, and Figures 1A and 2A. The Figure 12 embodiment depicts a plurality of such biosensors (devices) in an array. See paragraph [0039]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Wangyang be one of a plurality of devices in an array as taught by Aran because this is prima facie obvious as largely duplication of parts for a multiplied effect, namely allowing multiple different targets (e.g., disease markers) maybe assayed in a single device simultaneously. See MPEP 2144.04(VI)(B).
Claims 7, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gao in view of Aran et al. US 2019/0112643 A1 (hereafter “Aran”).
Addressing claim 7, as a first matter note that Gao meets all of the limitations of underlying claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) based on Gao above.
Gao does not disclose “. . . ., where the device is one of a plurality of devices in an array.”
Aran discloses a CRISPR-functionalized field-effect biosensor (device). See the title, Abstract, and Figures 1A and 2A. The Figure 12 embodiment depicts a plurality of such biosensors (devices) in an array. See paragraph [0039]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Gao be one of a plurality of devices in an array as taught by Aran because this is prima facie obvious as largely duplication of parts for a multiplied effect, namely allowing multiple different targets (e.g., disease markers) maybe assayed in a single device simultaneously. See MPEP 2144.04(VI)(B).
Addressing claim 14, as a first matter note that Gao meets all of the limitations of underlying claim 11. See the rejection of claim 11 under 35 U.S.C. 102(a)(1) based on Gao above.
Wangyang does not disclose “. . . ., where the graphene is blocked with at least one of ethanolamine hydrochloride, amino-polyethylene glycol alcohol, or a combination thereof.”
Aran discloses a CRISP-functionalized graphene field-effect biosensor. See Figure 1A. Preparing this biosensor involves graphene blocking by “using amino-PEGS-alcohol and ethanolamine hydrochloride”. See paragraph [0073].
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the graphene in the device of Gao blocked with amino-PEGS-alcohol and ethanolamine hydrochloride as taught by Aran because it is prima facie obvious simple substitution of one known element (graphene blocking agent) for another to obtain predictable results (see MPEP 2143(I)(B)), especially as Gao already discloses using aqueous alcohol amine solution as a blocking agent:
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(see Gao page 7).
Addressing claim 15, as a first matter note that Gao meets all of the limitations of underlying claim 10. See the rejection of claim 10 under 35 U.S.C. 102(a)(1) based on Gao above.
Gao does not disclose “. . . ., where the device is one of a plurality of devices in an array.”
Aran discloses a CRISPR-functionalized field-effect biosensor (device). See the title, Abstract, and Figures 1A and 2A. The Figure 12 embodiment depicts a plurality of such biosensors (devices) in an array. See paragraph [0039]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Gao be one of a plurality of devices in an array as taught by Aran because this is prima facie obvious as largely duplication of parts for a multiplied effect, namely allowing multiple different targets (e.g., disease markers) maybe assayed in a single device simultaneously. See MPEP 2144.04(VI)(B).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Wangyang or Gao as applied to claims 1-4, 6, and 8 above, and further in view of Aran.
Addressing claim 17, Sun does not disclose “. . . ., where the device is one of a plurality of devices in an array.”
Aran discloses a CRISPR-functionalized field-effect biosensor (device). See the title, Abstract, and Figures 1A and 2A. The Figure 12 embodiment depicts a plurality of such biosensors (devices) in an array. See paragraph [0039]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Sun be one of a plurality of devices in an array as taught by Aran because this is prima facie obvious as largely duplication of parts for a multiplied effect, namely allowing multiple different targets (e.g., disease markers) maybe assayed in a single device simultaneously. See MPEP 2144.04(VI)(B).
Claims 9 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wangyang in view of Aran et al. US 2022/0365024 A1 (hereafter “Aran II”).
Addressing claim 9, as a first matter note that Wangyang meets all of the limitations of underlying claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not disclose “[a] microfluidic device comprising the device of Claim 1.“
Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Wangyang be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
Addressing claim 17, as a first matter note that Wangyang meets all of the limitations of underlying claim 10. See the rejection of claim 10 under 35 U.S.C. 102(a)(1) based on Wangyang above.
Wangyang does not disclose “[a] microfluidic device comprising the device of Claim 10.“
Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Wangyang be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
Claims 9 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Gao in view of Aran II.
Addressing claim 9, as a first matter note that Gao meets all of the limitations of underlying claim 1. See the rejection of claim 1 under 35 U.S.C. 102(a)(1) based on Gao above.
Gao does not disclose “[a] microfluidic device comprising the device of Claim 1.“
Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Gao be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
Addressing claim 17, as a first matter note that Gao meets all of the limitations of underlying claim 10. See the rejection of claim 10 under 35 U.S.C. 102(a)(1) based on Gao above.
Gao does not disclose “[a] microfluidic device comprising the device of Claim 10.“
Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Gao be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Wangyang or Gao as applied to claims 1-4, 6, and 8 above, and further in view of Aran II.
Addressing claim 9, Sun does not disclose “[a] microfluidic device comprising the device of Claim 1.“
Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Sun be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Wangyang in view of Fu.
Addressing claim 18, Wangyang discloses a method of detecting a nucleic acid (see the title ), the method comprising:
disposing on a graphene field-effect transistor, a solution comprising crRNA, Cas13a and a target RNA or a solution comprising crRNA, Cas12 and a target DNA (both of the claimed embodiments are disclosed by Wangyang. See Figure 1, the first paragraph of Summary of the Invention, page 1; and Examples 1-5 on pages 3-5 (Examples 1-3 relate to Cas13a and Examples 4 and 5 relate to Cas12a));
where the graphene field-effect transistor comprises:
a source electrode (as a first matter note the following in the Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection.);
a drain electrode (as a first matter note the following in the first paragraph of Summary of the Invention, page 1,“ When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” One of ordinary skill in the art would recognize the source electrode in Figure 1. See annotated Figure 1 at the end of this claim rejection. ); and
a graphene layer disposed between the source electrode and the drain electrode; ( “The graphene field effect transistor (gFET) sensor is a field effect transistor device made of graphene as the channel material.” See the last paragraph of Background technique, which is on page 1. Also, “On the other hand, in order to further improve the detection sensitivity, the present application provides another nucleic acid detection method, which uses a field effect transistor to amplify the signal of CRISPRCas13a/
Cas12a trans-cleavage immobilized on the graphene surface (as shown in Figure 2).[italicizing by the Examiner]” See page 2.);
cleaving the target RNA or the target DNA with the Cas13a or Cas12 respectively (see Figure 1. Also, note “Cas13a is activated to cleave R-polyN20, resulting in a shift of the transfer characteristic curve to the right.” See page 4 (under Example 2 (3. Detection)). Additionally, “When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface,
and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain in the gFET. [italicizing by the Examiner]” See the first paragraph of Summary of the Invention, page 1.);
cleaving reporter molecules from the graphene surface (see Figure 1 and the first paragraph of Summary of the Invention, page 1 );
changing a composition of the solution that comprises the target RNA or a composition of the solution that comprises the target DNA (this step is implied by
Figure 1 and the first paragraph of Summary of the Invention, page 1);
measuring the source-drain current by measuring a change in a gate voltage at a constant source-drain voltage (see Figure 3 (“[Fig.]3 is a graph of the experimental results of Example 1.” See page 3, yonder Description of drawings. Also, “When the target nucleic acid activates Cas13a/Cas12a, Cas13a/Cas12a can rapidly cut ssRNA/ssDNA immobilized on the graphene surface, and thousands of cuts occur per second, resulting in a rapid change in the current between the source and drain
in the gFET. The transfer characteristic curve shifts, enabling ultrasensitive detection of target nucleic acids. [italicizing by the Examiner]“ See the first paragraph of Summary of the Invention, page 1.).
Wangyang, though, does not disclose the claim 18 limitation “where the graphene layer is functionalized with a reporter molecule selected from the group consisting of polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, . . . .” However, Wangyang does disclose that the reporter molecule may be a random combination of nucleotides U, A, T, G, and/or C:“Further, the length of the ssRNA or ssDNA is a random sequence of 10-30 nt.” See Wangyang page 2. Also see the sequences listed in Table 1. To have the reporter molecule in Wangyang to be polyUn, polyAn, polyTn, polyGn, polyCn, or a combination thereof, rather than a random sequence of the relevant nucleotides is prima facie obvious because a rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. See MPEP 2144.0(I). Also, homology and isomerism are facts which must be considered with all relevant facts in determining obviousness. See MPEP 2144.09(II).
Wangyang also does not disclose the claim 18 limitation “relating a change in a charge neutrality point to an identity of the nucleic acid; where a change in the charge neutrality point is proportional to a change in the drain current.” As a first matter the Examine notes that the phrase “charge neutrality point” is understood as described in Fu:
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See Fu page 2 of 7.
Fu discloses biosensing near the neutrality point of graphene using a graphene-FET biosensor having p-DNA immobilized on the graphene channel. See the title, and Figures 1 and 4. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to relate a change in a charge neutrality point to an identity of the nucleic acid; where a change in the charge neutrality point is proportional to a change in the drain current as taught by Fu in the method of Wangyang because (1) as seen in Fu Figure 1 it would only require modification of the electrical circuitry associated with the gate electrode, rather than structural or compositional modification of the graphene-FET, and (2) as disclosed by Fu, “
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See Fu page 5 of 7.
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Addressing claim 19, there is no indication that nucleic acid amplification is performed when the device of Sun is used as intended.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Wangyang in view of Fu as applied to claims 18 and 19 above, and further in view of Aran II and Weng et al. ACS Sens. 2023, 8, 1489−1499 with supplemental information (hereafter “Weng”).
Addressing claim 20, Wangyang does not disclose “determining nucleic acid concentration on a microfluidic device that comprises the graphene field-effect transistor.”
As for the claim limitation “a microfluidic device that comprises the graphene field-effect transistor…”, Aran II discloses a system and apparatus for direct or indirect target substance signal measurement include an integrated circuit with an array of 2D FETs with corresponding 2D transistor channels and a gate area for receiving a volume of liquid with one or more chemical or biological target substances. See the Abstract. Aran II further discloses using cas12 or cas13 enzyme and a fluidic device or a set of one or more microfluidic channels may be provided to create a flow of liquid parallel or perpendicular to an integrated circuit so that the liquid contacts a channel that has the FET array. See Aran II paragraphs [0137], [0205], and [0215]. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the device of Wangyang be part of a microfluidic device similarly as taught by Aran II because then the operation of device may be significantly automated using well-known microfluidic “plumbing” (micropumps, microvalves, and micro reservoirs, for example) to dispense sample and reagents in a pre-programmed manner and then later wash the microchannels and device for re-use.
As for the claim limitation “determining nucleic acid concentration . . . .”, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to do so because (1) as shown by Weng page 1491, the paragraph beginning with “In the case of the CRISPR Cas12a-gFET biosensor . . . “ and Figures 2(B) and 2(C), the nucleic acid concentration may be easily determined from the shift in the charge neutrality point (CNP) in the Ids versus Vg p0lot (see Wangyang Figure 3 and Weng Figure 2(B)) from before cleavage to after cleavage; and (2) this will make the method of Wnagyang as modified by Fu more useful, especially if the target nucleic acid is biomarker for disease.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER STEPHAN NOGUEROLA whose telephone number is (571)272-1343. The examiner can normally be reached on Monday - Friday 9:00AM-5:30 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Luan Van can be reached on 571 272-8521. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER S NOGUEROLA/ Primary Examiner, Art Unit 1795
1 Note that Examiner assumes that “crRNA” stands for CRISPR RNA.
2 The Examiner assumes that “graphite” should actually be “graphene”, which is otherwise used throughout the Wangyang disclosure.
3 Note that Examiner assumes that “crRNA” stands for CRISPR RNA.
4 The Examiner assumes that “graphite” should actually be “graphene”, which is otherwise used throughout the Wangyang disclosure.
5 Note that Examiner assumes that “crRNA” stands for CRISPR RNA.
6 Gao Figur3s 3 and 4 seem to establish at least femtomolar capability.
7 Note that Examiner assumes that “crRNA” stands for CRISPR RNA.
8 Gao Figur3s 3 and 4 seem to establish at least femtomolar capability.
9 Available online 30 November 2022.
10 Note that Examiner assumes that “crRNA” stands for CRISPR RNA.
11 The Examiner assumes that “graphite” should actually be “graphene”, which is otherwise used throughout the Wangyang disclosure.