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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6, in the reply filed on April 23rd, 2026 is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6 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.
Claim 1 recites “identifying a target nucleic acid...using a guide ribonucleic acid (gRNA) and a programmable nuclease” wherein the step of “identifying” is indefinitely provided as the “use” of the gRNA and a programmable nuclease is undefined. To the extent the "using" language is intended to define a method of operating the device, it is indefinite because the claim fails to positively recite the necessary steps to perform the action. Applicant must recite the active steps corresponding to the recited “identifying a target nucleic acid in the fluid sample using a guide ribonucleic acid (gRNA) and a programmable nuclease” so as to provide what constitutes the presently indefinitely recited “using” step.
Examiner further notes that the “identification” step appears to be drawn to mere chemical binding processes of a gRNA and programmable nuclease to the sample occurring within the device and is not necessarily an active step of the invention. As such, the “using” step discussed above is further unclear as to if the providing of the “a guide ribonucleic acid (gRNA) and a programmable nuclease immobilized in a side channel” are positively required elements of the claim or are merely inferentially provided as intended workpieces used by an operator. Applicant may wish to amend the claim to recite a method step of “providing a guide ribonucleic acid (gRNA) and a programmable nuclease immobilized in a side channel” etc., followed by the addition of samples/reagents and then the subsequent detection step.
Further as in Claim 1, the claim recites “a side channel fluidically coupled to the microfluidic channel” wherein the sample/reagent are added to the microfluidic channel, and the nuclease/gRNA are immobilized in the side channel; however, no particular interaction between the sample/reagents and the nuclease/gRNA is provided, in which the identification of a target nucleic acid in the fluid sample is thus indefinitely set forth . Applicant may wish to clarify that the sample is injected into the microfluidic channel and travels through the side channel and contacs the nuclease/gRNA and be cleaved thereby.
Additionally, Claim 1 recites “causing cleavage of the detectable ligand” but further recites “detecting the detectable ligand from the cleaved reporter nucleic acid” wherein it appears Applicant may intend to recite “causing cleavage of the reporter nucleic acid” instead of the ligand (as nucleases cleave nucleic acids), or vice versa.
Claims 2-6 are further rejected as indefinite for their dependence on Claim 1.
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (WO 2020/028729 A1), hereinafter “Chen”, in view of Aran et al. (US 2019/0112643 A1), hereinafter “Aran”.
Regarding Claim 1, Chen teaches a method, comprising:
receiving in a microfluidic channel, a fluid sample ([0032]: “In some aspects, the method comprises one or more of the following steps: sliding the sliding layer to overlap the opening of the second chamber with the opening of the channel; moving the sample from the second chamber into the channel; aspirating the sample from the channel into the first side channel and mixing...”) and a reagent, wherein the reagent includes a reporter nucleic acid labeled with a detectable ligand ([0006]: “wherein the second chamber comprises a programmable nuclease and a reporter comprising a nucleic acid and a detection moiety...” – As discussed above, the second chamber opening is aligned with the opening of the channel to allow movement of fluids therebetween and being oscillated back and forth through the channel for mixing.);
identifying a target nucleic acid in the fluid sample using a guide ribonucleic acid (gRNA) and a programmable nuclease ([0005]: “In some aspects, the first channel, the second channel, or the third channels are connected to an air manifold. In some aspects, more than one chamber comprising a programmable nuclease and a reporter are fluidically connected to a single chamber comprising the sample.” – Abstract: “a guide nucleic acid targeting a target nucleic acid”) in a side channel connected to the main channel (See para. [0291] discussing branching channels and multiplexed assays using segregated respective guide RNA molecules of varying sequence.);
responsive to identifying the target nucleic acid in the fluid sample, causing cleavage of the detectable ligand ([0219]: “Once the detector nucleic acid is cleaved by the activated programmable nuclease, the detection moiety can be released or separated from the reporter and generates a detectable signal that is immobilized on a support medium.”); and
detecting the detectable ligand from the cleaved reporter nucleic acid in the side channel ([0219]: “Often the detection moiety is at least one of a fluorophore, a dye, a polypeptide, or a nucleic acid. Sometimes the detection moiety binds to a capture molecule on the support medium to be immobilized. The detectable signal can be visualized on the support medium to assess the presence or level of the target nucleic acid associated with an ailment, such as a disease, cancer, or genetic disorder.”),
as in Claim 1.
Further regarding Claim 1, Chen does not specifically teach the method discussed above wherein the guide ribonucleic acid (gRNA) and programmable nuclease are immobilized, as in Claim 1.
However, Aran teaches a respective CRISPR/programmable nuclease-based biosensor wherein CRISPR-Cas9 is immobilized on a surface of a graphene channel (Fig. 2B and [0016]) so as to provide for rapid and digital target detection (Abstract: “A digital biosensor for assaying a target nucleic acid and methods of using the biosensor for digitally detecting the target nucleic acid are disclosed “ -- See also [0033].), thereby offering higher throughput.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Chen wherein the guide ribonucleic acid (gRNA) and programmable nuclease are immobilized in their respective side branching channels and chambers connected thereto, such as suggested by Aran, so as to increase throughput of the device.
Regarding Claim 2, the prior art meets the limitations of Claim 1 as discussed above. Further, Chen teaches the method discussed above wherein a plurality of side channels are fluidically coupled to the microfluidic channel (See para. [0291] discussing branching channels and multiplexed assays using segregated respective guide RNA molecules of varying sequence.), each side channel including a respective pump ([0156]: “The method of any preceding embodiment, wherein the mixing chamber comprises a pneumatic pump for mixing, aspirating, and dispensing fluid in the device.” – As the pump is provided to a respective mixing chamber, one of ordinary skill in the art would find it obvious that, when a branching arrangement feeding multiple mixing chambers is used, that each mixing chamber comprise its own pump.), and wherein the method includes moving the fluid sample into each of the plurality of side channels by actuating the pumps in the side channels ([0182]: “The device of any preceding embodiment, wherein the mixing chamber comprises a pneumatic pump for mixing, aspirating, and dispensing fluid in the device.” – As the pumps are used for aspirating samples to a particular chamber/channel, the method includes moving the fluid sample into each of the plurality of side channels by actuating the pumps in the side channels. See also [0209]: “The method of any one of claims 73-76, wherein the method comprises one or more of the following steps: sliding the sliding layer to overlap the opening of the second chamber with the opening of the channel; moving the sample from the second chamber into the channel; aspirating the sample from the channel into the first side channel and mixing; sliding the sliding layer to overlap the opening of the channel with the opening of the third chamber; dispensing the sample into the third chamber; moving the sample from the third chamber into the channel; aspirating the sample from the channel into the second side channel and mixing; sliding the sliding layer to overlap the opening of the channel with the opening of the single chamber; and dispensing the sample into the single chamber. 78. The method of any one of claims 73-76, wherein the method comprises one or more of the following steps: sliding the sliding layer to overlap the opening of the second chamber with the opening of the channel; moving the sample from the second chamber into the channel; aspirating the sample from the channel into the first side channel and mixing; sliding the sliding layer to overlap the opening of the channel with the opening of the single chamber; and dispensing the sample into the single chamber. 79.”), as in Claim 2.
Regarding Claim 3, the prior art meets the limitations of Claim 2 as discussed above. Further, Chen teaches the method discussed above further including moving the fluid sample into each of the plurality of side channels in a sequential order by independently actuating the respective pumps in the sequential order (Since the samples are aspirated by respective pneumatic pumps as discussed above, such pneumatic pumps must necessarily be operated in a particular sequence commensurately as claimed, even if the sequence merely comprises activating all the pumps at once.), as in Claim 3.
Regarding Claim 5, the prior art meets the limitations of Claim 1 as discussed above. Further, Chen teaches the method discussed above wherein the detectable ligand is a fluorophore ([0013]: “In some aspects, the detection moiety comprises a fluorophore.”), and the reporter nucleic acid is labeled with the fluorophore and a quencher ([0061]: “a detector nucleic acid comprising a fluorophore attached to a quencher by a nucleic acid”), and wherein detecting the detectable ligand from the cleaved reporter nucleic acid in the side channel includes:
measuring a first signal in the side channel prior to receiving the fluid sample in the microfluidic channel; and measuring a second signal in the side channel responsive to receiving the fluid sample in the microfluidic channel; and identifying the target nucleic acid in the fluid sample responsive to the second signal exceeding the first signal (See paras. [0465-0466] discussing signal distinguishable from a baseline, wherein such an arrangement suggests measuring a first signal in the side channel prior to receiving the fluid sample, then detecting a target in response to the sample and reagents being injected into the channel, as such a baseline could only be acquired by performing measurements prior to sample/reagent addition.), as in Claim 5.
Regarding Claim 6, the prior art meets the limitations of Claim 1 as discussed above. Further, Chen teaches the method discussed above wherein the detectable ligand is an electrochemical reporter probe ([0108]: “The method of embodiment 120, wherein the detection signal is detected by...electrochemical detection...”), as in Claim 6.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Aran, as applied to Claims 1-3 and 5-6 above, and in further view of Kim et al. (US 2006/0199199 A1), hereinafter “Kim”.
Regarding Claim 4, the prior art meets the limitations of Claim 1 as discussed above. Further, Chen does not specifically teach the method discussed above including filtering, using plurality of filtration structures disposed orthogonal to the flow of the fluid sample in the microfluidic channel, polymerase or nuclease inhibiting compounds, as in Claim 4.
However, Kim teaches a preparation method for preparing clinical samples for nucleic acid amplification and the like wherein the sample is filtered to remove nucleic acid amplification inhibitors ([0035]: “After the sample is contacted to the carboxyl group-coated solid support, the solid support on which an amplification inhibitor is adsorbed is removed, and only a supernatant is used for nucleic acid amplification. The solid support on which an amplification inhibitor is adsorbed may be removed by centrifugation or filtration with a filter.” – [0042]: “a filter for filtering the beads may be installed in the channel 17. In this case, the beads on which PCR inhibitors are attached may not pass through the filter.”) so as to prevent inhibitory compounds from interfering with polymerase activity, wherein such compounds are known to similarly inhibit nuclease activity, thereby reducing errors related to inhibition of the active polymerase/nuclease required for the detection assays in Chen/Aran.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Chen/Aran including filtering, using plurality of filtration structures disposed orthogonal to the flow of the fluid sample in the microfluidic channel, polymerase or nuclease inhibiting compounds, such as suggested by Kim, so as to prevent inhibitory compounds from interfering with polymerase activity, wherein such compounds are known to similarly inhibit nuclease activity, thereby reducing errors related to inhibition of the active polymerase/nuclease required for the detection assays in Chen/Aran.
Further, one of ordinary skill in the art would find it obvious to provide additional filters so as to provide further filtration of the inhibitory complexes so as to further prevent inhibition of the assay’s active polymerase/nuclease enzyme. Mere duplication of parts has no patentable significance unless a new and unexpected result is produced – see MPEP 2144.04(VI)(B).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN KASS whose telephone number is (703)756-5501. The examiner can normally be reached Monday - Friday from 9:00 A.M. to 5:00 P.M. EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Charles Capozzi, can be reached at telephone number (571)270-3638. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/B.J.K./Examiner, Art Unit 1798
/NEIL N TURK/Primary Examiner, Art Unit 1798
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