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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 17-24 remain withdrawn. Claims 1-16 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claim 1 was objected to for minor informalities. In light of Applicant’s amendments to the claims submitted 1/27/2026, this objection has been withdrawn.
35 USC 112(b) Rejections
Claims 1-16 were rejected due to an indefiniteness issue associated with claim 1. In light of Applicant’s amendments to the claims submitted 1/27/2026, these rejections have been withdrawn. However, see new grounds of rejection below.
35 USC 103 Rejections
Claims 1-16 were rejected as being unpatentable over Cass et al. (WO 2018/189530 A1; cited in Applicant’s IDS) in view of Lu et al. (ACS Sensors, 2018), and various combinations of references.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been maintained. See “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejections presented in the Non-Final Rejection mailed 10/23/2025, Applicant argues that the previously cited references, Cass and Lu, do not teach the newly amended limitation of claim 1, where a lack of signal is generated when no analytes are bound to the detection element (Remarks, pages 10-11). Applicant states that their invention eliminates the need for analyte labeling and reduces false positives, which does not occur in Cass, as the reference teaches that a fluorophore is pre-attached to an analyte. Applicant states that the combination of Cass in view of Lu presented in the Non-Final Rejection would not result in a modified system described by Cass, but would simply use the system of Lu. This combination allegedly would change the principle of operation of the cited art, as the combination would require a substantial redesign and would materially affect the tMB system of Lu (Remarks, pages 11-12). There is also allegedly no reasonable expectation of success in using the tMB of Lu within the nanopore platform of Cass, the ordinary artisan would not be motivated to combine the teachings of Cass and Lu as stated by the Examiner, and the combination allegedly relies on impermissible hindsight (Remarks, page 13).
Regarding Applicant’s newly amended limitation to claim 1 and its relationship to the teachings of Cass in view of Lu, this limitation was actually addressed in the Non-Final Rejection in para. 37. Specifically, the rejection stated, “Finally, the ordinary artisan would be motivated to include the fluorophore/quencher on the molecular beacon aptamer and not on the target (as described by Cass alone) so that in the absence of the target, there would not be any fluorescence, and so that the ordinary artisan would not need to worry about adding a fluorophore to a target that may or may not be present in a sample – simplifying the method protocol once the required components and reagents are present. In the embodiment of Cass on pages 2-3 of the reference, the analyte is not stated to be labeled (contrast the method on pages 2-3 with that of page 4, which does describe the use of a labeled analyte). In the examples of Cass, several unlabeled analytes are used. Page 11, para. 6 states that human serum may contain targets with no indication of a label on said targets, and page 13 notes that unlabeled targets such as acetylcholinesterase and thrombin proteins were used. Additionally, compare the methods of claims 1 and 11 of Cass, where claim 1 is a method where the analyte need not be labeled and claim 11 describes labeling of the analyte. In Lu, the miRNA is the analyte, and this analyte is not labeled – see the Abstract, Scheme 1, and Figure 1. Therefore, both Cass and Lu are considered to teach the use of label-free analytes, providing the ordinary artisan with a reasonable expectation of success that the analyte could be unlabeled while the aptamer is labeled and the method would overall still function as intended.” Thus, Cass does teach unlabeled analytes, and as Lu already teaches the use of a fluorophore/quencher on their molecular beacon, the ordinary artisan would be capable of utilizing an unlabeled analyte with said molecular beacon in Cass in view of Lu. This combination also provides a motivation and a reasonable expectation of success, and addresses the newly added claim limitation directly. In conjunction with Cass teaching the use of simultaneous fluorescence and nanopore detection as discussed in para. 34 of the Non-Final Rejection, this is argued by the Examiner to read on the amendment to claim 1, particularly as Applicant does not point out alleged deficiencies in this aspect of the combination of Cass in view of Lu (see also the 35 USC 112(b) Rejections section below regarding this newly amended limitation).
As to Applicant’s argument that the proposed modification of Cass in view of Lu would result in the system taught by Lu and not a modified system of Cass, the Examiner argues that while the structures of Lu are being used in the overall method of Cass, Cass is still acting as the principle reference in terms of overall methodology. In fact, claim 1 of Cass describes a system where each element would function the same as the elements of the tMB shown in Scheme 1 of Lu – where the stem-forming oligonucleotide is single-stranded, and thus acts as the carrier, the molecular beacon contains a single-stranded region and a complementary portion to the stem-forming oligonucleotide, thus acting as the aptamer, and these structures form a complex when in the presence of an analyte, the miRNA. Cass then teaches in claim 4 that this complex may be detected via nanopore translocation. In the obviousness rejection, a particular embodiment of Cass also involving fluorescence detection was used to address optical detection, which was then used in combining fluorescence and nanopore detection with the structure of Cass in view of Lu. In attempting to limit the combination of references to either the system of Lu or a modified system of Cass, Applicant approaches piecemeal analysis of the references. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As to arguments that Cass in view of Lu would change the principle of operation of Lu, the principle operation of Lu is to detect a particular miRNA utilizing the tMB, and this would still be done in the method of Cass in view of Lu. Applicant argues that the molecular beacon cannot act as analogous to the aptamer taught in Cass, but the molecular beacon and aptamer have the same general function (being specific for a target and binding to a secondary carrier; see Cass Abstract). Applicant argues that utilizing the molecular beacon and stem-forming oligonucleotide of Lu in the method of Cass would require “substantial redesign of the recognition mechanism and probe architecture, including adaption to potentially much larger and structurally more complex binding regions,” (Remarks, page 12, para. 3). It is interpreted here that Applicant is referring to actually designing a molecular beacon and stem-forming oligonucleotide to have the same properties as the aptamers/carriers described by Cass (such as those properties described on pages 9-10 of the reference). As the molecular beacon and stem-forming oligonucleotide already form a stable complex structure with a target that can be optically detected (and Lu notes that tMBs have excellent selectivity, similar to an aptamer, see page 2438, column 1, para. 1), the only changes that may be required of the design of the tMB would be those that allow it to be detected during nanopore translocation, such as changes in molecular weight and charge (see Cass page 10, para. 4). Thus, it is possible that the combination of Cass in view of Lu would require redesign of the specific molecular beacon and stem-forming oligonucleotide of Lu. However, Lu already teaches that the structure of the tMB need not be rigidly fixed in order to be a functional detection mechanism – see Figures 1-3 and 5 for example, which show tMBs with slight differences in design from one another.
MPEP 2143.01 V states, “‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed. Cir. 2006). Thus, though slightly altering the design of the tMB to ensure successful use in the method of Cass in view of Lu may make said design process more complex, this alone does not obviate the obviousness rationale used to combine these references, particularly in view of the advantages gained by combining the references (e.g. early disease diagnosis, more accurate detection of a target due to use of two types of detection, etc.).
Regarding Applicant’s arguments regarding a lack of motivation to combine the references and that the Examiner has used impermissible hindsight, MPEP 2145 X (A) states, “Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). "A factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning…Rigid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007).” In the Non-Final Rejection, teachings from the cited references are used exclusively, with no reference to Applicant’s disclosure. In para. 36, which describes the initial combination of Cass in view of Lu, a motivation was provided (“Lu also provides motivation for the ordinary artisan by teaching the broad uses for molecular beacons, as well as diagnostic implications for their use. These would additionally motivate the ordinary artisan to detect miR-21 in the serum samples taught by Cass in order to provide early detection of cardio-cerebrovascular disease in patients. By providing early detection and potential diagnosis, medical interventions could be made earlier, improving patient outcomes.”) as well as a reasonable expectation of success (“As Cass already teaches that these structures comprise nucleotide sequences, this would simply amount to designing said sequences so that they appropriately hybridize to one another, that the molecular beacon aptamer is complementary to the target in its loop section, and that the molecular beacon aptamer contains a fluorophore and quencher at each end. Both Cass and Lu teach well-known fluorophores (Cass page 15, para. 3 and Lu Abstract), and Lu also teaches the well-known Black Hole Quencher (Abstract). Lu provides a reasonable expectation of success in creating these structures, as this reference shows that they can be both created and successfully used… As Lu already teaches that the molecular beacon and stem-forming oligonucleotide can be designed to detect this particular microRNA, there would be a reasonable expectation of success.”).
Applicant states that “Lu’s tMB assay is disclosed under controlled optical assay conditions…and provides no teaching that the same triplex mechanism would remain robust across clinical samples while also operating under voltage-driven nanopore translocation conditions,” (Remarks, page 13, para. 1). MPEP 2143.02 I states, “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019),” and MPEP 2143.02 II states, “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).” Furthermore, MPEP 2145 X (A) notes that express motivation found within the reference is not required for a determination of obviousness, and MPEP 2141.03 I states, “‘A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.’ KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). ‘[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.’ Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account ‘the inferences and creative steps that a person of ordinary skill in the art would employ.’ Id. at 418, 82 USPQ2d at 1396.” Taken together, while Lu may require particular assay conditions, this is true of many types of assays, and Lu explicitly notes that tMBs can be used with nanopores, stating that this use greatly expanded the application field of tMBs (page 2439, column 1, para. 1). In Cass, similar structures to those found in the tMBs (e.g. nucleic acids, fluorophores) are used successfully, and the reference teaches that nanopores have been used throughout the prior art to detect nucleic acids (e.g. page 1, para. 2), providing evidence that these structures may go through the nanopores successfully without being fundamentally altered. Cass also only notes particular assay conditions in terms of buffers or incubation when binding targets to probes (page 11, paras. 5-6), and it does not appear that specific conditions are required for nanopore translocation, other than those settings required to produce the ionic current (see Cass working examples). Thus, the Examiner argues that the ordinary artisan would be capable of utilizing the teachings of Cass and Lu together, along with ordinary creativity and knowledge available to one of ordinary skill in the art, to utilize assay conditions similar to those required for tMB/miR-21 hybridization conditions with a nanopore, even though the references individually do not teach this combination.
Applicant has also provided substantive arguments against the combination of Cass, in view of Lu, and further in view of Meller used in the rejection of claim 16. Specifically, Applicant states that the method of Meller and the claimed invention are different, particularly as Meller requires the use of labels and the claimed invention allegedly does not, and so utilizing Meller would render the reference inoperable for its intended purpose (Remarks, page 15).
Applicant’s arguments here conflate the addition of the guidance of Meller to the obviousness rejection with the use of the specific molecular beacon/nanopore sequencing methods of Meller. In para. 48 of the Non-Final Rejection, it states, “Meller teaches that measurements of fluorescence and current can be made for multiple samples (the examples in paras. 241-244 provide evidence of this, as they use two samples), and teaches comparison of simultaneous emission/current peaks with total emission/current measurements. Meller also teaches that these methods can be used to distinguish particular nucleotides from one another, and teaches that the methods of their invention can be used to detect mutations and single nucleotide polymorphisms (para. 96). Taken together, these would motivate the ordinary artisan to compare control and target samples to detect changes in nucleotide sequences, which could indicate a mutation in the target sequence… Meller teaches classifying sequences based on the resulting peak measurements (see para. 245 and Figures 5c), and so the ordinary artisan would be able to determine mutations in a target sequence regardless of the direction of difference present between control and target measurements.” Thus, the analysis methods of Meller are used with Cass in view of Lu to arrive at the claimed invention. Cass in view of Lu would produce similar simultaneous emission/current measurements to those shown in Figures 3-5 of Meller, and so the ordinary artisan would be capable of analyzing the results of Cass in view of Lu in the same manner as presented in Meller utilizing ordinary skill and creativity in the art. The specific molecular beacon methods described by Meller are not actually being implemented in Cass, in view of Lu, and further in view of Meller, and so no principle of operation of Meller is being altered.
Thus, Applicant’s arguments are overall not considered persuasive. The 35 USC 103 Rejections presented in the Non-Final Rejection have been maintained and are reiterated below.
Priority
The disclosure of the prior-filed application, Application No. GB 1902630.1, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, this application fails to provide support for instant claims 11-14 and 16, as this application makes no mention of the analyte being miRNA (instant claims 11-12), cancer being detected (instant claims 13-14), or the comparative methods described by instant claim 16. Subsequently, these claims will be given the priority date of the effective filing date of the PCT application, 2/27/2020.
Claim Rejections - 35 USC § 112(b)
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 1-16 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 is rejected due to the newly amended final wherein clause. Specifically, this clause states that in the absence of analyte binding “of the one or more analytes” to the “the at least one detection element,” no simultaneous current/emission signal is detected. This specific language encompasses the use of (or rather, lack of binding of) all of the analytes and all of the detection elements of the claim. However, earlier in the method, the creation of at least one complex containing the carrier/detection element/analyte and the generation of current and emission signals are required. Therefore, it is unclear how there would be a scenario in which no simultaneous signal from any of the totality of analytes would be generated, as at least one simultaneous signal is required by the method.
Claims 2-16 are rejected due to their dependence on rejected 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 1-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Cass et al. (WO 2018/189530 A1; cited in Applicant’s IDS) in view of Lu et al. (ACS Sensors, 2018).
Cass teaches methods of detecting one or more analytes using a carrier nucleic acid that contains at least one single-stranded region and an aptamer specific for the analyte that comprises a single-stranded portion complementary to the single-stranded region of the carrier nucleic acid. The carrier and aptamer are then contacted with the analyte in the sample, forming a complex. The complex is then detected (pages 2-3, joining text). The aptamer here thus is analogous to the detection element in the present invention (instant claim 4). The complex may be detected by voltage-driven translocation through a nanopore, where a change in nanopore conductance versus a control over time indicates the presence and location of the analyte in the complex (page 3, paras. 5-6). Several figures also show measurements of current over time (e.g. Figures 3B, 4D, 8A-8C, 9B, and 10A-10B).
Multiple aptamers can be present that are complementary to different single-stranded regions on the carrier nucleic acid, with no limit to how many can be provided (page 3, para. 1; instant claim 3).
The nanopore provided can be at the tip of a nanopipette (page 4, para. 1; instant claim 5). Cass shows that quartz nanopipettes may specifically be used (page 7, Figures 14 and 15 captions; instant claim 6).
Cass also teaches the use of lambda DNA for the carrier element (page 5, Figures 2 and 4 captions; instant claim 7).
The analyte of interest can be detected in serum (page 1, para. 1 and page 5, para. 1; instant claim 15).
Cass also teaches that detection can additionally be achieved by fluorescence detection (page 4, para. 2). This fluorescence detection was used in conjunction with nanopore detection in the embodiment shown in Figure 9 and explained on page 15, paras. 2-4. In particular, Cass shows both optical and electrical signals plotted simultaneously, and notes that “synchronized detection [was] visible on several occasions,” and “This work demonstrates that simultaneous electrical and optical detection is possible,” (page 15, para. 4). In the embodiment of their invention that uses this detection however, the target molecule has a fluorophore, and not the aptamer (page 15, para. 3). Thus, Cass does not teach that the aptamer may have a fluorophore and quencher.
Lu teaches the use of a triplex molecular beacon that is used to detect miR-21 (Abstract). Scheme 1 shows the basics of this structure and how it acts in the presence of a target (the structure is described in the joining para. of pages 2439-2440). The molecular beacon contains a fluorophore and quencher at either end, and contains a loop portion that is complementary to the target miRNA. The stem portion is complementary to a labelled stem-forming oligonucleotide. When the molecular beacon and oligonucleotide are bound, the fluorophore is quenched (see also Figure 1A). Upon target binding, the fluorophore present on the molecular beacon can be detected (Figure 1A). Lu also teaches that triplex molecular beacons can be used in nanopore sensing to detect specific macromolecules (page 2439, column 1, para. 1). This reference teaches that miR-21 in particular is a well-known biomarker for cardio-cerebrovascular disease (Abstract), and also notes the important and wide-ranging uses for molecular beacons (page 2438, column 1, para 1). Overall, Lu concludes that the triplex molecular beacon can be very useful in the early diagnosis of disease and can be used as a universal strategy for detecting miRNAs (page 2444, column 2, para. 1).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Lu in the method of Cass to arrive at the method of claims 1-2 and 10-12. Specifically, the ordinary artisan would be able to use the molecular beacon and stem-forming oligonucleotide structures of Lu as the aptamer and carrier molecules, respectively, in the method of Cass. As Cass already teaches that these structures comprise nucleotide sequences, this would simply amount to designing said sequences so that they appropriately hybridize to one another, that the molecular beacon aptamer is complementary to the target in its loop section, and that the molecular beacon aptamer contains a fluorophore and quencher at each end. Both Cass and Lu teach well-known fluorophores (Cass page 15, para. 3 and Lu Abstract), and Lu also teaches the well-known Black Hole Quencher (Abstract). Lu provides a reasonable expectation of success in creating these structures, as this reference shows that they can be both created and successfully used. Lu also provides motivation for the ordinary artisan by teaching the broad uses for molecular beacons, as well as diagnostic implications for their use. These would additionally motivate the ordinary artisan to detect miR-21 in the serum samples taught by Cass in order to provide early detection of cardio-cerebrovascular disease in patients. By providing early detection and potential diagnosis, medical interventions could be made earlier, improving patient outcomes. As Lu already teaches that the molecular beacon and stem-forming oligonucleotide can be designed to detect this particular microRNA, there would be a reasonable expectation of success.
Finally, the ordinary artisan would be motivated to include the fluorophore/quencher on the molecular beacon aptamer and not on the target (as described by Cass alone) so that in the absence of the target, there would not be any fluorescence, and so that the ordinary artisan would not need to worry about adding a fluorophore to a target that may or may not be present in a sample – simplifying the method protocol once the required components and reagents are present. In the embodiment of Cass on pages 2-3 of the reference, the analyte is not stated to be labeled (contrast the method on pages 2-3 with that of page 4, which does describe the use of a labeled analyte). In the examples of Cass, several unlabeled analytes are used. Page 11, para. 6 states that human serum may contain targets with no indication of a label on said targets, and page 13 notes that unlabeled targets such as acetylcholinesterase and thrombin proteins were used. Additionally, compare the methods of claims 1 and 11 of Cass, where claim 1 is a method where the analyte need not be labeled and claim 11 describes labeling of the analyte. In Lu, the miRNA is the analyte, and this analyte is not labeled – see the Abstract, Scheme 1, and Figure 1. Therefore, both Cass and Lu are considered to teach the use of label-free analytes, providing the ordinary artisan with a reasonable expectation of success that the analyte could be unlabeled while the aptamer is labeled and the method would overall still function as intended.
Thus, claims 1-7, 10-12, and 15 are prima facie obvious over Cass in view of Lu.
Regarding claims 8-9, Cass teaches that multiple aptamers can be provided that are specific for different analytes, and that each aptamer can be specific to a different single-stranded region on the same carrier nucleic acid (page 3, para. 1). Cass also teaches the fluorophore Atto 488 (page 15, para. 3). As noted above, Lu teaches the fluorophore FAM (Abstract). It would be prima facie obvious to the ordinary artisan to use different fluorophores for different aptamer structures specific to different analytes and carrier nucleic acids, as this would allow for the detection of specific targets, rather than just the presence of any target. If one analyte is present and another is absent, it may indicate a different clinical meaning than if both analytes are present or absent. It is noted that instant claim 8 requires a minimum of two fluorophores, corresponding to the at least two single-stranded regions described in i) of the claim. As Cass and Lu teach two fluorophores (FAM and Atto 488), the use of these two fluorophores in the manner described above meet the limitations of this claim.
Thus, claims 8-9 are prima facie obvious over Cass in view of Lu.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Cass et al. (WO 2018/189530 A1; cited in Applicant’s IDS), in view of Lu et al. (ACS Sensors, 2018), as evidenced by Pfeffer et al. (Drug Development Research, 2015).
Cass in view of Lu teaches the methods of claims 1-12 and 15, as described above. This method involves the detection of miR-21.
Pfeffer teaches that this miRNA can be a biomarker for various different cancers (Abstract). These include lung, ovarian, and prostate cancers (page 271, column 1, paras. 1-2), thereby meeting the limitations of instant clams 13-14.
Thus, claims 13-14 are prima facie obvious over Cass, in view of Lu, as evidenced by Pfeffer.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Cass et al. (WO 2018/189530 A1; cited in Applicant’s IDS) in view of Lu et al. (ACS Sensors, 2018), and further in view of Meller et al. (US 2013/0203610 A1).
Cass in view of Lu teaches the methods of claims 1-12 and 15, as described above. Regarding claim 16, Cass teaches a method where comparing the change in nanopore conductance of a target versus a control indicates the presence of an analyte. Specifically, the location of the change in conductance can indicate the position of the aptamer (page 3, para. 6). However, Cass does not teach these control compared conductance measurements in conjunction with fluorescence measurements, or any calculations similar to those described in instant claim 16.
Meller teaches use of molecular beacons and nanopore sequencing (Abstract). Particularly, Meller provides methods detailing simultaneous fluorescence emission and nanopore current measurements (Figures 3-5 and paras. 241-245). Using different combinations of two fluorophores on one or two molecular beacons, particular nucleotides could be examined, and these were viewed in light of nanopore current results. Fluorescent peaks were found to correspond with electrical peaks, and these were tallied in light of all detected signals to create ratio measurements (paras. 243-244 and Figures 4-5).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Meller in the method of Cass in view of Lu to arrive at the method of claim 16. Specifically, Cass in view of Lu already teaches simultaneous measurements of fluorescence emissions and current responses, as described above in the rejection of claim 1. Cass then goes on to teach that it is possible to measure control and target analytes with their methods, which would render it obvious to the ordinary artisan that this could also be done with the simultaneous fluorescence and current measurements. Meller teaches that measurements of fluorescence and current can be made for multiple samples (the examples in paras. 241-244 provide evidence of this, as they use two samples), and teaches comparison of simultaneous emission/current peaks with total emission/current measurements. Meller also teaches that these methods can be used to distinguish particular nucleotides from one another, and teaches that the methods of their invention can be used to detect mutations and single nucleotide polymorphisms (para. 96). Taken together, these would motivate the ordinary artisan to compare control and target samples to detect changes in nucleotide sequences, which could indicate a mutation in the target sequence. As to whether the ratio as taught by Meller would be a higher or lower value for the target sequence relative to the control, this would depend on the particular mutation that occurred and the resulting sequence. Meller teaches classifying sequences based on the resulting peak measurements (see para. 245 and Figures 5c), and so the ordinary artisan would be able to determine mutations in a target sequence regardless of the direction of difference present between control and target measurements.
Thus, claim 16 is prima facie obvious over Cass, in view of Lu, and in view of Meller.
Conclusion
No claims are currently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681