DETAILED ACTION
The present Office Action is responsive to the Amendment received on November 25, 2025.
Preliminary Remark
Claims 1-12, 14, 17, 18, 20, 22-24, 30, 31, 34, 35, 41, 43, 45, and 47-85 are canceled.
Claim Rejections - 35 USC § 112
The rejection of claims 13, 15, 16, 19, 21, and 27 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on July 25, 2025 is withdrawn in view of the Amendment received on November 25, 2025.
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.
The rejection of claims 13, 15, 16, 19, 21, 25-29, 32, 33, 36-40, 42, 44, and 46 under 35 U.S.C. 102(a)(1) as being anticipated by Whitman et al. (WO 2019/144107 A1, published July 2019; IDS ref), made in the Office Action mailed on July 25, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on November 25, 2025 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
With regard to claim 13, Whitman et al. teach a method of distinguishing subsets of partitions in a multiplex digital assay comprising a plurality of different target nucleic acids and a plurality of different probes, each different probe being specific for a different target nucleic acid and having a unique predetermined Tm in the presence of its target nucleic acid, and wherein the plurality of different probes are labeled with the same reporter (“each different duplex nucleic acid having the same signal generating label”, section [0009]), comprising the steps of:
detecting signals from the reporters of the plurality of probes at three or more different predetermined temperatures (“measuring a first signal from a labeled duplex nucleic acid at a first temperature … measuring a second signal from the labeled duplex nucleic acid at a second temperature … the method further comprises the steps of measuring a third signal at a third temperature”, section [0009]);
calculating at least two relational values between signals measured at the three or more different predetermined temperatures (“normalizing the first and second signals relative to the third signal”, section [0009]; “target nucleic acid is determined to be present when the ratio between the first signal and the second signal exceeds a predetermined threshold”, section [0019]); and
plotting at last two relational values against each other to distinguish subsets of partitions containing different combinations of the plurality of different target nucleic acids (“[p]lotting the ratio of partitions intensities between the sets of images permits calculation of the corresponding number of positive and negative partitions”, section [0106]).
With regard to claim 15, each probe forms a duplex in the presence of its specific target nucleic acid and the reporter emits signal of different intensity in the duplex conformation than in a single-stranded conformation (“at least one cleavable probe is labeled with a first member of a reporter-quencher pair and the at least one cleavable probe adopts a first conformation when hybridized to its target nucleic acid”, see claim 23; “the target-specific probe generates a first signal when in a first, single-stranded conformation”, section [0018]).
With regard to claim 16, the partitions are subjected to an amplification reaction prior to detecting, wherein the plurality of different probes are hybridized to their specific target nucleic acid (“providing a reaction mixture comprising the sample, at least one labeled, cleavable target-specific probe capable of specifically hybridizing to the target nucleic acid sequence … providing conditions to cause the labeled cleavable target-specific probe to hybridize to the target nucleic acid”, section [0017]), cleaving the hybridized probe to form truncated probes (“cleaving the probe that is specifically hybridized to the target nucleic acid to form a truncated probe”, section [0017), hybridizing the truncated probes to the respective capture sequence (“providing conditions to cause the truncated probe to hybridize to a capture sequence”, section [0017]; and extending the hybridized truncated probes to form duplexes, having predetermined Tms unique to each different probe (“measuring a second signal at a temperature below the predetermined Tm”, section [0017]; also, “measuring a first signal at a temperature below the predetermined Tm and a second signal at a temperature above the predetermined Tm”, claim 12, step (e)).
With regard to claim 19, the at least two relational values are calculated from signals detected at successive predetermined temperatures (see claim 12, step (e) and (f)).
With regard to claim 21, there is a difference of at least five degree Celsius between each of the three or more different temperatures at which signals are detected (see Fig. 1, Tm1 at 65oC, Tm2 at 75oC and Tm3 at 85oC; see also Figure 4, in combination with “the method further comprises the steps of measuring a third signal at a third temperature”, section [0009]).
With regard to claim 25, the artisans specifically teach the above-discussed steps to quantify the concentration of different target nucleic acids in a digital PCR employing a plurality of partitions (“the polymerase chain reaction (PCR) is an example of a reaction that may be performed within a partition … partitions are useful in digital PCR (dPCR) … partitioning the sample such that individual nucleic acid molecules contained in the sample are localized in many separate regions”, section [0083]; “process used to determine the number of input target copies using DMA in dPCR partitions … FIG. 3 shows the same three targets A, B, and C described … in various combinations among 36 partitions … designed to have unique melt temperatures Tm1, Tm2, and Tm3, wherein Tm1<Tm2<Tm3”, section [0102]).
With regard to claims 26 and 28, at least two relational values are calculated using the ratio of signals of detected in the three or more different predetermined temperatures (see claim 86, steps (h), (i), and (j) wherein three different ratios are calculated).
With regard to claim 27, the first and second signals are normalized relative to the third signal by subtracting the third signal from the first and second signals” (section [0019]).
With regard to claim 29, there is at last three degrees of Celsius difference between each of the three or more different temperatures at which the signals are detected (see Figure 1 and 2D; see also section [0009]).
With regard to claims 32 and 33, the method does not include determining the Tms of the plurality of different probes from the detected signals (because the assay measures the signals at a specific predetermined temperature and not over a period of time; “DMA … does not require the calculation of a Tm to identify a target nucleic acid sequence”, section [0091]).
With regard to claim 36, the method discussed above is a multiplexed detection dPCR (because each partition contains multiple targets with multiple probes that are specific to said multiple targets) and employs PCR amplification, detection of the signals from the probes (discussed above) with unique Tms, calculating the relational values, and producing a plotting (see Figures 5-7) for the plurality of partitions.
With regard to claim 37 and 39, calculating the at least two relational values comprises calculating ratios of signals detected at the three or more different predetermined temperatures (see claim 86, steps (h), (i), and (j) wherein three different ratios are calculated).
With regard to claim 38, the first and second signals are normalized relative to the third signal by subtracting the third signal from the first and second signals” (section [0019]).
With regard to claim 40, the reporter labels are same among the probes (see above-discussion in claim 13).
With regard to claim 42, there is at last three degrees of Celsius difference between each of the three or more different temperatures at which the signals are detected (see Figure 1 and 2D; see also section [0009]).
With regard to claim 44, the method does not include determining the Tms of the plurality of different probes from the detected signals (because the assay measures the signals at a specific predetermined temperature and not over a period of time; “DMA … does not require the calculation of a Tm to identify a target nucleic acid sequence”, section [0091]).
With regard to claim 46, each different probe emits signal of different intensity in the duplex conformation than in a single stranded conformation (see, “at least one cleavable probe is labeled with a first member of a reporter-quencher pair and the at least one cleavable probe adopts a first conformation when hybridized to its target nucleic acid”, see claim 23; “the target-specific probe generates a first signal when in a first, single-stranded conformation”, section [0018]).
Therefore, the invention as claimed is anticipated by Whitman et al.
Response to Arguments:
Applicants traverse the rejection.
Applicants state that claim 1 differs from the teachings of Whitman by the feature of “plotting the relational values against each other to determine which of the plurality of different targets are present” and that “[t]his provides the advantage of better distinguishing temperature dependent signals from different target duplexes in a single volume when all target duplexes are labeled with the same reporter” as represented in Fig. 8A-8C (Response).
This argument is not found persuasive. Applicants’ attention is directed to Fig. 14 (reproduced below):
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As shown, contrary to Applicants’ assertion, Whitman does detect the signals from the reporters of the plurality of different probes at three or more different predetermined temperatures (as evidenced by the top right figure (B)), and calculates at least two relational values between signals measured at the three or more different predetermined temperatures and plotting the two relational values against each other to distinguish subsets of partitions containing different combinations of the plurality of different target nucleic acids (see the plots for Target A, Target B, and Target C).
As well:
“D: Ratio of fluorescence intensity per partition calculated for the first temperature internal (T2/T1) … F: Ratio of fluorescence intensity per partition calculated for the second temperature interval (T3/T2); G: Ratio of fluorescence intensity per partition calculated for the third temperature interval (T4/T3)” (section [0040])
As clearly demonstrated, Whitman does calculate and plot at least two relational values against each other to distinguish subsets of partitions containing different combinations of the plurality of different target nucleic acids.
Next, Applicants state that the third signal measured at a temperature at which all labeled duplex nucleic acids in the reaction mixture are denatured does not alter fundamentally two-point nature of Whitman’s melt determination because the third temperature is used only as a normalization reference and thereby does not create an additional analytical interval nor produce another independent relational metric, etc. and that equating this feature with claim 13(b) limitation is traversed (Response).
Applicants’ attention is directed to Fig 14 above, wherein datapoints from four different predetermined temperatures. As well, Whitman explicitly teaches that, “minimum of n+1 images for target elucidation where n=the number of different target-specific probes that emit fluorescence at the same wavelength” (section [0096]).
As discussed herein, Whitman does teach the measurement of fluorescence at a temperature below/above each of the unique melting temperature of target specific probes, as well as calculating and plotting the ratio values for determining which partitions contain which targets.
Therefore, Applicants’ arguments are not found persuasive and the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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The rejection of claims 13, 15, 16, 19, 21, 25-29, 32, 33, 36-40, 42, 44, and 46 on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 17/808,180 (reference application), made in the Office Action mailed on July 25, 2025 is maintained for the reasons of record.
As well, the rejection of claims 13, 15, 16, 19, 21, 25-29, 32, 33, 36-40, 42, 44, and 46 on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,390,902 (herein, “the ‘902 patent”), made in the Office Action mailed on July 25, 2025 is maintained for the reasons of record.
Applicants’ arguments are not deemed fully responsive because Applicants’ arguments are directly copied from the rejection over Whitman et al. (i.e., WO 2019/144107). These arguments do not apply to the instant rejection as the instant rejection is over the pending claims of the reference application (i.e., 17/808,180) and patented claims of the ‘902 patent.
However, as it pertains to Applicant’s statement that the step of “plotting” the relational values for identification of partitions containing the respective target nucleic acid, the Office holds that such is an obvious application over the claims of the reference application for example because the claims already explicitly contain the step of taking the ratio of the intensity values collected between T1, T2, and T3, and that the change in these ratio values indicate the presence of the respective target nucleic acids in the partitions (see claim 1, steps j) through l)). The plotting such results to identify the partitions would have been an obvious extension of the conclusion steps rendered by steps k) and l), yielding no more than a predictable outcome.
The Rejection:
Claims of the reference application also claims a method of detecting multiple target nucleic acids from a sample utilizing a cleavable (see claim 6), target-specific probe having a unique Tm that is distinguishable from other target-specific probe, employing at least three different temperatures (T1, T2, and T3) at which the fluorescence values are measured in each partition (see claim 1(a), (b), (c)), acquiring resulting detection signals from the probes at each T1, T2, and T3 (steps (e)-(g)), followed by the calculation of the ratios at teach of the temperatures (steps (h)-(j)).
Claims of the reference application also claims that each of the cleavable, target-specific probes comprise the same signal-generating label thereon.
While the claims of the reference application do not claim that the method is for “quantification” or for a digital PCR purpose, or the degree of differences between T1, T2, and T3, one of ordinary skill in the art would have had the requisite knowledge in the relevant art of molecular diagnostics to recognize that the claims of the reference application which partitions the sample into a plurality of partitions would have been useful in a digital PCR amplification which a well-known quantification method that also uses partitioning a sample into a plurality of partitions to generate a signal from a target therein. Because the Tms utilized in the method of the reference application is indicative of the presence or absence of the target (for each cleavable-target specific probe), the detection of the signals generated from each of the partitions would have indicated either the presence or absence of the respective targets, allowing for quantification to be made based on Poisson Distribution which is employed in dPCR.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 February 18, 2026
/YJK/