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, drawn to a method of quantifying a target nucleic acid analyte by performing amplification (claims 1-25) in the reply filed on 06/07/2024 was acknowledged in the office action mailed 02/25/2025.
Applicant Response
Applicant's response, filed 07/29/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 3, 8-9, 11, 23 and 26-44 are cancelled.
Claim 45 is newly added.
Claims 1-2, 4-7, 10, 12-22, 24-25, and 45 are pending and under examination herein.
Claims 1-2, 4-7, 10, 12-22, 24-25, and 45 are rejected.
Priority
The instant application is the National Stage entry of PCT/US2019/041260 , International Filing Date: 07/10/2019, which claims priority from Provisional Application 62/764946 , filed 08/17/2018 and Provisional Application 62/696147 , filed 07/10/2018. As such, the effective filing date assigned to each of claims 1-2, 4-7, 10, 12-22, 24-25, and 45 is 07/10/2018.
Drawings
The drawings were accepted by the examiner in the office action mailed 10/22/22025.
Claim Rejections - 35 USC § 101
The rejection of claims 8-9 and 11 under 35 U.S.C. 101 is withdrawn in view of cancelation of the claim in the claim amendments filed 07/29/2026.
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4-7, 10, 12-22, 24-25 and 45 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. Newly recited portions are necessitated by claim amendments.
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea and a law of nature or natural phenomenon:
Claim 1recites performing a baseline adjustment on the fluorescent measurements to remove a component of each fluorescent measurement resulting from baseline drifting that has an adverse impact on target nucleic acid quantification accuracy, wherein performing the baseline adjustment comprises: (c1) determining a slope of the baseline segment between the starting cycle and the baseline end-cycle; (c2) for each of a plurality of cycles or times at which a fluorescence measurement was obtained after the baseline end-cycle, adjusting the fluorescence measurement by subtracting a fixed adjustment value dependent on the slope of the baseline segment and the baseline end- cycle, wherein the fixed adjustment value is the product of multiplying the slope of the baseline segment by the reaction cycle number of the baseline end-cycle; (d) leveling the fluorescence measurements from step (c2) so that no fluorescence measurement has a value less than zero; and (e) performing crosstalk correction on the fluorescence measurements from step (d) of each channel based on the fluorescence measurements of at least one other channel; and (f) determining a cycle threshold (Ct) value from values comprising at least a portion of the adjusted fluorescence measurements from step (e), or determining that the target nucleic acid analyte is absent or not present in an amount above a limit of detection, thereby quantifying the target nucleic acid analyte.
Claim 2 recites wherein the fixed adjustment value is less than the product of multiplying the slope of the baseline segment by reaction cycle numbers greater than the cycle number of the baseline end-cycle.
Claim 4 recites further comprising, after step (b) and before step (c), the step of smoothing at least a portion of the fluorescence measurements.
Claim 5 recites wherein smoothing comprises applying a moving average to the portion of the fluorescence measurements.
Claim 6 recites wherein applying the moving average comprises averaging across M cycles, wherein M is 3, 4, 5, 6, 7, 8, 9, 10, or 11.
Claim 7 recites wherein smoothing at least a portion of the fluorescence measurements comprises either polynomial curve fitting or spline smoothing.
Claim 10 recites wherein crosstalk correction comprises subtracting an estimate of bleed-through signal from a second fluorophore of a second detection probe from a fluorescence signal measured for the first fluorophore, wherein the second detection probe comprises the second fluorophore, wherein the second fluorophore and the first fluorophore have overlapping emission spectra, and wherein the estimate of bleed-through signal is dependent on contemporaneous fluorescence measurements from the second fluorophore and a predetermined ratio of observed fluorescence from the second fluorophore to expected bleed-through signal from the second fluorophore in the fluorescence measurements of the first fluorophore.
Claim 12 recites further comprising a conversion region exclusion step, wherein a user-defined number of cycles following initiation of the cycled amplification reaction are eliminated, thereby identifying the starting cycle of the baseline segment as the next remaining cycle number.
Claim 13 recites further comprising a baseline end-cycle identification step that comprises calculating slopes between fluorescence measurements for adjacent pairs of cycles in the cycled amplification reaction, and determining when a predetermined slope is reached, thereby identifying the baseline end-cycle.
Claim 14 recites further comprising a baseline end-cycle identification step that comprises calculating slopes between fluorescence measurements at adjacent pairs of cycles in the cycled amplification reaction, and determining when a predetermined percentage increase is reached, thereby identifying the baseline end-cycle.
Claim 17 recites wherein step (e) comprises: (i) subtracting a minimum value of the adjusted fluorescence measurements of step (d) from the maximum value of the adjusted fluorescence measurements of step (d), thereby providing a fluorescence range value; and (ii) determining that the target nucleic acid analyte is not present in an amount equal to or greater than a predetermined limit of detection if the fluorescence range value is less than or equal to a predetermined threshold.
Claim 18 recites wherein at least one adjusted fluorescence measurement after the baseline end-cycle is greater than or equal to a predetermined threshold, and wherein the Ct value is determined in step (d) as the earliest cycle number at which the adjusted fluorescence measurement is greater than or equal to the predetermined threshold.
Claim 19 recites wherein at least one adjusted fluorescence measurement from step (d) is greater than or equal to a predetermined threshold, and wherein the Ct value is determined from values comprising: (i) the cycle in which the earliest adjusted fluorescence measurement greater than or equal to the predetermined threshold occurred; (ii) the earliest adjusted fluorescence measurement greater than or equal to the predetermined threshold; or (iii) a value of an adjusted fluorescence measurement from a cycle preceding the cycle in which the earliest adjusted fluorescence measurement greater than or equal to the predetermined threshold occurred.
Claim 20 recites wherein the Ct value is estimated from an interpolation of fluorescence values between adjusted fluorescence measurements from the cycle in which the earliest adjusted fluorescence measurement greater than or equal to the predetermined threshold occurred and the preceding cycle.
Claim 21 recites wherein the interpolation is a linear interpolation.
Claim 22 wherein the CT value is a fractional cycle value corresponding to the predetermined threshold in the interpolation.
Claim 45 recites wherein performing the baseline adjustment further comprises:(c3) for each of a plurality of cycles or times at which a fluorescence measurement was obtained for the baseline segment, adjusting the fluorescence measurement by subtracting a variable adjustment value dependent on the slope of the baseline segment and the cycle or time at which the measurement was obtained.
These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, obtaining fluorescence measurements during a plurality of cycles of the cycled amplification reactions, performing a baseline adjustment, determining a slope of the baseline segment, adjusting the fluorescence measurements for the cycles, determining a Ct values of each channel, or determining whether the target nucleic acid analyte is absent or present, smoothing or leveling the measurements, leveling the measurements, performing crosstalk correction, a conversion region exclusion step to identify the starting cycle of the baseline segment as the next remaining cycle number, and the baseline end-cycle identification steps can be practically performing the human mind as claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Furthermore, the steps as claimed for determining a slope of the baseline segment, adjusting the fluorescence measurements for the cycles, determining a Ct values for each channel, smoothing or leveling the measurements, and performing crosstalk correction equate to organizing information and manipulating information through mathematical correlations and reciting a mathematical equation, similar to the concepts of taking existing information, manipulating the data using mathematical functions, and organizing this information into a new form in Digitech Image Techs., LLC v. Electronics for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014). Therefore, these limitations fall under the “Mathematical Concepts” grouping of abstract ideas. Claims 2, 5-7 and 17-22 further qualify the recited judicial exceptions. As such, claims 1-2, 4-7, 10, 12-22, 24-25, and 45 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions are not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception to affect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract ideas in a generic computing environment and merely indicating a field of use or technological environment in which to apply a judicial exception. Specifically, the claims recite the following additional elements:
Claim 1 recites wherein the method is performed using a nucleic acid analyzer that includes a thermocycler configured to regulate the temperature of two or more samples, at least one fluorometer comprising two or more channels, wherein each channel is configured to measure fluorescence from an associated one of the two or more samples, and a processor and a memory operably linked to the fluorometer and the thermocycler and storing instructions to be executed by the processor to perform steps of the method, (a) performing, with the thermocycler in communication with the processor, a cycled amplification reaction on the sample in the presence of a first detection probe labeled with a first fluorophore, wherein the first fluorophore exhibits target nucleic acid analyte-dependent fluorescence; (b) obtaining, with the at least one fluorometer in communication with the processor, fluorescence measurements during a plurality of cycles of the cycled amplification reaction, and storing the fluorescence measurements in the memory, wherein a plurality of the obtained fluorescence measurements constitute a baseline segment that begins at a starting cycle, and terminates at a baseline end-cycle that precedes detectable amplification of the target nucleic acid analyte .
Claim 15 recites wherein the first detection probe further comprises a quencher moiety in energy transfer relationship with the first fluorophore.
Claim 16 recites wherein the first detection probe further comprises a quencher or a FRET acceptor, and either: (i) comprises a self-complementary region and undergoes a conformational change upon hybridization to the target nucleic acid analyte that reduces quenching of or FRET transfer from the first fluorophore; or (ii) undergoes exonucleolysis following hybridization to the target nucleic acid analyte that releases the first fluorophore from the first detection probe, thereby resulting in increased fluorescence; or (iii) undergoes cleavage following hybridization to a fragment of a primary probe that was cleaved following hybridization to the target nucleic acid analyte, and cleavage of the first detection probe releases the first fluorophore, thereby resulting in increased fluorescence.
Claim 24 recites wherein the at least one fluorometer is configured to detect fluorescence in a plurality of channels.
Claim 25 recites wherein the cycled amplification reaction is a polymerase chain reaction.
These claims recite limitations for gathering data. The amplification reaction steps and obtaining fluorescence measurements steps are performed to gather data to perform the mental steps and mathematical processes, and the system components of the fluorometer and a thermocycler apparatus are equipment to collect data to perform the mental steps and mathematical processes, and there is no indication that these steps are impacted by the recited the judicial exception, and therefore the recited judicial exception is not integrated into these additional elements. These limitations equate to mere data gathering, which the courts have found to be insignificant extra-solution activity (see MPEP 2106.05(g)).
Furthermore, the claims also recites using a generic computing systems and computer program products to carry out instructions to implement an abstract idea on a computer. The use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, there is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself. As such, claims 1-2, 4-7, 10, 12-22, 24-25, and 45 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). Further analyzing the additional elements under step 2B, the additional elements as described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims under the 2B analysis, the limitations of performing a cycled amplification reaction on nucleic acid samples is well-understood, routine, conventional activity (see Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014). Furthermore, the prior art to Lo et al. (Clinical Applications of PCR 2006, Vol 16, Springer Science and Business Media; previously cited) discloses performing PCR with fluorescent primers, including using traditional hybridization probe design with an acceptor and donor fluorophore, using systems that can automate PCR with optical thermocyclers that regulate temperature and fluorometers that detect fluorescent probes is well-known in the art (Chapter 1, sections 10, 11.3, 11.5 -11.6; chapter 2, section 1-3; chap 3, section 3.5, fig 5). The instant specification also discloses such nucleic acid analyzers are commercially available (para 00176).
Furthermore, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, the additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception, and the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-2, 4-7, 10, 12-22, 24-25, and 45 are not patent eligible.
Response to applicant’s arguments
Applicant asserts the claims recite a practical application of the judicial exceptions by improving the functioning of the nucleic acid analyzer further asserts the claimed method improves the functioning of a nucleic acid analyzer by improving accuracy by quantifying and removing the fluorescent measurements which many have an adverse impact on the correct calculation of the cycle threshold (Ct), similar to those in Ex Parte Desjardins (Applicant’s Arguments, p 9, para 1-p 12, para 4).
It is respectfully submitted that this is not persuasive. The claims are not analogous to Ex Parte Desjardins, as the instant claims do not provide an improvement in computer technology. The claims also do not appear to provide an improvement to nucleic acid analyzers, but rather, the improvement appear to be to and provided solely by the analysis steps themselves; the nucleic acid analyzer itself does not seem affected by the recited judicial exceptions. As discussed in MPEP 2106.05(a), the judicial exception alone cannot provide the improvement and the improvement cannot be to the judicial exception itself. Therefore, there is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself and the claims are directed to an abstract idea. Therefore, the rejections are maintained.
Claim Rejections - 35 USC § 103
The rejection of claims 8 and 11 under 35 U.S.C. 103 as being unpatentable over Li (US20130273547A1; 10/05/2023 IDS; previously cited) and further in view of Lo et al. (Clinical Applications of PCR 2006, Vol 16, Springer Science and Business Media; previously cited; hereafter referred to as Lo) and Buse et al. (US 2016/0032358; newly cited; hereafter referred to as Buse) as evidenced by Heinz et al. (US20120221252A1; newly cited; hereafter referred to as Heinz) are withdrawn in view of cancelation of the claims in the claim amendments filed 07/29/2026.
Claims 1, 4-7, 12-22 and 24-25 under 35 U.S.C. 103 as being unpatentable over Li (US20130273547A1; 10/05/2023 IDS; previously cited) and further in view of Lo et al. (Clinical Applications of PCR 2006, Vol 16, Springer Science and Business Media; previously cited; hereafter referred to as Lo) and Buse et al. (US 2016/0032358; newly cited; hereafter referred to as Buse) as evidenced by Heinz et al. (US20120221252A1; newly cited; hereafter referred to as Heinz) are withdrawn in view of the claim amendments filed 07/29/2026 as none of the cited art appear to disclose performing crosstalk correction on the florescence measurements from the leveled measurements after performing baseline adjustments based on the fluorescence measurements of at least one other channel, and using these further cross-corrected measurements to determine a cycle threshold.
Conclusion
No claims allowed.
Claims 1-2, 4-7, 10, 12-22, 24-25, and 45 appear to be free from prior art, as the closest prior art to Li (US20130273547A1; 10/05/2023 IDS; previously cited) does not appear to teach or suggest performing crosstalk correction on the fluorescence measurements. While Li discloses methods to correct for high-sloped baseline observed in real-time PCR curves and provides a way of verifying amplification efficiency using a statistical approach, Li does not appear to disclose performing crosstalk correction on the florescence measurements from leveled measurements after performing baseline adjustments based on the fluorescence measurements of at least one other channel, and using these further cross-corrected measurements to determine a cycle threshold (abstract).
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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIDHI DHARITHREESAN whose telephone number is (571)272-5486. The examiner can normally be reached Monday - Friday 9:00 - 5:00.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/ Supervisory Patent Examiner, Art Unit 1687
