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 amendments and arguments filed 7/17/2025 are acknowledged and entered.
Status of Claims
Claims 1-9 and 11-20 are pending and examined on the merits.
Claim 10 is canceled.
Priority
The instant application claims the benefit of priority to U.S. Provisional Application No. 63/043,310 filed on 6/17/2020. Thus, the effective filing date of the claims are 6/17/2020.
Specification
The objection to the specification is withdrawn in view of Applicant’s amendments filed on 7/17/2025.
Claim Objections
The objections to claims 17 and 20 are withdrawn in view of Applicant's claim amendments filed on 7/17/2025.
Withdrawn Rejections
35 USC § 112(b)
The rejection of claims 1, 4-5, 11-12, and 18-19 under 35 U.S.C. 112(b) withdrawn in view of Applicant's claim amendments filed on 7/17/2025. Examiner notes that the amendments pertaining to claim 1 were also applied to independent claims 14 and 20.
Applicant's response filed 7/17/2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
Claim Rejections - 35 USC § 101
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 1-9 and 11-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. 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:
Claim 1: “optimizing, using a processor, the plurality of the first background signals from the plurality of the first optical signals for each of the plurality of the control samples, wherein the optimizing the plurality of the first background signals comprises subtracting a first predetermined intensity value of the plurality of the first background signals for the plurality of the control samples from the plurality of the second optical signals received for the target nucleic acid in the sample to obtain a first minimized mean baseline, wherein the first minimized mean baseline corresponds to the plurality of the second optical signals of a plurality of predetermined cycles from the second cycle number, whereinthe plurality of the second optical signals of the plurality of the predetermined cycles from the second cycle number corresponds to a second predetermined intensity value; subtracting, using the processor, the first minimized mean baseline from the plurality of the second optical signals”, provides mathematical calculations (subtracting background signals from optical signals to obtain a mean baseline) that are considered a mathematical concept, which is an abstract idea.
“validating, using the processor, each of the plurality of the subtracted second optical signals for the target nucleic acid in the sample against at least one of the plurality of the reference amplification curves”, provides an evaluation (validating signals against a reference) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“computing, using the processor, the quantity of the target nucleic acid in the sample from the validated plurality of the second optical signals obtained as the function of the second cycle number for the target nucleic acid in the sample, wherein computing the quantity of the target nucleic acid in the sample from the validated plurality of the second optical signals comprises performing an affine transformation to apply at least one of a linear transformation and a translation on the validated plurality of the second optical signals.”, provides a mathematical relationship (quantifying target nucleic acid in the sample as a function of cycle number) that is considered a mathematical concept, which is an abstract idea.
Claim 2: “plotting the plurality of the first optical signals detected as the function of the first cycle number for each of the plurality of the control samples to obtain a first amplification curve, wherein the first amplification curve represents a ratio of each of the plurality of the first optical signals to a passive reporter dye optical signal as the function of the first cycle number.”, provides mathematical relationships (plotting signals as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
Claim 3: “plotting the plurality of the second optical signals detected as the function of the second cycle number for the target nucleic acid in the sample to obtain a second amplification curve, wherein the second amplification curve represents a ratio of each of the plurality of the second optical signals to a passive reporter dye optical signal as the function of the second cycle number.”, provides mathematical relationships (plotting signals as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
Claim 4:
“projecting each of the plurality of the second optical signals on to the at least one of the plurality of the reference amplification curves, wherein the projecting each of the plurality of the second optical signals on to the at least one of the plurality of the reference amplification curves comprises determining whether each of the plurality of the second optical signals obtained as the function of the second cycle number for the target nucleic acid in the sample collapses on to the at least one of the plurality of the reference amplification curves;”, provides an evaluation (projecting signals on to a reference and determining concordance) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“determining a threshold value for the plurality of the second optical signals projected on to the at least one of the plurality of the reference amplification curves.”, provides an evaluation (determining a threshold) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 5: “plotting the plurality of the second optical signals projected on to the at least one of the plurality of the reference amplification curves to obtain a validated reference amplification curve.”, provides mathematical relationships (plotting signals as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
Claim 6: Dependent on claim 1 which recites one or more limitations that equate to an abstract idea.
Claim 7: “the linear transformation comprises scaling, and wherein the translation is selected from a group comprising a horizontal shift and a vertical scaling.”, provides mathematical relationships (scaling and translation of data) that are considered a mathematical concept, which is an abstract idea.
Claim 8: Dependent on claim 1 which recites one or more limitations that equate to an abstract idea.
Claim 9: Dependent on claim 1 which recites one or more limitations that equate to an abstract idea.
Claim 11: Dependent on claim 1 which recites one or more limitations that equate to an abstract idea.
Claim 12: Dependent on claim 1 which recites one or more limitations that equate to an abstract idea.
Claim 13: “normalizing the plurality of the first optical signals and the plurality of the second optical signals, wherein normalizing the plurality of the first and the second optical signals comprises determining a ratio of each of the plurality of the first and the second optical signals to a passive reporter dye optical signal.”, provides mathematical relationships (normalizing signal data by determine a ratio of signals) that are considered a mathematical concept, which is an abstract idea.
Claim 14: “optimizing, using the processor, the plurality of the background signals from the received plurality of first optical signals for each of the plurality of the control samples, wherein the optimizing the plurality of the background signals for the plurality of the control samples comprises subtracting a first predetermined intensity value of the plurality of the background signals for the plurality of the control samples from the plurality of the second optical signals received for the target nucleic acid in the sample to obtain a first minimized mean baseline, wherein the first minimized mean baseline corresponds to the plurality of the second optical signals of a plurality of predetermined cycles from the second cycle number, wherein the plurality of the second optical signals of the plurality of the predetermined cycles from the second cycle number corresponds to a second predetermined intensity value; subtracting, using the processor, the first minimized mean baseline from the plurality of the second optical signals;” provides mathematical calculations (subtracting background signals from optical signals to obtain a mean baseline) that are considered a mathematical concept, which is an abstract idea.
“optimizing, using a processor, the plurality of the first background signals from the plurality of the third optical signals for each of the plurality of the reference nucleic acids, wherein the optimizing the plurality of the first background signals comprises subtracting a second predetermined intensity value of the plurality of the first background signals for the plurality of the control samples from the plurality of the third optical signals received for the plurality of the reference nucleic acids to obtain a second minimized mean baseline, wherein the second minimized mean baseline corresponds to the plurality of the third optical signals of a plurality of predetermined cycles from the third cycle number, wherein the plurality of the third optical signals of the plurality of predetermined cycles from the third cycle number corresponds to a third predetermined intensity value; subtracting, using the processor, the second minimized mean baseline from the plurality of the third optical signals” provides mathematical calculations (subtracting background signals from optical signals to obtain a mean baseline) that are considered a mathematical concept, which is an abstract idea.
“generating, using the processor, a plurality of reference amplification curves from the subtracted plurality of the third optical signals” provides mathematical relationships (generating reference amplification curves involves plotting signals as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
“validating, using the processor, each of the plurality of the subtracted second optical signals detected for the target nucleic acid in the sample against the plurality of reference amplification curves, wherein validating each of the plurality of the subtracted second optical signals comprises” and “projecting each of the plurality of the second optical signals on to the plurality of the reference amplification curves; and determining a threshold for the plurality of the second optical signals projected onto at least one of the plurality of the reference amplification curves;” provides evaluations (validating signals against a reference, projecting signals onto a reference, and determining a threshold) that may be performed in the human mind and are therefore considered mental processes, which are abstract ideas.
“performing, using the processor, an affine transformation on the validated plurality of the second optical signals to determine the quantity of the target nucleic acid in the sample, wherein the affine transformation comprises at least one of a linear transformation and a translation.”, provides a mathematical relationship (transformation and translation of signal data to determine the quantity of nucleic acid in a sample) that is considered a mathematical concept, which is an abstract idea.
Claim 15: Dependent on claim 14 which recites one or more limitations that equate to an abstract idea.
Claim 16: Dependent on claim 14 which recites one or more limitations that equate to an abstract idea.
Claim 17: “projecting each of the plurality of the second optical signals on to the plurality of the reference amplification curves comprises determining whether each of the plurality of the second optical signal obtained as the function of the second cycle number for the target nucleic acid in the sample collapses on to at the least one of the plurality of the reference amplification curves.”, provides an evaluation (projecting signals on to a reference and determining concordance) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 18: Dependent on claim 14 which recites one or more limitations that equate to an abstract idea.
Claim 19: Dependent on claim 14 which recites one or more limitations that equate to an abstract idea.
Claim 20: “optimizing the plurality of the background signals from the detected plurality of the first optical signals for each of the plurality of the control samples, wherein the optimizing the plurality of the background signals for the plurality of the control samples comprises subtracting a first predetermined intensity value of the plurality of the background signals for the plurality of the control samples from each of the plurality of the second optical signals detected to obtain a first minimized mean baseline, wherein the first minimized mean baseline corresponds to the plurality of the second optical signals of a plurality of predetermined cycles from the second cycle number, wherein the plurality of the second optical signals of the plurality of predetermined cycles from the second cycle number correspond to a second predetermined intensity value; subtracting the first minimized mean baseline from the plurality of the second optical signals; optimizing the plurality of the first background signals from the plurality of the third optical signals for each of the plurality of the reference nucleic acids, wherein the optimizing the plurality of the first background signals comprises subtracting a second predetermined intensity value of the plurality of the first background signals for the plurality of the control samples from the plurality of the third optical signals received for the plurality of the reference nucleic acids to obtain a second minimized mean baseline, wherein the second minimized mean baseline corresponds to the plurality of the third optical signals of a plurality of predetermined cycles from the third cycle number, wherein the plurality of the third optical signals of the plurality of predetermined cycles from the third cycle number corresponds to a third predetermined intensity value; subtracting the second minimized mean baseline from the plurality of the third optical signals”, provides mathematical calculations (subtracting background signals from optical signals to obtain a mean baseline) that are considered a mathematical concept, which is an abstract idea.
“generating a plurality of reference amplification curves from the plurality of the subtracted third optical signals” provides mathematical relationships (generating reference amplification curves involves plotting signals as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
“validating each of the plurality of the subtracted second optical signals for the target nucleic acid in the sample detected against the plurality of reference amplification curves, wherein the validating each of the plurality of the second optical signals comprises projecting each of the plurality of the second optical signals on to the plurality of the reference amplification curves to determine a threshold for the plurality of the second optical signals;”, provides evaluations (validating signals against a reference) that may be performed in the human mind and is therefore considered mental processes, which is an abstract idea.
“computing an initial quantity of the target nucleic acid in the sample from the validated plurality of the second optical signals for the target nucleic acid in the sample obtained as the function of the second cycle number for the target nucleic acid in the sample, wherein computing the initial quantity of the target nucleic acid in the sample from the validated plurality of the second optical signals comprises performing an affine transformation on the validated plurality of the second optical signals, wherein the affine transformation comprises at least one of a linear transformation and a translation.”, provides mathematical relationships (quantifying target nucleic acid in the sample as a function of cycle number) that are considered a mathematical concept, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. Additionally, while some of the claims (1, 14, and 20) recite performing some aspects of the analysis with a “processor”, there are no additional limitations that indicate that this requires anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then it falls within the “Mental processes” grouping of abstract ideas. As such, claims 1-9 and 11-20 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 listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology Specifically, the claims recite the following additional elements:
Claim 1: “performing a first amplification reaction on a plurality of control samples in a first reaction chamber; receiving from a detector a plurality of first optical signals as a function of a first cycle number for the plurality of the control samples, wherein the plurality of the first optical signals comprises a plurality of first background signals; performing a second amplification reaction on the sample in a second reaction chamber; receiving from the detector a plurality of second optical signals as a function of a second cycle number for the target nucleic acid in the sample, wherein the plurality of the second optical signals comprise a plurality of second background signals”, provides insignificant extra-solution activities (performing amplification reactions and receiving data are pre-solution activities involving sample manipulation and data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 2: “detecting the plurality of the first optical signals for each of the plurality of the control samples at each cycle of the first amplification reaction, wherein each cycle of the first amplification reaction corresponds to the first cycle number”, provides insignificant extra-solution activities (detecting signals is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 3: “detecting the plurality of the second optical signals for the target nucleic acid in the sample at each cycle of the second amplification reaction, wherein each cycle of the second amplification reaction corresponds to the second cycle number”, provides insignificant extra-solution activities (detecting signals is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 14: “performing a first amplification reaction on a plurality of control samples in a first reaction chamber; receiving from a detector a first amplification curve representing a plurality of first optical signals as a function of a first cycle number for each of the plurality of control samples at each cycle of the first amplification reaction, wherein the plurality of the first optical signals comprises a plurality of background signals; performing a second amplification reaction on the sample in a second reaction chamber; receiving from the detector a second amplification curve representing a plurality of second optical signals as a function of a second cycle number for the target nucleic acid in the sample at each cycle of the second amplification reaction” and “receiving the plurality of the reference amplification curves, wherein each of the plurality of the reference amplification curves comprises a plurality of third optical signals corresponding to a reference sample, wherein each of the plurality of the reference amplification curves comprises the plurality of the third optical signals corresponding to a background region, an exponential growth region, and a plateau region” and “performing a plurality of third amplification reactions on a plurality of reference nucleic acids in a third reaction chamber; receiving from the detector a plurality of third optical signals as a function of a third cycle number for the plurality of the reference nucleic acids”, provides insignificant extra-solution activities (performing amplification reactions and receiving data are pre-solution activities involving sample manipulation and data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 20: “a plurality of reaction chambers for performing a first amplification reaction on a plurality of control samples, a second amplification reaction on the sample, and a third amplification reaction on a plurality of reference nucleic acids; a detector for detecting a plurality of first optical signals as a function of a first cycle number for the plurality of the control samples at each cycle of the first amplification reaction, a plurality of second optical signals as a function of a second cycle number for the target nucleic acid in the sample at each cycle of the second amplification reaction and a plurality of third optical signals as a function of a third cycle number for the plurality of the reference nucleic acids, wherein the plurality of the first optical signals comprises a plurality of background signals;”, provides insignificant extra-solution activities (performing amplification reactions and detecting signals are pre-solution activities involving sample manipulation and data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
“a processor comprising a memory for implementing program instructions of a computer- readable medium”, provides insignificant extra-solution activities (implementing program instructions are mere instructions to implement an abstract idea) that do not serve to integrate the judicial exceptions into a practical application.
The steps for performing amplification reactions, and receiving and detecting signal data are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are pre-solution activities involving sample manipulation and data gathering steps (see MPEP 2106.04(d)(2)). Furthermore, the limitations regarding implementing program instructions do not indicate that they require anything other than mere instructions to implement the abstract idea in a generic way or in a generic computing environment. As such, this limitation equates to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. Therefore, claims 1-9 and 11-20 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). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
As discussed above, there are no additional elements to indicate that the claimed “implementing program instructions” requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. Additionally, the limitations for performing reactions, and receiving and detecting signal data are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are demonstrated by applicant’s specification to be well-understood, routine, and conventional: “Quantitative polymerase chain-reaction (qPCR) measurements are a mainstay diagnostic tool for early disease detection. qPCR technique involves iterating or "cycling" a PCR reaction to double the amount of a target DNA segment in a sample and detecting fluorescence emission signals corresponding to new copy of target DNA generated during each cycle of the PCR reaction.” (para.0004). Finally, Taylor et al (US-7363168) reinforces the assertion that no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional: “Polymerase Chain Reaction (PCR) is a powerful technique commonly used in today's laboratories for specific amplification and detection of as little as a single copy of a target nucleic acid sequence.” (col 1, paragraph 1), and “Fluorescence intensities are detected during the annealing/extension period of each PCR cycle and the output of this detection is fed to a processor for storage and data manipulation.” (col 1, paragraph 2).
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. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-9 and 11-20 are not patent eligible.
Response to Arguments under 35 USC § 101
Applicant' s arguments filed 7/17/2025 are fully considered but they are not persuasive.
Regarding claim 1, applicant asserts that “The Office Action errs under the first prong of the Alice/Mayo test in its determination that the pending claims are ‘directed to’ the identified abstract idea.” (Remarks 7/17/2025 Page 2). The Examiner has indicated in the above rejection, in accordance with MPEP § 2106, claims found to recite statutory subject matter are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon. In the instant application, the claims recite an abstract idea for the reasons listed previously.
Applicant also asserts “Claim 1, as amended, recites a tangible subject matter and is inextricably tied to the physical process of performing amplification reactions on control samples in a reaction vessel”, which the Examiner has already conceded, that the independent claims recite statutory subject matter, as if they did not there would be no grounds for a 101 rejection. Additionally, the Examiner notes that the previous standard regarding a “useful, concrete, and tangible result” was the standard prior to 2010 which is not applied here.
Applicant asserts that “The Office Action improperly compares only a portion of claim 1 against an ineligible concept, without first considering the whole claim to examine its character, and as such, has not properly applied the second step of the Alice test. The Office Action has characterized individual features of the claim as separate abstract ideas. Because the Office Action performs this piece-meal approach to characterizing the claim, the Office Action improperly breaks the claim into small (and disconnected) pieces that are more easily characterized as abstract ideas in isolation from the context of the claim.” (Remarks 7/17/2025 Page 3).
The Examiner notes that MPEP 2106(I) states that if the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). In the “search for an ‘inventive concept’” (the second part of the Alice/Mayo test), the additional elements identified 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 because performing reactions (sample manipulation steps), receiving and detecting signal data (data gathering steps), and implementing program instructions using a processor (mere instructions) are all well-understood, routine, and conventional techniques that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Therefore, combining insignificant extra-solution activities with any of the identified judicial exceptions would not result in patent eligible subject matter because integrating well-understood, routine, and conventional techniques does not yield “significantly more” to a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon.
Applicant asserts that “Claim 1 as a whole is directed to an improved method for analyzing data generated by qPCR measurements to detect low initial concentrations of target nucleic acid while improving the quantitative accuracy and reproducibility of the analysis. The improved method utilizes the physical process of performing amplification reactions on control samples in a reaction vessel, obtaining background signals from the control samples, performing amplification reactions on samples in a reaction vessel, detects fluorescence emission signals of the samples using a detector, and applies a baseline subtraction technique to the fluorescence emission signals of the samples that avoids the use of empirical models by directly leveraging the behavior of appropriate control experiments, and the method can identify mutated strains of variants without the need for full genetic sequencing. This is not data analysis, which only occurs later, after the inventive steps have cleaned up the raw measured optical signals to obtain low-noise measurement data for analysis. Rather, the pre-conditioning of the raw measured fluorescence emission signals is part of the operation of the quantitative PCR system itself.” (Remarks 7/17/2025 Page 3). The Examiner has indicated that the “pre-conditioning” methods as described are demonstrated by the prior art cited in section 103 below, and have been indicated as insignificant extra-solution activities as recited in the 101 rejection above.
Applicant asserts that “While the claimed method uses mathematical calculations, they do so in an unconventional manner to effect a particular technological solution. In the present invention, as an initial preconditioning step, all fluorescence emission signals, including signals obtained from extraction blanks or non-template controls, obtained are normalized, and the normalization is dependent on the amplification chemistry. Unlike typical methods, which involve subtracting background signals obtained from signals obtained for samples, background signals obtained are instead subtracted from measurements of extraction blanks (or non-template controls) and then optimized to determine the amount of background that, when removed from sample signals obtained, minimizes the mean baseline and its variation. This baseline corresponds to the first few cycles of the amplification curve where there are too few fluorophores to detect.” (Remarks 7/17/2025 Page 4). The Examiner has indicated that the background subtraction method utilizing extraction blanks and/or NTCs are demonstrated by the prior are cited in section 103 below, and have been indicated as insignificant extra-solution activities as recited in the 101 rejection above.
Applicant asserts that the claims do not lack “significantly more” because they operate on “physical data obtained from a real-world system for determining quantity of a target nucleic acid in a sample” (Remarks 7/17/2025 Page 4). The examiner notes that data is not physical, and the distinction is moot, as this may be again an argument for pre 2010 standards of a 101 rejection. Quantifying a target nucleic acid is not a practical application, as it is merely a result of the method steps which amount to no more than insignificant extra-solution activities that do not serve to integrate the judicial exceptions into a practical application. A practical application of quantification would be utilizing this value for a practical purpose.
Therefore, the rejection of claim 1 is maintained, and because similar arguments apply for claims 14 and 20, the rejection for these other independent claims are also maintained. Claims 2-9 and 11-13 depend from independent claim 1 and claims 15-19 depend from independent claim 14, and are likewise rejected for these reasons.
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.
Claims 1-6, 9, 11-14, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (US-7363168) in view of Shain et al. (WO-2009086415).
Regarding independent claim 1, Taylor teaches a method for determining a quantity of target nucleic acid in a sample (Claim 1, “A method for determining an absolute or relative quantity of a target nucleic acid in a sample”), performing amplification reactions on a plurality of samples and receiving a plurality of optical signals as a function of cycle number for the samples (Col 10 lines 2-6, “During real-time PCR, actual signals or raw data for each given sample well of a multiple sample well holder inserted into a real-time PCR system … are detected at every cycle of the PCR amplification reaction”), optimizing signal data by subtracting first background signals from second optical signals to obtain a mean baseline (Col 1 lines 52-56, “The data obtained during amplification is normalized by the processor which identifies a baseline of background signals (the expected signal in a PCR tube in the absence of a target nucleic acid) and which removes background signals from observed signals.”), validating the sample optical signals against reference amplification curves (Col 3 lines 12-15, “Preferably, the adapted signal plot is compared to a first standard plot generated from a PCR reaction comprising a known amount of template concentration.”), and computing the quantity of target nucleic acid in the sample from the validated sample optical signals (Col 7 lines 25-29: “A "standard plot" refers to a plot generated by plotting an intensity of an optical signal (e.g., fluorescent intensity) as a function of known amount of a target template. A "standard plot" serves as a basis for quantifying an unknown amount of the target template in a sample.”).
Taylor does not teach performing an affine transformation to apply a linear transformation or a translation on the validated sample optical signals.
Shain teaches performing a scaling (a kind of affine transformation) on PCR data (para.0070 and 0071, and Figure 8: "Scaling does not affect analytical results. Scaling can be carried out in addition to normalization, in the absence of normalization, or before or after normalization.").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Taylor as taught by Shain for performing an affine transformation to apply a linear transformation or a translation on the validated sample optical signals in order to better visualize the signal data (Shain, para.0070: "Scaling is optional but can be performed to make it easier for a human operator to visualize the data."). One skilled in the art would have a reasonable expectation of success because affine transformations such as scaling, translation, rotation, reflection, and combinations thereof are well understood geometric transformations that preserve lines and parallelism, which is ideal for visualizing PCR signal data because it is critical that the relationship between samples is maintained for a proper comparison.
Regarding claims 2 and 3, Taylor in view of Shain teach the method of Claim 1 on which these claims depend. Taylor also teaches detecting optical signals at each cycle of the amplification reaction (Col 1 lines 35-36, “In real-time QPCR techniques, signals (generally fluorescent) are monitored as they are generated.”), and plotting amplification curves as a function of cycle number (Col 2 lines 25-27, “The method comprises plotting intensity of actual optical signal observed in a well as a function of cycle number for that well to obtain a first plot”).
Taylor does not teach that the amplification curve represents a ratio of each of the optical signals to a passive reporter dye optical signal as the function of cycle number.
Shain teaches that the amplification curve represents a ratio of each of the optical signals to a passive reporter dye optical signal as the function of cycle number (Para.0068, “One method involves dividing the target and control [optical signal] values at each cycle reading by the corresponding reference dye signal.”).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Taylor as taught by Shain for normalizing the sample signal data by performing a division of its signals by a reference dye signal to yield an amplification curve representing this ratio in order to correct for known imprecisions in fluorescence detection (Shain, Para.0045, “In PCR, data analysis can be made difficult by a number of factors. Accordingly, various steps can be performed to account for these factors. For example, captured light signals can be analyzed to account for imprecision in the light detection itself. Such imprecision can be caused by errors or difficulties in resolving the fluorescence of an individual dye among a plurality of dyes in mixture of dyes (described below as "bleedover"). Similarly, some amount of signal can be present (e.g., "background signal") and can increase even when no target is present (e.g., "baseline drift"). Thus, a number of techniques for removing the background signal, preferably including the baseline drift, trend analysis, and normalization are described herein and/or are known in the art.”), as well as for visualization and comparison purposes (Shain, Figure 9 shows a tab in the software interface for “Plot Normalized”). One skilled in the art would have a reasonable expectation of success because the error correction techniques described above are widely employed by practitioners of the same technology as pertains to the instant application (qPCR).
Regarding claim 4, Taylor in view of Shain teach the method of Claim 1 on which these claims depend. Taylor also teaches reference amplification curves from a reference sample having a background region, an exponential growth region, and a plateau region (Col 7 lines 25-29: “A "standard plot" refers to a plot generated by plotting an intensity of an optical signal (e.g., fluorescent intensity) as a function of known amount of a target template. A "standard plot" serves as a basis for quantifying an unknown amount of the target template in a sample.”), projecting sample optical signals on to the reference amplification curves and determining whether each of the optical signals collapses on to the reference amplification curves (Col 9 lines 55-62, “The best fit between a growth curve of one of the aliquots and the working curve for a standard is calculated, e.g., such as by a single-variable successive approximation method. The concentration of the standard whose working curve provides the best fit with the growth curve of the aliquot of the sample comprising unknown amounts of nucleic acids is taken as the concentration of the aliquot of the unknown sample.”, and Col 15 lines 51-54, “In one embodiment, the analyzing device also adjusts the starting and ending cycles, e.g., by comparing a measured growth curve to a calculated growth curve.”), and determining a threshold value for the projected sample optical signals (Abstract, “Particularly, the invention relates to algorithms for determining the threshold cycle for the first reliable detection of the amplified nucleic acid product.”).
Regarding claim 5, Taylor in view of Shain teach the method of Claim 1 on which this claim depends. Taylor also teaches plotting a plurality of optical signals projected on to at least one of the reference amplification curves to obtain a validated sample amplification curve (Col 2 lines 25-27, “The method comprises plotting intensity of actual optical signal observed in a well as a function of cycle number for that well to obtain a first plot”, Col 3 lines 12-15, “Preferably, the adapted signal plot is compared to a first standard plot generated from a PCR reaction comprising a known amount of template concentration.”, Col 7 lines 25-29, “A "standard plot" refers to a plot generated by plotting an intensity of an optical signal (e.g., fluorescent intensity) as a function of known amount of a target template. A "standard plot" serves as a basis for quantifying an unknown amount of the target template in a sample.”, and Col 15 lines 51-54, “In one embodiment, the analyzing device also adjusts the starting and ending cycles, e.g., by comparing a measured growth curve to a calculated growth curve.").
Regarding claim 6, Taylor in view of Shain teach the method of Claim 1 on which this claim depends. Taylor also teaches detecting a plurality of signals corresponding to an optical signal from at least one fluorescent dye (Col 10 lines 29-34, “In the present invention, the starting and ending cycle are determined individually and uniquely for each sample well and/or each dye being evaluated. For each sample well and/or dye, a first plot is generated by plotting the actual signals generated by a label in the sample well as function of cycle number.”).
Regarding claims 9 and 16, Taylor in view of Shain teach the method of Claims 1 and 14 on which these claims depend, respectively. Taylor also teaches a non-template control as a control sample (Col 10 lines 6-8, "One or more wells may serve as control wells by comprising all reagents used for the PCR amplification except for a nucleic acid template.").
Regarding claims 11-12, and 18-19, Taylor in view of Shain teach the method of Claims 1 and 14 on which these claims depend, respectively. Taylor also teaches DNA and RNA as a sample (Col 4 lines 43-46, “The adaptive baseline can be subtracted from the actual signal observed during a PCR amplification cycle and used to calculate the amount of a nucleic acid template in a PCR reaction.”, and Col 4 lines 51-53, “A "nucleic acid" is a covalently linked sequence of nucleotides (i.e., ribonucleotides for RNA and deoxyribonucleotides for DNA)”).
Regarding claim 13, Taylor in view of Shain teach the method of Claim 1 on which this claim depends.
Taylor does not teach normalizing the plurality of the first and the second optical signals by determining a ratio of each of the plurality of the first and the second optical signals to a passive reporter dye optical signal
Shain teaches a normalization method that represents a ratio of each of the optical signals to a passive reporter dye optical signal as a function of cycle number (Para.0068, “One method involves dividing the target and control [optical signal] values at each cycle reading by the corresponding reference dye signal.”).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Taylor as taught by Shain for normalizing the sample signal data by performing a division of its signals by a reference dye signal to yield an amplification curve representing this ratio in order to correct for known imprecisions in fluorescence detection (Shain, Para.0045, “In PCR, data analysis can be made difficult by a number of factors. Accordingly, various steps can be performed to account for these factors. For example, captured light signals can be analyzed to account for imprecision in the light detection itself. Such imprecision can be caused by errors or difficulties in resolving the fluorescence of an individual dye among a plurality of dyes in mixture of dyes (described below as "bleedover"). Similarly, some amount of signal can be present (e.g., "background signal") and can increase even when no target is present (e.g., "baseline drift"). Thus, a number of techniques for removing the background signal, preferably including the baseline drift, trend analysis, and normalization are described herein and/or are known in the art.”), as well as for visualization and comparison purposes (Shain, Figure 9 shows a tab in the software interface for “Plot Normalized”). One skilled in the art would have a reasonable expectation of success because the error correction techniques described above are widely employed by practitioners of the same technology as pertains to the instant application (qPCR).
Regarding independent claim 14, Taylor teaches a method for determining a quantity of target nucleic acid in a sample (Claim 1, “A method for determining an absolute or relative quantity of a target nucleic acid in a sample”), performing amplification reactions on a plurality of samples and receiving a plurality of optical signals as a function of cycle number for the samples (Col 10 lines 2-6, “During real-time PCR, actual signals or raw data for each given sample well of a multiple sample well holder inserted into a real-time PCR system … are detected at every cycle of the PCR amplification reaction”), optimizing signal data by subtracting background signals from second optical signals to obtain a mean baseline (Col 1 lines 52-56, “The data obtained during amplification is normalized by the pro