DETAILED ACTION
The amendment filed on 12/08/2025 has been entered.
Claims 1-2, 5-7, 9, and 10 were amended in the claim set filed on 12/08/2025.
Applicant's election with traverse of Group I (claims 1-6, 8, 10 and 11) in the reply filed on 08/08/2025 is acknowledged. The grounds for traversal were not persuasive. Group II (claim 7), drawn to a device; and Group III (claim 9), drawn to "software" are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II or III, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 08/08/2025. Since no claim is in condition for allowance, the request for reinstatement of claims 7 and 9 is not allowed at this time.
Claims 1-6, 8, 10 and 11 in the claim set filed on 12/08/2025 are currently under examination.
Response to the Arguments
Objections to the claim 6 in the previously mailed non-final has been withdrawn in light of applicants claim amendment.
Applicant’s arguments regarding previous rejection(s) of claim(s) 2-4 under 35 U.S.C. 112(b) have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejections of claim(s) 2-4 documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments.
Applicant’s arguments regarding previous rejection(s) of claim(s) 5 and 11 under 35 U.S.C. 112(b) have been fully considered but are not persuasive. The 35 U.S.C. 112(b) rejections of claim(s) 5 and 11 documented in the previously mailed non-final have been maintained.
Applicant’s arguments regarding previous rejection(s) of claim(s) 1-6,8 and 10-11 under 35 U.S.C. 103 have been fully considered but are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 6-8.
Applicant’s arguments regarding previous provisional rejections of claim1 under 35 nonstatutory double patenting have been fully considered and are persuasive. The provisional rejections of claim 1 under nonstatutory double patenting documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments on Pg. 8-9. However, upon further consideration, new ground(s) of rejection are made in view of Von Lerber.
The rejections for claims 1-6, 8, 10 and 11 are documented below in this Final Office Action are necessitated by claim amendments filed on 12/08/2025.
Priority
This application is a 35 U.S.C. § 371 National Stage Application of PCT/DE2021/100192, filed on February 25, 2021, which claims the benefit of priority to DE10 2020 202 361.1, filed on February 25, 2020.
Acknowledgment is made of applicant' s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of DE10 2020 202 361.1 has been submitted of the record on 08/16/2022.
An English translation of the foreign application DE10 2020 202 361.1 is required for the record to be considered for the priority date of February 25, 2020. Accordingly, the priority date of instant claims is determined to be February 25, 2021, the filing date of PCT/DE2021/100192.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 is indefinite over the limitations “a first ratio of a function value a first maximum of the probability density function (PDF) to a function value of a second maximum of the PDF is greater than 1” (ln 4-5). It is unclear what is intended by the limitation and what the ratio is intended to convey within the probability density function. Claim 11 depends on claim 5.
Claim 5 is indefinite over the limitations “a second ratio of a function value of a local minimum of the PDF between the first maximum and the second maximum of the PDF to a function value of the first maximum of the PDF is less than 0.7” (ln 6-7). It is unclear what is intended by the limitation and what the ratio is intended to convey within the probability density function (PDF). Claim 11 depends on claim 5.
Claim 5 is indefinite over the limitations “a width of a peak in the probability density function around the second maximum is greater than a specified reference value” (ln 8-9). It is unclear what is intended by the limitation and how the width peak relates to the second maximum. Claim 11 depends on claim 5.
Claim 11 is indefinite over the limitation “the ratio of the function value of the local minimum between the maxima to the function value of the first maximum is less than 0.6” (ln 4-5). It is unclear what is intended by the limitation and what the ratio is intended to convey within the probability density function.
Response to Arguments
Applicant's arguments filed 12/08/2025 (Pg. 6) with respect to claims 2-4 have been fully considered and are persuasive. Applicant's arguments filed 12/08/2025 (Pg. 6) with respect to claims 5 and 11 have been fully considered but are not persuasive. To clarify some instances argued in the response filed 12/08/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “In response to the indefiniteness rejection of claim 5, Applicant has amended the claim to clarify the limitations regarding the first and second ratios, in accordance with the description in the original specification at page 14, lines 4-16. However, the indefiniteness rejection of claim 5 based on the last clause regarding the width of a peak of the PDF is incorrect. The specification explains how this width value is determined at page 14, lines 24-36, which is in accordance with known PDF calculations. Claim 11 was also rejected as indefinite. Claim 11 has been amended in light of the amendment to claim 5, to be limited to defining the second ratio recited in claim 5.” (Pg. 6)
Response: Applicant’s arguments have been fully considered and found unpersuasive because applicants amendments do not overcome the indefiniteness of claims 5 and 11. It is still unclear according to the claim limitations, as the limitations of a probability density function (PDF) in the instant application was not defined in the claim or the claim from which it depends. Thus, the 35 U.S.C. 112(b) rejections regarding claims 5 and 11 are maintained.
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 1-6, 8, 10 and 11 remain/are rejected under 35 U.S.C. 101 because the claimed invention is directed towards mathematical relationships of creating a probability density function and establishing a presence or nonpresence of a DNA segment, without significantly more. The claim(s) recite(s) abstract ideas/mathematical relationships and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A method for conducting a quantitative polymerase chain reaction (qPCR) process, the method comprising: cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function; if the presence of the DNA strand segment is established, conducting the qPCR process; and if the nonpresence of the DNA strand segment to be established, stopping the qPCR process.
The limitations ”creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function” are considered abstract ideas – concepts relating to mathematical relationships or formulas. (See MPEP 2106.04(a)(2) Part IV).
The cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; and the limitations “conducting the qPCR process depending on the one of the presence and the nonpresence of the DNA strand segment to be detected” are considered to be active steps of qPCR. The active steps are routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the probability density function, baseline subtraction, presence and nonpresence of DNA strand segment, conduct the qPCR process, and method of qPCR processing execution.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract ideas.
With regard to claim 1, the claim recites “A method for conducting a quantitative polymerase chain reaction (qPCR) process, the method comprising: cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function; if the presence of the DNA strand segment is established, conducting the qPCR process; and if the nonpresence of the DNA strand segment to be established, stopping the qPCR process.”
The step of “creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function” is considered abstract ideas – concepts relating to mathematical relationships or formulas. (See MPEP 2106.04(a)(2)).
The cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; and conducting the qPCR process depending on the one of the presence and the nonpresence of the DNA strand segment to be detected are considered to be active steps of qPCR. The active steps are routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claim 1, the claim requires the routine and conventional active steps of executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; and conducting the qPCR process similar to that of Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016).
Von Lerber discloses “a method of high-resolution melting curve analysis for characterizing nucleic acid molecules such as PCR products having a distinct Tm using fluorescence is provided. The technique comprises modeling the raw melting curve data as a sum of at least two signal components, the first signal component representing the light intensity emitted by unbound/free fluorophores and the one or more second signal components representing the combined light intensity emitted by fluorophores bound to double stranded DNA. Numerical analysis is used to determine the values of the different components contributing to the total signal such that the model matches the raw fluorescence data as closely as possible. The method enables an improved resolution of mixtures of target nucleic acids even at non-saturating dye concentrations because it takes into account the effect of redistribution of intercalating dye from low-temperature duplexes to duplexes that melt at higher temperatures” (Abstract). Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require methods of creating the probability density function, determining baseline drift, linearizing the intensity values, subtracting baseline drift, establishing presence and nonpresence of DNA strand segment, conducting the qPCR process, executing the qPCR process which are all routine and conventional based on Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016) in view of Li et al. (“Li”; US Patent App. Pub. No. US 20130273547 A1, Oct. 17, 2013, Spiess et al. (“Spiess”; Impact of smoothing on parameter estimation in quantitative DNA amplification experiments. Clin Chem. 2015 Feb; 61(2): 379-88), Altmann et al. (“Altmann”; US Patent App. Pub. No. US 20130189702 A1, July 25, 2013), and Forootan et al. (“Forootan”; Methods to determine limit of detection and limit of quantification in quantitative real-time PCR (qPCR). Biomol Detect Quantif. 2017 Apr 29;12:1-6.).
Response to Arguments
Applicant's arguments filed 12/08/2025 (Pg. 11-12) with respect to claims 1-6, 8, 10 and 11 have been fully considered but are not persuasive. To clarify some instances argued in the response filed 12/08/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “The rejection is based on the assertion that independent claim 1 recites routine and conventional steps "similar to that of Von Lerber.” (Pg. 6)
Response: Applicant’s arguments have been fully considered and found unpersuasive because applicants amendments do not overcome the lack of patentably matter under U.S.C. 35 101. The previously presented and amended claims recite abstract ideas/mathematical relationships and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Applicants’ argument: “The rejection asserts that one of the cited references also discloses establishing the presence and nonpresence of DNA strand segments, but does not identify which reference, and more importantly does not establish that any of the cited art uses a feature of the probability density function to establish presence/nonpresence.” (Pg. 6)
Response: Applicant's arguments do not comply with 37 CFR 1.111(c) because instant claims do not recite any limitations that are not well-established, routine and conventional in view of the state of the art disclosed by the references cited. Further, Applicants do not show how the amendments overcome the teachings by cited references.
Claim Rejections - 35 USC § 103
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 1-2, 5, and 8 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016).
Von Lerber discloses a method of high-resolution melting curve analysis for characterizing nucleic acid molecules such as PCR products having a distinct Tm using fluorescence is provided. The technique comprises modeling the raw melting curve data as a sum of at least two signal components, the first signal component representing the light intensity emitted by unbound/free fluorophores and the one or more second signal components representing the combined light intensity emitted by fluorophores bound to double stranded DNA. Numerical analysis is used to determine the values of the different components contributing to the total signal such that the model matches the raw fluorescence data as closely as possible. The method enables an improved resolution of mixtures of target nucleic acids even at non-saturating dye concentrations because it takes into account the effect of redistribution of intercalating dye from low-temperature duplexes to duplexes that melt at higher temperatures. (Abstract)
Regarding claims 1 and 2, Von Lerber teaches a method comprising “melt curve analysis using PCR, preferably qPCR… Quantitative real-time PCR (qPCR) is a method in which fluorescent dyes are used to detect the amount of PCR product after each PCR cycle (see e.g. U.S. Pat. No. 5,994,056) --- It is the most sensitive method for the detection and quantitation of low abundance --- in samples.” (Para. 40). Von Lerber teaches a method wherein “The melting process of a given nucleic acid molecule population may be modeled by a probability density function descriptive of the melting behavior as a function of time, especially at and/or around the melting temperature Tm,i. As an example, the probability of the melting of the nucleic acid molecule population i may be assumed to follow normal distribution and hence the melting probability may be expressed as a function of temperature as a Gaussian probability density function” (Para. 69). Von Lerber teaches a method wherein “The normal distribution and the logistic distribution described herein serve as non-limiting examples of suitable probability density functions that can be applied to model the melting probability on basis of a parametric function. Moreover, the respective cumulative probability distributions serve as non-limiting examples of suitable sigmoid functions for modeling the respective overall numbers of binding locations as a function of temperature… the type of the distribution may be determined or approximated on basis of measured data, e.g. on basis of the melt curve or derivative thereof.” (Para. 76). “fluorescence signal descriptive of melt curve data over a temperature range, the fluorescence signal representing the intensity of the light emitted by said fluorophores as a function of temperature” and “melting behavior” read on intensity values. Von Lerber teaches a method wherein “the fluorescence signal F(T) subject to the modeling... may be a normalized fluorescence signal. The normalization may involve e.g. setting the value of the normalized fluorescence signal… to a given reference value…at a given reference temperature and normalizing the rest of the values of the fluorescence signal F(T) accordingly” (Para. 93). “normalized fluorescence signal” reads on modified intensity values having been corrected by a proportion of a fluorescence of a baseline drift curve of the qPCR process.
Furthermore, Von Lerber teaches “a novel method for analyzing a melt curve characterizing the melt of a solution comprising one or more populations of nucleic acid molecules and a constant number of fluorophores of at least first type is provided. Said method comprises obtaining a fluorescence signal descriptive of melt curve data over a temperature range, the fluorescence signal representing the intensity of the light emitted by said fluorophores as a function of temperature, modeling the fluorescence signal at a plurality of temperatures within the temperature range as a sum of a first signal component representing the combined light intensity emitted by unbound fluorophores of said first type in the solution at a given temperature and a set of one or more second signal components, each representing the combined light intensity emitted by said fluorophores bound to the respective nucleic acid molecule population at the given temperature, wherein the first signal component is provided as a product of a first term representing the relative number of unbound fluorophores of said first type at the given temperature and a second term representing the emission efficiency of an unbound fluorophore of said first type at said given temperature and wherein each second signal component is provided as a product of a respective third term representing the relative number of said fluorophores bound to the respective nucleic acid molecule population at the given temperature and a respective fourth term representing the emission efficiency of said fluorophore bound to the respective nucleic acid molecule population at said given temperature, and utilizing numerical analysis to determine the values of said first, second, third and fourth terms at said plurality of temperatures such that the difference between the fluorescence signal and the modeled fluorescence signal meets a predefined criterion” (Para. 8).
Thus, Von Lerber a method for conducting a quantitative polymerase chain reaction (qPCR) process, the method comprising: cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function; if the presence of the DNA strand segment is established, conducting the qPCR process; and if the nonpresence of the DNA strand segment to be established, stopping the qPCR process; and the creating step further comprising: creating the probability density function depending on modified intensity values, the modified intensity values being either (i) dependent on the intensity values or (ii) corresponding to the intensity values, the modified intensity values having been corrected by a proportion of a fluorescence of a baseline drift curve of the qPCR process.
The teachings of Von Lerber are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claims 5 and 8 depend on claim 1.
Regarding claim 5, Von Lerber teaches a method wherein “the probability of the melting of the nucleic acid molecule population i may be assumed to follow normal distribution and hence the melting probability may be expressed as a function of temperature as a Gaussian probability density function wherein T represents the temperature, the parameters Ni,0 represent the overall number of binding locations of the nucleic acid molecules of population i before essentially any melting has taken place, the parameters T m,i represent the melting temperature of the nucleic acid molecules of population i and the parameters σi represent the melt width of the nucleic acid molecule population i. The melting temperature Tm,i and the melt width σi are parameters characterizing a nucleic acid molecule population and hence these parameters may be e.g. employed to identify a nucleic acid molecule population.” (Para. 69).
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Thus, the teachings by Von Lerber render the claimed method of instant application prima facie obvious, wherein the claimed methods directed to one of the presence and the nonpresence of the DNA strand segment to be detected is established depending on a presence of at least one of the following features of the probability density function; a first ratio of a function value of a first maximum of the probability density function (PDF) to a function value of a second maximum of the PDF is greater than 1; a second ratio of a function value of a local minimum of the PDF between the first maximum and second maximum of the PDF to a function value of the first maximum of the PDF is less than 0.7; and a width of a peak in the probability density function around the second maximum is greater than a specified reference value.
Regarding claim 8, Von Lerber teaches a method wherein “a computer program for analyzing a signal descriptive of melt curve data” (Para. 1). Thus, Von Lerber teaches a method wherein the method is carried out by executing a computer program.
Therefore, the invention as recited in claims 1-2, 5 and 8 is prima facie obvious over the prior art Von Lerber et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method for conducting a quantitative polymerase chain reaction (qPCR) process according to the limitations of the instant application claims 1-2, 5 and 8 based on Von Lerber et al (Patent App. Pub. No. US 20160085908 A1).
Response to Arguments
Applicant' s arguments filed 12/08/2025 (Pg.12-13) with respect to claim 1-5, 7, 19-21, 25 and 26 have been considered but are not persuasive. To clarify some instances argued in the response filed 12/08/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “The Office Action fails to make the requisite findings to establish a prima facie case for obviousness… Moreover, the Office Action does not identify any excerpt in Von Lerber that describes the step of "establishing the presence or non-presence of a DNA strand segment" or the step of "conducting the qPCR process depending on the presence or non-presence.” (Pg. 7)
Response: In response to applicants’ arguments above, the invention as recited in claims 1-2, 5 and 8 is prima facie obvious over the prior art Von Lerber et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method for conducting a quantitative polymerase chain reaction (qPCR) process according to the limitations of the instant application claims 1-2, 5 and 8 based on Von Lerber et al (Patent App. Pub. No. US 20160085908 A1).
Furthermore, Von Lerber teaches a method for conducting a quantitative polymerase chain reaction (qPCR) process, the method comprising: cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; creating a probability density function from the intensity values of the qPCR curve; establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function; if the presence of the DNA strand segment is established, conducting the qPCR process; and if the nonpresence of the DNA strand segment to be established, stopping the qPCR process
The “establishing one of a presence and a nonpresence of a DNA strand segment to be detected depending on a presence of at least one feature of the probability density function” reads on any qPCR reaction where the abundance of a nucleic acid is measured by intensity. Thus, the presence or non-presence is established by the analysis of the intensity of bound fluorophores to the nucleic acid molecules by the utilizing numerical analysis to determine the values of said first, second, third and fourth terms at said plurality of temperatures such that the difference between the fluorescence signal and the modeled fluorescence signal meets a predefined criterion comparison to the intensity of unbound fluorophores. (Para. 8)
Applicants’ argument: “More significantly does not use a probability density function to determine whether a qPCR process should continue or should be stopped.” (Pg. 8)
Response: In response to the applicants’ argument above, Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections. Also, rather the qPCR process should continue or stop is conditional. Furthermore, if a qPCR process was initiated it will continue and eventually it will be stopped. Thus, it would be obvious to the ordinary artisan based on the claim limitations.
Applicants’ argument: “The Office Action appears to quote text from Von Lerber, but does not explain what in the quoted text corresponds to the limitations of claim 2, such as modified intensity values and baseline drift.” (Pg. 8)
Response: In response to the applicants’ argument above, the revised 35 U.S.C 103 rejection regarding claims 1-2 above recites “Von Lerber teaches a method wherein “the fluorescence signal F(T) subject to the modeling... may be a normalized fluorescence signal. The normalization may involve e.g. setting the value of the normalized fluorescence signal… to a given reference value…at a given reference temperature and normalizing the rest of the values of the fluorescence signal F(T) accordingly” (Para. 93).” previously recited in the non-final office action. “normalized fluorescence signal” reads on modified intensity values having been corrected by a proportion of a fluorescence of a baseline drift curve of the qPCR process.
Applicants’ argument: “Von Lerber does not describe using the width of a PDF peak to establish the presence or non-presence of a DNA strand.” (Pg. 8)
Response: In response to the applicants’ argument above, Von Lerber does appear to describe using the width of a PDF peak to establish the presence or non-presence of a DNA strand. Since the melting temperature Tm,i and the melt width σi are parameters characterizing a nucleic acid molecule population and hence these parameters may be e.g. employed to identify a nucleic acid molecule population.” (Para. 69), it would obvious that parameters would be able to characterize the identity and how many molecules are present or absent in a given population of DNA molecules.
Claim 3 remains/is rejected under 35 U.S.C. 103 as being unpatentable over Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016) as applied to claims 1 and 2 above, and further in view of Li et al. (“Li”; US Patent App. Pub. No. US 20130273547 A1, Oct. 17, 2013).
The teachings of Von Lerber are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claim 3 depends on claim 2, which depends on claim 1.
Regarding claim 3, Von Lerber teaches “Gaussian probability density function” (Para. 69). Gaussian reads on clustering algorithm. Von Lerber teaches a method wherein “the fluorescence signal F(T) subject to the modeling... may be a normalized fluorescence signal. The normalization may involve e.g. setting the value of the normalized fluorescence signal… to a given reference value…at a given reference temperature and normalizing the rest of the values of the fluorescence signal F(T) accordingly” (Para. 93). Von Lerber teaches a method wherein “normalization may be carried using reference temperature different from the one exemplified in the equation (18) and/or by employing a different normalization scheme” (Para. 95).
Von Lerber does not explicitly teach the limitation “linearizing the intensity values to be assigned to the baseline region with linear interpolation and subtracting, subsequently, a plot of the linearized intensity values of the baseline drift from the qPCR curve .
Li discloses methods correct for high-sloped baseline observed in real-time PCR curves and provides a way of verifying amplification efficiency using a statistical approach. The method teaches the conversion of fluorescent data points to transform the baseline from sloped to horizontal. Then, a 4-parameter logistic model is applied to simulate the PCR kinetics. A cycle number corresponding to a template concentration can then be determined at a inflection point defined by the model. (Abstract)
Regarding claim 3, Li teaches a method wherein “The baseline slope fitting curve can be a linear regression that is determined” (Para. 15; Figure 4) and “plot can be generated with fluorescent data points that are corrected to minimize baseline fluorescence, each corrected fluorescent data point… at cycle x…, being determined by subtracting the average fluorescence value of baseline…from each modified fluorescence value” (Para. 18). Thus, Von Lerber and Li teach a method further comprising determining the proportion of the fluorescence of the baseline drift by determining, with a clustering algorithm, intensity values to be assigned to a baseline region of the qPCR curve, linearizing the intensity values to be assigned to the baseline region with linear interpolation and subtracting, subsequently, a plot of the linearized intensity values of the baseline drift from the qPCR curve.
Von Lerber and Li are both considered to be analogous to the claimed invention because they are in the same field of processing qPCR fluorescence intensities. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of conducting a qPCR process as taught by Von Lerber to incorporate the method of linearizing the intensity values assigned to the baseline region with linear interpolation and subtracting, subsequently, a plot of the linearized intensity values as taught by Li and provide modified intensity values. Doing so would allow for correction of baseline drift.
Response to Arguments
Applicant's arguments filed on 12/08/2025 have been fully considered but they are not
persuasive. Arguments against Von Lerber are not persuasive as discussed above.
Claims 4 and 10 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016) as applied to claims 1 and 2 above, and further in view of Spiess et al. (“Spiess”; Impact of smoothing on parameter estimation in quantitative DNA amplification experiments. Clin Chem. 2015 Feb; 61(2): 379-88).
The teachings of Von Lerber are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claim 10 depends on claim 4, which depends on claim 2, which depends on claim 1.
Von Lerber does not explicitly teach the limitations “determining the modified intensity values by smoothing the qPCR curve with a filter” and “wherein the filter is a moving average filter”.
Spiess discloses “the selection of a smoothing algorithm is an important step in developing data analysis pipelines for real-time PCR experiments. We offer guidelines for selection of an appropriate smoothing algorithm in diagnostic qPCR applications. The findings of our study were implemented in the R packages chipPCR and qpcR as a basis for the implementation of an analytical strategy” (Abstract-Conclusion).
Regarding claims 4 and 10, Spiess teaches a method wherein “To reduce noise, several methods on the basis of local smoothing or filtering have been proposed in the literature, including robust locally weighted regression (lowess), (weighted) running mean (moving average), cubic splines, Kalman smoother, Friedman super smoother, Savitzky–Golay filter, and Whittaker smoother” (Pg. 380 Col. 1 Para. 2) and “We implemented… smoothing methods… within the qpcR” (Pg. 380, Materials and Methods-SMOOTHING METHODS AND PARAMETER SETTINGS, Para. 1). Thus, Von Lerber and Spiess teaches a method further comprising determining the modified intensity values by smoothing the qPCR curve with a filter; and wherein the filter is a moving average filter.
Von Lerber and Spiess are both considered to be analogous to the claimed invention because they are in the same field of processing qPCR fluorescence intensities. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of conducting a qPCR process as taught by Von Lerber to incorporate a filter as taught by Spiess and provide a method for determining the modified intensity values by smoothing the qPCR curve with a filter. Doing so would help to remove noise from the intensity values of the qPCR data.
Response to Arguments
Applicant's arguments filed on 12/08/2025 have been fully considered but they are not
persuasive. Arguments against Von Lerber are not persuasive as discussed above.
Claim 6 remains/is rejected under 35 U.S.C. 103 as being unpatentable over Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016) as applied to claims 1 and 2 above, and further in view of Altmann et al. (“Altmann”; US Patent App. Pub. No. US 20130189702 A1, July 25, 2013).
The teachings of Von Lerber are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claim 6 depends on claim 1.
Von Lerber does not explicitly teach the limitation “further comprising at least one of: signaling that a ct value is determinable; and determining the ct value from a parameterized presence function in response to the presence of the DNA strand segment to be detected being established”.
Altmann discloses improved procedure for determining the concentration or activity of an analyte in a sample. Specifically the invention provides an automated algorithm for the quality control of (RT-)qPCR reactions. Plotting the fluorescence intensity of a reporter dye divided by the fluorescence intensity of a passive reference dye against the cycle number leads to a so-called sigmoid function which is characterized by a background phase, an exponential growth phase and a plateau phase. Since the fluorescence intensity as a function of cycles relates to the initial number of template molecules in the sample, qPCR curves can be used to quantify the amount of RNA or DNA fragments in the sample by determination of a so-called Cq value.
Regarding claim 6, Altmann teaches a method wherein “To quantify the amount of DNA or mRNA fragments in a sample one now compares the fluorescence intensity to a pre-defined threshold and determines the cycle at which this threshold is reached for the first time…The (fractional) cycle at which the threshold is reached for the first time is called Ct value” (Para. 22) and “When using a TaqMan or a MX3005 to carry out the qPCR, the determination of the Ct values is done automatically by the associated software (SDS respectively MX Pro) except that the operator has to choose the threshold that shall be used when working with the TaqMan.” (Para. 23). Thus, Von Lerber and Altmann teach a method he step of conducting the qPCR process further comprising at least one of: signaling that a ct (cycle threshold) value is determinable; and determining the ct value from a parameterized presence function in response to the presence of the DNA strand segment to be detected being established.
Von Lerber and Altmann are both considered to be analogous to the claimed invention because they are in the same field of processing qPCR fluorescence intensities. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of conducting a qPCR process as taught by Von Lerber to incorporate the method of having determinable Ct value as taught by Altmann and provide method wherein a cycle threshold can be determined. Doing so would allow for a limit of detection to be established for the qPCR data.
Response to Arguments
Applicant's arguments filed on 12/08/2025 have been fully considered but they are not
persuasive. Arguments against Von Lerber are not persuasive as discussed above.
Claim 11 remains/is rejected under 35 U.S.C. 103 as being unpatentable over Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016) as applied to claims 1 and 5 above, and further in view of Forootan et al. (“Forootan”; Methods to determine limit of detection and limit of quantification in quantitative real-time PCR (qPCR). Biomol Detect Quantif. 2017 Apr 29;12:1-6.).
The teachings of Von Lerber are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claim 11 depends on claim 5, which depends on claim 1.
Von Lerber does not explicitly teach the limitation “the ratio of the function value of the local minimum between the maxima to the function value of the first maximum is less than 0.6”.
Forootan discloses “Quantitative Real-Time Polymerase Chain Reaction, better known as qPCR, is the most sensitive and specific technique we have for the detection of nucleic acids. Even though it has been around for more than 30 years and is preferred in research applications, it has yet to win broad acceptance in routine practice. This requires a means to unambiguously assess the performance of specific qPCR analyses. Here we present methods to determine the limit of detection (LoD) and the limit of quantification (LoQ) as applicable to qPCR. These are based on standard statistical methods as recommended by regulatory bodies adapted to qPCR and complemented with a novel approach to estimate the precision of LoD” (Abstract).
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Regarding claim 11, Forootan teaches a method wherein “the lowest amount of analyte (measurand) in a sample that can be detected with (stated) probability” (Pg. 1 para. 1). Forootan teaches a method comprising “The probability density function” (Pg. 2 Col. 2 Para. 3). Forootan teaches Figure 3 wherein the probability is less than 0.6 to detect the presence of 1 molecule. (See Figure 3 below).
Thus, Von Lerber and Forootan teach a method wherein the second ratio is less than 0.6.
Von Lerber and Forootan are both considered to be analogous to the claimed invention because they are in the same field of processing qPCR fluorescence intensities. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of conducting a qPCR process as taught by Von Lerber to incorporate the method wherein the presence of one DNA molecule is indicated by a probability ratio less than 0.6 as taught by Forootan and provide a method wherein the presence and the non-presence of the DNA strand segment to be detected is established depending on a presence of the following feature of the probability density function: the ratio of the function value of the local minimum between the maxima to the function value of the first maximum is less than 0.6. Doing so would allow for a greater probability of a DNA fragment presence in comparison to the non-presence to be established when detecting the molecules based on the probability density function.
Response to Arguments
Applicant's arguments filed on 12/08/2025 have been fully considered but they are not
persuasive. Arguments against Von Lerber are not persuasive as discussed above.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/904,301 in view of Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of copending Application No. 17/904,301 in view of Von Lerber.
Claim 1 of copending Application No. 17/904,301 are drawn to:
“1. (Currently amended) A method, which is computer implemented, for conducting a quantitative polymerase chain reaction (qPCR) process, the method comprising: cyclically executing qPCR cycles; measuring an intensity value of a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; evaluating shape of the qPCR curve with a data-based classification model which has been trained to provide a classification result depending on the shape of the qPCR curve; and conducting the qPCR process depending on the classification result from the evaluation of the shape of the qPCR curve.
The teachings of Von Lerber are documented above in the rejection of claims 1-6, 8, 10 and 11 under 35 U.S.C. 103.
Therefore, the invention as recited in claim 1 is prima facie obvious over the copending Application No. 17/904,301 in view of Von Lerber. One of ordinary skill in the art would have had a reasonable expectation of success given the claims of copending application and the teachings of Von Lerber. It would have been obvious to a method for conducting a quantitative polymerase chain reaction (qPCR) process according to the limitations recited in claim 1 of the instant application based on claim 1 of copending Application No. 17/904,301 in view of Von Lerber.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/904,302 in view of Von Lerber et al. (“Von Lerber”; US Patent App. Pub. No. US 20160085908 A1, March 24, 2016). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of copending Application No. 17/904,302 in view of Von Lerber.
Claim 1 of copending Application No. 17/904,302 are drawn to:
“1. (Currently amended) A method for conducting a quantitative polymerase chain reaction (qPCR) process method, comprising the following steps the method comprising: cyclically executing qPCR cycles; measuring a fluorescence at each qPCR cycle to obtain a qPCR curve composed of intensity values; determining a reaction efficiency for each qPCR cycle; correcting a respective intensity value of each respective qPCR cycle depending on the reaction efficiency determined for the respective qPCR cycle to obtain a corrected qPCR curve; and conducting the qPCR process depending on a shape of the corrected qPCR curve.”
The teachings of Von Lerber are documented above in the rejection of claims 1-6, 8, 10 and 11 under 35 U.S.C. 103.
Therefore, the invention as recited in claim 1 is prima facie obvious over the copending Application No. 17/904,302 in view of Von Lerber. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method for conducting a quantitative polymerase chain reaction (qPCR) process according to the limitations recited in claim 1 of the instant application based on claim 1 of copending Application No. 17/904,302 in view of Von Lerber.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments, see above, filed 12/08/2025 with respect to the rejection(s) of claim(s) 1 under nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Von Lerber. To clarify some instances argued in the response filed 12/08/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “The double patenting rejection in view of S.N. 17/904,302 is improper since the current claims of the '302 Application relate to measuring the area of a bubble formed in a PCR reaction chamber and does not relate to determining presence or non-presence of a DNA strand segment or to continuing or stopping the qPCR process based on the determination. It is believed that the claims of this application are patentably distinct from the claims of the '302 Application The claims do not relate to a probability density function or to continuing or stopping a qPCR process depending on the presence or non-presence. It is believed that the claims of this application are patentably distinct from the claims of the '301 Application.” (Pg. 9)
Response: Applicant’s arguments with respect to claim(s) 1 have been considered but are moot because the new ground of rejection. The arguments against Von Lerber are addressed in the responses above.
Conclusion of Response to Arguments
In view of the amendments, revised and new grounds of rejections and the above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682