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 .
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.
Applicant's response, filed on 04/20/2026, have been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Status of claims
Canceled:
2-3, 6, 8-9, 13-14, 18-20, 23
Pending:
1, 4-5, 7, 10-12, 15-17, 21-22
Amended:
1, 21-22
Withdrawn:
none
Examined:
1, 4-5, 7, 10-12, 15-17, 21-22
Independent:
1, 21
Allowable:
none
Priority
As detailed on the 11/14/2019 filing receipt, this application claims priority to PCT/KR2017/0053230 filed 05/19/2017. As a National stage filing, all claims have been interpreted as being accorded this priority date.
Withdrawn Rejections/Objections
The rejection of claims 1, 4-5, 7, 10-12, 14-17, and 21-22 under 35 U.S.C. §112(a), in the Office action mailed 10/23/2025 is withdrawn in view of the amendments filed 04/20/2026. However, a new rejection is applied as discussed below.
The rejection of claims 21-22 under 35 U.S.C. §112(b), in the Office action mailed 10/23/2025 is withdrawn in view of the amendments filed 04/20/2026.
The rejection of claims 1, 4-5, 7, 10-12, 14-17 and 21-22 under 35 U.S.C. §101, in the Office action mailed 10/23/2025 is withdrawn in view of the amendments filed 04/20/2026. However, a new rejection is applied as discussed below.
The rejection of claims 1, 4-5, 7, 10-12, 14 and 16-17 under 35 U.S.C. §103 over Wong in view of Mason, in the Office action mailed 10/23/2025 is withdrawn in view of the amendments filed 04/20/2026. However, a new rejection is applied as discussed below.
The rejection of claims 15 and 21-22 under 35 U.S.C. §103 over Wong in view of Mason and Gunstream 2011, in the Office action mailed 10/23/2025 is withdrawn in view of the amendments filed 04/20/2026. However, a new rejection is applied as discussed below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-5, 7, 10-12, 15-17 and 21-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 21 (Step C) recite “…applying a transformation algorithm to generate a calibrated amplification curve…,” which is not disclosed in the specification. Therefore, this limitation is new matter.
Dependent claims are rejected for depending on rejected claim.
Claim rejections - 101
35 USC 101 reads:
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.
For each rejection below, dependent claims are rejected similarly as not remedying the rejection, unless otherwise noted.
Judicial exceptions (JEs) to 101 patentability
Claims 1, 4-5, 7, 10-12, 15-17 and 21-22 are rejected under 35 USC 101 because the claimed inventions are not directed to patent eligible subject matter. After consideration of relevant factors with respect to each claim as a whole, each claim is directed to one or more judicially-recognized exceptions to patentability (JEs), i.e. an abstract idea, a natural phenomenon, a law of nature and/or a product of nature, as identified below. As set forth below, it is not clear that any element or combination of elements in addition to the JE(s), i.e. and "additional elements," either integrate the identified JE(s) into a practical application and/or is a non-conventional additional element, such that it is not clear that any claim is directed to significantly more than the identified JE(s).
MPEP 2106 organizes JE analysis into Steps 1, 2A (1st prong & 2nd prong) and 2B as analyzed below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: www.uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Analysis of claims 1, 4-5, 7, 10-12, 15-17 and 21-22
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Independent claim 1 is directed to a 101 process, here a “computer-implemented method for detecting a target analyte in a sample …," with process steps such as "performing … and detecting…"
Independent claim 21 is directed to a 101 machine or manufacture, here a “non-transitory computer readable storage medium containing instructions to configure a processor to perform a method for detecting a target analyte in a sample," with non-transitory elements such as "computer readable storage medium and processor."
[Step 1: claims 1, 4-5, 7, 10-12, 15-17 and 21-22: YES]
Step 2A, 1st prong: Do the claims recite a judicially-recognized exception (JE), e.g. a law of nature, a natural phenomenon or product, or an abstract idea (MPEP 2106.04.II.A.1 & .04(a))?
The MPEP at 2106.I, 2nd para. explains that JEs have been court-recognized as occurring in at least four types: abstract ideas, laws of nature and natural phenomena (including natural products).
MPEP § 2106.04(a)(2) further explains that abstract ideas may be grouped as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
• certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people);
and/or
• mental processes (procedures for observing, evaluating, analyzing/ judging and
organizing information).
Regarding the instant claims and with respect to Step 2A, 1st prong, at least preliminarily these claims recite JEs in the form of abstract ideas, mathematical concepts and certain methods of organizing human activity as follows.
Mental processes and mathematical concepts recited include:
Claims 1 and 21 recite: “(b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine… applying a transformation algorithm to generate a calibrated amplification curve…wherein the calibrated signal value is obtained by dividing the signal value at each of the cycles in the amplification curve by a background-representing signal at a reference cycle selected within a background region of the amplification curve…detecting, by the processor, the target analyte in a sample qualitatively or quantitatively using the calibrated amplification curve.” The process of detecting a signal, applying transformation algorithm and detecting the target analyte qualitatively or quantitatively involves analyzing, evaluating, judging, observing and organizing data, which could be performed with the human mind and/or with pen and paper.
Claim 11 recites: “wherein the reference cycle is selected from a reference cycle group of each amplification curve, wherein the reference cycle group of each amplification curve is provided in the same manner to each other.” The process of selecting could be performed with the human mind or with pen and paper, which involves selecting a value from a list and assigning it as the reference cycle.
Claim 12 recites: “wherein an identical reference cycle is provided for calibrating each amplification curve of the plurality of amplification curves.” The process of providing could be performed with the human mind or with pen and paper, which involves selecting and assigning a reference cycle.
Claim 22 recites: “...detecting a target analyte in a sample...” The process of detecting involves analyzing, evaluating, observing and judging data that could be performed with the human mind or with pen and paper.
Mathematical concepts recited include:
Claims 1 and 21 recite: “…applying a transformation algorithm to generate a calibrated amplification curve…wherein the calibrated signal value is obtained by dividing the signal value at each of the cycles in the amplification curve…detecting, by the processor, the target analyte in a sample qualitatively or quantitatively using the calibrated amplification curve.” The process of applying a transformation algorithm, quantitating and dividing requires carrying out a series of mathematical calculations and are involved with mathematical concepts and formulas.
Claim 12 recites: an identical reference cycle is provided for calibrating each amplification curve of the plurality of amplification curves. The process of calibrating requires carrying out a series of mathematical calculations and are involved with mathematical concepts and formulas.
Claim 14 recites: “wherein a total signal change value of a representative standard amplification curve is provided identically for calibrating each of the plurality of the amplification curves.” This process requires carrying out a series of mathematical calculations to calibrate and determine the total signal change and are involved with mathematical concepts and formulas.
Claim 17 recites: “wherein the amplification curve of the step (a) is a amplification curve of which a blank signal value is removed.” This process requires carrying out a series of mathematical calculations to remove blank signal value and are involved with mathematical concepts and formulas.
[Step 2A, 1st prong: claims 1, 4-5, 7, 10-12, 15-17 and 21-22: YES]
Step 2A, 2nd prong: Are the above-identified JEs integrated into a practical application (MPEP 2106.04.II.A.2 & .04(d))?
Generally regarding Step 2A, 2nd prong
MPEP 2106.04(d).I lists the following considerations for evaluating whether additional elements integrate a judicial exception into a practical application:
An improvement in the functioning of a computer, or an improvement to other technology or technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Additionally, the courts have also identified limitations that did not integrate a judicial exception into a practical application:
Merely reciting a phrase such as "apply it" (or an equivalent) along with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP 2106.05(f);
Adding insignificant extra-solution activity to the judicial exception, as discussed in MPEP 2106.05(g); and
Generally linking the use of a judicial exception to a particular technological environment or field of use, as discussed in MPEP 2106.05(h).
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). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that equate to mere instructions to implement an abstract idea or insignificant extra solution activity. Specifically, the instant claims recite the following additional elements:
claim 1: the recited "a computer-implemented method…(a) performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine; (b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve…calibrated signal value is obtained…" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 5: the recited "…RT-PCR generates signals..." step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 10: the recited "amplification curve comprises a plurality of amplification curves obtained from the plurality of RT-PCRs" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 14: the recited "...representative standard amplification curve is provided" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 21: the recited "A non-transitory computer readable storage medium containing instructions to configure a processor to perform...," "(a) receiving an amplification curve, wherein the amplification curve is obtained by performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine;(b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve" and "... (c) processing, by a processor operatively connected to the RT-PCR machine...calibrated signal value is obtained…detecting, by the processor…"step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 22: the recited "(a) a computer processor and (b) the computer readable storage medium of claim 21 coupled to the computer processor." step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
Claims 4, 7 and 15-16 do not recite additional elements.
Claims 4, 7 and 15-16 provide information on what the data represents and do not change the character of the data obtaining step beyond mere data gathering activity.
The additional elements of claims 1, 5 and 10, as discussed above, equate to mere data gathering and outputting, which amounts to insignificant extra solutional activity (see MPEP 2106.05(g)). The additional elements of claims 1 and 21-22 equate to mere data gathering and outputting via generic computer components, such as receiving data at a computer or outputting data, amount to insignificant extra-solution activity as set forth by the courts in Mayo, 566 U.S. at 79, 101 USPQ2d at 1968 and OIP Techs., Inc, v, Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015). Also, the additional elements of computer readable storage media include storing and retrieving information, such as computer program instructions in memory. Storing and retrieving information in memory were identified by the courts as well-understood, routine and conventional in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93. The use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more as identified by the courts in Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). As such, as currently recited, the claims do not appear to recite an improvement to technology or apply or use the recited judicial exception in some other meaningful way.
At this point in examination it is not yet the case that any of the Step 2A, 2nd prong considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of 1. an improvement, 2. treatment, 3. a particular machine or 4. a transformation is clear in the record.
For example, regarding the first consideration at MPEP 2106.04(d)(1), the record does not yet clearly disclose an explanation of improvement over the previous state of the technology field. An explanation of improvement requires detailed explanation applicable to all embodiments reasonably within the claim scope. In particular, such an explanation of improvement over the previous state of technology may include: identification of the technology field, the particular improvement, as particular as possible identification of any asserted improvements, explanation of a clear difference from the technology field, explanation that reasonably all embodiments within the claim scope result in the asserted improvement, and an extension of the explanation as far as possible to include the result of an identified practical application. The claims do not yet clearly result in such an improvement. See MPEP 2106.04(d) and (d)(1).
[Step 2A, 2nd prong: claims 1, 4-5, 7, 10-12, 15-17 and 21-22: NO]
Step 2B: Do the claims recite a non-conventional arrangement of additional elements (i.e. elements in addition to any identified JE) (MPEP 2106.05)?
All elements of claims 1, 4-5, 7, 10-12, 15-17 and 21-22 are part of one or more identified JEs (as described above), except for elements identified here as conventional elements in addition to the above JEs:
Elements of the following claims are additional elements but nonetheless are conventional elements of a laboratory or computing environment, conventional data gathering elements or conventional post-processing elements:
claim 1: the recited "a computer-implemented method…(a) performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine; (b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve…calibrated signal value is obtained…" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 5: the recited "…RT-PCR generates signals..." step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 10: the recited "amplification curve comprises a plurality of amplification curves obtained from the plurality of RT-PCRs" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 14: the recited "...representative standard amplification curve is provided" step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 21: the recited "A non-transitory computer readable storage medium containing instructions to configure a processor to perform...," "(a) receiving an amplification curve, wherein the amplification curve is obtained by performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine;(b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve" and "... (c) processing, by a processor operatively connected to the RT-PCR machine...calibrated signal value is obtained…detecting, by the processor…"step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
claim 22: the recited "(a) a computer processor and (b) the computer readable storage medium of claim 21 coupled to the computer processor." step/element, as evidenced by MPEP 2106.05(g), e.g. "insignificant extra solution activity" since the recitation is a conventional element of a laboratory and/or computing environment, conventional data gathering/input elements, and/or conventional post-processing or output elements.
Claims 4, 7 and 15-16 do not recite additional elements.
Claims 4, 7 and 15-16 provide information on what the data represents and do not change the character of the data obtaining step beyond mere data gathering activity.
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g)). Furthermore, limitations that equate to mere data gathering and outputting via generic computer components, such as receiving data at a computer or outputting data, amount to insignificant extra-solution activity as set forth by the courts in Mayo, 566 U.S. at 79, 101 USPQ2d at 1968 and OIP Techs., Inc, v, Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015). Also, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more as identified by the courts in Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). Additionally, RT-PCR processes, RT-PCR machines and obtaining amplification curves are well understood and conventional activity in the field as discussed by Wong (published 2005, cited on the 08/21/2024 “Notice of References Cited” form 892). Wong teaches "Real-time PCR has become one of the most widely used methods of gene quantitation because it has a large dynamic range, boasts tremendous sensitivity, can be highly sequence-specific, has little to no post-amplification processing, and is amenable to increasing sample throughput" (Abstract) and PCR amplification curve is discussed in Figure 2, page 78.
[Step 2B: claims 1, 4-5, 7, 10-12, 15-17 and 21-22: NO]
Summary and conclusion regarding claims 1, 4-5, 7, 10-12, 15-17 and 21-22
Summing up the above 101 JE analysis of claims 1, 4-5, 7, 10-12, 15-17 and 21-22, each viewed as a whole and considering all elements individually and in combination, no claim recites limitations that transform the claim, finally interpreted as directed to the above-identified JE(s), into patent eligible subject matter.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional element in the claims has been addressed, alone and in combination, to determine whether the additional elements integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. Individually, the limitations of the claims and the claims as a whole have been found to be patent ineligible under 35 U.S.C. 101.
Response to 35 USC § 101 Arguments (Remarks 04/20/2026, pages 12-14)
Applicant amended claims 1 and 21-22.
Applicant argues that under Step 2A, Prong Two claims 1 and 21 integrate the alleged judicial exception into a practical application. Applicant states that claims 1 and 21 introduce a signal-level calibration technique that operates directly on amplification curve data, rather than on hardware components by applying a transformation algorithm to transform an amplification curve into a calibrated amplification curve. Applicant states that the claims provide technical improvements of reduced inter-instrument signal variation, reduced intra-instrument signal variation, improved robustness against optical component aging and drift, and enhanced reproducibility of amplification curves without hardware adjustment. Applicant further states that these improvements directly affect the technical operation and output accuracy of PCR detection systems and not merely the downstream data interpretation.
In response, Applicant’s arguments are not persuasive because any improved accuracy is due to the recited abstract idea of applying a transformation algorithm to transform an amplification curve into a calibrated amplification curve. Applying a transformation algorithm to transform an amplification curve into a calibrated amplification curve, as indicated above, is the abstract idea of both mental processes and mathematical concepts and formula. The claimed subject matter does not provide an improvement in the operation of a RT-PCR machine or a computer. Instead, any improvement is due to an improved abstract idea. An improvement directed to an improvement to the JE is not sufficient to provide for patent eligibility. For the judicial exceptions (JEs) to be integrated into a practical application, the additional elements have to apply, rely on or use the JE in way that imposes a meaningful limit on the claims to provide an improvement. As stated in MPEP 2106.05(a), the judicial exception alone cannot provide the technical improvement. The improvement can be provided by one or more additional elements as seen in Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)) in subsection II. In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception as seen in Finjan, Inc. v. Blue Coat Sys., Inc., 879 F.3d 1299, 1303-04, 125 USPQ2d 1282, 1285-87 (Fed. Cir. 2018)).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 4-5, 7, 10-12, 14, 16-17 and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong ("Real-time PCR for mRNA quantitation." Biotechniques 39.1 (2005): 75-85, published 2005; cited on the 08/21/2024 “Notice of References Cited” form 892) in view of Orpana ( US 2012/0101740 A1; published Apr. 26, 2012, cited on the attached “Notice of References Cited” form 892).
Regarding independent claim 1, Wong teaches the claim limitation of (a) performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine with Figure 1 (page 76). Figure 1 depicts steps performed when measuring gene expression using real-time PCR. RNA is first isolated and characterized for quantity and integrity. If performing a one-step reaction, RNA is used as a template for the real-time PCR assay, and reverse transcription occurs during the assay. During a two-step reaction, cDNA is first synthesized and then used as a PCR template. The steps performed on the real-time PCR machine are shown in blue, the time during which raw fluorescence data are collected, adjusted, and manipulated to generate the output data used for analysis. For normalizing results with multiple housekeeping genes, a normalization factor must be calculated for each individual sample. Dividing the fluorescent data by its normalization factor produces the normalized data, which is followed by statistical analysis (Figure 1 caption).
Wong teaches the claim limitation of (b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve, wherein the amplification curve comprises cycles and signal values at the cycles with “Absolute quantitation uses serially diluted standards of known concentrations to generate a standard curve. The standard curve produces a linear relationship between Ct and initial amounts of total RNA or cDNA, allowing the determination of the concentration of unknowns based on their Ct values. This method assumes all standards and samples have approximately equal amplification efficiencies. In addition, the concentration of serial dilutions should encompass the levels in the experimental samples and stay within the range of accurately quantifiable and detectable levels specific for both the real-time PCR machine and assay.” (page 76, col. 3, para. 2).
Wong teaches wherein the calibrated amplification curve comprises cycles and calibrated signal values at the cycles, wherein the calibrated signal value is obtained by dividing the signal value at each of the cycles in the amplification curve by a background-representing signal at a reference cycle selected within a background region of the amplification curve with “Rn is the intensity of fluorescent emission of the reporter dye divided by the intensity of fluorescent emission of the passive dye (a reference dye incorporated into the PCR master mix to control for differences in master mix volume)” (Figure 2 caption, page 78) and “During the linear ground phase (usually the first 10–15 cycles), PCR is just beginning, and fluorescence emission at each cycle has not yet risen above background. Baseline fluorescence is calculated at this time. At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually 10 times the standard deviation of the baseline) than background levels.” (page 75, col. 3, para. 2).
Wong teaches (d) detecting, by the processor, the target analyte in a sample qualitatively or quantitatively using the calibrated amplification curve with “∆Rn is calculated as the difference in Rn values of a sample and either no template control or background, and thus represents the magnitude of signal generated during PCR.” (Figure 2 caption, page 78).
Wong teaches using software to generate a PCR amplification curve in Figure 2 (Figure 2 caption, page 78). It is obvious to one of ordinary skill in the art that a computer with a processor is used to run the software program.
Wong does not explicitly teach the claim limitation of (c) processing, by a processor operatively connected to the RT-PCR machine, the amplification curve by applying a transformation algorithm to generate a calibrated amplification curve in claim 1. However, this limitation is taught by Orpana as discussed below.
Orpana teaches (c) processing, by a processor operatively connected to the RT-PCR machine with “The present method described above is implemented in a processor, such as a processor in a stand-alone computer, a network attached computer or a data acquisition device such as a real-time PCR machine” (para. [0247]).
Orpana teaches applying a transformation algorithm to generate a calibrated amplification curve with “A Logit-Log transformation of the obtained data is performed and a calibration curve is generated.” ([0026]).
It would have been prima facia obvious to combine the teachings of Wong and Orpana to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Wong to include a computer and processor as taught by Orpana for the purpose of processing data. A person of ordinary skill in the art would have also been motivated to modify the method of Wong to include applying a transformation algorithm to generate a calibrated amplification curve as taught by Orpana to linearizes the calibration curve and thus significantly increases the dynamic range of the assay (para. [0026]). Furthermore, there would have been a reasonable expectation of success, since both Wong and Orpana teach methods that pertain to RT-PCR.
Regarding claim 4, Wong teaches the recited the amplification curve of the target analyte has information indicating the presence or absence of the target analyte in the sample at least with "At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually10 times the standard deviation of the baseline) than background levels. The cycle at which this occurs is known as Ct in ABI Prism® literature (Applied Biosystems, Foster City, CA, USA) or crossing point (CP) in LightCycler® literature (Roche Applied Science, Indianapolis, IN, USA) (2,10). This value is representative of the starting copy number in the original template and is used to calculate experimental results (2). During the log-linear phase, PCR reaches its optimal amplification period with the PCR product doubling after every cycle in ideal reaction conditions" (Page 75, Col. 3, Para. 2).
Regarding claim 5, Wong teaches the recited the RT-PCR generates signals in a dependent manner on the presence of the target analyte in the sample at least with "At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually10 times the standard deviation of the baseline) than background levels. The cycle at which this occurs is known as Ct in ABI Prism® literature (Applied Biosystems, Foster City, CA, USA) or crossing point (CP) in LightCycler®literature (Roche Applied Science, Indianapolis, IN, USA) (2,10). This value is representative of the starting copy number in the original template and is used to calculate experimental results (2). During the log-linear phase, PCR reaches its optimal amplification period with the PCR product doubling after every cycle in ideal reaction conditions" (Page 75, Col. 3, Para. 2).
Regarding claim 7, Wong teaches the recited the target analyte is a target nucleic acid molecule at least with "...the greater the quantity of target DNA in the starting material, the faster a significant increase in fluorescent signal will appear..." (Page 75, Col. 1, Para. 1).
Regarding claim 10, Wong teaches the recited the RT-PCR comprises a plurality of RT-PCRs for the same-typed target analyte performed in different reaction vessels; wherein the amplification curve comprises a plurality of amplification curves obtained from the plurality of RT-PCRs with "During the validation of microarray results, which tends to have only a few samples and several target genes, it is reasonable to use a DNA binding dye" (Page 83, Col. 3, Para. 2) and with “Intra-assay variation quantifies the amount of error seen within a single assay when the same template is run multiple times on the same plate with the same reagents. Intra-assay variation can be calculated for every single sample of every reaction if the real-time PCR experiments are performed in triplicate, with a pooled variance for all sets of PCR triplicates representing statistical power (41).” (page 82, col. 2, para. 3).
Regarding claim 11, Wong teaches the recited the reference cycle is selected from a reference cycle group of each amplification curve, wherein the reference cycle group of each amplification curve is provided in the same manner to each other at least with "During the linear ground phase (usually the first 10–15 cycles), PCR is just beginning, and fluorescence emission at each cycle has not yet risen above background. Baseline fluorescence is calculated at this time. At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually10 times the standard deviation of the baseline) than background levels. The cycle at which this occurs is known as Ct in ABI Prism® literature (Applied Biosystems, Foster City, CA, USA) or crossing point (CP) in LightCycler® literature (Roche Applied Science, Indianapolis, IN, USA) (2,10). This value is representative of the starting copy number in the original template and is used to calculate experimental results (2). During the log-linear phase, PCR reaches its optimal amplification period with the PCR product doubling after every cycle in ideal reaction conditions" (Page 75, Col. 3, Para. 2).
Regarding claim 12, Wong teaches the recited an identical reference cycle is provided for calibrating each amplification curve of the plurality of amplification curves at least with "During the linear ground phase (usually the first 10–15 cycles), PCR is just beginning, and fluorescence emission at each cycle has not yet risen above background. Baseline fluorescence is calculated at this time. At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually10 times the standard deviation of the baseline) than background levels. The cycle at which this occurs is known as Ct in ABI Prism® literature (Applied Biosystems, Foster City, CA, USA) or crossing point (CP) in LightCycler® literature (Roche Applied Science, Indianapolis, IN, USA) (2,10). This value is representative of the starting copy number in the original template and is used to calculate experimental results (2). During the log-linear phase, PCR reaches its optimal amplification period with the PCR product doubling after every cycle in ideal reaction conditions" (Page 75, Col. 3, Para. 2).
Regarding claim 16, Wong teaches the recited the amplification curve of the step (a) is a modified amplification curve at least with Figure 2 (Page 78). Figure 2 depicts Phases of the PCR amplification curve. The PCR amplification curve charts the accumulation of fluorescent emission at each reaction cycle. The curve can be broken into four different phases: the linear ground, early exponential, log-linear, and plateau phases. Data gathered from these phases are important for calculating background signal, cycle threshold (Ct), and amplification efficiency. Rn is the intensity of fluorescent emission of the reporter dye divided by the intensity of fluorescent emission of the passive dye (a reference dye incorporated into the PCR master mix to control for differences in master mix volume). ∆Rn is calculated as the difference in Rn values of a sample and either no template control or background, and thus represents the magnitude of signal generated during PCR.
Regarding claim 17, Wong teaches the recited wherein the amplification curve of the step (a) is a amplification curve of which a blank signal value is removed at least with Figure 2 (Page 78). Figure 2 depicts Phases of the PCR amplification curve. The PCR amplification curve charts the accumulation of fluorescent emission at each reaction cycle. The curve can be broken into four different phases: the linear ground, early exponential, log-linear, and plateau phases. Data gathered from these phases are important for calculating background signal, cycle threshold (Ct), and amplification efficiency. Rn is the intensity of fluorescent emission of the reporter dye divided by the intensity of fluorescent emission of the passive dye (a reference dye incorporated into the PCR master mix to control for differences in master mix volume). ∆Rn is calculated as the difference in Rn values of a sample and either no template control or background, and thus represents the magnitude of signal generated during PCR.
Regarding independent claim 21, Wong teaches the claim limitation of (a) receiving an amplification curve, wherein the amplification curve is obtained by performing a real-time polymerase chain reaction (RT-PCR) for the target analyte using an RT-PCR machine with Figure 1 (page 76). Figure 1 depicts steps performed when measuring gene expression using real-time PCR. RNA is first isolated and characterized for quantity and integrity. If performing a one-step reaction, RNA is used as a template for the real-time PCR assay, and reverse transcription occurs during the assay. During a two-step reaction, cDNA is first synthesized and then used as a PCR template. The steps performed on the real-time PCR machine are shown in blue, the time during which raw fluorescence data are collected, adjusted, and manipulated to generate the output data used for analysis. For normalizing results with multiple housekeeping genes, a normalization factor must be calculated for each individual sample. Dividing the fluorescent data by its normalization factor produces the normalized data, which is followed by statistical analysis (Figure 1 caption).
Wong teaches the claim limitation of (b) detecting, at each cycle, a signal generated from the RT-PCR by the RT- PCR machine to obtain an amplification curve, wherein the amplification curve comprises cycles and signal values at the cycles with “Absolute quantitation uses serially diluted standards of known concentrations to generate a standard curve. The standard curve produces a linear relationship between Ct and initial amounts of total RNA or cDNA, allowing the determination of the concentration of unknowns based on their Ct values. This method assumes all standards and samples have approximately equal amplification efficiencies. In addition, the concentration of serial dilutions should encompass the levels in the experimental samples and stay within the range of accurately quantifiable and detectable levels specific for both the real-time PCR machine and assay.” (page 76, col. 3, para. 2).
Wong teaches wherein the calibrated amplification curve comprises cycles and calibrated signal values at the cycles, wherein the calibrated signal value is obtained by dividing the signal value at each of the cycles in the amplification curve by a background-representing signal at a reference cycle selected within a background region of the amplification curve with “Rn is the intensity of fluorescent emission of the reporter dye divided by the intensity of fluorescent emission of the passive dye (a reference dye incorporated into the PCR master mix to control for differences in master mix volume)” (Figure 2 caption, page 78) and “During the linear ground phase (usually the first 10–15 cycles), PCR is just beginning, and fluorescence emission at each cycle has not yet risen above background. Baseline fluorescence is calculated at this time. At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually 10 times the standard deviation of the baseline) than background levels.” (page 75, col. 3, para. 2).
Wong teaches (d) detecting, by the processor, the target analyte in a sample qualitatively or quantitatively using the calibrated amplification curve with “∆Rn is calculated as the difference in Rn values of a sample and either no template control or background and thus represents the magnitude of signal generated during PCR.” (Figure 2 caption, page 78).
Wong teaches using software to generate a PCR amplification curve in Figure 2 (Figure 2 caption, page 78). It is obvious to one of ordinary skill in the art that a computer with a processor is used to run the software program.
Wong does not explicitly teach the claim limitation of non-transitory computer readable storage medium, (c) processing, by a processor operatively connected to the RT-PCR machine, the amplification curve by applying a transformation algorithm to generate a calibrated amplification curve in independent claim 21 and a computer processor and the computer readable storage medium in claim 22. However, this limitation is taught by Orpana as discussed below.
Orpana teaches (c) processing, by a processor operatively connected to the RT-PCR machine with “The present method described above is implemented in a processor, such as a processor in a stand-alone computer, a network attached computer or a data acquisition device such as a real-time PCR machine” (para. [0247]).
Orpana teaches applying a transformation algorithm to generate a calibrated amplification curve with “A Logit-Log transformation of the obtained data is performed and a calibration curve is generated.” ([0026]).
Oparna teaches non-transitory computer readable storage medium in with “It is further object of this invention to provide a computer program to be stored on a computer readable storage medium to configure a processor to perform a method for calibrating a data set of a target analyte in a sample.” (para. [0011]).
Regarding claim 22, Oparna teaches a computer processor and the computer readable storage medium with “It is further object of this invention to provide a computer program to be stored on a computer readable storage medium to configure a processor to perform a method for calibrating a data set of a target analyte in a sample.” (para. [0011]).
It would have been prima facia obvious to combine the teachings of Wong and Orpana to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Wong to include a non-transitory computer readable storage medium and processor as taught by Orpana for the purpose of processing and storing data. A person of ordinary skill in the art would have also been motivated to modify the method of Wong to include applying a transformation algorithm to generate a calibrated amplification curve as taught by Orpana to linearizes the calibration curve and thus significantly increases the dynamic range of the assay (para. [0026]). Furthermore, there would have been a reasonable expectation of success, since both Wong and Orpana teach methods that pertain to RT-PCR.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable Wong ("Real-time PCR for mRNA quantitation." Biotechniques 39.1 (2005): 75-85, published 2005; cited on the 08/21/2024 “Notice of References Cited” form 892) as applied to claims 1, 4-5, 7, 10-12, 16-17 and 21-22 above, in view of Orpana (US 2012/0101740 A1; published Apr. 26, 2012, cited on the attached “Notice of References Cited” form 892) and Gunstream 2011 (U.S. Patent No US 8,084.260 B2, published Dec. 27, 2011; cited on the 02/24/2024 “Notice of References Cited” form 892).
Wong and Orpana are applied to claims 1, 4-5, 7, 10-12, 16-17 and 21-22 as discussed above.
Wong does not teach wherein the plurality of the RT-PCRs is performed on different instruments from each other of claim 15. However, these limitations were known in the art at the time of the effective filing date of the invention, as taught by Gunstream 2011.
Regarding claim 15, Gunstream 2011 teaches the recited plurality of the RT-PCRs is performed on different instruments from each other at least with Gunstream’s claims 11, 12, and 13 (Column 16, Line 19).
Gunstream’s Claim 11 of the reference discusses a method of calibrating a spectral detector instrument position specifically comprising: receiving a plate comprising a plurality of wells, each at a different respective well position, and containing one or more potential targets and a plurality of spectrally distinguishable species in each well of the plate; exposing each well in the plate to an excitation source that emits light and causes one or more of the plurality of spectrally distinguishable species to fluoresce in correlation to the presence of the one or more of the one or more potential targets; measuring the initial signal values received from the plurality of spectrally distinguishable species at each of the different respective well positions; and adjusting the respective initially measured signal values using respective calibration factors for each well position and each of the spectrally distinguishable species, each of the calibration factors being derived from a calibration plate having predetermined relative concentrations of each of the plurality of spectrally distinguishable species, wherein the respective calibration factors compensate for respective differentials between a respective measured signal response in the calibration plate compared with a predetermined signal response for each of the plurality of spectrally distinguishable species, and the calibration factors generated for each well compensate for variations in spectral responses due to many different angles of entry of the light into the different wells of the plurality and wherein a predetermined concentration of one or more probes includes a passive reference and the concentration of each probe is determined with respect to the passive reference.
While claim 12 of the reference discusses the method of reference claim 11 further comprising: directly using the adjusted respective initially measured signal values collected from multiple instruments in an experiment and reference claim 13 discusses the method of reference claim 12, wherein the respective initially measured signal values are collected over time from each of the multiple instruments.
Rationale for combining
It would have been prima facia obvious to combine the teachings of Wong, Orpana and Gunstream 2011 to achieve the claimed invention. Gunstream 2011’s method for the creation of calibration factors are not only useful to compensate for differences between several instruments or the same instrument over time but also for the spectral variation occurring from well-to well (Column 4, line 7). Gunstream 2011 also teaches that the calibration factor can be applied in real-time to correct the signal data being detected (Column 4, line 14). Thus, Gunstream 2011’s method allows for an accurate representation of the spectral response of the underlying species being measured in different well locations on a tray and across multiple instruments (Column 6, line 53). Therefore, a person of ordinary skill in the art would have been motivated to modify the method of Wong and Orpana by applying the calibration factors on RT-PCR performed on different RT-PCR instruments as taught by Gunstream 2011 to accurately compensate for differences between instruments. Furthermore, there would have been a reasonable expectation of success, since both Wong, Orpana and Gunstream 2011 teaches methods that pertain to spectral calibration.
Response to 35 USC §103 Arguments, 04/20/2026 (Pages 12-14 of Remarks)
Applicant amended claims 1 and 21-22.
Applicant argues that Wong, Mason and Gunstream fail to describe "the calibrated amplification curve" of claim 1. Applicant states that the signal value from a calibrator as described in Wong is not obtained from an amplification curve for a target analyte because the calibrator is an external standard or a reference sample. Applicant further states that Wong fails to describe the use of a background-representing signal value as an analyte-insusceptible signal value. Applicant also states that Mason and Gunstream fail to remedy the deficiencies of Wong.
In response, Applicants remarks are not persuasive. As discussed in the 35 USC 103 rejection section above, Wong teaches a calibrated amplification curve and use of a background-representing signal value as an analyte-insusceptible signal value. with “During the linear ground phase (usually the first 10–15 cycles), PCR is just beginning, and fluorescence emission at each cycle has not yet risen above background. Baseline fluorescence is calculated at this time. At the early exponential phase, the amount of fluorescence has reached a threshold where it is significantly higher (usually 10 times the standard deviation of the baseline) than background levels.” (page 75, col. 3, para. 2) and Figure 2 (page 78).
Conclusion
No claims are allowed.
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.
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/K.K./Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
