DETAILED ACTION
Applicant’s response, filed 20 May 2025, has 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.
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 .
Claim Status
Claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 are pending and examined herein.
Claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 are rejected.
Priority
Claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 are granted the claim to the benefit of priority to U.S. Provisional applications 62/872439 and 62/855261 filed 10 July 2019 and 31 May 2019 respectively. Thus, the effective filling date of claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 is 31 May 2019.
Drawings
The objection to the drawings in Office action mailed 05 February 2025 is withdrawn in view of the amendment received 20 May 2025.
The drawings received 20 May 2025 are objected to because figures 3 and 3 continued should be labeled with the same number followed by a capital letter (i.e. 3A and 3B). The standards for drawings 37 C.F.R. 1.84(u) states that “partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter” (see MPEP 608.02(V)). Appropriate correction is required.
Specification
The objection to the disclosure in Office action mailed 05 February 2025 is withdrawn in view of the amendment received 20 May 2025.
Claim Objections
The objection to claim 56 in Office action mailed 05 February 2025 is withdrawn in view of the amendment received 20 May 2025.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112/b of claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 in Office action mailed 05 February 2025 for reciting “at least about 90%” is withdrawn in view of the amendment of “at least 90%” received 20 May 2025.
The rejection on the ground of 112/b of claims 26 and 27 in Office action mailed 05 February 2025 for reciting “at a depth of at least about 100x to 5,000x” and “at least a depth of at least about 100-1000x” respectively is withdrawn in view of the amendment of “about 100x to 5000x” and “about 100-1000x” received 20 May 2025.
The rejection on the ground of 112/b of claim 56 in Office action mailed 05 February 2025 for reciting “the method of claim 55” is withdrawn in view of the amendment of “the method of claim 54” received 20 May 2025.
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 4, 23-27, 29, 30, 32, 35, 37, 41, 42, 61, and 62 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.
Claims 4, 23, 24, 41,and 61 recites the limitation "said biological sample ". There is insufficient antecedent basis for this limitation in the claim. The indefiniteness arises because the claim does not make clear what “said biological sample” is. This rejection could be overcome by amendment of the phrase to “said urine sample”. Claims 25-27, 29, 30, 32, 35, and 37 are further rejected by virtue of their dependency on a rejected claim. For the sake of furthering examination, this limitation will be interpreted as being “said urine sample”.
Claim 42 recites the limitation "said report". There is insufficient antecedent basis for this limitation in the claim. The indefiniteness arises because the claim does not make clear what “said report” is. For the sake of furthering examination, claim 42 will be interpreted as presenting data on an electronic device.
Claim 62 recites “a database from a urine sample that is configured to store a dataset” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear what constitutes as “a database from a urine sample”. The specification does not provide a clear and precise definition of the limitation, nor would one skilled in the art recognize the metes and bounds of said limitation. For the sake of furthering examination, this limitation will be interpreted as a database that is configured to store a dataset obtained from a urine sample.
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, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61 fall under the statutory category of a process. Claims 62 and 65 fall under the statutory category of a machine.
(Step 2A prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
Independent claims 1, 62, and 65 recite a mental process of “using a trained algorithm comprising a logistic regression classifier to process said dataset to determine a quantitative measure…” and “based at least in part on said based at least in part on said quantitative measure, identifying or providing an indication of said urologic condition of said subject…”.
Independent claim 1, 62, and 65 recite a mathematical concept of “using a trained algorithm comprising a logistic regression classifier to process said dataset to determine a quantitative measure…”.
Dependent claim 5 recites a mental process of “identifying or providing an indication of said urologic condition of said subject to be with two or more of…”. Dependent claim 8 recites a mental process of “identifying or providing an indication of said urologic condition…”. Dependent claim 14 recites a mental process of “identifying or providing an indication of said urologic condition…”. Dependent claim 20 recites a mental process of “identifying or providing an indication of said urologic condition…”. Dependent claim 52 recites a mental process of “monitoring said urologic condition…”.
The claims recite a process of determining a quantitative measure from a dataset of a subject indicative of a status of a urological condition then using the quantitative measure to identify the status of the subject and then report the status from the analysis. The BRI of the method are mental steps of evaluating data to make a prediction of a status of a subject. The human mind is capable of evaluating data to make predictions. Further, the claims recite a mathematical concept because using a trained algorithm comprising a logistic regression classifier to process a dataset to determine a quantitative measure is a verbal equivalent of a mathematical calculation to be performed because determining a quantitative measure using input is a mathematical calculation. Further, the instant specification provides “The trained algorithm may be configured to accept a plurality of input variables and to produce one or more output variables based on the plurality of input variables” (instant specification [070]) which is a description of a mathematical function. Dependent claims 54 and 56 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept. Therefore, claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 recite an abstract idea.
(Step 2A prong 2)
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). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claim 1 of “processing a urine sample…”, the additional element in claim 2 of “wherein the urine sample is urine or a derivative thereof”, the additional element in claim 4 of limiting the processing to be PCR, the additional element in claim 23 of subjecting a sample to conditions to isolate, enrich, or extract nucleic acids and assay the nucleic acids, the additional element in claim 24 of sequencing the nucleic acids (claim 25 limits the sequencing to be massively parallel sequencing, claims 26 and 27 limits the sequencing depth of the sequencing, claim 29 limits the sequencing to comprise amplification, and claim 30 limits the amplification to comprise PCR), the additional element in claim 32 of using probes to selectively enrich nucleic acids (claim 35 limits the genomic loci that are being enriched), the additional element in claim 37 of “performing error suppression of said plurality of sequence reads by one or more of: (i) paired-end sequencing to correct sequencing errors…”, the additional element in claim 41 of the urine sample is processed without nucleic acid isolation, enrichment, or extraction, and the additional element in claim 61 which limits the sample to be a cell-free sample or a cell-associated sample do not integrate the judicial exceptions into a practical application because these steps are insignificant extra solution activity of data gathering. These additional elements constitute as insignificant extra solution activity because the additional elements interact with the judicial exceptions by providing data to be processed by the judicial exceptions.
The additional element in claims 42 of electronically outputting data and providing an output on a graphical user interface does not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of outputting data.
The additional elements in claims 50 and 51 of providing said subject with a therapeutic intervention and wherein said therapeutic intervention comprises surveillance and/or secondary clinical testing, surgery, chemotherapy, radiotherapy, immunotherapy, or a combination thereof, or modification of a current course of treatment does not integrate the judicial exception into a practical application because this step is not a particular treatment. This step is not a particular treatment because the subject is not required to have a urological condition (the algorithm determines the absence of a urological condition of a subject). Thus, it would not be appropriate to administer a subject with a therapy when there is no presence of a condition.
The additional elements in claims 62, and 65 of a generic computer and a non-transitory computer readable medium to perform judicial exceptions does not integrate the judicial exception into a practical application because this is applying the judicial exception to a generic computer environment without an improvement to computer technology.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 1, 2, 4, 5, 8, 14, 20, 23-27, 29, 30, 32, 35, 37, 41, 42, 50-52, 54, 56, 61, 62, and 65 are directed to the abstract idea.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claim 1 of processing a biological sample obtained or derived from said subject to generate a dataset is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019; previously cited) and page 508 of Dudley et al. (Cancer discovery 9.4 (2019): 500-509; previously cited).
The additional element in claim 2 of wherein the biological sample is urine or a derivative thereof is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and page 508 of Dudley et al. (Cancer discovery 9.4 (2019): 500-509).
The additional element in claim 4 of wherein processing said biological sample comprises polymerase chain reaction (PCR) is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on pages 112 and 113 of Mamanova et al. (Nat Methods 7, 111–118 (2010); previously cited) which reviews target enrichment strategies for next generation sequencing which includes PCR.
The additional elements in claim 23 of (i) subjecting said biological sample to conditions that are sufficient to isolate, enrich, or extract a plurality of nucleic acid molecules, and (ii) assaying said plurality of nucleic acid molecules to generate said dataset is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing.
The additional element in claim 24 of extracting a plurality of DNA molecules from said biological sample, and subjecting said plurality of DNA molecules to sequencing to generate a plurality of sequencing reads, wherein said dataset comprises said plurality of sequencing reads is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing.
The additional element in claim 25 of wherein said sequencing is massively parallel sequencing is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing.
The additional element in claims 26 and 27 of wherein said sequencing is performed at a depth of at least about 100X is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and page 115 figure 3 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which shows sequence depths over 100x.
The additional element in claim 29 of wherein said sequencing comprises nucleic acid amplification is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing.
The additional element in claim 30 of wherein said nucleic acid amplification comprises polymerase chain reaction (PCR) is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing which includes PCR.
The additional element in claim 32 of using probes configured to selectively enrich said plurality of nucleic acid molecules corresponding to a panel of one or more genomic loci is conventional as shown on pages 534 and 535 of Ward et al. (BJU Int, 124: 532-544 2019) and page 508 of Dudley et al. (Cancer discovery 9.4 (2019): 500-509) and on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing which includes hybrid capture.
The additional element in claim 35 of wherein said panel of said one or more genomic loci comprises at least 50,000 distinct genomic loci is conventional as shown on page 112 figure 1 of Mamanova et al. (Nat Methods 7, 111–118 (2010)) which reviews target enrichment strategies for next generation sequencing which includes hybrid capture that captures at least 100,000 exons which is interpreted as distinct genomic loci.
The additional elements in claim 37 of performing error suppression of said plurality of sequence reads by one or more of: (i) paired-end sequencing to correct sequencing errors is conventional as shown on Buermans et al. (Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1842.10 (2014): 1932-1941; previously cited) which reviews sequencing methods which includes paired-end sequencing.
The additional element in claim 41 of wherein said biological sample is processed without nucleic acid isolation, enrichment, or extraction is conventional as shown by Heitzer et al. (Clinical Chemistry, Volume 61, Issue 1, 1 January 2015, Pages 112–123; previously cited) which reviews cell-free DNA analysis in the context of cancer. Cell-free DNA analysis does not have a step of extraction because the DNA is already separated from the cell.
The additional element in claim 61 of wherein said biological sample is a cell-free sample or a cell-associated sample is conventional as shown on page 534 of Ward et al. (BJU Int, 124: 532-544 2019) and page 508 of Dudley et al. (Cancer discovery 9.4 (2019): 500-509).
The additional elements in claim 42 of electronically outputting data are conventional as shown by MPEP 2106.05(b) and 2106.05(d)(II).
The additional elements in claims 50 and 51 of providing said subject with a therapeutic intervention for said urologic condition and wherein said therapeutic intervention comprises surgery, chemotherapy, radiotherapy, immunotherapy, or a combination thereof Crabb et al. (British medical bulletin 128.1 (2018): 85-95; newly cited) which reviews the latest treatment options for bladder cancer which includes chemotherapy, immunotherapy, radiotherapy, and surgery.
The additional elements in claims 62 and 65 of a generic computer and a non-transitory computer readable medium are conventional as shown by MPEP 2106.05(b) and 2106.05(d)(II).
Thus, the additional elements do not amount to significantly more than the judicial exception.
Response to Arguments
Applicant's arguments filed 20 May 2025 have been fully considered but they are not persuasive.
Applicant argues that the present claims do not rely on generic computer environment for identifying or providing the indication of the urologic condition, and they do not rely on a conventional computable readable medium. That is at least because as detailed above the optimization steps (on the processing of the urine sample and library preparation, and on the algorithm itself) that have been developed yielded both improved processing of the sample and increased sequencing quality, as well as a more efficient and more accurate algorithm, overall providing an improved method of identifying or monitoring a urologic condition of a subject, based on the analysis of a urine sample, as compared to standard methods used in the technical field (Reply p. 15).
This argument has been fully considered but found to be not persuasive. It is noted that claim 1 is not limited to an improved processing and sequencing quality because the claim does not recite a specific set of active steps other than a broad limitation of processing a urine sample to generate a dataset (the step of sequencing is not required by the independent claim). Further, the determination of an improvement to technology has two steps, the identification of additional elements (the technology) and an evaluation of the interaction between the judicial exceptions with these additional to determine if the improvement is realized in the additional elements. The interaction between processing the urine sample and the judicial exception is only to provide data to be processed by the judicial exceptions. Therefore, the step of processing a urine sample is insignificant extra solution activity of data gathering. Also, using a trained algorithm and identifying (or monitoring) a urological condition in a subject fall under the judicial exception itself. Although an improvement may be in the abstract idea itself, the improvement is not realized in the additional element and therefore not integrated into a practical application (MPEP 2106.05(a)(II) “an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology”).
Applicants argues by relying on a trained algorithm that comprises a logistic regression classifier, the identification/monitoring of the urologic conditions relies on an unconventional computer environment, which provides significant extra solution activity which translate into the identification and monitoring of urologic conditions, from a urine sample, and with improved sensitivity, specificity, PPR and NPV as compared to what was conventionally obtained in the field. Applicants submit that the specific algorithm used in the claimed method, as applied to a dataset obtained from a urine sample is a clear practical application of any alleged recited judicial exception, as any alleged mathematical concept or mental step is applied, relied on
and used to allow the classifier to provide each of the one or more output values with one of a fixed number of possible values indicating a classification of the biological sample by the classifier (Reply p. 15-16).
This argument has been fully considered but found to be not persuasive. It is noted that using a trained algorithm and identifying/monitoring the urological condition are part of the judicial exceptions. The claims utilize a computer merely as a tool to perform the abstract ideas and do not change the functionality of a computer (i.e. the computer itself is not functioning in a different manner than generic computer implementing abstract ideas to process data). Further, although improved accuracy of sensitivity, specificity, PPR, and NPV are achieved these metrics fall within the abstract idea itself and can not be relied upon to show unconventionality (which is reserved for analyzing additional elements in the claim see MPEP 2106.05(d)). Further, the additional element (e.g., processing a urine sample) does not integrate the judicial exceptions into a practical application because the additional element only interacts with the judicial exceptions (e.g., using a trained algorithm and identifying/monitoring a urological condition) by providing the data to be processed by the judicial exceptions.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.).
Independent claim 1 is directed to (a) processing a urine sample obtained or derived from said subject to generate a dataset, wherein said dataset is indicative of a presence, absence, or relative assessment of said urologic condition of said subject,
Heijden et al. shows processing a urine sample from a subject to generate a dataset detect and monitor bladder cancer (Heijden et al. page 3 right col. and page 5 left col.).
(b) using a trained algorithm comprising a logistic regression classifier to process said dataset to determine a quantitative measure indicative of said presence, absence, or relative assessment of said urologic condition of said subject, wherein the trained algorithm is trained using a first set of independent training samples associated with presence of the urologic condition and a second set of independent training samples associated with absence of the urologic condition,
Heijden et al. shows building a three-gene methylation classifier model of multiple markers by logistic regression and using this classifier for the detection of bladder cancer from a urine sample (Heijden et al. page 5 right col.). The description of how the model is trained is not an active step of the method and using a model trained in this manner is not patentably distinct from a model that is used in the same manner to produce the same output. Thus, the trained algorithm is anticipated by the logistic regression classifier as shown by Heijden et al. because it is used in the same manner and produces the same output.
(c) based at least in part on said quantitative measure, identifying or providing an indication of said urologic condition of said subject with one or more of: a sensitivity of at least 90%, a specificity of at least 90%, a positive predictive value of at least 90%, and a negative predictive value of at least 90%, thereby identifying or monitoring a urologic condition of a subject.
Heijden et al. shows combining the three-gene methylation classifier and urine cytology results showed an improved diagnostic performance with a sensitivity (i.e. SN) of 96% and a negative predictive value (i.e. NPV) of 92% (Heijden et al. page 7 right col.).
Independent claim 62 is directed a computer system for identifying or monitoring a urologic condition of a subject comprising: a database from a urine sample that is configured to store a dataset indicative of a presence, absence, or relative assessment of said urologic condition of said subject, and one or more computer processors operatively coupled to said database,
Heijden et al. shows data obtained from urine samples that is indicative of the presence of bladder cancer is received into a computer environment and processed in a computer environment utilizing software (Heijden et al. page 5 left col. and page 5 right col.).
wherein the one or more computer processor to perform the steps of use a trained algorithm comprising a logistic regression classifier to process said dataset to determine a quantitative measure indicative of said presence, absence, or relative assessment of said urologic condition of said subject, wherein the trained algorithm is trained using a first set of independent training samples associated with presence of the urologic condition and a second set of independent training samples associated with absence of the urologic condition,
Heijden et al. shows building a three-gene methylation classifier model of multiple markers by logistic regression and using this classifier for the detection of bladder cancer from a urine sample (Heijden et al. page 5 right col.). Heijden et al. shows utilizing R-software and SPSS v23.0 for calculations which is software implemented on a computer system (Heijden et al. page 5 right col.). The description of how the model is trained is not an active step of the method and using a model trained in this manner is not patentably distinct from a model that is used in the same manner to produce the same output. Thus, the trained algorithm is anticipated by the logistic regression classifier as shown by Heijden et al. because it is used in the same manner and produces the same output.
(c) based at least in part on said quantitative measure, identifying or providing an indication of said urologic condition of said subject with one or more of: (i) a sensitivity of at least 90%, (ii) a specificity of at least 90%, (iii) a positive predictive value of at least 90%, and (iv) a negative predictive value of a least 90%.
Heijden et al. shows combining the three-gene methylation classifier and urine cytology results showed an improved diagnostic performance with a sensitivity (i.e. SN) of 96% and a negative predictive value (i.e. NPV) of 92% (Heijden et al. page 7 right col.).
Independent claim 65 is directed a non-transitory computer readable medium which causes a one or more computer processors to perform the steps of (a) obtaining a dataset from a urine sample from the subject indicative of a presence, absence, or relative assessment of said urologic condition
Heijden et al. shows data obtained from urine samples that is indicative of the presence of bladder cancer is received into a computer environment and processed in a computer environment utilizing software (Heijden et al. page 5 left col. and page 5 right col.).
(b) using a trained algorithm comprising a logistic regression classifier to process said dataset to determine a quantitative measure indicative of said presence, absence, or relative assessment of said urologic condition of said subject, wherein the trained algorithm is trained using a first set of independent training samples associated with presence of the urologic condition and a second set of independent training samples associated with absence of the urologic condition,
Heijden et al. shows building a three-gene methylation classifier model of multiple markers by logistic regression and using this classifier for the detection of bladder cancer from a urine sample (Heijden et al. page 5 right col.). Heijden et al. shows utilizing R-software and SPSS v23.0 for calculations which is software implemented on a computer system (Heijden et al. page 5 right col.). The description of how the model is trained is not an active step of the method and using a model trained in this manner is not patentably distinct from a model that is used in the same manner to produce the same output. Thus, the trained algorithm is anticipated by the logistic regression classifier as shown by Heijden et al. because it is used in the same manner and produces the same output.
(c) based at least in part on said quantitative measure, identifying or providing an indication of said urologic condition of said subject with one or more of: (i) a sensitivity of at least 90%, (ii) a specificity of at least 90%, (iii) a positive predictive value of at least 90%, and (iv) a negative predictive value of a least 90%
Heijden et al. shows combining the three-gene methylation classifier and urine cytology results showed an improved diagnostic performance with a sensitivity (i.e. SN) of 96% and a negative predictive value (i.e. NPV) of 92% (Heijden et al. page 7 right col.).
Claim 2 is directed to wherein said urine sample is urine or a derivative thereof.
Heijden et al. shows processing urine samples from patients to acquire urinary cell pellets (Heijden et al. page 3 right col.).
Claim 4 is directed to wherein processing said urine sample comprises polymerase chain reaction (PCR).
Heijden et al. shows processing the urine sample comprises performing PCR on the sample (Heijden et al. page 5 left col.).
Claim 5 is directed to wherein (c) comprises identifying or providing an indication of said urologic condition of said subject with two or more of: a sensitivity of at least 90%, a specificity of at least 90%, a positive predictive value of at least 90%, and a negative predictive value of at least 90%, thereby identifying or monitoring a urologic condition of a subject.
Heijden et al. shows combining the three-gene methylation classifier and urine cytology results showed an improved diagnostic performance with a sensitivity (i.e. SN) of 96% and a negative predictive value (i.e. NPV) of 92% (Heijden et al. page 7 right col.).
Claim 8 is directed to wherein (c) comprises identifying or providing an indication of said urologic condition of said subject with a sensitivity of at least 90%.
Heijden et al. shows combining the three-gene methylation classifier and urine cytology results showed an improved diagnostic performance with a sensitivity (i.e. SN) of 96% (Heijden et al. page 7 right col.).
Claim 14 is directed to wherein (c) comprises identifying or providing an indication of said urologic condition of said subject with a positive predictive value (PPV) of at least 90%.
Heijden et al. shows the positive predictive value in the training set of the methylation test + cytology reached 90% (Heijden et al. supplementary information Table S3).
Claim 23 is directed to subjecting said biological sample to conditions that are sufficient to isolate, enrich, or extract a plurality of nucleic acid molecules, and (ii) assaying said plurality of nucleic acid molecules to generate said dataset. Claim 24 is directed to further comprising extracting a plurality of DNA molecules from said biological sample, and subjecting said plurality of DNA molecules to sequencing to generate a plurality of sequencing reads, wherein said dataset comprises said plurality of sequencing reads. Claim 25 is directed to wherein said sequencing is massively parallel sequencing.
Heijden et al. shows extracting nucleic acids from a urine sample and assaying the nucleic acids through Pyrosequencing (i.e. a massively parallel sequencing assay) to generate a dataset (Heijden et al. page 3 right col. and page 5 left col.).
Claim 29 is directed to wherein said sequencing comprises nucleic acid amplification. Claim 30 is directed to wherein said nucleic acid amplification comprises polymerase chain reaction (PCR).
Heijden et al. shows performing a sequencing protocol which performs nucleic acid amplification by a polymerase chain reaction (Heijden et al. page 5 left col.).
Claim 32 is directed to using probes configured to selectively enrich said plurality of nucleic acid molecules corresponding to a panel of one or more genomic loci.
Heijden et al. shows using primers to amplify the regions of interest in specific genes (Heijden et al. page 5 left col.).
Claim 42 is directed to presenting data on an electronic device.
Heijden et al. shows utilizing several software applications for the analysis of the DNA methylation data which is software implemented on a computer system that presents information of an analysis (Heijden et al. page 5 right col.).
Claim 54 is directed to wherein said urological condition is selected from the group consisting of bladder cancer, kidney cancer, and prostate cancer.
Heijden et al. shows detecting bladder cancer (Heijden et al. page 5 right col.).
Claim 61 is directed to wherein the urine sample is a cell-free sample or a cell-associated sample.
Heijden et al. shows the urine sample is a cell-associated sample (Heijden et al. page 3 right col.).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above in view of Jiao et al. (Quant Biol 4, 320–330 (2016); newly cited).
Claim 20 is directed to wherein (c) comprises identifying or providing an indication of said urologic condition of said subject with an Area Under Curve (AUC) of at least 90%.
Heijden et al. identifying or providing an indication of said urologic condition of said subject with an Area Under Curve (AUC) of at least 0.90.
Jiao et al. shows the measure of AUC as a measure the performance of the predictor (Jiao et al. page 327 left col.). Jiao et al. further shows these performance metrics are used to determine how well the model performs a task (Jiao et al. page 324 left col.). It would have been obvious to one of ordinary skill in the art to routinely optimize models through training practices which result in predictions with the highest level of AUC because this would indicate better model performance for the given task.
It would have been further obvious to one of ordinary skill in the art before the effective filling date to routinely optimize the AUC of the model in Heijden et al. which shows an AUC of 0.86 through training processes because the measure of AUC is used to measure the performance a predictor (Jiao et al. page 327 left col.). One would have a reasonable expectation of success because the trained model in Heijden may be routinely optimized using training processes to provide an increase in the AUC of the model indicating a high performance in model prediction.
Claim 26, 27 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above, and further in view of Masser et al. (Epigenetics & Chromatin 6, 33 (2013); newly cited).
Heijden et al. does not show wherein said sequencing is performed at a depth of about 100x to 5000x, wherein said sequencing is performed at a depth of about 100x-1000x or performing error suppression of said plurality of sequence reads by one or more of: (i) paired-end sequencing to correct sequencing errors
Claim 26 is directed to wherein said sequencing is performed at a depth of about 100x to 5000x. Claim 27 is directed to wherein said sequencing is performed at a depth of about 100x-1000x.
Like Heijden et al., Masser et al. shows performing sequencing to analyze DNA methylation patterns. Masser et al. shows achieving 1000x sequencing depth is sufficient for accurate methylation quantitation and a confidence interval does not significantly improve at depths greater than 1000x (Masser et al. page 7 left col.).
Claim 37 is directed to further comprising performing error suppression of said plurality of sequence reads by one or more of: (i) paired-end sequencing to correct sequencing errors
Like Heijden et al., Masser et al. shows performing sequencing to analyze DNA methylation patterns. Masser et al. shows performing pair-end sequencing as a quality assurance measure (Masser et al. page 9 right col. and page 10 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the sequencing method of Heijden et al. with the paired-end sequencing and sufficient sequencing depth shown in Masser et al. because this would give a sequencing method that increases quality assurance of the sequencing data and have a sufficient depth for accurate methylation quantitation (Masser et al. page 7 left col., page 9 right col., and page 10 left col.). One would have a reasonable expectation of success because the sequencing of Heijden et al. and Masser et al. is used to analyze DNA methylation.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above, in view of Lee et al. (Cancer letters 340.2 (2013): 171-178; newly cited).
Claim 35 is direct to wherein said panel of said one or more genomic loci comprises at least 50,000 distinct genomic loci.
Heijden et al. does not show wherein said panel of said one or more genomic loci comprises at least 50,000 distinct genomic loci.
Like Heijden et al., Lee et al. shows an enrichment technique for bisulfite sequencing for methylation analysis. Lee et al. shows hybrid capture for the analysis of 51,551 targets (Lee et al. page 173 table 1 col 5).
It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the hybrid capture method of Ward et al. in view of Yuan et al. in view of Jiao et al. with hybrid capture method for capturing 51,551 targets of Lee et al. because this would give a method that gives the ability to capture a large number of targets of interest using a flexible probe design method (Lee et al. page 173 table 1 col. 5). One would have a reasonable expectation of success because Heijden et al. shows the use of targeted sequencing while Lee et al. shows the ability to target 51,551 regions for DNA methylation analysis.
Claims 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above, and further in view of Crabb et al. (British medical bulletin 128.1 (2018): 85-95; previously cited).
Claim 50 is directed to providing said subject with a therapeutic intervention. Claim 51 is directed to wherein said therapeutic intervention comprises (i) surveillance and/or secondary clinical testing, (ii) surgery, chemotherapy, radiotherapy, immunotherapy, or a combination thereof, or (iii) modification of a current course of treatment.
Heijden et al. does not show providing said subject with a therapeutic intervention or wherein said therapeutic intervention comprises (i) surveillance and/or secondary clinical testing, (ii) surgery, chemotherapy, radiotherapy, immunotherapy, or a combination thereof, or (iii) modification of a current course of treatment.
When combined with Heijden et al., Crabb et al. shows a treatment step to be performed after the classifying the subject to have bladder cancer. Crabb et al. shows treating bladder cancer in a subject using chemotherapy or immunotherapy (Crabb et al. page 90 right col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to combine reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have combined the method of using a classifier to predict bladder cancer in a subject of Heijden et al. with treating the subject with chemotherapy or immunotherapy because this would give a comprehensive method of diagnosing an individual and treating the individual with effective medication which is normally used in treatment (Crabb et al. page 90 right col.). One would have a reasonable expectation of success because the output prediction of a subject having cancer in of Heijden et al. can be combined with treating the subject with cancer.
Claims 41 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above, and further in view of Heitzer et al. (Clinical Chemistry, Volume 61, Issue 1, 1 January 2015, Pages 112–123; previously cited).
Claim 41 is directed to wherein said biological sample is processed without nucleic acid isolation, enrichment, or extraction. Claim 52 is directed to monitoring said urologic condition, wherein said monitoring comprises assessing said urologic condition of said subject at a plurality of time points, wherein said assessing is based at least on said identification or said indication of urologic condition determined in (c) at each of said plurality of time points.
Heijden et al. does not show wherein said biological sample is processed without nucleic acid isolation, enrichment, or extraction and monitoring comprises assessing said urologic condition of said subject at a plurality of time points, wherein said assessing is based at least on said identification or said indication of urologic condition determined in (c) at each of said plurality of time points.
Like Heijden et al., Heitzer et al. shows performing liquid biopsies and sequencing cell-free DNA in the context of cancer. Heitzer et al. shows liquid biopsy to monitor therapy responses and therapy which shows collecting data at multiple time points to assess the present condition and cell-free DNA analysis does not have a step of extraction because the DNA is already separated from the cell. (Heitzer et al. page 113 figure 1).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to combine reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have combined the method of detecting bladder cancer using biological samples of Heijden et al. with assessing the condition at different time points using cell-free DNA of Heitzer et al. because this would allow for a method that can detect therapy response and resistance which may lead to more informed therapeutic options during the course of the disease (Heitzer et al. page 113 figure 1). One would have a reasonable expectation of success because Heitzer et al. shows this assessment of a condition at different time points can be performed using cell-free DNA due to the non-invasive nature of the data collection and Heijden et al. DNA for the analysis.
Claim 56 is rejected under 35 U.S.C. 103 as being unpatentable over van der Heijden et al. (Clin Epigenet 10, 71 (2018); newly cited) (herein after Heijden et al.) as applied to claims 1, 2, 4, 5, 8, 14, 23-25, 29, 30, 32, 42, 54, 61, 62, and 65 above, and further in view of Hoque et al. (Journal of the National Cancer Institute 98.14 (2006): 996-1004; newly cited).
Claim 56 is directed to wherein determining a quantitative measure indicative of said presence, absence, or relative assessment of bladder cancer of said subject comprises determining quantitative measures of one or more bladder cancer-associated genomic loci selected from the group consisting of TP53, KDM6A, MLL2, ARID1A, PIK3CA, RHOA, CDKN2A, PPARG, ATM, PTEN, BEND3, and PLEKHS1.
Heijden et al. determining quantitative measures of one or more bladder cancer-associated genomic loci selected from the group consisting of TP53, KDM6A, MLL2, ARID1A, PIK3CA, RHOA, CDKN2A, PPARG, ATM, PTEN, BEND3, and PLEKHS1.
Like Heijden et al., Hoque et al. shows utilizing methylation patterns in urine DNA for bladder cancer detection. Hoque et al. shows the methylation pattern of CDKN2A is a diagnostic biomarker for bladder cancer (Hoque et al. page 996 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the genes used for detecting bladder cancer using methylation data of Heijden et al. by including the methylation pattern of CDKN2A as shown in Hoque et al. because CDKN2A is a diagnostic biomarker for bladder cancer which can be detected in a urine sample (Hoque et al. page 996 left col.). One would have a reasonable expectation of success because both Heijden et al. and Hoque et al. shows using methylation data from genes to detect bladder cancer from urine samples.
Response to Arguments
Applicant's arguments filed 20 May 2025 have been fully considered but they are not persuasive because the Applicant’s amendments necessitated a new grounds of rejection relying different prior art.
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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/J.E.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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