DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response
Applicant’s response, filed 03/16/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claims Status
Claims 1-24 were previously pending.
Claims 1-7, 10, and 20 are canceled.
Claims 25 and 26 are new.
Claims 8, 9, 11-19, and 21-26 are pending.
Claims 8, 9, 11-19, and 21-26 are examined.
Information Disclosure Statement
The Information Disclosure Statements filed 03/16/2026 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
It is noted that certain references lack appropriate page numbers as is required under 37 CFR 1.97. The Examiner has annotated the references herein. Applicant is kindly reminded to provide proper citations in compliance with 37 CFR 1.97 in all future submission to the office.
Withdrawn Objections/Rejections
The objection to the Specification is withdrawn in view of the amendments submitted
The objection to claims 3, 10, and 20 is moot because the claims are hereby canceled.
The rejection of claims 1, 3, 8, 10, 16, 18, and 20 is withdrawn in view of the amendments submitted and Applicant’s Arguments filed in this response pertaining to the recitation of “one or more CpG islands (CGIs) shown in Tables 1-4)
The rejection of claims 1-3, 5-10, 12-20, and 22-24 under 35 USC 103 over Mahajan et al. in view of Barany et al. is withdrawn in view of the amendments submitted.
The rejection of claims 4, 11, and 21 under 35 USC 103 over Mahajan et al. in view of Barany et al. and further in view of Charlton is withdrawn in view of the amendments submitted.
Claim Rejections - 35 USC § 112
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 8, 9, 11-19, and 21-26 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. This is a new grounds of rejection as necessitated by claim amendments.
With respect to claims 8 and 18, the claims recite the limitation of “performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject; performing quantitative PCR or next generation sequencing of nucleic acids”. The claims are indefinite because it is unclear if the PCR or next generation sequencing is performed on the nucleic acids of the additional sample, or on a different set of nucleic acids.
With further respect to claims 8 and 18, the claims recite the limitation of “analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of the additional sample”. The claims are indefinite because it is unclear if this is a step of analyzing the results determined in the previous step of performing quantitative PCR or sequence to determine methylation statuses, or is another step of determining methylation statuses, because the previous step does not specify which sample it is performed on, but this step recites “target nucleic acids of the additional sample”. It is not clear if this step is simply identifying the determined methylation statuses of only target nucleic acids due to the previous issues of indefiniteness.
The remaining claims are dependent upon independent claims 8 and 18 and do not remedy the issues of indefiniteness, and thus are also rejected for being indefinite.
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 8, 9, 11-19, and 21-26 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to an abstract idea of mental steps, mathematic concepts, or a natural law without significantly more. Any newly recited portion is necessitated by claim amendment.
The MPEP at MPEP 2106.03 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of
matter?
(2A)(1) Are the claims directed to a judicially recognized exception, i.e. a law of nature,
a natural phenomenon, or an abstract idea?
(2A)(2) If the claims are directed to a judicial exception under Prong One, then is the
judicial exception integrated into a practical application?
(2B) If the claims are directed to a judicial exception and do not integrate the judicial
exception, do the claims provide an inventive concept?
With respect to step (1): Yes, the claims are directed to methods.
With respect to step (2A)(1): The claims are direct to abstract ideas of mental processes and mathematical concepts.
“Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection” (MPEP 2106.04). Abstract ideas include mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (procedures for observing, evaluating, analyzing/judging and organizing information (MPEP 2106.04(a)(2)). Laws of nature or natural phenomena include naturally occurring principles/relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature (MPEP 2106(b)).
Mental processes recited in claim 8
obtaining a positive initial sample result in a subject initially identifies as having, or at risk for, a GI cancer, wherein the initial sample result was obtained using an initial cancer diagnostic test that analyzes an initial blood or stool sample obtained from the subject, the initial cancer diagnostic test selected from one of […] detection of ctDNA mutations and/or ctDNA fragment size
analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of the additional sample of the subject
Mathematic concepts recited in claim 8:
generating a machine-learned prediction using the analyzed methylation statuses of the plurality of genomic sites from target nucleic acids of the additional sample of the subject to determine a risk for GI cancer, thereby confirming or contradicting the positive initial sample result
Mental processes recited in claim 18:
screening high-risk subjects of a patient population as having, or at risk for, a GI cancer using initial samples obtained from the subject by performing an initial cancer diagnostic test, wherein the initial cancer diagnostic test analyzes an initial blood or stool sample obtained from each subject, the initial cancer diagnostic test selected from one of […] detection of ctDNA mutations and/or ctDNA fragments size
identifying one or more subjects at risk for cancer based on results from the initial cancer diagnostic test
analyzing methylation statuses of a plurality of genomic sites from target nucleic acids the additional sample of the subject
Mathematic concepts recited in claim 18:
generating a machine-learned prediction using the analyzed methylation statuses of the plurality of genomic sites from target nucleic acids of the additional samples of the subject to determine a risk for GI cancer thereby confirming or contradicting a positive initial cancer diagnostic test
Dependent claims 11-14, and 21-24 recite additional steps that either are directed to abstract ideas or further limit the judicial exceptions in independent claims 1, 8, and 19, and as such, are further directed to abstract ideas. Hence, the claims explicitly recite numerous elements that individually and in combination constitute abstract ideas. The relevant recitations are:
Claims 11, and 21: “deploying a machine learning model that analyzes methylation statuses for a plurality of CpG sites located in at least 500 CGIs”
Claims 12, and 22: “the classification of the initial sample detects false positive samples with at least 60% sensitivity”
Claims 13, and 23: “the classification of the initial sample detects false positive samples with at least 60% specificity”
Claims 14, and 24: “the classification of the initial sample detects false positive samples with at least 80% sensitivity at 90% specificity”
The abstract ideas in the claims are evaluated under Broadest Reasonable Interpretation (BRI) and determined herein to each cover mental processes and mathematic concepts because the claims recite no more than an analysis of genetic data to determine methylation status and further perform mental processes and mathematic concepts to classify a sample as a true positive or false positive.
With respect to step (2A)(2): The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone or in combination to determine if the judicial exception is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exception, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
Claim 8 recites the following additional elements that are not abstract ideas:
performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject
performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids
Claim 18 recites the following additional elements that are not abstract ideas:
performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject
performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites location in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids
The steps of performing bisulfite conversion and performing qPCR of sequencing are directed to steps of data gathering as they generate the data on which the judicial exceptions are performed. 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)).
Dependent claims 9, 10, 15-17, 19, 20, 25, and 26 are directed to elements of data gathering as they gather the data on which the judicial exceptions are performed. 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)).
None of these dependent claims recite additional elements, alone or in combination, which would integrate a judicial exception into a practical application.
Lastly, the claims have been evaluated with respect to step (2B): Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims lack a specific inventive concept. Under said analysis, Applicant is reminded that the judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP at 2106.05(d)(I), determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to claim 8 and 18: The additional elements of bisulfite conversion of nucleic acids obtained from an additional sample from the subject, and performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids. The prior art to Liu et al. (“Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA”, IDS reference) discloses commercially available kits for bisulfite conversion of cfDNA and standard hybridization capture conditions, followed by paired-end sequencing on Illumina NovaSeq (page 5). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claims 9, and 19: The additional element of a colonoscopy does not rise to the level of significantly more than the judicial exception. The prior art to Molloy et al. (10,526,642 B2, patented January 2020, cited in prior Office Action) discloses that localized cancer is usually diagnosed through colonoscopy (column 1, line 55). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claims 10, and 20: The additional elements of the initial cancer diagnostic test comprising one or more of COLOGUARD®(Exact Sciences), SHIELD™ (Guardant Health), Freenome Multiomic Blood Test (Freenome), Everylywell fecal immunohistochemical test (FIT), Pinnacle BiolabsFIT, iDNA HPV test, and imaware Prostate Cancer screening test do not rise to the level of significantly more than the judicial exception. The prior art to Barany et al. (US 2022/0243263 A1, published August 2022, cited in prior Office Action) discloses that the most common protein marker for colorectal cancer is based on detecting hemoglobin from blood in the stool and is known as the FOBT or FIT test (paragraph [0302]). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 15: The additional elements of the methylation status of the genomic sites are obtained by performing an assay, the assay comprises performing one or more of sequencing of target nucleic acids, hybrid capture, methylation-specific PCR, an assay that generates sequence information, and sequencing a clone library generated from a template immortalized library do not rise to the level of significantly more than the judicial exception. As referenced in the MPEP at 2106.05(d).II. with respect to Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546, analyzing DNA to provide sequence information or detect allelic variants is a well-understood, routine, and conventional activity. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 16: The additional elements of the assay comprises obtaining converted cfDNA, selectively amplifying target regions of the converted cfDNA, and sequencing amplicons comprising the amplified target regions to determine the methylation statuses of the plurality of genomic sites do not rise to the level of significantly more than the judicial exception. The prior art to Barany et al. discloses that tumor tumor-specific CpG methylations have been detected in the plasma from patients with a variety of solid tumors through various techniques involving bisulfite conversion of unmethylated cytosines (paragraph [0007]). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 17: The additional element of the converted cfDNA comprises bisulfite converted cfDNA does not rise to the level of significantly more than the judicial exception. The prior art to Charlton (US 2025/0270650 A1, effectively filed 12/12/2023, cited in prior Office Action) discloses that methods of deaminating cytosine are known in the art, including bisulfite conversion (paragraph [0048]). Furthermore, the prior art discloses several commercially available kits to perform the bisulfite conversion (paragraph [0049]). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claims 25 and 26: The additional element of the plurality of genomic sites comprise a plurality of CpG sites located in at least 1000 CGIs or portions of at least 1000 CGIs shown in Tables 1-4 does not rise to the level of significantly more than the judicial exception. As referenced in the MPEP at 2106.05(d).II. with respect to Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546, analyzing DNA to provide sequence information or detect allelic variants is a well-understood, routine, and conventional activity. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations 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 lacking.
Response to Arguments
Applicant states that “The claims as amended are not directed to natural phenomena, or abstract ideas, including mental steps or mathematical concepts. Rather, the amended claims are limited in a meaningful way by reciting a particular type of analysis (i.e., performing bisulfite conversion to generate bisulfite converted nucleic acids and selectively amplifying those nucleic acids) using a particular set of target regions (selected from Tables 1-4) that cannot be performed mentally or reduced to mere observation of natural correlations.”
It is respectfully submitted that this is not persuasive. Although the steps of performing bisulfite conversion and selectively amplifying are not abstract ideas, these steps do not change that the claims are directed to an abstract idea. The claims are directed to methods of analysis, and thus abstract ideas of mental processes and mathematical concepts. The claims are not directed to only being a method for performing bisulfite conversion and amplification. These steps function as data gathering for the judicial exceptions. 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)). Therefore, the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “The amended claims now recite additional elements that impose meaningful limits on any alleged judicial exception and integrate it into a practical application. Specifically, the claims recites: (1) ‘performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject’; and (2) ‘performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CPG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids.’ These steps are additional elements and are not directed to abstract ideas or mental processes as they cannot be performed in the human mind. […] Here, the additional elements should be found to integrate the alleged judicial into a practical application for achieving an improvement to other technology or technical field. Specifically, the improvement of the claimed invention can be found in the improved precision of a cancer test. […] First, the additional elements effect a transformation of a particular article to a different state or thing and are not mere data-gathering steps of field-of-use limitations. The claimed method transforms nucleic acids through bisulfite conversion into chemically modified nucleic acids. This transformed nucleic acid population is then subjected to quantitative PCR or next generation sequencing directed to specific CpG sites selected from Tables 1-4. Each transformation step produces a physically and informationally distinct product. Second, the additional elements apply or use the alleged judicial exception in a meaningful way beyond generally linking the exception to a particular technological environment. The claims do not merely observe a natural correlation between methylation and cancer; rather, they prescribe a specifical technical pathway (e.g., bisulfite conversion followed by target sequencing of defined CpG sites from Tables 1-4) to generate a machine-learned prediction that improves the precision of an initial cancer diagnostic test.”
It is respectfully submitted that this is not persuasive. The limitations of performing bisulfite conversion and selective amplification are directed to data gathering steps as these generate the data on which the judicial exceptions are performed. 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, these are not an improvement to the technology, as bisulfite conversion and amplification to determine methylation levels is already done in the art. The prior art to Barany et al. discloses that tumor tumor-specific CpG methylations have been detected in the plasma from patients with a variety of solid tumors through various techniques involving bisulfite conversion of unmethylated cytosines (paragraph [0007]). Therefore the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “claims 8 and 18 now recite the following additional elements : (1) ‘obtaining nucleic acids from an additional sample from the subject’; (2) ‘performing bisulfite conversion of the obtained nucleic acids’; and (3) ‘performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids.’ Even assuming, arguendo, that any individual element were considered convention in isolated, the ordered combination of these elements constitutes a non-conventional and non-generic arrangement that amounts to significantly more than any alleged judicial exception. Here, the claimed combination describes a specific, ordered sequence of physical and chemical transformations, including obtaining nucleic acids from an additional sample, chemically converting those nucleic acids via bisulfite treatment, and then subjecting the bisulfite-converted nucleic acids to quantitative PCR or next generation sequencing targeted to a defined set of CpG sites selected from Tables 1-4. This enables the generation of a machine-learned prediction that improved the precision of an initial cancer diagnostic test. This ordered combination is not a merge aggregation of routine steps; rather, it reflects a specific, multi-step technical methodology that yields ‘an improved performance metric comprising… that outperforms the cancer test 120 by itself.’”
It is respectfully submitted that this is not persuasive. The prior art to Liu et al. discloses commercially available kits for bisulfite conversion of cfDNA and standard hybridization capture conditions, followed by paired-end sequencing on Illumina NovaSeq (page 5). Furthermore, The prior art to Barany et al. discloses that tumor tumor-specific CpG methylations have been detected in the plasma from patients with a variety of solid tumors through various techniques involving bisulfite conversion of unmethylated cytosines (paragraph [0007]). Furthermore, the prior art to Charleston et al. discloses that methods of deaminating cytosine are known in the art, including bisulfite conversion (paragraph [0048]). Thus, the additional elements of claims 8 and 18 are routine and convention and do not rise to the level of significantly more than the judicial exceptions. Therefore, the rejection under 35 USC 101 is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 8, 9, 11-19, and 21-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-83 of copending Application No. 19/009,609. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the Specification of Application ‘609. Any newly recited portion is necessitated by claim amendments.
Instant Claims
Application ‘609
Claim
Limitation
Claim
Limitation
8
A method for improving precision of a cancer test, the method comprising: obtaining a positive initial sample result in a high-risk subject initially identified as having, or at risk for, a gastrointestinal (GI) cancer, wherein the initial sample result was obtained using an initial cancer diagnostic test that analyzes an initial blood or stool sample obtained from the subject, the initial cancer diagnostic test selected from one of a fecal immunochemical test of the initial stool sample, a fecal occult blood test, detection of blood and abnormal DNA in the initial stool sample, detection of ctDNA mutations and/or ctDNA fragment size and/or expression of proteins associated with cancer in the initial blood sample; performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject; performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids; analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of the additional sample of the subject; generating a machine-learned prediction using the analyzed methylation statuses of the plurality of genomic sites from target nucleic acids of the additional sample of the subject to determine a risk for GI cancer, wherein the absence of the cancer signal signifies that the biological sample does not have a presence of or is not at risk for GI cancer, thereby confirming or contradicting the positive initial sample result.
1
A method for detecting a true positive or a false positive initial sample result in a subject initially identified as having, or at risk for, cancer, the method comprising: analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of a biological sample of the subject; determining whether the biological sample has a presence or absence of a cancer signal to confirm or contradict the initial identification that the high risk subject is at risk for cancer, wherein the absence of the cancer signal signifies that the biological sample does not have a presence of or is not at risk for a plurality of cancers, wherein at least one cancer of the plurality of cancers is a different cancer that differs from the cancer for which the subject was initially identified as high risk; and classifying the initial sample as a true positive biological sample or a false positive biological sample responsive to the determination.
4
wherein the cancer is a gastrointestinal (GI) cancer.
6
wherein the initial sample result was obtained using an initial cancer diagnostic test
9
wherein the initial cancer diagnostic test is one or more of: a fecal immunochemical test of the initial stool sample, a fecal occult blood test, detection of blood and abnormal DNA in the initial stool sample, detection of ctDNA mutations and/or ctDNA fragment size and/or expression of proteins associated with cancer in the initial blood sample
8
wherein the initial blood or stool sample and the biological sample are different samples
18
obtaining converted cell free DNA (cfDNA); selectively amplifying target regions of the converted cfDNA; and sequencing amplicons comprising the amplified target regions to determine the methylation status of the plurality of genomic sites
19
wherein the converted cfDNA comprises bisulfite converted cfDNA
15
wherein the plurality of genomic sites comprise a plurality of CpG sites
16
wherein the plurality of CpG sites are located in one or more CpG islands or portions of one or more CpG islands shown in Tables 1-4
24
wherein analyzing methylation statuses of the plurality of genomic sites from target nucleic acids of the sample comprises applying a trained machine learning model
9
wherein the initial blood or stool sample was previously obtained during a colonoscopy of the subject
3
wherein the biological sample is obtained during a colonoscopy of the subject
10
wherein the initial cancer diagnostic test comprises one or more of COLOGUARD® (Exact Sciences), SHIELDTM (Guardant Health), Freenome MultiomicBlood test (Freenome), Everlywell fecal immunohistochemical test (FIT), Pinnacle Biolabsl FIT, iDNA HPV test, and imaware Prostate Cancer screening test
10
wherein the cancer diagnostic test comprises one or more of COLOGUARD@ (Exact Sciences), SHIELDTM (Guardant Health), FreenomeMultiomic Blood test (Freenome), Everlywell fecal immunohistochemical test (FIT), Pinnacle Biolabsl FIT, iDNA HPV test, and imaware Prostate Cancer screening test
12
wherein the classification of the initial sample detects false positive samples with at least 60% sensitivity
30
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
13
wherein the classification of the initial sample detects false positive samples with at least 60% specificity
30
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
14
wherein the classification of the initial sample detects false positive samples with at least 80% sensitivity at 90% specificity
30
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
15
wherein the methylation statuses of the plurality of genomic sites are obtained by performing an assay, wherein the assay comprises performing one or more of: sequencing of target nucleic acids; hybrid capture; methylation-specific PCR; an assay that generates sequence information; and sequencing a clone library generated from a template immortalized library
17
wherein the methylation statuses of the plurality of genomic sites are obtained by performing an assay, wherein the assay comprises performing one or more of a. sequencing of target nucleic acids; b. hybrid capture; c. methylation-specific PCR; d. an assay that generates sequence information; and e. sequencing a clone library generated from a template immortalized library
16
wherein performing the assay comprises: obtaining converted cell free DNA (cfDNA); selectively amplifying target regions of the converted cfDNA; and sequencing amplicons comprising the amplified target regions to determine the methylation statuses of the plurality of genomic sites
18
wherein performing the assay comprises: obtaining converted cell free DNA (cfDNA);selectively amplifying target regions of the converted cfDNA; and sequencing amplicons comprising the amplified target regions to determine the methylation statuses of the plurality of genomic sites
17
wherein the converted cfDNA comprises bisulfite converted cfDNA
19
wherein the converted cfDNA comprises bisulfite converted cfDNA
18
A method for improving precision of a cancer test, the method comprising: screening high-risk subjects of a patient population as having, or at risk for, a gastrointestinal (GI) cancer using initial samples obtained from the subjects by performing an initial cancer diagnostic test, wherein the initial cancer diagnostic test analyzes an initial blood or stool sample obtained from each subject, the initial cancer diagnostic test selected from one of a fecal immunochemical test of the initial stool sample, a fecal occult blood test, detection of blood and abnormal DNA in the initial stool sample, detection of ctDNA mutations and/or ctDNA fragment size and/or expression of proteins associated with cancer in the initial blood sample; identifying one or more subjects at risk for cancer based on results from the initial cancer diagnostic test; for each of the one or more subjects at risk for cancer: performing bisulfite conversion of nucleic acids obtained from an additional sample from the subject; performing quantitative PCR or next generation sequencing of nucleic acids to determine methylation statuses of a plurality of genomic sites comprising a plurality of CpG sites located in one or more CpG islands (CGIs) or portions of one or more CpG islands (CGIs) shown in Tables 1-4 of the bisulfite-converted nucleic acids; analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of the additional sample of the subject; generating a machine-learned prediction using the analyzed methylation statuses of the plurality of genomic sites from target nucleic acids of the additional sample of the subject to determine a risk for GI cancer, thereby confirming or contradicting a positive initial cancer diagnostic test.
31
A method for improving precision of a cancer test, the method comprising: identifying a subject at risk for cancer due to an initial sample result from a cancer diagnostic test; analyzing methylation statuses of a plurality of genomic sites from target nucleic acids of a biological sample of the subject; determining whether the biological sample has a presence or absence of a cancer signal to confirm or contradict the initial identification that the high risk subject is at risk for cancer, wherein the absence of the cancer signal signifies that the biological sample does not have a presence of or is not at risk for a plurality of cancers, wherein at least one cancer of the plurality of cancers is a different cancer; and classifying the initial sample as a true positive biological sample or a false positive biological sample responsive to the determination
34
wherein the cancer is a gastrointestinal (GI) cancer
38
wherein the initial cancer diagnostic test is one or more of: a fecal immunochemical test of the initial stool sample, a fecal occult blood test, detection of blood and abnormal DNA in the initial stool sample, detection of ctDNA mutations and/or ctDNA fragment size and/or expression of proteins associated with cancer in the initial blood sample
8
wherein the initial blood or stool sample and the biological sample are different samples
18
obtaining converted cell free DNA (cfDNA); selectively amplifying target regions of the converted cfDNA; and sequencing amplicons comprising the amplified target regions to determine the methylation status of the plurality of genomic sites
19
wherein the converted cfDNA comprises bisulfite converted cfDNA
44
wherein the plurality of genomic sites comprise a plurality of CpG sites
45
wherein the plurality of CpG sites are located in one or more CpG islands or portions of one or more CpG islands shown in Tables 1-4
53
wherein analyzing methylation statuses of the plurality of genomic sites from target nucleic acids of the sample comprises applying a trained machine learning model
19
wherein the initial blood or stool sample was previously obtained during a colonoscopy of the subject
33
wherein the biological sample is obtained during a colonoscopy of the subject
20
wherein the initial cancer diagnostic test comprises one or more of COLOGUARD® (Exact Sciences), SHIELDTM (Guardant Health), Freenome Multiomic Blood test (Freenome), Everlywell fecal immunohistochemical test (FIT), Pinnacle Biolabsl FIT, iDNA HPV test, and imaware Prostate Cancer screening test
39
wherein the cancer diagnostic test comprises one or more of COLOGUARD@ (Exact Sciences), SHIELDTM (Guardant Health), Freenome Multiomic Blood test (Freenome), Everlywell fecal immunohistochemical test (FIT), Pinnacle Biolabsl FIT, iDNA HPV test, and imaware Prostate Cancer screening test
22
wherein the classification of the initial sample detects false positive samples with at least 60% sensitivity
59
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
23
wherein the classification of the initial sample detects false positive samples with at least 60% specificity
59
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
24
wherein the classification of the initial sample detects false positive samples with at least 80% sensitivity at 90% specificity
59
wherein the method detects false positive samples at an accuracy of at least 80% sensitivity at 90% specificity
Although the claims of application No. ‘609 are silent with regard to the limitation “analyzes methylation statuses for a plurality of CpG sites located in at least 500 CGIs” of claims 4, 11, and 21 of the instant claims and 1000 CGIs of claims 25 and 26, paragraph [0069] of the Specification of Application ‘609 discloses that the analysis involves analyzing at least 500 CGIs or at least 1000 CGIs. Thus, it would be obvious to one of ordinary skill in the art to analyze CpG sites from at least 500 or at least 1000 CGIs in view of the disclosure of the application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant request that the double patenting rejection be held in abeyance until the claims are otherwise deemed allowable.
The double patenting rejection is maintained. It is respectfully submitted that this rejection cannot be held in abeyance as a terminal disclaimer or a filing showing that the claims subject to the rejection are patentably distinct from the reference claims is necessary for further consideration of the rejection of the claims. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated (see MPEP 804.I.B.1).
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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/E.A.S./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
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