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 .
Claims Status
Claims 1-5, 9-11, 13-18, 20, 23-26, 28-34, & 38-40 filed on 11/06/2025 are pending. Claims 19 & 35 are withdrawn from consideration as being drawn to a non-elected invention. Claims 11, 15, 28, & 30-32 are currently under examination directed to the elected species of plasma in claims 11, 30, & 31, of stomach cancer in claims 15 & 32, and of all primer pairs (SEQ ID NOs: 1-16) in claim 28 (see response dated 03/19/2025). The cancellation of claims 7 and 21 without prejudice and the addition of new claims 38-40 in the reply filed on 11/06/2025 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 101
Claims 1-5, 9-11, 13-18, 20, 23-26, 29-34, 38, & 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method obtaining a plurality of sequence reads or treating a sample with bisulfite and amplifying the bisulfite-treated sample followed by detection and assigning of a methylation status of altered or normal to each genomic segment, in which the biological sample is identified as with cancer if at least one of the genomic segments is assigned an altered methylation status or without cancer if none of the genomic segments are assigned an altered methylation status. This recitation is a natural correlation between altered or unaltered methylation status and a biological sample from a subject being with or without cancer. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “obtaining a plurality of sequence reads of a methylation sequencing assay”, which broadly encompasses reading a report, and recites “assigning a methylation status of altered or normal” and “identifying the biological sample from a subject with/without cancer” which encompasses conclusions and determinations which can occur entirely within the mind. Finally, the claimed invention recites comparing methylation of CpG sites of the sequence reads to a normal control which are directed to mathematical concepts and calculations. These limitations are directed to abstract ideas. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of obtaining a plurality of sequence reads, assigning a methylation status of altered or normal, comparing methylation of CpG sites of the sequence reads to a normal control, and identifying the biological sample from a subject as with or without cancer as a result of the assigned methylation status, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “administering a therapeutically effective amount of an anti-cancer agent” to the patient, this step is conditional as it is if the biological sample is identified as a sample from a subject with cancer according to the assigned methylation status in claim 1 & 20. Additionally, these elements are generally recited, and are considered nothing more than instructions to apply the law of nature. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of obtaining a biological sample from the subject is considered insignificant post solution activity. The steps of detecting methylation and assigning a methylation status of altered or normal are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This analysis holds for generally recited limitations such as “treating sample with bisulfite”, “amplifying genomic segments”, “PCR amplification”. These steps/ elements are not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the steps of obtaining a plurality of sequence reads covering genomic segments containing genomic positions of “chr6: 88876741, chr6: 150286508, … and chr17: 46655394” and assigning a methylation status of altered or normal to each of the genomic segments are active steps that cannot reasonably be “performed in the mind” and are not directed to an abstract idea under Step 2A of the patent eligibility framework and for at least this reason, the amended claims are not directed to a patent ineligible abstract idea. This argument has been thoroughly reviewed but was not found persuasive. First, as discussed above and previously, the recitation of “obtaining a plurality of sequence reads of a methylation sequencing assay” broadly encompasses reading a report which is directed to an abstract idea (see MPEP §2106.04(a)(2)(III)(B). Second, as discussed above and previously, the recitation of “assigning a methylation status of altered or normal” and “identifying the biological sample from a subject with/without cancer” encompasses evaluation and judgment which encompasses conclusions and determinations which can occur entirely within the mind (see MPEP §2106.04(a) & MPEP §2106.04(a)(2)(III)(A)).
The response also asserts that claims 1 and 20 are patent eligible at least because the combination of elements recited in these claims is not well-understood, routine, or conventional and therefore provides an inventive concept and amounts to significantly more than the judicial exception itself. Specifically, the response asserts that claim 1 requires a specific set of genomic positions and a specific methylation state, claims 2-5, 9, & 14 require specific protocols for processing the sequence read data to determine if the cancer biomarker is hypermethylated or not, claims 10 & 13 require a specific sequence assays, claim 11 requires specific sample types, claim 17 further requires treating the patient with an anti-cancer agent, and claim 18 requires computer implementation. Further, the response asserts that the Office does not even cite any reference in support of its false conclusion that the combination of elements recited in the applicants claims is well-understood, routine, or conventional activity. These arguments have been thoroughly reviewed but were not found persuasive. First, citation of a reference is not a standard for determining patent eligibility under 35 U.S.C. 101. Second, as discussed above and previously, although the claims recite “administering a therapeutically effective amount of an anti-cancer agent” to the patient, this step is conditional as it is if the biological sample is identified as a sample from a subject with cancer according to the assigned methylation status in claim 1 & 20. In addition, as discussed above and previously, the step of obtaining a biological sample from the subject is considered insignificant post solution activity. The steps of detecting methylation and assigning a methylation status of altered or normal comprising genomic segments containing genomic positions (therefore comprising detection of methylation of additional genomic segments and positions and not just the genomic segments containing the genomic positions listed in claim 1) are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This analysis holds for generally recited limitations such as “treating sample with bisulfite”, “amplifying genomic segments”, “PCR amplification” drawn to protocols, sequence assays, and sample types. These steps/ elements are not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Therefore, when viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 102
Claim(s) 1, 9-11, 13-16, 18, 20, 24-26, & 29-33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Allen Chan (Allen Chan et al.; PNAS, Vol. 110, pages 18761-18768, November 2013), as cited in the IDS dates 02/03/2022.
Regarding amended claim 1, Allen Chan teaches detection of genome-wide (covering genomic segments that contain the genomic positions of chr6:88876741, chr6:150286508, chr7:19157193; chr10:14816201, chr12:129822259, chr14:89628169, chr17:40333009, and chr17:46655394) hypomethylation (assigning a methylation status of altered) in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer (identifying the biological sample from a subject with or without cancer) (abstract lines 1-25; significance paragraph lines 1-13). Allen Chan teaches assessing the methylation profile (methylation status) by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin, and then comparing this methylation profile (methylation status) between plasma DNA samples from hepatocellular carcinoma (HCC) patients and healthy patients (comparing methylation of CpG sites of the sequence reads covering the respective genomic segments to a normal control) in which the bins are assigned as hypomethylated (altered) or healthy (normal) (pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8; pg. 18762-18763 paragraph bridging pg. 18762 & pg. 18763 lines 1-16; pg. 18763 column 1 1st full paragraph lines 1-17; pg. 18765 paragraph bridging column 1 & 2 lines 1-11). Allen Chan also teaches detection of genome-wide (genomic segments are plus or minus 50 to 300 bases of the genomic position) hypomethylation in plasma HCC and healthy samples by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin (abstract lines 1-25; significance paragraph lines 1-13; pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8).
Regarding claim 9, Allen Chan teaches determining the methylation density (MD) for each 1-Mb region, referred to as a bin, and then determining the number of bins within the genome that was hypomethylated as a percentage of the total number of bins analyzed within the genome (pg. 18762-18763 paragraph bridging pg. 18762 & pg. 18763 lines 1-16). Allen Chan also teaches the in the plasma samples of the HCC patients a median of 34.1% of bins showed hypomethylation (at least two bins (genomic segments) assigned as hypomethylated (altered methylation)) in classifying the samples as positive for cancer (pg. 18763 column 1 1st full paragraph lines 1-17; Table 1).
Regarding claim 10, Allen Chan teaches detection of genome-wide hypomethylation in plasma through massively parallel bisulfite sequencing (abstract lines 1-3; pg. 18762 column 1 1st full paragraph lines 1-5).
Regarding claim 11, Allen Chan teaches obtaining plasma DNA samples from HCC and healthy patients (pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 13, Allen Chan teaches obtaining plasma DNA samples from HCC and healthy patients in which the plasma samples contain cell-free DNA (cell-free DNA comprising the genomic segments (pg. 18761 column 1 1st full paragraph lines 1-7; pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 14, Allen Chan teaches for bisulfite sequencing the samples are bisulfite-converted, then amplified with PCR, purified, and then sequenced (pg. 18768 column 1 1st full paragraph lines 1-7; pg. 18768 column 1 2nd full paragraph lines 1-4).
Regarding claim 15, Allen Chan teaches detection of genome-wide hypomethylation were detected in a variety of cancers including hepatocellular carcinoma (abstract lines 1-8; pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 16, Allen Chan teaches obtaining the plasma sample (biological sample) from HCC and healthy patients (from the subject) (pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 18, Allen Chan teaches the use of Methy-Pipe for alignment and identification of methylated cytosines (implemented at least in part using a computer) (pg. 18768 column 1 3rd full paragraph lines 1-14).
Regarding amended claim 20, Allen Chan teaches detection of genome-wide (covering genomic segments that contain the genomic positions of chr6:88876741, chr6:150286508, chr7:19157193; chr10:14816201, chr12:129822259, chr14:89628169, chr17:40333009, and chr17:46655394) hypomethylation (assigning a methylation status of altered) in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer (identifying the biological sample from a subject with or without cancer) (abstract lines 1-25; significance paragraph lines 1-13), in which in the bisulfite sequencing the samples are treated with bisulfite, amplified, and sequenced (pg. 18768 column 1 1st full paragraph lines 1-7; pg. 18768 column 1 2nd full paragraph lines 1-4). Allen Chan teaches assessing the methylation profile (methylation status) by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin, and then comparing this methylation profile (methylation status) between plasma DNA samples from hepatocellular carcinoma (HCC) patients and healthy patients (comparing methylation of CpG sites of the sequence reads covering the respective genomic segments to a normal control) in which the bins are assigned as hypomethylated (altered) or healthy (normal) (pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8; pg. 18762-18763 paragraph bridging pg. 18762 & pg. 18763 lines 1-16; pg. 18763 column 1 1st full paragraph lines 1-17; pg. 18765 paragraph bridging column 1 & 2 lines 1-11). Allen Chan also teaches detection of genome-wide (genomic segments are plus or minus 50 to 300 bases of the genomic position) hypomethylation in plasma HCC and healthy samples by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin (abstract lines 1-25; significance paragraph lines 1-13; pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8).
Regarding claim 24, Allen Chan teaches for bisulfite sequencing the samples are bisulfite-converted, then amplified with PCR, purified, and then sequenced (pg. 18768 column 1 1st full paragraph lines 1-7; pg. 18768 column 1 2nd full paragraph lines 1-4).
Regarding claim 25, Allen Chan teaches all of the bisulfite-converted products (bisulfite-converted genomic segments) are amplified with PCR (single multiplex PCR amplification including amplification of each of the genomic segments (pg. 18768 column 1 1st full paragraph lines 1-7).
Regarding claim 26, Allen Chan teaches detecting methylation in plasma DNA samples from HCC and healthy patients in which the plasma samples contain cell-free DNA (cell-free DNA comprising the genomic segments (pg. 18761 column 1 1st full paragraph lines 1-7; pg. 18762 column 1 1st full paragraph lines 1-4) and further treating the samples with bisulfite, amplifying the bisulfite-converted products (bisulfite-converted genomic segments), and then sequencing the amplified products (amplified bisulfite-converted genomic segments) (pg. 18768 column 1 1st full paragraph lines 1-7; pg. 18768 column 1 2nd full paragraph lines 1-4).
Regarding claim 29, Allen Chan teaches determining the methylation density (MD) for each 1-Mb region, referred to as a bin, and then determining the number of bins within the genome that was hypomethylated as a percentage of the total number of bins analyzed within the genome (pg. 18762-18763 paragraph bridging pg. 18762 & pg. 18763 lines 1-16). Allen Chan also teaches the in the plasma samples of the HCC patients a median of 34.1% of bins showed hypomethylation (at least two bins (genomic segments) assigned as hypomethylated (altered methylation)) in classifying the samples as positive for cancer (pg. 18763 column 1 1st full paragraph lines 1-17; Table 1).
Regarding claim 30 & 31, Allen Chan teaches obtaining plasma DNA samples from HCC and healthy patients (pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 32, Allen Chan teaches detection of genome-wide hypomethylation were detected in a variety of cancers including hepatocellular carcinoma (abstract lines 1-8; pg. 18762 column 1 1st full paragraph lines 1-4).
Regarding claim 33, Allen Chan teaches obtaining the plasma sample (biological sample) from HCC and healthy patients (from the subject) (pg. 18762 column 1 1st full paragraph lines 1-4).
Response to Arguments
The response traverses the rejection. The response asserts that unlike Allen Chen, which relies on the sequencing of whole genomes and detection of genome-wide hypomethylation, the amended claims require “assigning a methylation status of altered or normal to each of the genomic segments” wherein each genomic segment is “plus or minus 50 to 300 bases” of particular genomic positions chr6:88876741, chr6:150286508, …, and chr17:46655394. Further, the response asserts that Allen Chen does not teach the combination of limitations recited in claims 1 and 20 (from which claims 9-11, 13-16, 18, 20, 24-26, & 29-33 depend, directly or indirectly), and therefore cannot anticipate these claims. This argument has been thoroughly reviewed but was not found persuasive, as discussed more above and previously, Allen Chen teaches detection of genome-wide (therefore comprising genomic segments that contain the genomic positions of chr6:88876741, chr6:150286508, chr7:19157193; chr10:14816201, chr12:129822259, chr14:89628169, chr17:40333009, and chr17:46655394) hypomethylation (assigning a methylation status of altered) in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer (identifying the biological sample from a subject with or without cancer) (abstract lines 1-25; significance paragraph lines 1-13). In addition, the recitation of “plus or minus 50 to 300 bases” is very broad and is given its broadest reasonable interpretation to encompass genomic segments that comprises the genomic positions above (plus) 50 to 300 bases from the genomic positions (genomic segments can comprise the genomic position above (plus) 300 bases from the genomic position) and genomic segments that comprises the genomic positions below (minus) 50 to 300 bases from the genomic positions. Further, Allen Chan also teaches detection of genome-wide (comprising genomic segments are above (plus) or below (minus) 50 to 300 bases from the genomic position) hypomethylation in plasma HCC and healthy samples by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin (abstract lines 1-25; significance paragraph lines 1-13; pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8). Therefore, Allen Chan teaches all of the limitations in amended claims 1 and 20.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 2-5, 38, & 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen Chan (Allen Chan et al.; PNAS, Vol. 110, pages 18761-18768, November 2013), as cited in the IDS dates 02/03/2022, in view of Singer (Singer; American Journal of Respiratory Cell and Molecular Biology, Vol. 61, pages 417-428, June 2019).
The teachings of Allen Chan with respect to claim 1 are discussed above and incorporated herein.
Regarding amended claims 2-4, Allen Chan does not teach calculating a ratio according to X1 and X2 (see claim 2), according to X3 and X4 (see claim 3), or according to X5 and X6 (see claim 4).
Singer teaches methods for quantifying CpG methylation through a ratio that represent the average methylation at unique cystines, β, measured in a population of cells from a sample in which β is calculated by summing the methylated calls from the methylated extraction procedure (F1 or F2, F3 or F4, or F5 or F6, see claims 2, 3, & 4, respectively) divided by the total number of reads at that position (F1 + F2, F3 + F4, or F5 + F6, see claims 2, 3, & 4, respectively) (pg. 423 paragraph bridging column 2 & 3 lines 1-20). Singer also teaches that the cytosine residue may be completely unmethylated (no CpG sites are methylated (see claim 4) which encompasses less than 40% of CpG sites are methylated (see claim 2) and less than 20% of CpG sites are methylated (see claim 3)) or that the cytosine residue may be completely methylated (all CpG sites are methylated (see claim 4) which encompasses at least 60% of CpG sites are methylated (see claim 2) and at least 80% of CpG sites are methylated (see claim 3)) (pg. 423 paragraph bridging column 2 & 3 lines 5-8). Finally, Singer teaches that sounds scientific and mathematical principles are important to facilitate discoveries involving DNA methylation in the context of epigenetic phenomena and that using DNA methylation as a biomarker requires high-resolution techniques for analysis (pg. 426 paragraph bridging column 2 & 3 lines 1-9 & 30-39).
Allen Chan and Singer are considered to be analogous to the claimed invention because they are all in the same field of detection and analysis of DNA methylation. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of assigning a methylation status as altered or normal in Allen Chan to incorporate the calculation of the ratios for assigning the methylation status as summing the methylated calls from the methylated extraction procedure divided by the total number of reads at that position as taught in Singer because Singer teaches that doing so would provide sound scientific and mathematical principles that can be applied in detection of DNA methylation as a biomarker.
Regarding amended claim 5 & new claims 38 & 39, Allen Chan teaches that a bin is hypomethylated if its mean methylation density was 3 standard deviations (SDs) or more (at least 2 standard deviations) below the mean of the corresponding bin of the healthy reference (control) group (pg. 18762-18763 paragraph bridging pg. 18762 & pg. 18763 lines 11-14).
Singer teaches methods for quantifying CpG methylation through a ratio that represent the average methylation at unique cystines, β, measured in a population of cells from a sample in which β is calculated by summing the methylated calls from the methylated extraction procedure (F1 or F2) divided by the total number of reads at that position (F1 + F2) (pg. 423 paragraph bridging column 2 & 3 lines 1-20). Singer also teaches that the cytosine residue may be completely unmethylated providing β=0 or that the cytosine residue may be completely methylated providing β=1 and, then depending on the number of unmethylated and methylated cytosines β, can range continuously range from 0 to 1 leading to an increase in the ratio β as the number of methylated cytosines increase (pg. 423 paragraph bridging column 2 & 3 lines 5-20). Finally, Singer teaches that sounds scientific and mathematical principles are important to facilitate discoveries involving DNA methylation in the context of epigenetic phenomena and that using DNA methylation as a biomarker requires high-resolution techniques for analysis (pg. 426 paragraph bridging column 2 & 3 lines 1-9 & 30-39).
Allen Chan and Singer are considered to be analogous to the claimed invention because they are all in the same field of detection and analysis of DNA methylation. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of assigning a methylation status as altered or normal and assigning an altered methylation status if 3 SDs or more below the normal control in Allen Chan to incorporate the calculation of the ratios as summing the methylated calls from the methylated extraction procedure divided by the total number of reads at that position when assigning a methylation status as taught in Singer because Singer teaches that doing so would provide sound scientific and mathematical principles that can be applied in detection of DNA methylation as a biomarker.
Claim(s) 17 & 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen Chan (Allen Chan et al.; PNAS, Vol. 110, pages 18761-18768, November 2013), as cited in the IDS dates 02/03/2022, in view of Lewandowska (Lewandowska & Bartoszek; Mutagenesis, Vol. 26, pages 475-487, May 2011).
The teachings of Allen Chan with respect to claims 1 & 20 are discussed above and incorporated herein.
Regarding claim 17, Allen Chan does not teach administering a therapeutically effective amount of an anti-cancer agent if identified from a subject with cancer.
Lewandowska teaches that DNA methylation pattern (methylation status) seen in cancer cells (from a subject with cancer) can be used in cancer diagnostics and treatment (abstract lines 13-15). Lewandowska further teaches a variety of different anti-cancer drugs and administering these anti-cancer therapeutics that act at the epigenome level are very promising (administering a therapeutically effective amount of an anti-cancer agent) in the treatment of cancer (pg. 479 column 2 2nd full paragraph lines 1-11; pg. 480 column 1 1st full paragraph lines 1-7; pg. 481 column 1 4th full paragraph lines 1-9).
Allen Chan and Lewandowska are considered to be analogous to the claimed invention because they are all in the same field of DNA methylation analysis. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting the methylation status altered or normal for identifying a sample as with or without cancer in Allen Chan to incorporate the administration of a therapeutically effective amount of an anti-cancer drug if a sample is identified as with cancer as taught in Lewandowska because Lewandowska teaches that doing so would provide a very promising method in the treatment of cancer.
Regarding claim 34, Allen Chan does not teach administering a therapeutically effective amount of an anti-cancer agent if identified from a subject with cancer.
Lewandowska teaches that DNA methylation pattern (methylation status) seen in cancer cells (from a subject with cancer) can be used in cancer diagnostics and treatment (abstract lines 13-15). Lewandowska further teaches a variety of different anti-cancer drugs and administering these anti-cancer therapeutics that act at the epigenome level are very promising (administering a therapeutically effective amount of an anti-cancer agent) in the treatment of cancer (pg. 479 column 2 2nd full paragraph lines 1-11; pg. 480 column 1 1st full paragraph lines 1-7; pg. 481 column 1 4th full paragraph lines 1-9).
Allen Chan and Lewandowska are considered to be analogous to the claimed invention because they are all in the same field of DNA methylation analysis. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting the methylation status altered or normal for identifying a sample as with or without cancer in Allen Chan to incorporate the administration of a therapeutically effective amount of an anti-cancer drug if a sample is identified as with cancer as taught in Lewandowska because Lewandowska teaches that doing so would provide a very promising method in the treatment of cancer.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen Chan (Allen Chan et al.; PNAS, Vol. 110, pages 18761-18768, November 2013), as cited in the IDS dates 02/03/2022.
The teachings of Allen Chan with respect to claim 20 are discussed above and incorporated herein.
Regarding claim 23, Allen Chan does not teach the genomic segments correspond to the genomic sequence comprising or consisting of SEQ ID NOs: 25-32.
However, the recitation of comprising SEQ ID NOs: 25-32 is very broad and includes larger sequences that encompasses SEQ ID NOs: 25-32. Allen Chan teaches detection of genome-wide (covering genomic segments that contain the genomic positions of chr6:88876741, chr6:150286508, chr7:19157193; chr10:14816201, chr12:129822259, chr14:89628169, chr17:40333009, and chr17:46655394) hypomethylation in plasma HCC and healthy samples as a marker for cancer by determining the methylation density (MD) for each 1-Mb region (genomic segments covering the genome), referred to as a bin (abstract lines 1-25; significance paragraph lines 1-13; pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8). Allen Chan also teaches that genome-wide detection of methylation is a powerful general approach for the detection of multiple cancers (significance paragraph lines 1-5).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that detecting methylation profiles in the 1-Mb regions (bins) spanning the genome (genomic segments covering the genome) as a marker for cancer taught by Allen Chan encompasses genomic segments that correspond to the genomic sequence comprising SEQ ID NOs: 25-32 as Allen Chan teaches that doing so would provide a powerful approach for the detection of multiple cancers.
Response to Arguments
The response traverses the rejection. The response asserts that Allen Chen is discussed above and further that Singer fails to teach or suggest any particular genomic segments or regions that might be altered in patients with or without cancer. The response also asserts that Singer fails to remedy the deficiencies of Allen Chen. This argument has been thoroughly reviewed but was not found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, Singer is not relied upon for teaching or suggesting particular genomic segments in patients with or without cancer and instead, Allen Chen teaches the limitations of amended claim 1 as discussed above and for the reasons set forth above.
The response also asserts that Allen Chen is discussed above and further that Lewandowska fails to teach or suggest any particular genomic segments or regions that might be altered in patients with or without cancer. The response also asserts that Lewandowska fails to remedy the deficiencies of Allen Chen. This argument has been thoroughly reviewed but was not found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, Lewandowska is not relied upon for teaching or suggesting particular genomic segments in patients with or without cancer and instead, Allen Chen teaches the limitations of amended claims 1 & 20 as discussed above and for the reasons set forth above.
The response also asserts that amended claim 20, from which claim 23 depends from, specifies that “the genomic positions are plus or minus 50 to 300 bases of the genomic positions” and accordingly, the genomic positions of the claim are not “very broad” and do not include “detection of genome-wide hypomethylation”. This argument has been thoroughly reviewed but was not found persuasive. First, amended claim 20 is a method comprising (open) amplifying genomic segments from a bisulfite-treated sample wherein the genomic segments contain the listed genomic positions in lines 5-7 of amended claim 20 and Allen Chen teaches detection of genome-wide (therefore comprising genomic segments that contain the genomic positions of chr6:88876741, chr6:150286508, chr7:19157193; chr10:14816201, chr12:129822259, chr14:89628169, chr17:40333009, and chr17:46655394) hypomethylation. Therefore, as currently amended, claim 20 comprises the detection of genomic positions listed in lines 5-7 of amended claim 20 and detection of methylation at additional genomic positions and does not exclude detection of genome-wide hypomethylation. Second, the recitation of “plus or minus 50 to 300 bases” is very broad and is given its broadest reasonable interpretation to encompass genomic segments that comprises the genomic positions above (plus) 50 to 300 bases from the genomic positions (genomic segments can comprise the genomic position above (plus) 300 bases from the genomic position) and genomic segments that comprises the genomic positions below (minus) 50 to 300 bases from the genomic positions. Further, Allen Chan also teaches detection of genome-wide (comprising genomic segments are above (plus) or below (minus) 50 to 300 bases from the genomic position) hypomethylation in plasma HCC and healthy samples by determining the methylation density (MD) for each 1-Mb region (genomic segment), referred to as a bin (abstract lines 1-25; significance paragraph lines 1-13; pg. 18761-18762 paragraph bridging pg. 18761 & pg. 18762 lines 1-8).
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1-5, 9-11, 13-18, 20, 23-26, 28-34, & 38, & 39 are rejected. Claim 28 would be allowable if rewritten to include all of the limitations of the base claim and any intervening claims. New claim 40 is allowable.
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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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682