DETAILED ACTION
Notice of Pre-AIA or AIA
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 9-11, 17-22, 39, 40, & 42 filed on 09/09/2025 are pending. Claims 12, 84, & 85 are withdrawn from consideration as being drawn to a non-elected invention. Claim 11 is currently under examination directed to the elected species of cancer (see response dated 02/06/2025). 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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 § 112
Claim 20 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.
Regarding claim 20, the recitation of “the relative abundance is an end density of sequence reads covering the first set of CpG sites” in lines 4-5 of the claim is unclear. The specification at paragraph [0018] defines “a “rate” of DNA molecules ending on a position relates to how frequently a DNA molecules ends on the position. Such a rate can be referred to as an “end density””, how is this position determined? What distinguishes a DNA molecule ending on a position being referred to in an end density from any other genomic position if the DNA molecule?
Response to Arguments
The response asserts that the applicant is unclear about the rejection of claim 20 under 35 U.S.C. 112(b). The response asserts that a position in a reference genome is clear and is a standard term used by the skilled person and that an end of a DNA fragment corresponds to the last nucleotide, so after alignment it is clear which positions (e.g., one on either end) at which the DNA fragment ends and thus the claims do address the determination of the position of the cell-free DNA fragments. This argument has been thoroughly reviewed but was not found persuasive as it is clear to the skilled person how to determine a end position on a DNA fragment. However, the claim recites the limitation of “the relative abundance is an end density of sequence reads covering the first set of CpG sites” in lines 4-5 of the claim and therefore are directed towards determining the relative abundance as an end density and not the relative abundance of an end position of a DNA fragment. Further, the instant specification at paragraph [0018] defines “a “rate” of DNA molecules ending on a position relates to how frequently a DNA molecules ends on the position” and this position is not further defined. Does the rate of DNA molecules ending on a position require this position to be at the end of a DNA molecule? Ending at a different position along the DNA molecule and not at the end position?
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 § 101
Claims 9-11, 17-22, 39, 40, & 42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation 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 for analyzing a biological sample of cell-free DNA to determine a relative abundance of at least 100,000 cell-free DNA fragments covering a first set of CpG sites to determine a condition in a subject. This recitation is a natural correlation between relative abundance of CpG methylation sites and a subject has a condition. 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 steps of: “identifying”, “receiving”, “aligning”, “determining”, and comparing the relative abundance to a reference value which are recitations of abstract ideas because they encompass conclusions and determinations which can occur entirely within the mind. 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 identifying a first set of CpG sites, receiving sequence reads, aligning the sequence reads to the reference genome, determining a relative abundance, and comparing the relative abundance to a reference value to determine a condition in a subject, however, this does not integrate the JE into a practical application because it is a mere data gathering steps to use the correlation and does not add a meaningful limitation to the method.
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).
The steps of “to determine” a condition of the subject 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 step is 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 number (100,000) of cell-free DNA fragments is too large for someone to practically analyze mentally and accordingly receiving sequencing reads, aligning sequencing reads, and determining using the aligned sequence reads cannot be practically performed mentally. This argument has been thoroughly reviewed but was not found persuasive. First, if a claim recites a limitation that can practically be performed in the human mind, with or without the use of a physical aid such as pen and paper, the limitation falls within the mental processes grouping (see MPEP §2106.04(a)(2)(III)(B)). Therefore, it may take long, however these steps could be performed with the use of a physical aid such as with a pen and paper. Second, regardless of the recitations of abstract ideas of receiving sequencing reads, aligning sequencing reads, and determining using the aligned sequence reads recited in the claim, there are still other judicial exceptions recited in the claims including the recitation of a natural correlation between relative abundance of CpG methylation sites and a subject has a condition and the recitation of steps of “identifying” and “comparing” the relative abundance to a reference value which are recitations of abstract ideas. Further, these judicial exceptions are not integrated into a practical application or have step/elements that add significantly more to the judicial exceptions as discussed above.
The response also asserts that claim 1 provides an improvement in the accuracy of determining whether the subject has a condition and therefore provides a practical application, as the instant specification teaches that there is a link between nuclease activity and cfDNA methylation in human plasma and, therefore, the method of claim 1 can be used to accurately determine whether a subject has a condition and therefore provides a practical application. This argument has been thoroughly reviewed but was not found persuasive as the claims recite steps of identifying a first set of CpG sites, receiving sequence reads, aligning the sequence reads to the reference genome, determining a relative abundance, and comparing the relative abundance to a reference value to determine a condition in a subject, however, this does not integrate the JE into a practical application because it is a mere data gathering steps to use the correlation and does not add a meaningful limitation to the method.
The response also asserts that the combination of the following additional limitations of receiving sequence reads, aligning sequence reads, determining using the aligned sequence reads a relative abundance of the at least 100,000 cfDNA fragments covering the first set of CpG sites are unconventional. This argument has been thoroughly reviewed but was not found persuasive as the steps of “to determine” a condition of the subject 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 step is 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)).
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) 9, 17-19, 21, 22, 39, 40, & 42 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Chan (Chan et al.; PNAS, Vol. 111, pages E5302-E5311, November 2014), as cited on the IDS dated 02/15/2023.
Regarding amended claim 9, Chan teaches a method parallel genomic and methylomic sequencing for the identification of plasma DNA (cell-free DNA) aberrations in patients with systemic lupus erythematosus (SLE) (abstract lines 1-16). Chan teaches “the genome-wide methylation density of plasma DNA for each case refers to the proportion of CpG sites deemed to be methylated among all of the CpG sites covered by sequence reads (29). The genome-wide methylation density of the active SLE group (70.1% ± 4.5%) was significantly reduced compared to both the healthy individuals (74.3% ± 1.4%, P = 0.0367 …) and the inactive SLE group (74.4% ± 1.3%, P = 0.0118…)” (pg. E5305 -E5306 paragraph bridging pg. E5305 & E5306 lines 1-9). Chan does not say determining CpG sites that are all hypomethylated or all hypermethylated but hypomethylated and hypermethylated are relative terms and given how broadly the specification defines hypomethylation and hypermethylation (paragraph [0034] of specification of instant application) the examiner is interpreting Chan determining the methylation density of plasma DNA in the SLE group (first CpG site) as significantly reduced (hypomethylated) compared to healthy individuals (reference genome). Chan then teaches “the methylation densities of each 1-Mb bin across the genome … the plasma DNA methylation densities of the SLE patients were compared with the mean methylation density obtained from the 10 healthy individuals of the corresponding bin” (pg. E5306 column 1 1st full paragraph lines 1-5). Chan further teaches “Methy-Pipe was used to align converted reads to the two preconverted reference human genomes (pg. E5310 column 2 3rd full paragraph lines 1-3 & 10-11). Chan also teaches “it is noteworthy that the active SLE group showed greater reductions in methylation densities with progressive shortening of the plasma DNA fragments compared with the healthy individuals and patients in the inactive SLE group” (pg. E5306 paragraph bridging column 1 & 2 lines 13-16). Finally, Chan teaches that the plasma of SLE patients showed an increased proportion of short DNA fragments that are less than or equal to 115 bp compared to healthy individuals in which the median percent of short plasma DNA fragments in the plasma of active SLE patients was 31% compared to 10% in healthy individuals (around 3,000,000,000 base pairs in the human genome*0.31 (31% of short DNA fragments present in SLE patients)/115 bases (length of short DNA fragments as defined by Chan) = around 8 million short DNA fragments present in SLE patients samples (sequencing at least 100,000 cell-free DNA fragments in the biological sample of the subject)) (pg. E5305 column 1 1st full paragraph lines 1-13; pg. E5305 column 1 2nd full paragraph lines 1-12; Fig. 3). The examiner is interpreting Chan comparing methylation densities of each 1-MB bin across the genome with the use of Methy-Pipe to align the converted reads as aligning sequence reads to reference genome (healthy individuals) and further the examiner is interpreting the discovery of the active SLE group showing greater reductions in methylation densities with progressive shortening of the plasma DNA fragments as determining a relative abundance of cell-free DNA fragments covering the first set of CpG sites (the SLE group) compared to a reference value (healthy individuals) to determine a condition in a subject (active or inactive SLE).
Regarding amended claim 17, Chan teaches “it is noteworthy that the active SLE group showed greater reductions in methylation densities with progressive shortening of the plasma DNA fragments compared with the healthy individuals and patients in the inactive SLE group” (pg. E5306 paragraph bridging column 1 & 2 lines 13-16). In addition, Chan teaches that the plasma of SLE patients showed an increased proportion of short DNA fragments that are less than or equal to 115 bp compared to healthy individuals in which the median percent of short plasma DNA fragments in the plasma of active SLE patients was 31% compared to 10% in healthy individuals (around 3,000,000,000 base pairs in the human genome*0.31 (31% of short DNA fragments present in SLE patients)/115 bases (length of short DNA fragments as defined by Chan) = around 8 million short DNA fragments present in SLE patients samples (sequencing at least 100,000 cell-free DNA fragments in the biological sample of the subject)) (pg. E5305 column 1 1st full paragraph lines 1-13; pg. E5305 column 1 2nd full paragraph lines 1-12; Fig. 3), in which the examiner is interpreting determining a relative abundance of cell-free DNA fragments covering the first set of CpG sites (the SLE group) compared to a reference value (healthy individuals) in which the healthy individuals are interpreted to encompass the second set of CpG sites.
Regarding amended claim 18 & claim 19, Chan teaches “We reported in a previous study that shorter DNA fragments tend to be more hypomethylated (29)” (pg. E5306 paragraph bridging column 1 & 2 lines 1-2). Chan also teaches “we determined the methylation densities of DNA fragments of different sizes ranging from 20 to 250 bp, using sequence reads that covered at least 1 CpG site” (pg. E5306 paragraph bridging column 1 & 2 lines 7-9). The examiner is interpreting this teaching of Chan as determining the cell-free DNA fragments having a specified size in a specified size range (20 to 250 bp).
Regarding amended claims 21 & 22, Chan teaches “Bins with methylation densities that were more than 3 SDs lower or higher than the mean of the control group, namely with z-scores below -3 or above +3, were deemed as significantly hypo- and hypermethylated, respectively” (pg. E5306 column 1 1st full paragraph lines 5-8). Chan further teaches “it is noteworthy that the active SLE group showed greater reductions in methylation densities with progressive shortening of the plasma DNA fragments compared with the healthy individuals and patients in the inactive SLE group” (pg. E5306 paragraph bridging column 1 & 2 lines 13-16). The examiner is interpreting these teachings of Chan as the relative abundance of the cell-free DNA fragments as a statistical value of a size distribution of the DNA fragments that are deemed as significantly hypomethylated which correlate to the progressive shortening (in bp size) (first size) of the plasma (cell-free) DNA fragments in the active SLE group compared to patients in the inactive and healthy groups (second size).
Regarding claims 39 & 40, Chan teaches “Bins with methylation densities that were more than 3 SDs lower or higher than the mean of the control group, namely with z-scores below -3 or above +3, were deemed as significantly hypo- and hypermethylated, respectively” (pg. E5306 column 1 1st full paragraph lines 5-8). The examiner is interpreting this teaching of Chan as comparing a methylation level in the reference genome (healthy individuals) and determining the methylation level is below or above a threshold to determine hypomethylation or hypermethylation, respectively.
Regarding claim 42, Chan teaches “the percentages of bins with significant hypomethylation among the healthy individuals, inactive and active SLE patients are shown in Fig. 2C” (pg. E5306 column 1 1st full paragraph lines 9-11; Figure 2C). In addition, Chan teaches that the plasma of SLE patients showed an increased proportion of short DNA fragments that are less than or equal to 115 bp compared to healthy individuals in which the median percent of short plasma DNA fragments in the plasma of active SLE patients was 31% compared to 10% in healthy individuals (pg. E5305 column 1 1st full paragraph lines 1-13; pg. E5305 column 1 2nd full paragraph lines 1-12; Fig. 3). The examiner is interpreting this teaching of Chan as the relative abundance comprises a percentage of fragments covering the first set of CpG sites (the SLE group).
Response to Arguments
The response traverses the rejection. The response asserts that Chan teaches identifying regions of the subjects specific genome that are aberrantly methylated relative to a control group of healthy individuals and that in contrast claim 9 requires identifying a first set of CpG sites that are all hypomethylated or all hypermethylated in a reference genome. Further, the response asserts that Chan fails to disclose CpG sites that hypo- or hyper- methylated in the reference genome and instead Chan teaches a 1-Mb bin in the genome of a subject that is aberrantly methylated in comparison with a 1-Mb bin in and alleged reference genome (i.e., the genome of a control subject) and thus, the alleged hypo- or hyper- methylation taught by Chan is not identified for the reference genome. These arguments have been thoroughly reviewed but were not found persuasive. First, as discussed above and previously, Chan teaches the genome-wide methylation density of plasma DNA for each case refers to the proportion of CpG sites deemed to be methylated among all of the CpG sites covered by sequence reads and Chan teaches measuring the methylation densities of each 1-Mb bin across the entire genome in the active SLE, inactive SLE, and healthy samples. Therefore, Chan does not just teach measuring in a 1-Mb bin in the genome of a subject and instead teaches measuring in 1-Mb bins spanning the entire genome. Second, Chan teaches comparing methylation densities of each 1-MB bin across the entire genome with the use of Methy-Pipe to align the converted reads to healthy individuals samples in which the sequencing reads of the healthy individuals samples comprises a reference genome and, therefore, the hypo- or hyper- methylation taught in Chan is identified through comparison in a reference genome.
The response also asserts that methylation density is a measure of the amount of CpG sites that are methylated and instead claim 9 teaches a relative abundance of cell-free DNA fragments that cover a set of CpG sites and the coverage of CpG sites by the cell-free DNA molecules can be determined regardless of methylation and is therefore not the same as methylation density. Further, the response asserts that Chan is silent to determining coverage of CpG sites by cell-free DNA fragments and therefore fails to teach, disclose, or suggest a relative abundance of at least 100,000 cell-free DNA fragments covering the first set of CpG sites. These arguments have been thoroughly reviewed but were not found persuasive. First, Chan teaches that the active SLE group showed greater reductions in methylation densities with progressive shortening of the plasma DNA fragments compared with the healthy individuals and patients in the inactive SLE group and that the plasma of SLE patients showed an increased proportion of short DNA fragments that are less than or equal to 115 bp compared to healthy individuals in which the median percent of short plasma DNA fragments in the plasma of active SLE patients was 31% compared to 10% in healthy individuals (around 3,000,000,000 base pairs in the human genome*0.31 (31% of short DNA fragments present in SLE patients)/115 bases (length of short DNA fragments as defined by Chan) = around 8 million short DNA fragments present in SLE patients samples (sequencing at least 100,000 cell-free DNA fragments in the biological sample of the subject)) (pg. E5305 column 1 1st full paragraph lines 1-13; pg. E5305 column 1 2nd full paragraph lines 1-12; pg. E5306 paragraph bridging column 1 & 2 lines 13-16; Fig. 3). Therefore, Chan teaches determining coverage of CpG sites by cell-free DNA fragments (reductions in methylation densities (coverage of CpG sites) showing progressive shortening of DNA fragments compared to healthy samples) and Chan teaches determining the relative abundance of these short DNA fragments in active SLE samples compared to healthy individuals comprising around 8 million short DNA fragments present in active SLE samples (relative abundance of at least 100,000 cell-free DNA fragments covering the first set of CpG sites).
Finally, the response asserts that claims 17-19, 21, 22, 39, 40, & 42 each depend from and further limit the amended independent claim 9 and are therefore patentable for at least the same reasons that independent claim 9 is patentable. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
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) 10 & 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chan (Chan et al.; PNAS, Vol. 111, pages E5302-E5311, November 2014), as cited on the IDS dated 02/15/2023, in view of Serpas (Serpas et al.; PNAS, Vol. 116, pages 641-649, December 2018).
The teachings of Chan with respect to claim 9 is discussed above and incorporated herein.
Regarding amended claims 10 & 20, the recitation of “the relative abundance is an end density of sequence reads covering the first set of CpG sites” in lines 4-5 of claim 20 is unclear. The specification at paragraph [0018] defines “a “rate” of DNA molecules ending on a position relates to how frequently a DNA molecules ends on the position. Such a rate can be referred to as an “end density””, how is this position determined? What distinguishes a DNA molecule ending on a position being referred to in an end density from any other genomic position if the DNA molecule?
Chan teaches a method parallel genomic and methylomic sequencing for the identification of plasma DNA (cell-free DNA) aberrations in patients with systemic lupus erythematosus (SLE) (abstract lines 1-16), however Chan fails to teach determining aberrations in the SLE (diseased) sample in relation to the role of nucleases (claim 10) and that the relative abundance is an end density (claim 20).
Serpas teaches a method for determining aberrations in the fragmentation of plasma (cell-free) DNA in samples where the nuclease, DNASE1L3, was deleted (abstract lines 1-9). In addition, Serpas teaches “Dnase1l3-deficient mice develop anti-DNA IgG antibodies and progressive systemic-lupus erythematosus (SLE)-like disease (20), and we had previously [referring to Chan] demonstrated that human subjects with SLE had a variety of plasma DNA aberrations that were related to binding of anti-DNA antibodies to plasma DNA (21) … we examined mice doubly deficient in DNASE1L3 and CD40LG to distinguish between the primary effects of DNAS1L3 deficiency and secondary effects of anti-DNA response in such mice” (pg. 642 column 1 1st full paragraph lines 5-14). The examiner is interpreting this teaching of Serpas as determining aberrations in a diseased (SLE) in relation to the role of nucleases (DNASE1L3). In addition, Serpas teaches “our findings demonstrate that DNASE1L3 plays a role in circulating plasma DNA homeostasis by enhancing fragmentation and influencing end-motif frequencies” (abstract lines 22-24) and “the loss of DNASE1L3 reduced the frequencies of the most common sequence motifs of the plasma DNA ends” (pg. 643 paragraph bridging column 1 & 2 lines 26-28). The examiner is interpreting these teachings of Serpas as the relative abundance is an end density (frequency of end-motifs). Finally, Serpas teaches that the nuclease, DNASE1L3, was a component in the mechanism for generating circulating DNA fragments and that further analysis of nucleases with relation to circulating DNA can aid in the development of strategies for using the circulating DNA in molecular diagnostics.
Chan and Serpas are considered to be analogous to the claimed invention because they are all in the same field of sequencing for the detection of aberrations in cell-free DNA in disease samples. 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 determining a condition of SLE as taught in Chan to incorporate the analysis of a sample deficient in a nuclease (like DNASE1L3) and measuring end motif frequencies in the cell-free DNA fragments as taught in Serpas because Serpas teaches that doing so can aid in the development of strategies for the use of circulating DNA in molecular diagnostics.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chan (Chan et al.; PNAS, Vol. 111, pages E5302-E5311, November 2014), as cited on the IDS dated 02/15/2023, in view of Allen Chan (Allen Chan et al.; PNAS, Vol. 110, pages 18761-18768, November 2013).
The teachings of Chan with respect to claim 9 is discussed above and incorporated herein.
Regarding claim 11, Chan fails to teach the condition is cancer.
Allen Chan teaches a method of detecting genome-wide hypomethylation with parallel bisulfite (methylomic) sequencing as a marker for cancer through the detection of copy number aberrations in the plasma (cell-free) DNA in patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor (abstract lines 1-8). Finally, Allen Chan teaches this method of analyzing plasma hypomethylation may be a relatively cost-effective approach for cancer detection and monitoring (abstract lines 13-25).
Chan and Allen Chan are considered to be analogous to the claimed invention because they are all in the same field of parallel methylomic sequencing for the detection of aberrations in cell-free DNA samples. 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 level of SLE through parallel methylomic sequencing as taught in Chan to incorporate the detection of hypomethylation and aberrations in a cell-free DNA cancer sample as taught in Allen Chan because Allen Chan teaches that doing so would provide a cost-effective approach for cancer detection and monitoring.
Response to Arguments
The response traverses the rejection. The response asserts that Serpas and Allen Chan fail to cure the deficiencies noted above with respect to Chan nor are Serpas or Allen Chan relied upon in such a manner. The response further asserts that because the cited references, alone or in combination, fail to disclose or suggest each and every element of amended independent claim 9 such that amended claims 9 is patentable over the cited references and that claims 10, 11, & 20 each depend from and further limit amended independent claim 9 and are therefore patentable for at least the same reasons the independent claim is patentable. These arguments have been thoroughly reviewed but were not found persuasive as, as discussed above, Chan teaches each and every element of amended independent claim 9 and for the reasons set forth above.
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 9-11, 17-22, 39, 40, & 42 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682