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 .
Claim Status/Action Summary
This action is in response to the papers filed on February 20, 2026.
Claim 213 was canceled in the response. Claims 209-212 and 214-228 are under examination. No other claims are currently pending in the present application.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections to the specification and drawings have been withdrawn in view of the amendments to the specification. Sequence identifiers for the sequences present in Figure 2B are present in the substitute specification dated August 18, 2023 in the Brief Description of the drawings at paragraph [0039]. A replacement black and white version of Figure 2B has been filed in the response.
The objection to claim 226 has been withdrawn in view of the amendments to the claims.
The 112(b) and 112(d) rejections of record have been withdrawn in view of the amendments to the claims.
The 102 rejection of record over Mitra et al. has been withdrawn in view of the amendment to the independent claim, now requiring “target nucleic acids comprise cell free DNA”.
Priority
The present application was filed on February 20, 2023 and claims the benefit of U.S. Provisional Application 63/432,006, filed on December 12, 2022, and 63/312,2022, filed on February 20, 2022.
“Tables 1-4” are required by claim 221. Table 1 is present in the priority documents as Table A. Tables 2-4 don’t appear in the priority documents, and were added as supplements to the specification on February 20, 2023. Therefore, claim 221 enjoys the benefit of the February 20, 2023 filing date.
Drawings
The drawings with the replacement figure 2B filed on February 20, 2026 are acceptable.
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 209-212 and 214-228 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
This rejection has been updated as necessitated by the amendments to the claims.
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, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to a process that involves a natural principle and judicial exceptions.
Step 2A prong I
The claims are taken to be directed to a natural phenomenon and abstract ideas.
Claim 209 is directed to a method for determining a signal informative of a health condition from an individual comprising obtaining target and reference nucleic acids from a sample from the individual, wherein the target nucleic acids comprise cell free DNA and wherein the reference nucleic acids comprise genomic DNA from cells of the individual, generating sequence information from the target and reference nucleic acids, and combining the sequence information to generate the signal.
Claim 210 specifies that the health condition is a cancer.
Claims 211, 212, and 214 further require that the nucleic acids are obtained from a single sample of any one of several body fluids (claim 211) by fractionating the sample (claim 212) or wherein the cells of the individual are peripheral blood mononuclear cells or polymorphonuclear cells (claim 214).
Claim 215 requires that the “combining” step requires aligning the sequence information from the target and reference nucleic acids and determining a difference between the two sets of sequence information.
Claim 216 requires the sequence information comprises methylation information.
Claims 217-221 require that the sequence information comprises a plurality of phased methylation sequence information derived from 2 or more sources generated by aligning target sequences to long reference sequences that may be a maternal and paternal chromosome.
Claim 222 requires the “generating” step comprises performing one or more of the following assays: a) sequencing target and/or reference nucleic acids via targeted sequencing, whole genome sequencing, or whole genome bisulfite sequencing, b) shallow and/or deep sequencing, c) a nucleic acid amplification assay, or d) “an assay that generates methylation information”.
Claim 223 requires performing both shallow and deep sequencing.
Claim 224 specifies the shallow sequencing is performed for the reference nucleic acids and the deep sequencing is performed for the target nucleic acids.
Claims 225-226 define the relative terms “shallow” and “deep” sequencing.
Claim 227 requires comparing sequence information between two or more genomic sites in the target nucleic acids.
Claim 228 further requires determining a difference between the target and reference sequence information to remove baseline signatures, comparing between two or more methylated loci in the signal, and generating “a prediction of presence or absence of the health condition based on the comparison”.
A comparison to control is an abstract idea. (See MPEP 2106.04(a)(2)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014).
A correlation that preexists in the human is an unpatentable phenomenon. The association between the level or amount of methylation of the POU4F1 gene and pancreas cancer presence, evolution, or outcome is a law of nature/natural phenomenon. The “determining a signal informative of a health condition” and “generating a prediction” steps recited by claims 209 and 228 respectively, amount to no more than an “instruction to apply the natural law.” These “determining a signal” and “generating a prediction” steps amount to no more than a mental step. Even if the step requires something more such has to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end. Furthermore, the claims do not require the process user to do anything in light of the correlation between “the signal” and “a health condition”. The steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Step 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite additional elements that integrate the exception into a practical application of the exception.
Claim 209 is directed to a process that involves the judicial exceptions of a law of nature/natural phenomenon (i.e. the presence/absence/amount of a particular naturally occurring nucleic acid or nucleic acid modification (e.g. DNA methylation) and “a signal” informative of a health condition (i.e. the presence/absence or some other naturally occurring qualifier of a naturally occurring health condition). Claim 1 is further directed to the abstract idea of “combining the sequence information” from target and reference nucleic acids (i.e. a comparison to a control).
Claims 210, 214, 216-217, and 219-221 do not recite additional method steps. Rather, these steps require that the “health condition” or “target… and reference nucleic acids” comprise certain specific health conditions or types of nucleic acid information (i.e. methylation information) or that the samples recited by the independent claim are particular types of samples (i.e. biological samples, comprising particular cells, etc.)
Claims 215, 218, and 227-228 are directed to particular data processing steps (i.e. “aligning”, “determining a difference”, “categorizing”, and determining/comparing ratios derived from the sequencing information). As such, these steps are not an integration of the exception into a particular practical application. Rather, these are mere data processing steps and mental processes.
Claims 222-226 are directed to “generating sequence information” by particular “assay[s] that generate methylation information” comprising shallow and/or deep sequencing. These steps are not an integration of the exception into a particular application. Rather, these steps are data gathering steps required to perform the method of “determining a signal…”.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to “generating sequence information” are mere data gathering steps that amount to extra solution activity to the judicial exception. Claims 222 recites that generating sequence information comprises performing an assay, wherein the assay comprises one or more of: a) sequencing of target and or reference nucleic acids by targeted sequencing, whole genome sequencing, or whole genome bisulfite sequence; b) shallow sequencing and/or deep sequencing; c) a nucleic acid amplification assay; or d) an assay that generates methylation information. This step tells users to generate the sequencing information by methods comprising reduced-representation sequencing assays, whole genome sequencing assays, whole genome bisulfite sequencing assays, any depth of sequencing, any assay involving nucleic acid amplification (i.e. PCR, etc.), or any assay that generates methylation information (i.e. methyl-DNA-immunoprecipitation sequencing, methylation-specific PCR, methylation-specific-hybridization, digestion of non-methylated DNA with methylation-sensitive restriction enzymes, bisulfite sequencing, etc.) The claims do not recite a new, innovative method for generating sequence information. Methods for determining sequencing information (including those for determining methylation information) were well known in the art at the time the invention was made. The prior art, for example Liu et al., “Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA”, Annals of Oncology, Vol 31, Iss 6. 2020, pg 745-759 Published March 30, 2020, teach methods for determining cancer signatures (i.e. signals informative of a health condition) comprising measuring DNA methylation by whole genome bisulfite sequencing in cell-free DNA, tumor biopsies, and white blood cells (i.e. peripheral blood mononuclear cells) from individuals with cancer and control individuals without cancer (Liu et al., page 748, column 2, paragraph 4). The claims do not require the use of any particular non-conventional reagents. When recited at this very high level of generality, there is no meaningful limitation that distinguishes these steps from well understood, routine, and conventional activities prior to applicant’s invention and at the time the application was filed.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to arguments
The response asserts that the amended independent claim requiring: “obtaining target nucleic acids and reference nucleic acids from a sample from the individual, wherein the target nucleic acids comprise cell free DNA (cfDNA) and wherein the reference nucleic acids comprise genomic DNA from cells of the individual…” (emphasis in response) allegedly overcomes the 101 rejection of record for the following reasons:
The response asserts the amended claims are not directed to natural phenomena or abstract ideas, but to “a specific intra-individual analysis methodology requiring specific types of nucleic acids (i.e. cfDNA and genomic DNA from cells) as well as nucleic acid processing steps that cannot be performed mentally or reduced to mere observation of natural correlations. Further, the response asserts the “combining the sequence information…to generate the signal…” step “is not a mere mental comparison or observation of a natural correlation” because “sequence information of nucleic acids represents large-scale data that cannot readily be processed and combined simply in the human mind”.
These assertions/arguments have been thoroughly reviewed and are not persuasive.
As described in the 101 rejection above, the claims are directed to a method of determining a signal informative of a health condition (i.e. observing the correlation between the presence of the “signal” and a “health condition”), wherein the signal is a generic relative abundance (i.e. “sequence information”) of cell free DNA present in a sample (more narrowly; the amount of methylation at any locus in cfDNA relative to “genomic” DNA derived from cells from the same sample in some dependent claims) relative to “genomic DNA” present in cells in the same sample. The claims generically require “combining” the two types of sequence information to generate a signal (i.e. encompassing a simple comparison between the “target” cfDNA and the “reference” genomic DNA from cells (i.e. a comparison to an internal control). Therefore, the claims appear to encompass any method for observing the natural correlation that occurs in the human subject.
The assertion that steps recited in addition to the recited judicial exception (obtaining target nucleic acids; generically recited by unspecified methods) and (generating sequence information from the two populations of naturally occurring DNA; again generically recited by unspecified methods) is not persuasive because these steps are generically recited mere data gathering steps that appear to encompass any methods of “obtaining” the naturally occurring nucleic acids (i.e. any method of sample collection) and “generating sequence information” (i.e. any method of observing/identifying the naturally occurring nucleic acids). Likewise, the “combining the sequence information” step is generically recited to encompass any method of comparing the amount/presence/identity of the naturally occurring nucleic acid molecules in the human subject.
Finally, the assertion that the requirements that the cell-free and “genomic” DNA populations are obtained from “a single sample” and the combination of the sequence information derived therefrom represents an “unconventional and non-routine methodology for generating the signal informative of the health condition” is not persuasive at least because of the previously cited teachings of Liu et al. or Chiu et al.
Briefly, Liu et al. teach obtaining target and reference nucleic acids by fractionating peripheral blood into plasma (i.e. cell free DNA) and buffy coat fractions (i.e. genomic DNA from peripheral blood mononuclear cells or polymorphonuclear cells), respectively (Liu et al., supplementary information page 10-11), “peripheral blood from patients were collected… isolated into plasma and buffy coat… cell free DNA was extracted from plasma…” [and] “samples subjected to whole-genome bisulfite sequencing… included cfDNA… and WBCs” (i.e. white blood cells; buffy-coat cells)… and up to 75 ng of plasma DNA or gDNA was subjected to bisulfite conversion… and sequenced” measuring DNA methylation by whole genome bisulfite sequencing in cell-free DNA, tumor biopsies, and white blood cells (i.e. peripheral blood mononuclear cells) from individuals with cancer and control individuals without cancer (Liu et al., page 748, column 2, paragraph 4).
Similarly, as previously described, Chiu et al. teach differentiating subjects with cancer from subjects without cancer by comparing methylation sequence information between buffy coat (i.e. comprising white blood cells from blood) and plasma (i.e. cell free DNA) within an individual (Chiu et al., paragraph 0273), wherein “blood samples were collected from [a patient]… plasma and buffy coat were harvested after centrifugation of the blood samples (Chiu et al., paragraph 0267).
Therefore, both Liu et al. and Chiu et al. do, in fact, teach obtaining sequencing information of target nucleic acids comprising cfDNA (plasma DNA) and reference nucleic acids from cells (buffy coat; WBC) from a single sample and combining (i.e. comparing) the sequencing data from the two DNA fractions.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 209-212 and 214 are/remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al., “Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA”, Annals of Oncology, Vol 31, Iss 6. 2020, pg 745-759 (Published March 30, 2020).
This rejection has been updated as necessitated by the amendments to the claims and the cancellation of claim 213.
Regarding claim 209-210, Liu et al. teach methods for determining cancer signatures (i.e. signals informative of a health condition) comprising measuring DNA methylation by whole genome bisulfite sequencing in cell-free DNA, tumor biopsies, and white blood cells (i.e. peripheral blood mononuclear cells) from individuals with cancer and control individuals without cancer (Liu et al., page 748, column 2, paragraph 4).
Regarding claims 211, 212, and 214, Liu et al. teach obtaining target and reference nucleic acids by fractionating peripheral blood into plasma (i.e. cell free DNA) and buffy coat fractions (i.e. genomic DNA from peripheral blood mononuclear cells or polymorphonuclear cells), respectively (Liu et al., supplementary information page 10-11).
Response to arguments
The response asserts that Liu et al. does not teach obtaining target and reference nucleic acids from a sample from the individual (e.g., both target and reference nucleic acids are from a single sample from the same individual).
This assertion is not persuasive at least because Liu et al., do, in fact, teach obtaining target and reference nucleic acids by fractionating peripheral blood into plasma (i.e. cell free DNA) and buffy coat fractions (i.e. genomic DNA from peripheral blood mononuclear cells or polymorphonuclear cells), respectively (Liu et al., supplementary information page 10-11), “peripheral blood from patients were collected… isolated into plasma and buffy coat… cell free DNA was extracted from plasma…” [and] “samples subjected to whole-genome bisulfite sequencing… included cfDNA… and WBCs” (i.e. white blood cells; buffy-coat cells)… and up to 75 ng of plasma DNA or gDNA was subjected to bisulfite conversion… and sequenced” measuring DNA methylation by whole genome bisulfite sequencing in cell-free DNA, tumor biopsies, and white blood cells (i.e. peripheral blood mononuclear cells) from individuals with cancer and control individuals without cancer (Liu et al., page 748, column 2, paragraph 4).
The further argument that Liu et al. additionally utilize non-cancer controls in some embodiments of the methods disclosed therein is not persuasive at least because the present claims are recited with open “comprising” claim language: “a method… comprising… [positively recited steps]”.
The response further asserts that Liu et al. do not teach “combining the sequence information from the target nucleic acids… and the reference nucleic acids…). This assertion is likewise not persuasive. Liu et al. teach combining data comprising data from cf-DNA and WBCs derived from the same samples of cancer patients (see above) to derive a capture panel of sites that are differentially methylated.
Therefore, for these reasons and the reasons already of record, the rejections are maintained.
Claims 209-212, 214-217, 219-222, and 227-228 are/remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chiu et al., WO 2014/043763 A1 (published March 27, 2014).
This rejection has been updated as necessitated by the amendments to the claims and the cancellation of claim 213.
Regarding claim 209, Chiu et al. teach identifying methylation differences between nucleic acids obtained from hepatocellular carcinoma (HCC) patients’ plasma (i.e. target nucleic acids from cell-free nucleic acids) and buffy coat (i.e. reference nucleic acids from a sample comprising peripheral blood mononuclear cells or polymorphonuclear cells) (i.e. identifying signals informative of a health condition). Chiu et al. teach generating the sequence information by whole genome bisulfite sequencing and comparing the methylation density of the nucleic acids obtained from the plasma (i.e. cell-free DNA) and the buffy coat (i.e. PBMCs or polymorphonuclear cells) (i.e. combining the sequence information to generate the signal informative of the health condition) (Chiu et al., paragraphs 0267-0269).
Therefore, Chiu et al. teach each and every method step recited by claim 209.
Regarding claim 210, Chiu et al. teach the health condition is Hepatocellular Carcinoma (i.e. a cancer) (Chiu et al., paragraphs 0267-0269).
Regarding claims 211-212, Chiu et al. teach nucleic acids were obtained from plasma and buffy coat that were harvested after centrifugation of the blood samples (i.e. from a single blood sample by fractionation) (Chiu et al., paragraph 0267). Chiu et al. further teach buffy coat methylation is most similar to that of non-tumoral liver tissue (i.e. the buffy coat nucleic acids comprise genomic DNA and are the reference nucleic acids) and methylation of nucleic acids from plasma is between that of the non-tumoral and tumor tissues (i.e. cell free DNA comprises tumor DNA; is the target nucleic acids) (Chiu et al., paragraphs 0268).
Regarding claim 214, Chiu et al. teach the reference nucleic acids are derived from buffy coat (i.e. comprising PBMCs or polymorphonuclear cells) (Chiu et al., paragraphs 0267).
Regarding claim 215, Chiu et al. teach aligning the nucleic acids from the target and reference nucleic acids and determining a difference between the sequence information obtained from the reference and target nucleic acids (Chiu et al., paragraphs 0242-0252).
Regarding claim 216, Chiu et al. teach that the sequence information comprises methylation sequence information of the target nucleic acids (Chiu et al., paragraphs 0242-0252).
Regarding claim 217 and 219-221, Chiu et al. teach the sequence information comprises phased (i.e. parent-of origin-resolved) genome-wide methylation sequence information from a maternal and paternal chromosome for a plurality of genomic sites (i.e. imprinting status of gene loci) (Chiu et al., paragraphs 0253-0256 and Figures 15 and 26) including at CpG islands (Chiu et al., paragraph 0047).
Regarding claim 222, Chiu et al. teach generating sequence information comprises whole genome bisulfite sequencing (Chiu et al., paragraph 0090)
Regarding claim 227, Chiu et al. teach calculating methylation ratios for each CpG site by determining ratios between methylated and unmethylated alleles (i.e. two or more genomic sites from the target nucleic acids) (Chiu et al., paragraph 0099)
Regarding claim 228, Chiu et al. teach determining differentially methylated regions (i.e. a difference between the sequence information of the target and reference nucleic acids) by removing background DNA methylation from the signal and calculating methylation density amongst genomic bins (i.e. ratios of methylation levels amongst two or more CpG sites) (Chiu et al., paragraphs 0271-0275). Chiu et al. further teach comparing methylation density between cancer patients and healthy individuals allows for using plasma DNA methylation as a biomarker for the detection and monitoring of cancer (i.e. generating a prediction of presence or absence of a health condition).
Response to arguments
The response asserts that Chiu et al. does not anticipate the claims because the response asserts that Chiu et al does not teach “combining sequence information from the target nucleic acids and the reference nucleic acids…to generate a signal informative of a health condition”.
This assertion has been thoroughly reviewed and is not persuasive at least because Chiu et al. does, in fact, teach differentiating subjects with cancer from subjects without cancer by comparing (i.e. combining) methylation sequence information between buffy coat (i.e. comprising white blood cells from blood) and plasma (i.e. cell free DNA) within an individual (Chiu et al., paragraph 0273), wherein “blood samples were collected from [a patient]… plasma and buffy coat were harvested after centrifugation of the blood samples (Chiu et al., paragraph 0267) (i.e. the DNA inputs are from the same sample).
Therefore, for these reasons and those already of record, the rejections are maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 209, 217-218, and 222-226, are/remain rejected under 35 U.S.C. 103 as being unpatentable over Chiu et al., WO 2014/043763 A1 (published March 27, 2014) in view of Maestri et al., “A Long-Read Sequencing Approach for Direct Haplotype Phasing in Clinical Settings”, Int. J. Mol. Sci. 2020, 21(23), 9177 (published December 1, 2020).
This rejection has been updated as necessitated by the amendments to the claims and the cancellation of claim 213.
Regarding claim 209, Chiu et al. teach identifying methylation differences between nucleic acids obtained from hepatocellular carcinoma (HCC) patients’ plasma (i.e. target nucleic acids from cell-free nucleic acids) and buffy coat (i.e. reference nucleic acids from a sample comprising peripheral blood mononuclear cells or polymorphonuclear cells) (i.e. identifying signals informative of a health condition). Chiu et al. teach generating the sequence information by whole genome bisulfite sequencing and comparing the methylation density of the nucleic acids obtained from the plasma (i.e. cell-free DNA) and the buffy coat (i.e. PBMCs or polymorphonuclear cells) (i.e. combining the sequence information to generate the signal informative of the health condition) (Chiu et al., paragraphs 0267-0269).
Regarding claim 217, Chiu et al. teach the sequence information comprises phased (i.e. parent-of origin-resolved) genome-wide methylation sequence information from a maternal and paternal chromosome for a plurality of genomic sites (i.e. imprinting status of gene loci) (Chiu et al., paragraphs 0253-0256 and Figures 15 and 26) including at CpG islands (Chiu et al., paragraph 0047).
Regarding claim 218, Chiu et al. teach the sequence information comprises haplotype-resolved sequence information only where the observed locus comprises sequence differences between the two chromosomes (i.e. are “heterozygous loci”) (Chiu et al., paragraph 0372-0373). Chiu et al. teach that genomic DNA (i.e. reference nucleic acids) were sheared to approximately 200bp prior to bisulfite conversion and sequenced by 75bp paired-end Illumina sequencing (Chiu et al., paragraphs 0500-0502) yielding around 4x genome-wide coverage for reference nucleic acids and around 2x coverage for target nucleic acids (Chiu et al., figure 1A).
Chiu et al. do not teach aligning target nucleic acid reads to reference nucleic acids wherein the reference nucleic acid sequence reads comprise at least 500 bases.
However, Maestri et al. teach a method comprising long-read sequencing for more rapid and cost-effective haplotype reconstruction for the interpretation of disease relative to short-read sequencing (Maestri et al, page 9, paragraph 1-2). Maestri et al. teach haplotype reconstruction using read lengths between 11,276 and 13,276 bases (Maestri et al., page 12, paragraph 2), while direct haplotyping with short-read sequencing is typically limited to ~600bp due to the maximum read length of these techniques (Maestri et al., page 9 paragraph 1). Maestri et al. teach that while long-read nanopore sequencing allows for rapid and cost-effective haplotyping due to the long read lengths produced by the technique, the per-base accuracy “is not yet on par with short-read platforms” and may complement short-read technologies for variant phasing (Maestri et al., page 9 paragraph 2).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the method taught by Chiu et al. for identifying haplotype-resolved methylation differences between reference and target nucleic acid samples (i.e. genomic DNA from extracted from buffy coat cells and cell-free plasma DNA) using short-read sequencing with the method taught by Maestri for improved phasing of variants over longer haplotype blocks using nanopore sequencing to complement high-accuracy per-base short-read sequencing data.
The ordinary artisan would have been motivated to combine the long-read sequencing techniques to rapidly and cheaply phase genomic variants between homologous chromosomes (i.e. “maternal” and “paternal” chromosomes) in genomic DNA extracted from circulating WBCs (i.e. “buffy coat” cells) with a reasonable expectation of success because of the teaching of Maestri that nanopore sequencing is a cost-effective solution for direct variant phasing, particularly in the context of complementing short-read sequencing data that exhibits higher-per base accuracy (i.e. calling methylated nucleotides), but is limited in terms of haplotype reconstruction due to the maximum sequence length afforded by short-read sequencing techniques (Maestri et al., page 9).
Regarding claim 222, Chiu et al. teach generating sequence information comprises whole genome bisulfite sequencing (Chiu et al., paragraph 0090)
Regarding claim 223-226, Maestri et al. teach correct reference haplotypes were identified by whole genome sequencing using short read sequencing at 33x coverage (i.e. shallow sequencing) and long read sequencing at 60x coverage (i.e. deep sequencing) (Maestri et al., page 8).
Response to arguments
The response asserts that “the office has failed to establish a prima facie case of obviousness as the cited references fail to teach all the limitation of the claims” and identifies “as discussed above, with respect to the 102 rejections, Chiu et al. fails to teach at least “combining sequence information from the target nucleic acids… and the reference nucleic acids…”… [and] Maestri et al. does not remedy this deficiency.
This assertion has been thoroughly reviewed and is not persuasive. As discussed in the response to arguments against the 102 rejection of record over Chiu et al., this prior art reference does, in fact, teach “combining” said sequence information. As described above, Chiu et al., does, in fact, teach differentiating subjects with cancer from subjects without cancer by comparing (i.e. combining) methylation sequence information between buffy coat (i.e. comprising white blood cells from blood) and plasma (i.e. cell free DNA) within an individual (Chiu et al., paragraph 0273), wherein “blood samples were collected from [a patient]… plasma and buffy coat were harvested after centrifugation of the blood samples (Chiu et al., paragraph 0267) (i.e. the DNA inputs are from the same sample).
Therefore, for these reasons and those already of record, the rejections are 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.
Claim 209 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/009,567 (herein referred to as ‘567). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘567 anticipate the present claim 209.
Claim 1 of ‘567 recites a method for tracking tumor heterogeneity (i.e. determining a signal informative of a health condition) comprising: obtaining an intra-individual analysis comparing background-corrected methylation information from target nucleic acids from the first biological sample (i.e. obtaining target nucleic acids and generating target sequence information) to methylation information from reference nucleic acids from the first biological sample and… determining a change in signal between a first and second set of background-corrected methylation information… to track tumor heterogeneity (i.e. combining the sequence information to generate a signal informative of a health condition.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 209 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of U.S. Patent No. 11,788,152 B2 (herein referred to as ‘152). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘152 anticipate the present claim 209.
Claim 9 of ‘152 recites a method for detecting circulating tumor DNA in a blood sample of a subject (i.e. a signal informative of a health condition) comprising obtaining target and reference nucleic acids from a blood sample of the subject, wherein the reference nucleic acids comprise genomic DNA from PBMCs or polymorphonuclear cells of the subject, generating a dataset comprising methylation information (i.e. sequence information) from the target and reference nucleic acids, and combining the methylation information to generate background-corrected methylation information and analyzing the background-corrected methylation information to detect the presence of circulating tumor DNA in the blood sample (i.e. combining the sequence information to generate the signal informative of the health condition).
Claim 209 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of U.S. Patent No. 12,275,998 B2 (herein referred to as ‘998). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘998 anticipate the present claim 209.
Claim 10 of ‘998 recites a method for detecting circulating tumor DNA in a blood sample of a subject, comprising obtaining target and reference nucleic acids from a blood sample of a subject, wherein the reference nucleic acids comprise genomic DNA from PBMCs or polymorphonuclear cells, generating data comprising methylation information from the target and reference nucleic acids, and combining the methylation information from the target and reference nucleic acids to generate background-corrected methylation information and performing a second analysis to detect the presence of the circulating tumor DNA (i.e. combining the sequence information to generate a signal informative of the health condition).
Response to arguments
The response requests that the double patenting rejections be held in abeyance until allowable subject matter is reached. This request has been noted, however MPEP 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance, includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejections are maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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