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 .
Priority
This application claims priority to provisional 63/425,667, filed November, 15, 2022.
Elections/Restrictions
Applicant’s election with traverse of species (c): methods requiring measurement of a head-to-tail deletion on chromosome 6, in the reply filed on April 27, 2026, is acknowledged.
Claims 1-7 are pending in the application. Claim 1 is the generic claim. Claims 2-7 depend from claim 1. Claims 2 and 3 are readable on the elected species only insofar as they encompass the head-to-tail deletion on chromosome 6 (chr6:g.51,874,769_51,880,809del). Claims 4-7 are readable on the elected species. The non-elected subject matter within claims 2 and 3 directed to the head-to-tail deletion on chromosome 5, the tail-to-head duplication on chromosome 5, and the tail-to-head duplication on chromosome 15 is withdrawn from further consideration pursuant to 37 CFR 1.142(b).
The traversal is not found persuasive for the following reasons:
Applicant first argues that the search for the identified species substantially overlaps. This argument is not persuasive. The claimed structural variants occur at distinct genomic loci on different human chromosomes, namely chromosome 5, chromosome 6, and chromosome 15. Each chromosomal locus requires a separate prior art search directed to the specific chromosomal region and the specific structural variant occurring at that region. A prior art search directed to a head-to-tail deletion at chr6:g.51,874,769_51,880,809del would not retrieve prior art directed to a head-to-tail deletion on chromosome 5 at chr5:g.46,486,069_46,541,284del, a tail-to-head duplication on chromosome 5 at chr5:g.46541462_46496661dup, or a tail-to-head duplication on chromosome 15 at chr15:g.17394590_17093403dup, because each variant is defined by distinct chromosomal coordinates, distinct flanking sequences, and a distinct rearrangement type. Additionally, the head-to-tail deletions and tail-to-head duplications are structurally distinct rearrangements involving different molecular mechanisms, and each rearrangement type requires its own search strategy directed to the specific structural class. Applicant has not identified any specific prior art reference that would be retrieved by a single search directed to all six species, nor has Applicant identified any common search query, classification, or controlled-vocabulary term that would substantially reduce the search burden across the species. The mere assertion of overlap, without supporting evidence, is insufficient to overcome the showing of distinct fields of search set forth in the restriction requirement. See MPEP 818.03(c).
Applicant further argues that the issues regarding patentability are the same for these species. This argument is not persuasive. As set forth in the restriction requirement, the species are independent or distinct because the alternative types of measured structural variant occur on different chromosomes and require detection of different specific chromosomal structures, and these species are not obvious variants of each other based on the current record. Prior art relevant to one species, for example a reference disclosing a head-to-tail deletion on chromosome 6, would not necessarily render obvious to a tail-to-head duplication on chromosome 15, because the chromosomal location, the rearrangement type, and the genomic context differ. Accordingly, there is a serious search and/or examination burden for the patentably distinct species . The mere assertion that patentability issues are the same, without supporting evidence, is insufficient to overcome the showing of independence and distinctness set forth in the restriction requirement. See MPEP 818.03(c).
For at least the above reasons, the requirement is deemed proper and is therefore made FINAL. Applicant’s election with traverse of species (c) is acknowledges, and the restriction requirement is maintained.
Status of Claims
Claims 1-7 are pending and currently under examination to the extent of elected species pertaining to measurement of a head-to-tail deletion on chromosome 6.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The eligibility of claims under 35 U.S.C. 101 is analyzed under the two-part framework set forth in MPEP § 2106. Under this framework, the claims are first evaluated to determine whether they fall within a statutory category and whether they are directed to a judicial exception, and, if so, whether the claims as a whole recite additional elements that integrate the exception into a practical application or otherwise amount to significantly more than the exception itself. See Gottschalk v Benson, 409 U.S. 63, 67 (1972). Considering the claims as a whole, including all additional elements both individually and in ordered combination, the claims fail to meet the requirements for patent eligibility under 35 U.S.C. 101.
Step 1: Statutory Category
The claimed invention is directed to a process.
Step 2A Prong 1: Does the Claim Recite a Judicial Exception?
The claims are directed to a judicial exception. Claim 1 recites:
A method for detecting congenital heart disease (CHD) in a fetus, comprising: (a) obtaining a blood sample from a pregnant female; (b) extracting a fetal genomic DNA from the maternal blood sample; (c) measuring a level of the fetal genomic DNA for a panel of CHD- susceptible structural variants selected from a head-to-tail deletion or a tail-to-head duplication occurring on human chromosome 5, 6 or 15; (d) applying each of the measured fetal genomic DNA of the panel of CHD-susceptible structural variants against a database created by analyzing measured fetal genomic DNA levels of control subjects with no CHD; wherein the applying compares the expression level for each of the CHD-susceptible structural variants to fetal genomic DNA levels of control subjects using whole-genome sequencing, wherein the database comprises a threshold value for the expression level for each of the CHD-susceptible structural variants; and (e) indicating that the pregnant female has an increased risk of expecting a fetus with CHD if the measured fetal genomic DNA of the panel of CHD- susceptible structural variants is greater than the threshold value.
The bolded and italicized portions of step (e) recite a naturally occurring correlation between the level of CHD-susceptible structural variants present in fetal genomic DNA and the risk of congenital heart disease in the fetus. That correlation exists in nature independent of any human action: the relationship between the presence of head-to-tail deletions or tail-to-head duplications on human chromosome 5, 6, or 15 in the fetal genome and the fetus’s underlying risk of CHD is a consequence of the fetus’s own genome and is not created by the recited measuring or comparing step. The cited correlation is therefore a law of nature and natural phenomenon. See Mayo Collaborative Services v Prometheus Laboratories, Inc., 566 U.S. 66, 77 (2012); MPEP 2106.04(a)(2)(II). The natural character of this correlation is further confirmed by the scientific literature, which documents the relationship between copy-number and structural variation on chromosomes 5, 6, and 15 and the risk of CHD as a naturally occurring biological relationship. See Glessner et al., Tomita-Mitchell et al., and Castiglione et al. The claims are therefore taken to be directed to a judicial exception.
Step 2A Prong 2: Is the judicial Exception Integrated into a practical Application?
The judicial exception is not integrated into a practical application. The additional elements recited in claim 1 beyond the natural correlation are limited to (a) obtaining a blood sample from a pregnant female, (b) extracting fetal genomic DNA from the maternal blood sample, (c) measuring the level of the fetal genomic DNA for the panel of CHD-susceptible structural variants by whole genome sequencing, and (d) applying each measured level against a database of control-subject levels that comprises a threshold value. These additional elements amount to nothing more than routine pre-solution data gathering followed by a conventional post-solution comparison of the gathered data to a threshold derived from control-subject data. The sample-collection, extraction, and sequencing steps are mere data-gathering activities ancillary to the recited natural correlation, and the database/threshold comparison us a conventional post-solution use of the correlation. Such activities do not impose a meaningful limit on the judicial exception. See MPEP 2106.05(g) (insignificant extra-solution activity); MPEP 2106.04(d).
The Federal Circuit has held that obtaining cell-free fetal DNA from maternal plasma and detecting it using known techniques is a conventional implementation of a natural phenomenon and does not impose a meaningful limit on the exception. See Ariose Diagnostics, Inc. v. Sequenom, Inc., 788F.3d 1371, 1377 (Fed. Cir. 2015). The workflow recited in claim 1, maternal blood sampling, cffDNA extraction, next generation/whole genome sequencing of the fetal DNA, structural variant calling, and case/control database comparison against a threshold value, is well understood, routine, and conventional in the prenatal genomics and CHD genetics fields. The claims do not recite any improvement to sample preparation, sequencing chemistry, variant calling methodology, or any other technical field; they recite generic data gathering followed by a generic comparison to a threshold. For these reasons, the judicial exception is not integrated into a practical application. See MPEP 2106.04(d); MPEP 2106.05(g).
Step 2B: Does the Claim Add Significantly More than the Judicial Exception?
The additional elements identified above, considered both individually and as an ordered combination, do not amount to significantly more than the judicial exception. Each of the recited additional elements is well understood, routine, and conventional in the relevant art, as established by multiple non-patent publications and by the applicant’s own specification. See Berkheimer v HP INC.; MPEP 2106.05(d)(II) (multiple publications describing an element are sufficient evidence of WURC status).
Obtaining a maternal blood sample and extracting fetal genomic DNA. Obtaining a blood sample from a pregnant female and recovering cell-free fetal DNA (cffDNA) from that sample is a conventional non-invasive prenatal testing (NIPT) procedure that was well-established long before the effective filing date. See Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377 (Fed. Cir. 2015) (recovery of cffDNA from maternal plasma using known techniques is conventional); Huang et al. (describing NIPT based prenatal CHD screening using maternal plasma cffDNA as an established clinical workflow).
Measuring the level of fetal genomic DNA for the panel of structural variants by whole-genome sequencing. Whole-genome and next-generation sequencing of fetal or genomic DNA to detect CHD associated copy number and structural variants is a well understood, routine, and conventional approach in the CHD genetic field. See Liu et al., Glessner et al., and Tomita-Mitchell et al.
Structural variant/CNV detection from sequencing data using the established bioinformatics tools. Detection of structural variants and indels from whole genome sequencing data using off the shelf bioinformatics pipelines is also well-understood, routine, and conventional. See Wala et al. and Chen et al.
Applying the measured fetal genomic DNA against a database of control subject levels using a threshold value. Comparing measured variant levels in case subjects against a database of control subject levels, and using a threshold derived from that control distribution to call risk, is routine case/control analytical paradigm in the CHD genetics field. See Glessner et al., Tomita-Mitchell et al., and Liu et al.
The WURC status of these additional elements is reinforced by the applicant’s own specification, which describes the isolation of cell-free DNA from maternal blood by centrifugation and known enrichment techniques, the performance of whole-genome sequencing as a standard examination of the fetal genome, and the use of off-the-shelf bioinformatic tools, including BWA, samtools, PICARD, SvABA, Manta, and Plink2, in accordance with well-established methods. See Spec. [0026], [0027], [0044]-[0049]. Simply appending well-understood, routine, and conventional activities previously known to the industry, specified at a high level of generality, is not enough to qualify as significantly more than the judicial exception. See MPEP 2106.05(I)(A); MPEP 2106.05(d). For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim 2 depends from claim 1 and further recites that the CHD-susceptible structural variants are markers expressed in a database of CHD subjects and not present in the database of control subjects. This limitation further describes the recited natural correlation between the structural variants and CHD risk and does not change the eligibility analysis. Claim 2 is therefore rejected for the same reasons as claim 1.
Claim 3 depends from claim 1 and further recites specific genomic coordinates for the CHD-susceptible structural variants, including a head-to-tail deletion at chr6:g.51,874,769_51,880,809del. The recited coordinates identify the naturally occurring loci at which the recited correlation is observed and further describe the natural exception itself. See Castiglione et al. and Glessner et al. Claim 3 is therefore rejected for the same reasons as claim 1.
Claim 4 depends from claim 1 and further recites that the blood sample is obtained through non-invasive prenatal testing (NIPT). NIPT is a well-understood, routine, and conventional sample-collection modality in the prenatal-genomics field. See Huang et al. See Ariosa, 788 F.3d at 1377. Claim 4 is therefore rejected for the same reasons as claim 1.
Claim 5 depends from claim 1 and further recites a risk assessment performed using a rigorous and precise algorithm based on a dataset of CHD cases and controls. No specific algorithm is recited, and the generic computation of a risk score from case/control data is itself a mental process within the abstract-idea exception. See Glessner et al. Claim 5 is therefore rejected for the same reasons as claim 1.
Claim 6 depends from claim 1 and further recites analyzing maternal genomic DNA to assess the genetic risk of CHD in the fetus. This limitation adds an additional conventional data-gathering and comparison step and further recites the same kind of natural correlation as the parent claim. See Glessner et al. and Tomita-Mitchell et al. Claim 6 is therefore rejected for the same reasons as claim 1.
Claim 7 depends from claim 5 and further recites that the risk assessment is performed in conjunction with fetal echocardiography and maternal serum screening. Both fetal echocardiography and maternal serum screening are conventional, standard-of-care prenatal screening modalities, and their addition as adjunct tests does not change the eligibility analysis. See Huang et al. Claim 7 is therefore rejected for the same reasons as claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 4, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 2020/0058372 A1) in view of Liu et al. (Front Genet 10:819, 2019), Tomita-Mitchell et al. (Physiol Genomics 44:518-541, 2012), Wala et al. (Genome Res 28(4):581-591, 2018), and Chen et al. (Bioinformatics 32(8):1220-1222, 2016).
Regarding claim 1, the claim recites, “A method for detecting congenital heart disease (CHD) in a fetus, comprising: obtaining a blood sample from a pregnant female; extracting a fetal genomic DNA from the maternal blood sample; measuring a level of the fetal genomic DNA for a panel of CHD-
susceptible structural variants selected from a head-to-tail deletion or a tail- to-head duplication occurring on human chromosome 5, 6 or 15; applying each of the measured fetal genomic DNA of the panel of CHD-susceptible structural variants against a database created by analyzing
measured fetal genomic DNA levels of control subjects with no CHD; wherein the applying compares the expression level for each of the CHD-susceptible structural variants to fetal genomic DNA levels of control subjects using whole-genome sequencing, wherein the database comprises a threshold value for the expression level for each of the CHD-susceptible structural variants; and indicating that the pregnant female has an increased risk of expecting a fetus with CHD if the measured fetal genomic DNA of the panel of CHD- susceptible structural variants is greater than the threshold value.”
Claim 1 is parsed into the following discrete limitations:
Obtaining a blood sample from a pregnant female;
Extracting a fetal genomic DNA from the maternal blood sample;
Measuring a level of the fetal genomic DNA for a panel of CHD-susceptible structural variants selected from a head-to-tail deletion of chromosome 6
Applying each of the measured fetal genomic DNA of the panel of CHD-susceptible structural variants against a database created by analyzing measured fetal genomic DNA levels of control subjects with no CHD;
Wherein the applying compares the expression level for each of the CHD-susceptible structural variants to fetal genomic DNA levels of control subjects using whole-genome sequencing, wherein the database comprises a threshold value for the expression level for each of the CHD-susceptible structural variants; and
Indicating that the pregnant female has an increased risk of expecting a fetus with CHD if the measured fetal genomic DNA of the panel of CHD-susceptible structural variants is greater than the threshold value.
Regarding limitation (a) recited in claim 1, Kim et al. teaches obtaining a maternal blood specimen as the input to a noninvasive prenatal testing workflow ([0005], [0037]-[0042]).
Regarding limitation (b) recited in claim 1, Kim et al. teaches isolating cell-free DNA (cfDNA) from maternal plasma to capture the fetal-origin cfDNA fraction present in the maternal circulation for downstream genomic analysis ([0106]; [0045]; [0218]; [0004]; [0308]).
Regarding limitation (c) recited in claim 1, Kim et al. teaches constructing libraries directly from the maternal plasma cfDNA, subjecting those libraries to massively parallel sequencing on a next-generation platform, aligning the resulting short reads to a reference human genome, and analyzing the aligned read data to detect fetal subchromosomal microdeletions and microduplications carried by the fetal fraction of the maternal plasma cfDNA ([0082]; [0302]; [0311] [0308]; [0093]; [0329]; [0019] [0024]); Kim et al. expressly contemplates extension of the disclosed cfDNA-NGS workflow beyond the whole-chromosome aneuploidy use case to clinically relevant subchromosomal copy-number changes by application of downstream analytic modules to the aligned cfDNA reads ([0022]; [0019]; [0028]-[0029]). Kim et al., however, does not explicitly teach that the panel of structural variants is a CHD-susceptible panel of head-to-tail deletion on chromosome 6. Regarding the CHD-susceptible panel aspect of limitation (c), Tomita-Mitchell teaches a genome-wide human gene copy number spectra analysis in congenital heart malformations, surveying CNV gain and loss events genome-wide in CHD probands and characterizing the recurrent CHD-associated CNV gain/loss spectrum across the genome, including identification of recurrently affected genomic intervals (Abstract; Fig. 4; Table 7; Table 5; Table 6; p. 539, col. 2); and Liu et al. teaches that rare CNVs at CHD-relevant loci are enriched in CHD phenotyped probands relative to unaffected reference individuals (p. 2, col. 1; p. 7; p. 5; p. 8, col. 1). Regarding the “head-to-tail deletion” terminology of limitation (c), Wala et al. teaches detection of deletions and tandem duplications from aligned short-read whole-genome sequencing by the SvABA local-assembly structural-variant caller (Abstract; p. 583, col. 1; Table 1; p. 588, col. 1; p. 582, col. 2), and Chen et al. teaches detection of deletions from aligned short-read data by the Manta structural-variant caller (Abstract; p. 1220; Table 1; p. 1221, col. 1); the “head-to-tail deletion” descriptor recited in claim 1 map to the same breakpoint orientations that the SvABA and Manta callers report under the conventional “deletion” label (Wala; Table 1; p. 583, col. 1)(Chen; p. 1221, col. 1; Table 1), which is a difference of nomenclature rather than of substance.
Regarding limitation (d) recited in claim1, Kim et al. does not explicitly teach a control-subject reference database against which detected variants are evaluated. Regarding limitation (d), Liu et al. teaches a case-control copy number variant burden analysis in congenital heart disease, comparing rare CNVs identified in CHD phenotyped case probands to those observed in unaffected reference individuals, and treats the case versus control cohort comparison as the means by which a CNV’s CHD relevance is established (Table 1; p. 2, col. 2; p. 5-6).
Regarding limitation (e) recited in claim 1, Kim et al. teaches that the comparison proceeds through massively parallel sequencing of library prepped maternal plasma cfDNA with alignment to a reference human genome ([0308], [0097], [0301], [0082], [0116], and [0122]). Kim et al., however, does not explicitly teach that the database comprises a threshold value for the expression level for each of the CHD susceptible structural variants. Regarding the threshold value aspect of limitation (e), Liu et al. teaches enrichment of rare CNVs at CHD relevant loci in case relative to controls and treats burden enrichment as the operative signal of CHD association (p. 7, col. 1; p. 2, col. 1; p. 5, col. 1; p. 6, col. 1; Fig. 1).
Regarding limitation (f) recited in claim 1, Kim et al. does not explicitly teach indicating increased CHD risk as a function of the per variant threshold comparison. Liu et al. teaches that burden enrichment of CHD relevant CNV’s in CHD phenotyped cases above the unaffected control baseline is the operative signal of CHD association (p. 2, col. 1; p. 7, col. 1; p. 2, col. 2; p. 5, col. 1; p. 6, col. 1).
The combined teachings of Kim et al., Liu et al., Tomita-Mitchell., Wala et al., and Chen et al., render claim 1 prima facie obvious. Kim’s et al. maternal plasma cfDNA-NGS pipeline, Liu’s et al. CHD case/control CNV burden framework, Tomita-Mitchell et al. CHD CNV gain/loss spectrum, and the SvABA structural variant caller of Wala et al. and the Manta structural variant caller of Chen et al. each occupy a recognized position in this routine practice, and their combination in the manner contemplated by claim 1 reflects nothing more than the predictable composition of recognized pipeline components in the manner that the prenatal-genomics field had already adopted at the relevant date.
It would have been obvious to combine prior art elements according to known methods to yield predictable results; a noninvasive prenatal screening method that takes maternal-plasma cfDNA as input (Kim et al.), processes that input library preparation, massively parallel sequencing, alignment, and structural variant calling (Kim et al., Wala et al., and Chen et al.), and evaluates the resulting breakpoint calls against a CHD case/control reference framework drawn from the CHD proband cohort (Liu et al. and Tomita-Mitchell et al.) yields the entirely predictable result of a noninvasive prenatal screen for CHD associated structural variants. CHD cohort case/control burden analysis (Liu et al. and Tomita-Mitchell et al.) is a known technique for assessing the CHD relevance of detected variants; applying that known technique to the structural variant call set produced by a Kim et al./Wala et al./Chen et al. pipeline improves the cdDNA-NGS screening method in the same way that case/control burden analysis improves any other variant calling workflow, by replacing an undifferentiated catalog of detected variants with a phenotype anchored interpretation. The Kim et al. cfDNA-NGS pipeline is a known method that was ready for improvement in the direction of CHD specific risk assessment: Kim’s et al. own disclosure expressly contemplates extension of the pipeline beyond whole-chromosome aneuploidies ([0022]; [0019]; [0028]; [0308]), and the SvABA and Manta structural variant callers (Wala et al. and Chen et al.) together with the CHD case/control reference framework (Liu et al. and Tomita-Mitchell) were the recognized improvements available in the art to make the extension to CHD associated structural variants.
A person of ordinary skill in the art would have had a reasonable expectation of success in combining the cited references in the manner contemplated by claim1. The factual basis for that expectation is that each element of the combination was independently and well-established in the prior art before the effective filing date. Maternal plasma cfDNA-NGS pipelines proceeding from blood collecting through cfDNA isolation, library preparation, massively parallel sequencing, alignment, and downstream variant analysis were established by Kim et al. ([0308], [0097], [0301], [0082], [0116], and [0122]). CHD case/control CNV burden analysis on CHD proband cohorts was established by Liu et al. (p. 7, col. 1; p. 2, col. 1; p. 5, col. 1; p. 6, col. 1; Fig. 1) and by Tomita-Mitchell’s et al. CHD CNV gain/loss spectrum analysis (Abstract; Fig. 4; Table 7; Table 5; Table 6; p. 539, col. 2). Short read structural variant calling by local assembly methods was established by Wala et al. for SvABA (Abstract; p. 583, col. 1; Table 1; p. 588, col. 1; p. 582, col. 2) and by Chen et al. for Manta (Abstract; p. 1220; Table 1; p. 1221, col. 1);). The predictable result of the combination is the very result described in the application: a CHD-CNV detection method that operates on maternal plasma cfDNA input and reports an indication of fetal CHD risk based on genome-wide structural variant calls evaluated against a CHD case/control reference dataset. Where each pipeline element performs its independently established function in the combination and the case/control framework is itself anchored to the 1000 Genomes Project reference set mentioned in the instant application at [0048] drawn directly from the prior art, the skilled artisan would have proceeded to assemble the combined method with a reasonable expectation that the pipeline would operate as intended.
Regarding claim 2, the claim recites, “The method of claim 1, wherein the CHD-susceptible structural variants are specific markers are only expressed in a database created by analyzing measured fetal genomic DNA levels of CHD subjects and not presented in the database created by control subjects.” Kim et al. does not explicitly teach a CHD versus control differential presence framework. Liu et al. teaches that the operative signal of CHD association is enrichment of rare CNVs at CHD relevant loci in CHD phenotyped case probands relative to unaffected reference individuals (p. 7, col. 1; p. 2, col. 1; p. 5, col. 1; p. 6, col. 1; Fig. 1), i.e., variants that are present in the CHD case set and not present (or present only at baseline rate) in the control reference set; and Tomita-Mitchell further teaches identification of recurrently affected genomic intervals across the CHD cohort as the CHD specific component of the CNV gain/loss spectrum (Abstract; Fig. 4; Table 7; Table 5; Table 6; p. 539, col. 2). The motivation to combine and reasonable expectation of success are the same as fully articulated above for claim 1.
Regarding claim 4, the claim recites that “The method of claim 1, wherein the blood sample is obtained through non- invasive prenatal testing (NIPT).” Kim et al. teaches noninvasive prenatal testing methods that obtain a maternal blood specimen and isolate cell-free fetal DNA from maternal plasma for downstream NGS analysis ([0082]; [0302]; [0311] [0308]; [0093]; [0329]; [0019] [0024]).The motivation to combine and reasonable expectation of success are the same as fully articulated above for claim 1.
Regarding claim 5, the claim recites, “The method of claim 1, wherein the method further comprises a risk assessment for CHD in the fetus based on the presence of the CHD- susceptible structural variants, wherein the risk assessment for CHD is performed using a rigorous and precise algorithm based on a dataset of CHD cases and controls.” Claim 5 adds to claim 1 (i) the limitation of performing a risk assessment for CHD in the fetus based on the presence of the CHD- susceptible structural variants, and (ii) the limitation that the risk assessment is performed using a rigorous and precise algorithm based on a dataset of CHD cases and controls.
Regarding limitation (i) of claim 5: Liu et al. teaches that the case control CNV burden comparison yields a phenotype anchored CHD association assessment keyed to the presence of CHD relevant CNVs in the case set (Table 1; p. 2, col. 2; p. 7; Table 3), and Tomita Mitchel et al. teaches identification of recurrent CHD associated CNV intervals as the basis for CHD phenotype assessment (Abstract; p. 518, col. 2; p. 538, col. 2; p. 526, col. 2). The risks assessment output of the combined Kim/Liu/Tomita-Mitchell/Wala/Chen et al. method, applied to a maternal plasma cfDNA input is itself a CHD risk assessment based on the presence of the CHD susceptible structural variants identified by the pipeline.
Regarding limitation (ii) of claim 5 Kim et al. does not teach a rigorous case/control risk assessment algorithm. Liu et al. teaches a case-control copy number variant burden analysis as a rigorous statistical algorithm that compares rare CNVs identified in CHD phenotyped case probands to those observed in unaffected reference individuals, with burden enrichment treated as the operative signal of CHD association (p. 2, col. 2; p. 5, col. 1; p. 7, col. 1); Tomita-Mitchell et al. teaches the CHD CNV gain/loss spectrum across the CHD cohort that supplies the case-side dataset on which the burden analysis operates (p. 524, col. 2; p. 526, col. 2; p. 519, col. 1; Abstract). The motivation to combine and reasonable expectation of success are the same as fully articulated above for claim 1.
Regarding claim 6, the claim recites, “The method of claim 1, wherein the method further comprises analyzing maternal genomic DNA to assess the genetic risk of CHD in the fetus.” Kim et al. teaches that the cfDNA-NGS workflow operates on cell-free DNA isolated from maternal plasma, which fraction comprises maternal origin cfDNA fragments alongside the fetal cfDNA fraction; library preparation, massively parallel sequencing, and alignment proceed on the entire pooled maternal plasma cfDNA ([0311]; [0302]; [0106]; [0293] [0301]; [0308]; [0090]; [0115]-[0116]). The structural variant calling that operates on the aligned BAM input thereby processes reads derived from the maternal genomic DNA fraction as part of the same call set. Wala et al. teaches that SvABA calls deletions, tandem duplications, inversions, and translocation from aligned BAM input by local reassembly of discordant and split reads at the breakpoint locus (p. 583, col. 1; Table 1; p. 581, col. 1; p. 582, col. 2; Abstract; Fig. 1), and Chen teaches that Manta calls deletions, tandem duplications, insertions, inversions, and translocations from aligned short read data through graph based candidate breakpoint enumeration followed by local assembly and breakpoint refinement (Table 1; p. 1221, col. 1; p. 1220; p. 1221, col. 1; Abstract). The motivation to combine and reasonable expectation of success are the same as fully articulated above for claim 1.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 2020/0058372 A1) in view of Liu et al. (Front Genet 10:819, 2019), Tomita-Mitchell et al. (Physiol Genomics 44:518-541, 2012), Wala et al. (Genome Res 28(4):581-591, 2018), and Chen et al. (Bioinformatics 32(8):1220-1222, 2016), and further in view of Castiglione et al. (Cytogenet Genome Res, 2013) and Glessner et al. (Circ Res 115(10):884-896, 2013).
The Kim et al., Liu et al., Tomita-Mitchell et al., Wala et al., and Chen et al., combination set forth above with respect to claim 1 is carried forward in the rejection of claim 3 in its entirety. Castiglione et al. teaches chromosome 6 short arm structural rearrangements as a recognized chromosomal class associated with congenital heart disease phenotypes and reports CHD associated rearrangements localized to the short arm off chromosome 6 in CHD probands and in CHD phenotyped chromosomal rearrangement series (p. 2, col. 1; p. 13 col. 2; p. 7, col. 1; Table 2). Glessner et al. teaches the integrative genomic analysis of de novo copy number variants in the PCGC CHD cohort and reports and increased frequency of de novo CNVs in CHD probands across the genome, including chromosome 6, with identification of CHD associated CNV intervals from the PCGC cohort by case/control burden comparison (Abstract; p. 887, col. 2; Table 1; p. 891, col. 1)
There is not a single reference of record identifies the specific interval recited in the elected species, namely chr6:g.51,874,769_51,880,809del. The rejection of claim 3 does not rest on a teaching suggestion motivation theory specific to those coordinates. The rejection rests, rather on the predictable result of applying the prior art’s genome wide pipeline (Kim et al., Wala et al., and Chen et al.) cfDNA-NGS and SvABA Manta intersection workflow with the intersection admission described in the instant specification at [0045] to the prior art’s CHD cohort, the PCGC cohort interrogated in Liu et al., Glessner et al., and the instant specification at [0046], against the prior art’s unaffected reference set, the 1000 Genomes Project as admitted in instant specification at [0048] to produce the very small, focal, CHD associated deletions on chromosome 6.
Under MPEP 2143, rationale (D), the Kim/Liu/ Tomita-Mitchell/Wala/Chen combined method is a known method that was ready for improvement in the direction of identifying specific small CHD associated deletions, and Castiglione’s et al, chromosome 6 short arm CHD rearrangement class and Glessner’s et al. PCGC genome wide de novo CNV burden findings supply the prior art directions in which that improvement was already being pursued. As secondary support, under MPEP 2143, rationale (E), the candidate locus search space, once the PCGC cohort is interrogated genome wide by the SvABA/Manta intersection pipeline against the 1000 Genomes Project reference set, is a finite set of small, focal, statistically enriched CHD associated intervals; identification of any particular locus within that finite, identified, predictable solution set, including the chr6:g.51,874,769_51,880,809del interval situated within the chromosome 6 CHD associated class established by Castiglione and within the genome wide PCGC CHD-CNV class established by Glessner et al, was obvious to try with a reasonable expectation of success.
A person of ordinary skill in the art would, further have had a reasonable expectation of success in arriving at the elected chr6:g.51,874,769_51,880,809del species through application of the combined method. The factual basis for that expectation is as above, that the pipeline (Kim, Wala, Chen), the cohort (PCGC, Liu, and Glessner), the SV callers (SvABA: Wala; Manta: Chen), the statistical case/control burden framework (Liu, Tomita-Mitchell, Glessner) the unaffected reference set (1000 Genomes Project) and the chromosome 6 CHD association class (Castiglione, Glessner) were each independently and well established in the prior art before the effective filing date. Applying that established pipeline to that established reference set, and locating the resulting enriched signal within the established chromosome 6 CHD association class, the skilled artisan would have proceeded with a reasonable expectation that the elected chr6:g.51,874,769_51,880,809del species, a small, focal, chromosome 6 deletion of the class to which Castiglione and Glessner both point, would be among the outputs of the combined method.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 2020/0058372 A1) in view of Liu et al. (Front Genet 10:819, 2019), Tomita-Mitchell et al. (Physiol Genomics 44:518-541, 2012), Wala et al. (Genome Res 28(4):581-591, 2018), and Chen et al. (Bioinformatics 32(8):1220-1222, 2016), and further in view of Huang et al. (Risk Management Health Policy 14:345-355, 2021 January 27) and Donofrio et al. (Circulation 129(21):2183-2242, 2014).
Regarding claim 7, the claim recites, “The method of claim 5, wherein the risk assessment is performed in conjunction with other prenatal diagnostic tests, comprising fetal echocardiography and maternal serum screening.” The Kim et al., Liu et al., Tomita-Mitchell et al., Wala et al., and Chen et al., combination set forth above with respect to claim 1 is carried forward in the rejection of claim 7 in its entirety. Regarding the fetal echocardiography limitation of claim 7 the Kim et al., Liu et al., Tomita-Mitchell et al., Wala et al., and Chen et al., combination does not teach the use of fetal echocardiography as an adjunctive prenatal diagnostic test in conjunction with the genetic risk assessment of claim 5. Donofrio et al. teaches the diagnosis and treatment of fetal cardiac disease and describes fetal echocardiography and maternal serum screening as standard of care modalities in the prenatal evaluation of fetal cardiovascular risk (p. 2184, col. 1; p. 2185; p. 2193, Field Echocardiography; Table 3; Table 6). Huang et al. teaches the integration of noninvasive prenatal testing with adjunctive prenatal screening modalities in the management of pregnancies at risk for congenital fetal abnormalities, including the role of NIPT derived information alongside conventional prenatal screens (Abstract; p. 353, col. 2).
Under MPEP 2143, rationale (G), Donofrio’s et al American Heart Association standard of care statement supplies an express teaching, suggestion, and motivation to combine the genetic risk assessment of claim 5 with the recited adjunctive modalities of fetal echocardiography and maternal serum screening because Donofrio et al. identifies those modalities as the routine prenatal cardiology workup against which any additional risk assessment modality is to be integrated (p. 2184, col. 1; p. 2185; p. 2193, Field Echocardiography; Table 3; Table 6). The skilled artisan, presented with the genetic risk assessment produced by the Kim et al., Liu et al., Tomita-Mitchell et al., Wala et al., and Chen et al., combination of claim 5 and with Donofrio’s et al. standard of care framework would have been motivated to combine the genetic risk output with fetal echocardiography and maternal serum screening as the established prenatal cardiology workup, and Huang et al. confirms the routine practice of integrating NIPT-derived information into that workup (pp. 346-353). Under MPEP 2143, rationale (A), it would have been prima facie obvious to combine the genetic risk assessment of claim 5 (Kim et al., Liu et al., Tomita-Mitchell et al., Wala et al., and Chen et al., combination) with the established adjunctive prenatal-cardiology modalities of fetal echocardiography and maternal serum screening according to the established integration practice to yield the predictable result of a multimodal prenatal CHD risk evaluation.
A person of ordinary skill in the art would have had a reasonable expectation of success in combining the genetic risk assessment of claim 5 with the adjunctive modalities recited in claim 7. The factual basis for that expectation is that fetal echocardiography and maternal serum screening were established standard of care prenatal cardiology modalities (p. 2184, col. 1; p. 2185; p. 2193, Field Echocardiography; Table 3; Table 6), and the integration of NIPT derived genetic information into the conventional prenatal screening workup was the established routine practice in the field (Abstract; p. 353, col. 2). The combination contemplated by claim 7, adding the genetic risk assessment of claim 5 (whose own reasonable expectation of success basis is set forth in the rejection of claim 1 above and is carried forward) to the established echocardiography plus serum screening workup, is the routine application of the established standard of care framework to a new but compatible input modality, with no element of the combination operating outside its established function. The skilled artisan would therefore have proceeded to perform the combined risk assessment with a reasonable expectation that the integration would operate as intended.
Conclusion
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/BREANNA MARIE TAVERNINI/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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