DETAILED ACTION
The Applicant’s response, received 07 November 2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Status of the Claims
Claims 1-4 and 6-12 are pending.
Claims 1-4 and 6-12 are rejected.
Priority
Independent claim 1 and dependent claims 2-4 and 6-12 are not given the benefit of priority to U.S. Provisional Application Nos. 61/982,245, filed 21 April 2014; 61/987,407, filed 01 May 2014; 61/994,791 filed 16 May 2014; 62/066,514, filed 21 October 2014; 62/146,188, filed 10 April 2015; 62/147,377, filed 14 April 2015; and 62/148,173, filed 15 April 2015, because there is not support for the limitation reciting “the sequencing has a depth of read of at least 20,000 per target locus” (independent claim 1 and dependent claims 2-4 and 6-12) or the limitation reciting “the sequencing has a depth of read of at least 50,000 per target locus” (dependent claim 2).
Dependent claims 3, 4, and 6-12 are construed as incorporating by reference all the limitations of the claim from which they depend (claim 1), thereby requiring a depth of read of at least 20,000 per target locus.
Therefore, claims 1-4 and 6-12 are given the benefit of U.S. Patent Application No. 14/692,703, filed 21 April 2015. Support for the limitations reciting “the sequencing has a depth of read of at least 20,000 per target locus” (claims 1, 3, 4, and 6-12) and the limitation reciting “the sequencing has a depth of read of at least 50,000 per target locus” (claim 2) can be found at ¶ [00353] in the specification.
Therefore, the effective filing date of the claimed invention is 21 April 2015.
Terminal Disclaimer
As noted in the Office actions of record, the terminal disclaimers (three separate disclaimers) filed on 09 December 2024 for Patent No.: 11,530,454, Application Numbers 17/692,469 and 18/753,991, have been reviewed and are accepted. The terminal disclaimers have been recorded.
Information Disclosure Statement
The information disclosure statement (IDS) received 22 October 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112
The rejection of claims 1-4 and 6-12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 11 August 2025 is withdrawn in view of the amendment received 07 November 2025.
The Applicant’s amendment received 07 November 2025 has been fully considered, however after further consideration, new grounds of rejection are raised under 35 U.S.C. 112(a) & 112(b) in view of the amendment.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4 and 6-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the limitation “non-naturally occurring composition of amplified cell-free DNA,” however the Specification does not contain the term “non-naturally occurring composition” with regard to amplified cell-free DNA. Furthermore, there are no steps or guidance in the Specification to provide for amplification which results in a composition that is non-naturally occurring. This appears to be a new scope not contemplated nor supported by the present specification.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4 and 6-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite for reciting the limitation “non-naturally occurring composition of amplified cell-free DNA” at step (b) and at step (c), because it is unclear as to what the metes and bounds are with regard to the term “non-naturally occurring” (e.g., does the term “non-naturally occurring” intend to limit the claim to a composition created in vitro, and/or sequences that are generated because of alterations that might introduced at processing steps such as amplification and/or sequencing). Claim 1 is further indefinite because it is unclear as to which element of the “composition of amplified cell-free DNA” is “non-naturally occurring,” (e.g., is the non-naturally occurring element a linkage element associated with an adaptor or primer that is part of the amplification process?). The limitation “non-naturally occurring composition of amplified cell-free DNA” is interpreted to encompass a composition of cell-free DNA fragments with short synthetic sequences (e.g., adapters) ligated to both ends of the cell-free DNA fragments that enable, e.g., binding to the sequencer’s flow cell, and/or initiate amplification, and/or allow for sample indexing/barcoding; and/or short synthetic sequences (e.g., primers) hybridized to the previously attached adapters.
Claims 2-4 and 6-12 are indefinite for depending from claim 1 and for failing to remedy the indefiniteness of claim 1.
Claim Rejections - 35 USC § 101
The Applicant’s amendment received 07 November 2025 has been fully considered, however after further consideration, the rejection of claims 1-4 and 6-12 under 35 U.S.C. 101 in the Office action mailed 11 August 2025 is maintained with modification in view of the amendment.
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 1-4 and 6-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: mental processes, i.e., concepts performed in the human mind (e.g., observation, evaluation, judgement, opinion).
Claim Interpretation
The limitation “non-naturally occurring composition of amplified cell-free DNA” is interpreted to encompass a composition of cell-free DNA fragments with short synthetic sequences (e.g., adapters) ligated to both ends of the cell-free DNA fragments that enable, e.g., binding to the sequencer’s flow cell, and/or initiate amplification, and/or allow for sample indexing/barcoding; and/or short synthetic sequences (e.g., primers) hybridized to the previously attached adapters.
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 1-4 and 6-12 are directed to a method (i.e., a process) of preparing a non-naturally occurring composition of amplicons.
Therefore, these claims are encompassed by the categories of statutory subject matter, and thus, satisfy the subject matter eligibility requirements under Step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A: Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 1 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
to identify one or more disease-associated mutations (i.e., mental processes); and
determine the presence or absence of the one or more disease-associated mutations in the fetal cell-free DNA from the sequence reads (i.e., mental processes).
Dependent claims 3, 4, and 9-12 further recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below.
Dependent claim 3 further recites:
wherein the disease-associated mutations comprise a single nucleotide variant (SNV) (i.e., mental processes).
Dependent claim 4 further recites:
wherein the disease-associated mutations comprise an insertion or deletion (i.e., mental processes).
Dependent claim 9 further recites:
wherein the disease-associated mutations are associated with cystic fibrosis, sickle-cell disease, or muscular dystrophy (i.e., mental processes).
Dependent claim 10 further recites:
wherein if the sequencing on the cellular DNA sample of the pregnant woman identifies the pregnant woman as a carrier for a mutation associated with cystic fibrosis, the method further comprises determining whether the fetal cell-free DNA comprise a haplotype containing the mutation associated with cystic fibrosis (i.e., mental processes).
Dependent claim 11 further recites:
determining the most likely disease state of a fetus carried by the pregnant woman (i.e., mental processes).
Dependent claim 12 further recites:
wherein if the sequencing on the cellular DNA sample of the pregnant woman identifies the pregnant woman as a carrier for 22q11.2 deletion, the method further comprises determining whether the fetal cell-free DNA comprise a haplotype containing the 22q11.2 deletion.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., comparing sequence read data to a reference sequence to identify one or more mutations), and therefore recite judicial exceptions from the mental process grouping of abstract ideas.
Therefore, claims 1-4 and 6-12 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A: Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
The additional elements in independent claim 1 include:
performing sequencing on a cellular DNA sample of a pregnant woman, wherein the cellular DNA sample of the pregnant women is a buffy coat sample;
preparing a non-naturally occurring composition of amplified cell-free DNA by performing targeted multiplex amplification to amplify 10 to 500 target loci from cell-free DNA isolated from a plasma sample of the same pregnant woman or DNA derived therefrom, wherein the non-naturally occurring composition of amplified cell-free DNA comprises amplicons having a length of 50-150 bases, wherein the target loci encompass the one or more disease-associated mutations identified in the buffy coat sample of the same pregnant woman;
wherein the target loci are amplified together in the same reaction volume;
wherein the cell-free DNA isolated from the plasma sample comprises a mixture of fetal cell-free DNA and maternal cell-free DNA; and
analyzing the non-naturally occurring composition of amplified cell-free DNA by sequencing the amplicons to obtain sequence reads, wherein the sequencing has a depth of read of at least 20,000 per target locus.
The additional elements in dependent claims 2, 6, 7, and 8 include:
wherein the sequencing of step (c) has a depth of read of at least 50,000 per target locus (claim 2);
wherein the targeted multiplex amplification amplifies 10 to 50 target loci each encompassing a different disease-associated SNV mutation (claim 6);
wherein the targeted multiplex amplification amplifies 50 to 100 target loci each encompassing a different disease-associated SNV mutation (claim 7); and
wherein the method further comprises performing barcoding PCR prior to the sequencing of step (c) (claim 8).
The additional elements of performing sequencing on a cellular DNA sample of a pregnant woman, wherein the cellular DNA sample of the pregnant women is a buffy coat sample (claim 1); performing targeted multiplex amplification (claim 1; and claim 8 further limits the amplification step by performing barcoding PCR) to amplify 10 to 500 target loci (claims 6 and 7 further limit the target loci) from cell-free DNA isolated from a plasma sample of the same pregnant woman or DNA derived therefrom to obtain amplicons having a length of 50-150 bases, wherein the target loci encompass the one or more disease-associated mutations identified in the buffy coat sample of the same pregnant woman (claim 1); wherein the target loci are amplified together in the same reaction volume (claim 1); wherein the cell-free DNA isolated from the plasma sample comprises a mixture of fetal cell-free DNA and maternal cell-free DNA (claim 1); and sequencing the amplicons to obtain sequence reads, wherein the sequencing has a depth of read of at least 20,000 per target locus (claim 1; and claim 2 further limits the sequencing depth of read); are steps of gathering data for use in the claimed process (i.e., to determine the presence or absence of the one or more disease-associated mutations in the fetal cell-free DNA from the sequence reads), and are therefore insignificant extra-solution activities that do not integrate the recited judicial exceptions into a practical application (see MPEP 2106.05(g)).
Thus, the additionally recited elements amount to insignificant extra-solution data gathering activity, and as such, when all limitations in claims 1-4 and 6-12 have been considered as a whole, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 1-4 and 6-12 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 3, 4, and 9-12 do not recite any elements in addition to the judicial exception(s).
The additional elements recited in independent claim 1 and dependent claims 2, 6, 7, and 8 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of performing sequencing on a cellular DNA sample of a pregnant woman, wherein the cellular DNA sample of the pregnant woman is a buffy coat sample; performing targeted multiplex amplification to amplify 10 to 500 target loci from cell-free DNA isolated from a plasma sample of the same pregnant women to obtain amplicons having a length of 50-150 bases, wherein the target loci encompass the one or more disease-associated mutations identified in the buffy coat sample of the same pregnant women, wherein the cell-free DNA isolated from the plasma sample comprises a mixture of fetal cell-free DNA and maternal cell-free DNA; and sequencing the amplicons to obtain sequence reads, wherein the sequencing has a depth of read of at least 20,000 or 50,000 per target locus; are conventional.
Evidence of conventionality is shown by Deciu et al. (US 2013/0338933, as cited in the Office action mailed 11 August 2025).
Deciu et al. shows circulating cell-free DNA (CCF DNA) was extracted from plasma from pregnant women, and DNA was also extracted from maternal buffy coat samples for confirmation of maternal genotypes (para. [1167]); maternal DNA (i.e., buffy coat) samples were sequenced (para. [1174]); performing multiplex PCR of 67 SNPs and sequencing the ccf DNA from the plasma of a pregnant mother (para. [0119]; and FIG. 165); the amplification reaction is performed in a single vessel (e.g., tube, container, well on a plate) which sometimes is referred to as multiplexed amplification (paras. [0270] & [1170]); allele frequencies per targeted SNP measured for buffy coat DNA (maternal genotype) and the paired pregnant plasma DNA (maternal and fetal genotypes) (paras. [0121] & [0122]; and FIG. 167 & FIG. 168); the amplification reactions can be size-specific, e.g., greater than 100 base pair amplicons (para. [0102]), and in one example a total of 261 amplicons were used for validation with the minimum amplicon length being 108 base pairs (para. [1071]); and that amplicon nucleic acids have the same or substantially the same nucleotide sequence as the target nucleic acid (para. [0197]) and that in some embodiments, 100% of fetal nucleic acid is of a length of about 150 base pairs or less (para. [0195]) and in some cases, the genomic DNA target sequence length is 70 base pairs (para. [0216]); and sequencing amplicon libraries from plasma and buffy coat samples that generated reads such that the after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP (para. [1177]).
Further evidence of conventionality of performing sequencing on a cellular DNA sample of a pregnant woman to identify one or more disease-associated mutations, wherein the cellular DNA sample of the pregnant women is a buffy coat sample; performing targeted amplification of polymorphic loci and sequencing of maternal and placental cell-free DNA, and comparing with maternal SNPs in the buffy coat DNA; is shown by Bianchi et al. (Clinical Chemistry, 2014 (Published 19 Nov. 2013), Vol 60(1), pp. 78-87, as cited in the Office action mailed 11 August 2025). Bianchi et al. reviews noninvasive prenatal testing (NIPT) and autosomal and sex chromosome aneuploidy detection (Title; and Abstract), and shows differences in the technical approaches to sequencing of circulating cell-free DNA in the plasma of pregnant women, including isolating cell-free DNA and buffy coat DNA, targeted sequencing of tagged molecules, amplification of polymorphic loci (SNPs), and comparing the plasma DNA (maternal & plasma) with the maternal SNPs in the buffy coat DNA (FIG. 1); fetal cell-free DNA fragments are predominantly 143 bp in length (page 79, col. 1, para. 2); targeted sequencing with amplification of 192 loci that contain SNPs (p. 79, col. 2, para. 2); and incorporating maternal genotype information (i.e., from the buffy coat) with fetal cell-free DNA to construct fetal genotypes (page 79, bottom, to page 80, top).
Further evidence of conventionality is shown by Snyder et al. (Prenatal Diagnosis, 2013, Vol. 33, pp. 547-554, as cited in the Office action mailed 11 August 2025). Snyder et al. reviews noninvasive fetal genome sequencing (Title) and shows whole genome sequencing of a human fetus using only parental DNA samples and plasma from the pregnant mother (Abstract); and further shows an overview of noninvasive fetal genome sequencing (Figure 1) with sample collection steps including extracting parental DNA from either peripheral blood mononuclear cells (PBMC) or buffy coat, and isolating cell-free DNA (cfDNA) from the maternal plasma (step (a)); amplifying the extracted DNA and sequencing the amplicons to a high depth, and aligning reads to a reference genome to identify variant alleles carried by one or both parents (step (b)).
The additional element of multiplex amplification wherein the target loci are amplified together in the same reaction volume, is conventional. Evidence for the conventionality is shown by Beaulieu et al. (US 2005/0079521, as cited in the Information Disclosure Statement received 02 December 2024, and as cited in the Office action mailed 11 August 2025) and Leamon et al. (US 2012/0295819, as cited in the Information Disclosure Statement received 02 December 2024, and as cited in the Office action mailed 11 August 2025).
Beaulieu et al. shows that multiplex polymerase chain reaction (PCR) is a variant of PCR in which two or more target sequences can be amplified by including more than one pair of primers in the same reaction (para. [003]).
Leamon et al. shows that in some embodiments, the target-specific primers can be provided in one or more aliquots of target-specific primer pairs that can be pooled prior to performing the multiplex PCR reaction in a single amplification vessel or reaction chamber (para. [0198]).
Further evidence of conventionality of sequencing to a high depth of read (i.e., 20,000 reads per target locus (claim 1) and 50,000 reads per target locus (claim 2)) is shown by Rieneck et al. (Transfusion, 2013, Vol. 53, pp. 2892-2898, as cited in the Office action mailed 13 September 2024); Narayan et al. (Cancer Research, 2012, Vol. 72(14), pp. 3492-3498, as cited in the Office action mailed 11 August 2025); Zhang et al. (WO 2012/125848, as cited in the Office action mailed 11 August 2025); Kukita et al. (PLoS ONE, 2013, Vol. 8(11): e81468. doi: 10.1371/journal.pone.0081468, pp. 1-10, as cited in the Office action mailed 11 August 2025); Patel (WO 2013/138510, as cited in the Information Disclosure Statement received 02 December 2024, and as cited in the Office action mailed 11 August 2025); Ciccarelli et al. (WO 2010/019588, as cited in the Office action mailed 11 August 2025); and Leamon et al. (WO 2006/110855, as cited in the Information Disclosure Statement received 02 December 2024, and as cited in the Office action mailed 11 August 2025).
Rieneck et al. shows using next-generation sequencing on cell-free fetal DNA from maternal plasma (Title; and Abstract) and further shows amplification and subsequent deep sequencing and identification of all SNPs at a given position (page 2895, col. 2, para. 1) and a sequencing depth of approximately 100,000 reads (page 2895, col. 2, para. 2); and further shows sequencing results with the number of reads at the KEL1/2 SNP base position that range from hundreds of reads per SNP base to more than one million reads per SNP base position (Table 3).
Narayan et al. shows ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing (Title; and Abstract) and further shows obtaining a median depth of 108,467 read pairs per mutation site per sample (page 3494, col. 2, para. 1).
Zhang et al. shows a method for comprehensive sequence analysis using deep sequencing technology (Title; and Abstract) and further shows a clinically applicable deep sequencing technique using Next Generation Sequencing (NGS) in clinical diagnosis that demonstrates uniform coverage of each of the 16,569 bases of the mitochondrial genome at over 100,000-fold average reads per nucleotide, for example (paras. [0003] & [0010]).
Kukita et al. shows quantitative identification of mutant alleles derived from lung cancer in plasma cell-free DNA using deep sequencing data (Title; and Abstract) and further shows that read depth for one assay mostly exceeded 100,000 (page 8., col. 2, para. 2).
Patel shows measurement of nucleic acid variants using highly-multiplexed error-suppressed deep sequencing (Title; and Abstract) and further shows performing massively parallel sequencing on PCR amplicons derived from plasma DNA fragments and obtaining a median depth of 108,467 read pairs per mutation site per sample (page 35, para. 2).
Ciccarelli et al. shows a method for detecting or diagnosing genomic instability (Title; and Abstract) and further shows the average depth of coverage of sequencing (reads/base pair) in various samples ranging from 45,370 to 52,530 (para. [0008]).
Leamon et al. shows methods for determining sequence variants using ultra-deep sequencing (Title; and Abstract) and further shows a method to determine the nucleotide sequence of a polynucleotide region of interest at great depth, i.e., the number of individual sequence reads spanning a given region of interest, and that the depth may range from about 10 to about 1 million (page 4, lines 24-33).
The additional element of performing barcoding PCR prior to the sequencing is conventional. Evidence for the conventionality is shown by Shendure et al. (Nature Biotechnology, 2012, Vol. 30, No. 11, pp. 1084-1094, newly cited). Shendure et al. reviews the expanding scope of DNA sequencing (Title; and Abstract), and shows the basic workflow structure of sequencing experiments including the modification and tagging of extracted nucleic acids, e.g., barcoding (Figure 2(b)); and further shows sample indexing or molecular tagging by appending a synthetic index or barcode subsequence to all molecules in a given sequencing library (page 1090, col. 2, para. 3); and further shows an application of next-generation DNA sequencing to determine the functional consequences of genetic variation wherein the genetic manipulation included process steps of barcoding and PCR prior to sequencing (Table I, Ex. reference 93).
Therefore, when taken alone, all additional elements in claims 1-4 and 6-12 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as a combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 1-4 and 6-12 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments/remarks received 07 November 2025 have been fully considered, however they are not persuasive.
The Applicant states on page 5 (bottom) and page 6 (top) of the Remarks that as currently amended, the claims are not directed to a judicial exception, but to a method of preparing a composition of amplified DNA, which is a patent eligible process under the decision in Illumina v. Ariosa Diagnostics, 952 F.3d 1367 (Fed. Cir. 2020), and that in Illumina v. Ariosa Diagnostics, the Federal Circuit held that a claim reciting “[a] method for preparing a deoxyribonucleic acid (DNA) fraction from a pregnant human female useful for analyzing a genetic locus involved in a fetal chromosomal aberration, comprising (a) extracting DNA…; (b) producing a fraction of DNA extracted in (a)…; and (c) analyzing a genetic locus produced in (b)” is patent eligible because it is considered a method of preparation and not a method of diagnosis. The Applicant further states that the Federal Circuit stated “we conclude at step one of the Alice/Mayo test that the claims are not directed to a patent-ineligible concept, and we need not reach step two of the test.” The Applicant further states on page 6 (para. 3) that similar to the claim found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics, amended claim 1 of the instant application is directed to a method for preparing a preparation of amplified DNA, and similarly recite steps such as preparing a preparation of amplified DNA by performing amplification, and analyzing the preparation of amplified DNA, and accordingly, consistent with the Federal Circuit decision in Illumina v. Ariosa Diagnostics, the amended claims of the instant application are directed to methods of preparation, and are not directed to a patent-ineligible concept at step one of the Alice/Mayo test, and it is unnecessary to reach step two of the test.
These arguments are not persuasive, because first, the instant claims are analyzed for eligibility in accordance with their broadest reasonable interpretation, and are further analyzed based on the fact patterns set forth by the limitations recited in the claims. Thus, the eligibility analysis of the instant claims in the rejection above results in a different eligibility outcome than in Illumina v. Ariosa Diagnostics, not least because the decision before the Federal Circuit in Illumina v. Ariosa Diagnostics was based on whether or not the claims at issue recited a law of nature at step one of the Alice/Mayo test, which contrasts with the fact pattern of the instant claims and the above eligibility analysis of the instant claims, i.e., the above rejection does not determine that the instant claims recite a law of nature at eligibility Step 2A Prong One.
The Applicant states on page 7 (para. 1) of the Remarks that according to Example 31 of the USPTO Subject Matter Eligibility Examples (May 2016) (hereinafter “USPTO Example 31”), a technology is not routine and conventional merely because it had been discussed in scientific publications, but rather, it must be established that the technology was actually routinely or conventionally used by scientists at the time the invention was made and the application was filed. The Applicant further states (para. 2) that in USPTO Example 31, claim 70 was found patent eligible because it recites the use of scanning near-field optical microscopy (SNOM) for measuring hybridization of a DNA probe to a wild type gene, and that by way of background, USPTO Example 31 states that “the use of SNOM to study DNA hybridization had been discussed in several articles in widely-read scientific journals,” and that USPTO Example 31 further provides that “[a]lthough SNOM was known to scientists at the time the invention was made and the application was filed, e.g., because it had been discussed in several widely-read scientific journals, mere knowledge of this technique does not make the use of SNOM to detect DNA hybridization routine or conventional. The Applicant further states that, instead, the evaluation turns on whether the use of SNOM to detect DNA hybridization was actually routinely or conventionally used by scientists at the time the invention was made and the application was filed. The Applicant further states that the Applicant disagrees with the Office action (mailed 11 August 2025, pages 13-18) that cites multiple references that allegedly show that “all additional elements in claims 1-4 and 6-12 do not amount to significantly more than the above-identified judicial exceptions” and even “when evaluated as a combination, the additional elements fail to transform the exceptions into a patent-eligible application of that exception.”
These arguments are not persuasive, because first, the Eligibility Examples are hypothetical and only intended to be illustrative of the claim analysis performed using MPEP 2106, and of the particular issues noted in the Example. The Examples should be interpreted based on the fact patterns set forth in a particular Example, as other fact patterns may have different eligibility outcomes, as evidenced in the rejection of the instant claims above. Second, the fact pattern of the hypothetical USPTO Example 31 eligibility analysis differs from the fact pattern in the eligibility analysis of the instant claims, not least because with hypothetical USPTO Example 31, SNOM was known to scientists at the time the invention was made and the application was filed, because it had been discussed in several widely-read scientific journals, whereas in contrast, the multiple references cited at Step 2B in the eligibility analysis of the instant claims provide evidence that scientists were actually using the instantly claimed steps identified as additional elements at 2A Prong Two (and carried over to Step 2B for further analysis).
The Applicant summarizes and disputes the references used at Step 2B in the eligibility analysis on pages 7-9 of the Remarks, and states on page 9 (para. 3) that accordingly, the present claimed invention was not routinely and conventionally used at the time the application was filed, and amounts to significantly more than the above-identified judicial exception.
These arguments are not persuasive, because the combination of references cited at Step 2B provide evidence of conventionality of the additional elements identified at Step 2A Prong Two and carried over to Step 2B for further analysis, as noted and discussed in the above rejection.
The Applicant states on page 9 (para. 4) of the Remarks that USPTO Example 31 further explained that a claim that only recites a mental step of comparing “at a high level of generality that merely requires comparison of two pieces of information and imposes no limits on how the comparison is performed” is patent ineligible. The Applicant further states that the method claim found ineligible in USPTO Example 31 had only one step, and the additional elements of the claim did not further define how the method should be performed, whereas in sharp contrast, the present claims recite multiple tangible, biochemical steps for obtaining genetic data combined with further steps for how the genetic data are used to determine the presence or absence of a genetic mutation in the fetal cfDNA, and accordingly, in view of USPTO Example 31, the present claims are not directed to an abstract idea because the claims recite a multistep method, wherein each step has meaningful limits on how the method is performed.
These arguments are not persuasive, because hypothetical claim 1 of the hypothetical USPTO Example 31 was determined to recite an abstract idea at Step 2A (USPTO Subject Matter Eligibility Examples (May 2016), page 25, para. 3) and further determined to not recite any additional elements or combination of additional elements that would be sufficient to ensure that the claim amounts to significantly more than the judicial exceptions at Step 2B (Ibid., para. 5). Thus, the Applicant’s attempt at analogizing the instant claims to hypothetical claim 1 of hypothetical USPTO Example 31 is not persuasive, because the fact pattern of hypothetical claim 1 of hypothetical USPTO Example 31 is not analogous to the fact pattern of instant claim 1.
The Applicant states on page 10 (para. 1) of the Remarks that the instant claims are patent eligible because when viewed as a whole the claims amount to significantly more than the judicial exception. The Applicant further states that among a list of limitations that qualifies as “significantly more,” the presently claimed invention add limitations, that, when the claim is considered as a whole, qualify as (1) improvement to the technical field; and (2) non-routine and non-conventional limitations. The Applicant further states (para. 2) that the presently claimed invention significantly improves on prenatal diagnostic technology available in the marketplace, based on evaluation of fetal cfDNA from maternal blood samples for the presence of a disease-associated mutation. The Applicant further states (para. 3) that the Patent Act of 1952 sets forth the categories of subject matter eligible for patent protection: “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 therefore, subject to the conditions and requirements of this title.” The Applicant further states (para. 5) that the 35 U.S.C. 101 statute emphasizes that “any new and useful improvement” in that subject matter ensures the eligibility of the subject matter, and points to Research Corp. Technologies v. Microsoft Corp., 627 F.3d 859, 867 (Fed. Cir. 2010), and further states that as noted in Research Corp. Technologies, 627 F.3d at 869, specific improvement or commercial application to technologies in the marketplace is sufficient to traverse the coarse eligibility filter of 101. The Applicant further points to Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1066 (Fed. Cir. 2011) (holding that a method of lowering the risk of chronic immune-mediated disorder is eligible). The Applicant further states that likewise, the presently claimed invention significantly improves on genetic testing available in the marketplace, because identifying the targets first in the maternal sample, the workflow requires far fewer sequencing targets while maintaining sensitivity through deep sequencing, and is performed non-invasively allowing mass screening and regular follow-up, and results in lower cost and faster turnaround time than conventional genetic testing technology.
These arguments are not persuasive, because first, and as noted and discussed in the foregoing responses to arguments and in the above rejection, when the claims as a whole are considered at Step 2A Prong Two, that is, the limitations containing the judicial exception as well as the additional elements in the claim besides the judicial exception need to be evaluated together to determine whether the claim integrates the judicial exception into a practical application, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, i.e., the claims do not recite any additional elements that apply, rely on, or use the judicial exception(s) in a manner that imposes a meaningful limit on the judicial exception (MPEP 2106.04(d)). Second, a conclusion of whether a claim is eligible at Step 2B requires that all relevant considerations be evaluated, which comprises steps of: (1) carrying over the identification of any additional element(s) in the claim from Step 2A Prong Two; (2) carrying over the conclusions from Step 2A Prong Two on the considerations discussed in MPEP §§ 2106.05(a) - (c), (e) (f) and (h); (3) re-evaluating any additional element or combination of elements that was considered to be insignificant extra-solution activity per MPEP § 2106.05(g), because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and (4) evaluating whether any additional element or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP § 2106.05(d). As noted in the rejection above, when all additional elements in claims 1-4 and 6-12 have been evaluated individually and in combination at Eligibility Step 2B, they are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exceptions (MPEP 2106.05(II)).
The Applicant states on page 11 (para. 2) of the Remarks that non-conventional features of the claimed invention also satisfy the “significantly more” test, and points to Research Corp. Technologies, 627 F.3d at 869 (Fed. Cir. 2010) (citing Diamond v. Diehr, 450 U.S. 175, 188 (1981)), and further states that on the issue of whether the present claims add limitations other than what is well-understood, routine, and conventional in the field, the claim must be considered as a whole, and it is inappropriate to dissect the claims into disintegrated elements. The Applicant further states that the U.S. Supreme Court in Diehr started the entirety analysis, “[t]hose steps [in Diehr’s patent] included steps that sound utterly old and routine…. Indeed, even the Arrhenius equation was well-known in the art, but in combination was eligible.” The Applicant points to Mayo Collaborative Servs. V. Prometheus Labs., Inc., 132 S. Ct. 1289, 1298 (2012) (citing Diehr at 188) and further states that the combinatorial approach was later endorsed by the Court –“[A] new combination of steps in a process may be patentable even though all the constituents of the combination were well known and in common use before the combination was made.” The Applicant further states (para. 3) that the present claims, when considered as a whole, form a non-routine and unconventional method for determining the presence or absence of one or more disease-associated mutations in a fetus, which is performed in a non-invasive manner based on a combined biochemical and bioinformatics analysis of cell-free DNA, in sharp contrast to conventional art. The Applicant further states that, in particular, the steps of amended claim 1, when taken as a whole, were not routine, conventional, or well-known in genetic testing technology at the priority date of the present application, and thus, when taken as a whole, the required steps of the amended claims allow for a novel and inventive method for determining presence or absence of one or more disease-associated mutations in a fetus, based on sequencing of maternal DNA to first identify the disease-associated mutations, followed by amplification and sequencing of cell-free DNA at the identified disease-associated mutations, that can be performed non-invasively, allowing mass screening and regular follow-up, and result in lower costs and faster turn-around than conventional genetic testing technology.
These arguments are not persuasive, because first, and as noted and discussed in the foregoing responses to arguments and in the above rejection, a conclusion of whether a claim is eligible at Step 2B requires that all relevant considerations be evaluated, which comprises steps of: (1) carrying over the identification of any additional element(s) in the claim from Step 2A Prong Two; (2) carrying over the conclusions from Step 2A Prong Two on the considerations discussed in MPEP §§ 2106.05(a) - (c), (e) (f) and (h); (3) re-evaluating any additional element or combination of elements that was considered to be insignificant extra-solution activity per MPEP § 2106.05(g), because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and (4) evaluating whether any additional element or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP § 2106.05(d). As noted in the rejection above, when all additional elements in claims 1-4 and 6-12 have been evaluated individually and in combination at Eligibility Step 2B, they are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exceptions (MPEP 2106.05(II)). Second, and as noted and discussed in the foregoing responses to arguments and in the above rejection, the cited references at Step 2B provide evidence of conventionality of the additional elements identified at Step 2A Prong Two and carried over to Step 2B for further analysis.
Claim Rejections - 35 USC § 102
The amendment received 07 November 2025 has been fully considered, however after further consideration, the rejection of claims 1, 2, 3, 6, 7, 8, 9, 10, 11, and 12 under 35 U.S.C. 102(a)(1) as being anticipated by Deciu et al. in the Office action mailed 11 August 2025 is maintained in view of the amendment.
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 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 1, 2, 3, 6, 7, 8, 9, 10, 11, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deciu et al. (US 2013/0338933, as cited above, and as cited in the Office action mailed 11 August 2025).
Claim Interpretation
The limitation “non-naturally occurring composition of amplified cell-free DNA” is interpreted to encompass a composition of cell-free DNA fragments with short synthetic sequences (e.g., adapters) ligated to both ends of the cell-free DNA fragments that enable, e.g., binding to the sequencer’s flow cell, and/or initiate amplification, and/or allow for sample indexing/barcoding; and/or short synthetic sequences (e.g., primers) hybridized to the previously attached adapters.
Regarding claims 1, 10, and 12, Deciu et al. shows circulating cell-free DNA (CCF DNA) was extracted from plasma from pregnant women, and DNA was also extracted from maternal buffy coat samples for confirmation of maternal genotypes (para. [1167]) and in certain embodiments a genetic variation for which the presence or absence is identified for a subject is associated with a medical condition (para. [0648]); maternal DNA (i.e., buffy coat) samples were sequenced (para. [1174]); performing multiplex PCR of 67 SNPs and sequencing the ccf DNA from the plasma of a pregnant mother (para. [0119]; and FIG. 165); the amplification reaction is performed in a single vessel (e.g., tube, container, well on a plate) which sometimes is referred to as multiplexed amplification (paras. [0270] & [1170]); amplification (e.g., PCR)-based approaches that involve multiplex PCR with primers having a first capture probe incorporated into certain loci-specific forward PCR primers and adapter sequences incorporated into loci-specific reverse PCR primers to thereby generate amplicons (para. [0289]); allele frequencies per targeted SNP measured for buffy coat DNA (maternal genotype) and the paired pregnant plasma DNA (maternal and fetal genotypes) (paras. [0121] & [0122]; and FIG. 167 & FIG. 168); the amplification reactions can be size-specific, e.g., greater than 100 base pair amplicons (para. [0102]), and in one example a total of 261 amplicons were used for validation with the minimum amplicon length being 108 base pairs (para. [1071]); and that amplicon nucleic acids have the same or substantially the same nucleotide sequence as the target nucleic acid (para. [0197]) and that in some embodiments, 100% of fetal nucleic acid is of a length of about 150 base pairs or less (para. [0195]) and in some cases, the genomic DNA target sequence length is 70 base pairs (para. [0216]); and sequencing amplicon libraries from plasma and buffy coat samples that generated reads such that the after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP (para. [1177]); and in certain embodiments a genetic variation for which the presence or absence is identified for a subject is associated with a medical condition (para. [0648]).
The claim 10 limitation reciting “determining whether the fetal cell-free DNA comprise a haplotype containing the mutation associated with cystic fibrosis” is not required under the broadest reasonable interpretation because the limitation is contingent on whether or not the sequencing on the cellular DNA sample of the pregnant women identifies the pregnant women as a carrier for a mutation associated with cystic fibrosis. The claim 12 limitation reciting “determining whether the fetal cell-free DNA comprise a haplotype containing the 22q11.2 deletion” is not required under the broadest reasonable interpretation because the limitation is contingent on whether or not the sequencing on the cellular DNA sample of the pregnant women identifies the pregnant women as a carrier for 22q11.2 deletion. Therefore, claims 10 and 12 are rejected with claim 1.
Regarding claim 2, Deciu et al. shows sequencing amplicon libraries from plasma and buffy coat samples that generated reads such that the after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP (para. [1177]).
Regarding claims 3, 6, and 7, Deciu et al. shows determining the presence or absence of a genetic variation, e.g., fetal aneuploidy (paras. [0610] – [0612]) (claim 3);
Deciu et al. further shows 10 or more polymorphic nucleic acid targets are enriched (page 237, col. 2, AE27) (claim 6); and Deciu et al. further shows multiplex reactions targeting 67 SNP loci (para. [1170]), and further shows that SNPs may be selected from any SNP selection criteria such as being located on certain chromosomes suspected of having a genetic variation, e.g., aneuploidy (para. [0275]) (claim 7).
Regarding claim 8, Deciu et al. shows using a PCR reaction to incorporate molecular index barcodes (para. [0289]).
Regarding claim 9, Deciu et al. shows that a pregnancy-associated disorder refers to any condition or disease that may affect a pregnant woman, the fetus, or both, and can include cystic fibrosis (para. [0133]).
Regarding claim 11, Deciu et al. shows methods for analysis and processing of data that can provide one or more outcomes, where the term “outcome” refers to a conclusion that predicts and/or determines a risk or probability of the presence or absence of a genetic variation (e.g., an aneuploidy, a copy number variation) in a subject (e.g., a fetus) (para. [0621]).
Response to Arguments
The Applicant’s arguments/remarks received 07 November 2025 have been fully considered, however they are not persuasive.
The Applicant states on page 12 (para. 5) that Deciu does not disclose, either expressly or inherently, the specific method recited in claim 1. The Applicant further states on page 13 (para. 1) that Deciu’s general teachings on multiplex SNP amplification and maternal/fetal genotyping do not disclose or suggest the sequential, patient-specific, disease-mutation-targeted workflow of instant claim 1. The Applicant further states (para. 2) that there is no disclosure in Deciu that the target loci for plasma amplification are chosen based on the results of the maternal buffy-coat sequencing step, and that Deciu’s SNPs are pre-selected population markers, not dynamically selected, patient-specific loci encompassing disease-associated mutations. The Applicant further states (paras. 3 & 4) that Deciu discloses sequencing buffy coat DNA to confirm maternal genotype, not to identify one or more disease-associated mutations in that maternal DNA, and further that there is no teaching or suggestion that Deciu performs disease-association analysis of maternal genotypes, but rather, Deciu uses maternal buffy coat sequencing solely to control for and subtract maternal background in fetal aneuploidy or SNP analysis, and thus Deciu fails to disclose the claimed purpose of step (a): identifying one or more disease-associated mutation in the maternal genome.
These arguments are not persuasive, not least because Deciu is directed to methods and processes for non-invasive assessment of genetic variations (Title) and shows determining the fraction of fetal nucleic acid comprises analyzing one or more loci in sample nucleic acid, wherein at least one of the one or more loci vary between fetal nucleic acid and maternal nucleic acid by mapping to reference genome, and further that the one or more loci comprise one or more polymorphic sites, comprising the steps of (1) enriching (i.e., amplifying) nucleic acid in a first part of the test sample for a plurality of polymorphic sites, (2) obtaining nucleotide sequences for some or all of the polymorphic sites by a sequencing process, (3) analyzing the nucleotide sequences of (2), and (4) determining the fraction of fetal nucleic acid based on the analysis of (3), wherein the polymorphic sites and number thereof result in at least five polymorphic sites being informative for determining the fetal fraction (para. [0012]) (suggesting at least that the polymorphic sites targeted for enrichment are first identified from a maternal genomic sequence having been mapped to a reference genome to target polymorphic sites).
The Applicant states on page 14 (para. 1) of the Remarks that there is no teaching or suggestion in Deciu of determining the presence or absence of one or more disease-associated mutations in the fetal cell-free DNA that were identified in the cellular DNA sample of the pregnant woman, and that the disclosure by Deciu at para. [0648] are not first identified in the maternal cellular DNA and then their presence or absence determined in the fetal cfDNA.
These arguments are not persuasive, because as noted in the foregoing response to arguments, the polymorphic sites are first identified by mapping a maternal sample to a reference genome, followed by subsequent steps of (1) enriching (i.e., amplifying) nucleic acid in a first part of the test sample for a plurality of polymorphic sites, (2) obtaining nucleotide sequences for some or all of the polymorphic sites by a sequencing process, and (3) analyzing the nucleotide sequences of (2).
The Applicant states on page 14 (para. 2) of the Remarks that the claim requires a sequencing depth of at least 20,000 per target locus, however Deciu only shows an exemplary upper limit as high as 71,619 reads per SNP, but there is not teaching in Deciu of a required minimum depth for detecting disease-associated variants in fetal cfDNA, and further states that Deciu does not teach that a depth of at least 20,000 is necessary or even used for disease-mutation detection, and accordingly, as Deciu fails to teach every element of the claimed methods, the claims are novel.
These arguments are not persuasive, at least because Deciu shows at least one embodiment with a sequencing read depth of at least 20,000 reads per locus, as discussed in the above rejection.
Claim Rejections - 35 USC § 103
The Applicant’s amendment received 07 November 2025 has been fully considered, however after further consideration, the rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over Deciu et al. as applied to claim 1 under 35 U.S.C. 102 above, and further in view of Shendure et al. in the Office action mailed 11 August 2025 is maintained in view of the amendment.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Deciu et al. (US 2013/0338933, as cited above) as applied to claims 1 under 35 U.S.C. 102 above, and further in view of Shendure et al. (WO 2013/177581, as cited in the Office action mailed 11 August 2025).
Deciu et al. as applied to claim 1 under 35 U.S.C. 102 above, does not show wherein the disease-associated mutations comprise an insertion or deletion.
Regarding claim 4, Shendure et al. shows methods for a comprehensive prediction and detection of a fetal genome sequence using cell-free fetal-derived DNA from maternal plasma (para. [0022]) including a method of predicting inheritance of one or more parental genetic abnormalities including a deletion or an insertion (para. [0023]-[0026]). Shendure et al. further shows that parental DNA is extracted from peripheral blood mononuclear cells (PBMC) or buffy coat, while cfDNA is isolated from the maternal plasma (para. [0020]); and targeted sequencing (para. [0050]).
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 shown by Deciu et al. as applied to claim 1 under 35 U.S.C. 102 above, by incorporating methods of genome sequencing of a human fetus, as shown by Shendure et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Deciu et al. and Shendure et al., because Shendure et al. shows methods for predicting inheritance or transmission of an allele from one or more maternal-only heterozygous sites from a maternal genomic sequence to a fetal genome sequence (Abstract). This modification would have had a reasonable expectation of success because both Deciu et al. and Shendure et al. are directed to the detection of mutations in fetal genomic sequences.
Response to Arguments
The Applicant’s arguments/remarks received 07 November 2025 have been fully considered, however they are not persuasive.
The Applicant states on page 14 (bottom) that this rejection depends upon Deciu teaching each and every aspect of independent claim 1, which it does not for the reasons explained above. The Applicant further states that Shendure fails to cure the deficiencies of Deciu, nor was it cited for this purpose, but rather, Shendure was cited for allegedly teaching “methods for a comprehensive prediction and detection of a fetal genome sequence using cell-free fetal-derived DNA from maternal plasma including a method of predicting inheritance of one or more genetic abnormalities including a deletion or an insertion.” The Applicant further states that the Office action also alleges that Shendure “further shows that parental DNA is extracted from peripheral blood mononuclear cells (PBMC) or buffy coat, while cfDNA is isolated from the maternal plasma; and targeted sequencing. The Applicant further states that in Shendure, maternal genomic DNA (e.g., from buffy coat) is used to determine maternal haplotypes and phase parental variants, which is used to infer fetal genome statistically from cfDNA, however Shendure does not use buffy coat to identify specific disease-associated mutations in the mother, and accordingly, the cited references, either alone, or in combination, fail to teach each and every step of the claimed invention.
These arguments are not persuasive, because the Shendure reference is relied upon in combination with Deciu, and cited specifically to show that mutations can comprise an insertion or deletion, as discussed in the rejection above, along with the corresponding motivation statement for why one of skill in the art would have been motivated to combine the references.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687