DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 21, 2025 has been entered.
Change of Examiner
The examiner of record has been changed to Young J. Kim in Group Art Unit 1681. All future correspondences should be directed to the undersigned.
Preliminary Remark
Claims 2-4, 6, 8, 11-18, 20-29, 31, 32, 34-36, 38-40, 42-107, 109, and 112 are canceled.
Claims 113-119 are new.
Claims 30, 33, and 37 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention without traverse.
Information disclosure statement
The IDS received on October 21, 2025 is proper and is being considered by the Examiner.
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, 5, 7, 9, 10, 19, 41, 108, 110, 111, and 113-119 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 because the claim recites that the method amplifies a plurality of amplicons comprising SINEs (Short Interspersed Nucleotide Elements), but the dependent claim 19 recites an interval range that far exceeds what is typically accepted in the art as “short” interspersed element.
For this rejection, the Office relies on Applicants’ own publication (PNAS, February 2018, vol. 115, no. 8, pages 1871-1876), wherein Applicants published a similar method that amplifies what is known as LINEs (Long Interspersed Nucleotide Elements). In this publication, LINEs are described as having a genomic interval of 500 kb (or 500,000 bps, see Fig. 1, also “LINEs within 4,361 genomic intervals, each containing 500 kb of sequence … read counts within each 500-kb genomic intervals within a sample are compared”, page 1872, 1st column, 3rd paragraph).
Claim 19 recites that the genomic internals comprise from about 100 nucleotides to about 125,000,000 (i.e., 12.5 Mb), that encompasses an interval length of LINEs. Therefore, claim 1 is indefinite in what the claim means by reciting amplicon comprises SINEs, or how this distinguishes itself from LINEs as both are generically known in the art as being retrotransposons.
Claims 5, 7, 9, 10, 19, 41, 108, 110, 111, and 113-119 are indefinite by way of their dependency on claim 1.
Clarification is required.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 5, 7, 9, 19-21, 23- 24, 26, 41 and 108-112 under 35 U.S.C. 103 as being unpatentable over Xie et al. (Nucleic Acids Res., Vol. 37(13), p. 4331-4340) in view of Raymond et al. (WO 2018/039463), made in the Office Action mailed on July 23, 2025 is withdrawn in view of the Amendment received on October 21, 2025.
Rejections – New Grounds, Necessitated by Amendment
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, 5, 7, 9, 19, 41, 108, 110, 111, and 113-119 are rejected under 35 U.S.C. 103 as being unpatentable over Kinde et al. (PLoS One, July 2012, vol. 7, issue 7, e41162, pages 1-8) in view of Douville et al. (PNAS, February 20, 2018, vol. 115, no. 8, pages 1871-1876), Boyle et al. (PNAS, 1990, vol. 87, pages 7757-7761), and Murata et al. (Scientific Reports, October 2017, vol. 7, pages 1-8).
With regard to claims 1 and 119, Kinde et al. teach a method of detecting aneuploidy in a subject’s sample via use of a massively parallel sequencing means, wherein the method produces amplification products with the use of a single pair of primers for the purposes of karyotyping:
“commercially available tests for circulating fetal DNA aneuploidy involve the preparation of whole genome libraries and the analysis of sufficient number of sequences on the relevant chromosomes to reliably detect small differences in copy number. The preparation of whole genome libraries involves several sequential steps” (page 1, 2nd column, bottom paragraph to page 2, 1st column, 1st paragraph)
“We reasoned that this process could be simplified if a defined number of fragments from throughout the genome could be amplified using a single primer pair, obviating the need for end-repair, terminal 3’-dA addition, or ligation to adapters.” (page 2, 1st column, 2nd paragraph)
Therefore, Kinde et al. teach a method of testing for the presence of aneuploidy in a genome of a mammal (i.e., maternal fetal DNA is tested), comprising:
amplifying a plurality of chromosomal sequences in a DNA sample obtained from a mammal with a single pair of primers complementary to the chromosomal sequence to form a plurality of amplicons (see above), wherein the plurality of amplicons comprise sequences from a plurality of different chromosomes (“allowing amplification of well-dispersed, repeated elements”, page 2, 1st column, bottom paragraph; also “number of uniquely assigned tags per experiment spanned 12-fold range (1,343,382 to 16,015,347)”, page 6, 1st column, 3rd paragraph; 31,547,988 high quality tags per individual … could be uniquely mapped to one of an average of 23,681 unique chromosomal positions”, page 6, 2nd column, 3rd paragraph; see also Fig. 2);
determining at least a portion of the nucleic acid sequence of the plurality of amplicons to generate amplicon sequences (FAST-SeqS, see also page 6, 1st column 3rd paragraph);
mapping the amplicon to a reference genome (“[w]e recovered an average of 31,547,988 high quality tags per individual … could be uniquely mapped to one of an average of 23,681 unique chromosomal positions”, page 6, 2nd column, 3rd paragraph);
dividing the amplicon sequences into a plurality of genomic intervals;
quantifying read counts for amplicon sequences mapped to the genomic intervals (“organizing our data into a list of positions [i.e., intervals] … each associated with a tag count, we were able to apply standard quantile normalization to FAST-SeqS data”, page 4, 1st column, 1st paragraph; applies for steps (d) and (e)); and
comparing the read counts of the amplicon sequences in the genomic intervals on a chromosome arm to an expected distribution (from reference sample), thereby testing for the presence of aneuploidy in the genome of the mammal (see Fig. 3(A); also “one determines the mean and standard deviation of tag counts lying within a chromosome of interest in a group of reference samples (e.g., samples with known euploid content), and then creates a standardized score (i.e., z-score) for a chromosome of interest for each sample … outliers are easily detected because they have a z-score > 3.0 … indicates that the normalized tag count of the outlier exceeds the mean of the reference group by at least three standard deviations”, page 4, 1st column, bottom paragraph to page 5, 1st column, 1st paragraph).
With regard to claims 5, 9, 110, and 111 the DNA is a biological sample from a subject (“DNA was obtained from normal spleen, peripheral blood, white blood cells (WBCs, or plasma from patients”, page 2, 1st column, 3rd paragraph).
With regard to claim 7, the sample is from plasma (see above).
With regard to claim 41, at least 300,000 amplicons are formed in the step of amplifying using said single primer pair (“[w]e recovered an average of 31,547,988 high quality tags per individual … could be uniquely mapped to one of an average of 23,681 unique chromosomal positions”, page 6, 2nd column, 3rd paragraph).
With regard to claim 113, the expected distribution is a normal distribution (i.e., distribution based on euploidy).
With regard to claims 114 and 115, z-score is generated and analyzed (see pages 4 and 5).
Kinde et al. explicitly teach that their method employs single pair of primers that target repetitive nucleotide element found within the human genome (“FAST-1 amplification primers … allowing amplification of well-dispersed, repeated elements”, page 2, 1st column, bottom paragraph), but do not explicitly teach the use of all types of such elements that can be utilized in their method.
Consequently, SINEs are not targeted by the single pair of primers, and therefore, the artisans are silent with respect to the genomic intervals being from about 100 to 125,000,000 nucleotides (claim 19).
As well, the amplicons generated in the method of Kinde et al. have an average amplicon length range of 124 to 142 bp, which is slightly beyond that of 10-110 bps (claim 108)
Kinde et al. do not explicitly teach that the amount of starting sample DNA is between 0.01 pg to 500 pg.
While Kinde et al. explicitly teach that the method is for determining aneuploidy, the artisans do not explicitly utilize machine learning for classification (claims 116), when making an aneuploidy call (claim 117), based on the z-score (claim 118).
Douville et al. teach a method of utilizing machine-learning to determine aneuploidy status from amplification products produced by single pair of primers directed to LINEs:
“single primer pair can be used to amplify 38,000 long interspersed nuclear elements (LINEs) by FAST-SeqS … even in single cells derived from preimplantation embryos … We describe here … WALDO … an algorithm for amplicon-based aneuploidy detection … WALDO can be applied to identify chromosome arm gains or losses with improved sensitivity and equivalent specificity compared to previous approaches. Furthermore, we incorporate machine learning to make genome-wide aneuploidy calls, in which samples are classified according to their aneuploidy status” (page 1872, 1st column, 2nd paragraph)
Boyle et al. teach a well-recognized means amplifying SINEs for karyotyping (“we present an analysis of the chromosomal distribution of LINE and SINE sequences …” (page 7757, 2nd column, 3rd paragraph).
Murata et al. teach that starting DNA amounts in the picogram amounts can be amplified and analyzed (“[n]inety-picogram, or two-hundred and ninety picograms of mixed DNA samples were used in PCR …”, page 6).
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 combine the teachings of Kinde et al. with the teachings of Douville et al., Boyle et al. and Murata et al., thereby arriving at the invention as claimed for the following reasons.
Kinde et al. teach a method of detecting aneuploidy in a human sample, wherein the artisans teach the use of a single pair of primers that target well-dispersed, repeated elements, as well as mapping, dividing into genomic intervals and comparing the read counts in the genomic intervals. While the artisans did not explicitly teach that other types of dispersed elements could be utilized in their method, one of ordinary skill in the art would have recognized that other prior art known repeat elements that are well-dispersed would have also yielded a predictable outcome.
Indeed, in combination with Douville et al. teaching that another prior art known, well-dispersed repeat element, LINEs, a known retrotransposable element is used in a similar process as that of Kinde et al. with the addition of utilizing machine learning for calculating the Z-score taught by Kinde et al. for classifying the aneuploidy status, one of ordinary skill in the art would have also have expected another retrotransposable element, SINEs, which had already been known in the art to be used in ploidy determination (i.e., karyotype, as taught by Boyle et al.) would have also yielded same predictable outcome when assayed in combination with the method taught by Kinde et al. and Douville et al.
As to the amount of starting DNA that can be utilized in the picogram range, such would have been within the reasonable expectation of successful range of amplification in view of the sensitivity demonstrated by Murata et al., yielding no more than a predictable outcome.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
The Office reiterates that claim 10 is free of prior art.
The closest prior art if Kinde et al., wherein the pair of primers employed to amplify their dispersed repeat elements show the below homology to that of SEQ ID NO: 1:
SEQ ID NO: 1 cgacgtaaaa cgacggccag tnnnnnnnnn nnnnnnn ggt gaaaccccgt ctctaca
CGACGTAAAA CGACGGCCAG TNNNNNNNNN NNNNNNN ACA CAGGGAGGGG AACAT
Kinde et al. (R1-for a, see Table S2, supplemental, attached)
As seen the sequence from 5’ end of the primer to the last base, “N”, these regions are identical as they are directed to a universal primer binding sequence and identifier sequences typically used in a commercially available next-gen sequencing reaction. The region following thereafter to the 3’ end, however, are different as this region is the region that anneals to the SINEs as presently claimed. As no prior art teaches or suggests this primer or the region to be targeted, the primers of the SEQ ID number pair 1 and 10 are deemed free of prior art. As well, their 95% homolog is also deemed free of prior art as the sequence variance within the length of the SEQ ID number reasonably allows for inclusion of mutations and/or modifications for optimization.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 March 27, 2026
/YJK/
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