DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .2. This action is in response to the amendment filed on 24 June 2026. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn.
In particular, the previous objection to the drawings has been obviated by the filing of the replacement drawings. The drawings filed on 24 June 2026 are accepted.
The previous objection to the specification has been obviated by the amendment to the specification.
Election/Restrictions
3. In the reply of 22 December 2025, Applicant elected species (i) of "methods that require enriching a cfDNA fraction from a sample of a pregnant woman for fetal nucleic acids" without traverse.
In the reply filed on 24 June 2026, the claims were amended so that no claim is currently limited to species (i).
The response of 24 June 2026 states:
“Applicant's articulated intent was to include combinations, and the response was phrased as such to convey that it did not want to exclude claims that only explicitly recited size-based enrichment (like option (i)) or in silico enrichment of sequences (like options (ii) or (iii)). For example, original claim 27 only explicitly recited size-based enrichment steps, while original claim 28 only recited in silico enrichment steps, but the specification makes clear these methodologies are intended to be employed together.
Consistent with Applicant's statement that its "election of (i) should include (i) and any combination of (ii) and/or (iii) so long as they are not expressly excluded," independent claims 11, 27, and 29 have been amended to explicitly recite such combinations. Applicant understands that such amendments are not considered improper or non-responsive, as MPEP § 821.03 and 37 CFR 1.145 are "not applicable where a provisional election of a single species or a group of patentably indistinct species was made in accordance with MPEP § 803.02 and applicant amends the claims such that the elected species or group is canceled." See MPEP § 821.03. Accordingly, Applicant respectfully requests consideration of these claims.”
However, Applicant was required to elect a single species or a single specific combination of species. Applicant did not elect a combination of species. Rather, Applicant elected the single species of (i). As discussed previously, if Applicant had wanted the election of species to be (i) and (ii) OR if Applicant had wanted the election of species to be (i) and (iii), then Applicant was required to elect that particular combination of species. An election of (i) alone and/or (i) and (ii) and/or (i) and (iii) and/or (i), (ii) and (iii) is not responsive because such an election does not elect a specific species or a specific combination of species
In view of the amendment to cancel the originally elected species of (i) alone , examination has been extended to species (iii) – i.e., as set forth in the restriction requirement of 23 October 2025, species (iii) is:
PNG
media_image1.png
102
658
media_image1.png
Greyscale
Note also that in the reply of 24 June 2026, Applicant did not elect a new specific species – i.e., one of the remaining species recited in the claims – i.e., the species of (iii) alone; the combination of (i) and (ii); the combination of (i) and (iii); or the combination of (i), (ii) and (iii).
Claim Status
4. Claims 1-13, 15-20, and 25-31 are pending.
Claim 28 reads on the now elected species and has been examined herein.
Claims 1-13, 15-20, 25-27 and 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Modified Claim Rejections - 35 USC § 101
5. 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 28 is rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature.
The claims recite the correlation between a trajectory and allele balance – i.e., “establishing a trajectory based on the allele balance.” As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
Regarding Step 2A, prong one, the claims recite the judicial exception of
an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Claim 28 requires “establishing a trajectory based on the allele balance of the at least two windows.” As broadly recited, the “establishing a trajectory” can be accomplished by critical thinking processes wherein the allele balance is used to predict an outcome or property.
Claim 28 also requires “performing read-length-based analysis in which an allele balance for a nucleic acid sequence of interest is established in at least two windows of the sequence library.” As broadly recited, this step encompasses reviewing the sequencing results / reads to determine the frequency / percentage of an allele in a sequencing window for a sample. This step can be accomplished by critical thinking processes and thereby is an abstract idea. To any extent that this recitation may require the use of a computer, the use of a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
See MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited step of sequencing a cfDNA sample are part of the data gathering process necessary to observe the judicial exception. This step does not practically apply the judicial exception. As set forth in MPEP 2106.05(g), steps of gathering data to be used in a claimed process are pre-solution activity and do not integrate a judicial exception into a practical application.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the additionally recited step of sequencing a cfDNA sample to produce a cfDNA library was well-known, routine and conventional in the prior art. See, for example, the previously cited teachings of Welker et al (High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening. Genetics in Medicine. 15 Nov. 2020. 23: 443-450, and Supplementary Information, p. 1-7) and Osteras et al (U.S. 20150275290), each discussed in detail in the Office action of 27 March 2026. See also Hu et al (J Trends Med. 2019. 17:124, p. 1-9) which teaches methods of obtaining a plasma sample from a pregnant woman; extracting cfDNA from the sample; using end-repair, adapter ligation and PCR amplification to generate a NIPS library; using magnetic beads to separate DNA fragments with a cut-off size of 160 bp and then sequencing the enriched fraction of fetal cfDNA (p. 2, col. 2). Liang et al (Scientific Reports. 2018. 8: 17675, p. 1-8) also teaches methods comprising obtaining a plasma sample from a pregnant woman; extracting cfDNA from the plasma sample; generating a cfDNA library; selecting cfDNA that is a size ranging from 100 to 150 bp (i.e., having a cutoff of 150 bp) and then sequencing the size-selected / enriched cfDNA (e.g., p. 6 “”cfDNA extraction and library construction”, “Library size selection” and “Sequencing and data analysis”).
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Further, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
New Claim Rejections - 35 USC § 102
6. 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.
Claim(s) 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (U.S. 20130310260).
Kim teaches a method for processing cell-free DNA (cfDNA) from a maternal sample, wherein the cfDNA comprises cell-free fetal DNA (cffDNA) and cell-free maternal DNA (cfmDNA; e.g., para [0006], [0021],and [0201-0208]). Kim teaches sequencing the cfDNA (thereby generating a sequence library – i.e., a collection of sequenced cfDNA); and performing a read-length based analysis of the sequenced cfDNA to determine the frequency of each allele at a polymorphic site in the sample (i.e., “allele balance”; e.g., para [0201] and [0300]) in at least two windows (e.g., para [0334], [0339], [0375-0376] and [0770]). Kim also teaches that the results of the above sequencing assay are used to determine the amount of fetal nucleic acid in the cfDNA sample, which amount of fetal DNA (or fetal fraction) is then considered in further analysis (i.e., “establishing a trajectory”; para [0202]):
“the amount of fetal nucleic acid is determined in a sample after sample nucleic acid is processed and prepared, which amount is utilized for further assessment. In some embodiments, an outcome comprises factoring the fraction of fetal nucleic acid in the sample nucleic acid (e.g., adjusting counts, removing samples, making a call or not making a call).”
Accordingly, Kim teaches a method comprising: sequencing a cfDNA sample comprising cell-free fetal (cffDNA) and cell-free maternal DNA (cfmDNA) to prepare a sequence library; performing read-length-based analysis in which an allele balance for a nucleic acid sequence of interest is established in at least two windows of the sequence library; and establishing a trajectory based on the allele balance of the at least two windows.
7. Claim(s) 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (“Determination of fetal DNA fraction from the plasma of pregnant
women using sequence read counts” Prenatal Diagnosis. 2015. 35: 810-815).
Kim teaches a method for processing cell-free DNA (cfDNA; ccfDNA therein) from a plasma sample of a pregnant woman, wherein the cfDNA comprises cell-free fetal DNA (cffDNA) and cell-free maternal DNA (cfmDNA; e.g., abstract and p. 810; p. 813, col. 2 first para). Kim teaches sequencing the cfDNA (thereby generating a sequence library – i.e., a collection of sequenced cfDNA); and performing a read-length based analysis of the sequenced cfDNA to determine the frequency of each allele at a polymorphic site in the sample (i.e., “allele balance”; e.g., p. 811-812 “Sample data and processing”, “SNP-based fetal DNA fraction” and “SeqFF method”; and Figure 1).
Kim (p. 813 final para to p. 814 first para) also teaches using the results of the above sequencing assay to provide an outcome – i.e., “establishing a trajectory”:
“Knowledge of fetal DNA fraction will have direct impact on the clinical accuracy of NIPT for fetal copy number variation. For example, a euploid sample with a very high fetal DNA fraction and a marginally elevated z-score (potential false positive) can be correctly classified given the mismatch between the z-score and the fetal component. Samples with low fetal fraction can be resequenced at an adequately increased sequencing depth.”
Kim further teaches that the results of the sequencing assay establish a pattern (i.e., trajectory) regarding regions of the fetal and maternal genome that are present at a higher proportion in cfDNA (p. 814, col. 1):
“The second advance brought forth by our study is the observation that certain regions of the genome have different maternal and fetal ccfDNA representation. This observation supports the hypothesis that fetal ccfDNA is derived from placental cells undergoing apoptosis with a trimming of a ~20bp linker DNA fragment between nucleosome cores. In addition, DNA in a developing placenta is in a hypomethylated
state, perhaps as a result of increased genome-wide levels of transcription.23,24 Taken together, this suggests that fetal ccfDNA may be more likely to originate from genomic regions with increased euchromatic DNA structure resulting in observed differential fragment length distribution and nonuniformity in coverage relative to maternal ccfDNA.”
Accordingly, Kim teaches a method comprising: sequencing a cfDNA sample comprising cell-free fetal (cffDNA) and cell-free maternal DNA (cfmDNA) to prepare a sequence library; performing read-length-based analysis in which an allele balance for a nucleic acid sequence of interest is established in at least two windows of the sequence library; and establishing a trajectory based on the allele balance of the at least two windows.
8. Claim(s) 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lo et al (CA3105349; published 07 November 2019).
Lo et al teaches a method for processing cell-free DNA (cfDNA) from a maternal sample, such as a plasma sample, wherein the cfDNA comprises cell-free fetal DNA (cffDNA) and cell-free maternal DNA (cfmDNA; e.g., para [0004], [0092], [0095], [0142-0146] and [0212]). Lo teaches sequencing the cfDNA (thereby generating a sequence library – i.e., a collection of sequenced cfDNA); and performing a read-length based analysis of the sequenced cfDNA to determine the dosage of each allele or to determine allele imbalance at a polymorphic site in the sample (i.e., “allele balance”) in at least two windows (e.g., para [0075], [0108], [0142-0146]). Lo also teaches that the results of the above sequencing assay are used to determine the amount of fetal nucleic acid in the cfDNA sample, which information is used to further evaluate the sample (i.e., “establishing a trajectory”; para [045-0146]):
[0145] In another embodiment, the two fetally-derived molecules carrying the T
allele would be given a higher weight in the RMD analysis because these two molecules ended on a short-preferred ending position. Different weight can be given to the molecules ending on the short-preferred ending positions, for example but not limited to 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3 and 3.5.
[0146] As an example, the criteria for determining whether a locus is heterozygous can be a threshold of two alleles each appearing in at least a predetermined percentage (e.g., 30% or 40%) of reads aligned to the locus. If one nucleotide appears at a sufficient percentage (e.g., 70% or greater) then the locus can be determined to be homozygous in the particular tissue.
Lo also teaches:
“[0152]…. The DNA molecules ending at set S within a region (enriched for fetal DNA) can be used to detect if there is a sequence imbalance for the fetal DNA. As examples, the parameter value may include a ratio of S/L of a test region and S/L of one or more reference regions, or just a ratio of first number of DNA
molecules ending on short-preferred ends in a test region and a second number of DNA molecules ending on short-preferred ends in one or more reference regions.
[0153] The data thus suggested that the size-tagged preferred end sites were general footprints of short and long DNA molecules in the plasma, irrespective of their origin (e.g. fetal versus maternal). Furthermore, fetal DNA molecules showed a higher proportion of molecules covering the Set S preferred end sites compared to maternal DNA. Accordingly, a ratio of an S/L value for a test region and one or more reference regions can be used as a parameter value that is compared to a reference value to discriminate between classifications of a sequence imbalance.”
Thus, Lo teaches that the results can be used to establish a trajectory / detect if there is a sequence imbalance for the fetal cfDNA.
Accordingly, Lo teaches a method comprising: sequencing a cfDNA sample comprising cell-free fetal (cffDNA) and cell-free maternal DNA (cfmDNA) to prepare a sequence library; performing read-length-based analysis in which an allele balance for a nucleic acid sequence of interest is established in at least two windows of the sequence library; and establishing a trajectory based on the allele balance of the at least two windows.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-0731. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CARLA J MYERS/Primary Examiner, Art Unit 1682
Prosecution Insights