DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Office Action: Notice
Any objection or rejection of record in the previous Office Action, mailed 10/21/2025, which is not addressed in this action has been withdrawn in light of Applicants' amendments and/or arguments. This action is FINAL.
Claim Status
Claims 1, 11 and 16 have been amended (1/21/2026). Claim 5 is canceled (1/21/2026). No new matter was added. Thus, claims 1, 3-4, and 6-16 are under examination.
Rejections Withdrawn
Claim Rejections - 35 USC § 112 (b)
The 112(b) rejection for claim 16 for 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matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), is withdrawn in view of Applicant’s amendments of claim 16 for use of the term “preferably.”
Claim Rejections - 35 USC § 103
The rejection of claims 1 and 3-16 under 35 U.S.C. 103 as being unpatentable over Mortimer et al., (WO 2017/181146 A1, published 10/19/2017), in view of Sun et al. (“Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing”, PNAS, published 3/13/2018 from IDS 4/13/2022), is withdrawn in view of Applicant’s amendments of independent claims 1 and 11, as well as the cancellation of claim 5. Specifically, amended independent claims 1 and 11 now require the identification of genomic regions based on statistically significant differences in the frequency of read endpoints between two tissue types present in a mixture of cfDNA fragments, wherein the difference is defined by a p-value of less than 0.05 via probes that are designed relative to such statistically defined regions and satisfy specific structural constraints; including specified probe length, GC content, and positional spacing from regions harboring copy number variations or repetitive DNA elements. These probe limitations are integrated into a specific multi-step analytical workflow including fragment selection based on size and positional information, clustering into multiple distributions, detection of hotspots of non-random fragmentation, and computation of a classification score for detecting chromosomal abnormalities.
In comparison to the prior claim set (9/30/2025), independent claims 1 and 11 were directed generally to cfDNA analysis using probe-based enrichment, sequencing, fragment categorization, and classification of chromosomal abnormalities. Mortimer was relied upon for teaching probe-based cfDNA analysis, clustering of fragment data and statistical analysis (Paragraphs 124, 157, 182), while Sun was relied upon for teaching size-based categorization of cfDNA fragments and improved detection of fetal chromosomal abnormalities based on fragment size differences (Abstract, Introduction). It was determined that one of ordinary skill in the art would have been motivated to combine these teachings to improve detection accuracy in cfDNA-based diagnostics.
New Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-4 and 6-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The claims recite methods for detecting chromosomal abnormality in a mixed sample by obtaining cell-free DNA fragments, preparing sequencing libraries, analyzing fragment distributions, and categorizing fragments into clusters. The claims further include detecting hotspots of non-random fragmentation using cfDNA fragments from cluster distributions. Additional claims 11-16 add steps for selecting overlapping fragments, double enrichment of placenta-derived fragments, and using the method and kit for fetal genetic testing.
Specifically, in step (f) of independent claim 1 and steps (l) and (m) of independent claim 11, the instant claims recite utilizing the size, start and/or stop information of sequenced cfDNA fragments to select a fraction of cfDNA fragments, categorize the fragments into cluster distributions, detect hotspots of non-random fragmentation, combine selected cluster distributions, and renewed emphasis on computing a classification score by comparing fragment numbers on a target chromosome and a reference chromosome via detecting a chromosomal abnormality when the score is above a highly defined cut-off value. These limitations are directed to the abstract idea of analyzing information to identify a biological condition, including mathematical concepts and mental processes. In particular, categorizing fragment data into distributions, comparing counts between chromosomes with renewed emphasis on generating a classification score to determine whether the score exceeds a threshold are forms of data analysis, evaluation, and decision-making that can be performed conceptually or with pen and paper, even if carried out using generic laboratory and sequencing technology.
Although the claims apply this analysis to cfDNA fragment information, the additional recited steps do not integrate the exception into a particular application. Step (f) nor steps (l) and (m) of the two independent claims do not recite a particular improvement in sequencing technology, probe technology, or computer functionality, but instead uses known fragment characteristics as inputs for downstream analysis and classification. The claims therefore amount to collecting biological data and applying ules, comparisons and threshold-based evaluation to that data to reach a diagnostic conclusion, which is insufficient to render the claim patent eligible.
The integration of the judicial exception into the claims does not render them patent eligible because the claims are written at a high level of generality and merely use well-known, routine, and conventional techniques in the field.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES.
The claims provide for a method comprising:
obtaining biological samples containing cfDNA fragments
preparing sequencing libraries from the cfDNA fragments
hybridizing probes to the cfDNA fragments
isolating bound cfDNA fragments to probes
sequencing the isolated cfDNA fragments
utilizing size and distribution information to select fragment subsets
categorizing and combining cfDNA fragments into cluster distributions (first, second and third tiers) based on specific length parameters for later use in prenatal diagnostic tests
detecting hotspots of non-random fragmentation using fragments from the first cluster
defining fragment length ranges for cluster distributions via computation of classification scores based on chromosomal abnormality and copy number changes
Thus, the claims are directed to a statutory category (i.e., process).
Step 2A, Prong One — Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES.
The claims recite data analysis processes involving the categorization of DNA fragments into clusters based on size distributions and detecting fragmentation patterns based on overlap characteristics. This mental process of analyzing size distributions, identifying patterns and performing statistical analysis for fetal genetic testing on enriched placental DNA corresponds to an abstract idea having no particular concrete form. The detection of hotspot, with a renewed emphasis on chromosomal abnormalities and cutoff values, through data analysis similarly represents a mental process. This, the claimed invention describes judicial exceptions corresponding to abstract ideas.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
The claim limitations are considered to be; (a) mental processes of categorizing fragments into cluster distributions based on length, detecting hotspots of non-random fragmentation, analyzing size distributions, selecting fragments based on characteristics in order to determine which fragments to combine from different clusters and detection of chromosomal abnormalities selected via cutoff values, and (b) data gathering steps for obtaining biological samples, preparing sequencing libraries, followed by isolating and sequencing bound fragments.
While the claims include physical library steps, these steps are recited at a high level of generality and amount to mere data gathering activities necessary to perform the abstract mental processes. The methods of sample preparation, hybridization, and sequencing are described generically without specific improvements or unconventional elements that would integrate the mental processes into a practical application. The focus of the claims remains on the abstract analysis of the fragment data rather than a practical application of the analysis results.
The claimed process does not apply the judicial exception in a way that meaningfully limits the abstract idea. There is no indication that the combination of elements improves the functioning of a computer or any other technology. The steps provide data to perform the abstract categorization and analysis, but do not integrate those judicial exceptions into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether ra claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
However, the additional elements of the instant application, individually and in combination, do not amount to “significantly more.” Under the Step 2B analysis, the “physical” elements/steps of, “obtaining samples”, “preparing libraries”, and “performing sequencing” represent well-understood, routine, and conventional activities previously known in the industry. These techniques were widely practiced in the field of DNA analysis prior to the filing date, as evidenced by the state of the art. Additionally, as in instant claims 11-15, the application of these steps for the enrichment of placental DNA and application to fetal testing were also all-well understood practices. The claims do not add specific limitations beyond what was routine and convenient, nor do they provide improvements to the technology of DNA analysis. The combination of steps taken together does not provide an inventive concept when viewed as a whole.
For example, Mortimer et al. (WO 2017/181146 A1, published 10/19/2017, previously cited in Office Action 10/21/2025) discloses sequencing captured cfDNA molecules to detect markets at frequencies as low as 0.005% (Paragraph 12, lines 1-5). Further, Mortimer discloses conventional techniques for isolating cell-free DNA using commercial kits (Paragraph 12, lines 1-5) and describes sequence capture methods using oligonucleotide-specific probes (Paragraph 152, lines 1-5) that hybridize the sequences of interest for further serial ctDNA testing for initial metastatic diagnosis (Paragraph 308, lines 1-5). Mortimer also discloses that these probes are suited for individualized clusters, typically suited for individualized capture of key tumor markers (Paragraph 167, lines 1-5) that typically span 60-120 bases (Paragraph 152, lines 1-5) and have the usability for application in fetally-derived fragments including the detection of deletions, duplications and aneuploidy (Paragraph 10, lines 1-5).
Further, Namsaraev et al. (WO 2018/081130, published 10/24/2017, from IDS 4/13/2022) discloses methods for analyzing DNA fragments through bioinformatics procedures to identify sequences originating from specific chromosomes (Paragraph 217, lines 1-10). Specifically, Namsaraev discloses individualized methods of analyzing a biological sample, including a mixture of cell-free nucleic acid molecules, to determine a level of pathology in a subject from the collected biological sample following implementation of statistical approaches for size distribution of the plurality of nucleic acid molecules (Paragraph 8, lines 5-10).
Further, Namsaraev discloses conventional approaches for handling repeat regions and copy number variations, including determining non-random fragmentation patterns in fetal-specific ending positions (Paragraph 350, lines 1-5).
Additionally, Sun et al. (“Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing”, PNAS, published 3/13/2018 from IDS 4/13/2022) discloses that methods identifying non-random fragmentation patterns in plasm DNA were well-understood, including correlating different fragment size distributions with chromatin accessibility (Abstract). Further, Sun discloses separating plasma DNA reads into short (60-155 bp) and long (170-250 bp) categories, later used in Poisson distribution-based statistical models to analyze fragment end sites (Results: Size-Tagged Preferred End Sites). Additionally, Sun discloses that the analysis of DNA fragment end patterns, including alterations and variations, has shown applicability for more widespread usage in noninvasive molecular diagnostics, including prenatal testing based on the dependence of fetal- and maternal-specific preferred end sites (Abstract; Introduction, Paragraph 3).
Therefore, providing automation to well-known analytical methods using standard molecular techniques to implement abstract ideas of fragment analysis and categorization via size was routine and conventional before the effective filing date of the claimed invention.
Simply appending routine and conventional activities previously known to the industry, specified at a high level of generality to the to the abstract ideas of DNA fragment analysis and hotspot detection does not qualify the claims for a judicial exception and/or generally linking the use of the judicial exception(s) to a particular technological environment or field of use, and are not found to be enough to qualify as “significantly more.” The processes of “obtaining biological samples comprising cfDNA fragments”, “preparing sequencing libraries”, “categorizing fragments into cluster distributions” and “detecting hotspots of non-random fragmentation” indicates whether or not the relationship between fragment size distributions and chromosomal abnormalities exists. Additionally, the claimed size-based categorization and fragmentation analysis for non-invasive prenatal testing (i.e., mutation detection), while implemented using specific numerical ranges and statical approaches, remain fundamentally abstract analytical processes implemented through conventional molecular biology methods. This information simply tells a practitioner about the relevant natural correlation, at most adding a suggestion that the researcher should take those biological relationships into account. When viewed both individually and as an ordered combination, the claimed elements fail to supply an inventive concept because these techniques were well-understood, routine and conventional activities that a practitioner would have thought of when instructed to analyze cell-free DNA fragments for genetic testing.
This information simply tells a practitioner about the relevant natural law, at most adding a suggestion that the medical researcher should take those laws into account. Thus, when viewed both individually and as an ordered combination, the claimed elements/steps in addition to the identified judicial exception are found insufficient to supply an inventive concept because the elements/steps are considered conventional and specified at a high level of generality. The claim limitations do not transform the abstract idea that they recite into patent-eligible subject matter because “the claims simply instruct the practitioner to implement the abstract idea with routine, conventional activity.”
Therefore, claims 1, 3-4 and 6-16 do not qualify as patent-eligible subject matter because they are directed to an abstract idea of data analysis without significantly more transformative elements.
Conclusions
No claim is 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
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/ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684
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