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 .
Claim Status
Claims 1-2 and 4-24 are pending.
Claims 1-2 and 4-24 are rejected.
Claim 3 is canceled.
Claim 24 is new.
Claims 1, 13, and 22 are independent.
Claims 1, 13, and 22 are objected to.
Office Action Outline
Rejections applied
Abbreviations
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
102, 103
JE
Judicial Exception
X
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 08/26/2025 filing receipt, this application is a Continuation-In-Part (CIP) bypass of PCT/US2023/083199 filed 12/08/2023, which claims priority to Provisional Application 63/431,572 filed 12/09/2022.
Overview of Withdrawal/Revision of Objections/Rejections
In view of the amendment and remarks received 01/26/2026:
• The claim objections are withdrawn. New claim objections are asserted below.
• The 112(f) interpretation is no longer asserted; the terms “detector module,” “classifier,” “modeler," and “output module” have been deleted.
• The 112(b) rejection is withdrawn; the clarity issues have been resolved by deleting "output module" and "the modeler" respectively from claims 1 and 20.
• The 101 rejection is maintained with revision.
• The 103 rejection is withdrawn for the following reasons: The claims are free of the
analogous art at least because close art, e.g., Adalsteinsson, (cited in the IDS received 06/09/2025), in view of Alexandrov, (cited on the 10/24/2025 form PTO-892), in view of Gulhan, (cited in the IDS received 06/09/2025), either individually or in obvious combination, does not teach the recited combination of "apply a trained model to the classified localized disruptions to obtain, for each of the classified localized disruptions, a confidence score indicative of a degree to which the corresponding classified localized disruption is associated with a repair pathway..." and "generate a composite score based on the confidence scores which corresponds to a specific subset of the classified localized disruptions, the specific subset selected based on discriminative power of the one or more features of the classified localized disruptions for a target condition corresponding to the repair pathway, whereby (i) execution of the signal-processing heuristic and/or (ii) application of the trained model increases a signal-to-noise ratio (SNR) in detecting the target condition in samples having a low fraction of tumor-derived DNA." Additionally, Applicant's 01/26/2026 remarks at pp.15-22 supported the withdrawal of the 103 rejection.
Claim Objections
Claims 1, 13, and 22 are objected to because of the following informalities:
The step beginning with "detect" of claims 1, 13, and 22, includes the recitation "... based on at least one of: (i) a number of supporting unique sequencing fragments; (ii) a distance from a sequencing read end; (iii) a proximity to a germline variant; (iv) a proximity to another disruption; (v) a genomic region complexity; or (vi) a minimum unique read depth;". This recitation includes a total of six semicolons, the first five of which should be replaced with commas. The last semicolon, after "unique read depth" is acceptable. Appropriate correction is required.
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 1-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04(a)). Note, the MPEP at 2106.04(a)(2) & 2106.04(b) further explains that abstract ideas and laws of nature are defined as:
• mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations);
• certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
• mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
• laws of nature and natural phenomena are naturally occurring principles/ relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1 Analysis:
Claims 1-2, 4-12, and 24 are directed to a 101 machine, here a system; claims 13-21 are directed to a 101 process, here a method; claims 22-23 are directed to a 101 machine or manufacture, here non-transitory computer-readable storage media (CRM); as such, claims 1-2 and 4-24 are directed to a related system, method, and CRM, which fall under categories of statutory subject matter. (See MPEP § 2106.03). (Step 1: Yes.)
Step 2A, Prong One Analysis:
The claims recite judicial exceptions (JEs) of mathematical concepts, mental processes, and a law of nature as follows:
Independent claims 1, 13, and 22 recite mental process and mathematical concepts to:
• detect localized disruptions (microhomology deletions or indels) based on reads and exclude localized disruption candidates based on number of fragments, distance, proximity to germline or to another disruption, region complexity, or minimum read depth
• assign signature classes to the detected localized disruptions
• apply a trained model to the classified localized disruptions to obtain scores indicative of a degree to which the classified localized disruptions are associated with a repair pathway
• generate a composite score based on the confidence scores which corresponds to a specific subset of the classified localized disruptions
• provide a classification record based on the composite score, and indicate a treatment when the state is positive. (The digital aspect is characterized as an additional element of data outputting below at Step 2A Prong Two.)
Dependent claims 2, 4-12, 14-21, and 23-24 recite mental process and mathematical concepts as follows:
• exclude localized disruption candidates based at least in part on relative positioning of the localized disruption candidates (claims 2, 14, and 23)
• exclude candidate localized disruptions based on a distance between adjacent candidate localized disruptions or based on whether the candidate localized disruptions are situated in low-complexity regions of the signal series. (claims 4 and 15)
• claims 5 and 16 further limit the repair pathway and/or the target condition respectively of claim 1 and 13.
• confidence scores are based on distinguishing an HRD-positive indel signature from an HRD-negative indel signature (claims 6 and 19)
• claims 7 and 20 further limit the confidence scores respectively of claims 1 and 13, and recite abstract ideas for: a posterior probability...wherein a composite score is a sum of probabilities for deletions, and wherein the composite score at least as great as a threshold indicates HRD positivity.
• claim 8 further limits the threshold of claim 7 to indicate classification state of HRD positivity is ~ 1.
• claim 9 further limits the output treatment of claim 1.
• a multinomial mixture model (claims 10 and 17)
• optimize the model on an expectation-maximization optimization algorithm (claims 11 and 18)
• requiring localized disruption candidates be supported by at least two unique fragments to qualify as localized disruptions (claims 12 and 21)
• claim 24 further limits the subset of claim 1.
A law of nature is recited in the correlation between the localized disruptions (microhomology deletions or indels), the repair pathway, and the target condition.
Step 2A, Prong One Summary: The claims recite judicial exceptions in the form of abstract ideas (characterized as mental processes and mathematical concepts) and a law of nature. Considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in independent claim 1, 13, and 22 (e.g., detect deletions or indels based on reads, assign signature classes, apply a trained model to the classified deletions or indels, output related to a target condition, output a treatment, etc.) are directed to processes that may be performed in the human mind, or with pen and paper, as there are no details recited in the claims which would prevent mental performance (and as such, the mathematical concepts are also considered to be mental processes). Regarding sequence analysis of reads to detect deletions or indels, this analysis inherently involves the use of mathematical concepts to represent and statistically process genetic sequence data. In the case of the instant claims, the limitations for detecting deletions or indels based on reads, assigning signature classes, applying a trained model to the classified deletions or indels, etc., inherently recite mathematical concepts such as discussed in throughout the Specification, e.g., at paragraphs [0048-0049], [0118], and [0224-225], etc. When considering the recited mathematical concepts and mental processes, such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Finally, the law of nature correlates naturally occurring genotype of microhomology deletions or indels, associated with a repair pathway, with the target condition.
Therefore, the claims recite elements that constitute judicial exceptions in the form of an abstract ideas and a law of nature. (Step 2A, Prong One: Yes.)
Step 2A, Prong Two Analysis:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions, abstract ideas in this instance, then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see MPEP § 2106.04(d)]. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
MPEP § 2106.04(d)(I) lists the following example considerations for evaluating whether judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The claims recite additional elements as follows:
Additional elements of data gathering, inputting, and outputting: Claims 1, 13, and 22 recite additional elements of receiving data and providing (outputting) digital data. Data gathering steps are additional elements which perform functions of inputting, collecting, and outputting the data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology [see MPEP § 2106.04(d)(I)].
Additional elements of computer components: Claims 1 and 22 recite the additional elements of a system comprising a processor and/or a non-transitory computer readable storage medium. The claims require only generic computer components, which do not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP § 2106.04(d)(1) and MPEP § 2106.05(f)).
Further concerning the additional elements of computer components of claims 1 and 22, the MPEP 2106.05(f) discusses limitations identified by the courts that do not integrate a judicial exception into a practical application. These limitations include: merely including instructions to implement an abstract idea on a computer or merely using a computer as a tool to perform an abstract idea, as in claims 1 and 22. As such, there is not yet an improvement to technology shown at Step 2A Prong Two. See MPEP 2106.05(f).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception into a practical application. (Step 2A, Prong Two: No).
Step 2B analysis:
Because the additional claim elements do not integrate the judicial exceptions (i.e., the abstract ideas) into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering, inputting, and outputting: The additional elements for receiving data and providing (outputting) digital data of claims 1, 13, and 22 do not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; determining the level of a biomarker in blood by any means; using polymerase chain reaction to amplify and detect DNA; detecting DNA or enzymes in a sample; analyzing DNA to provide sequence information or detect allelic variants; and amplifying and sequencing nucleic acid sequences, etc. [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity. Therefore the additional elements of data gathering and outputting do not provide an inventive concept needed to amount to significantly more than the judicial exception.
Additional elements of computer components: The additional elements of a system, a processor, and/or a non-transitory computer readable storage medium of claims 1 and 22, do not cause the claims to rise to the level of significantly more than the judicial exception; these are conventional computer components, generically claimed and discussed at Specification [0059-0073]. The computer system and components do not cause the claims to rise to the level of significantly more than the judicial exception as they do not provide an inventive concept.
Further regarding the conventionality of additional elements, the MPEP at 2106.05(b) and 2106.05(d) presents several points relevant to conventional computers in regard to Step 2A Prong Two and Step 2B, including:
• A general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions, does not qualify as a particular machine (see 2106.05(b)(I)), as in the case of claim 1 and 22, which are interpreted to recite conventional computer components.
• Integral use of a machine to achieve performance of a method may integrate the recited judicial exception into a practical application or provide significantly more, in contrast to where the machine is merely an object on which the method operates, which does not integrate the exception into a practical application or provide significantly more (see 2106.05(b)(II). In the instant claims, the recited system, processor, and non-transitory computer readable storage medium are used in detecting deletions or indels from reads, assigning classes, applying trained models, etc., and as such, the processor and memory act only as a tool to perform the steps of data analysis, and do not integrate the exception into a practical application or provide significantly more.
• Use of a machine that contributes only nominally or insignificantly to the execution of the claimed method (e.g., in a data gathering step or in a field-of-use limitation) would not integrate a judicial exception or provide significantly more (see 2106.05(b)(III). The processor and non-transitory computer readable storage medium of claim 1 and 22 used in performing data analysis does not impose meaningful limitations on the claims.
All limitations of claims 1-23 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. (Step2B: NO.)
Therefore, the claims, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non patent-eligible subject matter.
Response to Applicant Arguments - 35 USC § 101:
Applicant's arguments filed 01/26/2026 regarding the 101 rejection (remarks, p. 9-15) have been fully considered, but they are not yet persuasive.
Regarding Step 2A Prong One Arguments:
Applicant asserts (p.9-11):
• "The claims do not recite a mental process... Amended claim 1 (and analogously claims 13 and 22)...involves analyzing millions of raw sequencing reads to: (1) Detect localized disruptions...(2) Filter candidates...and(3) Score individual events... steps involve high-throughput data processing that is not practically feasible for any human to perform given the millions of raw sequencing reads involved... A human cannot mentally scan millions of DNA fragments...and apply a probabilistic model to each one" (p.10, ¶2-4).
• "The claims "involve" math/ AI, but do not "recite" it... Here, claim 1...does not recite the specific mathematical equations, weight matrices, or algorithmic formulas used by the model...but it does not claim the math itself" (bridging p.10-11).
The arguments are not yet persuasive, as the claims recite JEs which include mental processes and mathematical concepts at Step 2A Prong One of the 101 analysis above.
The claims do not recite millions of reads; however, even considering the analysis of millions of reads, such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea, such that claims can recite a mental process even if they are claimed as being performed on a computer (see MPEP 2106.04(a)(2)(III)(C)).
The limitations for detecting deletions or indels based on reads, assigning signature classes, applying a trained model to the classified deletions or indels, etc., inherently recite mathematical concepts such as discussed in throughout the Specification, e.g., at paragraphs [0048-0049], [0118], and [0224-225], etc.
Regarding Step 2A Prong Two Arguments:
Applicant asserts (p.11-15):
Regarding a "Particular Improvement Over the State of the Art," Applicant asserts:
• "... the claimed system enables a new capability.. not previously achievable: accurate detection of repair pathway associated conditions directly from low tumor fraction samples, including cfDNA representing tumor fractions as low as ~1 %. Prior methods...were developed for tumor biopsies, which require high tumor purity and which assume the presence of large scale genomic scars that are unrecoverable in liquid biopsy data" (p.12, ¶1).
• "The present invention does not merely increase accuracy. It enables a new testing modality...that increases the signal-to-noise ratio (SNR) of microhomology dependent indels in highly noisy cfDNA read environments. This constitutes a concrete technological advancement" (p.12, ¶2).
The attempt to show improvement by both a new capability, not previously achievable, as well as by an increase in accuracy over the state of the art is acknowledged, however, the arguments are not yet persuasive.
With respect to a new capability for analysis including cfDNA with tumor fractions as low ~1%: The claims do not recite analysis of cfDNA, nor do they limit "low tumor fraction" to ~1%. If the improvement relies on involvement of cfDNA samples and a level of tumor fraction, this could be amended into the claims; however, the analysis of low tumor fractions in cfDNA is considered to be shown by the prior art. (Additionally, see the discussion in the 112(b) rejection for the term "low" above.)
With respect to accuracy and Figs. 4D and 7C, the DirectHRD method is acknowledged to show increased AUC in Fig.4D (over CHORD) and in Fig.7C (over CHORD+Strelka). However, both Fig 4D and Fig. 7C use tumor fractions of original (undiluted), 5%, and 2%, which does not show the claimed improvement of tumor fractions as low as ~1 %.
Regarding a "Clear Difference from the Prior Field" and "Ways in which the Claimed Features Achieve the Improvements," Applicant asserts:
• "... The Specification demonstrates that the claimed pipeline succeeds at tumor fractions (~1 % ) where...prior approaches provide no meaningful detection signal. See, e.g., FIGs. 5A, 5B, 8B-8E, 9A-9C, l lA-1lC, 15A-E" (bridging p.12-13).
• "...The Specification demonstrates empirically that this pipeline yields reproducible pathway associated detection performance at tumor fractions where prior technologies fail entirely" (p.13, ¶ 7).
The arguments are not yet persuasive because the success of the method at tumor fractions of ~1% is not yet shown. It may be helpful to point out specifically where success regarding ~1% tumor fraction is disclosed or otherwise provide further explanation in this regard.
Regarding "Integration Into a Practical Application (Nexus)," Applicant asserts:
• The claims recite providing a digital classification record indicating the sample's classification state...and, where applicable, indicate an associated treatment" (p.14, ¶3).
• "This is ...a computationally enabled diagnostic workflow that permits non-invasive detection of repair pathway associated conditions where no prior method functioned, and supports downstream decisions such as selection of synthetic lethal therapies" (p.14, ¶4).
• "...allowing for treatment of newly discovered patients who would not have been detected or treated before" (p.14, ¶4).
In general, the arguments for the Nexus are persuasive, however, when taking in account the arguments for the ~1% tumor fraction and cfDNA samples, the arguments do not yet show an improvement to technology at Step 2A prong Two.
Regarding Step 2B arguments:
Applicant asserts (p.15, ¶ 15):
• "...the additional elements, considered as an ordered combination, supply an "inventive concept" beyond any abstract idea or law of nature.
• "The examiner has not identified...(the) algorithmic features as "well-understood, routine, conventional," and they plainly are not. Accordingly, the claims recite significantly more than a judicial exception."
The arguments regarding Step 2B are not persuasive because there is not significantly more shown at Step 2B, in that the additional elements of data gathering and generic computer components are conventional and insignificant, even when the claim is considered as a whole. The algorithmic features of the invention are not additional elements, but were identified at Step 2A Prong One as judicial exceptions of abstract ideas (mental processes and mathematical concepts) and a law of nature. The additional elements, individually and in combination, do not amount to significantly more than the judicial exception itself, even when considering the claim as a while, and do not provide an inventive concept.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Meredith A Vassell whose telephone number is (571)272-1771. The examiner can normally be reached 8:30 - 4:30.
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, KARLHEINZ SKOWRONEK can be reached at (571)272-9047. 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.
/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686