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 .
Applicant’s amendments and arguments, filed 6/11/2026, have been entered and considered, but are not completely persuasive.
Claims 1, 5-7, 12-20, 27-28, and 109-115 are pending. Claims 109-115 are newly added. All other claims have been canceled.
The corrected drawings have been received and are suitable for examination.
The rejections under 35 USC 102 over Snyder, Kang, Guo and Li are withdrawn.
The rejection under 35 USC 103 over Li in view of Sun is withdrawn.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
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.
Claims1, 5-7, 12-20, 27-28, and 109-115 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental steps, mathematic concepts, organizing human activity, or a natural law without significantly more.
Applicant is directed to MPEP 2106 for the most current and complete guidelines in the analysis of patent- eligible subject matter.
With respect to step (1): YES. The claims are drawn to statutory categories: computer-implemented processes.
With respect to step (2A) (1): YES. The claims recite an abstract idea, law of nature and/or natural phenomenon.
Mathematic concepts, Mental Processes or Elements in Addition (EIA) in the claim(s) include:
1. (Original) A method of determining a cellular origin of at least a subset of deoxyribonucleic acid (DNA) molecules from a cell-free DNA (cfDNA) sample obtained from a subject at least partially using a computer, the method comprising:
(EIA: preamble stating the goal of the method, and the source of the sample: an element of data gathering)
(a) sequencing at least the subset of DNA molecules from the cfDNA sample to identify a set of DNA molecules of unknown cellular origin from the cfDNA sample, wherein member DNA molecules in the set of DNA molecules comprise a genomic region in common with one another, and wherein the sequencing comprises, for a given member DNA molecule:
(i) obtaining a length of the given member DNA molecule;
(ii) obtaining a midpoint-to-midpoint offset of a midpoint of the given DNA molecule from a midpoint of the genomic region in the given DNA molecule;
(EIA- a step of data gathering: sequencing a sample; AND a mathematic concept of measuring lengths of the sequence reads AND a mental step of observing and identifying a mid-point offset.)
(b) generating a length distribution set and a midpoint-to-midpoint offset distribution set for the member DNA molecules;
(Mathematic concept of creating mathematic distributions which describe a property. [0016-0018, 0116-0120, 00130] “[0130] Method 200 also includes comparing (typically using a computer) the distribution of the properties … or a statistical transformation of one or more components of the distribution…”)
(c) estimating a fraction of member DNA molecules, if any, within the cfDNA sample that originate from a targeted cellular origin using the length distribution set and the midpoint-to-midpoint offset distribution set for member DNA molecules comprising the genomic region, thereby generating a per-region fraction estimate based on the genomic region;
(Mathematic concept of calculating or estimating fractions that describe a property: origination from a targeted cellular origin. [0017-0018, 00115, 00119-00120, 00127] “an estimate of Θi,j”)
(d) aggregating the per-region fraction estimates, each based on a genomic region of a plurality of genomic regions for the cfDNA sample to generate a sample classification score for the cfDNA sample; and
(Mathematic concept of adding, multiplying, or otherwise combining the fractional estimates; [00123] one type of aggregation is transformation into a z-score, or calculating the means of the z-scores.)
(e) classifying the cfDNA sample as comprising DNA molecules from cells of the targeted cellular origin when the sample classification score for the cfDNA sample exceeds a reference classification score, thereby determining the cellular origin of at least the subset of DNA molecules from the cfDNA sample obtained from the subject.
(Mental process of comparing one score value to a reference score, and judging whether one exceeds the other. Alternatively, a mathematic concept of one data value being less than or greater than another. [00128])
5. (Previously Presented) The method of claim 1, wherein the plurality of genomic regions comprise one or more regions of differential chromatin organization between at least two cell types.
(Mental concept modification, defining “genomic regions”.)
6. (Previously Presented) The method of claim 1, wherein the plurality of genomic regions comprise one or more transcriptional factor binding regions, one or more distal regulatory elements (DREs), one or more repetitive elements, one or more intron-exon junctions, and/or one or more transcriptional start sites (TSSs).
(Mental concept modification, defining “genomic regions”.)
7. (Original) The method of claim 6, wherein the one or more transcriptional factor binding regions comprise one or more CTCF binding regions.
(Mental concept modification, defining “genomic regions”.)
12. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a tumor cell.
(Mental process modification, specifying the phenotype of the cellular origin)
13. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a non-tumor cell.
(Mental process modification, specifying the phenotype of the cellular origin)
14. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a fetal cell.
(Mental process modification, specifying the phenotype of the cellular origin)
15. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a maternal cell.
(Mental process modification, specifying the phenotype of the cellular origin)
16. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a cell from a transplant donor subject.
(Mental process modification, specifying the phenotype of the cellular origin)
17. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a cell from a transplant recipient subject.
(Mental process modification, specifying the phenotype of the cellular origin)
18. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules or the targeted cellular origin comprises a non-diseased cell.
(Mental process modification, specifying the phenotype of the cellular origin)
19. (Previously Presented) The method of claim 1, wherein the cellular origin of the subset of DNA molecules comprises a diseased cell, thereby diagnosing a disease in the subject.
(Mental process modification, specifying the phenotype of the cellular origin)
20. (Previously Presented) The method of claim 19, further comprising administering one or more therapies to the subject to treat the disease in the subject.
(EIA, a generic treatment step)
27. (Previously Presented) The method of claim 1, comprising estimating a maximum likelihood that a fraction of DNA molecules in a given distribution set originates from the targeted cellular origin, using the equations of:
PNG
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660
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where Pr is probability, Θ is the fraction of DNA molecules in the given distribution set that originate from the targeted cellular origin, ML is the maximum likelihood, D is a collection of DNA molecules {d1, d2,..., dN} from a test sample, n is a given DNA molecule in the given distribution set, dn is a set of observed variables that represent observed fragmentomics and epigenetic information, zn is a latent/hidden variable that represents a targeted or normal cell of origin, and Θ is a set of parameters that are estimated from control genomic regions on a targeted panel or from a reference set of cfDNA samples with DNA molecules from normal cells and cfDNA samples with DNA molecules from targeted cells.
(Mathematic concept modification spelling out how the estimations or ML calculations are performed)
28. (Original) The method of claim 27, wherein dn = (xn, yn, kn, qn),where n is the given DNA molecule in the given distribution set, xn is an offset of a midpoint of the given DNA molecule from a center of the genomic region of that given DNA molecule, yn is a length of the given DNA molecule, kn is a number of CpG sites in the given DNA molecule, and qn is a methyl binding domain (MBD) partition of the given DNA molecule.
(Mathematic concept modification spelling out how the estimations or ML calculations are performed)
109. (New) The method of claim 1, wherein in (a), the method further comprises (iii) obtaining an epigenetic status or pattern exhibited by the given DNA molecule.
(Mental step of observing methylation of a DNA molecule and making a judgement as to the epigenetic status or pattern.)
110. (New) The method of claim 109, wherein in (b), the method further comprises generating an epigenetic distribution set for the member DNA molecules exhibiting the epigenetic status or pattern.
(Mathematic concept of creating mathematic distributions which describe a property. [0016-0018, 0116-0120, 00130] “[0130] Method 200 also includes comparing (typically using a computer) the distribution of the properties … or a statistical transformation of one or more components of the distribution…”)
111. (New) The method of claim 110, wherein in (c), the estimating the fraction of member DNA molecules comprises using the length distribution set, the midpoint-to-midpoint offset distribution set, and the epigenetic distribution set for member DNA molecules comprising the genomic region.
(Mathematic concept of calculating or estimating fractions that describe a property: origination from a targeted cellular origin. [0017-0018, 00115, 00119-00120, 00127] “an estimate of Θi,j”)
112. (New) The method of claim 109, wherein the member DNA molecules comprise one or more methylation sites, one or more acetylation sites, one or more ubiquitylation sites, one or more phosphorylation sites, one or more sumoylation sites, one or more ribosylation sites, one or more citrullination sites, one or more histone post-translational modification sites, and/or one or more histone variant sites.
(EIA- a description of data gathered.)
113. (New) The method of claim 112, wherein the epigenetic status or pattern comprises a methylation status of the one or more methylation sites, an acetylation status the one or more acetylation sites, a ubiquitylation status of the one or more ubiquitylation sites, a phosphorylation status of the one or more phosphorylation sites, a sumoylation status of the one or more sumoylation sites, a ribosylation status of the one or more ribosylation sites, a citrullination status of the one or more citrullination sites, a histone post-translational modification status of the one or more histone post-translational modification sites, and/or a histone variant status of the one or more histone variant sites.
(Mental step of observing particular status of a DNA molecule and making a judgement as to the status or pattern.)
114. (New) The method of claim 1, wherein 112, wherein the epigenetic status or pattern comprises one or more of: a methylation pattern, an acetylation pattern, a ubiquitylation pattern, a phosphorylation pattern, a sumoylation pattern, a ribosylation pattern, a citrullination pattern, a histone post-translational modification pattern, and/or a histone variant pattern.
(Mental step of observing particular status of a DNA molecule and making a judgement as to the status or pattern.)
115. (New) The method of 114, wherein the methylation pattern comprises a 5- methylcytosine (5mC) pattern and/or a 5-hydroxymethylcytosine (5hmC) pattern.
(EIA- a step related to data gathered.)
Natural law embraced by the claim(s): The claims embrace the naturally occurring correlations between changes in cfDNA information and a phenotype: a cell of origin, or disease. This correlation exists whether or not it is measured.
With respect to step 2A (2): NO, the claims do not provide a practical application. The claimed additional elements are analyzed alone, or in combination to determine if the JE is integrated into a practical application (MPEP 2106.05(a-c, e, f and h)).
Claim(s) 1, 112, 115 recite(s) the additional non-abstract element(s) of data gathering, or a description of the data gathered.
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data needed to carry out the JE. The data gathering does not impose any meaningful limitation on the JE, or how the JE is performed. The additional limitation (data gathering) must have more than a nominal or insignificant relationship to the identified judicial exception. (MPEP 2106.04/.05, citing Intellectual Ventures LLC v. Symantec Corp, McRO, TLI communications, OIP Techs. Inc. v. Amason.com Inc., Electric Power Group LLC v. Alstrom S.A.).
Claim(s) 20 recite(s) the additional non-abstract element (EIA) of a treatment or prophylaxis:
The identified treatment step fails to integrate the JE into a practical application, as the step does not “affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition” see (MPEP 2106.04(d)(2)).
Claim(s) 1 recite(s) the additional non-abstract element (EIA) of a general-purpose computer system or parts thereof.
The EIA do not provide any details of how specific structures of the computer elements are used to implement the JE. The claims require nothing more than a general-purpose computer to perform the functions that constitute the judicial exceptions. The computer elements of the claims do not provide improvements to the functioning of the computer itself (as in DDR Holdings, LLC v. Hotels.com LP); they do not provide improvements to any other technology or technical field (as in Diamond v. Diehr); nor do they utilize a particular machine (as in Eibel Process Co. v. Minn. & Ont. Paper Co.). Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not recite integrate that JE into a practical application.
Dependent claim(s) 5-7, 12-19, 27-28, 109-111, 113-114 recite(s) an abstract limitation to the JE reciting additional mathematic concepts, or mental processes. Additional abstract limitations cannot provide a practical application of the JE as they are a part of that JE.
In combination, the limitations of data gathering, for the purpose of carrying out the JE, using a general-purpose computer merely provide extra-solution activity, and fail to integrate the JE into a practical application.
With respect to step 2B: NO, the claims do not provide a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). The additional elements were considered individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to claim(s) 1: The limitation(s) identified above as non-abstract elements (EIA) related to data gathering do not rise to the level of significantly more than the judicial exception.
The claims require epigenetic and/or sequence information from cfDNA samples, including length and midpoint information.
Jaimovich (WO2019/236478 A1) obtains epigenetic and sequence read information, where length of sequence reads [0126] and midpoint offsets are obtained [0148].
Zotenko (WO2020/006369 A1) obtains epigenetic and sequence read information, where length of sequence reads [0007], and midpoint offsets are obtained [0007, 0233-0234, 0238].
Curtis (US2019/0287654 A1) obtains epigenetic and sequence read information, including length of sequence reads [0230] and midpoint offsets [0119, 0231, 0234, 0237].
Henikoff (WO2019/060907 A1) obtains epigenetic and sequence read information, including length of sequence reads [00786] and midpoint offsets [00786].
Underhill (US 2019/0106737 A1) obtains epigenetic and sequence read information, including length of sequence reads [0104, 0138, 0140-0145] and midpoint offsets [0132]
These elements meet the BRI of the identified data gathering limitations. As such, the prior art recognizes that this data gathering element is routine, well understood and conventional in the art (as in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook).
In the specification at [00243] it is disclosed that the steps identified as data gathering can be met using publicly available data, from public databases, such as ENCODE.
Activities such as data gathering do not improve the functioning of a computer, or comprise an improvement to any other technical field. The limitations do not require or set forth a particular machine, they do not effect a transformation of matter, nor do they provide an unconventional step (citing McRO and Trading Technologies Int’l v. IBG). Data gathering steps constitute a general link to a technological environment. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp.,).
With respect to claim(s) 1: the limitations identified above as non-abstract elements (EIA) related to general-purpose computer systems do not rise to the level of significantly more than the judicial exception.
Each of Jaimovich, Zotenko, Curtis, Henikoff and Underhill disclose computer systems or computing elements which meet the BRI of the claimed computer system or computer system elements, comprising input, output/ display, a processor, and memory.
As such, the prior art recognizes that these computing elements are routine, well understood and conventional in the art.
The specification, at [00227-00240] discloses the use of routine general-purpose computers for carrying out the invention, and/or the use of commercially available computer system elements.
These elements do not improve the functioning of the computer itself, or comprise an improvement to any other technical field (Trading Technologies Int’l v IBG, TLI Communications). They do not require or set forth a particular machine (Ultramercial v. Hulu, LLC., Alice Corp. Pty. Ltd v. CLS Bank Int’l), they do not effect a transformation of matter, nor do they provide an unconventional step. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook, Versata Development Group v. SAP America).
Dependent claim(s) 5-7, 12-19, 27-28, 109-111, 113-114 each recite a limitation requiring additional mathematic concepts or mental processes. Additional abstract limitations cannot provide significantly more than the JE as they are a part of that JE (MPEP 2106.05).
In combination, the data gathering steps providing the information required to be acted upon by the JE, performed in a generic computer or generic computing environment fail to rise to the level of significantly more than that JE. The data gathering steps provide the data for the JE, which is carried out by the general-purpose computers. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Applicant’s arguments:
Applicant’s arguments have been carefully considered, but they are not fully persuasive.
With respect to the argument that the step of sequencing is not mere data gathering, and that the claim as a whole integrates the JE into a practical application, Applicant fails to particularly detail what aspect of step 2A-2 is argued to integrate the identified JE into a practical application.
MPEP 2106.04(d): “The Supreme Court and Federal Circuit have identified a number of considerations as relevant to the evaluation of whether the claimed additional elements demonstrate that a claim is directed to patent-eligible subject matter… Additional discussion of these considerations, and how they were applied in particular judicial decisions, is provided in MPEP § 2106.05(a) through (c) and MPEP § 2106.05(e) through (h).”
Relevant instances of limitations that have been shown to integrate a JE into a practical application include:
“• An improvement in the functioning of a computer, or an improvement to other technology or technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);”
The claims do not affect the recited computer, thus arguments in regard to an improvement to the computer itself are not persuasive. With respect to an improvement to technology, it is unclear how the per-region fraction estimates are used to generate a cellular origin in the classification step, thus the claims do not clearly improve the identification of a cellular origin of cfDNA in a sample.
“• Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and”
The claims provide generically-stated sequencing of a subset of cfDNA from a sample, in the step identified as the additional element of data gathering. This sequencing is not the result of carrying out the JE, and the sequencing can be carried out whether or not the JE is applied.
“• 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 do not clearly apply the JE in a way other than linking the JE to the analysis of cfDNA from a sample.
Relevant limitations that did not integrate a judicial exception into a practical application:
“• Adding insignificant extra-solution activity to the judicial exception, as discussed in MPEP § 2106.05(g); and”
The sequencing step represents necessary data gathering, to obtain the data required to carry out the steps of the JE. The data gathering steps are not changed by the JE, the JE avails itself of the data gathered.
“• Generally linking the use of a judicial exception to a particular technological environment or field of use, as discussed in MPEP § 2106.05(h).”
The claims link the use of the JE to the technological environment of samples containing cfDNA, a field of use limitation. “At least in part using a computer” merely indicates that the JE could be performed using a computer, as a field of use limitation.
With respect to the arguments regarding step 2B and the argued improvement, these arguments are not persuasive.
As set forth above, the elements in addition to the JE is the sequencing step, where a subset of cfDNA is sequenced and the use of a computer. The analysis of this step carries over the analysis from step 2A-2 and further considers whether the element in addition represents routine, well understood and conventional activity, considers the claim as a whole, and considers whether the claim recites an inventive concept.
The step of sequencing a subset of cfDNA from a sample, where the cfDNA have at least one region in common was shown to be routine, well understood and conventional in the art of cfDNA analysis by citation to:
Jaimovich (WO2019/236478 A1) obtains epigenetic and sequence read information, where length of sequence reads [0126] and midpoint offsets are obtained [0148].
Zotenko (WO2020/006369 A1) obtains epigenetic and sequence read information, where length of sequence reads [0007], and midpoint offsets are obtained [0007, 0233-0234, 0238].
Curtis (US2019/0287654 A1) obtains epigenetic and sequence read information, including length of sequence reads [0230] and midpoint offsets [0119, 0231, 0234, 0237].
Henikoff (WO2019/060907 A1) obtains epigenetic and sequence read information, including length of sequence reads [00786] and midpoint offsets [00786].
Underhill (WO2019/0106737 A1) obtains epigenetic and sequence read information, including length of sequence reads [0104, 0138, 0140-0145] and midpoint offsets [0132].
These same citations also utilize general-purpose computers for analysis of sequencing data.
As such, the claims do not provide a specific inventive concept.
With respect to the arguments regarding an improvement, it is unclear specifically how Applicant’s claims represent an improvement over the prior art. It is unclear if Applicant is intending to argue that the claimed methods are more accurate in determining a cellular origin, or some other specific improvement. These arguments do not clearly provide a nexus between the JE, the improvement, and a real-world recognition or application of the JE. As set forth above, it is unclear how the per-region estimates are used to actually identify a cellular origin of a cfDNA.
Further, with respect to the arguments regarding the alleged improvement, it is unclear that the independent claims recite all the necessary and sufficient steps required to achieve that improvement. MPEP 2106.05(a): “An important consideration in determining whether a claim improves technology is the extent to which the claim covers a particular solution to a problem or a particular way to achieve a desired outcome, as opposed to merely claiming the idea of a solution or outcome. McRO, 837 F.3d at 1314-15, 120 USPQ2d at 1102- 03; DDR Holdings, 773F.3d at 1259, 113 USPQ2d at 1107.”
The MPEP sets forth that “if the examiner concludes the disclosed invention does not improve technology, the burden shifts to applicant to provide persuasive arguments supported by any necessary evidence to demonstrate that one of ordinary skill in the art would understand that the disclosed invention improves technology. Any such evidence submitted under 37 CFR 1.132 must establish what the specification would convey to one of ordinary skill in the art and cannot be used to supplement the specification.” Applicant’s arguments cannot take the place of evidence.
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 MARY K ZEMAN whose telephone number is 5712720723. The examiner can normally be reached on 8am-2pm M-F. Email may be sent to mary.zeman@uspto.gov if the appropriate permissions have been filed.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry Riggs can be reached on 571 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY K ZEMAN/ Primary Examiner, Art Unit 1686
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