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 .
Election/Restrictions
Applicant’s election of (A) the “fragmentome feature” of a sequence motif and (B) a cancer classification in the reply filed on 03/09/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 3-5 and 14 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/09/2026.
Status of Claims
Applicant’s amendment filed 03/09/2026 is acknowledged. Claims 3-5 and 14 are withdrawn. Claims 1-18, 20, and 26 are pending in the instant application and claims 1-2, 6-13, 15-18, 20, and 26 are the subject of this non-final office action.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 6-13, 15-18, 20, and 26 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 2, claim 1 recites “determining a value of a fragmentomic feature of each ... fragment corresponding to each sequence in the group of sequence reads; determining one or more relative frequencies of ... fragments having values of the fragmentomic feature in a set of one or more value ranges”. Claim 2 recites “the fragmentomic feature is a sequence motif corresponding to an ending sequence of an end of the ... fragment, and the one or more value ranges are one or more sequence motifs”. See also withdrawn claims 3-5 recite that the one or more value ranges are one or more “size ranges”; “topological forms”; or “nucleosomal footprints”.
It is not clear what the “value” of the “fragmentomic feature” is intended to represent. For example, claim 7 recites “determining one or more sequence motifs corresponding to one or more ending sequences of a corresponding ... fragment; determining one or more relative frequences of a set of the one or more sequence motifs”, which otherwise appears to be intended to be a species of claim 2.
It also is not clear whether the “value ranges” are intended to refer to a set of all possible values of the fragmentome feature, a difference between the highest and lowest values, or to grouping of elements (e.g., the “one of more” of claim 7) or even another range of another element with a “value”, such as genomic region. If the “one or more” is intended, it is noted that where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). If the term “range” in claim 1 is used by the claim to mean “a set,” while the accepted meaning is “a set of all possible values” or “a difference between the highest and lowest values,” the term is indefinite because the specification does not clearly redefine the term.
Claim 6 is indefinite for depending on claim 1 and not rectifying the deficiency.
Regarding claim 12, the claim recites “the sequence motif is at the 5’ end”. It is unclear what the 5’ end is relative to, e.g., the sequence read, the fragment (and if so, which strand when double stranded), the genomic regions (i.e., the strand of the mapping genome), or something else.
Regarding claims 1, 7-9, and 16-18, the claims recite “relative frequency” and/or “relative frequencies”.
Claims 1 recites “determining one or more relative frequencies of ... fragments having values of the fragmentomic feature in a set of one or more value ranges, wherein the one or more value ranges occurs in a differential rate in chromatin immunoprecipitation followed by sequencing for the histone modification ... than in sequencing without chromatin immunoprecipitation”.
Claims 7 and 17 recite “determining one or more relative frequencies of a set of the one or more sequence motifs, wherein the set of the one or more sequence motifs occurs at a higher rate in chromatin immunoprecipitation followed by sequencing for the histone modification associated with the one or more genomic regions than in sequencing without chromatin immunoprecipitation”.
It is not clear what the denominator for the reference population is intended to be, e.g., some other plurality of sequencing reads, another group of genomic regions, etc. Is the “wherein” clause attempting to define the two sets of sequencing reads to be used in the generation of the relative frequency or is it only intend to serve as a property of the set?
Claims 2, 6-13, 15-18, 20, and 26 are likewise indefinite for depending on claims 1, 7-9, or 16-18 and not rectifying the deficiency.
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 1-2, 6-13, 15-18, 20, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) abstract ideas. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to processes (methods).
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Independent claims 1, 7, and 17 each recite abstract ideas. Identifying, determining, and comparing each represent mental processes (e.g., evaluation, judgment, forming an opinion), which may be performed by the human mind. The claims also recite mathematical concepts as at least determining relative frequencies and aggregate values and comparing the aggregate value to one or more calibration values may be considered mathematical calculations under the broadest reasonable interpretation. These steps each encompass an act of calculating using mathematical methods to determine a variable or number. The determining of an amount (claim 1), determining a fractional concentration (claim 7), and estimating a first value (claim 17) each also encompass a mental process and/or calculation.
See MPEP 2106.04(a).
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claims 1-2 and 6, claim 1 recites “receiving a plurality of sequence reads” (e.g., being handed reads on paper). Such amounts to mere data gathering. Claim 1 also recites “identifying a group of sequence reads located in ... genomic regions ... associated with a target tissue type”. In addition to the abstract idea, such amounts to selecting a particular data source/type of data to be manipulated, i.e., insignificant extra-solution activity. See MPEP 2106.05(g).
Claim 2 reads on the abstract idea(s) and claim 6 further recites steps of comparing and determining that further recite mental processes and/or calculations for the same reasons.
As all steps encompass only abstract ideas or insignificant extra-solution activity, the judicial exception(s) are not integrated into a practical application.
Regarding claims 7-12, and 15-16, claim 7 also recites a step of “receiving” sequence reads and identifying, which amount to data gathering or selection of a particular data source/type for the same reasons. Determining a fractional concentration encompasses the abstract ideas of a mental process and/or a calculation.
Claim 8 recites applying the determining of relative frequencies and aggregate values to each calibration sample, and thus recites additional abstract ideas as previously discussed.
Claims 9, 10-12, and 13 are directed to the identities of the aggregate value, the sequence motif, and the target tissue type, respectively, and thus are directed to the abstract idea(s).
Claim 15 recites further determining a classification of a level of cancer, and thus encompasses a mental process and/or a calculation for the same reasons a previously described.
Claim 16 recites further identifying a second group of sequence reads and repeating the same steps for second sequence motifs, aggregate values, fractional concentrations, etc. and as such encompasses the same abstract ideas and/or insignificant extra-solution activity as discussed above.
As all steps encompass only abstract ideas or insignificant extra-solution activity, the judicial exception(s) are not integrated into a practical application.
Regarding claims 17-18, 20, and 26, claim 17 also recites a step of “receiving” sequence reads and identifying, which amount to data gathering or selection of a particular data source/type for the same reasons.
Claim 18 further recites determining a relative frequency and an aggregate value for each calibration sample, thereby further reciting abstract ideas, for the same reasons as discussed previously.
Claim 20 recites the target tissue type and is thus directed to the abstract ideas.
Claim 26 recites further measuring the sizes of the fragments using the sequence reads, determining size frequency(ies), determining an aggregate value for the size frequency(ies), and comparing the aggregate value to calibration value(s). Measuring sizes of the fragments using reads encompasses a mental process (e.g., forming a judgment about the relative size by looking at the reads) and/or a calculation (e.g., adding the number of bases in the mapped read). Determining and comparing likewise encompass the same for the reasons previously discussed.
As all steps encompass only abstract ideas or insignificant extra-solution activity, the judicial exception(s) are not integrated into a practical application.
Step 2B. Does the claim amount to significantly more?
As discussed in MPEP 2106.05(I), the inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 573 U.S. at 21-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added)); RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract").
Likewise, the courts have also found that insignificant extra-solution activity is not sufficient to qualify as “significantly more”. See MPEP 2106.05(A).
As the claims fail to require more than abstract idea(s) and insignificant extra-solution activity, the claims do not amount to significantly more.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 6-13, 15-18, 20, and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lo (WO 2020/125709 A1; published 06/25/2020) in view of Lo – 2013 (US 2013/0237431) and Zotenko (WO 2020/176659 A1; published 09/03/2020).
Regarding claims 1-2, 7, and 17, Lo teaches a method of analyzing a biological sample, the biological sample including cell-free DNA fragments (entire document, e.g., claim 1, Fig. 19, para [0161-182]), the method comprising :
receiving a plurality of sequence reads of the cell-free DNA fragments (para [0161] and [0084]), wherein the plurality of sequence reads include ending sequences corresponding to ends of the cell-free DNA fragments (para [0060]);
identifying a group of sequence reads located in one or more genomic regions (para [0161]);
for each sequence read of the group of sequence reads, determining one or more sequence motifs corresponding to one or more ending sequences of a corresponding cell-free DNA fragment (para [0161]; Fig 19, 1920);
determining one or more relative frequencies of a set of the one or more sequence motifs (Fig. 19, 1930; para [0162]);
determining an aggregate value of the one or more relative frequencies (para [0164]);
comparing the aggregate value to one or more calibration values (para [0166]);
determining a fractional concentration of cell-free DNA fragments from the target tissue type using the comparison, wherein the one or more calibration values are determined from one or more calibration samples whose fractional concentrations of cell-free DNA fragments from the target tissue type are known (para [0108]: “Given an entropy measurement for the calibration sample, a comparison of the two entropy values (one for the test sample and one for the calibration sample) can provide a fractional concentration for the test sample using the measured concentration in the calibration sample; instant claim 7), i.e.
estimating a first value for a characteristic of the target tissue type using the comparison, wherein the one or more calibration values are determined from one or more calibration samples whose values for the characteristic of the target tissue type are known (instant claim 17; see also para [0268]: “the property of the clinically relevant DNA [of] the biological sample can be a fractional concentration”).
It is also noted that Lo teaches gestational age and level of disease (see claim 15 below; instant claim 17).
Lo teaches both physical (para [0252-258]) and in silico enrichment to select certain DNA fragments based on epigenetic characteristics (para [0259]) and teaches mapping the sequence reads to specific regions (para [0161]). Lo teaches identifying the plurality of cfDNA fragments using a tissue-specific epigenetic marker to filter DNA fragments for ones that are from or likely from an exemplary tissue (para [0176]).
Lo teaches that particular end motifs can be selected on the basis of differences (para [0162]), and teaches using calibration samples or other reference samples not used for calibrating the fractional concentration (para [0163]). Lo suggests epigenetic markers for analyzing differential end motif patterns between groups of DNA molecules in the invention (para [0101]). Lo teaches that measuring a fractional concentration of clinically-relevant DNA can be performed using a tissue-specific epigenetic marker (para [0170]).
Lo teaches determining an index for an exemplary characteristic by comparing reads with said characteristic over the total reads covering that site, wherein such reads may be obtained using reagents the preferentially hybridize to DNA fragments with said characteristic (para [0069]).
Lo teaches that the fractional concentration can be a number, numerical range, or other classification and the aggregate value may be an array (para [0080]) or the final or intermediate output of a machine learning model (para [0165]) (instant claim 1).
Lo teaches that different tissues have preferred fragmentation patterns during apoptosis and selecting certain genomic regions for plasma DNA end motif analysis to improve the discriminative power in classifying diseased patients and control subjects (para [0232]; see also para [0227]).
Regarding claims 8 and 18, Lo teaches calculating an aggregate value for each calibration sample (para [0167]) corresponding to relative frequences of the set of one or more sequence motifs measured using cfDNA fragments in the one or more calibration samples (para [0166]). Lo teaches an example of such an aggregate value being associated with a known fractional concentration (para [0108]). See also para [0168-172].
Regarding claim 9, Lo teaches the aggregate value may be entropy, a sum of relative frequencies, or a vector of relative frequencies (entire document, e.g., para [0080]).
Lo teaches that an aggregate value may be a separation value (para [0073]) and a separation value may be a ratio (para [0072]).
Regarding claim 10, Lo teaches the sequence motif may be a k-mer having various numbers of bases including 1-7 (para [0087]).
Regarding claims 11-12, Lo teaches using the motif including the nucleotide at the end of the cfDNA (Fig. 1, techniques 140 and 160; instant claim 11) and that with the 5’ of the reference genome viewed as the start, Lo teaches using a first end motif at the 5’ end (Fig. 1, ; para [0088-89]; instant claim 12).
Lo teaches using the top set of one or more sequence motifs (para [0163]).
Regarding claim 13, Lo teaches the tissue type may be liver, hematopoietic, or placental (para [0171]).
Regarding claims 15 and 20, Lo teaches determining a level of a disease (para [0186]), including a level of pathology for cancer (para [0187], [0191-200], and [0031-34]; Fig. 23-26; instant claim 15) and that the DNA may be derived from an organ that has cancer (para [0171]; instant claim 20).
Regarding claim 16, Lo teaches measures of relative frequences of sequence end motifs of cfDNA in mixtures of cfDNA from various tissues (Abstract). See also para [0002].
Regarding claim 26, Lo teaches Lo teaches synergistic analysis with conventional metrics of detecting tissue origin to improve performance of detection, wherein one such is size and teaches using a separate cutoff (para [0221-223]). To perform such a size analysis, Lo teaches measuring a fractional concentration using a size and incorporates by reference Lo – 2013 (Lo, para [0170]; see [0223]), which teaches calculating a parameter based on a statistical measure of a size profile of DNA fragments, comparing the first value to a calibration value, and estimating the fractional concentration of the clinically relevant DNA (Lo – 2013 claim 1) and that the parameter may be the frequency (Lo – 2013, para [0101] and [0106]).
Lo fails to explicitly teach:
wherein each of the one or more genomic regions has a histone modification associated with a target tissue type (claims 1-2, 7 and 17);
wherein the set of the one or more sequence motifs occurs at a higher rate in chromatin immunoprecipitation followed by sequencing for the histone modification associated with the one or more genomic regions than in sequencing without chromatin immunoprecipitation (claims 1-2, 7 and 17);
determining an amount of the histone modification in the biological sample using the comparison (claim 1-2) and to compare this amount to one or more second calibration values to determine a fractional concentration or classification (claim 6);
repeating the steps for a second set of genomic regions that have a second histone modification associated and determining a second fractional concentration from a second tissue type (claim 16);
Zotenko teaches using both fragmentomic and epigenetic information in a method of determining the cellular origin of cfDNA, wherein fragmentomic information is represented by the molecule’s endpoints and the epigenetic information is the identity of protein complexes bound to the molecule such as histone post-translational modifications (para [0110-112]).
Zotenko teaches training a classifier using differential genomic sections that comprise epigenetic loci from epigenetic information from DNA molecules of a plurality of control samples (claim 56), wherein such epigenetic loci may be one or more histone post-translational modification sites (para [013]; [079]). Zotenko incorporates by reference paper citations regarding histone modifications for such epigenetic loci (para [0150]). Zotenko teaches two or more partitions when obtaining epigenetic information from cfDNA (para [0151]).
Zotenko teaches the use of databases from studies employing comprehensive genomic profiling of tumors including Chip-seq and whole genome sequencing (WGS) to develop a set of markers (para [0190]; see also [0242], which uses ChIP-seq and WGS to identify profiles).
Zotenko teaches normalization (para [0261], i.e., a relative frequency) and estimating a fraction of DNA molecules originating from “inactive” and “active” sources (para [018], [022]; claim 62: “theta is a fraction of DNA molecule originating from an inactive cellular source”), wherein “active” are molecules bound to an exemplary protein (para [064]) and “inactive” are those not bound to an exemplary protein (para [083]), i.e., an determining an “amount” of said exemplary protein by comparing an aggregated value to a calibration value, wherein the artisan would understand that the estimated fraction of “active”/bound protein may be obtained by 1 – theta (instant claim 1). Zotenko transforming theta to generate a z-score to use as a classifier (claim 26), wherein the z-scores compare theta to the mean i.e., a second calibration value (claim 25; instant claim 6).
Zotenko teaches that the fragmentation pattern of cfDNA molecules in plasma and other sample types carries information about chromatin organization of the cells/tissues from which it originates as it tend to be fragmented around DNA bound proteins and that the location of DNA binding proteins is highly tissue specific, thus can be used to amplify signal coming from cells or tissues (para [0107]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized genomic regions associated with a histone modification associated with a target tissue type given the teachings of Zotenko regarding epigenetic loci in the method of analyzing end motifs in a cfDNA sample of Lo and the teaching of both in utilizing both fragmentomic and epigenetic information. In doing so, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized ChIP-seq based on such histone post-translational modification as both Lo and Zotenko teach/suggest enrichment of cfDNA molecules relevant to tissue type discrimination and Zotenko utilize ChIP-seq to do so, wherein optimizing for a set of top sequence(s) would result in a set of one or more sequence motifs that occur in a higher rate in ChIP-seq for the histone modification than sequencing without ChIP. The artisan would have been so motivated by the desire to amplify signal coming from cells/tissues, as taught by Zotenko, and to improve the discriminatory power, as taught by Lo (instant claims 1-2, 7, and 17). It is noted that where Zotenko teaches multiple epigenetic loci, histone PTMs are an obvious species of the genus as Zotenko provides multiple papers directed to histone PTM loci that would be expected to improve predictability. See MPEP 2144.08.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to determine an amount of the histone modification using the comparison and to utilize said amount to determine a classification as such a probabilistic mixture model and z-scores of Zotenko represent an obvious species of the genus of machine learning models taught by Lo, wherein such are well known in the art (instant claims 1-2 and 6). See MPEP 2144.08.
While it is noted that claim 10 recites “a sequence motif of the set of sequence motifs” and claim 12 then limits that one motif of the set to the 5’, such that utilizing a set that includes both ends would also meet the claim, as is taught by Lo, it likewise would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized 5’ end motifs as such represents the optimization of the number of top motifs wherein the 5’ end motifs may perform the best and/or would be obvious to try as there are two ends of a molecule and it would be obvious to choose among each side or both, wherein such would be predictable with a reasonable expectation of success given the teachings of Lo of the use of such start motifs (instant claim 12). See MPEP 2144.05(II) and 2143.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have repeated the analysis for a second set of genomic regions with a second histone modification associated to determine a second target tissue as Zotenko suggests considering additional histone post-translational modification epigenetic loci and generating two or more partitions when generating epigenetic information [i.e., the histone PTM ChIP-seq], such that it would be obvious to repeat the step as a duplication of parts for an additional histone PTM and tissue type (instant claim 16). See MPEP 2144.04(VI)(B).
There would be a strong expectation of success as both Lo and Zotenko teach or suggest using both fragmentomic/sequence information and epigenetic annotations/information in cfDNA using computational and sequencing means.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 6-13, 15-18, 20, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4,6-7, 10-21, 28-35, 37-38, and 54-57 of copending Application No. 16721619 in view of over Lo (WO 2020/125709 A1; published 06/25/2020), Lo – 2013 (US 2013/0237431) and Zotenko (WO 2020/176659 A1; published 09/03/2020). This is a provisional nonstatutory double patenting rejection.
Both sets of claims are directed to performing an assay on a plurality of cfDNA from a biological sample, wherein the sequencing reads include ending sequences; for each of the cfDNA fragments, determining a sequence motif for each of the plurality of cfDNA fragments, corresponding to an end motif pattern of a set; and determining a collective property of the end motif pattern set and using it to determine a classification of the DNA using one or more calibration sample whose fractional concentration is known (claim 11). ‘619 claim 19 further recites measuring the fractional concentration and determining aggregate values of calibration samples. ‘619 recites filtering the cf DNA to identify the fragments (claim2). ‘619 recites applying the method to determine a level of pathology (claim 1) where the tissue is cancer (claim 10). ‘619 recites determining the top M sequence motifs (claims 29 and 32), the aggregate value/collective property may be a sum (claim 35) or the final/intermediate output of the machine learning model (claim 37). ‘619 teaches sequence motifs that are 7 bases or less (claim 54) or 2, 3, or 4 bases (claim 57).
The claims of ‘619 does not explicit teach:
that the filtering is for histone modification-associated genomic regions (claims 1-2, 7, and 17);
wherein the set of the one or more sequence motifs occurs at a higher rate in chromatin immunoprecipitation followed by sequencing for the histone modification associated with the one or more genomic regions than in sequencing without chromatin immunoprecipitation (claims 1-2, 7 and 17);
determining an amount of the histone modification in the biological sample using the comparison (claim 1-2) and to compare this amount to one or more second calibration values to determine a fractional concentration or classification (claim 6);
using one motif at the 5’ end (claim 12);
repeating the steps for a second set of genomic regions that have a second histone modification associated and determining a second fractional concentration from a second tissue type (claim 16);
the sizes of the cfDNA fragments are used to determine an aggregate value and compare to a calibration value to estimate a first value for the characteristic (claim 26).
As described and cited in the 103 rejection above, Lo, Lo – 2013, and Zotenko teach or suggest:
filter for histone modification-associated genomic regions (claims 1-2, 7, and 17);
optimizing such that the set of the one or more sequence motifs occurs at a higher rate in chromatin immunoprecipitation followed by sequencing for the histone modification associated with the one or more genomic regions than in sequencing without chromatin immunoprecipitation (claims 1-2, 7 and 17);
determining an amount of the histone modification in the biological sample using the comparison (claim 1-2) and comparing this amount to one or more second calibration values to determine a fractional concentration or classification (claim 6);
repeating the steps for a second set of genomic regions that have a second histone modification associated and determining a second fractional concentration from a second tissue type (claim 16);
the sizes of the cfDNA fragments are used to determine an aggregate value and compare to a calibration value to estimate a first value for the characteristic (claim 26).
Lo, incorporating by reference Lo – 2013, teaches that different tissues have preferred fragmentation patterns during apoptosis and selecting certain genomic regions for plasma DNA end motif analysis to improve the discriminative power in classifying diseased patients and control subjects (para [0232]; see also para [0227]).
Zotenko teaches that the fragmentation pattern of cfDNA molecules in plasma and other sample types carries information about chromatin organization of the cells/tissues from which it originates as it tend to be fragmented around DNA bound proteins and that the location of DNA binding proteins is highly tissue specific, thus can be used to amplify signal coming from cells or tissues (para [0107]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized genomic regions associated with a histone modification associated with a target tissue type given the teachings of Zotenko regarding epigenetic loci in the method of analyzing end motifs in a cfDNA sample of ‘619 and the teaching of both Zotenko and Lo in utilizing both fragmentomic and epigenetic information. In doing so, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized ChIP-seq based on such histone post-translational modification as both Lo and Zotenko teach/suggest enrichment of cfDNA molecules relevant to tissue type discrimination and Zotenko utilize ChIP-seq to do so, wherein optimizing for a set of top sequence(s) would result in a set of one or more sequence motifs that occur in a higher rate in ChIP-seq for the histone modification than sequencing without ChIP. The artisan would have been so motivated by the desire to amplify signal coming from cells/tissues, as taught by Zotenko, and to improve the discriminatory power, as taught by Lo (instant claims 1-2, 7, and 17). It is noted that where Zotenko teaches multiple epigenetic loci, histone PTMs are an obvious species of the genus as Zotenko provides multiple papers directed to histone PTM loci that would be expected to improve predictability. See MPEP 2144.08.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to determine an amount of the histone modification using the comparison and to utilize said amount to determine a classification as such a probabilistic mixture model and z-scores of Zotenko represent an obvious species of the genus of machine learning models taught by ‘619 and Lo, wherein such are well known in the art (instant claims 1-2 and 6). See MPEP 2144.08.
While it is noted that claim 10 recites “a sequence motif of the set of sequence motifs” and claim 12 then limits that one motif of the set to the 5’, such that utilizing a set that includes both ends would also meet the claim, as is taught by Lo, it likewise would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized 5’ end motifs as such represents the optimization of the number of top motifs wherein the 5’ end motifs may perform the best and/or would be obvious to try as there are two ends of a molecule and it would be obvious to choose among each side or both, wherein such would be predictable with a reasonable expectation of success given the teachings of Lo of the use of such start motifs (instant claim 12). See MPEP 2144.05(II) and 2143.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have repeated the analysis for a second set of genomic regions with a second histone modification associated to determine a second target tissue as Zotenko suggests considering additional histone post-translational modification epigenetic loci and generating two or more partitions when generating epigenetic information [i.e., the histone PTM ChIP-seq], such that it would be obvious to repeat the step as a duplication of parts for an additional histone PTM and tissue type (instant claim 16). See MPEP 2144.04(VI)(B).
There would be a strong expectation of success as Lo and Zotenko teach or suggest using both fragmentomic/sequence information and epigenetic annotations/information in cfDNA using computational and sequencing means and each is directed towards classifying pathologies or other characteristics of tissues represented by cfDNA in samples.
Conclusion
No claims allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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