Patent Application 18820166 - CANCER DETECTION AND CLASSIFICATION USING

Title: CANCER DETECTION AND CLASSIFICATION USING METHYLOME ANALYSIS

Application Information

Invention Title: CANCER DETECTION AND CLASSIFICATION USING METHYLOME ANALYSIS
Application Number: 18820166
Submission Date: 2025-04-08T00:00:00.000Z
Effective Filing Date: 2024-08-29T00:00:00.000Z
Filing Date: 2024-08-29T00:00:00.000Z
Examiner Employee Number: 72605
Art Unit: 1683
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 4

Cited Patents

The following patents were cited in the rejection:

US 0299812🔗
US 0144848🔗

Office Action Text

Detailed Action

► The preliminary Amendment filed 04 NOV 2024 has been entered. Claim(s) 28-57 is/are pending.

► The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.

► Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 28-50 is drawn to a method of determining whether a subject has or is at risk of having a disease which comprises in part computer processing a plurality of sequence reads obtained from cell-free nucleic acids to identify a methylation profile a mutation profile and/or a fragment length profile in said nucleic acid, classified in Class C12Q, subclass 1/68.
II. Claims 51-57 Claims drawn to a method of determining whether a subject has or is at risk of having a disease and/or which comprises analyzing a cell-free nucleic acid of said subject which analysis comprises determining a methylation level in a DMR listed in Tables 5-6, classified in C12Q, subclass 1/68.

► The inventions are distinct, each from the other for the following reason.
Inventions I and II are drawn to related but patentably distinct inventions. The method(s) of Group I comprises limitations not required by Group II, for example, the method of Claim 1 requires any of identify a methylation profile, a mutation profile, and/or a fragment length profile while the method of Group II only comprises obtaining a methylation profile. Meanwhile the invention the Group II requires the search and consideration of all of the DMRs recited in Table 5 and 6 a limitation not required by the invention of Group I.

► Should the applicant elect Group II, an additional species election is required. Claims 51-57 are directed to the following patentably distinct species (i.e. the specific DMRs recited in Claim 5-6).The species recited by Tables5-6 are independent or distinct because each species represents specific methylation structures that are represented by different nucleic structures that have different biochemical effects on the biological pathways. In addition, these species are not obvious variants of each other based on the current record. Applicant is required under 35 U.S.C. 121 to elect a single disclosed species for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, 51-57 are generic. There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: different searches of the electronic databases. Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including anyclaims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.

► Because these inventions are distinct for the reasons given above and the necessity for non-coextensive literature searches, restriction for examination purposes as indicated is proper. There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: different searches of the electronic databases.

► The applicant is advised that the response to this requirement, to be complete, must include an election of the invention to be examined even though the requirement be traversed (37 CFR 1.143). The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and
specifically point out supposed errors in the election and/or species requirement, the election
shall be treated as an election without traverse. Traversal must be presented at the time
of election in order to be considered timely. Failure to timely traverse the requirement
will result in the loss of right to petition under 37 CFR 1.144. If claims are added after
the election, applicant must indicate which of these claims are readable on the elected
species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of
patentably indistinct species from which election is required, are not patentably distinct,
applicant should submit evidence or identify such evidence now of record showing them
to be obvious variants or clearly admit on the record that this is the case. In either
instance, if the examiner finds one of the species unpatentable over the prior art, the
evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35
U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration
of claims to additional species which depend from or otherwise require all the limitations
of an allowable generic claim as provided by 37 CFR 1.141.

► Applicant is reminded that upon the cancelation of claims to a non-elected
invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one
or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).

► In response to a telephonic inquiry the applicant elected Group I, Claim(s) 28-50 without traverse for further prosecution. As such, Group II, Claim(s) 51-57 are withdrawn from further consideration. An action wherein Claim(s) 28-50 are considered follows:

35 U.S.C. 112(b)/ 112 (pre-AIA ), second paragraph

► 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.

Claim Rejection(s) under 35 U.S.C. 112(b)/ 112 (pre-AIA ), second paragraph

► Claim(s) 28-50 is/are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite in that it fails to point out what is included or excluded by the claim language.
Claim 28 is rejected under 35 U.S.C. 112, second paragraph, as being unclear because it is not clear as to the metes and bounds of what is meant the phrase “removed from said mutation profile. Likewise, Claims 36 and 43 recites “removed from the methylation profile”.

35 U.S.C. 102

► The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that may form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –

(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.

(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.

35 U.S.C. 103

► 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 Rejection(s) under 35 U.S.C. 103

► Claim(s) 28-30, 32 43, 47-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Talasaz [US 2015/0299812 – hereinafter “Talasaz”] in view Feng et al. [US 20200160936 – hereinafter “Feng”] ; Liu et al. [J. of Biomedical Informatics 49:119-133(2014) – hereinafter “Liu”] and Underhill et al. [PLOS Genetics 12(7) : 24 pgs(2016) – hereinafter “Underhill”].

Claim 28 is drawn to a method for determining whether a subject has or is at risk of having a disease, comprising:
(a) providing a cell-free nucleic acid sample derived from a subject, wherein said cell-
free nucleic acid sample comprises a plurality of nucleic acid molecules;
(b) subjecting said plurality of nucleic acid molecules, or derivatives thereof, to
sequencing to generate a plurality of sequencing reads;
(c) computer processing said plurality of sequencing reads to identify, for said
plurality of nucleic acid molecules, at least one profile, wherein said at least one profile
comprises (i) a methylation profile, (ii) a mutation profile, or (ii1) a fragment length profile,
wherein any variant that is present in a genomic DNA sample obtained from one or more
peripheral blood leukocytes obtained from said subject is removed from said mutation
profile; and
(d) using said at least one profile to determine whether said subject has or is at risk of
having said disease.
Talasaz teach a system and method for determining whether a subject has or is at risk of having a disease (e.g. cancer), see para 60 and 120 which comprises genetic profiling (e.g.mutation profiling, see para 385 and/or methlymation profling, see para 204) which method and system involves detecting the presence and/or absence of diagnostic profiles by analyzing e.g. sequencing) cell free nucleic acid (i.e.. cfDNA) obtained from a subject and compared to reference control (i.e. data obtained from normal healthy controls)
Talasaz further teach analyzing their obtained data through bioinformatic processing.(i.e.computer processing) in order to determine if a subject has or is at risk of having a disease. See at least the abstract and paras 6, 128-143, 201-205, 308, 312-318, 346 and 385.
As regards the limitation(s) which requires identifying a methylation profile and/or a mutation profile and the comparison thereof (Claims 37-38, 51-54-57). Talasaz clearly teach generating a methylation profile and a mutation profile. For example, see at least para 204 wherein these inventors teach :
“After sequencing data of cell free polynucleotide sequences is collected, one or more bioinformatics processes may be applied to the sequence data to detect genetic features or aberrations such as copy number variation, rare mutations (e.g., single or multiple nucleotide variations) or changes in epigenetic markers, including but not limited to methylation profiles. In some cases, in which copy number variation analysis is desired, sequence data may be: 1) aligned with a reference genome; 2) filtered and mapped; 3) partitioned into windows or bins of sequence; 4) coverage reads counted for each window; 5) coverage reads can then be normalized using a stochastic or statistical modeling algorithm; 6) and an output file can be generated reflecting discrete copy number states at various positions in the genome. In other cases, in which rare mutation analysis is desired, sequence data may be 1) aligned with a reference genome; 2) filtered and mapped; 3) frequency of variant bases calculated based on coverage reads for that specific base; 4) variant base frequency normalized using a stochastic, statistical or probabilistic modeling algorithm; 5) and an output file can be generated reflecting mutation states at various positions in the genome.”
Also consider para 205, wherein Talasaz clearly teach “determining whether a subject has or is at risk of having a disease such as cancer:
The system and/or method of the invention may be “used for the identification, detection, diagnosis, treatment, staging of, or risk prediction of various genetic and non-genetic diseases and disorders including cancer. It may be used to assess subject response to different treatments of said genetic and non-genetic diseases, or provide information regarding disease progression and prognosis.”

As regards the limitation which reads “wherein any variant that is present in a genomic DNA sample obtained from one or more peripheral blood leukocytes obtained from said subject is removed from said mutation profile.” Talasaz clearly teach “filtering” their data (e.g. sequencing data), see at least paras 204 recited above, ”Filtering” is a term of the art which involves the removal of erroneous data from biological analyses which can confound/ bias the findings of an assay and, which in turn, can act to undermine the validity of conclusions drawn from data sets, making it crucial to identify and adjust for them in bioinformatic analyses. In support of this interpretation consider Vanderweyer et al. [Genome Medicine 6:74 (2014) – hereinafter “Vanderweyer”].
That said, while Talasaz generally teach “filtering” as noted above, these inventors do not explicitly teach : “wherein any variant that is present in a genomic DNA sample obtained from one or more peripheral blood leukocytes obtained from said subject is removed from said mutation profile”. However this processing step was as known as evidenced by Fang. See at least for example para 55 wherein Fang teaches:
By using a reference pool made of small DNA fragments isolated from whole blood, and by amplifying short fragments of DNA in serum or other bodily fluids, the method of the present invention advantageously reduces the influence of this putative contamination by filtering out fragments whose methylation coincide in tumor DNA and DNA of peripheral blood leukocytes.
As regards the limitation which comprises the “computer processing” of the sequencing reads/data, Talasaz while teaching the use of computers, see at least for example, para 157-165 these inventors does not explicitly teach the phrase “computer processing” but rather teach “bioinformatics processing”, see at least para 204.. However, it was well known that “bioinformatics processing” is generally performed using computers (i.e. by computer processing) , see, for example, the abstract in Liu. Accordingly absent an unexpected result, it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method of Talasaz in view of Feng wherein the bioinformatics processing disclosed by these inventors is carried out with the aid of a computer(s) (i.e. by computer processing). The PHOSITA would have been motivated to make this modification in order to gain the efficiency and speed inherent to the use of computers.
Thus it is asserted that Talasaz in view Feng and Liu teach a method for determining whether a subject has or is at risk of having a disease which comprises most of the limitations of Claim 28 except these inventors do not teach identifying/obtaining “a fragment length profile”. However, it was well known that individuals with a certain disease (e.g. cancer) have cfDNA fragment length profiles distinct from healthy individuals. Consider, for example, Underhill, see the entire document. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method of Talasaz in Feng and Liu wherein rather than, or in addition to, obtaining a mutation profile, see at least paras 128-146, 204-205 of Talasaz, and/or a methylation profile, see at least para 204 in Talasaz, a fragment length profile is also obtained as taught by Underhill. The PHOSITA would have been motivated to make this modification in order to provide health care providers with as much information as possible, in order to inform any diagnostic and/or therapeutic decisions required of said providers when treating said individual at risk of said for a disease.

As regards Claim 29, see the reasoning outlined above against Claim 28. Also note that Talasaz explicitly teach identifying a “methylation profile” and a “mutation profile” (i.e.. at least two of the three profiles recited).

Claim 30, Talasaz explicitly teach identifying “prostate cancer”, as well as, numerous other types of cancers (e.g. colon/rectum cancers), see at least para 308.

Claim 32 is drawn to an embodiment of the method of Claim 30 wherein said plurality of nucleic acid molecules comprises circulating tumor DNA (hereinafter ctDNA).
This limitation is considered inherent to the samples of Talasaz as ctDNA was known to be present in patients afflicted with cancer. In support of this position consider at least Pantel et al. [Cancer Discovery 6(5) :479-491(2016) – hereinafter “Pantel”].

As regards Claim 43, note that Talasaz teach “filtering” NGS data as noted above.

Underhill teach the limitation(s) of Claim 47. See at least for example the abstract.

As regards Claim 48, De Carvalho clearly teach enrichment of DMRs/CpG islands, see at least paras 8-13 and 84-90.
As regards Claim 49, De Carvalho clearly teach enrichment using filler DNA, see at least paras 61 and 81..
As regards Claim 50, De Carvalho clearly teach in at least one embodiment of their invention(s) the use of “bisulfite sequencing”, see at least para(s) 8 and 82 in DeCarvalho.

► Claim(s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Talasaz in view Feng; Liu and Underhill as applied above against Claims 28-30 and further in view of Stansky et al. [Science 333:1157-1160(2011) – hereinafter “Stansky”].
Claim 31 is drawn to an embodiment of the method of Claim 30 wherein the cancer is head and neck squamous cell carcinoma (hereinafter HNSCC).
Talasaz in view Feng; Liu and Underhill reasonably suggest a method for determining whether a subject has or is at risk of having a disease comprising most of the limitations recited by Claim 31 for at least the reason(s) outlined above against Claims 28-30 except these refernces fail to teach detect diagnosing treating HNSCC. However this disease was known as evidenced by Stransky, see at least the abstract. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method suggested by Talasaz in view Feng; Liu and Underhill wherein the disease targeted for detection is HNSCC. The PHOSITA would have been motivated to make the modification in order to aid in the diagnosis and treatment of HNSCC.

► Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Talasaz in view Feng; Liu and Underhill as applied above against Claims 28-30 and further in view of Kalinich et al. [PNAS114(5) :1123-1128 (JAN 2017) – hereinafter “Kalinich”].
Claim 33 is drawn to an embodiment of the method of Claim 30 wherein said plurality of nucleic acid molecules comprises circulating tumor RNA (hereinafter ctRNA).
Talasaz in view Feng; Liu and Underhill reasonably suggest a method for determining whether a subject has or is at risk of having a disease comprising most of the limitations recited by Claim 33 for at least the reason(s) outlined above against Claims 28-30 except these refernces fail to explicitly teach ctRNA or its analysis. However as ctRNA was known to be present in patients afflicted with cancer as was the analysis thereof as evidenced by at least Kalinich see at least the abstract. Kalinich teach detecting and analyzing ctRNA in hepatocellular carcinoma -hereinafter HCC. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method suggested by Talasaz in view Feng; Liu and Underhill wherein at least one of the nucleic acid(s) targeted for analysis is ctRNA. The PHOSITA would have been motivated to make the modification in order to aid in the diagnosis of HCC as suggested by Kalinich.

► Claim(s) 34-42, 44, 48-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Talasaz in view Feng; Liu and Underhill as applied above against Claims 28-30 and further in vew of De Carvalho et al.[US 2019/0144848 - hereinafter “De Carvalho”].
Claim 34 is drawn to an embodiment of the method of Claim 30 wherein said methylation profile comprises a plurality of DMRs.
Talasaz in view Feng; Liu and Underhill reasonably suggest a method for determining whether a subject has or is at risk of having a disease comprising most of the limitations recited by Claim 34 for at least the reason(s) outlined above against Claims 28-30 except these refernces fail to teach analysis of DMRs. However the analysis of DMRs was known as evidenced by at least De Carvalho, see at least paras 87-88. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method suggested by Talasaz in view Feng; Liu and Underhill wherein DMRs are included in said analysis as suggested by De Carvalho. The PHOSITA would have been motivated to make the modification in order to aid in the diagnosis cancer.
Claim 35 is drawn to an embodiment of the method of Claim 34 wherein said plurality of said DMRs are ctDNA derived.
De Carvalho teach this limitation, see at least paras 87-88.

As regards Claim 36, note that at least Talasaz teach “filtering” NGS sequencing data to remove results which confound the analyses of said data. Also see Feng at para 55.
As regards Claim 37-38 De Carvalho teach analyzing both hypo-/unmethylated and hypermethylated DMRs see at least paras 15-17 and Fig. 7. De Carvalho does not teach the genomic number limitation(s) recited. The limitation(s) recited, without more is/are considered prima facie obvious as thousands of DMRs were known as was the association thereof with a plurality of different caner types. The PHOSITA, absent a showing, would have been motivated by the prior art to include with any analysis performed the analysis all known DMR regions in order to fully identify any signals known to be indicative of cancer.
.

As regards Claim 39-40, De Carvalho does not teach the size and/or number DMRs analyzed. However, absent a showing of some criticality, this limitation does not appear to provide a patentable distinction over the prior art of record in light of ambiguity of definitions found in the prior art defining what is meant by “Differentially Methylated Regions” (i.e. “DMRs”). Although no concrete definition exist in the prior art, “DMRs” are broadly defined by the art (Official Notice) to be “genomic regions with different DNA methylation status across different biological samples (e.g. normal vs cancerous) and are regarded as possible functional regions involved in gene transcriptional regulation”. Likewise, CpG islands (a subset of DMRs) are also ambiguously defined. For example, Marsh et al. [US 2020/01656575 – hereinafter “Marsh”] teach, see para 65, “ CpG Islands are defined by the UCSC Genome Browser as domains with greater than 50% G+C nucleotide content, greater than 0.60 ratio of Observed to Expected frequency of CpG sites, and a minimum length of 200 nucleotides. See also Saxonov et al. [PNAS 103(5) : 1412-1417 (2006) – hereinafter “Saxonov”] and Wang et al. [Bioinformatics 20(7) : 1170-1177(2004- hereinafter “Wang”] for additional clarification as to the definition of the terms DMRs and/or CpG island.

As regards Claim 41, absent an unexpected showing, it would have been prima facie obvious to the PHOSITA to include data in said analyses obtained from healthy controls having a same or a similar set of risk factors as the patients exhibiting a given disease.

As regards Claim 42, see at least para 201 in Talasaz.

Non-Statutory Obviousness-type 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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b). 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.

NSODP Rejection(s)
► Claim 28-50 is/are provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claim 1-27 of US Patent No. 12,031, 184 and/or claim 1-27 of US Patent No. 12,227,737. Although the conflicting claims are not identical, they are not patentably distinct
Provisional NSODP Rejection(s)
► Claim 28-50 is/are provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claim 55-101 of copending Application No. 18/067,661 Although the conflicting claims are not identical, they are not patentably distinct This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Conclusion

C. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ethan Whisenant whose telephone number is (571) 272-0754. The examiner can normally be reached Monday-Friday from 8:30 am -5:30 pm EST or any time via voice mail. If repeated attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Cynthia Wilder, can be reached at (571) 272-1791.
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.
The Central Fax number for the USPTO is (571) 273-8300. Please note that the faxing of papers must conform with the Notice to Comply published in the Official Gazette, 1096 OG 30 (November 15, 1989). Information regarding the status of an application may be obtained from the Patent Center system. Status information for published applications may be obtained through the Patent Center. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ETHAN C WHISENANT/
Primary Examiner, Art Unit 1683
ethan.whisenant@uspto.gov

EXAMINER SEARCH NOTES

26 MAR 2025 - ECW

Databases searched: All available via PE2E SEARCH
CAplus, Medline and BIOSIS via STNext; and Google Scholar (note the search terms used below)

Reviewed the parent(s), if any, and any search(es) performed therein : see the BIB data sheet

Reviewed, the search(es), if any, performed by prior examiners including any international examiners.

Planned Search

Search terms:

All Inventor(s) e.g. Bratman S? C?/au
DNA or genomic DNA or gDNA
Cell -free (DNA or RNA or nucleic) or( cfDNA or cfRNA)
Circulating tumor (DNA or RNA or
ctDNA or ctRNA
Sequenc$
(Methylation or mutation or fragment length) profile$
Peripheral blood leukocytes or PBL$2 or white blood cells or WBC$2
Disease or cancer
Differentially methylated regions or DMR
Enrich$
Bisulfite sequencing
Filler (DNA or RNA or nucleic)
► See the Examiner’s PE2E SEARCH notes/strategy in IFW