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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed on July 17, 2026 in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 17, 2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on July 17, 2026.
Claims 1-7, 10 and 12-20 were previously pending. No claims amendment are made in the response filed on 07/17/2026.
Claims 1-7, 10 and 12-20 are currently pending and under consideration.
No rejection has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains a new double patenting rejection based on an updated search.
Response to Arguments
Applicant's arguments filed on July 17, 2026 have been fully considered.
Claim Rejections - 35 USC § 103
In the prior Office Action (Final Office Action- 04/21/2026):
Claims 1-7, 10 and 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Diehn, in view of Berlin, as evidenced by Bennett.
These rejections are maintained in this Office Action for reasons below.
Applicant argues that the rejections above should be withdrawn (Remarks, page 5-7). Applicant's arguments have been fully considered but are not found persuasive.
Applicant argues that the rejection relies on hindsight "because the cited disclosures are directed toward fundamentally different clinical purposes, rely on opposing design philosophies, and describe technical methodologies that are incompatible with one another." (Remarks, page 5).
Each of the points above has been fully considered and addressed below. As a general matter, however, it is noted that the arguments are not persuasive because they rely on unsupported assumptions regarding the knowledge of a skilled artisan, and those assumptions appear inconsistent with the common knowledge in the art.
Applicant is reminded that as the arguments of counsel cannot take the place of evidence in the record, assertions made without objective evidence from relevant references are insufficient to overcome the prior art rejections under 35 USC 103. It is noted that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600,602, 145 USPQ 716, 718 (CCPA 1965).
First, Applicant argues the references have "different clinical purposes," asserting that "Diehn focus on tracking patient-specific somatic mutations to monitor molecular residual disease. Such methods are utilized after a patient has already been diagnosed and after a biopsy of the tumor has been procured, and thus the tissue of origin is already known" and in contrast "Berlin focused on early cancer detection." (Remarks, p. 6)
This is not persuasive. The references do not teach away because they do not explicitly criticize, discredit, or otherwise discourage the claimed features.
Berlin does not teach away from cancer monitoring in patient already diagnosed with cancer, instead it explicitly supports this application by teaching that its method can be employed to monitor the progression of a tumor (metastasis) after treatment in a patient-specific, individual manner ([0190] "the method can, for example, be employed to monitor the progression of a tumour (metastasis) after treatment and thereby allows to optimise the dosage of said treatment or adjusting to a different treatment in a patient specific individual manner."; [0081] " These kits will not only be of interest for an improved preventive medicine and early detection of cancer but also to monitor a tumours performance after therapy.")
Diehn also teaches that its method is useful in detecting early stage cancers ([00469] "CAPP-Seq may accurately quantify cell-free tumor DNA from early and advanced stage tumors."; [00763] "Here we demonstrate the technical performance and explore the clinical utility of CAPP-Seq in patients with early and advanced stage NSCLC"). A skilled artisan would also understand early stage cancer include those distant cancer sites that later developed from the spread of cancer in metastasis.
Therefore, these references provide compatible teachings.
Applicant also asserts that, because Diehn requires a primary tumor to be biopsied, the tissue of origin of that tumor is already known. So there would be no reason to determine the tissue of origin. (Remarks, page 5).
This is not persuasive as it overlooks the well-known fact that cancer spreads. The term "primary tumor" itself distinguishes the original tumor from other tumors, including metastatic tumors.
It was well-known in the art that cancer can spread by metastasis, which pose serious threat in cancer care as "metastases, rather than primary tumours, are responsible for most cancer deaths. " (see Chambers 1, Abstract) By the time the primary tumor is detected, the cancer might already have spread to secondary sites but remain undetected (see Chambers, p. 570, left-hand col, para. 2 ; p. 53, left-hand col, para 1.). Although surgical resection and therapy may treat a primary tumor, metastatic disease remains a significant clinical concern because of its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents (see Valastyan 2, p. 1, para 1), thereby contribute to residual disease and later relapse. Therefore, there is a clear unmet need to monitor and treat metastatic disease, this is common knowledge in the art.
This background is provided for clarity of record and reflects commonly knowledge in the art. The cited references themselves also support this point.
Both Diehn and Berlin expressly teach that their cfDNA analysis approaches are applicable to monitoring the presence of metastases.
Diehn teaches:
“[0016] In some embodiments, the ctDNA content in an individual' s blood, or blood derivative, sample is determined at one or more time points, optionally in conjunction with a therapeutic regimen. The presence of the ctDNA correlates with tumor burden, and is useful in monitoring response to therapy, monitoring residual disease, monitoring for the presence of metastases, monitoring total tumor burden, and the like.”
Berlin teaches performing analysis of free floating DNA of an individual who has been diagnosed with liver cancer, to determine whether the cancer has spread to kidneys or not ([0107]) and that its method can "be employed to monitor the progression of a tumour (metastasis) after treatment and thereby allows to optimise the dosage of said treatment or adjusting to a different treatment in a patient specific individual manner." ([0190]).
Accordingly, Berlin and Diehn are related in their shared objective of monitoring tumor progression after treatment, including monitoring for metastases. The reason to identify where, and in which organ tissue, cancer is present is also clearly explained by Berlin: organ specific information enables physician to provide more detailed and targeted care, as most available diagnostic or therapeutic measures are specific to the organ involved ([0082] lines 39-43).
Applicant then argues that the cited references "rely on opposing design approaches that do not easily integrate," because "[i]f a skilled artisan were to add Berlin's generalized tissue of- origin epigenetic markers to Diehn's highly targeted panel, they would be forced to divert sequencing reads away from the known somatic mutations that indicate residual disease." (Remarks, page 6-7)
This argument is not persuasive. Applicant provides no objective evidence supporting this assertion regarding the knowledge of a skilled artisan. The argument appears to assume that sequencing reads are strictly limited and zero-sum. This is incorrect.
A skilled artisan would have readily understood that in sequencing experiments, such as Illumina sequencing taught in Diehn (see [00493] for example), it is "very easy to increase the coverage or sequence depth" as needed, see Illumina 3:
"In Illumina sequencing experiments, it is very easy to increase the coverage or sequence depth, if you later decide you need more data. Provided you still have your original sample, you can just sequence more, and combine the sequencing output from different flow cells. " (p. 2, "When to Sequence More").
Accordingly, as sequencing coverage is a function of read number (Illumina, p. 1), a skilled artisan would have had the skill and knowledge to adjust the number of reads generated in sequencing to reach the appropriate coverage. If additional depth or coverage were needed, the skilled artisan would know that they can just sequence more.
Third, Applicant argues that Diehn and Berlin are technically incompatible because "Berlin relies on bisulfite treatment to determine methylation states" and "[a] skilled person would readily recognize that bisulfite conversion is a notoriously harsh chemical process that causes fragmentation and degradation of the DNA sample." (Remarks, page 7).
This is not persuasive. The notion that bisulfite treatment may be harsh does not establish that it is incompatible with the variant-calling method of Diehn. Applicant has not provided any objective evidence showing that bisulfite-treated DNA cannot be used for variant identification as taught by Diehn.
Applicant's position is also inconsistent with the knowledge in the art, which shows that variant identification can be performed using bisulfite-treated DNA. See Chiu 4([0076]; [0059]; [0238] for examples); see also Liu 5(abstract for example).
Therefore, the asserted bisulfite treatment does not support technical incompatibility.
Regarding Applicant's assertion of hindsight, it is noted that the rejection's conclusion of obviousness is properly made. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But So long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In this instant case, the rejections under 35 U.S.C. 103 made in the previous Office Action and maintained herein meet both conditions. The conclusion of obviousness in the rejections are based on the knowledge of one or ordinary skill in the art at the time of filling and does not rely on knowledge derived solely from applicant's disclosure. This is evidenced by the fact that all claim limitations are taught or suggested by the cited prior art references.
For the reasons above, Applicant's arguments are unpersuasive. Accordingly, the rejections are maintained.
Priority
For the instant claims 1-7, 10 and 12-20 in this U.S. Application, the applicant claims priority of US provisional Application NOs. 62/322,783; 62/322,786; 62/322,773; 62/322,784 ; and 62/322,775, all of which have a filling date on 04/14/2016.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For purpose of applying prior art, claim 1 recites a step of "enriching a plurality of the polynucleotides for a sequencing panel of genomic regions to generate an enriched set of polynucleotides," using capture probes, and "wherein the sequencing panel comprises a plurality of subpanels."
Under BRI, this step encompasses enriching polynucleotides using different subpanels, where probe capture for the subpanels may be performed together in the same vessel or capture mixture, or performed separately. This interpretation is consistent with the application’s disclosure because neither the claim nor the specification specifically define how enrichment using a panel comprising subpanels must be carried out. The term "panel" generally refers to a set of markers, such as a gene panel, and describes the information being targeted rather than requiring a particular enrichment workflow. The specification broadly states that targeted analysis of different genomic regions, such as somatic variants, can be used in combination with epigenetic signatures ([0236] "These methods can also be used to infer the tissue of origin of the tumor and/or a measure of tumor burden in combination with other techniques described herein for determining variants (e.g., germline or somatic variants) contained within the sample… while somatic variants can correlate to certain types of cancer specifically based on the affected genes, pathways and percentages of the variants. This information can then be used in combination with epigenetic signatures… ").
Therefore, any prior art approach comprising enrichment using capture probes for a panel that includes the claimed subpanels, meets this limitation "enriching a plurality of the polynucleotides for a sequencing panel of genomic regions to generate an enriched set of polynucleotides."
For the purpose of applying prior art, claim 5 recites "wherein the determining the consensus sequence is performed on a base by base basis." The application's disclosure does not expressly define the phrase "base by base basis."
Therefore, under BRI, this phrase is interpreted to encompass any approach with single-nucleotide base resolution.
For the purpose of applying prior art, claim 16 recites the term “read budget," which is not expressly defined in the application's disclosure.
The specification provides the following relevant description regarding "read budget" in para. [0241]:
"The amount of sequencing data that can be obtained from a sample is finite, and constrained by such factors as the quality of nucleic acid templates, number of target sequences, scarcity of specific sequences, limitations in sequencing techniques, and practical considerations such as time and expense. Thus, a “read budget” is a way to conceptualize the amount of genetic information that can be extracted from a sample. A per-sample read budget can be selected that identifies the total number of base reads to be allocated to a test sample comprising a predetermined amount of DNA in a sequencing experiment. The read budget can be based on total reads produced, e.g., including redundant reads produced through amplification. Alternatively, it can be based on number of unique molecules detected in the sample. In certain embodiments read budget can reflect the amount of double-stranded support for a call at a locus. That is, the percentage of loci for which reads from both strands of a DNA molecule are detected." [emphasis added]
Thus, in light of the specification and under BRI, the term "read budget" is interpreted to encompass any amount of information related to sequencing 6, such as number of reads allocated in a sequencing run, sequencing coverage, and sequencing depth.
For the purpose of applying prior art, claim 16 recites "wherein the plurality of cfDNA molecules comprises no more than a pre-determined amount of DNA." The specification does not expressly define the term "pre-determined amount of DNA."
Therefore, under BRI, an amount that is "no more than a pre-determined amount of DNA" is interpreted to encompass any amount, as a pre-determined amount can be any arbitrarily chosen value for any reason, and there will always be an amount less than any specified value.
Maintained 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.
Claims 1-7, 10 and 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Diehn (WO2014151117A1 - Identification and use of circulating nucleic acid tumor markers; Published on 2014-09-25; cited as Foreign Patent Document #10 in IDS filed on 05/23/2024), in view of
Berlin (Berlin et al., US20050221314A1 - Method and device for determination of tissue specificity of free floating dna in bodily fluids; published 2005-10-06) , as evidenced by
Bennett (Bennett et al. Library construction for ancient genomics: single strand or double strand? Biotechniques. 2014 Jun 1;56(6):289-90, 292-6, 298, passim. doi: 10.2144/000114176. PMID: 24924389).
A) Diehn teaches methods for analyzing cell-free DNA (cf-DNA) using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq), for monitoring residual disease (e.g., Abstract; [0016]; [0029]).
Regarding claim 1, Diehn teaches a method comprising:
(a) obtaining a plurality of polynucleotides which are or are derived from cell-free deoxyribonucleic acid (cfDNA) molecules of the subject (Figure 1; Figure 6; [0720] “hybrid selection of cfDNA corresponding to regions of recurrent mutation for diagnosis and monitoring of cancer in an individual patient”; Figure 22);
(b) enriching a plurality of the polynucleotides for a sequencing panel of genomic regions to generate an enriched set of polynucleotides (Figure 1; [00851] enriching for tumor-specific markers in a patient using a custom, personalized selector library comprising a set of biotinylated oligonucleotides for “selective hybrid affinity capture of corresponding circulating tumor DNA (ctDNA) molecules,” thereby “allowing the tracking and quantitation of those mutations originally discovered in the primary tumor within the corresponding cfDNA.”),
wherein the enriching comprises
selecting the sequencing panel of genomic regions using information derived from cancer tumor biopsies (Figure 1; [00851] “tumor(s) from a patient known to have cancer are genotyped by profiling the tumor genome, exome, or targeted region expected to be enriched for somatic aberrations…The resulting lesions are then catalogued and used to build a custom, personalized selector comprising a set of biotinylated oligonucleotides for selective hybrid affinity capture of corresponding circulating tumor DNA (ctDNA) molecules”; [00590]; [00428]; [00485]; [00590]; [00437-00441]; [00767]), and
wherein the enriching is performed using capture probes specific for the genomic regions (Figure 1; [00851]; [00590]; [00428]; [00485]; [00590]; [00437-00441]),
wherein the genomic regions comprise single-nucleotide variants (SNVs) ([00428]; [00437-00441]),
(c) sequencing a plurality of the enriched set of polynucleotides at a sequence read depth of at least five thousand sequence reads per base to generate sequence reads ([00851] lines 11-14; [00430]; [00454] references Figure 12, which shows sequencing depth higher than 5000 reads per base; [00771] mean sequencing depth of ~5000X);
(d) computer processing a plurality of the sequence reads at least in part by aligning a plurality of the sequence reads to a reference genome to generate aligned sequence reads ([00790] Mapping and Quality Control of NGS Data. Paired-end reads were mapped to the hgl9 reference genome with BWA 0.6.2; [00414]; [00426]; [00836]); and
(e) computer processing a plurality of the aligned sequence reads to detect a variant corresponding to at least one of the single-nucleotide variants ([00851] The personalized selector would then be applied for capture of the fragments of interest, sequenced and analyzed in the same manner as the 'off-the-shelf' CAPP-Seq workflow, allowing the tracking and quantitation of those mutations originally discovered in the primary tumor within the corresponding cfDNA; [00590] producing a selector set comprising one or more genomic regions comprising the one or more mutations specific to the sequencing information of the tumor sample, the one or more mutations comprise SNV; [00437-00441]; [00655]; [00659]), thereby determining the molecular residual disease in the subject.
Diehn’s CAPP-Seq method involves using a panel of selectors comprising oligonucleotide probes for selective hybrid affinity capture that target regions of interest for enrichment ([0851]). While Diehn does not explicitly teach a subpanel of selectors for identifying tissue of origin which targets tissue-specific epigenetic markers, this feature is obvious in view of Berlin.
Berlin teaches methods for determining cell-free DNA tissue of origin based on the DNA’s methylation pattern (Abstract).
Berlin teaches the usefulness of cell free DNA as a cancer biomarker is limited because “detecting the level of free floating DNA does not on its own serve as a useful diagnostic method as the information gained is too unspecific to be of any use.” ([0090]).
Berlin then suggests in determining the origin of the cell-free DNA, “the diagnostic value of such an assay increases dramatically.” ([0091]) And explains that:
“This is because such an assay elucidates the location of said DNA and the possible cause. That way an early screen that does reveal the organ, tissue or cell type affected by a cell proliferative disease is highly advantageous. The information gained will aid the further diagnostic procedure. It tells the practitioner quite precisely what the next steps towards a more differentiated diagnosis would need to be and gives guidance as to which clinical specialist to refer the patient to.” ([0091])
Berlin discloses its solution to determine the tissue origin of cell-free DNA is based on the characteristic methylation patterns of certain genes that can be positively correlated with specific organs, tissues and cell types:
“The present invention provides a method for the analysis of circulating, free floating nucleic acids in bodily fluids. It discloses a means on how to predict which organ, tissue or cell type has developed a medical condition, by employing means of distinguishing between DNA originating from different healthy or different diseased tissues, organs or cell types of the human body. Characteristic methylation patterns of certain genes can be positively correlated with specific organs, tissues and cell types. Preferably the identification of the free floating DNA's origin, or in other words the determination of the organic source of a significant part of those circulating nucleic acids in said bodily fluid is done by an assay that detects methylation at specific CpG sites. It is especially preferred, to detect methylation by nucleic acid based methods, such as hybridization, sequencing and PCR, or even more preferably, by employing real-time PCR methods. The result of said analysis give further guidance to a practitioner on how to tailor a more differentiated diagnostic strategy. “([0093])
Berlin teaches probes designed to specifically only hybridize with the amplified version of bisulfite treated nucleic acid that has a methylation pattern characteristic for a specific organ ([0228] lines 9-12), for identification of the organ from which the cell-free DNA is from ([0229])).
In view of the above, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the CAPP-Seq methods of Diehn, to further include a subpanel of selectors comprising oligonucleotide probes that target tissue-specific, differentially methylated regions (i.e., epigenetic markers) for identifying tissue of origin, as taught by Berlin.
Both references teach analyzing cell free DNA for disease diagnosis, with Berlin providing a specific improvement by identifying the DNA tissue of origin through the detection of DNA methylation. Specifically, while Diehn’s sequencing of tumor-specific mutations can detect tumor-specific cfDNA, it does not allow for the determination of tissue of origin of the tumor-specific cfDNA or whether the tumor has metastasized. Berlin addresses this limitation by offering a solution to determine cfDNA tissue of origin.
Both Diehn ([0016]) and Berlin ([0107]; ([0190]) expressly teach that their cfDNA analysis approaches are applicable to monitoring the presence of metastases. Berlin and Diehn are related in their shared objective of monitoring tumor progression after treatment, including monitoring for metastases. The reason to identify where, and in which organ tissue, cancer is present is clearly explained by Berlin: organ specific information enables physician to provide more detailed and targeted care, as most available diagnostic or therapeutic measures are specific to the organ involved ([0082] lines 39-43).
Berlin’s tumor origin determination can be achieved by probe hybridization, which is the same technique Diehn employs for target enrichment in its sequencing methods. Thus, a skilled artisan would recognize a reasonable expectation of success, as both references operate within the same field of analyzing cell-free DNA and disclose technically compatible teachings.
A skilled artisan would have been motivated to apply this modification to link the general observation of increased DNA levels in bodily fluids, such as in serum, to the risk of a cell proliferative disease (e.g., cancer) in a specific tissue or organ, thereby enhancing the diagnostic value of a cell-free DNA assay, as suggested by Berlin.
B) Regarding claim 2, Diehn teaches the cfDNA molecules are uniquely tagged with respect to one another ([00851] lines 6-9; [00121]).
Regarding claim 3, Diehn teaches amplifying the cfDNA prior to sequencing (entire document; Fig 22; [00862] for examples), and determining a consensus sequence from sequence reads obtained from the sequencing to reduce errors from amplification or sequencing ( [00278]; [00402]).
Regarding claim 4, Diehn teaches determining the consensus sequence is performed on a molecule-by-molecule basis ([00278] Determining the consensus sequence based on the molecular barcode).
Regarding claim 5, Diehn teaches determining the consensus sequence is performed on a base by base basis ([00278] determining a consensus sequence for the genomic region comprising the one or more mutations, wherein a consensus nucleotide is determined for a base at a given position).
Regarding claim 6, Diehn teaches determining the consensus sequence is performed using molecular barcodes that tag individual cfDNA molecules derived from the subject ([00278] Determining the consensus sequence based on the molecular barcode).
Regarding claim 7, Diehn teaches comparing sequence information obtained from the plurality of polynucleotides to sequence information obtained from a cohort of healthy individuals ([00772]; [00445]; [00808]).
Regarding claim 10, Diehn teaches a plasma sample ([0046]; [00444]).
Regarding claim 12, Diehn teaches subject has previously received a treatment for a cancer ([00446]; [00739]; [00763]).
Regarding claim 13, Diehn teaches colorectal cancer, ovarian cancer, lung cancer, pancreatic cancer, and liver cancer ([00753], [0063]).
Regarding claim 14, Diehn teaches chemotherapy ([00774]).
Regarding claim 15, Diehn teaches subject does not detectably exhibit any symptoms of the cancer ([00776] lines 11-17).
Regarding claim 16, Diehn teaches sequencing is performed within a read budget that allocates a pre-determined total number of base reads ([00795] 250 million 100bp reads per lane; FIG. 5b, Gbs sequenced), wherein a given amount of cfDNA is used ([00454]; Figure 12).
Regarding claim 17, Diehn teaches multiple cfDNA samples are collected from the subject over a plurality of time points and analyzed ([0016]; [0029] for examples).
Regarding claim 18, Diehn teaches sequencing panel is selected to achieve a sensitivity of at least 85% ([0060] lines 5-6; [0063]) for lung cancer ([0088-0089]).
Regarding claims 19-20, Diehn teaches Y-shaped adaptors comprising barcodes that are between 2 and 32 nucleotides in length ([00401] lines 5-6; [00402] lines 9-10). Y-shaped adaptors are duplex tags which differentially label the complementary strands of the DNA, as evidenced by Bennett (Fig 1).
Double Patenting- Obvious Type -- New Rejections
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, 16 and 18 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3-4, 13-14 and 17-18 of U.S. Patent No. 11827942B2 in view of Griffith (Griffith et al., Optimizing cancer genome sequencing and analysis. Cell Syst. 2015 Sep 23;1(3):210-223. doi: 10.1016/j.cels.2015.08.015. PMID: 26645048; PMCID: PMC4669575.)).
Instant claim 1 recites:
A method for detecting molecular residual disease in a subject,
the method comprising:
(a) obtaining a plurality of polynucleotides which are or are derived from cell-free deoxyribonucleic acid (cfDNA) molecules of the subject (‘942 Patent, claim 1)
(b) enriching a plurality of the polynucleotides for a sequencing panel of genomic regions to
generate an enriched set of polynucleotides (‘942 Patent, claim 1),
wherein the enriching comprises selecting the sequencing panel of genomic regions using information derived from cancer tumor biopsies (‘942 Patent, claim 1. “wherein the one or more differentially methylated regions comprise at least one genomic region that is abnormally methylated in at least one specific cancer type,”), and
wherein the enriching is performed using capture probes specific for the genomic regions (‘942 Patent, claim 1”oligonucleotide probes comprising nucleotides that hybridize to one or more differentially methylated regions of the polynucleotides”),
wherein the genomic regions comprise single-nucleotide variants (SNVs) (‘942 Patent, claim18),
wherein the sequencing panel comprises a plurality of subpanels, including a subpanel for identifying tissue of origin which targets markers for a tissue of origin which are tissue-specific epigenetic markers (‘942 Patent, claim 3-4);
(c) sequencing a plurality of the enriched set of polynucleotides at a sequence read depth of at
least five thousand sequence reads per base to generate sequence reads (‘942 Patent, claim 13);
(d) computer processing a plurality of the sequence reads at least in part by aligning a plurality of the sequence reads to a reference genome to generate aligned sequence reads; and
(e) computer processing a plurality of the aligned sequence reads to detect a variant corresponding to at least one of the single-nucleotide variants (‘942 Patent, claim 18), thereby determining the molecular residual disease in the subject.
The claims of the ‘942 patent largely overlap with the instant claim 1. Although the ‘942 Patent does not claim a specific sequence read depth of at least five thousand sequence reads, this feature would have been obvious in view of the claimed context of targeted sequencing of the cancer genome, which could have over 10,000X coverage, as disclosed in Griffith (Abstract, “targeted sequencing provided over 10,000x” coverage”; see also Table 1, IDT custom capture(145target sites) sequenced with Illumina)
Griffith’s cancer genome sequencing methods including molecular detection of Subclonal populations that often escape treatment and thus contribute to residual disease (p. 210, right-hand col, lines 8-10; p.220, left-hand col, para 1).
Griffin further teaches sequence alignment to a reference genome (p. 222, right-hand col., para. 2; see also Table 2).
Griffin teaches: "Increased sequencing depth has the potential to enable sensitive detection of mutations corresponding to these subclonal populations and improve inference of a tumor’s clonal architecture." (p. 210, right-hand col, lines 10-12).
Given these teachings, it would have been obvious for one of ordinary skill in the art to apply a sequence read depth of at least five thousand sequence reads as taught in Griffin in the claimed targeted sequencing method in '950 patent. Both references are in the overlapping field of cancer genome sequencing, and Griffin teaches sequencing read depth is result effective variable for increased sensitivity in mutation detection, and targeted sequencing of the cancer genome, could have over 10,000 reads per base coverage.
The use of a known sequencing read depth represents a predictable use of prior art elements according to known methods to yield predictable results (see MPEP §2143).
Therefore, the instant claim 1 lacks patentable distinction over the ‘942 patent in view of Griffin.
Therefore, instant claims 1 is obvious over claims 1, 3-4, 13 and 18 of the ‘942 patent, in view of Griffin. Instant claims 16 and 18 are obvious over claims 14 and 17 of the ‘942 patent, in view of Griffin.
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
The prior art has disclosed a large number of methods for detecting tumor-specific genomic variants in cell-free DNA using sequencing:
Chan et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin. Chem. 59, 211–224 (2013); cited as NPL on IDS filed 01/27/2025, page 50;
Crowley, E. et al."Liquid biopsy: monitoring cancer-genetics " Nat. Rev. Clin. Oncol. advance online publication 9 July 2013; doi:10.1038/nrclinonc.2013.110;
Dawson et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013 Mar 28;368(13):1199-209. doi: 10.1056/NEJMoa1213261. Epub 2013 Mar 13. PMID: 23484797;
Leary et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010 Feb 24;2(20):20ra14. doi: 10.1126/scitranslmed.3000702. PMID: 20371490; PMCID: PMC2858564;
Diaz et al. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014 Feb 20;32(6):579-86. doi: 10.1200/JCO.2012.45.2011. Epub 2014 Jan 21. PMID: 24449238; PMCID: PMC4820760;
WO2014039556A1 - Systems and methods to detect rare mutations and copy number variation.
Methods for enriching cfDNA using tissue-of-origin specific epigenetic markers are known in the art:
Mann (WO2017083366A1 - Methods for determining the origin of dna molecules; Effective date: Nov 9, 2015) teaches using transcription factor that differentially binds to DNA molecules to determine an origin of a sample;
Chiu (WO2014043763A1- Non-invasive determination of methylome of fetus or tumor from plasma; published 2014-03-27) teaches using methylation changes detected in the plasma for inferring the origin or type of the cancer;
DOR (WO2015159292A2 - A method and kit for determining the tissue or cell origin of dna; Published 2015-10-22) teaches DNA of each cell type in the body carries unique epigenetic marks correlating with its gene expression profile, and that tissue-specific DNA methylation pattern of cfDNA can be used to determine its tissue of origin and hence to infer cell death in the source organ.
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681
1 Chambers, A., Groom, A. & MacDonald, I. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563–572 (2002). https://doi.org/10.1038/nrc865
2 Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011 Oct 14;147(2):275-92. doi: 10.1016/j.cell.2011.09.024. PMID: 22000009; PMCID: PMC3261217.
3 Illumina (Estimating Sequencing Coverage; 2014)
4 Chiu (WO2014043763A1- Non-invasive determination of methylome of fetus or tumor from plasma; published 2014-03-27)
5 Liu Y, Siegmund KD, Laird PW, Berman BP. Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data. Genome Biol. 2012 Jul 11;13(7):R61. doi: 10.1186/gb-2012-13-7-r61. PMID: 22784381; PMCID: PMC3491382.
6 See Illumina's Estimating Sequencing Coverage; published 2014; www.illumina.com/documents/products/technotes/technote_coverage_calculation.pdf
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