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 .
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on June 11, 2026. No claims amendment are made in the response filed on that date.
Claims 1-30 are currently pending, with claims 19-30 withdrawn.
Claims 1-18 are under consideration. This is the first action on the merits.
Election/Restrictions
Applicant's election with traverse of the following species in the reply filed on June 11, 2026 is acknowledged:
Species of sequencing method: A) method obtains sequence reads with a depth of read of 10,000 to 500,000 per target locus (claim 1)1;
Species of enriching : D) Probes capture by hybridization (claim 1; [0452] lines 8-15; [0110]).
The traversal is on the ground that “there is no serious burden upon the Office to examine all of the species together.” Applicant provides no further reasoning or evidence in support of this conclusionary statement. (See Remarks, p. 2)
This reply does not distinctly and specifically point out supposed errors in the election of species requirement, because the traversal consist only of a single-sentence, generic, conclusory statement, while the requirement for election of species clearly set forth the search and examination burden (Response to Election / Restriction Filed - 06/11/2026, p. 3, para. 3):
“The species are independent or distinct because the different species recite separate characteristics of such species, and there is no disclosure of relationship between species (see MPEP § 806.04(b)). In addition, these species are not obvious variants of each other based on the current record. The species necessitate separate searches, leading to serious search and/or examination burden (see MPEP § 808.01(a)) because the Species of sequencing method reflect different search requirements as they recite different features that involve distinct steps (e.g., calculate LOD or read depth); the Species of enriching reflect distinct enriching approaches that require different materials and steps, requiring separate searches; the Species of selective amplification reaction reflect different amplification approaches with different requirements for steps and materials, resulting in separate searches.
…
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: The species require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search queries); and/or the prior art applicable to one species would not likely be applicable to another species; and/or the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.”
Accordingly, 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)).
Claims 19-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1-18.
Priority
Regarding claim 1 and its dependent claims 2-18, the earliest priority is 04/21/2015 because the priority document (US Application 14/692,703 ) filed that date is the first to disclose "depth of read of 10,000 to 500,000 per target locus." ([00354] in specification).
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 the purpose of applying prior art, claims 6 and 7 recite "molecular barcode," which is a term not defined with any structural features or characteristics by the application's disclosure.
Thus, in the absence of any structural features that could further define and distinguish the recited terms, the term "molecular barcode" is interpreted as any nucleic acid sequence.
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.
Claim 16 is rejected under 35 U.S.C. 112(b), 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 claim 16, it recites "wherein the limit of detection is calculated by LOD-mr5, LOD-zs5.0, or LOD-zs5.0-mr," which is indefinite.
According to the specification, these terms refer to different methods for calculating limits of detection:
“[0690]The first method (denoted “LOD-mr5” in FIGS. 34 and 35 ) calculates the limit of detection based on a minimum of 5 reads being chosen as the minimum number of times a SNV is observed in the sequencing data to have sufficient confidence the SNV is actually present. The limit of detection is based on whether the observed the depth of read (DOR) is above this minimum of 5. The gray lines in FIGS. 34 and 35 indicate SNVs for which the limit of detection is limited by the DOR. In these cases, not enough reads were measured to reach the error limit of the assay. If desired, the limit of detection can be improved (resulting in a lower numerical value) for these SNVs by increasing the DOR.
[0691] The second method (denoted “LOD-zs5.0” in FIGS. 34 and 35 ) calculates the limit of detection based on the z-score. The Z-score is the number of standard deviations an observed error percentage is away from the background mean error. If desired, outliers can be removed and the z-score can be recalculated and this process can be repeated. The final weighted mean and the standard deviation of the error rate are used to calculate the z-score. The mean is weighted by the DOR since the accuracy is higher when the DOR is higher.
[0692] For the exemplary z-score calculation used for this example, the background mean error and standard deviation were calculated from all the other samples of the same sequencing run weighted by their depth of read, for each genomic locus and substitution type. Samples were not considered in the background distribution if they were 5 standard deviations away from the background mean. The orange lines in FIGS. 34 and 35 indicate SNVs for which the limit of detection is limited by the error rate. For these SNV's enough reads were taken to reach the 5 read minimum, and the limit of detection was limited by the error rate. If desired, the limit of detection can be improved by optimizing the assay to reduce the error rate.
[0693] The third method (denoted “LOD-zs5.0-mr5” in FIGS. 34 and 35 ) calculates the limit of detection based on the maximum value of the above two metrics.”
The key issue is that the claim uses specific terms such as "LOD-mr5," "LOD-zs5.0," and "LOD-zs5.0-mr5" for calculation methods, but the application's disclosure does not provide clear calculation steps that clearly define or describe what each of the calculation methods requires.
The specification does not expressly define these recited terms by any equation or specific calculation steps from which a limit of detection can be obtained from input values. Instead, the specification describes the differences between these methods only at a high-level. Therefore, it is unclear to a skilled artisan how each of the calculations should be carried out.
For "LOD-mr5," the specification states that "[t]he limit of detection is based on whether the observed the depth of read (DOR) is above this minimum of 5," ([0690]lines 3-5) but does not explain how the limit of detection is obtained when the observed depth of read is above or below this threshold.
For "LOD-zs5.0," the specification states the limit of detection is based on the z-score. And "[t]he Z-score is the number of standard deviations an observed error percentage is away from the background mean error." ([0691] lines 1-3). However, this disclosure does not explain what "error" refers to in this context, and how the observed error percentage or the background mean error is determined. Although para. [0692] states that, "[f]or the exemplary z-score calculation used for this example, the background mean error and standard deviation were calculated from all the other samples of the same sequencing run weighted by their depth of read, for each genomic locus and substitution type" ꟷ this still does not clarify what "error" refers to. For example, it is unclear whether "error" means a false positive or false negative in variant calling, a locus with too low or too high of read depth, or some other measurement.
For "LOD-zs5.0-mr5," the specification states that "the limit of detection based on the maximum value of the above two metrics." ([0693]). However, it is unclear what "based on" means in this context. For example, it is unclear whether the higher of the two LOD values (as determined by "LOD-mr5" and ""LOD-zs5.0") is the limit of detection, or whether further transformation of the data is required.
Accordingly, claim 16 is indefinite.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, "LOD-mr5," "LOD-zs5.0," and "LOD-zs5.0-mr5" are interpreted as encompassing any method for determining a limit of detection that involves read depth threshold, z-score, or a combination of these metrics.
Reasons for Lack of Rejection for Ineligible Subject Matter (35 USC 101)
The claimed invention in the claims filled on 01/14/2026 meets the criteria for patent-eligible subject matter under the guidelines set forth in MPEP § 2106.
The subject matter eligibility test is below:
Step 1 - Whether the Claim is to a Statutory Category: YES. The claims are drawn to a method, therefore to one of the of statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: Yes. The claim recites a judicial exception, namely a law of nature of natural phenomenon. Specifically, the claim recites the natural correlation between biomarkers (e.g., tumor biopsy-specific variants) in a tumor from a subject and those that are found in cell-free DNA of the same subject.
Step 2A Prong 2 - Whether the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application: No. The claim as a whole do not integrates the exception into a practical application of that exception.
The steps in claim 1 merely observes the naturally occurring correlation. This is evidenced by the fact that the method claim ends with the step of identifying tumor-biopsy-specific variants present in the nucleic acid sample. There is no further step that meaningfully applies the observed judicial exception in a practical application, such as a treatments step.
Step 2B- Whether a Claim Amounts to Significantly More: Yes.
According to MPEP§ 2106.05, The second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 217, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). An “inventive concept” is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
Limitations that the courts have found to qualify as "significantly more" when recited in a claim with a judicial exception include:
v. Adding a specific limitation other than what is well-understood, routine, conventional activity in the field, or adding unconventional steps that confine the claim to a particular useful application, e.g., a non-conventional and non-generic arrangement of various computer components for filtering Internet content, as discussed in BASCOM Global Internet v. AT&T Mobility LLC, 827 F.3d 1341, 1350-51, 119 USPQ2d 1236, 1243 (Fed. Cir. 2016) (see MPEP § 2106.05(d))
Here, the claims are found to be patent eligible because the specific combination of additional elements recited in claim 1, specifically selective enrichment of more than 50 targets ("selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume") and performing ultra-deep sequencing with "with a depth of read of 10,000 to 500,000 per target locus," are not considered routine and conventional in the art.
Therefore, the claims amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that 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.
Claims 1 and 3-18 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Diehn (WO2014151117A1 - Identification and use of circulating nucleic acid tumor markers; published on 2014-09-25; Effective filling date: 2014-03-12).
Diehn’s CAncer Personalized Profiling by Deep Sequencing (CAPP-Seq) method involves using a panel of selectors comprising oligonucleotide probes for selective hybrid affinity capture that target regions of interest for enrichment, such as tumor biopsy specific variants, for downstream sequencing analysis. (see Figure 1; [0851] for examples)
Regarding claim 1, Diehn teaches a method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject (Figure 1; see also example 2 in [00849-00851]), the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject ([00270]-[00271] producing a personalized selector set via sequencing a tumor in a subject via whole genome or whole exome sequencing; identifying genomic regions comprising one or more mutations based on the genotype of the tumor) and identifying 50 to 2,000 tumor biopsy-specific variants ([00238] selector comprise genomic coordinates pertaining to a plurality of genomic regions comprising 50 or more mutations in subject; [00288] genomic regions derived from 50 or more different genes; [00290] sequence information comprise genomic coordinates pertaining to 125 or more genomic regions.);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA ([00238] selector comprise genomic coordinates pertaining to a plurality of genomic regions comprising 50 or more mutations in subject; [00851] Cell-free DNA circulating in blood or body fluids are enriched using personalized selector via affinity based hybrid capture),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject ([00851] lines 1-6; 13-14, personalized selector comprising are built to selectively enrich tumor-specific mutations ),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume ([00851] lines 11-13, “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.”; [00862] following a PCR amplification reaction, selector probes are used to selective capture a subset of adaptor ligated, amplified cfDNA. Thus a skilled artisan would readily understand that the selective capture using probes set is applied to a single amplification reaction volume; see also [00876]); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA ([00851] lines 11-13) and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus (Fig. 2b shows read depth higher than 10,000), and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads ([00851] lines 11-13).
Regarding claim 3, Diehn teaches the tumor biopsy sample of the subject includes a tumor tissue from a solid tumor ([0012]).
Regarding claim 4, Diehn teaches the first cell-free DNA sample is obtained from a plasma sample of the subject ([0046]).
Regarding claim 5, Diehn teaches the first cell-free DNA sample comprises circulating tumor DNA ([0016]-[0017]; [0020]).
Regarding claim 6, Diehn teaches wherein step (b) comprises selectively enriching 50 to 500 target loci each including at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject, wherein the selective enrichment of the target loci is performed using 50 to 500 target- specific primers or probes in the same reaction volume ([00238] selector comprise genomic coordinates pertaining to a plurality of genomic regions comprising 50 or more mutations in subject; [00851] Cell-free DNA circulating in blood or body fluids are enriched using personalized selector via affinity based hybrid capture; [00862] following a PCR amplification reaction, selector probes are used to selective capture a subset of adaptor ligated, amplified cfDNA. Thus a skilled artisan would readily understand that the selective capture using probes set is applied to a single amplification reaction volume), wherein each DNA molecule in the selectively enriched DNA is tagged with a molecular barcode ([00851] lines 6-11).
Regarding claim 7, Diehn teaches wherein step (b) comprises selectively enriching 50 to 200 target loci each including at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject, wherein the selective enrichment of the target loci is performed using 50 to 200 target- specific primers or probes in the same reaction volume ([00238] selector comprise genomic coordinates pertaining to a plurality of genomic regions comprising 50 or more mutations in subject; [00851] Cell-free DNA circulating in blood or body fluids are enriched using personalized selector via affinity based hybrid capture; [00862] following a PCR amplification reaction, selector probes are used to selective capture a subset of adaptor ligated, amplified cfDNA. Thus a skilled artisan would readily understand that the selective capture using probes set is applied to a single amplification reaction volume), wherein each DNA molecule in the selectively enriched DNA is tagged with a molecular barcode([00851] lines 6-11).
Regarding claim 8, Diehn teaches designing target-specific primers or probes capable of hybridizing to the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (00849] Example 2: Designing a personalized selector set).
Regarding claim 9, Diehn teaches performing barcoding PCR prior to step (c) ([00851] lines 14-17).
Regarding claim 10, it requires performing the same selective enriching and sequence determining steps in claim 1, on a second nucleic acid sample. As discussed above, claim 1 is anticipated by Diehn, the additional feature in claim 10 is further performing the method in claim 1, to an additional nucleic acid sample. This feature is also anticipated by Diehn, which teaches that its method comprises obtaining sequencing information of cell-free DNA samples from two or more samples from the subject ([0056]; see also [00705]; [00722]; [00738]), and the two or more samples may be obtained from the individual over a period of time and compared for residual disease or tumor burden ([0029]).
Regarding claim 11, Diehn teaches the first cell-free DNA sample and the second cell-free DNA sample are taken from the same subject at different points in time ([0029]).
Regarding claim 12, Diehn teaches detecting recurrence and/or metastases of the cancer from the tumor biopsy-specific variants detected in the first nucleic acid sample or the second nucleic acid sample ([0016]; [0029]).
Regarding claim 13, Diehn teaches human subject (Fig. 1a; [00752]; [00823]).
Regarding claim 14, Diehn teaches lung cancer (Fig. 1b, non-small cell lung cancer (NSCLC)).
Regarding claim 15, Diehn teaches method identifies a tumor biopsy-specific variant present in the first nucleic acid sample or the second nucleic acid sample at a limit of detection of less than or equal to 0.015% (claim 2, detecting circulating tumor DNA at LOD of 0.001% ; [00469] CAPP-Seq identify mutant alleles down to 0.025% with a detection limit of <0.01%.).
Regarding claim 16, Diehn teaches that its method has a threshold of minimum read frequency for a mutation site being at least 5 or more reads ([00633]).
Regarding claim 17, Diehn teaches the depth of read is the number of sequence reads measured by a sequencer mapping to a target locus (Figure 2b; Figure 12b; [00454]; [00876] sequencing reads generated by Illumina sequencer; see also [00789]-[00790]).
Regarding claim 18, Diehn teaches tumor- specific variant ([00718]; [00851] lines 1-6, tumor-specific variants are obtained via comparing genotype of the cancer may be compared to a genotype of the germline of the same patient.).
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 2 is rejected under 35 U.S.C. 103 as being unpatentable over Diehn (WO2014151117A1 - Identification and use of circulating nucleic acid tumor markers; Effective filling date: 2014-03-12), in view of
Diaz (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),
Rabinowitz (US20120270212A1 - Methods for Non-Invasive Prenatal Ploidy Calling; Published on 2012-10-25), and
Forshew (Forshew, T. et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4, 136ra168 (2012)).
The teachings of Diehn are recited above and applied as for base claim 1.
Regarding claim 2, Diehn teaches performing deep sequencing to achieve ~10,000x depth of read for detecting mutant allele fractions in circulating tumor DNA ([00763]).
Although Diehn does not explicitly teach obtaining sequence reads with a depth of read of 20,000 to 250,000, this feature is obvious in view of the knowledge in the prior art.
Rabinowitz teaches highly efficient highly multiplexed targeted PCR to amplify DNA followed by high throughput sequencing to determine allele frequencies at target locus (entire document, [0064] for example).
Rabinowitz teaches sequencing depth as "depth of read2" (DOR) ([0521] for example, see also [0221], [0299] for general teachings regarding DOR), and although it does not explicitly disclose depth of read of 20,000 to 250,000 per target locus, Rabinowitz describes DOR as a tunable parameter that can be adjusted based on experimental/application needs.
Specifically, Rabinowitz explains that DOR is influenced by factors such as the degrees of enrichment for each target locus and the overall throughput of the sequencing run ([0221]). It further states that different depth may be desirable for different applications and that insufficient read depth may result in excessive noise, rendering the data unreliable (([0300]). Thus, adjusting sequencing depth of reads would have been routine optimization based on specific application needs.
Indeed, a skilled artisan would recognize that detecting rare mutations in tumor tissue and ctDNA requires high sensitivity, typically on the order of 0.01% or lower (see Diaz, Fig. 1).
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Forshew, cited by Diaz (Ref 37 in Diaz), provides further insights regarding DOR requirements to achieve sufficient sensitivity and confidence level in detecting rare mutations with low allele frequencies in cell free DNA. Noting that detection of a variant at 0.2% allele frequency requires a sequencing depth of at least 5,000 reads, based on a minimum threshold of 10 supporting reads for confidence in detection:
“for example, a minimum of 10 reads implies that sequencing depth of 5000 would be required to detect mutations at AF as low as 0.2%. For alleles present at ~10 or fewer copies in the starting template, reproducibility would also be limited by sampling noise, because these alleles may be over- or underrepresented in any particular reaction.” (Forshew, page 3, right hand col, para 2, lines 14-19)
Accordingly, to achieve the higher sensitivity required for detecting rare mutations in tumor tissue and ctDNA at or below 0.01% ꟷ as indicated in Diaz ꟷ a person of ordinary skill in the art would understand that greater sequencing depth, on the order of at least 100,000 reads per locus, would be required. Therefore, the claimed depth of read of 20,000 to 250,000 per target locus, in the deep sequencing method for detecting mutant allele fractions in circulating tumor DNA, as disclosed in Diehn, would have been considered prima facie obvious in view of the combined teachings of Diaz and Rabinowitz and the knowledge in the field. There would have been a reasonable expectation of success because sequencing depth is a result-effective variable known to be subject for optimization. A person of ordinary skill in the art, motivated to achieve higher sensitivity in mutation detection, would have found it obvious to increase sequencing depth.
Double Patenting- Obvious Type
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, 4-5, 8, 14 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8, 10-11 and 15-16 of U.S. Patent No.11486008B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '008 Patent.
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘008 Patent, claims 1, 16);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘008 Patent, claims 1, 15),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘008 Patent, claim 1),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘008 Patent, claim 1); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘008 Patent, claim 1, 10).
Therefore, instant claims 1, 2, 4 and 18 are obvious over claims 1, 10, 15-16 of the '008 patent. Instant claims 5, 8, 14 are obvious over claims 2, 8, 11 of the '008 patent, respectively.
Claims 1-2, 4, 10-11, 15 and 18 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 10-13 and 17-18 of U.S. Patent No. 11319596B2 in view of Forshew (Forshew, T. et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4, 136ra168 (2012) )
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘596 Patent, claim 1, 11, 18) ;
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA(‘596 Patent, claim 1, 11, 17),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘596 Patent, claim 1, 11),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘596 Patent, claim 1, 11); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘596 Patent, claim 1).
The claims of the '596 patent largely overlap with the instant claim 1. While the '596 patent claims performing high-throughput sequencing for the detection of SNV mutation that is present in less than or equal to 0.015% of the cell-free DNA having the SNV locus is detected from the sequence reads, it does not explicitly claim a depth of read of 10,000 to 500,000 per target locus. This feature is obvious in view of Forshew.
Forshew provides insights regarding depth of read requirements to achieve sufficient sensitivity and confidence level in detecting rare mutations with low allele frequencies in plasms cell free DNA. Noting that detection of a variant at 0.2% allele frequency requires a sequencing depth of at least 5,000 reads, based on a minimum threshold of 10 supporting reads for confidence in detection (Forshew, page 3, right hand col, para 2, lines 14-19).Accordingly, to achieve the sensitivity required for detecting SNV mutations at or below 0.015% ꟷ as indicated in claim 1 of the ‘596 Patent ꟷ a person of ordinary skill in the art would understand that greater sequencing depth, on the order of at least 66,666 reads per locus, would be required. Therefore, the claimed depth of read of 10,000 to 500,000 per target locus would have been considered obvious in view of the claimed detection sensitivity in the ‘596 Patent and Forshew.
Therefore, instant claims 1-2,4,10-11, 15 and 18 are obvious over claims 1, 11, 17-18 of the ‘596 Patent, in view of Forshew. Instant claims 5; 8; 12; 14 are obvious over claims 2; 10;
12; 13 of the '596 Patent, in view of Forshew.
Claims 1-2, 4-5, 8, 10-12, 14-15 and 18 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 10, 12-15, 19 of U.S. Patent No. 11408037B2 in view of Forshew (Forshew, T. et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4, 136ra168 (2012)).
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘037 Patent, claim 1, 10, 13);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘037 Patent, claim 1, 13, 19),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘037 Patent, claim 1),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘037 Patent, claim 1, 13); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘037 Patent, claim 1).
The claims of the '037 patent largely overlap with the instant claim 1. While the '037 patent claims performing high-throughput sequencing for the detection of SNV mutation that is present in less than or equal to 0.015% of the cell-free DNA having the SNV locus is detected from the sequence reads, it does not explicitly claim a depth of read of 10,000 to 500,000 per target locus. This feature is obvious in view of Forshew.
Forshew, provides insights regarding depth of read requirements to achieve sufficient sensitivity and confidence level in detecting rare mutations with low allele frequencies in plasms cell free DNA. Noting that detection of a variant at 0.2% allele frequency requires a sequencing depth of at least 5,000 reads, based on a minimum threshold of 10 supporting reads for confidence in detection (Forshew, page 3, right hand col, para 2, lines 14-19).
Accordingly, to achieve the sensitivity required for detecting SNV mutations at or below 0.015% ꟷ as indicated in claim 1 of the ‘037 Patent ꟷ a person of ordinary skill in the art would understand that greater sequencing depth, on the order of at least 66,666 reads per locus, would be required. Therefore, the claimed depth of read of 10,000 to 500,000 per target locus would have been considered obvious in view of the claimed detection sensitivity in the ‘037 Patent and Forshew.
Therefore, instant claims 1-2, 4, 15 and 18 are obvious over claims 1, 10, 13, 19 of the ‘037 Patent, in view of Forshew. Instant claims 5; 8; 10-12, 14 are obvious over claims 3, 12, 2, 14-15 of the '037 Patent, in view of Forshew.
Claims 1-2, 4, 8, 10-12, 14-15 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10-12 of U.S. Patent No. 11414709B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '709 patent.
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘709 patent, claims 1, 11, 12);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘709 patent, claims 1-2, 11, 12),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘709 patent, claims 1, 11),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘709 patent, claims 1, 11, 12); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘709 patent, claims 1, 11).
Therefore, instant claims 1-2, 4, 8, 15 are obvious over claims 1-2, 11-12 of the '709 patent. Instant claims 10-12, 14 and 18 are obvious over claims 10, 3, 11 of the '709 patent, respectively.
Claims 1-2, 4-5, 8 14, 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 10, 13 of U.S. Patent No. 11530454B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '454 patent.
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘454 Patent, claim 1);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘454 Patent, claim 1),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject(‘454 Patent, claim 1),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘454 Patent, claim 1); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘454 Patent, claim 1).
Therefore, instant claims 1-2, 4 and 18 are anticipated by claim 1 of the '454 patent. Instant claims 5, 8, 14 are anticipated by claims 2, 10, 13 of the '454 patent, respectively.
Claims 1-5, 8-9, 13-14 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 10-11 and 13-14 of U.S. Patent No. 12203142B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '142 patent.
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘142 Patent, claim 1);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘142 Patent, claim 1),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘142 Patent, claim 1),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume (‘142 Patent, claim 1); and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads (‘142 Patent, claim 1).
Therefore, instant claims 1, 4, 18 are anticipated by claim 1 of the '142 patent. Instant claims 2-3, 5, 8-9, 13-14 are anticipated by claims 5, 10-11, 13-14 of the '142 patent, respectively.
Claims 1-2, 4-5, 8-9, 13-14, 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, 26-27, 29, 35 of copending Application No. 17/692,469 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 02/13/2026) of the '469 application.
Instant claim 1 recites:
A method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor biopsy-specific variants in a blood, plasma, serum, or urine sample of the subject, the method comprising:
(a) performing whole exome sequencing or whole genome sequencing on nucleic acids derived from a tumor biopsy sample of the subject and identifying 50 to 2,000 tumor biopsy-specific variants (‘469 Application, claim 16, 32);
(b) selectively enriching 50 to 2,000 target loci from a first nucleic acid sample derived from a first cell-free DNA sample obtained from blood, plasma, serum, or urine of the subject to obtain a first set of selectively enriched DNA (‘469 Application, claim 16),
wherein the 50 to 2,000 of the target loci each includes at least one of the tumor biopsy-specific variants identified in the tumor biopsy sample of the subject (‘469 Application, claim 16),
wherein the selective enrichment of the target loci is performed using 50 to 2,000 target-specific primers or probes in the same reaction volume(‘469 Application, claim 16) ; and
(c) determining the sequence of at least some of the first set of the selectively enriched DNA and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor biopsy-specific variants present in the first nucleic acid sample from the sequence reads ((‘469 Application, claim 16).
Therefore, instant claim 1, 2, 4, 18 are anticipated by claims 16, 32 of the '469 application. Instant claims 5, 8-9, 13-14 are anticipated by claims 18, 26, 27, 35, 29 of the '469 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Prior Art
Other prior art also teach detecting tumor-specific genomic variants in cell-free DNA using PCR and 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);
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 (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).
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681
1 Claims 19-30 are withdrawn as being drawn to non-elected species B.
2 Depth of reads is a measure of how many reads cover a given locus of the genome. See www.goldenhelix.com/blog/a-hitchhikers-guide-to-next-generation-sequencing-part-2/ ; Dec 9, 2010
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