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 .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 19, 2026 has been entered. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn.
Claims 1-2, 4-14, 17-18, and 21 are currently pending and have been examined herein.
Claim Rejections - 35 USC § 101
3. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4-14, 17-18, and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite laws of nature.
The claims recite “analyzing the growth rate of circulating tumor DNA comprising the patient specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient” (clm 1, step f).
The claims recite “wherein the colorectal patient having a fast tumor growth rate has reduced overall survival compared to the colorectal cancer patient having a slow tumor growth rate (clm 17).
The claims recite “wherein the growth rate of the circulating tumor DNA comprising the patient specific cancer mutations is determined based on the amount of circulating tumor DNA in the first, second, and third liquid biopsy samples” (clm 18).
Thus the claims recite (i) a correlation between the amount of ctDNA and the growth rate of ctDNA; (ii) a correlation between the growth rate of ctDNA and tumor relapse and/or growth; and (iii) a correlation between the growth rate of ctDNA and overall survival. These types of correlations are a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
The claims recite “determine the growth rate of the circulating tumor DNA comprising the patient specific cancer mutations between the first and the second liquid biopsy sample” (clm 1, step e). The “determining” step broadly encompasses an activity that can be performed in the human mind. The “determining” could be performed by reading a laboratory report and thinking about the change between the amount of ctDNA in the first and second liquid biopsy samples. There is nothing in the claim that suggests that the data analysis necessary to determine the growth rate is so complex and complicated that it could not be done in the human mind.
The claims recite “analyzing the growth rate of circulating tumor DNA comprising the patient specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient” (clm 1, step f). The “determining” step broadly encompasses a mental processes. For example, one may “determine” tumor relapse or growth by thinking about the growth rate. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions the claims recite the following steps:
(a) sequencing a plurality of nucleic acids isolated from a biological sample of the colorectal cancer patient to identify a plurality of patient-specific cancer mutations;
(b) preparing a first amplified DNA fraction from a first liquid biopsy sample collected from the colorectal cancer patient after surgery, first-line chemotherapy, adjuvant therapy, and/or neoadjuvant therapy, wherein the first liquid biopsy sample is blood, serum, plasma or urine, wherein preparing the first amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the first liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a);
(c) sequencing the amplified target loci from cell-free DNA isolated from the first liquid biopsy to generate sequence reads comprising the patient specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient specific cancer mutations in the first liquid biopsy sample;
(d) preparing a second amplified DNA fraction from a second liquid biopsy sample collected from the colorectal cancer patient after collection of the first liquid biopsy sample, wherein the second liquid biopsy sample is blood, serum, plasma or urine, wherein preparing the second amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the second liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a);
(e) sequencing the amplified target loci from cell free DNA isolated from the second liquid biopsy to generate sequence reads comprising the patient specific cancer mutations, quantify an amount of circulating tumor DNA comprising the patient specific cancer mutations in the second liquid biopsy sample.
These steps are NOT considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite the following steps:
(a) sequencing a plurality of nucleic acids isolated from a biological sample of the colorectal cancer patient to identify a plurality of patient-specific cancer mutations;
(b) preparing a first amplified DNA fraction from a first liquid biopsy sample collected from the colorectal cancer patient after surgery, first-line chemotherapy, adjuvant therapy, and/or neoadjuvant therapy, wherein the first liquid biopsy sample is blood, serum, plasma or urine, wherein preparing the first amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the first liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a);
(c) sequencing the amplified target loci from cell-free DNA isolated from the first liquid biopsy to generate sequence reads comprising the patient specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient specific cancer mutations in the first liquid biopsy sample;
(d) preparing a second amplified DNA fraction from a second liquid biopsy sample collected from the colorectal cancer patient after collection of the first liquid biopsy sample, wherein the second liquid biopsy sample is blood, serum, plasma or urine, wherein preparing the second amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the second liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a);
(e) sequencing the amplified target loci from cell free DNA isolated from the second liquid biopsy to generate sequence reads comprising the patient specific cancer mutations, quantify an amount of circulating tumor DNA comprising the patient specific cancer mutations in the second liquid biopsy sample.
These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The specification (para 0811) discloses the Signatera RUO assay. The Signatera™ (RUO) process starts with identifying and prioritizing somatic mutations from whole-exome sequencing of tumor and matched normal samples. Patient-specific multiplex-PCR assays targeting 16 somatic single-nucleotide and indel variants are then assayed by massively parallel sequencing in plasma samples collected throughout the patient's disease course to help detect and monitor circulating tumor DNA. As evidenced by Chen (Molecular Diagnosis & Therapy 11/1/2021 25(6) pages 757-774) Signatera™ is a tumor-informed ctDNA MRD assay that utilizes patient-specific tumor mutations to perform multiplex PCR amplification and subsequent NGS of cfDNA from plasma. The top 16 somatic variants (SNVs or indels) from WES of primary tumor tissue are first selected using paired whole blood sequencing to filter out germline variants and clonal hematopoiesis. Somatic variants are prioritized based on clonality, detectability, and frequency of mutation. Primers are designed against each of the top 16 tumor variants, followed by 16-plex PCR of plasma cfDNA isolated from subsequent blood samples collected after definitive treatment in the MRD setting. This approach enables ultra-deep sequencing of each target to an average depth of 100,000x and reduces background noise from non-tumor variants (page 760). Chen (Molecular Diagnosis & Therapy 11/1/2021 25(6) pages 757-774) further teaches that while not yet approved by the FDA, Signatera™ has been granted a total of three breakthrough device designations, one in May 2019 and two in March 2021, to accelerate phase III development and approval as a companion diagnostic for three different clinical indications. In September 2020, Medicare finalized a plan to approve full coverage for the use of Signatera™ for patients with stage II and III colorectal cancer (CRC) to inform adjuvant treatment after surgery and monitor recurrence.
Additionally the prior art of Zimmermann (US 2019/0316184 Pub 10/17/2019) discloses the Signatera RUO assay and teaches each of the steps/elements in addition to the judicial exceptions (see art rejections below).
Thus the teachings in the specification (as evidenced by Chen) and the prior art of Zimmermann demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the Signatera assay was well-known and commercially available.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 101. The Applicants argue that the claims as amended are similar to those found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics, 952 F.3d 1367 (Fed. Cir. 2020). They argue that the claims are directed to a patent eligible combination of active tangible steps of sequencing and preparing amplified DNA fractions, and not diagnostics. In particular, the preamble of the present claims recite a "method for preparing and sequencing a deoxynucleic acid (DNA) fraction from a liquid biopsy sample of a colorectal cancer patient," and the claims should therefore be considered a method of preparation and not a method of diagnostics. As explained in Illumina v. Ariosa Diagnostics, 952 F.3d 1367 (Fed. Cir. 2020), a claim reciting "[a] method for preparing a deoxyribonucleic acid (DNA) fraction from a pregnant human female useful for analyzing a genetic locus involved in a fetal chromosomal aberration, comprising (a) extracting DNA...; (b) producing a fraction of DNA extracted in (a)...; and (c) analyzing a genetic locus produced in
(b)" is patentable eligible because it is considered a method of preparation and not a method of diagnosis (p.1371).
This argument has been fully considered but is not persuasive. The instant claims are NOT analogous to those that were found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics. The instant claims recite (i) a correlation between the amount of ctDNA and the growth rate of ctDNA; (ii) a correlation between the growth rate of ctDNA and tumor relapse and/or growth; and (iii) a correlation between the growth rate of ctDNA and overall survival. These correlations are a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo. Additionally the claims recite numerous limitations that fall within the mental processes groupings of abstract ideas because they cover concepts performed in the human mind, including observations, evaluation, judgment, and opinion. It is maintained that the claims recite judicial exceptions and the rejection is appropriate.
Claim Rejections - 35 USC § 103
5. 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.
Claims 1-2, 4-14, 17-18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann (US 2019/0316184 Pub 10/17/2019) in view of Taub (WO 2022/031620 Filed 8/2/2021 with priority back to 63/060,004 Filed 8/1/2020 and 63/063,267 Filed 8/8/2020).
Regarding Claim 1 Zimmermann teaches using personalized ctDNA analysis to monitor colorectal cancer (Example 1). Zimmermann teaches that 130 patients with stage I-IV CRC, treated with curative surgery, and (optional) adjuvant chemotherapy were included. Plasma samples were collected longitudinally at baseline prior to surgery and at scheduled control visits after surgery (FIG. 20A).Whole-exome sequencing identified somatic mutations; following Signatera standard workflow, patient-specific multiplex-PCR assays targeting 16 somatic single-nucleotide and indel variants were assayed by massive parallel sequencing in plasma samples collected pre- and post-surgery, and during adjuvant therapy (FIG. 20B).
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Zimmermann teaches mutational profiles derived from pretreatment tumor biopsy and germline DNA whole exome sequences were used to design personalized assays targeting 16 variants specific to a patients' tumor to detect ctDNA in plasma (0834). Thus Zimmermann teaches a method for preparing and sequencing a DNA fraction from a liquid biopsy sample of a colorectal cancer patient comprising (a) sequencing a plurality of nucleic acids isolated from a biological sample of the colorectal cancer patient to identify a plurality of patient-specific cancer mutations; (b) preparing a first amplified DNA fraction from a first liquid biopsy sample collected from the colorectal cancer patient after surgery, wherein the first liquid biopsy sample is plasma, wherein preparing the first amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the first liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a); (c) sequencing the amplified target loci from cell free DNA isolated from the first liquid biopsy to generate sequence reads comprising the patient-specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient specific cancer mutations in the first liquid biopsy sample; (d) preparing a second amplified DNA fraction from a second liquid biopsy sample collected from the colorectal cancer patient after collection of the first liquid biopsy sample, wherein the second liquid biopsy sample is plasma, wherein preparing the second amplified DNA fraction comprises performing a multiplex amplification reaction to amplify a plurality of target loci from cell-free DNA isolated from the second liquid biopsy sample, wherein each of the target loci spans at least one patient-specific cancer mutation identified in step (a); (e) sequencing the amplified target loci from cell free DNA isolated from the second liquid biopsy to generate sequence reads comprising the patient-specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient-specific cancer mutations in the second liquid biopsy sample.
Regarding Claim 2 Zimmermann teaches mutational profiles derived from pretreatment tumor biopsy and germline DNA whole exome sequences were used to design personalized assays targeting 16 variants specific to a patients' tumor to detect ctDNA in plasma (0834). Thus Zimmermann teaches a method wherein the biological sample is a tumor tissue biopsy sample.
Regarding Claim 4 Zimmermann teaches mutational profiles derived from pretreatment tumor biopsy and germline DNA whole exome sequences were used to design personalized assays targeting 16 variants specific to a patients' tumor to detect ctDNA in plasma (0834). Thus Zimmermann teaches a method wherein step (a) comprises whole exome sequencing of the plurality of nucleic acids.
Regarding Claim 5 Zimmermann discloses performing targeted sequencing (para 0308). Further Zimmerman teaches that in some embodiments, selective amplification or enrichment are used to amplify or enrich target loci para 0543). Thus Zimmermann teaches a method that comprises targeted sequencing of the plurality of nucleic acids that have been enriched at a panel of cancer-associated genomic loci.
Regarding Claim 6 Zimmermann teaches a method wherein ctDNA status was established based on the first postoperative blood sample, which was drawn by week 6 and prior to start of ACT (para 0794, Fig 23A). Thus Zimmermann teaches a method wherein the first liquid biopsy sample is collected from the patient about 2-12 weeks (6 weeks) after surgery.
Regarding Claim 7 Zimmermann teaches a method wherein ctDNA status was established based on the first postoperative blood sample, which was drawn by week 6 and prior to start of ACT (para 0794, Fig 23A). Thus Zimmermann teaches a method wherein the first liquid biopsy sample is collected from the patient about 4-8 weeks (6 weeks) after surgery.
Regarding Claim 8 Zimmermann teaches that FIG. 87D shows ACT effect on ctDNA-positive patients, assessed by recurrence rate and longitudinal ctDNA status (para 0180). Thus Zimmermann teaches a method wherein a first liquid biopsy sample is collected from the patient after adjuvant chemotherapy (ACT) (see dots representing ctDNA to the right of the open rectangles which represent adjuvant chemotherapy).
Regarding Claim 9 Zimmermann teaches a method wherein ctDNA status was established based on the first postoperative blood sample, which was drawn by week 6 and prior to start of ACT (para 0794, Fig 23A). Thus Zimmermann teaches a method wherein the first liquid biopsy sample is collected from the patient about 4-8 weeks (6 weeks) after surgery.
Regarding Claim 10 Zimmermann teaches that plasma samples were collected longitudinally at baseline, day 30, and then every 3 months for 3 years (Fig 20A). Thus Zimmermann teaches a method wherein the second liquid biopsy sample is collected from the patient about 4-8 weeks (day 30) after the first liquid biopsy sample.
Regarding Claim 11 Zimmermann teaches selecting a set of at least 8 or 16 patient-specific single nucleotide variant loci based on somatic mutations identified in a tumor sample of a patient (para 0044). Thus Zimmermann teaches a method wherein the patient-specific cancer mutations comprises at least one somatic mutation.
Regarding Claim 12 Zimmermann teaches selecting a set of at least 8 or 16 patient-specific single nucleotide variant loci based on somatic mutations identified in a tumor sample of a patient (para 0044). Thus Zimmermann teaches a method wherein the patient-specific cancer mutations comprises at least one single nucleotide variant (SNV).
Regarding Claim 13 Zimmermann teaches selecting a plurality of genomic variant loci (e.g., SNV, indel, multiple nucleotide variant, and gene fusion) based on somatic mutations identified in a tumor sample of a patient (page 0080). Thus Zimmermann teaches a method wherein the patient-specific cancer mutations comprises at least one multi-nucleotide variant (MNV), indel, gene fusion, or structural variant.
Regarding Claim 14 Zimmermann teaches generating a set of amplicons by performing a multiplex amplification reaction on nucleic acids isolated from each blood or urine sample or a fraction thereof, wherein each amplicon of the set of amplicons spans at least one single nucleotide variant locus of a set of at least 8 or 16 patient-specific single nucleotide variant loci associated with the breast cancer, bladder cancer, or colorectal cancer, which have been selected based on somatic mutations identified in a tumor sample of the patient (para 0046). Thus Zimmermann teaches a method wherein the plurality of target loci comprises at least 8 or at least 16 target loci each spanning at least one patient-specific cancer mutation.
Claim 17 recites a “wherein” clause stating that “a colorectal cancer patient having a fast tumor growth rate has reduced overall survival compared to a colorectal cancer patient having a slow tumor growth rate”. As noted above, claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. In the instant case there are no active process steps of determining that the patient will have reduced overall survival recited in the claim.
Regarding Claim 18 Zimmermann teaches that plasma samples were collected longitudinally at baseline, day 30, and then every 3 months for 3 years (Fig 20A).
Thus Zimmermann teaches quantifying the amount of circulating tumor DNA in a third liquid biopsy sample longitudinally collected from the cancer patient after the second liquid biopsy sample.
Regarding Claim 21 Zimmerman teaches a method wherein capture by hybridization with hybrid capture probes is used to preferentially enrich the DNA (para 0543)
Zimmerman does not teach a method further comprising determining the growth rate of the circulating tumor DNA comprising the patient specific cancer mutations between the first and second liquid biopsy sample. Further Zimmerman does not teach analyzing the growth rate of circulating tumor DNA comprising the patient specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient.
However Taub teaches a method of evaluating a cancer patient to be given a cancer drug therapy that might cause hyper progression comprising the steps of: a. determining the rate of growth of the patient’s cancer by performing at least 2 measurements of circulating DNA prior to beginning of the therapy; b. determining the rate of growth of the patient’s cancer by performing at least 1 measurement of circulating DNA after beginning the therapy; c. continuing to administer the therapy if the rate of growth has not increased, or discontinuing the therapy if the growth rate has increased (page 5, lines 1-5). Taub teaches that often the rate of change in this ctDNA is then determined, in one embodiment the change from adjacent time points is calculated. This change is used to determine if the current therapy is appropriate or should be changed. In another embodiment simply the amount measured compared to the previous amount is determined. If the amount is increased therapy is changed. While it is not required, the rate of change prior to the beginning of therapy is compared to the rate of change on therapy; this requires two blood samples before therapy begins. Changes in the amount and rate of ctDNA during the first week of cytotoxic or targeted therapy and 2 weeks for immunotherapy may reflect acute killing and a decrease in the cancer and may be used as a marker of therapy effectiveness. As rarely an acute increase due to cancer death is seen, a repeat test may be done. Decreases even during this period mark therapy benefit. In contrast after this initial period, increases, especially increase separated by a week or more mark the need for a different therapy (page 19, lines 19-30). Taub teaches that in an individual patient the amount of ctDNA in the blood is a reliable indicator of the cancer growth and/or cancer burden and response to therapy (page 19, lines 5-6). Taub teaches that ctDNA in blood may be used to accurately determine the higher cancer burden or higher growth rate of cancer burden prior to therapy and the change in this growth rate. While an absolute increase in ctDNA (circulating tumor/cancer DNA) of 20% has been defined by some as molecular progression or molecular progressive disease (MPD), this invention has newly determined that a change in the slope of growth, as measured by any appropriate change in an appropriate measure of ctDNA indicated what is herein “Accelerating Progressive Disease” (APD). APD has not previously been used, the invention is using short half-life markers to determine any increase in rate of growth and using this to quickly stop the therapy associated with APD (page 18, lines 16-29).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zimmerman by determining the growth rate of the circulating tumor DNA comprising the patient specific cancer mutations between the first and second liquid biopsy sample and analyzing the growth rate of circulating tumor DNA comprising the patient specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient as suggested by Taub. As discussed above, Taub teaches monitoring the rate of change in ctDNA levels prior to treatment (at least 2 samples before therapy begins) and then over the course of treatment. Taub teaches that the amount of ctDNA in the blood is a reliable indicator of the cancer growth and/or cancer burden and response to therapy. Taub teaches that decreases in the rate of ctDNA are indicative of therapy benefit. Taub teaches that increases in the rate of ctDNA are indicative of the need for a different therapy because hyper progression might be occurring. Based on the teachings of Taub one of skill in the art would have been motivated to determine the growth rate of ctDNA between a first and second liquid biopsy sample for the benefits of being able to monitoring how a patient is responding to treatment. Further one of skill in the art would have been motivated to use the growth rate of ctDNA to detect tumor relapse or growth because the growth rate can be measured long before many lesions can be measured by imaging.
Response To Arguments
6. In the response the Applicants traversed the rejection under 35 USC 103 over Zimmermann in view of Taub. The Applicants argue that Taub does not teach or suggest “sequencing a plurality of nucleic acids isolated from a biological sample of the colorectal cancer patient to identify a plurality of patient-specific cancer mutations” and “sequencing the amplified target loci from cell-free DNA isolated from the first liquid biopsy to generate sequence reads comprising the patient-specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient- specific cancer mutations” as recited by the present claims. The ctDNA measured by Taub does not comprise patient-specific cancer mutations. Accordingly, Taub cannot teach or suggest to “determine the growth rate of the circulating tumor DNA comprising the patient-specific cancer mutations between the first and the second liquid biopsy sample” and “analyzing the growth rate of circulating tumor DNA comprising the patient-specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient” as recited by the present claims.
This argument has been fully considered but is not persuasive. Applicants are reminded that this is a 103 rejection and a combination of references have been relied upon to reject the claims. The primary reference (Zimmerman) teaches “sequencing a plurality of nucleic acids isolated from a biological sample of the colorectal cancer patient to identify a plurality of patient-specific cancer mutations” and “sequencing the amplified target loci from cell-free DNA isolated from the first liquid biopsy to generate sequence reads comprising the patient-specific cancer mutations and quantify an amount of circulating tumor DNA comprising the patient- specific cancer mutations”. Taub is NOT required to teach the analysis of patient specific cancer mutations because Zimmermann does this. The combination of Zimmerman and Taub would result in determination of the growth rate of the circulating tumor DNA comprising the patient-specific cancer mutations between the first and the second liquid biopsy sample and analysis of the growth rate of circulating tumor DNA comprising the patient-specific cancer mutations to determine whether the growth rate corresponds to tumor relapse or growth in the colorectal cancer patient. The rejection is maintained.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682