ETAILED 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 .
Applicant previously canceled claims 2, 9 and 16. Applicant newly adds claims 22 and 23. Claims 1, 3-8, 10-15 and 17-23 are currently pending and under examination. Any objection or rejection of record in the previous Office Action, which is not addressed in this action has been withdrawn in light of Applicant’s amendments and/or arguments. This action is Final.
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, 3-8, 10-15 and 17-21 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Maguire et al. (United States Patent Application Publication US 2017/0275689 A1, published September 28, 2017), previously cited in the March 07, 2025 Office Action. This rejection is modified and maintained as necessitated by amendments.
Regarding claim 1, Maguire teaches a personalized method for sequencing circulating tumor DNA (ctDNA) from a patient (Page 1, [0008], Page 21, [0214] and Page 24, [0234]). Maguire teaches sequencing DNA from a tumor sample and a non-tumor sample from a patient with a history of cancer (Page 2, [0015]). Maguire teaches enriching cell-free DNA (cfDNA) from a fluid sample obtained from the patient with a patient-specific panel of tumor-specific somatic mutations (Page 1, [0008], Page 10, [0112]-[0113], Page 21, [0214], Page 22, [0224] and Page 20, [0208]). Maguire teaches patient-specific panel comprises at least 10 insertions or deletions (indels), that are 1-50 bases in size (Page 2, [0015], Page 3, [0048], Pages 3-4, [0051], Page 4, [0058] and Pages 19-20, [0206]-[0207]). Maguire teaches sequencing the cfDNA enriched from the fluid sample obtained from the patient, thereby obtaining a plurality of sequence reads (Pages 22-23, [0227] and Page 3, [0044]). Maguire teaches a sequence read in the plurality of sequence reads corresponding to one or more of the at least 10 indels indicates the presence of ctDNA (Page 8, [0099], Page 3, [0048], Page 4, [0058], Page 9, [0109], Page 10, [0111]-[0113], Pages 19-20, [0206]-[0207], Page 21, [0214] and Pages 23-24, [0234]). Maguire teaches the method can detect the presence of ctDNA with a proportion of ctDNA in the fluid sample of about 1 e-5 to 1 e-6 (Page 9, [0109], Page 25, [0251]-[0256], Page 25, [0266] and Figs. 3-6).
Regarding claim 3, Maguire teaches enriching the cfDNA comprises contacting the cfDNA with a personalized set of probes specific for each of the tumor-specific somatic mutations of the patient-specific panel, thereby generating the enriched library (Page 11, [0122] and Page 10, [0111]-[0113]).
Regarding claim 4, Maguire teaches enriching the cfDNA comprises multiplex PCR using primers pairs specific for each of the tumor-specific somatic mutations of the patient-specific panel, thereby generating the enriched library (Page 8, [0097] and Page 10, [0111]-[0113]).
Regarding claim 5, Maguire teaches the fluid sample is whole blood, plasma, or serum (Page 3, [0044]).
Regarding claim 6, Maguire teaches repeating (c) and (d) on a second cell-free nucleic acid sample from the patient to generate a second enriched sample, wherein the second sample is taken at a different time point (Page 8, [0099], Pages 9-10, [0110] and Page 20, [0208]).
Regarding claim 7, Maguire teaches the patient-specific panel comprises at least 50 indels (Page 2, [0015], Page 3, [0048], Page 4, [0058] and Pages 19-20, [0206]-[0207]).
Regarding claim 8, Maguire teaches genomic rearrangements include copy number variants, translocations, and inversions (Page 2, [0015], Page 3, [0048]).
Regarding claim 10, Maguire teaches the patient-specific panel of tumor-specific somatic variants is obtained by aligning sequencing reads from the tumor sample to a reference genome and aligning sequencing reads from non-tumor sample to a reference genome (Page 20, [0207] and Page 23, [0230]).
Regarding claim 11, Maguire teaches the patient-specific panel of tumor-specific somatic variants is obtained by aligning sequencing reads from the tumor sample to sequencing reads from the non-tumor sample (Page 20, [0207]).
Regarding claim 12, Maguire teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises whole genome sequencing (Page 2, [0015]).
Regarding claim 13, Maguire teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises whole exome sequencing (Page 19, [0204]).
Regarding claim 14, Maguire teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises targeted sequencing (Page 2, [0015]).
Regarding claim 15, Maguire teaches the patient-specific panel does not comprise single nucleotide variants (e.g., large sections of DNA and/or mutations involving the whole chromosome, Page 3, [0048]).
Regarding claim 17, Maguire teaches determining an amount of cfDNA fragments comprising one or more of the subset panel of patient-specific somatic mutations, wherein the determined amount of cfDNA fragments reflects the tumor burden of the patient (Page 2, [0016] and Page 3, [0042]-[0043]).
Regarding claim 18, Maguire teaches the patient-specific panel comprises at least 10 different patient-specific somatic variants (Page 24, [0235]).
Regarding claim 19, Maguire teaches the patient-specific panel comprises at least 500 different patient-specific somatic variants (Page 24, [0235]).
Regarding claim 20, Maguire teaches the tumor is selected from adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, a brain/CNS tumor, breast cancer, Castleman disease, cervical cancer, colon or rectum cancer, endometrial cancer, esophagus cancer, a Ewing tumor, eye cancer, gallbladder cancer, a gastrointestinal carcinoid tumor, a gastrointestinal stromal tumor (GIST),gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic Syndrome, nasal cavity or paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity or oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, a pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor (Page 20, [0212]).
Regarding claim 21, A personalized method for sequencing circulating tumor DNA (ctDNA) from a patient (Page 1, [0008], Page 21, [0214] and Page 24, [0234]). Maguire teaches enriching cell-free DNA (cfDNA) from a fluid sample with about 1e-5 or 1e-6 of ctDNA obtained from a patient with a history of cancer using a patient-specific panel of tumor-specific somatic mutations (Page 2, [0015]-[0016], Page 7, [0096], Page 11, [0122], Page 9, [0109], Page 25, [0251]-[0256], Page 25, [0266] and Figs. 3-6). Maguire teaches patient-specific panel comprises at least 10 insertions or deletions (indels), that are 1-50 bases in size (Page 2, [0015], Page 3, [0048], Pages 3-4, [0051], Page 4, [0058] and Pages 19-20, [0206]-[0207]). Maguire teaches sequencing, using next generation sequencing, the cfDNA enriched from the fluid sample obtained from the patient, thereby obtaining a plurality of sequence reads (Pages 18-19, [0198], Page 19, [0201], Pages 22-23, [0227] and Page 3, [0044]). Maguire teaches a sequence read in the plurality of sequence reads corresponding to one or more of the at least 10 indels indicates the presence of ctDNA (Page 8, [0099], Page 3, [0048], Page 4, [0058], Page 9, [0109], Page 10, [0111]-[0113], Pages 19-20, [0206]-[0207], Page 21, [0214] and Pages 23-24, [0234]).
Regarding claim 22, Maguire teaches the fluid sample is whole blood, plasma, or serum (Pages 6-7, [0044] and Page 24, [00110]).
Regarding claim 23, Maguire teaches the patient-specific panel further comprises at least 50 indels (Page 2, [0015], Page 3, [0048], Page 4, [0058] and Pages 19-20, [0206]-[0207]).
Maguire teaches each and every limitation of claims 1, 3-8, 10-15 and 17-23, and therefore, Maguire anticipates claims 1, 3-8, 10-15 and 17-23.
Claims 1, 3-8, 10-15 and 17-23 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Kurtz et al. (United States Patent US 11,447,833 B2, published September 20, 2022). This rejection is modified and maintained as necessitated by amendments.
Regarding claim 1, Kurtz teaches a personalized method for sequencing circulating tumor DNA (ctDNA) from a patient (Column 21, Lines 51—Column22, Line 23). Kurtz teaches sequencing DNA from a tumor sample and a non-tumor sample from a patient with a history of cancer (Column 6, Lines 41-63 and Column 38, Lines 33-59). Kurtz teaches enriching cell-free DNA (cfDNA) from a fluid sample obtained from the patient with a patient-specific panel of tumor-specific somatic mutations (Column 7, Line 65—Column 8, Line3, Column 13, Lines 10-57, Column 21, Lines 51-52, Column 28, lines 34-39, Column 48, Lines 20-25, Column 76, Lines 44-59 and Column 77, Line 52—Column 78, Line 6). Kurtz teaches patient-specific panel comprises at least 10 insertions or deletions (indels), that are 1-50 bases in size (i.e., cfDNA with a first and second phased variant (PV) that may be indels; Column 19, Line 65—Column 20, Line 7, Column 23, Line 41—Column 24, Line 13, Column 25, Line 24—Column 26, Line 23, Column 6, Lines 23-27, Column 69, Lines 52-56, Column 16, Line 15, Column 41, Lines 48-63). Kurtz teaches sequencing the cfDNA enriched from the fluid sample obtained from the patient, thereby obtaining a plurality of sequence reads (Column 1, Line 62—Column 2, Line 20, Column 20, Lines 52-56 and Column 83, Lines 14-19). Kurtz teaches a sequence read in the plurality of sequence reads corresponding to one or more of the at least 10 indels indicates the presence of ctDNA and the method can detect the presence of ctDNA with a proportion of ctDNA in the fluid sample of about 1 e-5 to 1 e-6 (i.e., cfDNA with a first and second phased variant (PV) that may be indels… Detection of somatic variants occurring in phase can indicate the presence of cancer (ctDNA) in a diagnostic scan; Abstract, Column 5, Lines 52-55, Column 6, Lines 23-27, Column 7, Lines 25-30, Column 65, Lines 29-38, Column 22, Lines 47-59, Column 30, Lines 1-16, Column 19, Line 65—Column 20, Line 7, Column 23, Line 41—Column 24, Line 13, Column 25, Line 24—Column 26, Line 23, Column 69, Lines 52-56, Column 16, Line 15, Column 41, Lines 48-63 and Figs. 3G-H, 4A-B, 20 and 22A-B).
Regarding claim 3, Kurtz teaches enriching the cfDNA comprises contacting the cfDNA with a personalized set of probes specific for each of the tumor-specific somatic mutations of the patient-specific panel, thereby generating the enriched library (Column 29, Lines 4-18, Column 48, Lines 17-21 and claim 1)
Regarding claim 4, Kurtz teaches enriching the cfDNA comprises multiplex PCR using primers pairs specific for each of the tumor-specific somatic mutations of the patient-specific panel, thereby generating the enriched library (Column 72, Lines 43-47 and Column 38, Line 58—39, Line 9)
Regarding claim 5, Kurtz teaches the fluid sample is whole blood, plasma, or serum (Column 8, Lines 1-2).
Regarding claim 6, Kurtz teaches repeating (c) and (d) on a second cell-free nucleic acid sample from the patient to generate a second enriched sample, wherein the second sample is taken at a different time point (Column 32, Lines 4-15).
Regarding claim 7, Kurtz teaches the patient specific panel comprises at least 50 indels (Column 25, Line 24—Column 26, Line 23).
Regarding claim 8, Kurtz teaches the cfDNA genomic rearrangements include copy number variants, translocations, and inversions (Column 79, Lines 1-3 and Column 22, Lines 3-4, ).
Regarding claim 10, Kurtz teaches the patient-specific panel of tumor-specific somatic variants is obtained by aligning sequencing reads from the tumor sample to a reference genome and aligning sequencing reads from non-tumor sample to a reference genome (Claim 6).
Regarding claim 11, Kurtz teaches the patient-specific panel of tumor-specific somatic variants is obtained by aligning sequencing reads from the tumor sample to sequencing reads from the non-tumor sample (Claim 5).
Regarding claim 12, Kurtz teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises whole genome sequencing (Column 72, Lines 44-47 and Claims 1-2 and 5-6).
Regarding claim 13, Kurtz teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises whole exome sequencing (Column 72, Lines 44-47 and Claim 12).
Regarding claim 14, Kurtz teaches sequencing DNA from the tumor sample and the non-tumor sample from the subject comprises targeted sequencing (Column 23, Lines 26-29 and Column 45, Lines 1-33).
Regarding claim 15, Kurtz teaches the patient-specific panel does not comprise single nucleotide variants (Column 26, Lines 20-23, Column 29, Lines 44-50 and Figs. 1A and 1E).
Regarding claim 17, Kurtz teaches determining an amount of cfDNA fragments comprising one or more of the subset panel of patient-specific somatic mutations, wherein the determined amount of cfDNA fragments reflects the tumor burden of the patient (Column 22, Lines 30-40).
Regarding claim 18, Kurtz teaches the patient-specific panel comprises at least 10 different patient-specific somatic variants (Column 25, Lines 24-41)
Regarding claim 19, Kurtz teaches the patient-specific panel comprises at least 500 different patient-specific somatic variants (Column 6, Lines 23-32 and Column 25, Line 41—Column 26, Line 14).
Regarding claim 20, Kurtz teaches the tumor is selected from adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, a brain/CNS tumor, breast cancer, Castleman disease, cervical cancer, colon or rectum cancer, endometrial cancer, esophagus cancer, a Ewing tumor, eye cancer, gallbladder cancer, a gastrointestinal carcinoid tumor, a gastrointestinal stromal tumor (GIST),gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic Syndrome, nasal cavity or paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity or oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, a pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor (Column 59, Line 20—Column 61, Line 51).
Regarding claim 21, Kurtz teaches a personalized method for sequencing circulating tumor DNA (ctDNA) from a patient (Column 21, Lines 51—Column22, Line 23). Kurtz teaches enriching cell-free DNA (cfDNA) from a fluid sample with about 1 e-5 to 1 e-6 of ctDNA obtained from the patient with a patient-specific panel of tumor-specific somatic mutations (Column 7, Line 65—Column 8, Line3, Column 13, Lines 10-57, Column 21, Lines 51-52, Column 28, lines 34-39, Column 48, Lines 20-25, Column 76, Lines 44-59 and Column 77, Line 52—Column 78, Line 6 and Figs. 3G-H, 4A-B, 16, 20 and 22A-B). Kurtz teaches sequencing using Next Generation sequencing (Column 3, Lines 9-11). Kurtz teaches patient-specific panel comprises at least 10 insertions or deletions (indels), that are 1-50 bases in size (i.e., cfDNA with a first and second phased variant (PV) that may be indels; Column 19, Line 65—Column 20, Line 7, Column 23, Line 41—Column 24, Line 13, Column 25, Line 24—Column 26, Line 23, Column 6, Lines 23-27, Column 69, Lines 52-56, Column 16, Line 15, Column 41, Lines 48-63). Kurtz teaches sequencing the cfDNA enriched from the fluid sample obtained from the patient, thereby obtaining a plurality of sequence reads (Column 1, Line 62—Column 2, Line 20, Column 20, Lines 52-56 and Column 83, Lines 14-19). Kurtz teaches a sequence read in the plurality of sequence reads corresponding to one or more of the at least 10 indels indicates the presence of ctDNA (i.e., cfDNA with a first and second phased variant (PV) that may be indels… Detection of somatic variants occurring in phase can indicate the presence of cancer (ctDNA) in a diagnostic scan; Abstract, Column 5, Lines 52-55, Column 6, Lines 23-27, Column 7, Lines 25-30, Column 65, Lines 29-38, Column 22, Lines 47-59, Column 30, Lines 1-16, Column 19, Line 65—Column 20, Line 7, Column 23, Line 41—Column 24, Line 13, Column 25, Line 24—Column 26, Line 23, Column 69, Lines 52-56, Column 16, Line 15, Column 41, Lines 48-63 and Figs. 3G-H, 4A-B, 20 and 22A-B).
Regarding claim 22, Kurtz teaches the fluid sample is whole blood, plasma, or serum (Column 6, Lines 55-62 and Column 7, Line 65—Column 8, Line 3).
Regarding claim 23, Kurtz teaches the patient-specific panel further comprises at least 50 indels (Column 25, Line 24—Column 26, Line 23).
Kurtz teaches each and every limitation of claims 1, 3-8, 10-15 and 17-23, and therefore, Kurtz anticipates claims 1, 3-8, 10-15 and 17-23.
Response to Arguments
Applicant’s arguments and amendments filed March 23, 2026, with respect to the rejections under 35 U.S.C. § 102 have been fully considered but they are not persuasive. Therefore this rejection is maintained and modified as necessitated by applicant’s amendments as discussed above and below.
Applicant asserts ‘neither cited reference explicitly teaches a patient specific panel that comprises at least 10 indels that are 1-50 bases in size”.
However, as discussed above, Maguire discloses the term “SNP” refers to an indel variant of 100 bas pairs or less which falls within the range 1-50 bases in size. Maguire additionally discloses “the mutation, insertion, or deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides” on Pages 3-4, [0051] and that 10 to at least 400 different mutations may be identified. Moreover, Kurtz additionally discloses indels may be phased variants and that in a region comprising phased variants may have a length between about 25 nucleotides to about 50 nucleotides (Column 36, Lines 42-45) as well as, Kurtz discloses at least or up to 100,000 phased variants may be detected (Column 25, Line 10—Column 26, Line 230. Therefore Maguire and Kurtz do in fact disclose 10 indels that are 1-50 bases in size.
Applicant asserts “MRD methods are limited by the amount of blood that can be drawn for analysis and by the extremely low proportions of tumor cfDNA of about 1 e-4" but the presently claimed methods offer improved sensitivity and reduced error, "which allows the detection of somatic variants associated with the patient's cancer at extremely low proportions of tumor cfDNA of less than about le-5 to le-6.", [and] the art of record does not disclose the impact sensitivity such as detection of ctDNA at low proportions of about 1e-5 to 1e-6”.
As discussed above, Maguire discloses “The method provided herein combines analysis of patient-specific multiple somatic sites, e.g., single nucleotide polymorphisms (SNPs), which allows the detection of somatic mutations associated with the patient's cancer at extremely low proportions of tumor cfDNA of less than about 1e-3” on Page 9, [0109]. Additionally Maguire discloses using a cancer DNA sample with the proportions 0f 1e-5 and 1e-6 specifically at Page 25, [0255] and [0256]. Additionally Maguire discloses that detection of as low as 5 tumor molecules per 1,000,000 molecules sequenced was obtained in Page 25, [0266], and that the method provides for extremely high sensitivity (Page 24, [0242]). Moreover Kurtz additionally discloses “methods and systems of the disclosure …exhibit enhanced sensitivity…of detection of cancer derived nucleic acids”, Column 2, Lines 1-3, as well as “detectable ctDNA levels as low as 6 parts in 1,000,000. This increased sensitivity improved the lead-time of disease detection by ctDNA” Column 70, Lines 53-56. Therefore Maguire and Kurtz do in fact disclose extremely low proportions of tumor cfDNA of less than about le-5 to le-6 with an impact on sensitivity.
Therefore, all these reasons, and those listed above, Maguire, as well as Kurtz, anticipates the instant invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JESSICA D PARISI/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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