DETAILED ACTION
Applicant’s response, filed 7/27/2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Claim Status
Claims 2-6, 8, and 13 are cancelled.
Claims 1, 7, 9-12, and 14-20 are pending.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 1/16/2026.
Claims 1, 7, and 9-12 are examined on the merits.
Priority
The instant application is a 371 of PCT/EP2021/086243 filed on 12/16/2021, which claims benefit under U.S.C. 119 to European Application EP20215730.1 filed on 12/18/2020. At this point in examination, the effective filing date of claims 1, 7, and 9-12 is 12/18/2020.
Drawings
The drawings filed on 6/15/2023 are accepted.
Specification
The objection to the abstract filed 6/15/2023 is withdrawn in view of the amendments filed 7/27/2026.
Claim Objections
The objection to claim 12 is withdrawn in view of the claim amendments filed 7/27/2026.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendment.
Claim 9 recites wherein the sample can be a sample from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients. A sample is incapable of being classified as comprising tumor cfDNA if the sample is from a subject who is cancer-free, non-relapsed, or successfully treated. The specification does not disclose the sample being analyzed as coming from these types of subjects. Therefore, the specification fails to provide a written description that shows the inventor possessed the invention as recited in claim 9.
Claim Rejections - 35 USC § 112(b)
The previous rejection to claim 9 under 35 U.S.C. § 112(b) is withdrawn in view of the claim amendments filed 7/27/2026.
Claim Rejections - 35 USC § 101
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, 7, and 9-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion); and (c) natural phenomena/laws of nature. Any newly recited portions herein are necessitated by claim amendment.
Subject matter eligibility evaluation in accordance with MPEP 2106:
Eligibility Step 1: Claims 1, 7, and 9-12 are directed to a method (process) of classifying a sample as comprising cell-free tumor DNA. Therefore, these claims are encompassed by the categories of statutory subject matter and thus satisfy the subject matter eligibility requirements under Step 1.
[Step 1: YES]
Eligibility Step 2A: First, it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A, Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth described in the claim.
Claims 1, 7, and 9-12 recite the following steps which fall within the mental processes and/or mathematical concepts groups of abstract ideas, and/or laws of nature/natural phenomena, as noted below.
Independent claim 1 further recites:
(i) determining in a sample comprising a plurality of cell-free DNA (cfDNA) fragments the sequence coordinates of the start and/or stop, and of the start and/or stop plus and/or minus 1 base pair, of at least 100,000 cfDNA fragments by alignment to a reference sequence (i.e., mental processes);
(ii) determining the frequency of each coordinate determined in (i) in the plurality of cfDNA fragments comprised in the sample, wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i) (i.e., mental processes);
(iii) calculating the ratio of the frequency of each coordinate determined in (ii) over a corresponding reference frequency (i.e., mental processes, mathematical concepts);
(iv) calculating a diagnostic score from all ratios determined in (iii) said score being the weighted sum of all frequency ratios determined in (iii) (i.e., mental processes, mathematical concepts);
(v) determining a classification of the sample by comparing the diagnostic score to a reference score, wherein the sample is classified as comprising tumor cfDNA, if the diagnostic score value is higher than the mean of the reference score by at least one standard deviation of the reference score, wherein the reference score is calculated from one or more reference values (i.e., mental processes).
Dependent claim 7 further recites:
wherein the minimum amount of cfDNA fragments comprised within a sample to be analyzed is between 100 thousand to 500 thousand, 500 thousand to 1 million, 1 million to 2 million, 2 million to 5 million, or 5 million to 10 million, or 10 million to 20 million, or 20 million to 50 million, or 50 million to 500 million (i.e., mental processes; this is further information limiting the judicial exceptions).
Dependent claim 9 further recites:
wherein the sample can be a sample from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients (i.e., mental processes; this is further information limiting the judicial exceptions).
Dependent claim 10 further recites:
wherein step (i) comprises the determination of the nucleic acid sequence of at least a portion of the plurality of cfDNA fragments in the sample prior to the alignment to a reference sequence (i.e., mental processes; this is further information limiting the judicial exceptions).
Dependent claim 11 further recites:
wherein step (i) further comprises the enrichment of cfDNA fragments prior to the determination of the nucleic acid sequence of cfDNA fragments (i.e., mental processes; this is further information limiting the judicial exceptions).
Dependent claim 12 further recites:
wherein the sample is classified as comprising tumor cfDNA originating from a tumor selected from the group of blood cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, glioblastoma, colorectal cancer, head and neck cancer, a solid tumor, a benign tumor, a malignant tumor, an advanced stage of cancer, a metastasis or a precancerous tissue (i.e., mental processes, laws of nature; this is further information limiting the judicial exceptions).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As the claims are currently recited, the method can be performed by writing out the sequence alignments between samples with pen and paper and measuring the frequency of the coordinates used for calculating a score to classify a sample. Writing down the alignments and calculations and making decisions from them can be practically performed in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether the limitations are practical to perform in the human mind. The claims recite calculating ratios of frequencies and calculating a diagnostic score from the ratios, which are measurements considered as mathematical concepts. Claims are also determined to contain limitations that include naturally occurring principles/relations or nature-based products that are naturally occurring and therefore recite judicial exceptions from the laws of nature/natural phenomena grouping. The claims recite classifying a sample as comprising tumor cfDNA relating to a tumor, which is read as correlating the tumor cfDNA to a condition and considered law of nature.
Therefore, claims 1, 7, and 9-12 recite an abstract idea.
[Step 2A, Prong One: YES]
Eligibility Step 2A, Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that, when examined as a whole, integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
Claims 1, 7, and 9-12 do not recite any additional elements in addition to the judicial exception and therefore fail to integrate the abstract ideas into a practical application. See MPEP 2106.04.II.A.2.
[Step 2A, Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
Claims 1, 7, and 9-12 are drawn to a judicial exception and do not recite any additional elements that amount to significantly more than the judicial exception. Furthermore, an inventive concept cannot be furnished by a judicial exception. See MPEP 2106.05.I.
[Step 2B: NO]
Therefore, claims 1, 7, and 9-12 are patent ineligible under 35 U.S.C. § 101.
Response to Arguments
Applicant’s arguments, see pages 8-11, filed 7/27/2026, with respect to the rejection of claims 1, 7, and 9-12 under 35 U.S.C. § 101, have been fully considered but they are not persuasive.
With respect to the Applicant’s argument that claim 1 is not directed to a law of nature, a natural phenomenon, or an abstract idea, but instead is directed to a specific bioinformatics method applied to a technological field (cell-free tumor DNA) (pg. 8-9 of Applicant’s Remarks), this argument is not persuasive. The previously presented and amended claims recite determining sequence coordinates by alignment, determining frequencies of each coordinate, calculating ratios of the frequencies, calculating a diagnostic score from the ratios, and classifying a sample by comparing diagnostic scores, all of which are mental processes and/or mathematical concepts as described in the rejection above. See MPEP 2106.04(a).
With respect to the Applicant’s argument that claim 1 and its dependent claims are patent eligible because they provide an improvement to a technology, specifically reducing end-site uncertainty by explicitly incorporating
±
1 bp coordinate/motif analysis into the feature extraction and scoring pipeline to yield improved classification accuracy over prior approaches (pg. 9-10 of Applicant’s Remarks), this argument is not persuasive. Classifying a sample by determining sequence coordinates and frequencies, calculating diagnostic scores from ratios of frequencies, and comparing those diagnostic scores as recited in claim 1 are mental processes or mathematical concepts and do not contain additional elements that can integrate the claim into a practical application. It is important to note that the judicial exception alone cannot provide the improvement and that the improvement can only be provided by one or more additional elements. See MPEP 2106.05(a).
With respect to the Applicant’s argument that claim 1 recites elements, or a combination of elements, that are sufficient to ensure the claim amounts to significantly more than the exception, specifically providing a technological improvement by achieving improved detection of cancer or autoimmune diseases (pg. 11 of Applicant’s Remarks), this argument is not persuasive. Classifying a sample by determining sequence coordinates and frequencies, calculating diagnostic scores from ratios of frequencies, and comparing those diagnostic scores as recited in claim 1 are mental processes or mathematical concepts and do not contain additional elements that amount to significantly more than the judicial exceptions. It is important to note that the judicial exception alone cannot provide the improvement and that the improvement can only be provided by one or more additional elements. See MPEP 2106.05(a).
Therefore, the rejection to claims 1, 7, and 9-12 under 35 U.S.C. § 101 is maintained with modifications as necessitated by amendment of the claims, filed 7/27/2026.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection to claims 1, 7, and 9-12 under 35 U.S.C. 103 as being unpatentable over Namsaraev et al. [WO2018081130A1], in view of Jiang et al. (Proceedings of the National Academy of Sciences, 2018, 115(46), E10925-E10933), as provided in the IDS filed 6/15/2023, and Heitzer et al. (Genome Medicine, 2013, 5(30), 1-16), is withdrawn in view of the arguments filed 7/27/2026 because Heitzer et al. no longer applies to the limitations recited in claim 1.
Claims 1, 7, and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Namsaraev et al. [WO2018081130A1], in view of Jiang et al. (Proceedings of the National Academy of Sciences, 2018, 115(46), E10925-E10933), as provided in the IDS filed 6/15/2023.
With respect to claim 1:
Regarding the recited (i) determining in a sample comprising a plurality of cell-free DNA (cfDNA) fragments the sequence coordinates of the start and/or stop, and of the start and/or stop plus and/or minus 1 base pair, of at least 100,000 cfDNA fragments by alignment to a reference sequence, Namsaraev et al. discloses “In some embodiments, analyzing the first plurality of cell-free nucleic acid molecules or the plurality of cell-free nucleic acid molecules comprises receiving, at the computer system, the plurality of sequence reads; and aligning, by the computer system, the plurality of sequence reads to the reference genome to determine genomic positions for the plurality of sequence reads.” (pg. 9, para. [008], lines 3-7). Also, further discloses “As a high number of sequencing reads, in the order of hundreds of thousands to millions or even possibly hundreds of millions or billions (e.g., 100,000, 1,000,000 (1M), 10M, 100M, 1000M, or more reads), are generated from each sample in each run” (pg. 58, para. [00216], lines 1-3). Namsaraev et al. discloses that an “ending position” or “end position” can refer to the genomic coordinate, genomic identity, or nucleotide identity of the outermost base of a cell-free DNA molecule, which can correspond to either end of a DNA molecule and can be derived from sequence alignments (pg. 38-39, para. [00156], lines 1-16). This teaches that genomic positions of the start or stop, including the start or stop plus or minus 1 base pair, of at least 100,000 cell-free nucleic acid molecules were determined by alignment to a reference genome.
Namsaraev et al. does not disclose (ii) determining the frequency of each coordinate determined in (i) in the plurality of cfDNA fragments comprised in the sample, wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i).
However, Jiang et al. discloses “To quantify the extent of the size shortening, cumulative frequency plots were generated for the cell-free DNA with the tumor- or nontumor-associated preferred ends (SI Appendix, Fig. S7A) for each plasma sample.” (pg. E10929-E10930, col. 2, para. 2, lines 1-4). This teaches determining frequency plots for tumor- or nontumor-associated preferred end coordinates in cell-free DNA.
Jiang et al. does not disclose wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i).
However, Namsaraev et al. discloses that detectable “ending positions” or “end positions” can represent the biologically true end or the end is one or more nucleotides inwards or one or more nucleotides extended from the original end of the molecule e.g., 5’ blunting and 3’ filling of overhangs of non-blunt-ended double stranded DNA molecules by the Klenow fragment (pg. 38-39, para. [00156], lines 1-16). This teaches that frequencies can be determined for each coordinate while excluding the true end coordinate.
Namsaraev et al. does not disclose (iii) calculating the ratio of the frequency of each coordinate determined in (ii) over a corresponding reference frequency.
However, Jiang et al. discloses “Using the preferred end coordinates identified from the discovery sample pair, we calculated the ratios of the number of cell-free DNA molecules showing the tumor-associated preferred ends to those with the nontumor-associated preferred ends among the cell-free DNA samples of 90 HCC patients reported in our previous study” (pg. E10929, col. 1, para. 1, lines 2-7). This teaches calculating ratios of cell-free DNA molecules of each tumor-associated preferred end coordinate over corresponding cell-free DNA molecules of nontumor-associated preferred end coordinates.
Jiang et al. does not disclose (iv) calculating a diagnostic score from all ratios determined in (iii) said score being the weighted sum of all frequency ratios determined in (iii).
However, Namsaraev et al. discloses an end ratio (e.g., a ratio of a first amount of nucleic acid molecules ending on a first set of genomic positions to a second amount of nucleic acid molecules ending on a second set of genomic positions) can be used to determine a classification of a proportional contribution of a tissue type; in some embodiments, a combination of metrics (e.g., at least two of an end ratio, copy number, and nucleic acid fragment size) may be used to detect a condition (e.g., a tumor) in a subject (pg. 128-129, para. [00496]). Also, further discloses determining a weighted sum for each of a plurality of bases (pg. 138, para. [00535]). Namsaraev et al. further discloses a size-based z-score can be calculated using the mean and SD values of AF of control subjects (pg. 113, para. [00441]). This teaches calculating a diagnostic score comprising a weighted sum of frequency ratios.
Jiang et al. does not disclose (v) determining a classification of the sample by comparing the diagnostic score to a reference score, wherein the sample is classified as comprising tumor cfDNA, if the diagnostic score value is higher than the mean of the reference score by at least one standard deviation of the reference score, wherein the reference score is calculated from one or more reference values.
However, Namsaraev et al. discloses an end ratio (e.g., a ratio of a first amount of nucleic acid molecules ending on a first set of genomic positions to a second amount of nucleic acid molecules ending on a second set of genomic positions) can be used to determine a classification of a proportional contribution of a tissue type; in some embodiments, a combination of metrics (e.g., at least two of an end ratio, copy number, and nucleic acid fragment size) may be used to detect a condition (e.g., a tumor) in a subject (pg. 128-129, para. [00496]). Also, further discloses determining a weighted sum for each of a plurality of bases (pg. 138, para. [00535]). Namsaraev et al. further discloses a size-based z-score can be calculated using the mean and SD values of AF of control subjects (pg. 113, para. [00441]-[00442]). This teaches a z-score that compares the diagnostic score to a reference score, where the sample is classified as comprising tumor cfDNA if the z-score is greater than 3, which means the diagnostic score is higher than the mean of the reference score by at least one standard deviation.
It would have been prima facie obvious to one of ordinary skill in the art to modify the tumor detection method disclosed by Namsaraev et al. to incorporate the per-coordinate frequency ratios disclosed by Jiang et al. One would be motivated to incorporate the frequency ratios because in utilizing a multistep error reduction strategy, the specificity of somatic mutation identification among ctDNA was substantially enhanced and the PPV improved from 8.8 to 85%, as disclosed by Jiang et al. (pg. E10931, col. 2, para. 2, lines 1-4). Therefore, incorporating frequency ratios will improve tumor detection accuracy and efficiency. There is a likelihood of success, since both methods are of relevant plasma DNA analysis in relation to cancer and are well known in the field of molecular diagnostics.
With respect to claim 7:
Namsaraev et al. discloses “As a high number of sequencing reads, in the order of hundreds of thousands to millions or even possibly hundreds of millions or billions (e.g., 100,000, 1,000,000 (1M), 10M, 100M, 1000M, or more reads), are generated from each sample in each run” (pg. 58, para. [00216], lines 1-3). Also, further discloses “(d) performing a second assay comprising massively parallel sequencing of the cell-free nucleic acid in the second biological sample to generate sequence reads” (pg. 196, claim 1(d), lines 1-2, wherein the minimum amount of cfDNA fragments comprised within a sample to be analyzed is between 100 thousand to 500 thousand, 500 thousand to 1 million, 1 million to 2 million, 2 million to 5 million, or 5 million to 10 million, or 10 million to 20 million, or 20 million to 50 million, or 50 million to 500 million (claim 7)). This suggests that the amount of cell-free nucleic acid comprised within a sample to be analyzed or sequenced can be any of the thousands or millions listed above, which are within the ranges as described in the limitation.
With respect to claim 9:
Namsaraev et al. discloses “The terms “control,” “control sample,” “reference,” “reference sample,” “normal,” and “normal sample” can be used to describe a sample from a subject that does not have a particular condition, or is otherwise healthy. In an example, a method as disclosed herein can be performed on a subject having a tumor, where the reference sample is a sample taken from a healthy tissue of the subject.” (pg. 33, para. [00137], lines 1-5, wherein the reference samples can be samples from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients (claim 9)). This suggests that reference samples can be samples from cancer free patients.
With respect to claim 10:
Namsaraev et al. discloses “In some embodiments, the method comprises performing massively parallel sequencing on the cell-free nucleic acid molecules to generate sequence reads. In some embodiments, the method comprises determining an amount of the sequence reads that align to a reference genome” (pg. 10, para. [0015], lines 4-7, wherein step (i) comprises the determination of the nucleic acid sequence of at least a portion of the plurality of cfDNA fragments in the sample prior to the alignment to a reference sequence (claim 10)). This suggests determining nucleic acid sequence reads of at least a portion of cell-free nucleic acid fragments before alignment to a reference sequence.
With respect to claim 11:
Namsaraev et al. discloses “sequencing after target enrichment” (pg. 115, para. [00452], lines 3-6, wherein step (i) further comprises the enrichment of cfDNA fragments prior to the determination of the nucleic acid sequence of cfDNA fragments (claim 11)). This suggests enrichment of cfDNA fragments before determination of sequences.
With respect to claim 12:
Namsaraev et al. discloses “In some embodiments, the pathology is selected from the group consisting of bladder cancer, bone cancer, a brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, hematopoietic malignancy, leukemia, liver cancer, lung cancer, lymphoma, myeloma, nasal cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, ovarian cancer, prostate cancer, sarcoma, stomach cancer, and thyroid cancer.” (pg. 10, para. [0015], lines 18-23, wherein the sample is classified as comprising tumor cfDNA originating from a tumor selected from the group of blood cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, glioblastoma, colorectal cancer, head and neck cancer, a solid tumor, a benign tumor, a malignant tumors, an advanced stage of cancer, a metastasis or a precancerous tissue (claim 12)). This suggests that the sample is classified as comprising cell-free nucleic acid samples originating from a tumor caused by the listed pathologies.
Response to Arguments
Applicant’s arguments, see pages 12-14, filed 7/27/2026, with respect to the rejection(s) of claim(s) 1, 7, and 9-12 under 35 U.S.C. § 103 have been fully considered and are persuasive in part.
With respect to the Applicant’s argument that Jiang et al. and Heitzer et al. both fail to teach or suggest “determining the frequency of each coordinate determined in (i) in the plurality of cfDNA fragments comprised in the sample, wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i)” (pg. 13 of Applicant’s Remarks), this argument is not persuasive. Namsaraev et al. discloses that detectable “ending positions” or “end positions” can represent the biologically true end or the end is one or more nucleotides inwards or one or more nucleotides extended from the original end of the molecule e.g., 5’ blunting and 3’ filling of overhangs of non-blunt-ended double stranded DNA molecules by the Klenow fragment (pg. 38-39, para. [00156], lines 1-16). This teaches that frequencies can be determined for each coordinate while excluding the true end coordinate. Therefore, neither Jiang et al. nor Heitzer et al. is required to teach or suggest this limitation as it is taught in Namsaraev et al. See above.
With respect to the Applicant’s argument that Heitzer et al. does not calculate a weighted sum of single-nucleotide coordinate frequency ratios (pg. 13-14 of Applicant’s Remarks), this argument is persuasive. Therefore, the rejection to claims 1, 7, and 9-12 under 35 U.S.C. 103 as being unpatentable over Namsaraev et al. [WO2018081130A1], in view of Jiang et al. (Proceedings of the National Academy of Sciences, 2018, 115(46), E10925-E10933), as provided in the IDS filed 6/15/2023, and Heitzer et al. (Genome Medicine, 2013, 5(30), 1-16), is withdrawn. However, it was determined that Namsaraev et al. and Jiang et al. do teach the limitations. See above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. 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, 7, and 10-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 7-9 of U.S. Patent No. 18/267,622. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of U.S. Patent No. 18/267,622.
Regarding claim 1:
Regarding the recited method of classifying a sample as comprising cell-free tumor DNA, claim 1 of ‘622 discloses “a method of classifying a sample as comprising cell-free tumor DNA”.
Regarding the recited (i) determining in a sample comprising a plurality of cell-free DNA (cfDNA) fragments the sequence coordinates of the start and/or stop, and of the start and/or stop plus and/or minus 1 base pair, of at least 100,000 cfDNA fragments by alignment to a reference sequence, claim 1 of ‘622 discloses “i) determining in a sample comprising a plurality of cell-free DNA (cfDNA) fragments the sequence coordinates of the start and/or stop of at least 100,000 cfDNA fragments by alignment to a reference sequence”. Also, claim 1 of ‘622 discloses “iii) determining the frequency of: a) each sequence coordinate plus and/or minus 1 base pair determined in (i) in the plurality of cfDNA fragments comprised in the sample”.
Regarding the recited (ii) determining the frequency of each coordinate determined in (i) in the plurality of cfDNA fragments comprised in the sample, wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i), claim 1 of ‘622 discloses “iii) determining the frequency of a) each sequence coordinate plus and/or minus 1 base pair determined in (i) in the plurality of cfDNA fragments comprised in the same”. Also, claim 1 of ‘622 discloses “wherein the determination step (ii) excludes the start and/or stop sequence coordinate determined in (i)”.
Regarding the recited (iii) calculating the ratio of the frequency of each coordinate determined in (ii) over a corresponding reference frequency, claim 1 of ‘622 discloses “iv) calculating the ratio of each of the frequencies determined in (iii) a) and (iii) b) over a corresponding reference frequency”.
Regarding the recited (iv) calculating a diagnostic score from all ratios determined in (iii) said score being the weighted sum of all frequency ratios determined in (iii), claim 1 of ‘622 discloses “v) calculating a diagnostic score separately for each ratio determined in step (iv), said score being the respective weighted sum of all respective frequency ratios of step (iv)”.
Regarding the recited (v) determining a classification of the sample by comparing the diagnostic score to a reference score, wherein the sample is classified as comprising tumor cfDNA, if the diagnostic score value is higher than the mean of the reference score by at least one standard deviation of the reference score, wherein the reference score is calculated from one or more reference values, claim 1 of ‘622 discloses “vii) determining a classification of the sample by comparing the combined diagnostic score to a reference score, wherein the sample is classified as comprising tumor cfDNA, if the combined diagnostic score value is higher than the mean of the reference score by at least one standard deviation of the reference score, wherein the reference score is calculated from one or more reference values”.
Regarding claim 7:
Regarding the recited wherein the minimum amount of cfDNA fragments comprised within a sample to be analyzed is between 100 thousand to 500 thousand, 500 thousand to 1 million, 1 million to 2 million, 2 million to 5 million, or 5 million to 10 million, or 10 million to 20 million, or 20 million to 50 million, or 50 million to 500 million, claim 4 of ‘622 discloses “wherein the minimum amount of cfDNA fragments comprised within a sample to be analyzed is between 100 thousand to 500 thousand, 500 thousand to 1 million, 1 million to 2 million, 2 million to 5 million, or 5 million to 10 million, or 10 million to 20 million, or 20 million to 50 million, or 50 million to 500 million”.
Regarding claim 10:
Regarding the recited wherein step (i) comprises the determination of the nucleic acid sequence of at least a portion of the plurality of cfDNA fragments in the sample prior to the alignment to a reference sequence, claim 7 of ‘622 discloses “wherein step (i) comprises the determination of the nucleic acid sequence of at least a portion of the plurality of cfDNA fragments in the sample prior to the alignment to a reference sequence”.
Regarding claim 11:
Regarding the recited wherein step (i) further comprises the enrichment of cfDNA fragments prior to the determination of the nucleic acid sequence of cfDNA fragments, claim 8 of ‘622 discloses “wherein step (i) further comprises the enrichment of cfDNA fragments prior to the determination of the nucleic acid sequence of cfDNA fragments”.
Regarding claim 12:
Regarding the recited wherein the sample is classified as comprising tumor cfDNA originating from a tumor selected from the group of blood cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, glioblastoma, colorectal cancer, head and neck cancer, a solid tumor, a benign tumor, a malignant tumor, an advanced stage of cancer, a metastasis or a precancerous tissue, claim 9 of ‘622 discloses “wherein the sample is classified as comprising tumor cfDNA originating from a tumor selected from the group of blood cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, glioblastoma, colorectal cancer, head and neck cancer, a solid tumor, a benign tumor, a malignant tumors, an advanced stage of cancer, a metastasis or a precancerous tissue”.
Therefore, the invention as recited in claims 1, 7, and 10-12 is prima facie obvious over U.S. Patent No. 18/267,622. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method of classifying a sample as comprising cell-free tumor DNA according to the limitations recited in claims 1, 7, and 10-12 of the instant application based on claims 1, 4, and 7-9 of U.S. Patent No. 18/267,622.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments, see page 14, filed 7/27/2026, have been fully considered but they are not persuasive.
Applicant did not present any arguments and has requested that the rejection be held in abeyance until allowable subject matter (pg. 14 of Applicant’s Remarks). This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to MPEP § 804(I)(B)(1), as stated above from the previous rejection. Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jammy Luo whose telephone number is (571)272-2358. The examiner can normally be reached Monday - Friday, 9:00 AM - 5:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D Riggs can be reached at (571)270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.N.L./Examiner, Art Unit 1686
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
