DETAILED ACTION
It is noted that the examiner and art unit of record have changed since the previous Office 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 .
Election/Restrictions
Applicant’s election of Group I, claims 1, 7, and 9-12 drawn to a method of classifying a sample as comprising cell-free tumor DNA in the reply filed on 1/16/2026 is acknowledged. Because applicant did not include any details regarding Group III, the response is therefore incomplete and the election has been treated as an election without traverse (MPEP § 818.01(a)). The traversal is on the ground(s) that the special technical feature of the pending claims for Groups I and II is not determining the coordinates of start and/or stop of a cfDNA sequence aligned to a reference sequence, but rather determining a classification of the sample by comparing the diagnostic score to a reference score. Applicant argues that Lo et al. [US20190341127A1] fails to teach comparing the diagnostic score to a reference score and calculating a diagnostic score as described in the current claims. Thus, the submitted technical feature of Groups I and II define a contribution that the claimed subject matter makes over the prior art.
This is not found persuasive because Heitzer et al. discloses “Resulting normalized ratios were segmented using circular binary segmentation (CBS) [47] and GLAD [48] by applying the CGHweb [49] framework in R [50]. These segments were used for calculation of the segmental z-scores by adding GC-corrected read-count ratios (read-counts in window divided by mean read-count) of all the windows in a segment. Z-scores were calculated by subtracting mean sum of GC-corrected read-count ratios of individuals without cancer (10 for men and 9 for women) of same sex and dividing by their standard-deviation” (pg. 4, col. 1, para. 3, lines 1-10). This suggests a diagnostic score being calculated by adding normalized GC-corrected read-count ratios, later used in calculating for segmental z-scores.
Heitzer et al. also discloses “Z-scores were calculated by subtracting mean sum of GC-corrected read-count ratios of individuals without cancer (10 for men and 9 for women) of same sex and dividing by their standard-deviation” (pg. 4, col. 1, para. 3, lines 7-10). Also, further discloses “Plasma-Seq from these patients exhibited a wide range of copy number aberrations indicative of malignant origin, including those that have been previously reported in prostate tumors. For example, the three CRPC patients (that is, CRPC2-3, CRPC5) had high-level gains in a region on chromosome x including the AR locus. Over-representation of 8q regions was observed in all five patients and loss of 8p regions in three patients (CRPC5, CSPC2, and CSPC4) (Figure 3c).” (pg. 9, col. 1, para. 2, lines 1-9). This suggests that the diagnostic score is compared to a reference score calculated from GC-corrected read-count ratios of individuals without cancer through segmental z-scores. Heitzer et al. discloses “Accordingly, the genome-wide z-score was elevated for all prostate cancer patients and ranged from 125.14 (CRPC4) to 1155.77 (CSPC2) (see Additional file 1, Table S2). Furthermore, when we performed hierarchical clustering the normal samples were separated from the tumor samples (Figure 3b), suggesting that we can indeed distinguish plasma samples from individuals without malignant disease from those with prostate cancer.” (pg. 8, col. 2, para. 1, lines 6-13). This further supports that an individual is classified as comprising plasma samples indicative of malignant origin because a diagnostic score is higher than the mean of the reference score by at least one standard deviation of the reference score, described as an elevated z-score. Thus, the special technical feature is taught or suggested by Heitzer et al.
The requirement is still deemed proper and is therefore made FINAL.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on1/16/2026.
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.
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, 9-10, and 12 is 12/18/2020
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/15/2023 and 9/6/2023 are in compliance with the provisions of 37 CFR 1.97. A signed copy of the corresponding 1449 form has been included with this Office action.
Specification
Abstract exceeds 150 words and includes legal language such as “said” in line 6. Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Objections
Claim 12 is objected to because of the following informalities:
In claim 12, line 5, "a malignant tumors" should read as "a malignant tumor".
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation "the reference samples" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. It is unclear what the reference samples are and which steps in the method of claim 1 the reference samples are referred to. The rejection might be overcome by amending the claim to introduce clear antecedent basis for “the reference samples”. For compact prosecution, it is assumed that the preceding suggested will be implemented.
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.
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:
classifying a sample as comprising cell-free tumor DNA (i.e., mental processes);
(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 (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).
Dependent claim 9 further recites:
wherein the reference samples can be samples from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients (i.e., mental processes).
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).
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).
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 tumors, an advanced stage of cancer, a metastasis or a precancerous tissue (i.e., mental processes, laws of nature).
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 noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pencil and paper, and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. 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.
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, 9-10, and 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, 9-10, and 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, 9-10, and 12 are patent ineligible under 35 U.S.C. § 101.
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.
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, and Heitzer et al. (Genome Medicine, 2013, 5(30), 1-16).
With respect to claim 1:
Namsaraev et al. discloses “Methods are provided to improve the positive predictive value for cancer detection using cell-free nucleic acid samples.” (Section “Abstract”, line 1, method of classifying a sample as comprising cell-free tumor DNA (claim 1)). This suggests a method of classifying a sample as comprising cell-free nucleic acid samples from a tumor by using a positive predictive value for cancer detection.
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, (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)). 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). This suggests 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.
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 describes determining frequency plots for tumor- or nontumor-associated preferred end coordinates in cell-free DNA.
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 suggests 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.
Namsaraev et al. and Jiang et al. do 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, Heitzer et al. discloses “Resulting normalized ratios were segmented using circular binary segmentation (CBS) [47] and GLAD [48] by applying the CGHweb [49] framework in R [50]. These segments were used for calculation of the segmental z-scores by adding GC-corrected read-count ratios (read-counts in window divided by mean read-count) of all the windows in a segment. Z-scores were calculated by subtracting mean sum of GC-corrected read-count ratios of individuals without cancer (10 for men and 9 for women) of same sex and dividing by their standard-deviation” (pg. 4, col. 1, para. 3, lines 1-10). This suggests a diagnostic score being calculated by adding normalized GC-corrected read-count ratios, later used in calculating for segmental z-scores.
Namsaraev et al. and Jiang et al. do 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, Heitzer et al. discloses “Z-scores were calculated by subtracting mean sum of GC-corrected read-count ratios of individuals without cancer (10 for men and 9 for women) of same sex and dividing by their standard-deviation” (pg. 4, col. 1, para. 3, lines 7-10). Also, further discloses “Plasma-Seq from these patients exhibited a wide range of copy number aberrations indicative of malignant origin, including those that have been previously reported in prostate tumors. For example, the three CRPC patients (that is, CRPC2-3, CRPC5) had high-level gains in a region on chromosome x including the AR locus. Over-representation of 8q regions was observed in all five patients and loss of 8p regions in three patients (CRPC5, CSPC2, and CSPC4) (Figure 3c).” (pg. 9, col. 1, para. 2, lines 1-9). This suggests that the diagnostic score is compared to a reference score calculated from GC-corrected read-count ratios of individuals without cancer through segmental z-scores. Heitzer et al. discloses “Accordingly, the genome-wide z-score was elevated for all prostate cancer patients and ranged from 125.14 (CRPC4) to 1155.77 (CSPC2) (see Additional file 1, Table S2). Furthermore, when we performed hierarchical clustering the normal samples were separated from the tumor samples (Figure 3b), suggesting that we can indeed distinguish plasma samples from individuals without malignant disease from those with prostate cancer.” (pg. 8, col. 2, para. 1, lines 6-13). This further supports that an individual is classified as comprising plasma samples indicative of malignant origin because a diagnostic score is higher than the mean of the reference score by at least one standard deviation of the reference score, described as an elevated z-score.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method disclosed by Namsaraev et al. to incorporate the teachings disclosed by Jiang et al. and Heitzer et al. One would be motivated to make this modification 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). Furthermore, Heitzer et al. also discloses that tests for sensitivity and specificity of their approach suggested that tumor DNA concentrations at levels
≥
10% can be detected with a sensitivity of >80% and specificity of 80% (pg. 12, col. 2, para. 2, lines 1-4). There is a likelihood of success, since these are all teachings 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.
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 9-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 6-9 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.a. of ‘622 discloses “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.c.i. of ‘622 discloses “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, claim 1.c.i. of ‘622 discloses “determining the frequency of each sequence coordinate plus and/or minus 1 base pair determined in (i) in the plurality of cfDNA fragments comprised in the same”.
Regarding the recited (iii) calculating the ratio of the frequency of each coordinate determined in (ii) over a corresponding reference frequency, claim 1.d. of ‘622 discloses “calculating the ratio of each of the frequencies determined in (iii) a) and 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.e. of ‘622 discloses “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.g. of ‘622 discloses “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 9:
Regarding the recited wherein the reference samples can be samples from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients, claim 6 of ‘622 discloses “wherein the reference samples can be samples from cancer free patients, or from non-relapsed patients, or from successfully treated cancer patients”.
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 tumors, 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 9-12 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 9-12 of the instant application based on claims 1, 4, and 6-9 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.
Conclusion
No claims are allowed.
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/J.N.L./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
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