DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 43-61 pending and examined on the merits.
Claims 1-42 cancelled.
Priority
The instant application filed on 10/10/2022 is a CON of U.S. Application No. 15/661,942 filed on 7/27/2017 (patent granted 11/29/2022), and claims the benefit of priority to U.S. Provisional Patent Application No. 62/481,528 filed on 4/4/2017 and U.S. Provisional Patent Application No. 62/367,554 filed on 7/27/2016. Thus, the effective filing date of the claims is 7/27/2016.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Information Disclosure Statement
The IDS forms filed on 9/2/2025 have been entered and considered. A signed copy of the corresponding 1449 form with any deficiencies noted has been included with this Office action. The information disclosure statement filed 9/2/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. Specifically, the Non-Patent Literature Documents Cite No 45 and 59 are not provided.
Specification
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 instant abstract consists of only 25 words. A compliant description of the disclosure to assist readers in deciding whether there is a need for consulting the full patent text for details is required. Appropriate correction is required.
Claim Objections
Claim 43, 49, 53, and 61 objected to because of the following informalities:
Claim 43 lines 8-9, "with chromosome-specific shading. representing" should read "with chromosome-specific shading representing".
Claim 48 line 5, "to generate sequence reads quantification" should read "to generate sequence reads quantification,".
Claim 48 line 7, "thereby generating adjusted sequence read quantification," should read "thereby generating adjusted sequence read quantification, and".
Claim 49 line 2, "a baseline adjusted sequence read quantifications" should read "a baseline adjusted sequence read quantification".
Claim 53 lines 2-3 "summing the modified products, absolute values of the modified products, subtraction products or absolute values of the subtraction products" should read "summing the modified products, absolute values of the modified products, subtraction products, or absolute values of the subtraction products".
Claim 61 lines 1-2, "A method of evaluating the clinical effectiveness of a cancer therapy treatment comprising" should read "A method of evaluating the clinical effectiveness of a cancer therapy treatment comprising:". Also, lines 3-4 the step labels "a)" and "b)" should read "(a)" and "(b)" in order to be consistent with the formatting of claims 43 and 48.
Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
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.
Claims 43-61 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.
Claims 43, 46, 48, and 55-56 are apparently referring back to the "sequence read quantifications" as recited in step (a) of claims 43 or 48, but the phrase is recited as either “sequence reads quantification” or “sequence read quantification”, therefore the antecedent basis of the terms is not clear. These references should be corrected according to the phrasing suggested below.
Claim 43 recites "(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence read quantifications, (b) adjusting the sequence read quantification to reduce experimental bias, thereby generating adjusted sequence read quantifications". It is not clear which "sequence read quantification" (or quantifications) from the "plurality of genomic portions of a reference genome" of step (a) is being adjusted, or if all of them are to be adjusted. Examiner suggests the following phrasing: "(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate a sequence read quantification for each of the plurality of genomic portions, (b) adjusting each sequence read quantification to reduce experimental bias, thereby generating an adjusted sequence read quantification for each of the plurality of genomic portions".
Claims 43 and 50 recite "determining the absolute deviation from expectation for genomic portions in each of the one or more autosomes" (claim 43) and "determining the absolute value of the modified product or the subtraction product for each of the genomic portions" (claim 50). There is a lack of antecedent basis for "the absolute deviation" and "the absolute value" in the recited limitations. Examiner suggests amending both instances to "an" absolute deviation or value.
Claims 43 recites "determining the absolute deviation from expectation for genomic portions in each of the one or more autosomes". It is not clear what "expectation" is being deviated from in this limitation. The only mention of an "expectation" in the instant specification is in reference to Figure 18 which "shows a genome profile with deviation from expectation", and the y-axis is labeled "relative coverage". Therefore, to further prosecution, the deviation from expectation is interpreted as a deviation from an expected sequence read coverage.
Claim 48 recites "(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence reads quantification, (b) adjusting the sequence reads quantification to reduce experimental bias, thereby generating adjusted sequence read quantification, (c) modifying the adjusted sequence read quantifications". There is insufficient antecedent basis for “the adjusted sequence read quantifications” in (c) because (b) only requires generated “adjusted sequence read quantification”. As a result, it is not clear if a single quantification is being generated for the "plurality of genomic portions of a reference genome" or if there should be a sequence read quantification per genomic portion. Additionally, in step (b), it is not clear which "sequence reads quantification" from the "plurality of genomic portions of a reference genome" of step (a) is being adjusted (if multiple quantifications are carried out), or if all of them are to be adjusted. Examiner suggests the following phrasing: "(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate a sequence read quantification for each of the plurality of genomic portions, (b) adjusting each sequence read quantification to reduce experimental bias, thereby generating an adjusted sequence read quantification for each of the plurality of genomic portions".
Claim 49 recites "the generating a genomic instability number". There is a lack of antecedent basis for "the generating" of a genomic instability number because claim 48 does not recite a step of generating a genomic instability number. Additionally, claim 48 does not require "quantifications for each of the genomic portions", and therefore "the adjusted sequence read quantifications" lacks antecedent basis as well (however if claim 48 is amended as suggested, this phrasing in claim 49 will be consistent).
Claim 52 recites "scaling the sequence read quantifications for the genomic portions to the average, centered value or representative value of the sequence read quantifications". There is a lack of antecedent basis for "the average, centered value or representative value of the sequence read quantifications".
Claim 53 recites "the generating a genomic instability classification". There is a lack of antecedent basis for "the generating" of a genomic instability classification because claim 48 does not recite a step of generating a genomic instability classification.
Claim 54 recites "whereby the sequence read quantifications in (b) is the GC normalized quantification of sequence reads". Related to claim 48, as currently written, there are not multiple "sequence read quantifications" as referred to in claim 54 (only a "sequence reads quantification"). Additionally, because the quantifications referred to in claim 54 are being normalized, this term likely should read "the adjusted sequence read quantifications".
Claim 57 recites "wherein the subject is diagnosed with a cell proliferative condition according to the genomic instability number, and the subject is selected for a treatment of the cell proliferative condition according to the genomic instability number", which is recited more as an intended result of an analysis of the genomic instability number, rather than requiring a step of analyzing/comparing the genomic instability number to determine a diagnosis and selection of the subject for a treatment. The limiting effect of the wherein clause is not clear because it's not clear if the diagnosing and selecting is an intended result of the genomic instability number, or if Applicant intends for the claim to further comprise a step of determining a diagnosis and selection of the subject for a treatment based on an analysis of the genomic instability number.
Claim 58 recites "wherein the genomic instability number is generated for the subject at two or more time points during the treatment, and (i) the subject is identified as a responder to the treatment if after a time point of about 6 weeks to about 8 weeks of treatment the genomic instability number is less than a threshold value, or (ii) the subject is identified as a non-responder to the treatment if after the time point of treatment the genomic instability number is greater than the threshold value", which is recited more as an intended result of an analysis of the genomic instability number, rather than requiring a step of analyzing/comparing the genomic instability number to determine a responder category. The limiting effect of the wherein clause is not clear because it's not clear if the determination of responder category is an intended result of the genomic instability number generation at multiple time points during the treatment, or if Applicant intends for the claim to further comprise a step of determining a responder category based on an analysis of the genomic instability number at multiple time points.
All other claims depend from independent claims 43 and 48, and therefore are also rejection as being indefinitely under 35 USC 112(b).
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 43-61 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claims 43 and 61: “(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence read quantifications” provides an evaluation (mapping and quantifying sequence reads) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“(b) adjusting the sequence read quantification to reduce experimental bias, thereby generating adjusted sequence read quantifications”, “(d) determining the absolute deviation from expectation for genomic portions in each of the one or more autosomes”, and “(f) summing the areas representing the absolute deviation from expectation for genomic portions in one or more autosomes, thereby determining a genomic instability number (GIN) for the test sample” provides a mathematical calculation (normalizing read counts, and calculating deviations and sums) that is considered a mathematical concept, which is an abstract idea.
“(c) generating a genome profile plot of the nucleic acid sample with chromosome-specific shading. representing the adjusted sequence read quantifications in one or more autosomes” provides an evaluation (analyzing data and drawing graphical representations) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“(e) determining an area representing the absolute deviation from expectation for genomic portions in each of the one or more autosomes” provides an evaluation (determining deviant areas in autosomes) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 44: “the sample nucleic acid from the subject is circulating cell free nucleic acid” further limits the mental process abstract idea (mapping and quantifying sequence reads) of claim 43.
Claim 45: “the sample nucleic acid from the subject is a liquid biopsy sample” further limits the mental process abstract idea (mapping and quantifying sequence reads) of claim 43.
Claim 46: “adjusting the sequence read quantification is performed by one or more of SPCA, a GC normalization process, and a smoothing process” further limits the mathematical concept abstract idea (normalizing read counts) of claim 43.
Claim 47: “adjusting the sequence read quantifications are performed by SPCA” further limits the mathematical concept abstract idea (normalizing read counts) of claim 43.
Claim 48: “(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence reads quantification” provides an evaluation (mapping and quantifying sequence reads) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“(b) adjusting the sequence reads quantification to reduce experimental bias, thereby generating adjusted sequence read quantification, [and] (c) modifying the adjusted sequence read quantifications according to a baseline adjusted sequence read quantification for each of the genomic portions, thereby providing a modified product for each of the genomic portions” provides a mathematical calculation (normalizing and modifying read counts) that is considered a mathematical concept, which is an abstract idea.
Claim 49: “the generating a genomic instability number comprises subtracting a baseline adjusted sequence read quantifications from the adjusted sequence read quantifications for each of the genomic portions, thereby providing a subtraction product for each of the genomic portions” further limits the mathematical concept abstract idea (modifying read counts) of claim 48.
Claim 50: “determining the absolute value of the modified product or the subtraction product for each of the genomic portions” further limits the mathematical concept abstract idea (modifying read counts) of claim 48.
Claim 51: “the baseline is (i) an average sequence read quantifications for the genomic portions, (ii) a centered value of the sequence read quantifications for the genomic portions, or (iii) a representative value of the sequence read quantifications for the genomic portions” further limits the mathematical concept abstract idea (modifying read counts) of claim 48.
Claim 52: “scaling the sequence read quantifications for the genomic portions to the average, centered value or representative value of the sequence read quantifications” further limits the mathematical concept abstract idea (modifying read counts) of claim 48.
Claim 53: “the generating a genomic instability classification comprises summing the modified products, absolute values of the modified products, subtraction products or absolute values of the subtraction products for the genomic portions, thereby providing a genomic instability number” provides a mathematical calculation (summing products) that is considered a mathematical concept, which is an abstract idea.
Claim 54: “the adjusting comprises normalizing the quantification of sequence reads by a guanine-cytosine (GC) normalizing process that generates a GC normalized quantification of sequence reads for each of the genomic portions, whereby the sequence read quantifications in (b) is the GC normalized quantification of sequence reads” further limits the mathematical concept abstract idea (normalizing read counts) of claim 48.
Claim 55: “the adjusting the sequence read quantification is performed by one or more of SPCA, a GC normalization process, and a smoothing process” further limits the mathematical concept abstract idea (normalizing read counts) of claim 48.
Claim 56: “the adjusting the sequence read quantification is performed SPCA” further limits the mathematical concept abstract idea (normalizing read counts) of claim 48.
Claim 57: “the subject is diagnosed with a cell proliferative condition according to the genomic instability number, and the subject is selected for a treatment of the cell proliferative condition according to the genomic instability number” provides an evaluation (diagnosing and selecting a subject) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 58: “the genomic instability number is generated for the subject at two or more time points during the treatment, and (i) the subject is identified as a responder to the treatment if after a time point of about 6 weeks to about 8 weeks of treatment the genomic instability number is less than a threshold value, or (ii) the subject is identified as a non-responder to the treatment if after the time point of treatment the genomic instability number is greater than the threshold value” provides an evaluation (comparing GIN to a threshold to determine response category) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 59: “the cell proliferative disorder is a cancer” further limits the mental process abstract idea (diagnosing the subject) of claim 57.
Claim 60: “the treatment comprises administering at least one of an immunotherapeutic” further limits the mental process abstract idea (selecting a subject for a treatment) of claim 57.
Claim 61: “generating GINs corresponding to samples from two or more time points during the treatment, wherein a decrease in GIN during the treatment indicates that the treatment is effective” provides an evaluation (comparing GIN values between time points to determine response category) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 43-61 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claim 61: “obtaining two or more nucleic acid samples from two or more time points during the treatment” provides insignificant extra-solution activities (obtaining samples is a pre-solution activity involving sample gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
The step for obtaining samples is an insignificant extra-solution activity that do not serve to integrate the recited judicial exceptions into a practical application because it is a pre-solution activity involving sample gathering steps (see MPEP 2106.04(d)(2)). Therefore, claims 43-61 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). Furthermore, no inventive concept is claimed by these limitations as they are demonstrated to be well-understood, routine, and conventional by:
Van Dongen et al. ("The continuing value of twin studies in the omics era." Nature Reviews Genetics 13.9 (2012): 640-653); Page 640 col 1 paragraph 2 "Twin designs can provide insight into the genetic aetiology of disease development over time and can aid in the detection of biomarker profiles for medical conditions" and page 640 col 2 paragraph 2 "This Review addresses the continuing value of twin studies. We describe various twin study designs with examples of traditional applications, and we describe how twin approaches are now used for tracing disease-causing mutations and for studying various other newly emerging phenotypes (for example, the epigenome, transcriptome, metabolome, proteome and microbiome)"
Soon et al. ("High-throughput sequencing for biology and medicine." Molecular systems biology 9 (2013): 640); Page 3 Figure 1 legend "Dimensionality of the genome. The understanding of the human genome has expanded with advances of sequencing technologies, from (A) 1D sequencing of the human genome to (B) 2D mapping of SVs using methods such as paired-end sequencing, (C) 3D genome-wide chromosomal conformation capture using ChIA-PET and Hi-C, and (D) four dimensions across time"
Therefore, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional insignificant extra-solution activities.
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 43-61 are not patent eligible.
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.
Claims 43-45, 48-53, and 57-61 rejected under 35 U.S.C. 103 as being unpatentable over Chudova et al. (WO-2016094853).
Regarding Claims 43 and 61, Chudova teaches steps (a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate a sequence read quantification for each of the plurality of genomic portions, and (b) adjusting each sequence read quantification to reduce experimental bias, thereby generating an adjusted sequence read quantification for each of the plurality of genomic portions (as interpreted above) (Para.0470-471 and Figure 2D depicts the mapping, counting, and normalization steps described in limitations (a) and (b)).
Chudova also teaches step (c) generating a genome profile plot of the nucleic acid sample (Para.0256 "Figure 3B illustrates the coverage across chromosomes 21, 13, and 18 for many samples" suggests plotting a genome profile of position (x) by normalized read counts (y)).
Chudova also teaches step (d) determining the absolute deviation from expectation for genomic portions in each of the one or more autosomes (Para.0221 "The global profile comprises an expected parameter value in each bin obtained from a training set of unaffected training samples", para.0250 "The normalized and corrected coverage quantities are then noted for each bin and statistics such as standard deviation, median absolute deviation, and/or coefficient of variation are calculated for each bin", and para.0018 "the method further includes: providing a global size profile for the bins of the sequence of interest, wherein the global size profile comprises expected values of a size parameter in at least bins of the sequence of interest, and wherein the expected values of the size parameter is obtained from lengths of cell-free nucleic acid fragments in a training set of unaffected training samples comprising nucleic acids sequenced and aligned in substantially the same manner as the nucleic acid fragments of the test sample, the expected size parameter exhibiting variation from bin to bin" suggests determining a deviation from expected coverage per bin).
Chudova also teaches step (e) determining an area representing the absolute deviation from expectation for genomic portions in each of the one or more autosomes (Para.0256 "Figure 3B illustrates the coverage across chromosomes 21, 13, and 18 for many samples", and para.0256 suggests determining an area representing the deviation of expected sequence read coverage).
Chudova also teaches step (f) summing the areas representing the absolute deviation from expectation for genomic portions in one or more autosomes, thereby determining a genomic instability number (GIN) for the test sample (Para.0471 "4) combining features and scoring for aneuploidy detection" and para.0472 "The final score for fetal aneuploidy detection in the combined case was defined as the square root of the sum of squares of the two individual t-statistics, and a single threshold was applied to generate a call of "aneuploidy detected" versus "aneuploidy not detected"").
Chudova does not explicitly teach generating a genome profile plot of the nucleic acid sample with chromosome-specific shading representing the adjusted sequence read quantifications in one or more autosomes.
However, the chromosome-specific shading is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to the genome profile plot, as shown by Chudova. Therefore, the figure illustrating chromosome coverage shown by Chudova would perform equally as well in representing sequence read quantifications per chromosome in a plot, and such a modification fails to patentably distinguish over Chudova.
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the genomic profile plotting methods of Chudova with chromosome-specific shading in order to represent sequence read quantifications per chromosome in the plot. One skilled in the art would have a reasonable expectation of success because both methods are concerned with mapping, quantifying, and normalizing genome sequence reads for measuring genomic instability.
Regarding Claim 44, Chudova teaches the sample nucleic acid from the subject is circulating cell free nucleic acid (Para.0377 "Identification of genomic instabilities associated with cancers that can be determined in the circulating cfDNA in cancer patients is a potential diagnostic and prognostic tool").
Regarding Claim 45, Chudova teaches the sample nucleic acid from the subject is a liquid biopsy sample (Para.0069 "Such samples include, but are not limited to sputum/oral fluid, amniotic fluid, blood, a blood fraction, or fine needle biopsy samples (e.g., surgical biopsy, fine needle biopsy, etc.), urine, peritoneal fluid, pleural fluid, and the like").
Regarding Claims 48-49, Chudova teaches steps (a) and (b) similar to claim 43 (Para.0470-471 and Figure 2D depicts the mapping, counting, and normalization steps described in limitations (a) and (b)).
Chudova also teaches the claim 49 limitation of: the generating a genomic instability number comprises subtracting a baseline adjusted sequence read quantifications from the adjusted sequence read quantifications for each of the genomic portions, thereby providing a subtraction product for each of the genomic portions, which is a narrower limitation of step (c) of claim 48 (Para.0221 "In some embodiments, operation 2010 adjusts the normalized value of the parameter by subtracting the expected value of the parameter from the normalized value of the parameter").
Regarding Claims 50-51, Chudova teaches: determining the absolute value of the modified product or the subtraction product for each of the genomic portions; and the baseline is (i) an average sequence read quantifications for the genomic portions, (ii) a centered value of the sequence read quantifications for the genomic portions, or (iii) a representative value of the sequence read quantifications for the genomic portions (Para.0250 "The normalized and corrected coverage quantities are then noted for each bin and statistics such as standard deviation, median absolute deviation, and/or coefficient of variation are calculated for each bin").
Regarding Claim 52, Chudova teaches scaling the sequence read quantifications for the genomic portions to the average, centered value or representative value of the sequence read quantifications (Para.0253 "After the system computationally masks the bins, it computationally normalizes the coverage values in the bins that are not excluded by the masks [. . .] In some cases, the system normalizes the test sample coverage values (per bin) by dividing the count for the bin under consideration by the total number of all non-excluded sites aligning to all robust chromosomes in the reference genome. In some embodiments, the system normalizes the test sample coverage values (per bin) by performing a linear regression").
Regarding Claim 53, Chudova teaches the generating a genomic instability classification comprises summing the modified products, absolute values of the modified products, subtraction products, or absolute values of the subtraction products for the genomic portions, thereby providing a genomic instability number (Para.0472 "The final score for fetal aneuploidy detection in the combined case was defined as the square root of the sum of squares of the two individual t-statistics, and a single threshold was applied to generate a call of "aneuploidy detected" versus "aneuploidy not detected"").
Regarding Claim 57, Chudova teaches the subject is diagnosed with a cell proliferative condition according to the genomic instability number, and the subject is selected for a treatment of the cell proliferative condition according to the genomic instability number (Para.0423 "based on the results of the processor-implemented analysis, the method may further involve prescribing, initiating, and/or altering treatment of a human subject").
Regarding Claim 58, Chudova teaches the genomic instability number is generated for the subject at two or more time points during the treatment, and (i) the subject is identified as a responder to the treatment if after a time point of about 6 weeks to about 8 weeks of treatment the genomic instability number is less than a threshold value, or (ii) the subject is identified as a non-responder to the treatment if after the time point of treatment the genomic instability number is greater than the threshold value (Para.0015 "In some implementations, the method further involves using a copy number variation in the cancer genome to diagnose cancer, monitor the progress of cancer, and/or determine a treatment for cancer" and para.0382 suggests comparing genomic instability results (number of called CNVs in this case) to a reference value).
Regarding Claim 59, Chudova teaches the cell proliferative disorder is a cancer (Para.0377 "Identification of genomic instabilities associated with cancers that can be determined in the circulating cfDNA in cancer patients is a potential diagnostic and prognostic tool").
Regarding Claim 60, Chudova teaches the treatment comprises administering at least one of an immunotherapeutic (Para.0133 "CNV in the human genome significantly influence human diversity and predisposition to diseases (Redon et al., Nature 23 :444-454 [2006], Shaikh et al. Genome Res 19: 1682-1690 [2009]). Such diseases include, but are not limited to cancer, infectious and autoimmune diseases, diseases of the nervous system, metabolic and/or cardiovascular diseases, and the like" teaches autoimmune diseases being associated with genomic instability and therefore renders an immunotherapeutic treatment obvious).
Regarding Claim 61, Chudova teaches step (a) obtaining two or more nucleic acid samples from two or more time points during the treatment (Para.0015 "In some implementations, the method further involves using a copy number variation in the cancer genome to diagnose cancer, monitor the progress of cancer, and/or determine a treatment for cancer" suggests obtaining samples from two or more time points during a treatment).
Chudova also teaches steps (a) through (f) of claim 43 which this claim references as its step (b).
Chudova also teaches generating GINs corresponding to samples from two or more time points during the treatment, wherein a decrease in GIN during the treatment indicates that the treatment is effective (Para.0382 "Identification of an increased number of CNVs in the test sample, e.g., in comparison to a reference value is indicative of a risk of or pre-disposition for cancer in the subject. It will be appreciated that the reference value may vary with a given population. It will also be appreciated that the absolute value of the increase in CNV frequency will vary depending on the resolution of the method utilized to determine CNV frequency and other parameters. Typically, an increase in CNV frequency of at least about 1.2 times the reference value been determined to indicative of risk for cancer (see, e.g., U.S. Patent Publication No: 2010/0261183 Al), for example an increase in CNV frequency of at least or about 1.5 times the reference value or greater, such as 2-4 times the reference value is an indicator of an increased risk of cancer (e.g., as compared to the normal healthy reference population)" implies that a lower CNV frequency would imply a lower risk of cancer and would suggest effectiveness (an evaluation thereof) of a treatment during the monitoring of para.0015 "In some implementations, the method further involves using a copy number variation in the cancer genome to diagnose cancer, monitor the progress of cancer, and/or determine a treatment for cancer").
Claims 46-47 and 54-56 rejected under 35 U.S.C. 103 as being unpatentable over Chudova et al. (WO-2016094853) as applied to claims 43-45, 48-53, and 57-61, and further in view of Zang et al. (Nature communications 7.1 (2016): 11305).
Chudova et al. is applied to claims 43-45, 48-53, and 57-61.
Regarding claims 46-47 and 55-56, Chudova teaches the method of Claim 43 and 48 in which this claim depends/these claims depend, respectively.
Chudova does not explicitly teach adjusting the sequence read quantification is performed by one or more of SPCA, a GC normalization process, and a smoothing process (claims 46 and 55) nor adjusting the sequence read quantifications are performed by SPCA (claims 47 and 56).
However, Zang teaches applying sparse PCA to sequence read data as a normalization method (Page 2 col 1 paragraph 2 "For example, PCA have been used to solve such problems. As an extension of PCA, Sparse PCA uses the linear combination of a small subset of variables instead of all to generate the principal components and still explains most variances present in the data, while making the dimension reduction and bias removal clearer and easier to interpret").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the sequence read normalization teaching of Chudova using the sparse PCA teaching of Zang in order to correct for bias and integrate distinct genomic profiles (page 1 abstract "High-dimensional genomic data analysis is challenging due to noises and biases in high-throughput experiments. We present a computational method matrix analysis and normalization by concordant information enhancement (MANCIE) for bias correction and data integration of distinct genomic profiles on the same samples"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with processing and normalizing genomic sequence read data for application to copy number variant analysis.
Regarding claim 54, Chudova teaches the methods of Claim 48 on which this claim depends/these claims depend, respectively. Zang also teaches the adjusting comprises normalizing the quantification of sequence reads by a guanine-cytosine (GC) normalizing process that generates a GC normalized quantification of sequence reads for each of the genomic portions, whereby the sequence read quantifications in (b) is the GC normalized quantification of sequence reads (Page 3 col 2 paragraph 2 "Cell lines showing GC-content patterns that were farther away from average of all cell lines (Supplementary Fig. 2c) underwent a greater magnitude of MANCIE adjustment than the other cell lines (Fig. 2e and Supplementary Fig. 2d). This result indicates that MANCIE successfully corrected the GC-content biases in the DNase-seq data").
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 43-46, 48-55, and 57-61 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of US-11515003 in view of Chudova et al. (WO-2016094853). Although the claims at issue are not identical, they are not patentably distinct from each other because both involve mapping reads to a reference genome, quantifying reads in multiple portions of the genome reference, adjusting these quantifications (specifically by a guanine-cytosine (GC) normalizing process), determining deviation from expectation for genomic portions and determining an area representing said deviation, and summing said areas to determine a genomic instability number for a test sample.
While US-11515003 does not explicitly teach generating a genome profile plot of the nucleic acid sample with chromosome-specific shading representing the adjusted sequence read quantifications in one or more autosomes, it would have been obvious to one of ordinary skill in the art to modify these methods, with those taught by Chudova as described above for claim 43 of the instant application, in order to represent sequence read quantifications per chromosome in the plot (again, the chromosome-specific shading is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to the genome profile plot, as shown by Chudova. Therefore, the figure illustrating chromosome coverage shown by Chudova would perform equally as well in representing sequence read quantifications per chromosome in a plot, and such a modification fails to patentably distinguish over Chudova). One skilled in the art would have a reasonable expectation of success because both methods are concerned with mapping, quantifying, and normalizing genome sequence reads for measuring genomic instability.
Claims 47 and 56 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US-11515003 in view of Chudova et al. (WO-2016094853) as applied to Claims 43-45, 48-53, and 57-61, and further in view of Zang et al. (Nature communications 7.1 (2016): 11305). While US-11515003 does not explicitly teach adjusting the sequence read quantifications by SPCA, it would have been obvious to one of ordinary skill in the art to modify the sequence read normalization teaching of US-11515003 using the sparse PCA teaching of Zang in order to correct for bias and integrate distinct genomic profiles (page 1 abstract "High-dimensional genomic data analysis is challenging due to noises and biases in high-throughput experiments. We present a computational method matrix analysis and normalization by concordant information enhancement (MANCIE) for bias correction and data integration of distinct genomic profiles on the same samples"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with processing and normalizing genomic sequence read data for application to genome instability analysis.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Yang et al. LOHAS: loss-of-heterozygosity analysis suite. Genet Epidemiol. 2011 May;35(4):247-60. doi: 10.1002/gepi.20573. PMID: 21312262
Zhang et al., “A genomic instability score in discriminating nonequivalent outcomes of BRCA1/2 mutations and in predicting outcomes of ovarian cancer treated with platinum-based chemotherapy,” PLoS One, 9(12):e113169 (2013)
Kanwar et al. "Identification of genomic signatures in circulating tumor cells from breast cancer." International Journal of Cancer 137.2 (2015): 332-344
Burrell et al. "Replication stress links structural and numerical cancer chromosomal instability." Nature 494.7438 (2013): 492-496
Conclusion
No claims are allowed.
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/R.A.P./Examiner, Art Unit 1686
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
