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 .
Office Action: Notice
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/19/2025 has been entered.
Claim Status
Claim 10 has been amended (12/19/2025). Claims 11-14 are cancelled (12/19/2025). No new matter was added. Thus, claims 1-10 and 15-16 are under examination.
Rejections Withdrawn
Claim Rejections - 35 USC § 102
The rejection of claims 1-10 and 15-16 under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Namsaraev et al., (WO 2018/081130 A1, published 5/3/18, from IDS 5/13/24) is withdrawn in view of Applicant’s amendments of claim 10 and as a result of further clarification set forth in Applicant’s Remarks (12/19/2025).
New Rejections
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 1-9 and 15-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Regarding claims 1-9 and 15-16, the claims recite methods and specific steps for determining nucleic acid fragment origin and categorizing based on fragment origin and size, including specific laboratory procedures such as providing nucleic acid mixtures, preparing libraries, and performing sequence analysis, which is a statutory category of invention.
The integration of the judicial exception into the claims does not render them patent eligible because the claims are written at a high level of generality and merely use well-known, routine, and conventional techniques in the field.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES.
The claims provide for a method comprising:
providing nucleic acid mixtures
preparing sequencing libraries
hybridizing probes
isolating bound fragments
sequencing nucleic acids and determining fragment size of fragmented nucleic acids
categorizing fragments based on origin and specified size determination criteria
using standard probe parameters and conditions (i.e., GC content)
Thus, the claims are directed to a statutory category (i.e., process).
Step 2A, Prong One — Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES.
The claims recite abstract ideas including mental processes for determining fragment classification, sequence determination, and origin identification. These analytical steps can be performed through observation, evaluation, judgement, and opinion. Thus, the claimed invention describes judicial exceptions corresponding to abstract ideas.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
The claim limitations are considered to be mental processes including; (a) mental processes for determining fragment origin by identifying he subsets of nucleic acids which interact with probes, determining probability of correspondence through HSNRF detection, and determining and categorizing fragment class through sequence alignments, and (b) data gathering steps for obtaining nucleic acid samples, preparing sequencing libraries, followed by hybridizing probes and sequencing bound fragments based on specified GC content.
While the claims include physical library steps, these steps are recited at a high level of generality and amount to mere data gathering activities necessary to observe and perform the abstract mental processes. The methods of sample preparation, hybridization, and sequencing are described generically without specific improvements or unconventional elements that would integrate the mental processes into a practical application. The focus of the claims remains on observing and analyzing naturally occurring biological relationships rather than a practical application of the discovery.
The claimed process does not apply the judicial exception in a way that meaningfully limits the abstract idea. There is no indication that the combination of elements improves the functioning of a computer or any other technology. The steps provide data to perform the abstract categorization and analysis, but do not integrate those judicial exceptions into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether ra claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
However, the additional elements of the instant application, individually and in combination, do not amount to “significantly more.” Under the Step 2B analysis, the “physical” elements/steps of, “obtaining samples”, “preparing libraries”, and “performing sequencing” represent well-understood, routine, and conventional activities previously known in the industry. These techniques were widely practiced in the field of DNA analysis prior to the filing date, as evidenced by the state of the art. The claims do not add specific limitations beyond what was routine and convenient, nor do they provide improvements to the technology of DNA analysis. The combination of steps taken together does not provide an inventive concept when viewed as a whole.
For example, Ivanov et al. (“Non-random fragmentation patterns in circulating cell-free DNA reflect epigenetic regulation”, BMC Genomics, published 12/16/15, from IDS 5/13/24) discloses fundamental aspects of cfDNA analysis based on fragment copy number and their prevalence in nucleosome positioning (Introduction, Paragraph 3). Further, Ivanov discloses that cfDNA copy numbers are dependent on nucleosome positioning at given DNA loci, and systems (i.e., PCR primers) can be optimized for GC detection and library preparation (In cfDNA, the dept of coverage reflects nucleosome positions, Paragraph 1; Figure 3). Additionally, Ivanov discloses that although cfDNA is highly heterogeneous, representing numerous different tissues each of which has its own gene expression profiles, these changes can be monitored via fragment patterns and genomic features via expression levels (In cfDNA, the dept of coverage reflects nucleosome positions, Paragraph 2).
Further, Snyder et al. (“Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin”, Cell, published 1/14/17, from IDS 5/13/24) discloses methods for analyzing cfDNA fragmentation patterns and their correlation with tissue origins (Introduction, Paragraphs 1-3. Additionally, Snyder discloses that cfDNA analyzed is placental-based (i.e., trophoblasts) and that cfDNA-based screening for fetal genetic abnormalities is common in high-risk pregnancies (Introduction, Paragraph 2). Further, Snyder discloses that spacing for nucleosome pairs varies considerably depending on which cell types are used for screening processes, most often for genetic abnormalities (Figure 5A; Nucleosome spacing patterns inform cfDNA tissues-of-origin: Paragraph 1) via fast Fourier transformation (FFT) to detect mixtures of signals resulting from multiple cell types (Nucleosome spacing patterns inform cfDNA tissues-of-origin: Paragraph 5).
Additionally, Mortimer et al. (WO 2017/181146 A1, published 10/19/2017, from IDS 5/13/24) discloses that standard DNA capture methods using oligonucleotide probes of a specified base length (Paragraph 152, lines 1-5). Further, Mortimer discloses a routine probe design strategy and hybridization technique for detecting hotspot regions (Paragraph 157, lines 1-5). Additionally, Mortimer discloses that these probes are suited for individualized clusters, typically suited for individualized capture of key tumor markers (Paragraph 167, lines 1-5) that typically span 60-120 bases (Paragraph 152, lines 1-5) and have the usability for application in fetally-derived fragments including the detection of deletions, duplications and aneuploidy (Paragraph 10, lines 1-5).
Therefore, providing automation to well-known analytical methods using standard molecular techniques to implement abstract ideas of fragment analysis and categorization via size was routine and conventional before the effective filing date of the claimed invention.
Simply appending routine and conventional activities previously known to the industry, specified at a high level of generality to the to the abstract ideas of DNA fragment analysis and hotspot detection does not qualify the claims for a judicial exception and/or generally linking the use of the judicial exception(s) to a particular technological environment or field of use, and are not found to be enough to qualify as “significantly more.” The processes of “obtaining cfDNA fragments from a eukaryotic organism”, “preparing sequencing libraries”, “hybridizing probes to at least one location in said library” and “detecting hotspots of non-random fragmentation” indicates wither or not the relationship between fragment distributions and specialized detection vessels of various origin exists. Additionally, the claimed fragmentation categorization and analysis for origin determination (i.e., probe hybridization based on GC content), while implemented using specific base pair ranges and statistical approaches, remain fundamentally abstract analytical processes implemented through conventional molecular biology methods. This information simply tells a practitioner about the relevant natural correlation, at most adding a suggestion that the researcher should take those biological relationships into account. When viewed both individually and as an ordered combination, the claimed elements fail to supply an inventive concept because these techniques were well-understood, routine and conventional activities that a practitioner would have thought of when instructed to analyze cell-free DNA fragments for genetic testing.
This information simply tells a practitioner about the relevant natural law, at most adding a suggestion that the medical researcher should take those laws into account. Thus, when viewed both individually and as an ordered combination, the claimed elements/steps in addition to the identified judicial exception are found insufficient to supply an inventive concept because the elements/steps are considered conventional and specified at a high level of generality. The claim limitations do not transform the abstract idea that they recite into patent-eligible subject matter because “the claims simply instruct the practitioner to implement the abstract idea with routine, conventional activity.”
Therefore, claims 1-9 and 15-16 do not qualify as patent-eligible subject matter because they are directed to an abstract idea of data analysis without significantly more transformative elements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Namsaraev et al., (WO 2018/081130 A1, published 5/3/18, from IDS 5/13/24), in view of Underhill et al. (“Fragment Length of Circulating Tumor DNA”, PLOS Genetics, published 2016).
Regarding claims 1 and 2, Namsaraev teaches a method to improve the positive predictive value for cancer detection using cell-free nucleic acid samples in diagnostic applications via the analysis of the fragmentation patterns and size of cfDNA (Abstract; Figure 22), originating from a tissue sample from a non-human subject (i.e., laboratory or farm animal) (Paragraph 176, lines 1-3). Further, Namsaraev teaches the preparation of a sequencing library of analyzable DNA molecules using the template DNA molecules to obtain a plurality of sequence reads corresponding to the first plurality of cell-free DNA molecules (Paragraph 317, lines 1-5), including instances of duplication that only would become more relevant with i) a higher number of PCR cycles for amplifying the sequencing library; ii) an increased sequencing depth, and iii) a smaller number of DNA molecules in the original plasma sample (Paragraph 315, lines 5-10). Namsaraev teaches that the fraction or duplication rate in the sequencing or enriched library is between 5-30% (Paragraph 681, lines 5-10). Specifically, Namsaraev teaches that the specified rate can correspond to a frequency of how many nucleic acid molecules end on a position, and in some cases does not relate to a periodicity of positions having a local maximum in the number of
nucleic acid molecules ending on the position (Paragraph 159, lines 10-15). Further, Namsaraev teaches that a p-value can be determined using the corresponding number and the expected number, wherein the threshold corresponds to a cutoff p-value (i.e.., 0.01) and further the p-value being less than the cutoff p-value indicates that the rate is above the threshold (Paragraph 545, lines 1-5). Additionally, Namsaraev teaches that another example, the reference value can include a measured number of cell-free DNA molecules ending within the genomic
window from a sample identified as having a reduced amount of the first tissue type (Figures SIA, SIB; Paragraph 545, lines 5-10).
Following this, Namsaraev teaches, in order to efficiently capture viral DNA fragments from plasma, the use of probes hybridizing to autosomal regions of interest may be used (Paragraph 253, lines 1-5), including hotspot regions (Paragraph 350, lines 1-5). Additionally, Namsaraev teaches the importance of identifying the class of or proportional contribution of the nucleic acid fragment in relation to overall genomic position (Paragraph 714, lines 1-5). For example, Namsaraev teaches that the plasma DNA HCC-preferred ends are cancer- or HCC-specific, we studied the size profile of plasma DNA molecules showing the HCC- or HBV-preferred ends where a proportion of short DNA (< 150 bp) were detected among plasma DNA molecules ending with HCC-preferred ends, HBV-preferred ends or the shared ends (Paragraph 634, lines 1-5). Namsaraev teaches the determination of fragment and tumor type origin via plotting relative abundance of molecules ending at a particular nucleotide against the nucleotide coordinate for mapping the region, in order to create a 20 bp identifiable fragment (Paragraphs 321-322, lines 5-10, lines 1-5; Figure 36).
Regarding claim 3, Namsaraev teaches that the nucleic acid fragment of interest is cfDNA selected from a group comprising; fetal DNA fraction in a maternal plasma sample (Paragraph 343, lines 1-2), tumor-derived DNA can be shorter than the non-cancer-derived DNA (Figure 20), pathogen and host (Paragraph 700, lines 1-2) and a transplanted organ (Paragraph 149, lines 5-10).
Regarding claim 4, Namsaraev teaches specialized double-stranded probes to efficiently capture viral DNA fragments from plasma via hybridizing to viral genomes than human autosomal regions of interest covering each region with approximately 200 bp in size (Paragraph 253, lines 5-10). Further, Namsaraev teaches that each probe has specialized 5’ and 3’ ends because the identification of the preferred end is often associated with a particular physiological or pathological state (Paragraph 255, lines 10-15). Namsaraev also teaches a
combination of metrics (i.e., at least two of an end ratio, copy number, and nucleic acid
fragment size) may be used to detect a condition in a subject (Paragraph 496, lines 5-10). Specifically, Namsaraev teaches that there the non-random cell-free DNA
fragmentation process is precise down to the level of specific nucleotides (Figures 45D-E; Paragraph 366, lines 15-20), however probe binding occurs at a length ranging from 10-250 bp between the upper and lower cutoff values to minimize duplication in sequencing (Paragraph 436, lines 5-10), and in some embodiments can include hotspot regions for the end positions (Paragraph 353, lines 1-5). Further, Namsaraev teaches that preparation of probe-based sequencing conditions is determined based on GC contents of primers used (Paragraph 725, lines 5-10), specifically identifying while two bases having similar content percentages (i.e., between 30-70%) is considered heterozygous (Paragraph 241, lines 5-10).
Regarding claims 5 and 6, Namsaraev teaches that the proportional contribution of tissue type or origin of a fragment of DNA in a mixture can be determined by analysis of two or more calibration samples with known proportional concentrations (i.e., higher or lower) (Paragraph 294, lines 1-5; Figure 32). Further, Namsaraev teaches the ratio of the number of fragments divided by their known proportional concentrations (i.e., BIA ratios) for different groups of
subjects (Paragraph 462, lines 1-5; Figure 69). Specifically, Namsaraev teaches that these divisions or indexes can be indicative of having a condition or specific turmeric origin and range from 0.001 to 0.5 (Paragraph 479, lines 15-20).
Regarding claim 7, Namsaraev teaches that the probes are fixed to a support or a sample holder (i.e., flow cell) (Paragraph 716, lines 1-5; Figure 89).
Regarding claim 8, Namsaraev teaches capture probes can be biotinylated, and magnetic beads (e.g., streptavidin coated beads) are used to pull down or enrich the capture probes hybridized to a nucleic acid target (e.g., an EBV genome fragment) after library preparation (Paragraph 730, lines 1-5).
Regarding claim 9, Namsaraev teaches that preparation of probe-based sequencing conditions is determined based on GC contents of primers used (Paragraph 725, lines 5-10), specifically identifying while two bases having similar content percentages (i.e., between 30-70%) is considered heterozygous (Paragraph 241, lines 5-10).
Regarding claim 10, Namsaraev teaches a method of isolating fetal genomes that would be preferentially cleaved in the generation of plasma DNA (Paragraph 349, lines 1-5) using a blood sample. Specifically, Namsaraev teaches identification of a non-random fragmentation pattern in the plasma DNA following probe-based analysis (Paragraph 350, lines 1-5). Specifically, Namsaraev teaches that through the observation of peaks for the fragmented groups,
hotspots for the end positions of fetal- and maternal-derived DNA in maternal plasma, respectively, were observed (Paragraph 350, lines 5-10). Further, Namsaraev teaches that the analysis of the ending positions or regions of interest (i.e., hotspots) is performed via implementation of primers or probes covering the specific ending positions (Paragraph 452, lines 5-10). Also, Namsaraev teaches that a p-value can be determined using the corresponding number and the expected number, wherein the threshold corresponds to a cutoff p-value (i.e.., 0.01) and further the p-value being less than the cutoff p-value indicates that the rate is above the threshold (Paragraph 545, lines 1-5). Additionally, Namsaraev teaches that another example, the reference value can include a measured number of cell-free DNA molecules ending within the genomic window from a sample identified as having a reduced amount of the first tissue type (Figures SIA, SIB; Paragraph 545, lines 5-10).
Namsaraev teaches specialized double-stranded probes to efficiently capture viral DNA fragments from plasma via hybridizing to viral genomes than human autosomal regions of interest covering each region with approximately 200 bp in size (Paragraph 253, lines 5-10). Further, Namsaraev teaches that each probe has specialized 5’ and 3’ ends because the identification of the preferred end is often associated with a particular physiological or pathological state (Paragraph 255, lines 10-15). Namsaraev also teaches a
combination of metrics (i.e., at least two of an end ratio, copy number, and nucleic acid
fragment size) may be used to detect a condition in a subject (Paragraph 496, lines 5-10). Specifically, Namsaraev teaches that there the non-random cell-free DNA
fragmentation process is precise down to the level of specific nucleotides (Figures 45D-E; Paragraph 366, lines 15-20), however probe binding occurs at a length ranging from 10-250 bp between the upper and lower cutoff values to minimize duplication in sequencing (Paragraph 436, lines 5-10), and in some embodiments can include hotspot regions for the end positions (Paragraph 353, lines 1-5). Further, Namsaraev teaches that preparation of probe-based sequencing conditions is determined based on GC contents of primers used (Paragraph 725, lines 5-10), specifically identifying while two bases having similar content percentages (i.e., between 30-70%) is considered heterozygous (Paragraph 241, lines 5-10).
Regarding claims 15-16, Namsaraev teaches specialized double-stranded probes to efficiently capture viral DNA fragments from plasma via hybridizing to viral genomes than human autosomal regions of interest covering each region with approximately 200 bp in size (Paragraph 253, lines 5-10). Further, Namsaraev teaches that each probe has specialized 5’ and 3’ ends because the identification of the preferred end is often associated with a particular physiological or pathological state (Paragraph 255, lines 10-15). Namsaraev also teaches a
combination of metrics (i.e., at least two of an end ratio, copy number, and nucleic acid
fragment size) may be used to detect a condition in a subject (Paragraph 496, lines 5-10). Specifically, Namsaraev teaches that there the non-random cell-free DNA
fragmentation process is precise down to the level of specific nucleotides (Figures 45D-E; Paragraph 366, lines 15-20), however probe binding occurs at a length ranging from 10-250 bp between the upper and lower cutoff values to minimize duplication in sequencing (Paragraph 436, lines 5-10), and in some embodiments can include hotspot regions for the end positions (Paragraph 353, lines 1-5). Further, Namsaraev teaches that preparation of probe-based sequencing conditions is determined based on GC contents of primers used (Paragraph 725, lines 5-10), specifically identifying while two bases having similar content percentages (i.e., between 30-70%) is considered heterozygous (Paragraph 241, lines 5-10). Further, Namsaraev teaches that the proportion of cell-free DNA fragments below 150 base pairs in length in the subject's sample is determined, and the proportion is compared to a threshold value of 15% (Paragraph 743, lines 20-25).
Namsaraev does not teach or suggest determining fragment size without alignment to a reference genome, in order to define HSNRF sites between two tissue types as a primary factor for probe placement.
Underhill teaches methods to define distinct differences in fragment length size between ctDNAs and normal cell-free DNA (Abstract). Specifically, Underhill teaches that size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer and these findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA (Abstract). Further, Underhill teaches that prepared cell-free DNA libraries were enriched for regions of interest using a custom designed IDT Xgen capture probe set containing full exonic coverage for specified genes (Melanoma Samples: Paragraph 1). Underhill also teaches that observations provide compelling evidence that the fragment length of ctDNA is shorter than cell-free DNA from healthy cells and selection of shorter cell-free DNA fragments may improve mutant allele frequency (Figure 5) and for a comparison of cell-free DNA from 15 lung cancer patients and 9 healthy controls found a statistically significant difference in plasma concentration of cell-free DNA (Characteristics of Cell-Free DNA and ctDNA in Human Lung Cancer). Underhill also teaches that specifically, previous amplicon-based studies have shown that ctDNA is highly fragmented and occurs most commonly at a size <100 bp, while normal cell-free DNA is proportionally more represented at a size >400 bp and Underhill sought to determine the feasibility of detecting ctDNA associated with GBM by utilizing a xenograft tumor model to exploit genomic species differences to separate ctDNA from the background host animal benign cell-free DNA, in order to identify precise differences in fragment lengths between ctDNA and normal cell-free DNA, which were more narrow and more consistent than previously described (Introduction: Paragraphs 2-3).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to combine the cfDNA fragmentation and endpoint frequency analysis techniques taught by Namsaraev with the fragment length-based discrimination methods taught by Underhill because both references are directed to the same technical problem of improving detection and characterization of tumor-derived circulating DNA against a background of normal cell-free DNA. Namsaraev provides a framework for statistically analyzing non-random fragmentation patterns and fragment endpoints to distinguish tissue origin, while Underhill teaches that ctDNA exhibits reproducible and statistically significant fragment length differences relative to normal cell-free DNA and that selecting or analyzing shorter fragments substantially improves detection of tumor-derived DNA and mutant allele frequency. Incorporating Underhill’s fragment length teachings into Namsaraev’s fragmentation-based analysis represents the application of a known and biologically validated fragment-based discriminator to an existing cfDNA endpoint analysis method in order to improve sensitivity and accuracy of tissue-of-origin determination.
Further, a person of ordinary skill in the art would have had a reasonable expectation of success in making this combination because both Namsaraev and Underhill rely on well-established cfDNA sequencing, fragment analysis, and statistical evaluation techniques. Underhill demonstrates that fragment length differences between ctDNA and normal cell-free DNA are consistent, measurable, and biologically meaningful across multiple cancer types, while Namsaraev demonstrates that cfDNA fragmentation patterns and endpoint frequencies can be statistically evaluated to distinguish DNA originating from different tissues. Accordingly, applying Underhill’s fragment length-based discrimination to the cfDNA fragmentation analysis of Namsaraev would have predictably yielded improved identification and characterization of tumor-derived cfDNA without requiring undue experimentation.
Applicant’s Response: The Applicant argues that the primary reference, Namsaraev, does not teach or suggest the claimed invention because it relies on reference-genome alignment an does not disclose defining or selecting fragmentation sites based on statistically significant differences between tissue types. The Applicant further asserts that the fragment length differences alone, as taught in the art, do not render the claimed HSNRF-based methods obvious because the claims require a specific integration of fragment length analysis with statistically defined fragmentation endpoints.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered and are found to be partially persuasive, as discussed below.
Notably, the Applicant’s remarks and amendments of instant claims established that Namsaraev, alone, does not expressly disclose all claimed limitations, and accordingly the prior 35 USC 102 rejection was withdrawn. However, the instant claims remain unpatentable under 35 USC 103, as presented above.
The new 103 rejection addresses the deficiencies identified by the Applicant by combining Namsaraev with Underhill. While Namsaraev teaches statistically analyzing cfDNA fragmentation patterns and fragment endpoints to distinguish tissue origin, Underhill teaches hat tumor-derived ctDNA exhibits reproducible and statistically significant fragment length differences relative to normal cell-free DNA and that selection or analysis of shorter fragment lengths improves detection of ctDNA. Underhill therefore provides a known and biologically validated basis for incorporating fragment length discrimination into Namsaraev’s fragmentation analysis framework.
A person of ordinary skill in the art would have been motivated to combine these teachings because both references are directed to improving discrimination of tumor-derived DNA from background cfDNA, and Underhill demonstrates that fragment-length is a meaningful and reliable discriminator. Further, a reasonable expectation of success would have existed because both references rely on well-established cfDNA sequencing and statistical analysis techniques, and Underhill shows that fragment length differences are consistent and reproducible across cancer types (see MPE 2141, 2143). To overcome this rejection, the Applicant may amend the claims to expressly showcase that the claimed HSNRF-based analysis is incompatible with the fragment length teachings of Underhill (i.e., uniform or normalized fragment positions).
Accordingly, the Applicant’s arguments do not overcome the 103 rejection and claims 1-10 and a 15-16 remain rejected.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
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/ELIZABETH ROSE LAFAVE/
Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684