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 .
Priority
This application 18/286,081 filed on 10/06/2023 is a 371 national phase of PCT/US2022/023907 filed on 04/07/2022, and claims the benefit of provisional U.S. Patent Application No. 63/172,493, filed on 04/08/2021.
The priority date of claims 1,27, 49 and their dependent claims is determined to be 04/08/2021, the filing date of provisional U.S. Patent Application No. 63/172,493.
Status of Claims
Applicant’s amendments to claims filed 05/07/2026 in response to the Non-Final Rejection mailed 02/09/2026 are acknowledged.
Claims 1, 27, 50, 53, 55, and 56 are amended.
Claims 2, 3, 8, 28, 31, and 49 have been canceled.
Claims 1, 9, 10, 14-18, 20, 23, 25, 27, 42, 45, 47, 50, 53 and 55-56 are pending and under examination.
Response to Remarks filed 05/07/2026
The amendments and arguments presented in the papers filed 05/07/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 02/09/2026 listed below have been reconsidered as indicated.
a) The 35 USC 112(b) indefiniteness rejections of claim 8 have been withdrawn as moot in view of the cancellation of the claims.
b) The rejection of claims 1, 8, 10, 14-18, 20, 25, 49-50, and 55-56 under 35 U.S.C. 102 as being anticipated by Velculescu et al. (WO2019222657) is withdrawn in view of amendments to the claims and the cancellation of claims 8 and 49.
c) The rejections under 35 U.S.C. 103 of (1) claims 1, 2, 3, 27,28, 31,42, and 47 as being unpatentable over Velculescu et al. (WO2019222657) in view of Abdueva (US20190287645); (2) claim 9 as being unpatentable over Velculescu et al. (WO2019222657) (3) claims 23 and 53 as being unpatentable over Velculescu et al. (WO 2019222657) in view of Murtaza et al. (WO2021007462); and (4) claim 45 as being unpatentable over Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645) and Murtaza et al. (WO2021007462) are withdrawn in view of amendments to the claims.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Claim Rejections - 35 USC § 112(b)
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 1, 9,10, 14-18, 20, 23, 25, 27, 42, 45, 47, 50, 53 and 55-56 are 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 1 and 27 recite “calculating a score based on the cfDNA fragmentation profile -- the score having a range of 0 to 1”. Claim 1 further recites “the score being indicative of a likelihood of presence of cancer in the subject thereby detecting cancer in the subject; c) determining that the subject has cancer based on the score”. Claim 27 further recites “determining a likelihood of overall survival of the subject based on the score”. The limitations reciting “based on the score are unclear”. It is unclear what score(s) indicate the presence of cancer or the likelihood of survival or if any score inclusive of 0 or 1 indicates the presence of cancer.
Claims 9, 10, 14-18, 20, 23, 25, 50, 53, 55, and 56 are similarly indefinite because they directly or indirectly depend from claim 1.
Claims 42, 45, and 47 are similarly indefinite because they directly or indirectly depend from claim 27.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 25 recites the limitation “further comprising administering a cancer treatment to the subject”. Claim 1, which claim 25 depends from, includes the limitation in (d) “administering a cancer treatment to the subject”. Claim 25 repeats the limitation of claim 1 step (d) and fails to further limit claim 1 step (d). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1,9-10,14-18,20,23,25,27,42,45,47,50,53 and 55-56 remain/are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
This maintained rejection has been modified to address claim amendments filed on 05/07/2026.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process.
Step 2A, Prong One
The claims are taken to be directed to natural phenomena and abstract ideas, judicial exceptions.
Claim 1 is directed to a method for detecting cancer in a subject comprising “a) -- analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile; and b) classifying the subject as having cancer or not having cancer by calculating a score based on the cfDNA fragmentation profile, wherein calculating the score comprises: i) determining a ratio of short to long cfDNA fragments, ii) determining a Z-score for the cfDNA fragments by chromosome arm, iii) quantifying cfDNA fragment density using a computational mixture model analysis of cfDNA fragment sizes, and iv) fitting a cross-validated gradient boosted machine learning model to cancer status using output of i)-iii) as input features to define the score, the score having a range of 0 to 1, the score being indicative of a likelihood of presence of cancer in the subject, thereby detecting cancer in the subject; c) determining that the subject has cancer based on the score”.
Claim 1 as a whole is directed to a process that involves the judicial exception of a law of nature (i.e. the natural correlation between the cell-free DNA (cfDNA) fragmentation profile in a subject and the presence of cancer). Limitations reciting “indicative of” constitute natural correlations. A correlation that preexists in the human is an unpatentable phenomenon. The association between the relative abundances of nucleic acids of particular lengths in a human and the presence of cancer cells in the human is a law of nature/natural phenomenon.
In addition, claim 1 recites steps for “classifying the subject as having cancer or not having cancer by calculating a score based on the cfDNA fragmentation profile--; and ” determining that the subject has cancer based on the score”. These limitations are abstract mental processes (see MPEP 2106.04(a)(2)). As written, the classifying and determining steps encompass the mental steps of looking at cfDNA fragmentation profiles and scores and making mental judgements. Additionally, the step of calculating a score is a mathematical concept (see MPEP 2016.04(a)(2)(I)(C)). As written, the calculating step encompasses mathematical concepts such as mathematical calculations. Claims 9, 10, 14-18, 20, 23, 25, 50, 53, 55, and 56 depend from claim 1, and require the same steps of analyzing, classifying, determining, and calculating and are directed to the same law of nature.
Claim 18 recites the limitation “comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation“. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)(A)). As written, the comparing step encompasses the mental step of looking at two sets of cDNA fragmentation profiles and making mental judgements.
Claim 27 is directed to a method determining overall survival of a subject having cancer comprising “a) determining a cell-free DNA (cfDNA) fragmentation profile of a sample from the subject, the cfDNA fragmentation profile being determined by: processing the sample comprising cfDNA fragments into sequencing libraries; subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments; mapping the sequenced fragments to a genome to obtain windows of mapped sequences, and analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile; b) calculating a score based on the cfDNA fragmentation profile, wherein calculating the score comprises: i) determining a ratio of short to long cfDNA fragments of the sample, ii) determining a Z-score for cfDNA fragments of the sample by chromosome arm, iii) quantifying cfDNA fragment density using a computational mixture model analysis of cfDNA fragment sizes, and iv) fitting a cross-validated gradient boosted machine learning model to cancer status using output of i)-iii) as input features to define the score, the score having a range of 0 to 1; and c) determining a likelihood of overall survival of the subject based on the score, thereby determining overall survival of the subject”.
Claim 27 as a whole is directed to a process that involves the judicial exception of a law of nature (i.e. the natural correlation between the cell-free DNA (cfDNA) fragmentation profile in a subject and the likelihood of overall survival of the subject). A correlation that preexists in the human is an unpatentable phenomenon. The association between the relative abundances of nucleic acids of particular lengths in a human (i.e. the shape of the curve of cfDNA fragment size density) and the likelihood of survival in the subject is a law of nature/natural phenomenon.
In addition, claim 27 recites steps for “classifying the subject as having cancer or not having cancer by calculating a score based on the cfDNA fragmentation profile--; and ”determining a likelihood of overall survival of the subject based on the score--”. These limitations are abstract mental processes (see MPEP 2106.04(a)(2)). As written, the classifying and determining steps encompass the mental steps of looking at cfDNA fragmentation profiles and scores and making mental judgements. Additionally, the step of calculating a score is a mathematical concept (see MPEP 2016.04(a)(2)(I)(C)). As written, the calculating step encompasses mathematical concepts such as mathematical calculations.
Claims 42, 45, and 47 depend from claim 27, and thus require the same steps of classifying, determining, and calculating and are directed to the same law of nature.
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
Claims 1 and 27 additionally recite processing the sample comprising cfDNA fragments into sequencing libraries; subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments, mapping the sequenced fragments to a genome to obtain windows of mapped sequences, and analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile. However, these are not integrations of the exception into a practical application. Instead, these elements are data gathering required to perform the method.
Claims 1 and 27 further recite “fitting a cross-validated gradient boosted machine learning model to cancer status using output of i)-iii) as input features to define the score”. These steps are mere data analysis required to perform the method and as such are not integrations of the exception into a practical application.
Claims 1, 25, and 47 recite the limitation “administering a cancer treatment to the subject”. These are not an integration of the exception into a practical application. These steps do not recite any particular treatment that integrates the exception into a new and useful end or directed to a particular condition. Instead they recite treatment in a merely generic manner (See MPEP 2106.04(d)(2)).
Claims 9-10, 14-18, 20, 23, 25, 42, 45, 47, and 50, 53, and 55-56 further require limitations directed to analysis steps including size and score selection, and data processing that do not amount to significantly more than the judicial exception. Rather these steps are mere data gathering and analysis necessary to perform the claimed methods.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to administering a treatment are recited at a generic level. Steps directed to isolating cfDNA fragments, sequencing cfDNA fragments, and mapping sequenced fragments are techniques that are routine, conventional, and well-known in the art as demonstrated in the 103 rejections documented below.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity:
i. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546;
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments against Claim Rejection - 35 U.S. C § 101
The response asserts that amending the claims to include “fitting a cross-validated gradient boosted machine learning model to cancer status, determining that the subject has cancer based on the score, and administering a cancer treatment to the subject”, thereby integrating conventional steps such as utilizing the result for a clinical diagnosis and administering a treatment into the process that involves specific application is an inventive concept (p. 8-9). The response further asserts that the specific, non-conventional steps, taken as an ordered combination, represent significantly more than any alleged abstract idea or natural phenomenon (p. 9).
Applicant's arguments have been fully considered but are not persuasive.
The claims remain drawn to a law of nature. Further, the steps of processing cfDNA fragments into sequencing libraries; whole genome sequencing; mapping the sequenced fragments; analyzing, using a computer; calculating a score to determine that a subject has cancer remain routine and conventional steps classified as mere data gathering required to perform the method as described in the 101 rejection above and demonstrated in the 103 rejections below.
The response asserts that the mandatory treatment step provides a practical
application of the diagnostic determination, transforming the claims from mere data
gathering into a method that affects a concrete change in the patient's treatment (p. 9-10).
Applicant's arguments have been fully considered but are not persuasive.
The limitation “administering a cancer treatment to the subject” does not constitute a specific treatment that is particular to a cfDNA score outcome or profile. Instead the limitation is directed to the administration of any possible cancer treatment. The recited treatment in the rejected claims is at such a high level of generality that it is a mere invitation to "apply" the judicial exceptions.
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 1, 9, 10, 14-18, 20, 25, 27, 42, 47, 50, 55, 56 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645).
These are new rejections necessitated by claim amendments.
Regarding claim 1, Velculescu teaches a method for identifying a mammal (subject) as having cancer.
Regarding a), Velculescu teaches determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal (subject) by processing cfDNA fragments obtained from a sample obtained from the mammal into sequencing libraries, subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments, mapping the sequenced fragments to a genome to obtain windows of mapped sequences, and analyzing the windows of mapped sequences to determine cfDNA fragment lengths (p. 4, lines 11-17 and claim 1). A computer may be used to store and compare fragmentation profiles (p. 15, lines 10), which reads on the limitation “analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile”.
Regarding b), Velculescu teaches obtaining a score that could be used to classify individuals as likely healthy or having cancer (p. 11, lines 28-29; p. 32, lines 5-11). Velculescu further teaches, regarding step b) part i): determining the ratio of small cfDNA fragments to large cfDNA fragments (p.4, lines 22-24); regarding step b) part ii): obtaining an arm-specific Z-score (p. 31, line 22); regarding step b) part iii: determining cfDNA fragment density ( p. 8, lines 9-10 ; Figs. 3 and 4A).
However, Velculescu does not teach regarding step b) part iii), determining cfDNA fragment density by quantifying the cfDNA fragment density using a computational mixture model analysis of cfDNA fragment sizes.
Abdueva teaches methods for cfDNA fragmentome profiling that can be used to assess disease (e.g. cancer) (para 4), the method comprises calculating fragmentation density using a multivariate mixture of distributions (para 156). Abdueva further teaches the method may comprise using a computer to construct multi-parametric distribution of the fragments over positions in the genome (i.e. a density) (paras 5, 14). Abdueva states that mixture modeling analysis is a common probabilistic clustering technique useful for detecting abnormal conditions as in malignant cancer (para 335). Abdueva further states that summing densities of fragments using mixture modeling results in a quantitative measure of malignancy burden (para 337).
Regarding step b) part iv), Velculescu teaches using gradient tree boosting machine learning to process multiple outputs to determine a DELFI score that can be used to classify individuals as likely healthy or having cancer (p. 11, lines 16-29 and Fig. 14) and performing cross-validation to estimate prediction error (p. 32, lines11-12), with scores between 0 and 1 (Table 7) .
Velculescu further teaches that machine learning can be used for identifying an altered fragmentation profile in multiple parameters (e.g., using coverage of cfDNA fragments, cfDNA fragment size, coverage of chromosomes) (p. 18, lines 11-14) and teaches that a combined approach performs better than single feature analysis (Fig. 17 and p. 43, lines 1-11).
Neither Velculescu nor Abdueva teach fitting a cross-validated gradient boosted machine learning model to cancer status using the specific claimed input features.
Regarding c), Velculescu teaches detection of cancer using the DELFI score (Fig. 14, p. 11 lines 28-29).
Regarding d), Velculescu teaches administering a cancer treatment to the subject (claim 29).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Velculescu and Abdueva to arrive at the instantly claimed invention. The modification would have entailed (1) using a mixture model analysis of cDNA fragment density as taught by Abdueva to calculate cfDNA fragment density and (2) selecting as input for the gradient boosting model the features of (i) the ratio of small cfDNA fragments to large cfDNA fragments, (ii) arm-specific Z-scores, and cfDNA fragment density of Velculescu. One would have been motivated to use a mixture model analysis for the stated benefits of the production of a quantitative measure of malignancy. Regarding the mixture model analysis, the modification would further have entailed selecting an appropriate mixture model analysis. This is deemed a matter of routine optimization within the purview of one of skill in the art. Regarding selection of features for the gradient boosting model, the selection of input features is deemed a matter of routine optimization within the purview of one of skill in the art. Velculescu teaches comparing single and combined features for determining a reliable predictor. One of skill in the art would have been motivated to experiment with additional features in search of a more accurate predictor. In addition, the required input features of the instant invention were generated by the method of Velculescu and Abdueva. Both Velculescu and Abdueva recognized the strength of machine learning as a way to incorporate multiple metrics to generate an accurate classifier score. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 9, Velculescu teaches analyzing small cfDNA fragments from 100 bp to 150 bp in length and large cfDNA fragments from 151 bp to 220bp in length (p. 6, lines 24-26). Velculescu further teaches that the cfDNA fragmentation profile can include the sequence coverage of small cfDNA fragments, large cfDNA fragments, or both (p. 6, line 30 to p. 7 lines 1-2) and that the small cfDNA fragment can be from about 100 bp in length to about 150 bp in length and a large cfDNA fragment can be from about 151 bp in length to 220 bp in length (p. 16, lines 28-31 to p. 17 line 1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Velculescu to arrive at the instantly claimed invention. The modification would have entailed excluding fragments 5 bp larger than the minimum size small cfDNA fragments and 20 bp larger than the maximum size small cfDNA fragments. One would have been motivated to change the window of analysis in the routine course of data analysis or by the fact that mononucleosomal peaks are around 167 bp and could constitute a population of cDNA fragments of interest. Additionally, Velculescu teaches multiple ranges of cfDNA fragments to analyze, and even acknowledges that the provided cutoffs can be considered approximations (about) that can be modified between experiments. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 10, Velculescu teaches mapped sequences can include tens to thousands of windows (p. 4, lines 17-18 and claim 2).
Regarding claim 14, Velculescu teaches the cfDNA fragmentation profile can include a ratio of small cfDNA fragments to large cfDNA fragments in the windows of mapped sequences (p. 6, lines 24-25).
Regarding claim 15, Velculescu teaches the cfDNA fragmentation profile can include the sequence coverage of small and large cfDNA fragments in windows across the genome (p. 7, lines 1-2).
Regarding claim 16, Velculescu teaches the cfDNA fragmentation profile can be over the whole genome (p. 4, lines 24-25).
Regarding claim 17, Velculescu teaches the cfDNA fragmentation profile can be over a subgenomic interval (p. 4, line 25).
Regarding claim 18, Velculescu teaches comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile (p. 4, lines 29-30).
Regarding claim 20, Velculescu teaches the cancer can be breast cancer (p. 18, lines 21-22), which reads on a solid tumor.
Regarding claim 25, Velculescu teaches administering a cancer treatment to the mammal identified as having cancer (subject) (p. 3, lines 22-23).
Regarding claim 27, Velculescu teaches a method for identifying a mammal (subject) as having cancer that can be used to identify response to treatment (i.e. overall survival) (p. 19, lines 24-25) and determining progression-free survival (Table 6).
Regarding a), Velculescu teaches determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal (subject) by processing cfDNA fragments obtained from a sample obtained from the mammal into sequencing libraries, subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments, mapping the sequenced fragments to a genome to obtain windows of mapped sequences, and analyzing the windows of mapped sequences to determine cfDNA fragment lengths (p. 4, lines 11-17 and claim 1). A computer may be used to store and compare fragmentation profiles (p. 15, lines 10), which reads on the limitation “analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile”.
Regarding b), Velculescu teaches obtaining a score that could be used to classify individuals as likely healthy or having cancer (p. 11, lines 28-29; p. 32, lines 5-11). Velculescu further teaches, regarding step b) part i): determining the ratio of small cfDNA fragments to large cfDNA fragments (p.4, lines 22-24); regarding step b) part ii): obtaining an arm-specific Z-score (p. 31, line 22); regarding step b) part iii: determining cfDNA fragment density ( p. 8, lines 9-10 ; Figs. 3 and 4A).
However, Velculescu does not teach regarding step b) part iii), determining cfDNA fragment density by quantifying the cfDNA fragment density using a computational mixture model analysis of cfDNA fragment sizes.
Abdueva teaches methods for cfDNA fragmentome profiling that can be used to assess disease (e.g. cancer) (para 4), the method comprises calculating fragmentation density using a multivariate mixture of distributions (para 156). Abdueva further teaches the method may comprise using a computer to construct multi-parametric distribution of the fragments over positions in the genome (i.e. a density) (paras 5, 14). Abdueva states that mixture modeling analysis is a common probabilistic clustering technique useful for detecting abnormal conditions as in malignant cancer (para 335). Abdueva further states that summing densities of fragments using mixture modeling results in a quantitative measure of malignancy burden (para 337).
Regarding step b) part iv), Velculescu teaches using gradient tree boosting machine learning to process multiple outputs to determine a DELFI score that can be used to classify individuals as likely healthy or having cancer (p. 11, lines 16-29 and Fig. 14) and performing cross-validation to estimate prediction error (p. 32, lines11-12), with scores between 0 and 1 (Table 7) .
Velculescu further teaches that machine learning can be used for identifying an altered fragmentation profile in multiple parameters (e.g., using coverage of cfDNA fragments, cfDNA fragment size, coverage of chromosomes) (p. 18, lines 11-14) and teaches that a combined approach performs better than single feature analysis (Fig. 17 and p. 43, lines 1-11).
Neither Velculescu nor Abdueva teach fitting a cross-validated gradient boosted machine learning model to cancer status using the specific claimed input features.
Regarding step (c), Velculescu teaches the method can be used to identify response to treatment (p. 19, lines 24-25), which reads on likelihood of survival. In addition, Abdueva teaches the use of fragmentome analysis to determine cancer prognosis (i.e., likelihood of survival) (para 157).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Velculescu and Abdueva to arrive at the instantly claimed invention. The modification would have entailed (1) using a mixture model analysis of cDNA fragment density as taught by Abdueva to calculate cfDNA fragment density and (2) selecting as input for the gradient boosting model the features of (i) the ratio of small cfDNA fragments to large cfDNA fragments, (ii) arm-specific Z-scores, and cfDNA fragment density of Velculescu. One would have been motivated to use a mixture model analysis for the stated benefits of the production of a quantitative measure of malignancy. Regarding the mixture model analysis, the modification would further have entailed selecting an appropriate mixture model analysis. This is deemed a matter of routine optimization within the purview of one of skill in the art. Regarding selection of features for the gradient boosting model, the selection of input features is deemed a matter of routine optimization within the purview of one of skill in the art. Velculescu teaches comparing single and combined features for determining a reliable predictor. One of skill in the art would have been motivated to experiment with additional features in search of a more accurate predictor., In addition, the input features of the instant invention were generated by the method of Velculescu and Abdueva. Both Velculescu and Abdueva recognized the strength of machine learning as a way to incorporate multiple metrics to generate an accurate classifier score. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 42, Velculescu teaches the cancer can be breast cancer (p. 18, lines 21-22), which reads on a solid tumor.
Regarding claim 47, Velculescu teaches administering a cancer treatment to the mammal (subject) identified as having cancer (subject) (p. 3, lines 22-23).
Regarding claim 50, Velculescu teaches the cancer can be breast cancer (p. 18, lines 21-22), which reads on a solid tumor.
Regarding claim 55, Velculescu teaches the cancer treatment can be surgery, adjuvant chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy, targeted therapy, or any combinations thereof (p. 5, lines 29-31).
Regarding claim 56, Velculescu teaches the mammal (subject) can be human (p.6, line 10).
Claims 23, 45, 53 are rejected under 35 U.S.C. 103 as being unpatentable over Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645) as applied to claims 1, 9, 10, 14-18, 20, 25, 27, 42, 47, 50, 55, 56 above, and further in view of Murtaza et al. (WO2021007462).
This new rejection has been modified to address claim amendments
Regarding claims 23, 43, and 53, neither Velculescu nor Abdueva teach the cancer is a hematologic cancer.
Murtaza teaches cfDNA fragmentation can be used to detect diseases such as cancer (Abstract), including hematologic cancers, including leukemia and lymphoma (p. 18, line 26 and p. 20, lines 2-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Velculescu and Abdueva with Murtaza to arrive at the instantly claimed invention. The modification would have entailed using the method of Velculescu and Abdueva to detect hematologic cancer as taught by Murtaza. The modification would have involved a simple substitution of hematologic cancer as one of the targeted cancers of Velculescu. One would have been motivated to make the substitution in order to increase the usefulness of the method of Velculescu as a tool to detect cancers that are widespread such as leukemia and lymphoma and be able to treat a wider population of patients. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
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.
(I). Claims 1, 14-18, 27, and 55 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11 and 12 of U.S. Patent No. 10,975,431. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘431 patent teach all of the limitations of instant claims 1, 14-18, 27, 31, 49, and 55.
Regarding instant claims 1, 14,16, 18, 27, and 55, claim 1 of the ‘431 patent require identifying a subject as having cancer by determining a cell free DNA (cfDNA) fragmentation profile of sequenced fragments in a sample obtained from the subject, wherein the sequenced fragments are obtained through whole genome sequencing (WGS); mapping the sequenced fragments to a genome to obtain windows of mapped sequences; analyzing the windows of mapped sequences to determine the cfDNA fragmentation profile; analyzing the cfDNA fragmentation profile against a reference cfDNA fragmentation profile from a healthy subject; wherein the cfDNA fragmentation profile comprises a ratio of small cfDNA fragments to large cfDNA fragments; detecting that the cfDNA fragmentation profile is indicative of the subject as having cancer; administering to the subject identified as having cancer, an immunotherapeutic treatment suitable for the treatment of cancer, thereby treating the subject.
Regarding instant claims 15 and 17, claims 11 and 12 of the ‘431 patent require wherein the cfDNA fragmentation profile comprises small and large cfDNA fragments in windows across the genome (patent claim 11) and analyzing the cfDNA fragmentation profile relative to a reference cfDNA fragmentation profile over a subgenomic interval (patent claim 12).
(II). Claims 1, 10, 14-17, 25, and 56 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, 11,12, and 16 of U.S. Patent No. 10,982,279 in view of Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘279 patent teach limitations of instant claims 1, 10, 14-17, 25, and 56.
Regarding instant claims 1 and 25, claim 1 of the ‘279 patent requires processing cfDNA fragments obtained from a sample obtained from the mammal into sequencing libraries; subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments; mapping the sequenced fragments to a genome to obtain genomic intervals of mapped sequences; and, analyzing the genomic intervals of mapped sequences to determine cfDNA fragment lengths and determining the cfDNA fragmentation profile using the lengths; detecting a cfDNA fragmentation profile that is indicative of the mammal as having cancer; and administering to the mammal identified as having cancer, a therapeutic treatment suitable for treatment of the cancer.
Regarding limitations of instant claim 1 not taught by the claims of the patent, the teachings of Velculescu and Abdueva as they relate to these claims are given previously in this office action and are fully incorporated here.
Regarding instant claim 10, claim 2 of the ‘279 patent requires the mapped sequences comprise tens or hundreds to thousands of genomic intervals.
Regarding instant claim 14, claim 8 of the ‘279 patent requires the cfDNA fragmentation profile comprises a ratio of small cfDNA fragments to large cfDNA fragments in said windows of mapped sequences.
Regarding instant claim 15, claim 11 of the ‘279 patent requires the cfDNA fragmentation profile comprises the sequence coverage of small and large cfDNA fragments in genomic intervals across the genome.
Regarding instant claims 16 and 17, claim 12 of the ‘279 patent requires the cfDNA fragmentation profile is over the whole genome or a subgenomic interval.
Regarding instant claim 56, claim 16 of the ‘279 patent requires the mammal is a human.
(III). Claims 1, 20, 23, 25, and 55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3,14,15,17,and 19-22 of copending Application No. 18/844,348 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims of ‘348 teach all of the limitations of instant claims 1, 20, 23, 25, and 55.
Regarding instant claim 1, copending claim 1 requires determining a cell-free DNA (cfDNA) fragmentation profile of a sample from a subject; calculating a fragmentation score based on the cfDNA fragmentation profile, the score being indicative of a likelihood of presence of cancer in the subject; determining a ratio of short to long fragments and a fragment size distribution from the fragmentation profile, training a machine learning model using a set of features extracted from a plurality of fragmentation profiles of multiple subjects; and determining, by the machine learning model, a monitoring score for the sample based on the fragmentation score, the divergence score, and the model weights, the monitoring score being indicative of a level of a tumor-derived nucleic acid in the cfDNA of the sample.
Regarding instant claim 1, copending claim 21 requires the cfDNA fragmentation profile is determined by: obtaining and isolating cfDNA fragments from the subject; sequencing the cfDNA fragments to obtain sequenced fragments; mapping the sequenced fragments to a genome to obtain windows of mapped sequences; and analyzing the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile. Copending claim 3 requires the monitoring score has a range of 0 to 1
Regarding instant claim 20, copending claim 14 requires the cancer is a solid tumor.
Regarding instant claim 23, copending claim 15 requires the cancer is a lymphoma and copending claim 17 requires the cancer is a hematologic cancer.
Regarding instant claim 25, copending claim 19 requires administering a cancer treatment to the subject.
Regarding instant claim 55, copending claim 20 requires the cancer treatment is selected from the group consisting of surgery, adjuvant chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy, targeted therapy, or any combination thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(IV). Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/019,448 (reference application) in view of Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645).
Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims of ‘448 recites limitations of instant claim 1.
Regarding instant claim 1, copending claim 1 requires (a) processing a sample from the subject comprising cell free DNA (cfDNA) fragments into sequencing libraries; (b) subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments; (c) mapping the sequenced fragments to a genome to obtain windows of mapped sequences; (d) analyzing, using a computer, the windows of mapped sequences to determine cfDNA fragment lengths; determining that the subject has cancer based on cfDNA fragmentation, and administering a cancer treatment to the subject.
Regarding limitations of instant claim 1 not taught by the claims of the patent, the teachings of Velculescu and Abdueva as they relate to these claims are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments against Double Patenting
The response requests that non-statutory double patenting rejections be held in abeyance until claims are otherwise found to be allowable (p. 16-17).
Applicant's response has been fully considered but is not persuasive.
No terminal disclaimer has been filed and no argument has been presented
against the double patenting rejections.
Thus, for the reasons stated above, and those already of the record, the rejection
is maintained with modifications as presented above necessitated by claim amendments to the instant application and copending applications.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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