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 .
Claims 1-3, 8-10, 14-18,20,23,25, 27,28,31,42, 45, 47, 49, 50, 53, 56 are pending and currently under examination.
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.
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.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “low coverage” in claim 8 is a relative term which renders the claim indefinite. The term “low coverage” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The limitation "subjecting the cfDNA fragments to -- whole-genome sequencing to obtain the sequenced fragments" is rendered indefinite by use of the term "low coverage". The number of reads covering a reference genome encompassed by the term “low coverage” varies widely in the in the art.
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 1-3,8-10,14-18,20,23,25,27-28,31,42,45,47,49-50,53 and 55-56 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
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) determining a cell-free DNA (cfDNA) fragmentation profile of a sample from the subject, the cfDNA fragmentation profile being 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; and b) classifying the subject as having cancer or not having cancer by calculating a score based on the cfDNA fragmentation profile, the score being indicative of a likelihood of presence of cancer in the subject, thereby detecting cancer in the subject.”
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 (i.e. the shape of the curve of cfDNA fragment size density) and the presence of cancer cells in the human is a law of nature/natural phenomenon.
Claim 1 is directed to steps for “analyzing the windows of mapped sequences to determine cfDNA fragment lengths and generate the cfDNA fragmentation profile”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the analyzing step encompasses the mental step of looking at mapped sequences, making mental judgements, and generating a report.
Claim 1 is directed to steps for “classifying the subject as having cancer or not having cancer by calculating a score based on the cfDNA fragmentation profile--”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the classifying step encompasses the mental step of looking at cfDNA fragmentation profiles 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 2-3, 8-10, 14-18, 20, 23, and 25 depend from claim 1, and require the same steps of analyzing, classifying, and calculating and are directed to the same law of nature.
Claim 2 is directed to a method comprising the steps: ”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”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). The steps of determining a ratio, determining a Z-score, and quantifying density are mathematical concepts (see MPEP 2016.04(a)(2)(I)(C)). As written, the calculating step encompasses mathematical concepts such as mathematical calculations.
Claim 18 is further directed to a method that comprises “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; 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, and iv) using a machine learning model to process output of i)- iii) to define the score; 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.
Claim 27 is directed to steps for “calculating a score based on the cfDNA fragmentation profile--”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the classifying step encompasses the mental step of looking at cfDNA fragmentation profiles 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 28, 31, 42, 45, and 47 depend from claim 27, and require the same steps of calculating and are directed to the same law of nature.
Claim 49 is directed to a method of treating a subject having cancer comprising a) detecting cancer in the subject using the method of claim 1 and requires the same steps of analyzing, classifying, and calculating and are directed to the same law of nature.
Claims 50, 53, and 55-56 depend from claim 49, and require the same steps of analyzing, classifying, 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 31 recite the additional limitations “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”. However, these are not integrations of the exception into a practical application. Instead, these elements are data gathering required to perform the method.
Claims 25, 47, and 49 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 2-3, 8-10, 14-18, 20, 23, 25, 28, 31, 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 102 and103 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.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 8, 10, 14-18, 20, 25, 49-50, and 55-56 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Velculescu et al. (WO2019222657).
Regarding claim 1, Velculescu teaches a method for identifying a mammal as having cancer, the method comprising: determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal (subject), obtaining cfDNA fragments; processing (isolating) cfDNA fragments (p. 4, lines 11-13); 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 (p. 4, lines 14-17).
Velculescu further 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).
Regarding claim 8, Velculescu teaches subjecting the cfDNA fragments
to low coverage whole-genome sequencing (p. 3, lines 12-14).
Regarding claim 10, Velculescu teaches mapped sequences can include tens to thousands of windows (p. 4, lines 17-18).
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 49, Velculescu teaches a method for identifying a mammal as having cancer, the method comprising: determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal (subject), obtaining cfDNA fragments; processing (isolating) cfDNA fragments (p. 4, lines 11-13); 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 (p. 4, lines 14-17). Velculescu further 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).
Regarding step (b) Velculescu teaches administering a cancer treatment to the mammal 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).
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, 2, 3, 27,28, 31,42, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Velculescu et al. (WO 2019222657) in view of Abdueva (US20190287645).
The teachings of Velculescu as they relate to claim 1 are stated in the 102 rejection above in this office action.
Regarding claim 2, Velculescu teaches (i) determining the ratio of small cfDNA fragments to large cfDNA fragments (p.4, lines 22-24); (ii) obtaining an arm-specific Z-score (p. 31, line 22); (iii) determining cfDNA fragment density ( p. 8, lines 9-10 ; Figs. 3 and 4A); and (iv) using machine learning to process multiple outputs to determine a score (p. 11, lines 16-20 and Fig. 14).
Velculescu does not teach (ii) quantifying cfDNA fragment density using a computational mixture model analysis
Abdueva teaches methods for cfDNA fragmentome profiling that can be used to assess disease (e.g. cancer) (para 4), the method comprising 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).
Velculescu further states that machine learning can be used with the method for identifying an altered fragmentation profile in multiple parameters (e.g., using coverage of cfDNA fragments, fragment size of cfDNA fragments, coverage of chromosomes, and mtDNA) (p. 18, lines 11-14). Abdueva also teaches using machine learning to build classifiers from multiple metrics (paras 9-11 and 15).
Neither Velculescu nor Abdueva teach using a machine learning model to process output of i)-iii) as claimed to define the score.
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 adding the mixture analysis of cDNA fragment density to the machine learning model of Velculescu. One would have been motivated to do so for the benefit of an additional quantitative metric for cfDNA fragment association with cancer. 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 3, Velculescu teaches DELFI scores between 0 and 1 (Table 7).
Regarding claim 27, Velculescu teaches determining a cell free DNA (cfDNA) fragmentation profile in a sample obtained from a mammal (subject) (p. 3, lines 9-10).
Regarding step (b), Velculescu teaches (i) determining the ratio of small cfDNA fragments to large cfDNA fragments (p.4, lines 22-24); (ii) obtaining an arm-specific Z-score (p. 31, line 22); (iii) determining cfDNA fragment density ( p. 8, lines 9-10 ; Figs. 3 and 4A); and (iv) using machine learning to process multiple outputs to determine a score (p. 11, lines 16-20 and Fig. 14).
Velculescu does not teach (ii) quantifying cfDNA fragment density using a computational mixture model analysis
Abdueva teaches methods for cfDNA fragmentome profiling that can be used to assess disease (e.g. cancer) (para 4), the method comprising 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).
Velculescu further states that machine learning can be used with the method for identifying an altered fragmentation profile in multiple parameters (e.g., using coverage of cfDNA fragments, fragment size of cfDNA fragments, coverage of chromosomes, and mtDNA) (p. 18, lines 11-14). Abdueva also teaches using machine learning to build classifiers from multiple metrics (paras 9-11 and 15).
Neither Velculescu nor Abdueva teach using a machine learning model to process output of i)-iii) as claimed to define the score.
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 adding the mixture analysis of cDNA fragment density to the machine learning model of Velculescu. One would have been motivated to do so for the benefit of an additional quantitative metric for cfDNA fragment association with cancer. 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 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).
Regarding claim 28, Velculescu teaches DELFI scores between 0 and 1 (Table 7).
Regarding claim 31, Velculescu teaches a method for identifying a mammal as having cancer, the method comprising: determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal (subject), obtaining cfDNA fragments; processing (isolating) cfDNA fragments (p. 4, lines 11-13); 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 (p. 4, lines 14-17).
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).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Velculescu et al. (WO 2019222657).
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.
Claim(s) 23 and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Velculescu et al. (WO 2019222657) view of Murtaza et al. (WO2021007462).
The teachings of Velculescu as they relate to claims 1 and 49, which claims 23 and 53 depend from respectively, are stated in the 102 rejection above in this office action.
Regarding claims 23 and 53, Velculescu does not 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 Murtaza to arrive at the instantly claimed invention. The modification would have entailed using the method of Velculescu 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.
Claim(s) 45 is/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 claim 27 above, and further in view of Murtaza et al. (WO2021007462).
Regarding claim 45, 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 Murtaza to arrive at the instantly claimed invention. The modification would have entailed using the method of Velculescu 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, 2, 14-18, 27, 31, 49, 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, 2, 14-18, 27, 31, 49, and 55.
Regarding instant claims 1, 2, 14,16, 18, 27, 31 ,49, 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, 49 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.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘279 patent teach all of the limitations of instant claims 1, 10, 14-17, 25, 49 and 56.
Regarding instant claims 1, 25, and 49, 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 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, 2-3, 20, 23, 25, 49, 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, 2-3, 20, 23, 25, 49, and 55.
Regarding instant claims 1, 2, and 49, 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 claims 1 and 49, 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.
Regarding instant claim 3, 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 claims 25 and 49, 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). Claims 1 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/019,448 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims of ‘448 recites all of the limitations of instant claims 1 and 49.
Regarding instant claims 1 and 49, 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682