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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/24/2025 has been entered.
Applicants Amendment
Applicant’s amendment filed 3/24/2025 have been received and entered. No claim amendments appear to have been made.
Claims 1-17 are pending.
Election/Restriction
Applicant’s election of the specific species in the reply filed on 5/30/2024 was acknowledged, and upon initial search and review the restriction requirement was withdrawn.
Claims 1-17 are pending and currently under examination.
Priority
This application filed 2/7/2024, is a continuation of 18/167804 filed 2/10/2023, which is a continuation of 17/646473 filed 12/29/2021 now US Patent 11613787, which is a continuation of PCTUS2020/059526 filed 11/6/2020, which claims benefit to US provisional application 62/931688 filed 11/6/2019;
and is related to 18/435880 filed 2/7/2024 (updated from last action) which is a continuation of 18/167804 filed 2/10/2023 and 18/056652 filed 11/17/2022 also filed as continuations of 17/646473;
and is the parent of 18/481092 filed 10/4/2023;
and is related to US applications:
18/056656 filed 11/17/2022 (not docketed) which is a continuation of 17/661730 filed 5/2/2022 (now US Patent 11634779), which a continuation of 17/455209 filed 11/16/2021 (now US Patent 11447833), which is the parent to 17/820200 filed 8/16/2022 (ABN) and continuation 18/172957 filed 2/22/2023 (ABN), and is related to 17/646472 filed 12/29/2021 (now ABN), and is related to 17/308958 filed 5/5/2021 (docketed), and is related to 17/107688 filed 11/30/2020 (ABN) all by virtue of common inventors and claim of benefit to PCT/US2020/059526 and/or US provisional applications.
Applicants provide no comments regarding the summary of related applications.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/9/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is noted that for citations of office actions and opinions, there is no specific context of what was evaluated, but each have been reviewed for what was provided.
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).
Response to Applicants arguments
Applicants traverse the rejection arguing that the cited applications and patents do not recite ‘selectively removing cell-free nucleic acids from the sample that do not hybridize to the set of nucleic acid probes, thereby obtaining the fraction of cell-free nucleic acid from the subject’ as recited in claim 1.
In response, review of the claims of the noted applications in the rejections of record do appear to either recite or make obvious this limitation in view of the limitations and breadth of the instant claims. For example, patent 11,447833 (application 17/455209) the personalized probe set used in claim 1 are used to obtain an enriched cell free preparation (portion of claim 1 of ‘833):
“obtaining a personalized set of nucleic acid probes that have been designed to enrich for phased variant-containing nucleic acids from the six or more genomic regions;
preparing cell-free nucleic acids from the patient for sequencing; and
selectively enriching the prepared cell-free nucleic acids from the patient for phased variant-containing nucleic acids”
and while claim 1 above does not specifically recite ‘selectively removing cell free nucleic acids which do not hybridize’ the step of enriching is clearly drawn to this step as the probes are used to hybridize to targets of interest and enriching is a step which provides the hybridized nucleic acids to the exclusion or removal of nucleic acids which do nor hybridize, and appears contrary to the statement that the claims do not provide for the instant claims. Another example for Patent 11634779 (Application 17/661730) while drawn to a computerized method, it is a method which provides for phased variants for 1000 possible informative sequences related to cancer or a cancer state of subject as provided in steps:
“(b) processing, by the computer system, the sequencing data to identify one or more cell-free DNA molecules of the at least 1,000 cell-free DNA molecules, wherein identifying the one or more cell-free DNA molecules comprises aligning reads corresponding to each of the at least 1,000 cell-free DNA molecules to a reference genome, wherein each of the one or more cell-free DNA molecules comprises a plurality of phased variants relative to a sequence from the reference genome, wherein at least 10% of the one or more cell-free DNA molecules comprises a first phased variant of the plurality of phased variants and a second phased variant of the plurality of phased variants that are separated by at least one nucleotide; and
(c) analyzing, by the computer system, the identified one or more cell-free nucleic acid molecules to determine a cancer or a cancer state of the subject.”
and are considered encompassed and a necessary step of the instant claims for personalized probes and ‘obtaining a set of nucleic acid probes’ which are designed to harbor phased variants indictive of cancer in a subject as required by the instant claims as such types of probes cannot be created de novo and some information about the patient or cancer must first be obtained. While instant claim 1 is broader, the method of assessing for obtaining the necessary probes to successfully practice the instant claims appears to be encompassed in the present claims. Therefore, practicing the instant claims would necessarily require the practice of ‘779 and is an obvious use of sequences and probes that are informative about a cancer for a specific patient. Given this analysis and no specific arguments for each of the cited applications and patents, the rejections are maintained.
Previous rejections of record
Claims 1-17 stand rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Application 17/455209 filed 11/16/2021 (US Patent No. 11447833).
Although the claims at issue are not identical, they are not patentably distinct from each other because the steps of ‘209 are practiced in the instant methods to provide sequence reads with 2 or more phased variants in a single read (i.e. in cis), and the reads are obtained from cfDNA. Dependent claims provide for the same sample source and enrichment steps to provide for informative sequence reads. Independent claim 1 of ‘209 is provided for the record:
1. A method for preparing an enriched library of nucleic acids for sequencing, the method comprising:
identifying a patient-specific set of six or more genomic regions that have been shown to harbor a plurality of phased variants that are within 170 base pairs of each other;
obtaining a personalized set of nucleic acid probes that have been designed to enrich for phased variant-containing nucleic acids from the six or more genomic regions;
preparing cell-free nucleic acids from the patient for sequencing; and
selectively enriching the prepared cell-free nucleic acids from the patient for phased variant-containing nucleic acids from the six or more genomic regions via hybridization capture or amplification to form an enriched library of nucleic acids for sequencing;
wherein identifying the patient-specific set of six or more genomic regions that have been shown to harbor a plurality of phased variants comprises comparing sequencing data from a either a diseased sample from the patient or a cell-free DNA sample from the patient to sequencing data from a non-diseased sample from the patient;
wherein at least 10% of phased variant-containing nucleic acids from the library of nucleic acids have a first phased variant and a second phased variant that are separated from each other by at least one nucleotide.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of Application No. 17/661730 filed 5/2/2022 (now US Patent 11634779). Although the claims at issue are not identical, they are not patentably distinct from each other because the additional steps set forth in the instant claims are provided as obvious steps for obtaining sequence read data. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer. A copy of the pending independent claims are provided for comparison.
From ‘730:
1. A method comprising:
(a) obtaining, by a computer system sequencing data for at least 1,000 of cell-free DNA molecules from a subject;
(b) processing, by the computer system, the sequencing data to identify one or more cell-free DNA molecules of the at least 1,000 cell-free DNA molecules, wherein identifying the one or more cell-free DNA molecules comprises aligning reads corresponding to each of the at least 1,000 cell-free DNA molecules to a reference genome, wherein each of the one or more cell-free DNA molecules comprises a plurality of phased variants relative to a sequence from the reference genome, wherein at least 10% of the one or more cell-free DNA molecules comprises a first phased variant of the plurality of phased variants and a second phased variant of the plurality of phased variants that are separated by at least one nucleotide; and
(c) analyzing, by the computer system, the identified one or more cell-free nucleic acid molecules to determine a cancer or a cancer state of the subject.
Claims 1-17 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 17/308958 filed 5/5/2021 (docketed no action mailed).
Although the claims at issue are not identical, they are not patentably distinct from each other because the steps set forth ‘958 are used to provide sequence reads that represent phased variants that are analyzed or correlated to a condition. The instant claims encompass the steps and provide sequence read data that contains a variation which is an indel and is correlated and associated with a condition such as cancer. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer. A copy of the pending independent claim of ‘958 is provided for comparison.
4. (Amended) A computer-implemented method comprising:
(a) obtaining, by a computer system, sequencing data derived from a plurality of cell- free nucleic acid molecules obtained or derived from a subject;
(b) processing, by the computer system, the sequencing data to
(1) identify one or more cell-free nucleic acid molecules of the plurality of cell-free nucleic acid molecules, wherein each of the one or more cell-free nucleic acid molecules comprises a plurality of phased variants relative to a reference genomic sequence that are separated by at least one nucleotide, and
(2) identify one or more insertions or deletions (indels) relative to the reference qenomic sequence; and
(c) analyzing, by the computer system, the identified one or more cell-free nucleic acid molecules and the one or more indels to determine a condition of the subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-17 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/056656 filed 11/17/2022 (in prosecution). Although the claims at issue are not identical, they are not patentably distinct from each other because the steps set forth in the methods are used to provide sequence reads that represent phased variants that are analyzed or correlated to a condition. The instant claims encompass the steps and provide sequence read data that contains a variation which is an indel and is correlated and associated with a condition such as cancer. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer.
Claims 1-17 stand rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of 17/646473 filed 12/19/2021, now US Patent 11613787 (grand parent of present application). Although the claims at issue are not identical, they are not patentably distinct from each other because the additional steps set forth in the instant claims are provided as obvious steps for obtaining sequence read data. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer.
Claims 1-17 stand rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of 18/056652 filed 11/17/2022 now US Patent 11851716 and 18/167804 now US Paent 11965215 (also filed as continuations of parent 17/646473). Although the claims at issue are not identical, they are not patentably distinct from each other because the additional steps set forth in the instant claims are provided as obvious steps for obtaining sequence read data. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer.
Claims 1-17 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/167804 filed 2/10/2023 and 18/167803 filed 10/4/2023 (parent of instant application). Although the claims at issue are not identical, they are not patentably distinct from each other because the steps set forth are used to provide sequence reads that represent phased variants that are analyzed or correlated to a condition. The instant claims encompass the steps and provide sequence read data that contains a variation which is an indel and is correlated and associated with a condition such as cancer. While the claims set forth different amounts of reads, only one or more phased reads are required in the analysis step and the correlation to determining a condition such as cancer.
As noted in prosecution, 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-11 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
Response to Applicant’s arguments
Applicants summarize the basis of the rejection, and assert that given the region start and region end on the top of the table, the skilled artisan would understand each would refer to a regions, and that it refers to 10% of the entries in the table.
In response, the labels on the table are acknowledged however what is set forth in the tables are a listing of different portions of a chromosome with start and end points (‘regions’) and it is unclear what the probes are directed to meet the limitations required of the claims. Would one probe which is smaller than each of portions but for 10% of the listed entries be required, probes that span at least 10% of each of the listed entries be required for all the listings, or if in combination of the regions length probes that cover 10% of all the regions but not all of the listings is encompassed. The metes and bounds are ambiguous because there are alternative interpretations and it is unclear what is required of the probes to practice the method.
Applicants argue that the claims do not require that there is no requirement for the claims to provide preferred embodiments to satisfy the definiteness requirement.
In response, examiner acknowledged that preferred embodiments are not required to be in the claims nor necessarily needed to provide for clarity. However, claim 1 requires that the set of probes in step (b) are designed for enrichment of genomic regions known to harbor phased variants, and with respect to the tables and requirements of the claims, noting the teaching in the specification that supports that some of the regions listed are not known to harbor phased variants, the basis of the rejections alleges the metes and bounds are unclear because some of the regions are acknowledged not to contained phased variants and it is unclear how the probes are then to be designed using the list of regions in the table.
This is also compounded with the requirement of claim 1 and the necessity of the claims to comprise at least 10% of the regions, and it is unclear if then the regions even need to provide for phased variants as set forth in claim 1 or if the disclosure and description of the regions in the specification is inconsistent with the use set forth in the claims and that any 10% of any region, even if it did not harbor a phased variant would be encompassed by the probes designed in the dependent claims.
Again, the tables provide for coordinates but not any specific sequences to which the coordinates refer to and the metes and bounds of these limitations appear to be undefined as there is no reference to apply the start and end, and are relevant to a reference that is not provided. While the claims set forth and require ‘at least 10% of the regions set forth below’ it is unclear if this is 10% of the entirety of the genome the sequences possibly cover by these indicated references or 10% of the list or for any one specific section 10% of start/end region indicated. In light of evidence that some of the listed regions do not appear to harbor phased variants, it is unclear what is enriched or required of the probes of the claims. With respect to the requirement of the independent claims, the information that most of the regions set forth are not phased variants but included for genotyping, and it is unclear what specific sequences are required and in view of the information only ones indicated and labelled phase variants are to be included, or if the genotyping are considered to harbor specific variants considered phased variants within the breadth of the claims.
Providing sequences required or specific probes for phased variants associated with hematological cancer required of the claims would address the basis of the rejection.
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 1-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim analysis
Claim 1 has not been amended and still is generally directed to method of preparing cfDNA fraction with three steps of obtaining a sample, obtain probes to enrich genomic sequences with variants and produce a fraction by hybridization. The target regions of the genome should represent at least 10% of the nucleic acids where phased variants are within 170 bp which could be present on a cfDNA, or alternatively if any cfDNA does represent a phased variant among those contacted and selected of the ones isolated 10% of them should have 2 variants separated by at least one nucleotide. Dependent claims provide that the sample represents a hematological cancer such as lymphoma, a listing of probes to be used, and levels of enrichment to be achieved.
Response to arguments
Applicants summarize the response in the advisory action and provide an overview for 101 analysis noting the guidance of MPEP 2106.01 and argue that it is not sufficient to infer a mental step when evaluating for a judicial exception.
In response, the claims are evaluated for the breadth they encompass and specifically for step (b) in ‘obtaining’ and what is encompassed. In view of the evidence of record, this is not a term of art nor does there appear to be a specific disclosure of pre-existing probes that exist, thus obtaining is interpreted to encompass the discovery, design as well as the synthesis for later steps where they are used for hybridization. In view of the specification, dependent claims that list tables appear to provide regions of chromosomes some of the regions which appear to harbor informative phased variants, thus the claims appear to support that discovery and design are encompassed within the breadth of ‘obtaining’ and not simply an inference but rather necessary and required steps comprised in obtaining which are necessary to enable practice of the claims.
Applicants argue that the claims mirror the fact pattern of Illumina v. Ariosa and that physical steps for enrichment are not a judicial exception.
In response, as analyzed and discussed above, the instant claims clearly require mental steps in order to practice the claims, and depart from the fact pattern because the claims are not only ‘enrichment’. While step c) does provide hybridization and effective enrichment, step b) requires the discovery and design of the probes as a necessary step of obtaining which can subsequently be used for enrichment of step c). The physical steps of the claims are evaluated under Step 2B, and once informative or useful probes are known or obtained, steps for using such probes for enrichment and further characterization have been found to be known convention uses of probes. The evidence of record supports that such steps were well known and used to obtain sequences of interest from samples, and even probes to known genes associated with cancer were known and used. Further, it is acknowledged that the claims do not specifically recite any specific analysis steps required to provide for the set of probes used, however given the lack of evidence that such exist and for any given subject and every type of hematological cancer probe sets necessary to practice the claims, step b) for ‘obtaining’ has been interpreted to encompass and require these analysis steps as they appear to be necessary to meeting this limitation of the claims for description of the probe set that is ‘obtained’.
Further, the fact pattern of Ariosa can be differentiated from the present claims as the separation steps in the claims at issue were performed by differentiating the size of the cfDNA in the sample, and did not require discovery or design of probes for the enrichment step. In the decision and the basis of the invention, it was clear that it was based on the observation that fetal cfDNA on average was of a smaller size than that of the mother and the other cfDNA in the sample. Here, the invention is in part based broadly that phased variance exist in a genome and that they can be used in evaluating targets or sequences of interest. In Ariosa it appears that the court found that the judicial exception and/or observation of size difference was practically applied and used to separate fetal and mother cfDNA fractions present in a sample. Whereas here, the step of the claim sets forth ‘obtaining’, and given the guidance and evidence of record clearly requires further analysis for any given subject and for the many different types of hematological cancer known to exist, and does not provide a direct application of a judicial exception as was in Ariosa. Further, while phased variants were known in the art and there may be an expectation that variants present in the genome would also be present in the cfDNA, there is no specific disclosure to obtain such beyond analyzing a sample to determine if such phased variants exist for a population of individuals having a hematological cancer as set forth in the claims, and given this fact pattern step b0 for obtaining is considered to be directed to the judicial exception and analysis steps encompassed and required to meet the limitations of the claims.
As noted previously, one way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
Previous Rejection of record
For step 1 of the 101 analysis, claims 1-17 are found to be directed to a statutory category of a method/process.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of processing sequence data to design probes representative of phased variants associated with cancer. More specifically, the step of ‘obtaining a set of nucleic acid probes’ is considered to be directed to the process and requirement to practice this step that the set is ‘designed for enrichment of genomic regions that are known to harbor phased variants in a population of individuals having hematological cancer’. The specification and evidence of record fails to provide the necessary disclosure of what these sets are for the breadth of the claim. In review, the specification provides guidance on how to determine and potentially define such sets through the analysis of specific sample sources, but fails to provide sets are known or simply physically obtained for the breadth of the claims. The judicial exception of the claims is considered the necessary discovery and design encompassed in ‘obtaining’ as currently required of the claims.
More generally, the specification teaches that for “phased variants” the term is defined in Applicant’s specification refer to two or more mutations that occur in cis (i.e. on the same strand of a nucleic acid molecule). Therefore “phased variants” is interpreted to refer to two or more mutations that occur in cis on a single read. The types of mutations can be any type either being somatic mutations present in the germline or mutations that occur for example during the pathological process of cancer. The steps required for designing and of evaluating a linear sequence for variants/mutations/SNPs are instructional steps for processing the sequencing data to identify one or more cell-free nucleic acid molecules of the plurality of cell-free nucleic acid molecules, wherein each of the one or more cell-free nucleic acid molecules comprises a plurality of phased variants relative to a reference genomic sequence, wherein at least about 10% of the one or more cell-free nucleic acid molecules comprises a first phased variant of the plurality of phased variants and a second phased variant of the plurality of phased variants that are separated by at least one nucleotide; and analyzing the identified one or more cell-free nucleic acid molecules to determine a condition of the subject. The claim encompasses simply assessing a sequence read for possible variants in the read and providing the correlation if it exists of a condition and the variants identified. The judicial exception is a set of instructions for analysis of sequence data which appears to be a Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion).
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims do have an additional element to which the judicial exception is applied except to instruct to use sets once obtained broadly. Providing or designing target probes for enrichment are well known, however as reasoned above the step of obtaining requires knowledge which is not disclosed in the specification nor evidenced in the record. This judicial exception requires steps recited at high level of generality and requires analysis for any individual in which the method is practiced to provide the starting information for designing and obtaining sets to be used in subsequent steps, and is not found to be a practical application of the judicial exception as broadly set forth.
For step 2B of the 101 analysis, each of the independent claims does not require an additional element and to the extent obtaining sequence data about cfDNA they are found to be the steps of isolating sequences and in dependent claims for obtaining sequence data which subsequently is analyzed in the judicial exception. As such, the claims do not provide for any additional element to consider under step 2B which is considered significantly more. For the claims that provide no additional elements and are only instructions to analyze read data, it is noted that while it can be performed on a computer in explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process." Here, the claims require only identifying two variants in a read if present and do not appear to be so complex that it requires a computer. The additional elements of a computer system and data input are generic components and/or processes. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). Therefore, these additional elements do not integrate the recited judicial exception into a practical application. As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence data. While the instructions are stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer.
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 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 1-17 stand rejected under 35 U.S.C. 103 as being unpatentable over Mateo et al (J Clinical Oncology Oct 2012) and Kurtz (Personalized Risk Assessment and Disease Monitoring in Non-Hodgkin Lymphoma from Circulating Tumor DNA, 2017, Stanford University).
Response to Applicants’ arguments
Applicants argues that Mateo does not teach the limitations of claim 1 and that mutations associated with cancer are not phased variants nor does Mateo provide for fractionation and selection or that any of the phased variants are separated by at least one nucleotide.
In response, it is acknowledged that Mateo does not teach this limitations of the claim relative to isolating cell free nucleic acids from a sample, however, the evidence that informative phased variants exist in hematological samples relies on the teachings of Kurtz. More specifically, once informative sequences are known, there is a high level of skill in the art and expectation that one can use the probes to identify such sequences in a sample. The basis and rational of the rejection notes that Mateo is provided as evidence that variants in the genome associated with cancer which would be detectable in cfDNA exist and could be detected if present in a sample. While these are not indicated to be phased variants, Kurtz clearly provides that such sequences exist and are useful in obtaining samples for sequence analysis. With respect to the breadth of ‘phased variants’ it is noted that the specification teaches at [0048] that: “In some embodiments of any one of the methods disclosed herein, the set of nucleic acid probes is designed based on the plurality of phased variants that are identified by comparing (i) sequencing data from a solid tumor, lymphoma, or blood tumor of the subject and (ii) sequencing data from a healthy cell of the subject or a healthy cohort. In some embodiments, the healthy cell is from the subject. In some embodiments, the healthy cell is from the healthy cohort.”, and so Mateo was provided as further guidance and expectation that cfDNA as compared to normal cfDNA specifically provides for 238 identified differences and 19 targeted oncogenes that were correlated with cancer for analyzed samples that have been demonstrated in the art providing motivation and expectation that analysis of read data for these cancer types would yield similar results. Mateo was provided as a teaching within the breadth of the claims and as evidence of an expectation of success that phased variants encompassed by claims in a cancer patient sample could be targeted and identified similar to those identified in Kurtz et al.
Applicants argue that the dissertation of Kurtz is not prior art. Applicants provide an overview of MPEP 2128 and cite Cronyn and Acceleration Bay arguing that a shelved doctoral thesis in a library were not assessable and that a document on line is not always deemed a printed publication, respectively.
Applicants note that the dissertation was submitted to the Stanford Library system and was subject to an embargo for two years after the submission on Dec 9, 2017. Pointing to the declaration of Kurtz filed in a related application (17/107668), applicants argue it was the understanding and intent to pursue opportunities to seek patent protection. Further a declaration from Calter also filed in a related application (17/107668) indicates that the dissertation was under embargo for the two years and there is no record of the dissertation being printed or checked out for use. Applicants cite Cordis Corp and argue that ‘academic norms gave rise to an expectation that disclosures would remain confidential.
In response, the embargo and discussion in the declarations has been acknowledged. Initially, it is noted that the submission date of December 9, 2017 has not been contested throughout prosecution. With respect to arguments of the intent of Kurtz the inventor, this does not appear to be a factual consideration with respect to public availability, rather what standards the embargo imparts when used and applied to a document is what appears to be critical with respect to availability. With respect to guidance about embargos provided by the Stanford library at Standford Student Services, Submit your dissertation or thesis web page (duplicated below as found at https://studentservices.stanford.edu/my-academics/earn-my-degree/graduate-degree-progress/dissertations-and-theses/submit-your ) the guidance provided is:
Delayed Release (Embargo)
You, as the author, have the option to delay the release of a dissertation or thesis to search engines outside of Stanford and other third-party distributors. Under an embargo, the dissertation or thesis will be available online to Stanford-authenticated users, but not to readers outside the Stanford network.
Release delay options are: six months, one year, or two years. Embargos of longer than two years require the review and approval of the Subcommittee on Exceptions to Graduate Policy (S-EGP).
The embargo option may be appropriate for a student who wants to delay access to the dissertation or thesis for a limited amount of time in order to pursue other publications.
Embargos and Patent Protection
Please note that the laws of different jurisdictions vary on what constitutes a public disclosure that could prevent or impede one’s ability to obtain patent protection for inventions disclosed therein.
Stanford takes no position with regards to whether the delayed release of a dissertation or thesis will safeguard the ability to obtain patent protection for inventions disclosed therein. Instead, Stanford recommends that any patent filings relating to material described in the dissertation or thesis occur prior to submission, whether or not the dissertation or thesis is under delayed release.
With respect to availability, it has been acknowledged in the declarations and in prosecution that the dissertation was indexed on Stanford’s catalog system and available to anyone with access to the Stanford library and having a SUNet ID. Unlike the fact pattern of Cronyn where the dissertation was cataloged and available in a chemistry library that was not geerally accessible, here the dissertation was accessible in a library which appears to be publicly accessible to a large number of individuals unlike the those discussed in Cronyn and/or Bayer. Further, while it is argued that the printed copy or a request for an on-line version of the dissertation was not requested, again whether one accesses a prior art document or not does not appear to be a criteria of determining ‘availability’ as prior art (see also MPEP 2128 III). With respect to the inventor’s intent, the guidance for dissertation submission and use of an embargo within the Stanford library system appears to caution and disclaim any reliance on the embargo with respect to public disclosure considerations. The findings of Cordis are noted, however the fact pattern appears to be different from the instant fact pattern. The Kurtz dissertation was cataloged and available in printed and digital forms in the Stanford library system, while the ten page paper that was distributed as micrographs, and further which evidence supported and acknowledged that they were not distributed beyond those provided by Dr. Palmaz, were found not to be ‘publicly accessible’ given to the limited distribution and lack of access or copies being provided given the specific facts of the decision. The reliance on Cordis and the limited distribution of micrographs does not appear to align with the present fact pattern and availability of the Kurtz dissertation present in Stanford library system. Further, there is no legal obligation as presented with respect to availability and use of a dissertation required by Stanford nor the use of an embargo, and does not appear to be consistent with arguments of confidentiality or professional behavioral norms discussed in the Cordis decision to discount the Kurtz dissertation as prior art. Additionally, the fact pattern of Cronyn does not appear to be consistent with the availability of the Kurtz dissertation because the Kurtz dissertation was cataloged and publicly available within the Stanford library system, and access to the dissertation in printed and digital copies were also available. With respect to on line availability and the fact pattern of Acceleration Bay it is initially noted that the court relied on and stated:
“Whether a reference qualifies as a printed publication under § 102 is a legal conclusion based on underlying fact findings.6 Jazz Pharm., Inc. v. Amneal Pharm., LLC, 895 F.3d 1347, 1356 (Fed. Cir. 2018); accord Cooper Cameron Corp. v. Kvaerner Oilfield Prod., Inc., 291 F.3d 1317, 1321 (Fed. Cir. 2002). One such fact question is public accessibility, which we review for substantial evidence. Jazz Pharm., 895 F.3d at 1356. “Because there are many ways in which a reference may be disseminated to the interested public, ‘public accessibility’ has been called the touchstone in determining whether a reference constitutes a ‘printed publication’ . . . .” Id. (quoting In re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986)). A reference is considered publicly accessible if it was “disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it.” Id. at 1355–56 (citing In re Wyer, 665 F.2d 221, 226 (CCPA 1981)). As petitioner, Blizzard had the burden to prove Lin is a printed publication. See id. at 1356.”
With respect to the Lin reference discussed in the decision, the fact pattern is not similar to the instant fact pattern because Lin was simply posted on line and not cataloged nor available at a university library as was the Kurtz dissertation. Further, it is noted that Applicants acknowledge in their response that a print copy of the dissertation was available in the library in Stanford’s Special Collections and not simply an on-line publication as was the Lin reference. In either case, electronic copy or printed, it is noted that MPEP suggests that both would be considered ‘printed publication’. Specifically, it is noted:
“A reference is proven to be a "printed publication" "upon a satisfactory showing that such document has been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it." In re Wyer, 655 F.2d 221, 210 USPQ 790 (CCPA 1981) (quoting I.C.E. Corp. v. Armco Steel Corp., 250 F. Supp. 738, 743, 148 USPQ 537, 540 (SDNY 1966)) ("We agree that ‘printed publication’ should be approached as a unitary concept. The traditional dichotomy between ‘printed’ and ‘publication’ is no longer valid. Given the state of technology in document duplication, data storage, and data retrieval systems, the ‘probability of dissemination’ of an item very often has little to do with whether or not it is ‘printed’ in the sense of that word when it was introduced into the patent statutes in 1836.”
Applicants note that in prosecution the Kurtz reference was identified after the embargo and argue that one of skill in the art not having the dissertation available on public search engines until 2019 and that the ‘dissemination of the dissertation was effectively non-existent’. Further, using the search parameters as used in the declaration of Dr. Butte, Applicant argues that even if one were to search the Stanford catalog, the full text search of the dissertation was not available and one of skilled in the art of cell-free DNA community would not have been aware to search Stanford’s catalog nor motivated to search Stanford’s SearchWorks system during the embargo.
In response, these arguments are acknowledged but do not appear to be a requirement or applicable in assessing whether a reference is publicly available. While it is generally acknowledged that indexed search engines or full text searches can provide certain advantages, they do not appear consistent with assessing public availability. Further, in MPEP 2128 it is specifically noted that proof of anyone actually looking at a document is not a requirement stating:
‘There is no need to prove that someone actually looked at a publication when that publication is accessible to the public through a library or patent office. See In re Wyer, 655 F.2d 221, 210 USPQ 790 (CCPA 1981); In re Hall, 781 F.2d 897, 228 USPQ 453 (Fed. Cir. 1986). "A reference is considered publicly accessible 'upon a satisfactory showing that such document has been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it.' 'If accessibility is proved, there is no requirement to show that particular members of the public actually received the information.'" Jazz Pharm., Inc. v. Amneal Pharm., LLC, 895 F.3d 1347, 1355-1356 (Fed. Cir. 2018) (quoting Wyer, 655 F.2d at 226) and Constant v. Advanced Micro-Devices, Inc., 848 F.2d 1560, 1569, 7 USPQ2d 1057, 1062-63 (Fed. Cir. 1988)).’
In this case, given the evidence of record the Kurtz dissertation appears to have been accessible within the Stanford library system. A dissertation does not appear to comport with guidance of internal documents intended to be confidential, and while under an embargo was in place the fact pattern is not consistent with that of In re George. The simple question was one of accessibility to the public. Additionally, the courts have stated that: “"We have consistently held that indexing or searchability is unnecessary for a reference to be a printed publication." (see fact pattern provided in Jazz Pharm., Inc. v. Amneal Pharm., LLC, 895 F.3d 1347, 1359, 127 USPQ2d 1485,1493 (Fed. Cir. 2018) further suggesting arguments that different types of search would not identify the Kurtz dissertation do not apply in the availability of a reference as prior art.
Given the evidence of record while the embargo of the Kurtz dissertation is acknowledged, the printed and digital copies appeared to be accessible to the public as of Dec 9, 2017 and it qualifies as prior art. Accordingly, for the reasons above and of record the rejection is maintained.
Previous rejection and analysis of record
For completeness of the record, the rejection of record is provided. Claim 1 provides a method for preparing a cfDNA fraction comprising three steps of obtaining a sample, obtaining probes to enrich genomic sequences with variants and produce a fraction by hybridization. The target regions of the genome should represent at least 10% of the nucleic acids and that the variants are within 170 bp as exemplified by cfDNA but includes variants in genomic DNA. Further, the specification teaches that for “phased variants” the term is defined in Applicant’s specification refer to two or more mutations that occur in cis and encompass any type of variant, for example somatic SNP or allele differences among individuals or newly generated variations such as insertions, deletions or any type of mutation that may occur in cancer progression. Dependent claims set forth the variant is a SNP, can be more than two variants, provide tables of genomic regions of interest which can be enriched or analyzed, that the condition is related more specifically to cancer, that further steps of analysis are performed comparing normal and tumor samples, and the tumor is a solid tumor.
The use and identification of genomic variants or oncogenic mutations associated with cancer was well known as evidenced by Mateo et al. More specifically, Mateo et al provide an analysis of matched genomic and cfDNA samples and identify 238 oncogenic mutations using 19 targeted oncogenes (from Sequenom Panel 1.0). Mateo et al demonstrate a good correlation between the samples and discuss the difference that can be detected and differences from that of healthy volunteers and that between tumor and cfDNA (see for example table listing number of mutation sites for specific oncogenes from the panel). The use of specific targeted panel of informative probes for genes represent targeted portions of a genome, which can be detected with direct genome analysis or in cfDNA. While demonstrating that biological samples can be obtained, probe sets can be obtained which are capable of providing information about mutations or variations associated in specific genes and in cancer patients, and that they use of the Sequenom panel requires hybridization, Mateo et al do not produce a fraction, rather provide the analysis directly. Similarly, but for a broader range of genes, Kurtz who teaches a method for monitoring disease using circulating tumor-derived DNA (ctDNA) (Abstract) which comprises obtaining sequencing data from circulating tumor DNA (ctDNA) from a plasma sample from a subject (see for example Figure 3; Supplemental Figure C3-S5). Kurtz shows processing the sequencing data from the ct-DNA (Figure 4) to identify cell-free DNA molecules containing multiple mutations on a given read, or mutational haplotypes (i.e. a plurality of phased variants) (pg. 227, para. 1; Figure 26B, Figure 28A, e.g. # mutational haplotypes). This shows that all of the identified nucleic acid molecules (i.e. 100%) comprise a first and second phased variant, as recited in claim 1. Kurtz et al. further provides the first and second phased variants are separated by at least one nucleotide (Figure 28 B, e.g. each gray bar is a read, and mutations are colored letters). Further, Kurtz provides analyzing the allele fraction of the phased reporters (i.e. the identified one or more cell-free nucleic acid molecules) to detect the subject's relapse (i.e. to determine a condition of the subject (Figure 28 D). for specific methodology, the sequencing data for the subject (e.g. patient DLBCL002) was obtained using traditional CAPP-Seq, which does not involve background or sequencing error suppression (pg. 4, para. 3, e.g. the major limitation to CAPP-Seq is the background error-rate inherent in sequencing; pg. 227, para. 2), rather than with integrated digital error suppression enhanced CAPP-Seq, which involves error suppression (pg. 4, para. 3 to pg. 5, para. 1; pg. 224, para. 2). With respect to the specificity of the analysis Kurtz shows the frequency of the phased variants (i.e. a number of the plurality of phased variants) is indicative of relapse of the subject (Figure 28 D), and provides that the ratio of the plurality of phased variants and a number of single nucleotide variants is also indicative of the condition of the subject, given the ratio is merely the number of phased variants normalized by another number; that is, normalizing the number of the plurality of phased variants would not change that the number is indicative of a condition of the subject. In describing the read data, Kurtz shows the identified cell-free DNA molecules all (i.e. 100%) contain multiple mutations on a given read, or mutational haplotypes (i.e. a plurality of phased variants) (pg. 227, para. 1; Figure 26B, Figure 28A, e.g. # mutational haplotypes) and specific variants on the reads were mapped to the hg19 reference genome (pg. 17, para. 2; pg. 147, para. 2).
Kurtz teaches the use of CAPP-Seq to monitor tumor dynamics during therapy in a cohort of over 200 diffuse large B-cell lymphoma (DLBCL) patients, demonstrating the prognostic significance of changes in ctDNA levels as quickly as three weeks into treatment (Abstract, Page iv). This corresponds to the claim limitation of a method of monitoring progress of a condition. Kurtz teaches in Supplemental Figure C3-S9 that one or more patients has a mean ctDNA concentration of approximately 103 hGE/mL at diagnosis (page Supplemental Figure C3-S9, Figure 104). At diagnosis corresponds to the first timepoint. This corresponds to the claim limitation that at least 1,000 DNA molecules obtained from the subject at the first timepoint. Kurtz teaches in Figure 13B the change of ctDNA disease burden in response to treatment and during clinical progression in a patient with stage IIAX DLBCL (Figure 13, Page 85). Shown are the mean allele frequencies of all SNVs detected by CAPP-Seq (left y-axis) and the number of lymphoma DNA molecules per ml of plasma identified by lgHTS (right y-axis) over serial time points (x-axis) (Figure 13, Page 85). Figure 13B depicts multiple time points, which includes the first time point. From Figure 13B, it is interpreted that day 0, diagnosis, is the first timepoint that the data was obtained from the subject. This corresponds to the claim limitation of sequencing data for DNA molecules obtained from a subject at a first timepoint. From Figure 13B, it is interpreted that day 31 is the second timepoint that the data was obtained from the subject and it is subsequent to day 0. This corresponds to the claim limitation of sequencing data for a plurality of cell-free DNA molecules obtained from the subject at a second timepoint that is subsequent to the first timepoint. It is noted that Kurtz analyzed publically available whole genome sequencing (WGS) data from 79 patients with B-cell non Hodgkin lymhpomas, as well as WGS data from 145 patients with CLL (Page 227, Paragraph 1). We binned the genome into 170bp bins and assessed what fraction of patients contained two or more somatic alterations within each bin (Page 227, Paragraph 1). Shockingly, we observed a significant number of 170 bp regions recurrently containing multiple mutations (Figure 28A). This included many known targets of AID/AICDA, including /GH, IGUIGLL, IGK, BCL2, BCL6, and MYC. Indeed, when examining our own sequencing data, we frequently observe multiple mutations on a given read (Figure 28B) (Page 227, Paragraph 1). In fact, these mutational haplotypes or "phased reporters" are the defining feature of our sequencing panel, as shown in Figure 28C. In this figure, each SNV detected in DLBCL022 is represents a node along the circle (Page 227, Paragraph 1). If two mutations were ever seen on the same DNA molecule, they are connected by an arc, with the color of the arc representing the number of times two mutations were seen together. This exemplar patient demonstrates the frequency of these "phased reporters" - especially across the IGH locus on chromosome 14, but also in BCL6 on chromosome 3 in this patient with a known BCL6 translocation (Page 227, Paragraph 1). Mutational haplotypes or "phased reporters" taught by Kurtz is interpreted to be equivalent to phased-variant. Kurtz further teaches patient DLBCL002, initially presented in Figure 25. Recall that this patient, who ultimately had relapsed disease, had her disease detectable by traditional CAPP-Seq for 3 time-points leading up to and including the time of her relapse (Page 227, Paragraph 2). However, several samples prior to this sample were undetectable by CAPP-Seq. By going back and reanalyzing the same sequencing data for "phased reporters", we can detect ctDNA one time-point earlier than with single mutations alone (Figure 28D), at an allele fraction below the limit of detection for single mutations (Page 227, Paragraph 2). In Figure 28D, Kurtz teaches various time points for the identification of disease-derived phased-variant, which includes the first and second time point (Figure 28, Page 237). While Figure 28B teaches the identification of the genomic location of the disease-derived phased-variant (Figure 28, Page 237). Given the guidance of Kurtz, the claim limitation of the sequencing data for the at least 1,000 DNA molecules obtained from the subject at the first timepoint to identify and determine genomic locations of the at least 1,000 disease-derived phased-variant containing DNA molecules and the sequencing data for the plurality of cell-free DNA molecules obtained from the subject at the second timepoint to the genomic locations of the plurality of disease-derived phased-variant containing DNA. Additionally, Figure 28D also teaches the allele fraction of the phased reporters (Figure 28, Page 237), which is equivalent to the claim limitation of to assess an extent to which the cell-free DNA molecules from the subject at the second timepoint comprise disease-derived phased-variant containing cell-free DNA molecules. Kurtz further teaches the final selector design covered 1,053 genomic regions from 268 genes, totaling 242 kb (247 kb when including additional MYC regions). Biotinylated oligonucleotides were designed using the NimbleDesign portal (Roche NimbleGen) and genome build hg19 (NCBI Build 37.1/GRCh37). Kurtz also teaches Sequencing reads were mapped to the human genome (build hg19) (Page 1, Paragraph 2). hg19 (NCBI Build 37.1/GRCh37) corresponds to the claim limitation of a reference genomic sequence of at least 10 kb in length. Kurtz identify somatic alterations and track circulating tumor DNA (ctDNA), samples were sequenced by CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing) using either of two targeted sequencing panels (Page 147, Paragraph 2). Paired-end sequencing was performed on the lllumina HiSeq2500 or HiSeq4000 platform using custom adapters for sample multiplexing and molecular barcoding. Sequencing reads were mapped to the human genome (build hg19) followed by removal of PCR duplicates and technical artifacts (Page 147, Paragraph 2). The human genome taught by Kurtz is interpreted to be equivalent to the reference genome. This corresponds to the claim limitation of wherein the identity and genomic locations of the disease-derived DNA molecules are determined based on alignment of reads corresponding to each of the at least 1,000 DNA molecules to a reference genomic sequence of at least 10 kb in length. Kurtz teaches that all analyses were performed with the use of MATLAB, version 2017a, R Statistical Software version 3.4.1, and GraphPad Prism, version 7.0a. Calculation of AUC accounting for censorship was performed using the R 'survivalROC' package version 1.0.3 with default settings; calculation of IOI accounting for censorship was performed using the R 'survlDINRI' package with default settings (Page 165, Paragraph 2). Since, the analysis was performed using software (Page 165, Paragraph 2), it is well known in the art that a computer is required to execute the instructions of a software.
Kurtz teaches in Figure 13B the change of ctDNA disease burden in response to treatment and during clinical progression in a patient with stage IIAX DLBCL (Figure 13, Page 85). Shown are the mean allele frequencies of all SNVs detected by CAPP-Seq (left y-axis) and the number of lymphoma DNA molecules per ml of plasma identified by lgHTS (right y-axis) over serial time points (x-axis) (Figure 13, Page 85). Figure 13B depicts multiple time points, which includes the first time point. From Figure 13B, it is interpreted that day 0 is the first timepoint that the data was obtained from the subject. ctDNA is circulating tumor-derived DNA (ctDNA) that are blood based (Abstract, Page iv). Kurtz also teaches in Supplemental Figure C3-S9 that one or more patients has a mean ctDNA concentration of approximately 103 hGE/mL at diagnosis (page Supplemental Figure C3-S9, Figure 104). At diagnosis corresponds to the first timepoint. This corresponds to the claim limitation of the at least 1,000 DNA molecules obtained from the subject at the first timepoint are tumor-derived DNA molecules. Kurtz teaches in Figure 13B the change of ctDNA disease burden in response to treatment and during clinical progression in a patient with stage IIAX DLBCL (Figure 13, Page 85). Shown are the mean allele frequencies of all SNVs detected by CAPP-Seq (left y-axis) and the number of lymphoma DNA molecules per ml of plasma identified by lgHTS (right y-axis) over serial time points (x-axis) (Figure 13, Page 85). Figure 13B depicts multiple time points, which includes the first time point. From Figure 13B, it is interpreted that day 0 is the first timepoint that the data was obtained from the subject. ctDNA is circulating tumor-derived DNA (ctDNA) that are blood based (Abstract, Page iv). ctDNA are also cell free DNA. Kurtz also teaches in Supplemental Figure C3-S9 that one or more patients has a mean ctDNA concentration of approximately 103 hGE/mL at diagnosis (page Supplemental Figure C3-S9, Figure 104). At diagnosis corresponds to the first timepoint. Again, Kurtz analyzed publically available whole genome sequencing (WGS) data from multiple individuals comprising 79 patients with B-cell non Hodgkin lymhpomas, as well as WGS data from 145 patients with CLL (Page 227, Paragraph 1). We binned the genome into 170bp bins and assessed what fraction of patients contained two or more somatic alterations within each bin (Page 227, Paragraph 1). This corresponds to the claim limitation of wherein the sequencing data comprises whole genome sequencing data. Like noted above, Kurtz teaches the use of CAPP-Seq to monitor tumor dynamics during therapy in a cohort of over 200 diffuse large B-cell lymphoma (DLBCL) patients, demonstrating the prognostic significance of changes in ctDNA levels as quickly as three weeks into treatment (Abstract, Page iv). Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma (Page 17 paragraph 2). Lymphoma is a type of cancer. This corresponds to the claim limitation of wherein the disease is a cancer. Kurtz teaches in Figure 12 teaches determining tumor burden of patients (Figure 12, Page 83). At diagnosis, profiling of tumor DNA obtained from either tissue biopsies (indicated by a scalpel) or plasma (depicted as blood collection tubes) allows for the identification of patients with high tumor burden, non-GCB subtypes, and 'double hit' lymphoma (Figure 12, Page 83). This corresponds to the claim limitation of determining a cancer burden or a tumor burden of the subject. Additionally, Kurtz teaches Among the most promising clinical applications of ctDNA is its potential use for the detection of radiographically occult minimal residual disease (MRD). We profiled plasma samples at times of radiographic complete response (CR, n=30) or recurrence (n=8) from 11 patients, all of whom ultimately experienced disease progression despite therapy with curative intent (Page 62, Paragraph 2). While ctDNA was identified in all patients at the time of clinical relapse (Figure 14D), it was also detectable as MRD before relapse in at least one plasma sample in 8 of 11 patients (73%), with ctDNA concentrations as low as 0.003%) AF (0.11 hGE/mL) (Page 62, Paragraph 2). The mean elapsed time between the first ctDNA-positive time point and clinical relapse was 188 days, and all blood collections up to 3 months before relapse had ctDNA above the detection limit of our assay (Figure 14D) (Page 62, Paragraph 2). When directly compared to lgHTS, our method detected MRD in twice as many patients with a mean lead time of >2 months, suggesting potential advantages in the surveillance setting (Figure 14E and Supp. Figure C3-S10) (Page 62, Paragraph 2). The mean lead time of >2 months taught by Kurtz is interpreted to be equivalent to the second time point. Therefore, this corresponds to the claim limitation of wherein the extent to which the cell-free DNA molecules from the subject at the second timepoint comprise disease-derived phased- variant containing cell-free nucleic acid molecules is used to determine minimal residual disease. Kurtz teaches in Figure 18 Panels E and F show event free survival for patients receiving frontline and salvage therapy, respectively (Figure 18, Page 173). Panels G and H show overall survival for patients receiving frontline and salvage therapy, respectively (Figure 18, Page 173). Overall, Figure 18 E, F, G, and H show a drop in the probability of event free survival for patients and overall survival for patients receiving frontline and salvage therapy to less than 100% as time progresses until stabilization. This demonstrates that the data can show worsening of the condition. Kurtz teaches in Figure 13 improved noninvasive genotyping and monitoring of DLBCL tumor heterogeneity (Figure 13, Page 85). Partial response taught by Kurtz is interpreted to be equivalent to partial remission. Figure 13 B and C depicts partial response of the condition. Kurtz teaches in Figure 13 improved noninvasive genotyping and monitoring of DLBCL tumor heterogeneity (Figure 13, Page 85). Complete response taught by Kurtz is interpreted to be equivalent to full remission. Figure 13 B and C depicts complete response of the condition. Kurtz teaches in Figure 13 improved noninvasive genotyping and monitoring of DLBCL tumor heterogeneity (Figure 13, Page 85). From Figure 13B, it is interpreted that day 0 is the first time point and day 31 is the second time point. 31 days is at least about a week subsequent to the first time point. Kurtz teaches in Figure 13 B change of ctDNA disease burden in response to treatment and during clinical progression in a patient with stage IIAX DLBCL (Figure 13, Page 85). Shown are the mean allele frequencies of all SNVs detected by CAPP-Seq (left y-axis) and the number of lymphoma DNA molecules per ml of plasma identified by lgHTS (right yaxis) over serial time points (x-axis) (Figure 13, Page 85). From the graph in Figure 3, after day 0 there is a drop SNVs detected by CAPP-Seq and DNA molecules per ml of plasma identified by lgHTS, which is due to treatment after day 0 but before the day that the levels of molecules were measured, which is day 31. From Figure 13B, it is interpreted that day 0 is the first time point and day 31 is the second time point. Kurtz teaches in Figure 28D an improved detection of ctDNA through phased reporters (Figure 28D, Page 237). Improved detection of ctDNA taught by Kurtz is interpreted to be equivalent to enriching for cell-free DNA molecules. Figure 28D also teaches various time points for the identification of disease-derived phased-variant, which includes the first and second time point (Figure 28, Page 237). While Figure 28B teaches the identification of the genomic location of the disease-derived phased-variant (Figure 28, Page 237). Figure 16D depicts the ctDNA concentration of 105 hGE/ml at follow up for one or more of the rrDLBCL patients (Page 91, Figure 16D). Follow up is the second timepoint and there are at least 1,000 cell-free DNA molecules. Kurtz teaches in Figure 28 Haplotype sequencing and phased reporters detection using CAPP-Seq (Figure 28, Page 237). CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing) is an ultrasensitive capture-based targeted sequencing method (Page 57, Paragraph 3). Kurtz further teaches optimizing recovery of duplex molecules in CAPP-Seq is not a simple problem, as the molecular biology workflow contains numerous steps of pipetting, PCR, hybrid capture, etc. (Page 225, Paragraph 3). Capture-based targeted sequencing or hybrid capture taught by Kurtz is interpreted to refer to the hybridization capture. The use of CAPP-Seq for mutational haplotype detection as depicted in Figure 28B corresponds to the claim limitation of enriching for cell-free DNA molecules corresponding to the genomic locations identified in (b) comprises the use of hybridization capture probe sets. Kurtz teaches in Figure 28B that each gray bar is a single sequencing read; non-reference bases are shown with a colored letter (Figure 28, Page 237). From Figure 28B, Kurtz shows that the first and second phased variants are separated by at least one nucleotide (Figure 28, Page 237). Kurtz teaches that raw sequencing data were mapped to the hg19 reference genome and further processed using a specialized computational workflow that removes PCR duplicates and suppresses technical artifacts (Page 72, Paragraph 2).
Thus, it would have been obvious to modify the teachings of Kurtz to achieve the claimed invention. Kurtz’s method can interrogate many mutations simultaneously (Page 59, Paragraph 2). CAPP-Seq taught by Kurtz also achieved higher sensitivity than lgHTS and paired analyses (Page 59, Paragraph 1). Therefore, a person of ordinary skill in the art would have been motivated to modify the method taught by Kurtz to analyze numerous cell-free DNA molecules simultaneously with improved sensitivities to detect phase variants. Furthermore, there would have been a reasonable expectation of success, since Kurtz showed that the sequencing data obtained from a plasma sample can be analyzed to detect phased reporters (Page 227, Paragraph 2). Though the variants observed and describe are one or more bases apart, Kurtz does not explicitly show the first phased variant and the second phased variant are separated by at most 170 nucleotides. However, Kurtz shows detecting multiple mutations on a given read (i.e. the first phased variant and the second phased variant), and further shows the size of a typical cell-free DNA is approximately 170 base pairs (pg. 226, para. 3). It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have identified nucleic acid molecules with the first and second phased variants separated by no more than 170 nucleotides because Kurtz shows the first and second phased variants occur on the same read and that the size of a typical cell-free DNA is approximately 170 base pairs (pg. 226, para. 3), such that any two variants that occur on the same read are separated by at most approximately 170 base pairs. Further, it would have been further prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the statistical model for predicting the risk of relapse using identified amounts of ctDNA shown by Kurtz et al. (pg. 137, para. 3; pg. 155, para. 5; Supplemental Figure C4-S3 and C4-S14) to have determined the amount of ctDNA using the identified one or more cell-free nucleic acid molecules comprising the plurality of phased variants, shown by Kurtz. (Figure 28 D), rather than single variants. The motivation would have been to increase the specificity of ctDNA detection and reduce the background error-rate, as shown by Kurtz (pg. 226, para. 2). This modification would have had a reasonable expectation of success because Kurtz shows the sequencing data obtained from a plasma sample can be reanalyzed to detect phased reporters, rather than single reporters (pg. 227, para. 2). Therefore, the invention is prima facie obvious.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
The art of record demonstrates that the evaluation of variants in the genome were well known and an active area of study. Variations not in cancer such as that provided by Willems et al (Genome-wide profiling of heritable and de novo STR variations (Nat Methods 2017 June; 14(6): 590–592)) is provided to demonstrate additional type of phased variants present in STR were known and used in profiling the genome of individuals.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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/Joseph Woitach/Primary Examiner, Art Unit 1687
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