DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 126-155 are pending and under consideration in this action. Claims 1-125 were canceled in the amendment filed 8/24/2022.
Priority
The instant application claims domestic benefit to U.S. Provisional Application No. 63/189,602, filed 5/17/2021, as reflected in the filing receipt mailed 8/29/2022. The claim for domestic benefit for claims 126-155 is acknowledged. As such, the effective filing date of claims 126-155 is 5/17/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/24/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Specification
The abstract of the disclosure is objected to because it uses phrases that can be implied: “the present disclosure provides” and “the disclosure also provides”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 126-127 and 129 are objected to because of the following informalities:
Claims 126 and 127 recite the phrase ““(I) acquiring knowledge of loss of heterozygosity (LOH)…or homozygous single exon loss in a sample by” in lines 2-5 of the claims, which should be followed by a semi-colon, to include the appropriate punctuation (see MPEP 608.01(m)).
Claim 129 recites the phrase “functional mutation in a PTEN gene”, which should be corrected to “functional mutation in a phosphatase and tensin homolog (PTEN) gene” for clarity, as this is the first recitation of said gene in the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 126-155 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.
Claim 126 recites the limitations “acquiring knowledge of loss of heterozygosity (LOH) of one or more genes of interest, a loss-of-function of one or more genes of interest, the level of tumor mutational burden (TMB), or homozygous single exon loss in a sample using steps a)-d)” and “responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy” in lines 2-5 and 11-12 of the claim. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. The claim appears to be missing essential steps to determine information on the LOH of a gene, loss-of-function of a gene, TMB level, or homozygous single exon loss from the nucleic acids extracted in step (d). At minimum, the nucleic acids need to be sequenced and analyzed, but it is unclear if additional steps are necessary. Additionally, the claim appears to be missing essential method steps to determine an appropriate anti-cancer therapy, or the effective amount based on the knowledge of the LOH of a gene, loss-of-function of a gene, TMB level, or homozygous single exon loss acquired in step (I). It is unclear what steps are taken to determine the appropriate anti-cancer therapy, and what the correlation is to the effective amount of one or more than one of the LOH of a gene, loss-of-function of a gene, TMB level, or homozygous single exon loss. This rejection can be overcome by amendment of claim 126 to clarify the missing method steps. Claims 128-155 are also rejected due to their dependency from claim 126.
Claim 126 recites the limitations “the level of tumor mutational burden (TMB)”, “identifying the location of the sample in the tissue”, and “administering to the individual” in lines 4, 8, and 11 of the claim, respectively. There is insufficient antecedent basis for these limitations in the claim, since there is no prior mention of these phrases earlier in the claim. This rejection can be overcome by amendment of claim 126 to recite “a level of tumor mutational burden (TMB)”, “identifying a location of the sample in the tissue”, and “administering to an individual”. Claims 128-155 are also rejected due to their dependency from claim 126.
Claim 127 recites the limitations “the level of tumor mutational burden (TMB)”, and “identifying the location of the sample in the tissue” in lines 4 and 8 of the claim, respectively. There is insufficient antecedent basis for these limitations in the claim, since there is no prior mention of these phrases earlier in the claim. This rejection can be overcome by amendment of claim 127 to recite “a level of tumor mutational burden (TMB)”, and “identifying a location of the sample in the tissue”.
Claim 138 recites the limitations “providing the tissue comprising tumor cells of interest” and “extracting a sample from the tissue” in lines 5 and 6 of the claim, respectively. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear how steps e) and f) “to provide the tissue comprising tumor cells of interest”, and subsequently “extract the sample from the tissue” are different from the steps a) and b) of independent claim 126. Steps a) and b) recite “identifying a target region comprising tumor cells of interest in a tissue (i.e., providing a tissue with tumor cells of interest; the same as step e)) and “extracting the sample from the tissue” (i.e., the same as step f)). This rejection can be overcome by amendment of claim 138 to clarify how steps e) and f) are different from the identification and extraction steps a) and b) in claim 126. Claim 139 is also rejected due to its dependency from claim 138.
Claim 138 recites the limitations “assessing the level of enrichment of the tumor cells” and “in the remaining tissue” in lines 7 and 7-8 of the claim, respectively. There is insufficient antecedent basis for these limitations in the claim, since there is no prior mention of this phrases in claim 126, to which this claim depends. This rejection can be overcome by amendment of claim 138 to recite “assessing a level of enrichment of the tumor cells” and “in a remaining tissue”. Claim 139 is also rejected due to its dependence from claim 138.
Claim 141 recites the limitation “reduces the incidence of tissue insufficient for analysis” in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim, since there is no prior mention of this phrase in claim 126, to which this claim depends. This rejection can be overcome by amendment of claim 141 to recite “reduces an incidence of tissue insufficient for analysis”. Claim 142 is also rejected due to its dependence from claim 141.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 146 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 146 recites the limitation of “administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy”. This limitation fails to further limit claim 126, which recites “responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy” in step (II). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 126-155 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Step 1:
In the instant application, claims 126-154 are directed towards a method, and claim 155 is directed towards a system, which falls into one of the categories of statutory subject matter (Step 1: YES).
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant claims recite limitations that equate to one or more categories of judicial exceptions:
Claims 126 and 127 recites a mental process (i.e., an observation of the greatest density of tumor cells (the target region); see specification Para. [0315]) in “acquiring knowledge of loss of heterozygosity (LOH) of one or more genes of interest, a loss-of-function of one or more genes of interest, the level of tumor mutational burden (TMB), or homozygous single exon loss in a sample by a) identifying a target region comprising tumor cells of interest in a tissue”; and a mental process (i.e., an observation/visual inspection; see specification Para. [0013]) in “c) identifying the location of the sample in the tissue”.
Claim 128 recites a mental process (i.e., a repeating of observation in step c) above) in “wherein if the location of the sample does not overlap with the target region comprising tumor cells of interest, step c) is repeated”.
Claim 129 recites a mental process (i.e., an evaluation of the gene in LOH or loss-of-function) in “wherein the loss of heterozygosity (LOH) is LOH of a human leukocyte antigen (HLA) gene or the loss-of-function comprises detecting a loss-of-function mutation in a PTEN gene”.
Claim 130 recites mental processes (i.e., an evaluation of the sequence) in “analyzing the plurality of sequence reads” and “based on the analysis, detecting one or more mutations in the one or more genes of interest”.
Claim 138 recites a mental process (i.e., an evaluation of the level of enrichment) in “assessing the level of the tumor cells of interest in the sample and in the remaining tissue”; and a mathematical concept (i.e., an evaluation of two enrichment level values, or an evaluation of whether a value is above a threshold) in “if the level of enrichment of tumor cells of interest in the sample exceeds the level of tumor cells of interest in the remaining tissue or if the level of enrichment of tumor cells of interest in the sample exceeds a minimum threshold of tumor cells of interest”.
Claim 139 recites a mathematical concept (i.e., an evaluation of whether a value is above 25%) in “wherein the minimum threshold is 25% tumor cells of interest”.
Claims 141 and 142 recite mental processes (i.e., a comparison of the incidence of tissue insufficient for analysis between two methods) in “wherein the method reduces the incidence of tissue insufficient for analysis compared to a method not comprising steps c) and/or d)” and “wherein the incidence of tissue insufficient for analysis is reduced by at least 10% compared to the method not comprising steps c and/or d)”.
Claim 147 recites a mental process (i.e., an evaluation of the presence of a gene to determine the potential benefit from anti-cancer therapy) in “wherein (i) the presence of LOH of one or more genes of interest, (ii) the presence of the loss-of-function of one or more genes of interest, (iii) the level of TMB, or (iv) the presence of homozygous single exon loss in the sample identifies the individual as one who may or may not benefit from the anti-cancer therapy”.
Claim 148 recites a mental process (i.e., an evaluation of the gene in LOH or loss-of-function) in “wherein the loss of heterozygosity (LOH) is LOH of a human leukocyte antigen (HLA) gene or the loss-of-function comprises detecting a loss-of-function mutation in a PTEN gene”.
Claim 150 recites a mental process (i.e., an evaluation of the presence or absence of LOH in a gene, loss-of-function in a gene, homozygous single exon loss, or TMB level) in “detecting (i) the presence or absence of loss of heterozygosity (LOH) of one or more genes of interest, (ii) the presence or absence of a loss-of-function of one or more genes of interest, (iii) the level of tumor mutational burden (TMB), or (iv) the presence or absence of homozygous single exon loss in a sample extracted from a tissue from the individual according to the method of claim 126”.
Claim 151 recites a mental process (i.e., an evaluation of the presence of a gene to determine the potential benefit from anti-cancer therapy) in “wherein (i) the presence of LOH of one or more genes of interest, (ii) the presence of the loss-of-function of one or more genes of interest, (iii) the level of TMB, or (iv) the presence of homozygous single exon loss in the sample individual identifies the individual as one who may benefit from a treatment comprising an anti-cancer therapy”.
Claim 152 recites a mental process (i.e., an evaluation of whether an individual is a candidate for and will potentially benefit from an anti-cancer therapy) in “wherein responsive to the acquisition of said knowledge: (i) the individual is classified as a candidate to receive treatment with an anti-cancer therapy, or the individual is not classified as a candidate to receive treatment with an anti-cancer therapy; and/or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer therapy, or the individual is identified as unlikely to respond to a treatment that comprises an anti-cancer therapy”.
Claim 153 recites a mental process (i.e., evaluating the genes of interest, the level of TMB or the homozygous single exon loss) in “(b) providing an assessment of (i) the LOH of one or more genes of interest, (ii) the loss-of-function of one or more genes of interest, (iii) the level of TMB, or (iv) the homozygous single exon loss”.
Claim 154 recites a mental process (i.e., an evaluation of the presence or absence of LOH in a gene, loss-of-function in a gene, homozygous single exon loss, or TMB level) in “detecting (i) the presence or absence of loss of heterozygosity (LOH) of one or more genes of interest, (ii) the presence or absence of LOH of an HLA gene, (iii) the presence or absence of a loss-of-function mutation in a PTEN gene, (iv) the level of tumor mutational burden (TMB), or (v) the presence or absence of homozygous single exon loss in a sample extracted from a tissue from the individual according to the method of claim 126”.
Claim 155 recites a mental process (i.e., an evaluation of the sequence reads for presence of one or more genes, TMB, or homozygous single exon loss) in “(b) analyze the plurality of sequence reads for the presence of loss of heterozygosity (LOH) of one or more genes of interest, LOH of a human leukocyte antigen (HLA) gene, a loss-of-function mutation in a PTEN gene, tumor mutational burden (TMB), and/or homozygous single exon loss”; and a mental process (i.e., an evaluation of one or more genes, TMB, or homozygous single exon loss to determine if cancer can potentially be treated) in “(c) detecting cancer that may be treated with a treatment that comprises an anti-cancer therapy, based on the analyzing, LOH of one or more genes of interest, LOH of a HLA gene, a loss-of-function mutation in a PTEN gene, TMB, and/or homozygous single exon loss in the sample”.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)), and organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application (Step 2A, Prong One: YES).
Step 2A, Prong Two:
In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following independent claims recite limitations that equate to additional elements:
Claim 126 recites “extracting the sample from the tissue”, “if the location of the sample, overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample”, and “administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy”.
Claim 127 recites “extracting the sample from the tissue” and “if the location of the sample, overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample”.
Regarding the above cited limitations in claims 126 and 127 of (i) “extracting the sample from the tissue”; and (ii) “if the location of the sample, overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample”. These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before or after the recited judicial exceptions of acquiring knowledge of LOH, loss-of-function, the TMB level, or homozygous single exon loss through identification of regions in a tissue (see MPEP § 2106.04(d)).
Regarding the above cited limitation in claim 126 of (iii) administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy. This limitation equates to an insignificant, extra-solution activity.
MPEP § 2106.04(d)(2) recites:
“The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.”
Limitation (iii) recites an administration step that is not particular, as it recites broadly recites treatment with an anti-cancer therapy. The administration step therefore equates to instructions to “apply” the recited judicial exceptions in a generic way (see MPEP § 2106.04(d)(2)).
Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claims 130 and 138 recites further steps for gathering nucleic acid data; claims 131-137 and 143-145 further limit the extraction process or the type of tissue; claims 140 and 149 further limit the genes in the sample; claim 146 recites an extra-solution activity analogous to claim 126 above; and claim 155 recites generic computer components that equate to mere instructions to implement an abstract idea on a generic computer. As such, claims 126-155 are directed to an abstract idea (Step 2A, Prong Two: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant independent claims recite same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitations in claims 126 and 127 of (i) “extracting the sample from the tissue”; and (ii) “if the location of the sample, overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample. These limitations equate to laboratory techniques that are WURC limitations in the life science arts, as they are claimed in a merely generic manner (see MPEP § 2106.05(d)). Detecting DNA or enzymes in a sample is a WURC limitation in Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157, and Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017). Amplifying and sequencing nucleic acid sequences is a WURC limitation in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
Regarding the above cited limitation in claim 126 of (iii) administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy. This particular treatment consideration was evaluated in Step 2A, Prong Two above. Since the administration was not considered to be particular, therefore equating to instructions to “apply” the judicial exceptions in a generic way, this additional element does not meaningfully limit the judicial exception and does not provide an inventive concept for the claim as a whole (see MPEP § 2106.05(e)).
These additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 126-155 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 126-130, 134-138, 140, and 145-155 are rejected under 35 U.S.C. 103 as being unpatentable over Perera (U.S. Patent Application Publication, US 2020/0258597 A1; published 8/13/2020) in view of Frampton et al. (WIPO Application, WO 2017/151524 A1; cited in the IDS dated 8/24/2022; published 9/8/2017).
Regarding claim 126, Perera teaches a method for detecting loss of heterozygosity (LOH) of Human Leukocyte Antigen (HLA), and whether an HLA gene suffers from LOH can further determine appropriate treatment for patients with cancer (i.e., a method of treating or delaying progression of cancer) (Abstract and Para. [0131]). Perera further teaches that the computer-implemented method detects the LOH of HLA, including receiving next generation sequencing data collected from an isolated tissue biological sample from the subject, and generating and storing a report of the LOH status for each of the HLA alleles (i.e., acquiring knowledge of loss of heterozygosity (LOH) of one or more genes of interest) (Para. [0004]). Perera further teaches that the cancer can be treated by administering a therapy known to be effective against HLA-heterozygous cancers may be appropriate. For instance, a checkpoint inhibitor therapy may be appropriate for a subject with an HLA-heterozygous cancer (i.e., responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy) (Para. [0131]).
Regarding claim 127, Perera teaches the limitation of acquiring knowledge of loss of heterozygosity (LOH) of one or more genes of interest as described for claim 126 above.
Regarding claim 129, Perera teaches that processes are provided for detecting loss of heterozygosity of Human Leukocyte Antigen (HLA) in a subject using analysis of next generation sequencing data (i.e., wherein the loss of heterozygosity (LOH) is LOH of a human leukocyte antigen (HLA) gene) (Abstract).
Regarding claim 130, Perera teaches that DNA library preparation may include the ligation of adapters onto the DNA molecules (i.e., ligating one or more adaptors onto one or more nucleic acids extracted from the sample to produce ligated nucleic acids) (Para. [0044]). Perera further teaches that DNA libraries may be amplified and purified using reagents, for example Axygen MAG PCR clean up beads (i.e., amplifying one or more nucleic acids from the ligated nucleic acids to produce amplified nucleic acids) (Para. [0046]). Perera further teaches that the library amplification may be performed on a device, for example, an Illumina C-Bot2, and the resulting flow cell containing amplified target-captured DNA libraries may be sequenced on a next generation sequencer (i.e., capturing a plurality of the amplified nucleic acids corresponding to one or more genes of interest to produce captured nucleic acids and sequencing, by a sequencer, the plurality of the captured nucleic acids to obtain a plurality of sequence reads corresponding to the one or more genes of interest) (Para. [0051]). Perera further teaches that the bioinformatics pipeline may filter the sequence reads. Filtering the data may include correcting sequencer errors and removing (trimming) low quality sequences or bases, adapter sequences, contaminations, chimeric reads, overrepresented sequences, biases caused by library preparation, amplification, or capture, and other errors (i.e., analyzing the plurality of sequence reads) (Para. [0052]). Perera further teaches that each read in the file may be aligned to the location in the human genome having a sequence that best matches the sequence of nucleotides in the read. The files may be analyzed to detect genetic variants, including single nucleotide variants (SNVs), copy number variants (CNVs), gene rearrangements, etc. The systems and methods described herein may be used to determine whether a patient sample has HLA-LOH (i.e., based on the analysis, detecting one or more mutations in the one or more genes of interest) (Para. [0053]-[0056]).
Regarding claims 136, Perera teaches that the samples are processed by next generation sequencing (i.e., wherein the one or more nucleic acids extracted from the sample are analyzed by next-generation sequencing) (Para. [0038]).
Regarding claim 137, Perera teaches that the specimen may be any biological sample obtained from the patient, such as tumor tissue from a biopsy (i.e., wherein the tissue is from a biopsy) (Para. [0036]).
Regarding claim 138, Perera teaches that that the specimen may be any biological sample obtained from the patient, such as a tissue sample (e.g., tumor tissue from a biopsy) (i.e., providing the tissue comprising tumor cells of interest) (Para. [0036]).
Regarding claim 145, Perera teaches the detection of HLA-LOH in human tumors (i.e., wherein the individual is human) (Para. [0141]).
Regarding claim 146, Perera teaches the limitation of responsive to acquiring knowledge of (i) loss of heterozygosity (LOH) of one or more genes of interest, administering to the individual an effective amount of a treatment that comprises as anti-cancer therapy as described for claim 126 above.
Regarding claim 147, Perera teaches that the determination of whether an HLA gene suffers a LOH can help further determine whether certain treatment options may be appropriate for patients. When it is determined that the cancer in the subject does not have a loss of heterozygosity in the HLA gene, treating the cancer by administering a therapy known to be effective against HLA heterozygous cancers may be appropriate. For instance, a checkpoint inhibitor therapy may be appropriate for a subject with an HLA-heterozygous cancer (i.e., detecting loss of heterozygosity (LOH) of one or more genes of interest according to the method of claim 126, wherein (i) the presence of LOH of one or more genes of interest in the sample identifies the individual as one who may or may not benefit from the anti-cancer therapy) (Para. [0131]).
Regarding claim 148, Perera teaches the limitation of wherein the loss of heterozygosity (LOH) is LOH of a human leukocyte antigen (HLA) gene as described for claim 129 above.
Regarding claim 150, Perera teaches that a biological assay to test for the presence of any of the alleles (especially an allele reported by the algorithm to be lost from and/or not present in the tumor or cancer cells) is performed. For example, an assay, which may include fluorescence activated cell sorting (FACS), may be performed employing a number of antibodies, for example, one detecting HLA allele A*02, one detecting A*03, and one detecting B*07, to confirm the presence or the absence of various HLA alleles (i.e., detecting (i) the presence or absence of loss of heterozygosity (LOH) of one or more genes of interest in a sample extracted from a tissue from the individual) (Para. [0103]).
Regarding claim 151, Perera teaches that the determination of whether an HLA gene suffers a LOH can help further determine whether certain treatment options may be appropriate for patients. When it is determined that the cancer in the subject does not have a loss of heterozygosity in the HLA gene, treating the cancer by administering a therapy known to be effective against HLA-heterozygous cancers may be appropriate. For example, a cancer vaccine may be appropriate, such as a cancer vaccine targeted to a specific HLA allele (i.e., detecting (i) loss of heterozygosity (LOH) of one or more genes of interest, wherein (i) the presence of LOH of one or more genes of interest in the sample individual identifies the individual as one who may benefit from a treatment comprising an anti-cancer therapy) (Para. [0131])
Regarding claim 152, Perera teaches that the process may match a patient with clinical trials and/or a therapy/therapies that are likely to eliminate the cancer cells, based on HLA alleles that are present in cancer sample as predicted by the HLA LOH model. This may help a physician make a therapy decision or identify a matched set of possible therapies or clinical trials in which the patient may participate. In one example, the clinical trials are matched to the patient's HLA LOH results based on the trials having inclusion/exclusion criteria based on the presence of specific HLA alleles in tumor or cancer cells. Alternatively, the analysis shows that the patient may not respond to immunotherapies that target HLA alleles that have been lost in the patient sample, may or may not be eligible for clinical trials listing the loss or presence of those HLA alleles as inclusion or exclusion criteria (i.e., acquiring knowledge of (i) loss of heterozygosity (LOH) of one or more genes of interest, wherein responsive to the acquisition of said knowledge: (i) the individual is classified as a candidate to receive treatment with an anti-cancer therapy, or the individual is not classified as a candidate to receive treatment with an anti-cancer therapy; and/or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer therapy, or the individual is identified as unlikely to respond to a treatment that comprises an anti-cancer therapy) (Para. [0063] and [0102]).
Regarding claim 153, Perera teaches the schematic for the detection and analysis of HLA and HLA-LOH in Fig. 2. The output from the analysis compares the aligned HLA mapped reads for normal tumor tissue and calculates coverage metrics for each allele for the normal tissue and tumor tissue data (i.e., detecting (i) LOH of one or more genes of interest in a sample extracted from a tissue from the individual) (Fig. 2 and Para. [0066]-[0068]). Perera further teaches that a patient report is generated. The report may include information related to the lost or present HLA alleles including clinical trials for which the patient is eligible, therapies that may match the patient (for example, the systems and methods may be used as a companion diagnostic for these therapies) and/or adverse effects predicted if the patient receives a given therapy, based on the present or lost HLA alleles in the patient's tumor (i.e., providing an assessment of (i) the LOH of one or more genes of interest) (Para. [0062]-[0063]).
Regarding claim 154, Perera teaches a biological assay to test for the presence of any of the alleles (especially an allele reported by the algorithm to be lost from and/or not present in the tumor or cancer cells) is performed. For example, an assay, which may include fluorescence activated cell sorting (FACS), may be performed employing a number of antibodies, for example, one detecting HLA allele A*02, one detecting A*03, and one detecting B*07, to confirm the presence or the absence of various HLA alleles (i.e., detecting (i) the presence or absence of loss of heterozygosity (LOH) of one or more genes of interest, (ii) the presence or absence of LOH of an HLA gene in a sample extracted from a tissue from the individual) (Para. [0103]).
Regarding claim 155, Perera teaches that the computer-readable media includes executable computer-readable code stored thereon for programming a computer (e.g., comprising a processor(s) and GPU(s)) to the techniques herein. The processing units of the computing device may represent a CPU-type processing unit, a GPU-type processing unit, a field-programmable gate array (FPGA), another class of digital signal processor (DSP), or other hardware logic components that can be driven by a CPU. (i.e., a memory configured to store one or more program instructions and one or more processors configured to execute the one or more program instructions) (Para. [0138]). Perera further teaches that cancer samples are processed by DNA next generation sequencing (NGS), designed to sequence either the whole exome or a targeted panel of cancer-related genes, to generate DNA sequencing data, and the DNA sequencing data may be processed by a bioinformatics pipeline to generate HLA-LOH results (among other outputs) for each sample (i.e., obtain a plurality of sequence reads of one or more nucleic acids, wherein the one or more nucleic acids are derived from a sample extracted from a tissue) (Para. [0038]). Perera further teaches the overall schematic for detection and analysis of Human Leukocyte Antigen Class I (HLA) (i.e., analyze the plurality of sequence reads for the presence of loss of heterozygosity (LOH) of one or more genes of interest and LOH of a human leukocyte antigen (HLA) gene) (Fig. 2 and Para. [0066]). Perera further teaches that determination of whether an HLA gene suffers a LOH can help further determine whether certain treatment options may be appropriate for patients. For example, a cancer vaccine may be appropriate, such as a cancer vaccine targeted to a specific HLA allele (i.e., detecting cancer that may be treated with a treatment that comprises an anti-cancer therapy, based on the analyzing, LOH of one or more genes of interest or the LOH of a HLA gene) (Para. [0131]).
Perera does not teach identifying a target region comprising tumor cells of interest in a tissue; extracting the sample from the tissue; identifying the location of the sample in the tissue; if the location of the sample overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample; wherein the tissue is embedded in an embedding agent; wherein the embedding agent is resin or paraffin; assessing the level of enrichment of the tumor cells of interest in the sample and in the remaining tissue; if the level of enrichment of tumor cells of interest in the sample exceeds the level of tumor cells of interest in the remaining tissue or if the level of enrichment of tumor cells of interest in the sample exceeds a minimum threshold of tumor cells of interest, extracting one or more nucleic acids from the sample; and wherein the one or more genes of interest in the sample comprise ST7/RAY1, ARH1/NOEY2 … GNAS and/or GATA5.
Regarding claims 126 and 127, Frampton et al. teaches the process of sample receipt and DNA isolation in Fig. 1A. The tumor tissue is first identified in the specimen (i.e., identifying a target region comprising tumor cells of interest in a tissue). If the sample is not > 50% tumor, a macrodissection of the tumor specimen occurs before DNA isolation (i.e., extracting the sample from the tissue and identifying the location of the sample in the tissue). After macrodissection to enrich for tumor cells, the DNA is isolated (i.e., if the location of the sample overlaps with the target region comprising tumor cells of interest, extracting one or more nucleic acids from the sample) (Fig. 1A and Pg. 94, Lines 8-17).
Regarding claim 128, Frampton et al. teaches acquiring a sub-sample enriched for tumor cells, e.g., by macrodissecting tumor tissue from said tumor sample, from a tumor sample that fails to meet the reference criterion. Though not explicitly taught by Frampton et al., it would be obvious to one of ordinary skill in the art to repeat the macrodissection if the tumor subsample does not meet the specified reference criterion (i.e., wherein if the location of the sample does not overlap with the target region comprising tumor cells of interest, steps b) and c) are repeated) (Pg. 94, Lines 8-10).
Regarding claims 134, and 135, Frampton et al. teaches that the sample is preserved as a frozen sample or as a formaldehyde- or paraformaldehyde fixed paraffin-embedded (FFPE) tissue preparation (i.e., wherein the tissue is embedded in an embedding agent and wherein the embedding agent is paraffin) (Pg. 49, Lines 5-8).
Regarding claim 138, Frampton et al. teaches the limitation of extracting a sample from the tissue as described for claim 126 above. Frampton et al. further teaches that the method further comprises acquiring a sub-sample enriched for tumor cells, e.g., by macrodissecting tumor tissue from said tumor sample, from a tumor sample that fails to meet the reference criterion. The method also comprises acquiring a sub-sample enriched for non-tumor cells, e.g., by macrodissecting non-tumor tissue from said NAT in a tumor sample not accompanied by a primary control (i.e., assessing the level of enrichment of the tumor cells of interest in the sample and in the remaining tissue) (Pg. 94, Lines 8-10 and 15-17). Frampton et al. further teaches that if the sample >50% tumor, then the DNA will be isolated from the sample. If the sample is not >50% tumor, then macrodissection to enrich for tumor cells will occur before DNA isolation (i.e., if the level of enrichment of tumor cells of interest in the sample exceeds the level of tumor cells of interest in the remaining tissue or if the level of enrichment of tumor cells of interest in the sample exceeds a minimum threshold of tumor cells of interest, extracting one or more nucleic acids from the sample) (Fig. 1A).
Regarding claims 140 and 149, Frampton et al. teaches that the exemplary genes include, but are not limited to PTEN, SMAD2, SMAD4, TP53, ATM, BRCA1, BRCA2, MEN1, PRKAR1A, KRAS, BAP1, PTCH1, SMO, SUFU, NOTCH1, ARID1A, FBXW7, FHIT, APC, TSC2, NRAS, FLT3, EGFR, BRAF, JAK2, WT1, CBL, AKT1, SOCS1, RUNX1, AR, CEBPA, CDKN2A, and GNAS (i.e., wherein the one or more genes of interest in the sample comprise PTEN, SMAD2, SMAD4, TP53, ATM, BRCA1, BRCA2, MEN1, PRKAR1A, KRAS, BAP1, PTCH1, SMO, SUFU, NOTCH1, ARID1A, FBXW7, FHIT, APC, TSC2, NRAS, FLT3, EGFR, BRAF, JAK2, WT1, CBL, AKT1, SOCS1, RUNX1, AR, CEBPA, CDKN2A, and/or GNAS) (Pg. 64, Line 4 – Pg. 65, Line 9).
Therefore, regarding claims 126-130, 134-138, 140, and 145-155, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting loss of heterozygosity in a subject using next generation sequencing of Perera with the sample extraction method of Frampton et al. because enriching for a greater number of tumor cells (above a given threshold) is important in the detection of mutations present in low-purity samples of natural tumor DNA (Frampton et al., Pg. 91, Lines 30-32 and Pg. 94, Lines 4-10). One of ordinary skill in the art would be able to combine the teachings of Perera with Frampton et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards a method for analyzing DNA in a tumor sample. Therefore, regarding claim 126-130, 134-138, 140, and 145-155, the instant invention is prima facie obvious (MPEP § 2142).
Claims 131-133 are rejected under 35 U.S.C. 103 as being unpatentable over Perera in view of Frampton et al. as applied to claims 126-130, 134-138, 140, and 145-155 above, and further in view of Gilchrest et al. (U.S. Patent Application Publication US 2012/0238906 A1; published 9/20/2012).
Perera in view of Frampton et al., as applied to claims 126-130, 134-138, 140, and 145-155 above, does not teach wherein step b) comprises extracting the sample using a needle; wherein the needle is punched through the tissue, thereby extracting the sample; and wherein the needle is a disposable needle.
Regarding claim 131, Gilchrest et al. teaches the use of a needle biopsy to extract the sample from the tissue (i.e., wherein step b) comprises extracting the sample using a needle) (Para. [0125]).
Regarding claim 132, Gilchrest et al. teaches the use of a punch biopsy (biopsy in which tissue is obtained by a punch) to extract the sample from the tissue (i.e., wherein the needle is punched through the tissue, thereby extracting the sample) (Para. [0125]).
Regarding claim 133, Gilchrest et al. teaches that the "biopsy device" refers to any apparatus which can be used to conduct a biopsy procedure (i.e., the needle). In some embodiments, the biopsy device is a disposable biopsy device (i.e., wherein the needle is a disposable needle) (Para. [0125]-[0126]).
Therefore, regarding claims 131-133, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting loss of heterozygosity in a subject using next generation sequencing of Perera in view of Frampton et al. with the needle extraction of Gilchrest et al. because the needle allows for the exact sampling of tumor tissue sample obtained from a biopsy (Gilchrest et al., Para. [0055]-[0056]). One of ordinary skill in the art would be able to combine the teachings of Perera in view of Frampton et al. with Gilchrest et al. with reasonable expectation of success due to the same nature of the problem to be solved, since include a step of extracting a tumor sample from a tissue. Therefore, regarding claims 131-133, the instant invention is prima facie obvious (MPEP § 2142).
Claim 139 and 141-142 are rejected under 35 U.S.C. 103 as being unpatentable over Perera in view of Frampton et al. as applied to claims 126-130, 134-138, 140, and 145-155 above, and further in view Basu et al. (U.S. Patent Application Publication US 2015/0307947 A1; published 10/29/2015).
Regarding claim 141, Frampton et al. teaches that the percentage of tissues insufficient for analysis is 10-15%. This includes steps c) and d) as described in claim 126 above (Pg. 117, Lines 29-30).
Perera in view of Frampton et al., as applied to claims 126-130, 134-138, 140, and 145-155 above, does not teach wherein the minimum threshold is 25% tumor cells of interest; wherein the method reduces the incidence of tissue insufficient for analysis compared to a method not comprising steps c) and/or d); and wherein the incidence of tissue insufficient for analysis is reduced by at least 10% compared to the method not comprising steps c and/or d).
Regarding claim 139, Basu et al. teaches that the patient sample is subjected to microdissection to select areas enriched in tumor before performing molecular profiling. The percentage of tumor required can be at least 25% (i.e., wherein the minimum threshold is 25% tumor cells of interest) (Para. [0457]).
Regarding claims 141 and 142, Basu et al. teaches that if insufficient tumor sample is available, other techniques can be used to for detecting a gene mutation, such as fragment analysis (FA). Alternatively, the tumor can also be enriched using microdissection (Para. [0457]). Before microdissection, corresponding to steps b) and c) in claim 126, the tumor insufficient for analysis is 100%. Using steps b) and c), as described by Frampton et al. in claims 126 and 141 above, improves the incidence of tissue insufficient for analysis from 100% (Basu et al.) to 10-15% (Frampton et al.) (i.e., wherein the method reduces the incidence of tissue insufficient for analysis compared to a method not comprising steps c) and/or d) and wherein the incidence of tissue insufficient for analysis is reduced by at least 10% compared to the method not comprising steps c and/or d)).
Therefore, regarding claims 139 and 141-142, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting loss of heterozygosity in a subject using next generation sequencing of Perera in view of Frampton et al. with the minimum tumor threshold and improved incidence of tissue insufficient for analysis of Basu et al. because the analysis of Basu et al. provides more informed and effective personalized treatment options for any type of cancer (Basu et al., Para. [0006] and [0010]). One of ordinary skill in the art would be able to combine the teachings of Perera in view of Frampton et al. with Basu et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both incorporate a method for analyzing enrichment in tumors. Therefore, regarding claims 139 and 141-142, the instant invention is prima facie obvious (MPEP § 2142).
Claims 143 and 144 are rejected under 35 U.S.C. 103 as being unpatentable over Perera in view of Frampton et al. as applied to claims 126-130, 134-138, 140, and 145-155 above, and further in view Killian et al. (Increased tumor purity and improved biomarker detection using precision needle punch enrichment of pathology specimen paraffin blocks: Method validation and implementation in a prospective clinical trial. J Clin Oncol 38, 3622-3622 (2020); published 5/25/2020).
Perera in view of Frampton et al., as applied to claims 126-130, 134-138, 140, and 145-155 above, does not teach wherein the method step b) comprises extracting the sample using a needle and wherein the method results in a higher tumor purity compared to a method wherein step b) comprises extracting the sample using a razor blade; and wherein tumor purity is increased at least at least 10% compared to a method wherein step b) comprises extracting the sample using a razor blade.
Regarding claim 143, Killian et al. teaches that the tumor purity of specimens for each tissue block were compared following either no enrichment (UnE, n=46), pathologist-directed enrichment by straight razor blade (RBE, n=30) or precision needle punch (NPE, n=47). The mean computational tumor nuclei percentage (TN%) in the three groups were: UnE: 33%; RBE: 30%; and NPE: 52%. In the validation study, NPE had significantly higher purity than both UnE and RBE (p<0.001). Precision needle punch cores from tissue blocks have elevated tumor purity, and consequently, a greater number of successful genomic loss of heterozygosity determinations (i.e., wherein the method step b) comprises extracting the sample using a needle and wherein the method results in a higher tumor purity compared to a method wherein step b) comprises extracting the sample using a razor blade) (Abstract).
Regarding claim 144, Killian et al. teaches that straight razor blade (RBE) had a purity of 30%, while precision needle punch (NPE) had a precision of 52% (i.e., wherein tumor purity is increased at least at least 10% compared to a method wherein step b) comprises extracting the sample using a razor blade) (Abstract).
Therefore, regarding claims 143 and 144, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of detecting loss of heterozygosity in a subject using next generation sequencing of Perera in view of Frampton et al. with the extraction technique of Killian et al. because the elevated tumor purity gained when using precision needle punch provides a greater number of successful genomic loss of heterozygosity determinations. Furthermore, precision needle punches constitutes a best practice for enriching tumor cells from low-purity specimens (Killian et al., Abstract). One of ordinary skill in the art would be able to combine the teachings of Perera in view of Frampton et al. with Killian et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both include a step of extracting a tumor sample from a tissue. Therefore, regarding claims 143 and 144, the instant invention is prima facie obvious (MPEP § 2142).
Conclusion
No claims allowed.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687