DETAILED ACTION
Applicant’s response filed 04/27/2026 has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied.
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 127 and 156-174 are pending and under consideration in this action. Claims 126 and 128-155 were canceled in the amendment filed 04/27/2026. Claims 156-174 are newly added.
Priority
The instant application claims domestic benefit to U.S. Provisional Application No. 63/189,602, filed 05/17/2021, as reflected in the filing receipt mailed 08/29/2022. The claim for domestic benefit for claims 127 and 156-174 is acknowledged. As such, the effective filing date of claims 127 and 156-174 is 05/17/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/27/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Specification
The objection to the abstract is withdrawn in view of Applicant’s amendments to the Abstract filed 04/27/2026 (Applicant’s Remarks, Pg. 8).
Claim Objections
Withdrawn Objections
The objection to claims 126-127 and 129 are withdrawn in view of Applicant’s amendments to the claims or cancelation of the claims filed 04/27/2026 (Applicant’s Remarks, Pg. 8).
Newly Recited Objections
Claims 162 and 174 is objected to because of the following informalities:
Claim 162 recites “wherein predetermined threshold is about 20%”, which should be corrected to “wherein the predetermined threshold is about 20%” for clarity.
Claim 174 recites “wherein samples with the first tumor purity result in insufficient for analysis (TIFA)”, which should be corrected to include the correct abbreviation for TIFA, corresponding to “tissue insufficient for analysis (TIFA)”, as recited at least in Specification Para. [0055]. This objection can be overcome by amendment to recite “wherein samples with the first tumor purity result in tissue insufficient for analysis (TIFA)”.
Appropriate correction is required.
Response to Declaration
The declaration under 37 CFR 1.130 filed 04/27/2026 is sufficient to overcome the rejection of claims 143 and 144 based upon being unpatentable under 35 U.S.C. 103 as set forth in the last Office action because: the disclosure of Killian et al. was published on 05/25/2020, and this is within the one year grace period for inventor disclosures. Therefore, Killian et al. is disqualified as prior art under 35 U.S.C. 102(b)(1)(A).
Claim Interpretation
MPEP § 2111.04 recites:
The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Claim 127 recites the limitation “wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade”. The “extracting one or more nucleic acids from the specimen core” to “result in a higher tumor purity” is an intended result, since there are no steps whereby a higher purity is achieved as compared to extracting a sub-sample with a razor blade. Accordingly, since it is unclear what steps result in whether or not the extraction leads to higher tumor purity, this limitation is not given patentable weight.
Claim 164 recites the limitation “wherein the second tumor purity is higher than a tumor purity of a sample from the tissue sample extracted using only a razor blade”. Claim 165 recites the limitation “wherein the second tumor purity is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% higher than a comparison sample from the issue sample extracted using only a razor blade”. Claim 156, to which claims 164 and 165 depend, recites “wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity”. However, none of claims 156, 164, or 165 recite any positive steps for determining how the purity is achieved or any positive steps for extracting the sample using a razor blade. Accordingly, analogous to claim 127 above, claims 164 and 165 recite an intended outcome of the claimed method, and are not given patentable weight.
Claim Rejections - 35 USC § 112(b)
Withdrawn Rejections
The rejection of claims 126-155 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendments to the claims or cancelation of the claims filed 04/27/2026 (Applicant’s Remarks, Pg. 8-9).
Newly Recited Rejections
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 127 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 127 recites the limitations “extracting one or more nucleic acids from the specimen core; wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade” in lines 11-13 of the claim. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. The limitation reciting “extracting one or more nucleic acids from the specimen core” to “result in a higher tumor purity” is an intended result. There are no steps for determining that the extraction leads to any indication of “higher purity” as compared to extracting a sub-sample with a razor blade. This rejection can be overcome by amendment of claim 127 to clarify the steps or parameters indicating higher purity in the sample from the specimen core.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 146 under 35 U.S.C. 112(d) as being of improper dependent form is withdrawn in view of Applicant’s cancelation of the claim in the amendment filed 04/27/2026 (Applicant’s Remarks, Pg. 9).
Claim Rejections - 35 USC § 101
Maintained Rejections
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 127 and 156-174 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite 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 127 and 156-174 are directed towards a method, 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:
Claim 127 recites a mental process (i.e., an evaluation of nucleic acids to determine LOH, etc.) in “determining loss of heterozygosity (LOH) of one or more genes of interest, a loss-of-function of one or more genes of interest, a level of tumor mutational burden (TMB), or homozygous single exon loss in a tissue sample”; a mental process (i.e., an observation of the greatest density of tumor cells (the target region); see Specification Para. [0315]) in “identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section”; and a mental process (i.e., a comparison of tumor purity between two samples) in “wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade”.
Claim 156 recites a mental process (i.e., an observation of the greatest density of tumor cells (the target region); see Specification Para. [0315]) in “identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section, wherein the target region comprises a higher density of tumor cells compared to non-target regions of the tissue sample”.
Claim 157 recites a mental process (i.e., an observation of failed analysis) in “wherein tissue samples with the first tumor purity fail sequencing analysis due to low tumor purity”.
Claim 158 recites a mental process (i.e., an evaluation of tumor purity) in “wherein the first tumor purity is about 1%”.
Claim 159 recites a mental process (i.e., an evaluation of purity compared to a threshold) in “wherein the first tumor purity is below a predetermined threshold and the second tumor purity is above the predetermined threshold”.
Claim 160 recites a mental process (i.e., an evaluation of the predetermined threshold) in “wherein the predetermined threshold is based on a tumor purity required for successful sequencing analysis of one or more nucleic acids extracted from a tissue”.
Claim 161 recites a mental process (i.e., an evaluation of the predetermined threshold) in “wherein the predetermined threshold is between about 15% and 30%”.
Claim 162 recites a mental process (i.e., an evaluation of the predetermined threshold) in “wherein predetermined threshold is about 20%.
Claim 163 recites a mental process (i.e., an evaluation of the predetermined threshold) in “wherein the predetermined threshold is based on a tissue insufficient for analysis (TIFA)”.
Claim 164 recites a mental process (i.e., a comparison of tumor purities) in “wherein the second tumor purity is higher than a tumor purity of a sample from the tissue sample extracted using only a razor blade”.
Claim 165 recites a mental process (i.e., an evaluation of tumor purities) in “wherein the second tumor purity is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% higher than a comparison sample from the tissue sample extracted using only a razor blade”.
Claim 166 recites a mental process (i.e., an observation of tumor cell density to identify regions) in “wherein identifying the target region comprises identifying one or more sub-regions that have a higher density of tumor cells compared to non-target regions in the tissue sample”.
Claim 168 recites a mental process (i.e., an observation of the slide section) in “wherein the slide section of the tissue sample is Haematoxylin and Eosin (H&E) stained”.
Claim 169 recites a mental process (i.e., an observation of the tissue sample) in “wherein the tissue sample is a tumor biopsy”.
Claim 170 recites a mental process (i.e., an observation of the tissue sample) in “wherein the tissue sample is a formalin-fixed paraffin embedded (FFPE) tissue”.
Claim 171 recites a mental process (i.e., a comparison of tumor purities) in “wherein enriching tumor nuclei percentage comprises increasing tumor purity of the tissue sample from the first tumor purity to the second tumor purity”.
Claim 172 recites a mental process (i.e., an evaluation of tumor purities) in “wherein the first tumor purity is less than 20% and the second tumor purity is greater than about 20%”.
Claim 173 recites a mental process (i.e., an observation of failed analysis) in “wherein tissue samples having the first tumor purity fail sequencing analysis due to low tumor purity”.
Claim 174 recites a mental process (i.e., an evaluation of tumor purity to determine insufficiency) in “wherein samples with the first tumor purity result in insufficient for analysis (TIFA)”.
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.
Specifically, claim 127 involves nothing more than determining loss of heterozygosity, loss-of-function, level of tumor mutational burden, or homozygous single exon loss in a tissue sample, identifying a target region in a slide, and comparing the purity of the specimen core to the purity from an extraction with a razor blade. Claim 156 involves nothing more than identifying a target region in a slide with higher tumor cell density. Since there are no specifics in the methodology, determining loss of heterozygosity, loss-of-function, level of tumor mutational burden, or homozygous single exon loss in a tissue sample from the extracted nucleic acids, is something that under the BRI, one could perform mentally. Additionally, since there are no specifics in the methodology, identifying a target region in a slide, and comparing the purity of the specimen core to the purity from extraction with a razor blade, are something that under the BRI, one could perform mentally. Therefore, the claimed steps are not further defined beyond something that reads on merely looking at data and making a determination. As such, said steps are directed to judicial exceptions. 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 127 recites “generating a slide section from the tissue sample”; “extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region”; and “extracting one or more nucleic acids from the specimen core”.
Claim 156 recites “generating a slide section from a tissue sample, wherein the tissue sample has a first tumor purity”; “extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region, wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity”; and “extracting one or more nucleic acids from the specimen core”.
Regarding the above cited limitations in claims 127 and 156 of (i) generating a slide section from the tissue sample [wherein the tissue sample has a first tumor purity]; (ii) extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region [wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity]; and (iii) extracting one or more nucleic acids from the specimen core. The instant claim steps recite nothing more than data gathering using routine laboratory elements. The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); and detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)).
Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claim 167 recites an extra-solution alignment step analogous to limitations (i)-(iii) above. As such, claims 127 and 156-174 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. The instant independent claims recite the same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitations in claims 127 and 156 of (i) generating a slide section from the tissue sample [wherein the tissue sample has a first tumor purity]; (ii) extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region [wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity]; and (iii) extracting one or more nucleic acids from the specimen core. These limitations, when viewed individually and in combination, are well-understood, routine, and conventional (WURC) limitations as taught by Morlote et al. (Effects of Improved DNA Integrity by Punch Form Tissue Blocks as Compared to Pinpoint Extraction From Unstained Slides on Next-Generation Sequences Quality Metrics. Am. J. Clin. Path. 152(1): 27-35 (2019); published 3/20/2019; newly recited). Morlote et al. discloses a method for analyzing DNA quality and next-generation sequencing quality metrics from two methods of tissue harvesting (Abstract). Morlote et al. further discloses that one Haematoxylin & Eosin (H&E) slide from each selected formalin-fixed, paraffin-embedded (FFPE) block was cut and reviewed for adequacy and tumor cellularity (limitation (i)) (Pg. 28, Col. 2, Para. 1; and Pg. 29, Fig. 1). Morlote et al. further discloses that in the tissue punch method, up to three tissue cores were punched by a 1-mm disposable biopsy punch from the designated area of the paraffin blocks that matched to the H&E slide. Tumor cores have more than 10% neoplastic cells compared to the rest of the slide (limitation (ii)) (Pg. 28, Col. 2, Para. 1 and 4; and Pg. 29, Fig. 1). Morlote et al. further discloses that after the tissue cores were deparaffinized, and the tissue was incubated in lysis buffer, the DNA was extracted (limitation (iii)) ((Pg. 28, Col. 2, Para. 3 – Pg. 21, Col. 1, Para. 1; and Pg. 29, Fig. 1).
Additionally, the above cited limitation in claims 127 and 156 of (i) generating a slide section from the tissue sample [wherein the tissue sample has a first tumor purity]; (ii) extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region [wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity]; and (iii) extracting one or more nucleic acids from the specimen core. The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); and detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)).
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 127 and 156-174 are not patent eligible.
Response to Arguments under 35 U.S.C. 101
Applicant’s arguments filed 04/27/2026 have been fully considered but they are not persuasive.
1. Applicant argues that as amended, claim 127 does not recite a mental process. Claim 127 is directed to improving sequencing analysis using a method of determining loss of heterozygosity (LOH) of one or more genes of interest, a loss-of-function of one or more genes of interest, a level of tumor mutational burden (TMB), or homozygous single exon loss. According to the MPEP at 2106.04(a)(2)(III), mental processes are “defined as concepts performed in the human mind.” Determining these genetic and genomic signatures cannot be performed in the human mind because they require active physical steps for extracting nucleic acids from a sample (Applicant’s Remarks, Pg. 10).
It is respectfully submitted that this is not persuasive for the following reasons:
As described in the Step 2A, Prong One above, the following limitations recite judicial exceptions: (i) “determining loss of heterozygosity (LOH) of one or more genes of interest, a loss-of-function of one or more genes of interest, a level of tumor mutational burden (TMB), or homozygous single exon loss in a tissue sample”; (ii) “identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section”; and (iii) “wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade”. Regarding (i), the claim does not recite any active steps after the extraction of nucleic acids to determine the LOH, loss-of-function, TMB, or homozygous single exon loss. Since there no specifics or steps in the methodology, under the BRI, the analysis of extracted nucleic acids to determine the LOH, loss-of-function, TMB, or homozygous single exon loss reads on looking at data and making a determination. Regarding (ii), the instant Specification (see Para. [0315]) discloses that the H&E slide is analyzed and circles are drawn around the region(s) with the greatest density of tumor cells. This equates to an observation of tumor cells on a slide, which is a process capable of being performed in the human mind. Regarding (iii), the limitation equates to a comparison of tumor purity between the current method and a method wherein the sub-sample extracted with a razor blade. Since the claim does not require any active steps to extract the sub-sample using a razor blade, this limitation equates to a comparison of tumor purities, which is a process is capable of being performed in the human mind. Therefore, limitations (i)-(iii) recite abstract ideas.
Examiner also notes that the following limitations in amended claim 127 recite additional elements, which are not required to be performed in the human mind (see Step 2A, Prong Two above): “generating a slide section from the tissue sample”; “extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region”; and “extracting one or more nucleic acids from the specimen core”.
Therefore, claim 127 recites abstract ideas and this argument is not persuasive.
2. Applicant argues that even if claim 127 does recite a judicial exception, the claim as a whole integrates the judicial exceptions into a practical application and is eligible under Step 2A, Prong Two. A technical problem in the field of nucleic acid analysis is low tumor purity in tissue samples. See Paragraph [0051] of the instant application. Precision enrichment of tissue samples by "identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section; and extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region," improve reliability of nucleic acid analyses because fewer samples will drop out for insufficient tumor purity (Applicant’s Remarks, Pg. 11).
It is respectfully submitted that this is not persuasive for the following reasons:
MPEP § 2106.04(d)(II) recites:
The analysis under Step 2A Prong Two is the same for all claims reciting a judicial exception, whether the exception is an abstract idea, a law of nature, or a natural phenomenon (including products of nature). Examiners evaluate integration into a practical application by: (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception(s); and (2) evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application, using one or more of the considerations introduced in subsection I supra, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h).
The limitation of identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section has been identified as a judicial exception in Step 2A, Prong One above. The integration of a judicial exception into a practical application can only be achieved by additional elements, not by a limitation that recites a judicial exception. Thus, the recited limitation is not considered as an improvement in the reliability of nucleic acid analysis.
Additionally, the limitation of extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region was identified as an extra-solution step in Step 2A, Prong Two above. The step is recited at a high level of generality, and therefore equates to a well-understood routine and conventional laboratory technique. In fact, further analysis of the limitation at Step 2B shows that it is well-understood, routine, and conventional as taught by Morlote et al. (see at least Pg. 29, Fig. 1 of Morlote et al.). Therefore, these limitations do not recite an improvement in the field of nucleic acid analysis, and this argument is not persuasive.
3. Applicant argues that the examples in the Specification provide support for the improved reliability of nucleic acid analysis including the detection of LOH and TMB. Examples 2 and 3 demonstrate precision enrichment using the methods described in claim 127, provide for more successful detection of genomic loss of heterozygosity (gLOH), compared to samples that were not enriched (UnE) or were processed with pathology directed enrichment with a razor blade (NPE). Example 5 shows precision enrichment improves the ability to detect TMB in tissue samples when the precision enrichment method according to claim 127 is applied. Example 7 of the instant application as filed demonstrates that fewer samples are classified as tumor insufficient for analysis when precision enrichment was implemented in the workflow (Applicant’s Remarks, Pg. 11-12).
It is respectfully submitted that this is not persuasive for the following reasons:
Regarding examples 2 and 3, wherein the precision enrichment method provide for more successful detection of genomic loss of heterozygosity, compared to samples that were not enriched or were processed with pathology directed enrichment with a razor blade (NPE). The limitation that provides the comparison to extraction with a razor blade, wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade, recites a judicial exception, as described in Step 2A, Prong One and the arguments directly above. As described above, and following MPEP § 2106.04(d)(II), the integration of a judicial exception into a practical application can only be achieved by additional elements, not by a limitation that recites a judicial exception.
Regarding example 5, the additional elements recited in claim 127 are recited at a high level of generality, and therefore equate to data gathering using routine laboratory elements or as insignificant extra-solution activity. As recited in Step 2A, Prong Two above, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); and detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)). Further analysis of the additional elements in amended claim 127 in Step 2B above shows that all three additional elements are well-understood, routine and conventional as taught by Morlote et al.
MPEP 2106.05(a) recites:
After the examiner has consulted the specification and determined that the disclosed invention improves technology, the claim must be evaluated to ensure the claim itself reflects the disclosed improvement in technology. Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1316, 120 USPQ2d 1353, 1359 (Fed. Cir. 2016) (patent owner argued that the claimed email filtering system improved technology by shrinking the protection gap and mooting the volume problem, but the court disagreed because the claims themselves did not have any limitations that addressed these issues). That is, the claim must include the components or steps of the invention that provide the improvement described in the specification. However, the claim itself does not need to explicitly recite the improvement described in the specification (e.g., thereby increasing the bandwidth of the channel"). The full scope of the claim under the BRI should be considered to determine if the claim reflects an improvement in technology (e.g., the improvement described in the specification). In making this determination, it is critical that examiners look at the claim "as a whole," in other words, the claim should be evaluated "as an ordered combination, without ignoring the requirements of the individual steps." When performing this evaluation, examiners should be "careful to avoid oversimplifying the claims" by looking at them generally and failing to account for the specific requirements of the claims. McRO, 837 F.3d at 1313, 120 USPQ2d at 1100.
Additionally, regarding example 7, the alleged improvements indicated by Applicant are not commensurate in scope with the claimed invention. Applicant appears to assert that the claimed features decrease the number of samples classified as tumor insufficient for analysis (see Specification Para. [0331]). However, amended claim 127 does not provide any indication of a reduction in the number of samples that are classified as tumor insufficient for analysis. Therefore, it appears the alleged improvements are not commensurate in scope with the claimed invention. This argument is thus not persuasive.
4. Applicant argues that amended claim 127 is eligible under Step 2B. The Examiner provided references to support detecting DNA in a sample is routine, but the Examiner has not presented evidence to support extracting a specimen core with a needle in order to improve tumor purity of a sample for sequencing DNA, wherein extracting the specimen core with a needle results in improved tumor purity compared to previously described methods (e.g., razor-blade extraction) is well-understood, routine or conventional. (Applicant’s Remarks, Pg. 12).
It is respectfully submitted that this is not persuasive for the following reasons:
When analyzed under Step 2B, the additional elements of generating a slide section from the tissue sample; extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region; and extracting one or more nucleic acids from the specimen core, are all well-understood, routine and conventional as taught by Morlote et al. (see direct limitation mapping in Step 2B above).
Additionally, as described in the arguments above, the limitation of wherein extracting the specimen core results in a higher tumor purity than extracting a sub-sample with a razor blade recites a judicial exception and is not considered to provide significantly more than the judicial exceptions. Limitations that recite judicial exceptions are not required to be well-understood, routine and conventional. Therefore, when considered individually or as an ordered combination, the additional elements do not comprise an inventive concept that transforms the claimed judicial exceptions into a practical application, and this argument is not persuasive.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 156 and 166-170 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Morlote et al. (Effects of Improved DNA Integrity by Punch Form Tissue Blocks as Compared to Pinpoint Extraction From Unstained Slides on Next-Generation Sequences Quality Metrics. Am. J. Clin. Path. 152(1): 27-35 (2019); published 3/20/2019; newly recited).
This rejection is newly recited and necessitated by claim amendment.
Regarding claim 156, Morlote et al. teaches a method for analyzing DNA quality and next-generation sequencing quality metrics from two methods of tissue harvesting (i.e., a method of extracting nucleic acids) (Abstract). Morlote et al. further teaches that the samples were obtained from routine tissue processing of pathology specimens that were submitted for NGS analysis. One Haematoxylin & Eosin (H&E) slide from each selected formalin-fixed, paraffin-embedded (FFPE) block was cut and reviewed for adequacy and tumor cellularity by a molecular pathologist (i.e., generating a slide section from a tissue sample, wherein the tissue sample has a first tumor purity) (Pg. 28, Col. 2, Para. 1; and Pg. 29, Fig. 1). Morlote et al. further teaches that the area of interest was circled on the H&E slide. Samples with more than 20% neoplastic cells were preferred with a minimum acceptable tumor cellularity of 10% neoplastic cells (i.e., identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section, wherein the target region comprises a higher density of tumor cells compared to non-target regions of the tissue sample) (Pg. 28, Col. 2, Para. 1). Morlote et al. further teaches that for the tissue punch method, up to three tissue cores were punched by a 1-mm disposable Integra Miltex biopsy punch from the designated area of the paraffin blocks that matched to the H&E slide. Tumor cores have more than 10% neoplastic cells compared to the rest of the slide (i.e., extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region, wherein the specimen core has a second tumor purity, wherein the second tumor purity is higher than the first tumor purity) (Pg. 28, Col. 2, Para. 1 and 4; and Pg. 29, Fig. 1). Morlote et al. further teaches that after the tissue cores were deparaffinized, and the tissue was incubated in lysis buffer, the lysate was treated with RNAse A and then loaded onto the QIAcube instrument for automated purification of genomic DNA using the QIAamp extraction column (i.e., extracting one or more nucleic acids from the specimen core) (Pg. 28, Col. 2, Para. 3 – Pg. 21, Col. 1, Para. 1; and Pg. 29, Fig. 1).
Regarding claim 166, Morlote et al. teaches that in the area of interest, samples with more than 20% neoplastic cells were preferred with a minimum acceptable tumor cellularity of 10% neoplastic cells (i.e., wherein identifying the target region comprises identifying one or more sub-regions that have a higher density of tumor cells compared to nontarget regions in the tissue sample) (Pg. 28, Col. 2, Para. 1).
Regarding claim 167, Morlote et al. teaches that the H&E slide reviewed and marked by the pathologist is aligned with the FFPE block to punch the tissue core from the tumor area (i.e., wherein the method further comprises aligning the slide section with the tissue sample to identify the location corresponding to the identified target region) (Pg. 29, Fig. 1).
Regarding claim 168, Morlote et al. teaches that for the processing of pathology specimens, one H&E slide from each selected FFPE block was cut and reviewed for adequacy and tumor cellularity by a molecular pathologist (i.e., wherein the slide section of the tissue sample is Haematoxylin and Eosin (H&E) stained) (Pg. 28, Col. 2, Para. 1).
Regarding claim 169, Morlote et al. teaches that the samples were obtained from routine tumor tissue processing of pathology specimens (mainly colorectal adenocarcinoma, lung adenocarcinoma, melanoma, and glioblastoma) that were submitted for NGS analysis and included both biopsies and excisions (i.e., wherein the tissue sample is a tumor biopsy) (Pg. 28, Col. 1, Para. 5 – Col. 2, Para. 1).
Regarding claim 170, Morlote et al. teaches that samples of FFPE tumor tissue were harvested using either the Pinpoint Slide DNA Isolation System or the punch method (i.e., wherein the tissue sample is a formalin-fixed paraffin embedded (FFPE) tissue) (Pg. 25, Col. 1, Para. 5 – Col. 2, Para. 1).
Therefore, Morlote et al. teaches all the limitations in claims 156 and 166-170.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claim 127 is rejected under 35 U.S.C. 103 as being unpatentable over Morlote et al. (Effects of Improved DNA Integrity by Punch Form Tissue Blocks as Compared to Pinpoint Extraction From Unstained Slides on Next-Generation Sequences Quality Metrics. Am. J. Clin. Path. 152(1): 27-35 (2019); published 3/20/2019; newly recited) in view of Perera (U.S. Patent Application Publication, US 2020/0258597 A1; published 8/13/2020; previously cited).
Regarding claim 127, Morlote et al. teaches the limitations of generating a slide section from a tissue sample; identifying a target region comprising tumor cells of interest based on spatial variation in cellular content in the slide section; extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region; and extracting one or more nucleic acids from the specimen core as described for claim 156 under 35 U.S.C. 102 rejections above.
Morlote et al. does not teach determining loss of heterozygosity of one or more genes of interest, a loss-of-function of one or more genes of interest, a level of tumor mutational burden (TMB), or homozygous single exon loss in a tissue sample.
Regarding claim 127, 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 (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., determining loss of heterozygosity (LOH) of one or more genes of interest) (Para. [0004]).
Therefore, regarding claim 127, 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 punch method of analyzing DNA in tissue cores of Morlote et al. with the gene analysis of Perera because Perera provides a novel method for overcoming the limitations associated with next generation sequencing to efficiently and accurately detect LOH of HLA in a subject, especially in cancer cells within a subject (e.g., from the extracted nucleic acids from the specimen core) (Perera, Para. [0035]). One of ordinary skill in the art would be able to combine the teachings of Morlote et al. with Perera with reasonable expectation of success due to the same nature of the problem to be solved, since both incorporate a method for analyzing next generation sequencing data. Therefore, regarding claim 127, the instant invention is prima facie obvious (MPEP § 2142).
2. Claims 157-163 and 171-174 are rejected under 35 U.S.C. 103 as being unpatentable over Morlote et al. as applied to claims 156 and 166-170 above, and further in view of Basu et al. (U.S. Patent Application Publication US 2015/0307947 A1; published 10/29/2015; previously cited).
This rejection is newly recited and necessitated by claim amendment.
Morlote et al, as applied to claims 156 and 166-170 above, does not teach wherein tissue samples with the first tumor purity fail sequencing analysis due to low tumor purity (claim 157); wherein the first tumor purity is about 1% (claim 158); wherein the first tumor purity is below a predetermined threshold and the second tumor purity is above the predetermined threshold (claim 159); wherein the predetermined threshold is based on a tumor purity required for successful sequencing analysis of one or more nucleic acids extracted from a tissue (claim 160); wherein the predetermined threshold is between about 15% and 30% (claim 161); wherein predetermined threshold is about 20% (claim 162); wherein the predetermined threshold is based on a tissue insufficient for analysis (TIFA) (claim 163); wherein enriching tumor nuclei percentage comprises increasing tumor purity of the tissue sample from the first tumor purity to the second tumor purity (claim 171); wherein the first tumor purity is less than 20% and the second tumor purity greater than about 20% (claim 172); wherein tissue samples having the first tumor purity fail sequencing analysis due to low tumor purity (claim 173); and wherein samples with the first tumor purity result in insufficient for analysis (TIFA) (claim 174).
Regarding claim 157, Basu et al. teaches that in some embodiments of the invention, the precise technology used depends upon the amount of tumor sample that is available. A threshold amount of tumor sample can be set to perform certain tests. For example, a threshold amount of tumor can be set for determining whether or not to perform RT-PCR for gene expression analysis. If insufficient tumor sample is available, then another technique for measuring expression levels can be performed, such as IHC to measure protein expression. Alternately, if there is not enough sample to perform RT-PCR, then FISH is performed (i.e., wherein tissue samples with the first tumor purity fail sequencing analysis due to low tumor purity) (Para. [0457]).
Regarding claim 158, Basu et al. teaches that a threshold amount of tumor sample can be set to perform certain tests. The threshold takes into account the percentage of tumor in the sample. The percentage of tumor required can be at least 1%, or a sample containing 1% tumor nuclei (i.e., wherein the first tumor purity is about 1 %) (Para. [0457]-[0458]).
Regarding claim 159, Basu et al. teaches that a threshold amount of tumor sample can be set to perform certain tests, and the threshold can be set after microdissection as desired (Para. [0457]). For example, the threshold may comprise having a tumor sample with at least 1%, 2%, 3% … 97%, 98%, or 99% tumor nuclei in a sample after microdissection (i.e., wherein the first tumor purity is below a predetermined threshold and the second tumor purity is above the predetermined threshold) (Para. [0458]).
Regarding claim 160, Basu et al. teaches that in an embodiment, if sufficient tumor is available, RT-PCR is performed; otherwise, IHC or FISH are performed. For example, RT-PCR can be performed if the sample after microdissection comprises at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% tumor nuclei; otherwise IHC or FISH is performed (i.e., wherein the predetermined threshold is based on a tumor purity required for successful sequencing analysis of one or more nucleic acids extracted from a tissue) (Para. [0459]).
Regarding claims 161 and 162, Basu et al. teaches that the threshold to determine whether to run RT-PCR or IHC/FISH may comprise a tumor sample with at least 15%, 20%, 25%, or 30% tumor nuclei in a sample after microdissection (i.e., wherein the predetermined threshold is between about 15% and 30% and wherein predetermined threshold is about 20%) (Para. [0458]).
Regarding claim 163, Basu et al. teaches that a threshold amount of tumor can be set for determining whether or not to perform RT-PCR for gene expression analysis. If insufficient tumor sample is available, then another technique for measuring expression levels can be performed (i.e., wherein the predetermined threshold is based on a tissue insufficient for analysis (TIFA)) (Para. [0457]).
Regarding claim 171, Basu et al. teaches that in some embodiments, the patient sample is subjected to microdissection to select areas enriched in tumor before performing molecular profiling. After microdissection to improve tumor percentage, the percentage of tumor required can be at least 1%, 2%, 3% ... 97%, 98%, or 99%. The percentage can be expressed as a percentage of tumor nuclei (i.e., wherein enriching tumor nuclei percentage comprises increasing tumor purity of the tissue sample from the first tumor purity to the second tumor purity) (Para. [0457]).
Regarding claim 172, 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 (i.e., the first tumor purity before microdissection is insufficient; wherein the first tumor purity is less than 20%) (Para. [0457]). After enrichment through microdissection, the percentage of tumor required can be at least 20%, 25% … 97%, 98%, or 99% (i.e., wherein the second tumor purity is greater than about 20%) (Para. [0457]).
Regarding claim 173, Basu et al. teaches that a threshold amount of tumor sample can be set to perform certain tests. For example, a threshold amount of tumor can be set for determining whether or not to perform RT-PCR for gene expression analysis. If insufficient tumor sample is available, then another technique for measuring expression levels can be performed, such as IHC to measure protein expression. Alternately, if there is not enough sample to perform RT-PCR, then FISH is performed (i.e., wherein tissue samples having the first tumor purity fail sequencing analysis due to low tumor purity) (Para. [0457]).
Regarding claim 174, Basu et al. teaches that a threshold amount of tumor can be set for determining whether or not to perform RT-PCR for gene expression analysis. If insufficient tumor sample is available, then another technique for measuring expression levels can be performed (i.e., wherein samples with the first tumor purity result in insufficient for analysis (TIFA)) (Para. [0457]).
Therefore, regarding claims 157-163 and 171-174, 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 punch method of analyzing DNA in tissue cores of Morlote et al. with the purity threshold analysis of Basu et al. because the method of Basu et al. provides thresholds for sequencing analysis for insufficient tumor samples following microdissection (Basu et al., Para. [0457]). One of ordinary skill in the art would be able to combine the teachings of Morlote 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 157-163 and 171-174, the instant invention is prima facie obvious (MPEP § 2142).
Response to Arguments under 35 U.S.C. 102/103
Applicant’s arguments filed 04/27/2026 have been fully considered but they are not persuasive.
1. Applicant argues that the cited references alone or in combination (Perera, Frampton, Gilchrest, and Killian) do not teach or suggest generating a slide section from the tissue sample; identifying a target region comprising tumor cells; and extracting, using a needle, a specimen core from the tissue sample at a location corresponding to the identified target region. Nor do the references teach or suggest extraction of a specimen core results in a higher tumor purity than extraction of a sub-sample with a razor blade (Applicant’s Remarks, Pg. 13-17).
It is respectfully submitted that this is not persuasive for the following reasons:
Applicant’s arguments regarding the obviousness of the claims over Perera, Frampton, Gilchrest and Killian, as failing to teach the claimed slide generation, target region identification, needle extraction, and nucleic acid extraction, as in amended claim 127 and newly added claim 156 have been considered but they are not persuasive in view of the new grounds of rejection that relies on a new combination of references as necessitated by claim amendment (Applicant’s Remarks, Pg. 13-17).
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687
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