DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-8, 12-16, 18, and 38-43 are pending. Claims 9-11, 17, and 19-37 have been cancelled. Claims 1, 4, 13, 15-16, 18, 38-39, and 42-43 are amended. Claims 1-8, 12-16, 18, and 38-43 are under examination.
Response to Amendment
The Amendment filed 11/20/25 has been entered. Claims 1-8, 12-16, 18, and 38-43 are pending. Applicant’s amendment of claim 4 has overcome the objection previously set forth in the Non-Final Office Action mailed 8/22/25.
Response to Arguments
Applicant’s arguments, see pages 7-14, filed 11/20/25, with the respect to the rejections of claims 1-8, 12-16, 18, and 38-43 under 35 USC 101 and 103 have been fully considered and are persuasive. Therefore, the rejections documented in the Non-Final mailed on 8/22/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Final Office Action.
Claim Objections
Claim 38 is objected to because of the following informalities:
line 2 includes a typographical error of “arc” instead of “are”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-8, 12-16, 18, and 38-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
This new 101 rejection is necessitated by claim amendments filed 11/20/25.
Step 1: The claim is directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 1 recites “selecting a drug for treatment”, with the active method steps of “comparing”, “identifying”, and “selecting”. Claims 42 and 43 recite “selecting a drug for treatment”, with the active method steps of “comparing” and “selecting”. These limitations are abstract mental processes (see MPEP 2106.04(a)(2)(III)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claims 1-8, 12-16, 18, and 38-43 recite extra-solution, data-gathering limitations at high levels of generality.
Step 2B: The claim does not provide an inventive concept.
MPEP 2106.05(d)):
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:
• i. 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);
• ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs.
Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir.
2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115
USPQ2d 1152, 1157 (Fed. Cir. 2015);
• iii. 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);
• iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v.
Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
• v. Analyzing DNA to provide sequence information or detect allelic
variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546;
• vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119
USPQ2d at 1375;
• vii. Amplifying and sequencing nucleic acid sequences, University of Utah
Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d
1241, 1247 (Fed. Cir. 2014); and
• viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d
at 1247.
The claims end with the judicial exception. Additionally, methods of selecting drugs for treatment based on single-cell transcriptional profiles have been performed before and are not inventive (Garraway et al. (2018; US 2018/0100201 A1; USPGPub citation 1 in IDS filed on 3/1/22); and Regev et al. (2017; WO 2017/075294 A1)).
For the reasons set forth above, claims 1-8, 12-16, 18, and 38-43 are not directed to patent eligible subject matter.
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.
Claims 1-8, 12-16, 18, and 38-43 are rejected under 35 U.S.C. 103 as being unpatentable over Regev et al. (2017; WO 2017/075294 A1) in view of Garraway et al. (2018; US 2018/0100201 A1; USPGPub citation 1 in IDS filed on 3/1/22.
This new 103 rejection is necessitated by claim amendments filed 11/20/25.
(i) Regev et al. teaches limitations relevant to claims 1-5, 14-18, 40, and 42-43.
Relevant to claim 1 (a) - (c), Regev et al. teaches "The present invention relates to methods of measuring or determining or inferring RNA levels, e.g., massively parallel measuring or determining or inferring of RNA levels in a single cell or a cellular network or circuit in response to at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters involving sequencing DNA of a perturbed cell, whereby RNA level and optionally protein level may be determined in the single cell in response to the at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters" (paragraph 0020).
Further relevant to claim 1 (a) - (c), Regev et al. teaches "At least one perturbation may be introduced via a chemical agent, biological agent, an intracellular spatial relationship between two or more cells, an increase or decrease of temperature, addition or subtraction of energy, electromagnetic energy, or ultrasound" (paragraph 0027).
Further relevant to claim 1 (a) - (c), Regev et al. teaches "This methodology makes it possible to efficiently screen a large population of cells for applications such as single-cell drug screening" (paragraph 00277).
Relevant to claims 2-3, Regev et al. paragraph 00109 teaches data for 3 hour and 7 day timepoints.
Relevant to claim 4, Regev et al. teaches "The tissue sample may comprise or is from a biopsy from a mammalian subject. The mammalian subject may comprise a human subject. The biopsy may be from a tumor" (paragraph 0044).
Relevant to claim 5, Regev et al. teaches "The invention also involves perturbing by subjecting the cell to a chemical agent. Samples of chemical agents include, but are not limited to, an antibiotic, a small molecule, a hormone, a hormone derivative, a steroid or a steroid derivative" (paragraph 00208).
Relevant to claim 14, Regev et al. teaches "More technically, when attempting to fit the combinatorial interaction space, our approach is consistent with the general machine learning framework of finding a function f(x) that minimizes a loss function to best explain our observations y" (paragraph 00806).
Relevant to claims 15-16, Regev et al. teaches "Relation of perturbed cells to unperturbed states. In order to define the relationship between the cell states in the unperturbed cells and the perturbed cells, applicants projected the perturbed cells onto the same significant principal component vectors derived from the unperturbed cells" (paragraph 00905).
Relevant to claim 18, Regev et al. teaches "In one embodiment, fluorescent in situ hybridization methods are used in the present invention. The present invention allows a combined approach where cells can be fluorescently labeled by methods known in the art, and cells of interest can be selected for downstream profiling of cellular constituents. In addition, the assays of the present invention can be combined with in situ hybridization methods such as RNA and DNA FISH" (paragraph 00423).
Relevant to claim 40, Regev et al. teaches "Example 6: The linear model is robust, reproducible and predictive".
Relevant to claim 42 (a), Regev et al. teaches "Because of the single cell nature of the experiment, Perturb-seq can analyze heterogeneity in cell populations - distinguishing transcriptional effects associated with changes in cell state proportions from transcriptional responses within states" (paragraph 00792).
Relevant to claim 42 (a) - (b), Regev et al. teaches "The present invention relates to methods of measuring or determining or inferring RNA levels, e.g., massively parallel measuring or determining or inferring of RNA levels in a single cell or a cellular network or circuit in response to at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters involving sequencing DNA of a perturbed cell, whereby RNA level and optionally protein level may be determined in the single cell in response to the at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters" (paragraph 0020).
Further relevant to claim 42 (a) - (cb), Regev et al. teaches "At least one perturbation may be introduced via a chemical agent, biological agent, an intracellular spatial relationship between two or more cells, an increase or decrease of temperature, addition or subtraction of energy, electromagnetic energy, or ultrasound" (paragraph 0027).
Further relevant to claim 42 (a) - (b), Regev et al. teaches "This methodology makes it possible to efficiently screen a large population of cells for applications such as single-cell drug screening" (paragraph 00277).
Relevant to claim 43 (a), Regev et al. teaches "Because of the single cell nature of the experiment, Perturb-seq can analyze heterogeneity in cell populations - distinguishing transcriptional effects associated with changes in cell state proportions from transcriptional responses within states" (paragraph 00792).
Relevant to claim 43 (a) - (b), Regev et al. teaches "The present invention relates to methods of measuring or determining or inferring RNA levels, e.g., massively parallel measuring or determining or inferring of RNA levels in a single cell or a cellular network or circuit in response to at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters involving sequencing DNA of a perturbed cell, whereby RNA level and optionally protein level may be determined in the single cell in response to the at least one perturbation parameter or advantageously a plurality of perturbation parameters or massively parallel perturbation parameters" (paragraph 0020).
Further relevant to claim 43 (a) - (cb), Regev et al. teaches "At least one perturbation may be introduced via a chemical agent, biological agent, an intracellular spatial relationship between two or more cells, an increase or decrease of temperature, addition or subtraction of energy, electromagnetic energy, or ultrasound" (paragraph 0027).
Further relevant to claim 43 (a) - (b), Regev et al. teaches "This methodology makes it possible to efficiently screen a large population of cells for applications such as single-cell drug screening" (paragraph 00277).
Relevant to claim 43 (b), Regev et al. teaches "More technically, when attempting to fit the combinatorial interaction space, our approach is consistent with the general machine learning framework of finding a function f(x) that minimizes a loss function to best explain our observations y" (paragraph 00806).
(ii) Regev et al. is silent to specifics regarding limitations relevant to claims 1, 6-8, 12-13, 38-39, 41-43. However, these limitations were known in the prior art and taught by Garraway et al.
Relevant to claim 1 (d), Garraway et al. teaches "Cell lines listed in Table 11 from the Cancer Cell Encyclopedia Lines [citation] were used for flowcytometry analysis of the proportion of AXL-positive cells. Based on IC50 values for vemurafenib, Applicants selected seven cell lines that were predicted to be sensitive to MAP-kinase pathway inhibition, including WM88, IGR37, MELHO, UACC62, COLO679, SKMEL28 and A375 and three cell lines predicted to be resistant, including IGR39, 294T and A2058. These ten cell lines were used for drug sensitivity testing and pre-treatment and post-treatment analysis of the AXL-positive fraction" (paragraph 0579).
Relevant to claim 1 (d) - (e), Garraway et al. teaches "To further assess the connection between the AXL program and resistance to RAF/MEK inhibition, Applicants studied single-cell AXL expression in 18 melanoma cell lines from the CCLE [citation] (Table 11). Flow-cytometry demonstrated a wide distribution of AXL-positive cells, from <l % to 99% per cell line, which correlated with bulk mRNA levels and were inversely associated with sensitivity to smallmolecule RAF inhibition (Table 11). Next, Applicants treated 10 cell lines (Methods) with increasing doses of a RAF/MEK inhibitor combination (dabrafenib and trametinib) (Methods) and found a rapid increase in the proportion of AXL-positive cells in six cell lines with a small (<3%) pre-treatment AXL-positive population (FIG. 3E; FIG. 17A)… In summary, studies of both melanoma tumors and cell lines demonstrate that single-cell analysis can identify drug-resistant tumor cell subpopulations that become enriched during treatment with MAP-kinase targeted treatment" (paragraph 0603).
Relevant to claim 1 preamble and (f), Garraway et al. Abstract teaches "The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells, and provides compositions and methods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and selecting appropriate treatment regimens."
Relevant to claims 6-7, Garraway et al. teaches "Cells were treated with increasing doses of dabrafenib (D) and trametinib (T) at indicated doses…" (paragraph 0111).
Relevant to claim 8, Garraway et al. teaches "Approaches such as the foregoing may be adapted to provide methods of treating and/or increasing survival of a subject having a disease, such as a neoplasia…" (paragraph 0485).
Further relevant to claim 8, Garraway et al. claim 6 teaches that "the cancer comprises… a cancer of the… pancreas…"
Relevant to claim 12, Garraway et al. teaches "Cell lines listed in Table 11 from the Cancer Cell Encyclopedia Lines [citation] were used for flowcytometry analysis of the proportion of AXL-positive cells. Based on IC50 values for vemurafenib, Applicants selected seven cell lines that were predicted to be sensitive to MAP-kinase pathway inhibition, including WM88, IGR37, MELHO, UACC62, COLO679, SKMEL28 and A375 and three cell lines predicted to be resistant, including IGR39, 294T and A2058. These ten cell lines were used for drug sensitivity testing and pre-treatment and post-treatment analysis of the AXL-positive fraction" (paragraph 0579).
Relevant to claim 13, Garraway et al. teaches "These signatures are useful in methods of monitoring a cancer in a subject by detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes at a first time point, detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes at a second time point, and comparing the first detected level of expression, activity and/or function with the second detected level of expression, activity and/or function, wherein a change in the first and second detected levels indicates a change in the cancer in the subject" (paragraph 0187).
Further relevant to claim 13, Garraway et al. teaches "In an embodiment of the invention, these signatures are also useful for selecting or modifying therapies and treatments that would be efficacious in treating, delaying the progression of or otherwise ameliorating a symptom of cancer" (paragraph 0189).
Relevant to claims 38-39, Garraway et al. teaches "Heterogeneity in the Abundance of a Dormant, Drug-Resistant Melanoma Subpopulation. Collectively, the above observations implied that some treatment-naive melanoma tumors may harbor malignant cell subsets less likely to respond to targeted therapy. The transcriptional programs associated with two other principal components (PC4 and PC5) identified by our unbiased analysis directly support this notion… Thus, to a first approximation, these transcriptional programs resemble previously reported [citations] 'MITF-high' and 'MITF-low/AXL-high' ('AXLhigh') transcriptional profiles that distinguish melanoma tumors, cell lines and mice models. Notably, the 'AXLhigh' program has previously been linked to intrinsic resistance to RAF/MEK inhibition" (paragraphs 0599-0600).
Although Garraway et al. identifies a resistance profile, the skilled artisan would recognize that transcriptional profiles lacking the PC4 and PC5 resistance profiles would correspond to the contrasting responsive phenotype.
Relevant to claim 41, Garraway et al. Table 19 include PTMA and SRSF2 correlated with PC2 (not the resistant PC4-PC5).
Relevant to claim 42 (c), Garraway et al. teaches "Cell lines listed in Table 11 from the Cancer Cell Encyclopedia Lines [citation] were used for flowcytometry analysis of the proportion of AXL-positive cells. Based on IC50 values for vemurafenib, Applicants selected seven cell lines that were predicted to be sensitive to MAP-kinase pathway inhibition, including WM88, IGR37, MELHO, UACC62, COLO679, SKMEL28 and A375 and three cell lines predicted to be resistant, including IGR39, 294T and A2058. These ten cell lines were used for drug sensitivity testing and pre-treatment and post-treatment analysis of the AXL-positive fraction" (paragraph 0579).
Further relevant to claim 42 (c), Garraway et al. teaches "To further assess the connection between the AXL program and resistance to RAF/MEK inhibition, Applicants studied single-cell AXL expression in 18 melanoma cell lines from the CCLE [citation] (Table 11). Flow-cytometry demonstrated a wide distribution of AXL-positive cells, from <l % to 99% per cell line, which correlated with bulk mRNA levels and were inversely associated with sensitivity to smallmolecule RAF inhibition (Table 11). Next, Applicants treated 10 cell lines (Methods) with increasing doses of a RAF/MEK inhibitor combination (dabrafenib and trametinib) (Methods) and found a rapid increase in the proportion of AXL-positive cells in six cell lines with a small (<3%) pre-treatment AXL-positive population (FIG. 3E; FIG. 17A)… In summary, studies of both melanoma tumors and cell lines demonstrate that single-cell analysis can identify drug-resistant tumor cell subpopulations that become enriched during treatment with MAP-kinase targeted treatment" (paragraph 0603).
Relevant to claim 42 preamble and (d), Garraway et al. Abstract teaches "The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells, and provides compositions and methods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and selecting appropriate treatment regimens."
Relevant to claim 43 (c), Garraway et al. teaches "Cell lines listed in Table 11 from the Cancer Cell Encyclopedia Lines [citation] were used for flowcytometry analysis of the proportion of AXL-positive cells. Based on IC50 values for vemurafenib, Applicants selected seven cell lines that were predicted to be sensitive to MAP-kinase pathway inhibition, including WM88, IGR37, MELHO, UACC62, COLO679, SKMEL28 and A375 and three cell lines predicted to be resistant, including IGR39, 294T and A2058. These ten cell lines were used for drug sensitivity testing and pre-treatment and post-treatment analysis of the AXL-positive fraction" (paragraph 0579).
Further relevant to claim 43 (c), Garraway et al. teaches "To further assess the connection between the AXL program and resistance to RAF/MEK inhibition, Applicants studied single-cell AXL expression in 18 melanoma cell lines from the CCLE [citation] (Table 11). Flow-cytometry demonstrated a wide distribution of AXL-positive cells, from <l % to 99% per cell line, which correlated with bulk mRNA levels and were inversely associated with sensitivity to smallmolecule RAF inhibition (Table 11). Next, Applicants treated 10 cell lines (Methods) with increasing doses of a RAF/MEK inhibitor combination (dabrafenib and trametinib) (Methods) and found a rapid increase in the proportion of AXL-positive cells in six cell lines with a small (<3%) pre-treatment AXL-positive population (FIG. 3E; FIG. 17A)… In summary, studies of both melanoma tumors and cell lines demonstrate that single-cell analysis can identify drug-resistant tumor cell subpopulations that become enriched during treatment with MAP-kinase targeted treatment" (paragraph 0603).
Relevant to claim 43 preamble and (d), Garraway et al. Abstract teaches "The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells, and provides compositions and methods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and selecting appropriate treatment regimens."
(iii) Although Regev et al. does not explicitly teach the Garraway et al. limitations, it would have been prima facie obvious to the skilled artisan. It is noted that Regev et al. and Garraway et al. are analogous disclosures to the instant single cell transcriptional field.
The skilled artisan would have been motivated to include the Garraway et al. limitations within the Regev et al. perturb-seq methodology. Regev et al. teaches "This methodology makes it possible to efficiently screen a large population of cells for applications such as single-cell drug screening" (paragraph 00277). Garraway et al. Abstract teaches "The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells, and provides compositions and methods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and selecting appropriate treatment regimens." Garraway et al. teaches “a method for monitoring a subject undergoing a treatment or therapy for glioma comprising detecting a level of expression… of one or more signature genes of the glioma… in the absence of the treatment or therapy and comparing the level of expression… of one or more signature genes… in the presence of the treatment or therapy, wherein a difference in the level of expression… in the presence of the treatment or therapy indicates whether the patient is responsive to the treatment or therapy” (paragraph 0040).
Thus, the skilled artisan would be motivated to adapt the Regev et al. method of “efficiently screen[ing] a large population of cells for applications such as single-cell drug screening” to include the Garraway et al. limitations in order to determine “whether the patient is responsive to the treatment or therapy”.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Regev et al. in view of Garraway et al., as discussed in the preceding paragraphs.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682