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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/16/2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
No claims have been newly amended, added, or cancelled. Claims 3, 5, and 12 are cancelled. Claims 1-2, 4, 6-11, and 13-17 are pending in the instant application and the subject of this non-final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
Rejections Maintained/New Grounds of Rejection
Status of Prior Rejections/Objections:
The objection to the specification regarding trademarks is withdrawn in view of the amendment.
The prior art rejections under 35 USC 103 directed to claims 1, 2, 4, 6-11, and 13-17 as being unpatentable over Basile and Severyn, as evidenced by Boregowda are withdrawn in view of the amendments and upon further consideration.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1:
The claim appears to be referring to gene amplification (i.e., an increase in the number of copies of a gene) in “an amplification in a gene”. The preposition should be “of” in this case.
The claim also recites two score “bins” based on a threshold in step (c) set forth in (i) and (ii). The two score sections are missing a connecting conjunction, i.e., “and”.
Appropriate correction is required.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 1-2, claim 1 recites “said threshold corresponding to an expression level … in a control cell”. The specification recites that “the indefinite article ‘a’ … include[s] plural referent unless the context clearly dictates otherwise” (pg. 3, para 5, spanning pg. 4). Accordingly, the threshold corresponding to an expression level in a control cell was interpreted to encompass expression levels in one or more control cells, including average expression levels of a plurality of cells (e.g., claim 2).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4, 6-11, and 13-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
Regarding claims 1-2, 4, 6-11, and 13-17, the amended claim 1 recites “An invitro cell-based screening method to identify compounds effective in the treatment of cancer, wherein said cancer is characterized by cells that are characterized by an over-activated signaling pathway … comprising
contacting a cell … wherein said cell … comprises an activating mutation in … or amplification in a gene encoding a protein comprised in said signaling pathway with
an inhibitor of said signaling pathway; and
a test compound;
determining an expression level of SOX2 and/or a gene under transcriptional control of SOX2 for said cell … ; and
assigning to said test compound a score, wherein
said score is high and indicating identification of a compound effective in the treatment of cancer if said expression level of SOX2 and/or said gene under transcriptional control of SOX is below a predetermined threshold … corresponding to and expression level … in a control cell treated solely with said inhibitor …;
said score is low if said expression level of SOX2 and/or of said gene under transcriptional control of SOX2 is equal to or above said predetermined threshold;
wherein the gene under transcriptional control of SOX 2 is selected from the group consisting of …”
The claims are broad. They encompass indicating identification of compounds effective in the treatment of any cancer (aside from claims 8 and 14) based on the expression levels of any of 29 genes plus SOX2, wherein the expression encompasses mRNA and/or protein (see, e.g., claim 4). This is indicated in any cell type of any genetic background so long as it comprises an activating mutation or amplification in a signaling pathway being inhibited by the inhibitor considered. Any signaling pathway may be inhibited/mutated (aside from claims 6-11, 13, and 15-17). The claims encompass determining the expression level for said cell for the purposes of the threshold at any point (i.e., including before the contacting).
The claims further encompass any test compounds, wherein specification recites “test compounds include, but are not limited to, small molecule compounds, nucleic acids, siRNAs, mirRNAs, shRNAs, proteins, peptides, antibodies, antibody fragments, aptamers, carbohydrates and lipids” (pg. 13, para 1). There are no structures, figures, diagrams, or formulas that fully set forth the claimed test compounds.
In contrast to this, the specification provides data on a single experiment characterized as a “screen” (pg. 15, para 1; Fig. 3). It is noted that Remarks dated 12/16/2025, pg. 6-7 discusses the interpretation of “screening” and the distinction between “tools to investigate a gene of interest” such as siRNAs and “test compounds”. Applying that the instant disclosure for a reduction to practice of in a disclosed “screen” would (i.e., Example 3) would disclose only the generic species of “Drug” as an exemplary test compound. Even taking a broader view of “screen” and “test compounds”, the number of species described or otherwise supported by data is very limited compared to the breath claimed and serves to highlight the variability spanning the genera claimed.
The specification recites that progression free survival can be extended by combination therapy by co-targeting BRAF and MEK [with inhibitors] (pg. 1, Background, para 1), i.e., an inhibitor of a signaling pathway and a compound known to be effective in the treatment of cancer. In contrast, the working examples present data showing that in A375-P cells [metastatic melanoma cell line comprising BRAF V600E] the combination of BRAFi PLX4720 and MEKi AZD6244 leads to an increase of SOX2 mRNA levels beyond either individual inhibitor and an increase of FOXD3 mRNA levels relative to PLX4720 alone but a decrease relative to AZD6244 alone (Fig. 1H; pg. 13, para 4, spanning pg. 14). As either compound could be considered the signaling pathway inhibitor or the test compound and both are taught to be effective in the treatment of cancer, such presents unpredictability in use of the expression level of SOX2 or a gene under transcriptional control of SOX2 compared to a control cell treated solely with the inhibitor of said pathway.
Additionally, the claimed algorithm based on the control cell threshold relies on detectable levels of expression of the chosen gene(s) in the control cell, such that high score/indication of a compound effective in the treatment of cancer may be obtained via a decrease in expression level in a “hit” in the screen. The data presented on gene levels is confined to that induced by an inhibitor of a signaling pathway, the limited number of melanoma cell lines, and, as described previously, the limited inhibitors PLX4720 and to a lesser extent AZD6244. This “stemness and EMT signature” comprising SOX2 and downstream genes is shown in A375-P cells [malignant melanoma cell line] (Fig. 1A-1C) and repeated in part in the additional cell lines UACC-62 [melanotic melanoma cell line] and MM080326 cells [possible typo of “M080306” or “MM386”, which are both melanoma cell lines] (pg. 13, para 5, spanning pg. 14; Fig. 1D).
However, the expression changes are notably variable across the cell lines: A375-P has a peak of ~10x control of SOX2, ~20x control of FOXD3, and ~3.5x control of CD24; UACC-62 has ~10x control of SOX2, ~25x control of FOXD3, and ~10x control of CD24; and MM080326 has ~3x control of SOX2, ~15x control of FOXD3, and ~10x control of CD24. Also, despite having the highest mRNA expression at 48 hours with a steady increase in UACC-62, SOX2 protein expression shows a peak at 24 hours and a baseline level of expression at 48 hours. This contrasts with A375-P cells, which show a peak at 12 or 24 hours of mRNA expression and a slight drop in 48 hours for mRNA, and show a peak in protein expression at 24 hours with only a slight drop at 48 hours of protein expression. Together, this indicates a high level of variability in SOX2 expression both in the timing and in the type of expression apparently dependent on the cell line (i.e., genetic background).
Further, the list of transcriptionally increased genes upon treatment with BRAFi PLX4720 in A375-P cells includes only five of the list of claimed genes (FOXD3, CD24, VGLL3, SOX2, and ALPP; Fig. 1C) in Fig. 1H. In Fig. 1D, only SOX2 and FOXD3 described are described for UACC-62 and MM080326.
Wherein the single “screen” comprising “immunofluorescence staining of SOX2 in BRAF V600E-mutated human melanoma cells” in Fig. 3 (pg. 15, para 1; Fig. 3) is described, a single image each of DMSO, DMSO+drug, MAPKi, and MAPKi+drug cells is provided. No further information, such as the quantification of the levels, is given. While the MAPKi condition has the highest brightness cells, there are also notably dark cells including those that appear darker than the cells of MAPKi+drug, indicating variability in the SOX2 level amongst the control cells. The example describes the “protective effect” of SOX2 from MAPKi in Fig 2 (pg. 14, para 1, spanning pg. 15), but these findings are limited to A375-P cells.
The art also highlights a high level of variability across the genera claimed due to the genetic backgrounds of the cells. Roller (Roller DG, et al. Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas. Oncotarget. 2016 Jan 19;7(3):2734-53.) teaches that analysis of transcriptional and proteomic changes following blockade of MAP Kinase signaling [i.e., MAPK inhibition] has revealed a “stunning complexity in adaptive responses” (pg. 2735, col 1, para 2). Roller also reports that chemical genetic screens with diverse drug combinations to probe the [MAPK] melanoma cell signaling network for novel functional interactions and identify drug combinations effective on mutant RAF and RAS melanoma found that no single drug combination or subset of drug combinations was found to be synergistic in either all of the RAF or all of the RAS melanoma mutant lines, indicating that the underlying signaling network of each melanoma line was different even when the primary driver (RAF or RAS) was the same (pg. 2735, col 1, para 2).
Weina (Weina K, Utikal J. SOX2 and cancer: current research and its implications in the clinic. Clin Transl Med. 2014 Jul 4;3:19) teaches a set of known transcriptional targets of SOX2 across a cancer related to functions comprising stemness and cell proliferation, and describes contradictory research in colorectal and gastric cancers related to the function in cell proliferation, as well as contradictory research in breast cancer regarding the role in promoting invasion/migration/metastasis (Fig. 2). Weina states that the contradictory effect of SOX2 suggests that SOX2 plays a differential role depending on the type of cancer (pg. 5, col 1, lines 9-11; see also pg. 5, col 1, para 2, spanning col 2).
Schaefer (Schaefer SM, et al. Sox2 is dispensable for primary melanoma and metastasis formation. Oncogene. 2017 Aug;36(31):4516-4524) recites the controversial nature of the role of SOX2 in melanoma and the diversity of experimental results relating to the roles in melanoma (Abstract; pg. 4521, col 2, para 1). Schaefer teaches its experiments in which CRISPR-Cas9 is used to inactivate SOX2 in human melanoma cells and conditional inactivation of Sox2 is performed in genetically engineered mouse models (Abstract). Schaefer teaches that in both models loss of SOX2/Sox2 did not affect melanoma initiation, growth, or metastasis formation (Abstract). Schaefer concludes that the discrepancies between their findings and others may indicate that SOX2 can exert certain activities in melanoma cells such as in isolated cells exposed to various culture conditions or in the non-physiological environment encountered by human cells upon xenotransplantation into immunocompromised mouse models or the heterogeneity of melanoma (Abstract; pg. 4521, col 2, para 1).
Therefore, given the breadth of the claims that encompass the genera of cancers, signaling pathways (and mutations thereof), inhibitors, test compounds, cell types (encompassing the activating mutations but otherwise of any origin), timing of expression analysis, and genes under which the score is assessed compared to the limited description, in particular based on SOX2 for the directionality claimed, provided by the application, particularly with regard to the reduction to practice, the skilled artisan would not reasonably conclude that the applicant had possession of the full breadth of the claims at the time of filing.
For this reason, the disclosure is not sufficient to meet the 35 USC 112(a) written description requirements.
Claim 1-2, 4, 6-11, and 13-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding claims 1-2, 4, 6-11, and 13-17, the amended claim 1 recites “An invitro cell-based screening method to identify compounds effective in the treatment of cancer, wherein said cancer is characterized by cells that are characterized by an over-activated signaling pathway … comprising
contacting a cell … wherein said cell … comprises an activating mutation in … or amplification in a gene encoding a protein comprised in said signaling pathway with
an inhibitor of said signaling pathway; and
a test compound;
determining an expression level of SOX2 and/or a gene under transcriptional control of SOX2 for said cell … ; and
assigning to said test compound a score, wherein
said score is high and indicating identification of a compound effective in the treatment of cancer if said expression level of SOX2 and/or said gene under transcriptional control of SOX is below a predetermined threshold … corresponding to and expression level … in a control cell treated solely with said inhibitor …;
said score is low if said expression level of SOX2 and/or of said gene under transcriptional control of SOX2 is equal to or above said predetermined threshold;
wherein the gene under transcriptional control of SOX 2 is selected from the group consisting of …”
First, the claims are broad. They encompass indicating identification of compounds effective in the treatment of any cancer (aside from claims 8 and 14) based on the expression levels of any of 29 genes plus SOX2, wherein the expression encompasses mRNA and/or protein (see, e.g., claim 4). This is indicated in any cell type of any genetic background so long as it comprises an activating mutation or amplification in a signaling pathway being inhibited by the inhibitor considered. Any signaling pathway may be inhibited/mutated (aside from claims 6-11, 13, and 15-17). The claims encompass determining the expression level for said cell for the purposes of the threshold at any point (i.e., including before the contacting).
Second the amount of direction and presence of working examples is limited and presents unpredictability of SOX and downstream genes as a determinant of the effectiveness in the compounds. The specification teaches that progression free survival can be extended by combination therapy by co-targeting BRAF and MEK [with inhibitors] (pg. 1, Background, para 1), i.e., an inhibitor of a signaling pathway and a compound known to be effective in the treatment of cancer. In contrast, the working examples present data showing that in A375-P cells [metastatic melanoma cell line comprising BRAF V600E] the combination of BRAFi PLX4720 and MEKi AZD6244 leads to an increase of SOX2 mRNA levels beyond either individual inhibitor and an increase of FOXD3 mRNA levels relative to PLX4720 alone but a decrease relative to AZD6244 alone (Fig. 1H; pg. 13, para 4, spanning pg. 14). As either compound could be considered the signaling pathway inhibitor or the test compound and both are taught to be effective in the treatment of cancer, such presents unpredictability in use of the expression level of SOX2 or a gene under transcriptional control of SOX2 compared to a control cell treated solely with the inhibitor of said pathway.
Additionally, the claimed algorithm based on the control cell threshold relies on detectable levels of expression of the chosen gene(s) in the control cell, such that high score/indication of a compound effective in the treatment of cancer may be obtained via a decrease in expression level in a “hit” in the screen. The data presented on gene levels is confined to that induced by an inhibitor of a signaling pathway, the limited number of melanoma cell lines, and, as described previously, the limited inhibitors PLX4720 and to a lesser extent AZD6244. This “stemness and EMT signature” comprising SOX2 and downstream genes is shown in A375-P cells [malignant melanoma cell line] (Fig. 1A-1C) and repeated in part in the additional cell lines UACC-62 [melanotic melanoma cell line] and MM080326 cells [possible typo of “M080306” or “MM386”, which are both melanoma cell lines] (pg. 13, para 5, spanning pg. 14; Fig. 1D).
However, the expression changes are notably unpredictable across the cell lines: A375-P has a peak of ~10x control of SOX2, ~20x control of FOXD3, and ~3.5x control of CD24; UACC-62 has ~10x control of SOX2, ~25x control of FOXD3, and ~10x control of CD24; and MM080326 has ~3x control of SOX2, ~15x control of FOXD3, and ~10x control of CD24. Also, despite having the highest mRNA expression at 48 hours with a steady increase in UACC-62, SOX2 protein expression shows a peak at 24 hours and a baseline level of expression at 48 hours. This contrasts with A375-P cells, which show a peak at 12 or 24 hours of mRNA expression and a slight drop in 48 hours for mRNA, and show a peak in protein expression at 24 hours with only a slight drop at 48 hours of protein expression. Together, this indicates a high level of unpredictability in SOX2 expression both in the timing and in the type of expression apparently dependent on the cell line (i.e., genetic background).
Further, the list of transcriptionally increased genes upon treatment with BRAFi PLX4720 in A375-P cells includes only five of the list of claimed genes (FOXD3, CD24, VGLL3, SOX2, and ALPP; Fig. 1C) in Fig. 1H. In Fig. 1D, only SOX2 and FOXD3 described are described for UACC-62 and MM080326.
In addition, the working examples describe a single “screen” comprising “immunofluorescence staining of SOX2 in BRAF V600E-mutated human melanoma cells” in Fig. 3 (pg. 15, para 1; Fig. 3), providing a single image of DMSO, DMSO+drug, MAPKi, and MAPKi+drug cells. No further information, such as the quantification of the levels, is provided. While the MAPKi condition has the highest brightness cells, there are also notably dark cells including those that appear darker than the cells of MAPKi+drug, indicating unpredictability in the SOX2 level amongst the control cells. The example describes the “protective effect” of SOX2 from MAPKi in Fig 2 (pg. 14, para 1, spanning pg. 15), but these findings are limited to A375-P cells.
Third, the art teaches a high level of unpredictability with regarding the expression of SOX2 due to the genetic background of the cell. Roller (Roller, 2016, as cited above in the written description rejection) teaches that analysis of transcriptional and proteomic changes following blockade of MAP Kinase signaling [i.e., MAPK inhibition] has revealed a “stunning complexity in adaptive responses” (pg. 2735, col 1, para 2). Roller also reports that chemical genetic screens with diverse drug combinations to probe the [MAPK] melanoma cell signaling network for novel functional interactions and identify drug combinations effective on mutant RAF and RAS melanoma found that no single drug combination or subset of drug combinations was found to be synergistic in either all of the RAF or all of the RAS melanoma mutant lines, indicating that the underlying signaling network of each melanoma line was different even when the primary driver (RAF or RAS) was the same (pg. 2735, col 1, para 2).
Specifically, Roller conducted a screen to find clinically useful drug combinations using either PLX4720 or two other inhibitors of the MAP Kinase pathway in two way combinations with 58 drugs or clinically relevant tool compounds in 12 BRAFV600E melanoma cell lines, finding that the overall effective combinations were different for each cell line, despite being driven by BRAFV600E (pg. 2735, col 1, para 3, spanning col 2). Roller teaches that gene expression analysis confirmed that, even when cells were sensitive to the combination of PLX4720 and lapatinib, the adaptive changes in intracellular signaling in response to BRAF inhibition differed and the mechanism(s) by which lapatinib or masitinib were synergistically cytotoxic differed (pg. 2735, col 1, para 3, spanning col 2). Roller concludes that intrinsic and adaptive resistance to BRAF inhibition in BRAFV600E melanomas occurs by multiple mechanisms that differ substantially, dependent on the broader genetic and epigenetic landscape of the cancer cells that shape the underlying architecture of cell signaling networks (pg. 2735, col 1, para 3, spanning col 2).
In contrast to the data presented in the instant application in A375-P cells, Roller also teaches a differential expression analysis of cells treated PLX4720 alone compared to control cells for the cell lines DM331, SKMEL24, and SKMEL28 (BRAF mutant cells; see Fig. 2 and 7), notably failing to find differential expression upon treatment of SOX2 and FOXD3 or the other of the 5 genes in A375-P cells (Supplementary Table 2). Roller recites that A375 had a robust transcriptional response PLX4720, which is expected given its strong sensitivity to the drug, contrasting with the slightly resistant and non-synergistic line HT144 and the highly resistant line DM331, which showed very modest transcriptional responses, whereas SKMEL24 and SKMEL28, both of which are partially resistant to PLX4720 as a single agent showed very large drug induced changes in transcription pattern (pg. 2741, col 2, para 2). Roller states that each line’s transcriptional response occupies an individual cluster, with few genes demonstrating significant responses across multiple lines.
Of the claimed list, only VGLL3, FBXO15, and ETV4 were identified in PLX4720 vs control in at least one cell type in Roller (Supplementary Table 2), wherein ETV4 was decreased relative to control, indicating a level of unpredictability in use as a threshold for indicating identification of a compound effective in the treatment of cancer when the level drops below said threshold. Roller also teaches differing protein expression levels of Nanog in response to PLX4720 in a panel of 12 BRAF V600E and 4 BRAF wt cell lines comprising increases and decreases relative to untreated cells (Fig. 5, 5th from the top), indicating unpredictability in the SOX2 transcriptional pathway in protein expression. In summary, Roller teaches that “there is considerable divergence in the gene expression changes induced by each RTK inhibitor and in each cell line” (pg. 2742, col 1, para 1).
In addition, Weina (Weina, 2014, as cited in the written description rejection) teaches a set of known transcriptional targets of SOX2 across a cancer related to functions comprising stemness and cell proliferation, and describes contradictory research in colorectal and gastric cancers related to the function in cell proliferation, as well as contradictory research in breast cancer regarding the role in promoting invasion/migration/metastasis (Fig. 2). Weina states that the contradictory effect of SOX2 suggests that SOX2 plays a differential role depending on the type of cancer (pg. 5, col 1, lines 9-11; see also pg. 5, col 1, para 2, spanning col 2).
Further, in contrast to the claimed relationship between SOX2 expression and effectiveness in the treatment of cancer, Schaefer (Schaefer, 2017, as cited in the written description rejection) recites the controversial nature of the role of SOX2 in melanoma and the diversity of experimental results relating to the roles in melanoma (Abstract; pg. 4521, col 2, para 1). Schaefer teaches its experiments in which CRISPR-Cas9 is used to inactivate SOX2 in human melanoma cells and conditional inactivation of Sox2 is performed in genetically engineered mouse models (Abstract). Schaefer teaches that in both models loss of SOX2/Sox2 did not affect melanoma initiation, growth, or metastasis formation (Abstract). Schaefer concludes that the discrepancies between their findings and others may indicate that SOX2 can exert certain activities in melanoma cells such as in isolated cells exposed to various culture conditions or in the non-physiological environment encountered by human cells upon xenotransplantation into immunocompromised mouse models or the heterogeneity of melanoma (Abstract; pg. 4521, col 2, para 1).
Taken together, the artisan would conclude that SOX2 lacks a clearly predictable role as an oncogene across cancers, including in the described melanoma, and that even within a cancer type such as melanoma and within a mutation class such as BRAF activating mutations, there is a high level of unpredictability in expression patterns of cells treated with inhibitors of BRAF, including of SOX2 and genes said to be under its control. The suggestion by Schaefer that the findings in the art regarding the oncogenic nature of SOX2 may be at least in part due to an artifact of the experimental system introduce unpredictability regarding the assertion that a decrease in the level of SOX2 or downstream genes would indicate a compound effective in the treatment of cancer, particularly absent data linking the unknown test “drug” in the instant “screen” experiment to cancer treatment efficacy, particularly in a combination medicament.
Thus, there is a high degree of unpredictability and corresponding degree of experimentation required due to the breadth of the claims; the minimal direction and working examples provided by the inventors for meaningfully identifying a compound effective in the treatment of cancer using SOX2 or the other claimed genes; and the teachings of the art regarding the strong influence on expression levels on relevant genes from the genetic background of cells used in screens and the unpredictable nature of SOX2’s roles as an oncogene both across cancers and within melanoma. Balanced only against the high level of skill in the art, it is held that the level of experimentation to utilize the scope of inventions claimed would be undue.
For this reason, the claims do not comply with the 112(a) enablement 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 1-2, 4, 6-11, and 13-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) abstract ideas. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a process/method.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Claim 1 recites an in vitro cell-based screening method to identify compounds effective in the treatment of cancer, comprising determining an expression level for a cell or plurality of cells; and assigning to a test compound a score wherein said score is high and indicating identification of a compound effective in the treatment of cancer if said expression level is below a predetermined threshold; said score is low if said expression level is equal to or above said predetermined threshold corresponding to an expression level in a control cell.
The steps of determining an expression level and assigning said score encompass abstract ideas. Namely, the determining an expression level encompasses mental processes (e.g., observations, evaluations, judgements) and/or mathematical calculations (including those that may be performed by the human mind), for example, applying an algorithm count the number of reads that map to isoforms of the chosen gene or direct visualization of an image of stained protein/in situ hybridized of mRNA (see, for example, instant specification pg. 7, para 1). Likewise, assigning the test score to the compound also encompasses mental processes (e.g., observations, evaluations, judgements) and/or mathematical calculations (including those that may be performed by the human mind), including basic comparisons of two numbers or visual evaluations.
In claim 2 where the expression level is limited to the average expression level, the claims further reiterate the abstract ideas as performing an average calculation is a mathematical calculation, including one that may be performed by the human mind.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claims 1-2, the claim further recites contacting a cell or plurality of cells with an inhibitor of a signaling pathway and a test compound and that the cell/plurality of cells comprises an activating mutation in a gene encoding a protein comprised in said signaling pathway or an amplification in a gene encoding a protein comprised in said signaling pathway.
The step of contacting is a matter of mere data gathering that is necessary for all such instances of the abstract ideas. See MPEP 2106.05(g). The determining of an expression level may also be considered such data gathering, see, e.g., Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968.
The limitation that the expression level be an average maintains the abstract nature of those steps of the claim, as an average is a mathematical calculation.
Regarding claim 4, the claim requires that the determining is by analyzing protein expression and/or mRNA expression. The claim does not require steps of analyzing, but merely a determination by analyzing the types of expression. Thus, the step still encompasses an abstract idea of a mental process and/or mathematical calculation as this limitation merely recites the particular data utilized in the determining (e.g., visual image of protein/mRNA expression or data in a table representing protein/mRNA expression).
Regarding claims 6, 9-11, and 15-17, the claims represent limitations directed to the selection of cells (e.g., via the signaling pathway and mutations therein) and/or of particular inhibitors. Such represents essential data gathering for the judicial exception(s) and is insufficient to integrate the claims into a practical application. See MPEP 2106.04(d)(I) and 2106.05(g).
Regarding claims 7-8 and 13-14, the limitations are directed to the cancer. The cancer is recited in the preamble, wherein it imposes the structure of the “over-activated signaling pathway” that the mutation in the cell/plurality of cells and the inhibitor corresponds to and in the score assignment. The cancer in “the treatment of cancer” is also recited in the assignment of the test compound score as what the compound is effective in treating. Accordingly, the limitations are directed to selecting a particular data source to be manipulated in the judicial exceptions and are a part of the abstract “indication” being asserted in step (c). Neither is sufficient to integrate the claims into a practical application. See MPEP 2106.04(d)(I) and 2106.05(g).
The activating mutation/amplification in claim 13 is directed to a selection of data and is insufficient to integrate the claims for the same reasons.
Step 2B. Does the claim amount to significantly more?
The analysis from Step 2A Prong 2 is reiterated.
As above, the score assignment and determination of an efficacious treatment encompasses an abstract idea. Even if the scoring system were novel, MPEP 2105.06(I) recites that the inventive concept cannot be furnished by the judicial exception and the “novelty” of any element or steps in a process is of no relevance to determining whether the subject matter itself falls within the 101 categories of patentable subject matter.
The courts have found that adding insignificant extra solution-activity to the judicial exception is not sufficient to represent significantly more. Thus, even if the determination of an expression level were narrowed beyond an abstract idea to any of the well-known and conventional means of assessing expression level, such contacting and determining of expression in steps (a) and (b) represent essential data gathering that is also well-known and routine (i.e., insignificant extra-solution activity). For example, Sun (Sun X, et al. High-throughput methods for combinatorial drug discovery. Sci Transl Med. 2013 Oct 2;5(205):205rv1) teaches that combination drug treatments have been used for over 30 years and that high-dimensional data capture technologies, such as transcriptome sequencing, expression and protein microarrays, and drug screening are being applied to evaluate drug combinations (pg. 1, col 2, para 1). Roller (Roller, 2015, as discussed and cited in the 112(a)), more specifically, teaches the contacting of cells with an activating mutation with an inhibitor and a test compound and determining an expression level for the cell both subsequent to contacting with both drugs and with only the inhibitor, wherein such is applied over an average of cells for proteins and mRNA (entire document, e.g., Supplementary Table 2).
The remaining limitations are directed to the abstract idea and/or choices of cells/signaling pathways/inhibitors that amount to selecting a particular type of data to be manipulated in the judicial exception, i.e., insignificant extra solution activity.
Thus, taken as a whole, the claims do not represent significantly more than the judicial exception.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-2, 4, 6-11, and 13-17 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
In particular, the amended claims recite that the score indicates identification of a compound effective in the treatment of cancer and the art rejections have been withdrawn in view of this amendment and upon further consideration.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636