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 .
Priority
This application 17/929,062 filed on 09/01/2022 claims the benefit of provisional U.S. Patent Application No. 63/240,308, filed on 09/02/2021.
The priority date of claims 1, 12, 18, and 26 and their respective dependent claims 2-11, 13-17, 19-25, and 27-36 is determined to be 09/02/2021, the filing date of provisional U.S. Patent Application No. 63/240,308.
Status of Claims
Applicant’s amendments to claims filed 10/16/2025 in response to the Non-Final Rejection mailed 07/29/2025 are acknowledged.
Claims 1, 3-4, 12, 14, 18, 22-23, 26, and 28-29 are amended.
Claims 7, 17, and 32 have been canceled.
Claims 1-6, 8-16, 18-31, and 33-36 are pending and under examination.
Response to Remarks filed 10/16/2025
The amendments and arguments presented in the papers filed 10/16/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 07/29/2025 listed below have been reconsidered as indicated.
a) The objections to the specification regarding the use of trade names or marks are withdrawn in view of the amendments to the specification.
b) The 35 USC 112(b) indefiniteness rejections of claims 1-36 have been withdrawn in view of the amendments to claims and cancellation of claims.
c) The rejection of claims 1-3, 5, 6, 8, 11, 18-28, 30-31, 33, and 36 under 35 U.S.C. 102(a)(1) as being anticipated by Jerby et al. (WO 2019/070755) are withdrawn in view of the amendments to the claims.
d) The rejection of claims 1, 4, 12-16, 18, 22, and 29 under 35 U.S.C. 103 as being unpatentable over Jerby et al. (WO 2019/070755) are withdrawn in view of the amendments to the claims.
e) The rejection of claims 1, 7, 9-10, 12, 17, 26, and 32- 35 under 35 U.S.C. 103 as being unpatentable over Jerby et al. (WO 2019/070755) in view of Weiss et al. (Anatomic position determines oncogenic specificity in melanoma. 2021. bioRxiv. p. 1-85. posted 08/20/2021) are withdrawn in view of the amendments to the claims.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Claim Rejections - 35 USC § 112(b) - new
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4, 12, 22, and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
These are new rejections necessitated by claim amendments.
Claim 4 recites the limitation “converting the deconvoluted scRNA-seq sequence data to a single readout”. There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the deconvoluted scRNA-seq sequence data” is intended to refer to the deconvoluted scRNA-seq sequence data from steps (c) or (d) of claim 1 which the claim depends from. For examination purposes, “the deconvoluted scRNA-seq sequence data” is interpreted as the deconvoluted scRNA-seq sequence data from step (d).
Claim 12 step (e) recites the limitation “converting the deconvoluted scRNA-seq sequence data to a single readout”. There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the deconvoluted scRNA-seq sequence data” is intended to refer to the deconvoluted scRNA-seq sequence data from steps (c) or (d) of claim 12. For examination purposes, “the deconvoluted scRNA-seq sequence data” is interpreted as the deconvoluted scRNA-seq sequence data from step (d).
Claim 22 recites the limitation “converting the deconvoluted scRNA-seq sequence data to a single readout”. There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the deconvoluted scRNA-seq sequence data” is intended to refer to the deconvoluted scRNA-seq sequence data from steps (c) or (d) of claim 18, which the claim depends from. For examination purposes, “the deconvoluted scRNA-seq sequence data” is interpreted as the deconvoluted scRNA-seq sequence data from step (d).
Claim 29 recites the limitation “converting the deconvoluted scRNA-seq sequence data to a single readout”. There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the deconvoluted scRNA-seq sequence data” is intended to refer to the deconvoluted scRNA-seq sequence data from steps (c) or (d) of claim 26, which the claim depends from. For examination purposes, “the deconvoluted scRNA-seq sequence data” is interpreted as the deconvoluted scRNA-seq sequence data from step (d).
Claim Rejections - 35 USC § 101- modified
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 4, 12-16, 22-25, and 29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
These are modified rejections necessitated by claim amendments.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process, a method.
Step 2A, Prong One
The claims are taken to be directed to abstract ideas (mathematical concepts), a judicial exception.
Claim 4 is directed to a method comprising “converting the deconvoluted scRNA-seq sequence data to a single readout”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)). As written, the converting step encompasses mathematical concepts such as mathematical calculations.
Claim 12 step (e) is directed to a method comprising “converting the deconvoluted scRNA-seq sequence data to a single readout”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)). As written, the converting step encompasses mathematical concepts such as mathematical calculations.
Claims 13-16 depend from claim 12, and require the same step of “converting the deconvoluted scRNA-seq sequence data to a single readout”.
Claim 14 is directed to a method comprising “when it is determined that the melanoma tumor will respond to ICI treatment, an effective amount of an ICI treatment is administered to the subject; or when the melanoma tumor will not respond to ICI treatment, administering to the subject a therapeutically effective amount of an alternative non-ICI therapy”. This limitation is an abstract idea (see MPEP 2106.04(a)(2)). As written, the determining and administering steps encompass the mental process of making a judgement.
Claim 22 is directed to a method comprising “converting the deconvoluted scRNA-seq sequence data to a single readout”. This limitation is an abstract idea (see MPEP 2106.04(a)(2)). As written, the converting step encompasses mathematical concepts such as mathematical calculations.
Claim 23 is directed to a method comprising “when the melanoma tumor will respond to ICI treatment, administering to the subject a therapeutically effective amount of an ICI treatment; or when the melanoma tumor will not respond to ICI treatment, administering to the subject a therapeutically effective amount of an alternative non-ICI therapy”. This limitation is an abstract idea (see MPEP 2106.04(a)(2)). As written, the steps encompass the mental process of making a judgement.
Claims 24 and 25 depend from claim 23, and require the same step of “when the melanoma tumor will respond to ICI treatment, administering to the subject a therapeutically effective amount of an ICI treatment; or when the melanoma tumor will not respond to ICI treatment, administering to the subject a therapeutically effective amount of an alternative non-ICI therapy”.
Claim 29 is directed to a method comprising “converting the deconvoluted scRNA-seq sequence data to a single readout”. This limitation is an abstract idea (see MPEP 2106.04(a)(2)). As written, the converting step encompasses mathematical concepts such as mathematical calculations.
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
Regarding claim 4, while claim 1 recites “(a) obtaining a melanoma tumor sample from a subject;(b) performing scRNA-seq of the melanoma tumor sample and obtaining scRNA-seq sequence data;(c) executing on a processor, deconvoluting the scRNA-seq sequence data using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype of volar-like (v-mel) melanocyte-derived melanoma or non- volar cutaneous-like (c-mel) melanocyte-derived melanoma; and(d) deconvoluting the scRNA-seq sequence data using a second gene signature to calculate an estimate of the total number of cells in the melanoma tumor sample that express the second gene signature; wherein when the calculated estimate of the total number of cells in the melanoma tumor sample that express the second gene signature reaches a critical threshold value, the melanoma tumor will not respond to immune checkpoint inhibition (ICI) treatment”, this is not an integration of the exception into a practical application. Instead, these elements are data gathering and data analysis required to perform the method. Obtaining a tumor, performing single-cell RNA sequencing and deconvoluting sequencing data to stratify cell types are all routine and conventional methods.
While claim 12 recites ”(a) obtaining a melanoma tumor sample from a subject; (b) performing scRNA-seq of the melanoma tumor sample and obtaining scRNA-seq sequence data; (c) on a processor, deconvoluting the scRNA-seq sequence data using a first gene signature to stratify the melanoma tumor into a specific melanoma cell subtype; (d) deconvoluting the scRNA-seq sequence data using a second gene signature to calculate an estimate of the total number of cells in the melanoma tumor sample that express the second gene signature”, this is not an integration of the exception into a practical application. Instead, these elements are data gathering and data analysis required to perform the method. Obtaining a tumor, performing single-cell RNA sequencing and deconvoluting sequencing data to stratify cell types are all routine and conventional methods.
Regarding claims 22 and 23, while claim 18 recites “(a) obtaining a melanoma tumor sample from the subject;(b) performing RNA hybridization of the melanoma tumor sample using a targeted RNA probe panel to obtain targeted transcript expression data;(c) executing on a processor, deconvoluting the targeted transcript expression data using a first gene signature from the targeted RNA probe panel to stratify the melanoma into a specific melanoma cell subtype of volar-like (v-mel) melanocyte- derived melanoma or non-volar cutaneous-like (c-mel) melanocyte-derived melanoma; and(d) deconvoluting the targeted transcript expression data using a second gene signature from the targeted RNA probe panel to calculate an estimate of the total number of cells in the tumor sample that express the second gene signature; wherein when the calculated estimate of the total number of cells in the tumor sample that express the second gene signature reaches a threshold value, the tumor will not respond to immune checkpoint inhibition (ICI) treatment” , this is not an integration of the exception into a practical application. Instead, these elements are data gathering and data analysis required to perform the method. Obtaining a tumor, performing RNA hybridization and deconvoluting expression data to stratify cell types are all routine and conventional methods.
Regarding claim 29, while claim 26 recites “(a) obtaining one or more melanoma tumor samples from a subject;(b) performing RNA sequencing of the one or more melanoma tumor samples and obtaining bulk transcriptomic data;(b) performing transcript counting on the bulk transcriptomic data to obtain transcript expression data; using a first gene signature to stratify the melanoma into a specific melanoma cell subtype or origin of volar-like (v-mel) melanocyte-derived melanoma or non-volar cutaneous- like (c-mel) melanocyte-derived melanoma; and(d) deconvoluting the transcript expression data using a second gene signature to calculate an estimate of the total number of cells in the melanoma tumor sample that express the second gene signature or determine the cell differentiation state; wherein when the calculated estimate of the total number of cells in the melanoma tumor sample that express the second gene signature reaches a threshold value, the melanoma will not respond to immune checkpoint inhibition (ICI) treatment” , this is not an integration of the exception into a practical application. Instead, these elements are data gathering and data analysis required to perform the method. Obtaining a tumor, performing bulk transcriptomics and deconvoluting sequencing data to stratify cell types are all routine and conventional methods.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to obtaining a melanoma tumor sample; performing scRNA-Seq, RNA hybridization or bulk transcriptomics, and deconvoluting gene signatures are techniques that are routine, conventional, and well-known in the art as demonstrated in the 103 rejections documented below.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity:
i. 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
ii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247. For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments against Claim Rejection - 35 U.S. C § 101
The response asserts that claims 4, 12, 22, and 29 are amended to clarify their integration into the practical application of stratifying the melanoma cells into volar-like (v-mel) melanocyte-derived melanoma or non-volar cutaneous- like (c-mel) melanocyte-derived subtypes and specify an active step of "converting the deconvoluted scRNA-seq sequence data to a single readout." Applicant argues that these elements transform the claim into a practical application that applies mathematical concepts, rather than being drawn to a mathematical concept (p. 15-16).
Applicant's arguments have been fully considered but are not persuasive.
The claims as amended remain drawn to a mathematical concept. Stratifying cells into subtypes based on gene expression is data analysis that is considered routine and conventional in the art and was well known in the art at the time of filing as explained above and in the 103 rejection below. Further, the active step of “converting –- to a single readout” remains a mathematical concept.
The response further asserts that amendments to claims 14 and 23 transform the claim into a practical application and integrate whether the melanoma tumor will respond into the practical applications of administering a treatment and stratifying the melanoma cells into volar-like (v-mel) melanocyte- derived melanoma or non-volar cutaneous-like (c-mel) melanocyte-derived subtypes (p. 16).
Applicant's arguments have been fully considered but are not persuasive.
The claims as amended remain drawn to a mental process. Stratifying cells into subtypes based on gene expression is data analysis that is considered routine and conventional in the art and was well known in the art at the time of filing as explained above and in the 103 rejection below.
Claim Rejections - 35 USC § 103 - New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-6, 8-16, 18-31, and 33-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jerby et al. (WO 2019/070755) in view of Belote et al. (Single cell analysis of human site-specific melanocyte differentiation and the decoding of developmental programs in melanoma. 2020. bioRxiv. p. 1-32. posted 05/28/2020).
These are new rejections necessitated by claim amendments filed on 10/16/2025.
Regarding claim 1, Jerby teaches methods for detecting gene signatures for the treatment and prognosis of cancer (para 4) and stratifying patients (para 29) comprising: obtaining a tumor sample (para 282) from melanoma (para 57); performing scRNA-seq (Fig. 1 and para 386); on a processor, deconvoluting the reads (para 581) and detecting gene signatures associated with specific subtypes (para 176), which reads using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype. Jerby further teaches detecting an immune checkpoint inhibitor resistance (ICR) gene signature (which reads on the second gene signature) (para 19) and calculating the total number of cells expressing the ICR signature (Fig. 2B) with a threshold value determined for immune checkpoint inhibitor resistance (ICR) (Fig. 2B).
Regarding step (c), Jerby teaches uveal and cutaneous melanoma subtypes (paras 421, 460) but does not teach using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype of volar-like (v-mel) melanocyte-derived melanoma or non- volar cutaneous-like (c-mel) melanocyte-derived melanoma
Belote teaches a gene signature for sorting and stratifying cells into volar-like or non-volar cutaneous melanocyte types (p. 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment (para 171, 176-177) and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 2, Jerby teaches an acral melanoma sample (para 307).
Regarding claim 3, Jerby teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is below a threshold value, the melanoma tumor will respond to ICI treatment) (para 48), and administering a checkpoint inhibitor and a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is above a threshold value, the melanoma tumor will not respond to ICI treatment) (para 13).
Regarding claim 4, Jerby does not teach verbatim converting the deconvoluted scRNA-seq sequence data to a single readout; wherein when the value of the single readout is positive, the melanoma tumor will not respond to ICI treatment; or wherein when the value of the single readout is negative, the melanoma tumor will respond to ICI treatment.
However, Jerby teaches deconvolution using multiple gene signatures from transcriptomes (paras 178 and 19), calculating a high ICR score and low ICR score (see for example para 17), and oncogenic ICR scores (see for example Fig. 2B). Jerby further teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is not positive, the melanoma tumor will respond to ICI treatment) (para 48), and administering a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is positive, the melanoma tumor will not respond to ICI treatment) (para 13). Jerby states that ICR in patients is unpredictable, hampering appropriate selection of patients for therapies and rational enrollment to clinical trials (para 5) .
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jerby to arrive at the instantly claimed invention. One would have been motivated to do so for the stated goal of improving predictability of ICR. It would have been obvious to try, as shown in Jerby, different calculations for ICR scores. Determining a deconvolution scoring system would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success since Jerby calculated multiple scoring systems for determining ICR and applied those scores to the determination of treatment responsiveness. There would further have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 5, Jerby teaches treatment with pembrolizumab (para 98).
Regarding claim 6, Jerby teaches IL2 as a non-ICI immunotherapy (para 631).
Regarding claims 8, 9, and 10, Jerby teaches a gene signature comprising NTRK2 (p. 366, Table 29) but does not teach its use for stratifying melanoma subtypes (claim 8); or the expression of the claimed genes is associated with a volar-like (claim 9) or non-volar cutaneous-like (claim 10) melanocyte-derived melanoma subtype.
Regarding claims 8, 9, and 10, Jerby teaches a gene signature comprising NTRK2 (p. 366, Table 29) but does not teach its use for stratifying melanoma subtypes (claim 8); or the expression of the claimed genes is associated with a volar-like (claim 9) or non-volar cutaneous-like (claim 10) melanocyte-derived melanoma subtype.
Regarding claim 8, Belote teaches a gene signature that includes NTRK2 and HPGD (Fig. 1D and Table S1).
Regarding claim 9, Belote teaches upregulated expression of NTRK2 is associated with volar-like melanocytes. (Fig. 1D and Table S1).
Regarding claim 10, Belote teaches upregulated expression of HPGD is associated with non-volar cutaneous-like melanocytes HPGD (Fig. 1D and Table S1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 11, Jerby teaches an immune checkpoint inhibitor resistance (ICR) gene signature in a tumor comprising SERPINF1 (para 19).
Regarding claim 12, Jerby teaches methods for detecting gene signatures for the treatment and prognosis of cancer (para 4) and stratifying patients (para 29) comprising: obtaining a tumor sample (para 282) from melanoma (para 57); performing scRNA-seq (Fig. 1 and para 386); on a processor, deconvoluting the reads (para 581) and detecting gene signatures associated with specific subtypes (para 176), which reads using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype. Jerby further teaches detecting an immune checkpoint inhibitor resistance (ICR) gene signature (which reads on the second gene signature) (para 19) and calculating the total number of cells expressing the ICR signature (Fig. 2B) with a threshold value determined for immune checkpoint inhibitor resistance (ICR) (Fig. 2B).
Regarding step (c), Jerby teaches uveal and cutaneous melanoma subtypes (paras 421, 460) but does not teach using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype of volar-like (v-mel) melanocyte-derived melanoma or non- volar cutaneous-like (c-mel) melanocyte-derived melanoma
Belote teaches a gene signature for sorting and stratifying cells into volar-like or non-volar cutaneous melanocyte types (p. 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment (para 171, 176-177) and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding step (e), Jerby does not teach verbatim converting the deconvoluted scRNA-seq sequence data to a single readout; wherein when the value of the single readout is positive, the melanoma tumor will not respond to ICI treatment; or wherein when the value of the single readout is negative, the melanoma tumor will respond to ICI treatment.
However, Jerby teaches deconvolution using multiple gene signatures from transcriptomes (paras 178 and 19), calculating a high ICR score and low ICR score (see for example para 17), and oncogenic ICR scores (see for example Fig. 2B). Jerby further teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is not positive, the melanoma tumor will respond to ICI treatment) (para 48), and administering a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is positive, the melanoma tumor will not respond to ICI treatment) (para 13). Jerby states that ICR in patients is unpredictable, hampering appropriate selection of patients for therapies and rational enrollment to clinical trials (para 5) .
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jerby to arrive at the instantly claimed invention. One would have been motivated to do so for the stated goal of improving predictability of ICR. It would have been obvious to try, as shown in Jerby, different calculations for ICR scores. Determining a deconvolution scoring system would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success since Jerby calculated multiple scoring systems for determining ICR and applied those scores to the determination of treatment responsiveness. There would further have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 13, Jerby teaches an acral melanoma sample (para 307).
Regarding claim 14, Jerby teaches the method comprises administering an immunotherapy if an ICR signature is not detected (it is determined that the tumor will respond to ICI treatment) (para 48), and administering a checkpoint inhibitor and a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (it is determined that the tumor will not respond to ICI treatment) (para 13).
Regarding claim 15, Jerby teaches treatment with pembrolizumab (para 98).
Regarding claim 16, Jerby teaches IL2 as a non-ICI immunotherapy (para 631).
Regarding claim 18, Jerby teaches methods for detecting gene signatures for the treatment and prognosis of cancer (para 4) and stratifying patients (para 29) comprising: obtaining a tumor sample (para 282) from melanoma (para 57); detecting signature genes by RNA hybridization (para 187) using a kit with oligonucleotide probes for hybridization to RNA (i.e. a RNA probe panel) (para 60); on a processor, deconvoluting the reads (para 581) and detecting gene signatures associated with specific subtypes (para 176). Jerby further teaches detecting an immune checkpoint inhibitor resistance (ICR) gene signature (second gene signature) (para 19) and calculating the total number of cells expressing the signature (Fig. 2B) with a threshold value determined for immune checkpoint inhibitor resistance (ICR) (Fig. 2B).
Regarding step (c), Jerby teaches uveal and cutaneous melanoma subtypes (paras 421, 460) but does not teach using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype of volar-like (v-mel) melanocyte-derived melanoma or non- volar cutaneous-like (c-mel) melanocyte-derived melanoma
Belote teaches a gene signature for sorting and stratifying cells into volar-like or non-volar cutaneous melanocyte types (p. 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment (para 171, 176-177) and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 19, Jerby teaches an acral melanoma sample (para 307).
Regarding claim 20, Jerby teaches the use of formalin-fixed, paraffin-embedded (FFPE) tissue slides (para 637).
Regarding claim 21, Jerby teaches an immune checkpoint inhibitor resistance (ICR) gene signature in a tumor comprising SERPINF1 (para 19).
Regarding claim 22, Jerby does not teach verbatim converting the deconvoluted scRNA-seq sequence data to a single readout; wherein when the value of the single readout is positive, the melanoma tumor will not respond to ICI treatment; or wherein when the value of the single readout is negative, the melanoma tumor will respond to ICI treatment.
However, Jerby teaches deconvolution using multiple gene signatures from transcriptomes (paras 178 and 19), calculating a high ICR score and low ICR score (see for example para 17), and oncogenic ICR scores (see for example Fig. 2B). Jerby further teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is not positive, the melanoma tumor will respond to ICI treatment) (para 48), and administering a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is positive, the melanoma tumor will not respond to ICI treatment) (para 13). Jerby states that ICR in patients is unpredictable, hampering appropriate selection of patients for therapies and rational enrollment to clinical trials (para 5) .
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jerby to arrive at the instantly claimed invention. One would have been motivated to do so for the stated goal of improving predictability of ICR. It would have been obvious to try, as shown in Jerby, different calculations for ICR scores. Determining a deconvolution scoring system would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success since Jerby calculated multiple scoring systems for determining ICR and applied those scores to the determination of treatment responsiveness. There would further have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 23, Jerby teaches the method comprises administering an immunotherapy if an ICR signature is not detected (it is determined that the tumor will respond to ICI treatment) (para 48), and administering a checkpoint inhibitor and a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (it is determined that the tumor will not respond to ICI treatment) (para 13).
Regarding claim 24, Jerby teaches treatment with pembrolizumab (para 132).
Regarding claim 25, Jerby teaches IL2 as a non-ICI immunotherapy (para 631).
Regarding claim 26, Jerby teaches methods for detecting gene signatures for the treatment and prognosis of cancer (para 4) and stratifying patients (para 29) comprising: obtaining a tumor sample (para 282) from melanoma (para 57); performing bulk RNA-Seq (Fig. 1 and para 85); on a processor, deconvoluting the reads (para 581) and detecting gene signatures associated with specific subtypes (para 176). The gene signatures I can be further deconvolution of bulk expression data such that gene expression is assigned to malignant cells and non- malignant cells (para 44). Jerby further teaches detecting an immune checkpoint inhibitor resistance (ICR) gene signature (second gene signature) (para 19) and calculating the total number of cells expressing the signature (Fig. 2B) with a threshold value determined for immune checkpoint inhibitor resistance (ICR) (Fig. 2B).
Regarding step (c), Jerby teaches uveal and cutaneous melanoma subtypes (paras 421, 460) but does not teach using a first gene signature to stratify the melanoma tumor sample into a specific melanoma cell subtype of volar-like (v-mel) melanocyte-derived melanoma or non- volar cutaneous-like (c-mel) melanocyte-derived melanoma
Belote teaches a gene signature for sorting and stratifying cells into volar-like or non-volar cutaneous melanocyte types (p. 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment (para 171, 176-177) and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 27, Jerby teaches an acral melanoma sample (para 307).
Regarding claim 28, Jerby teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is below a threshold value, the melanoma tumor will respond to ICI treatment) (para 48), and administering a checkpoint inhibitor and a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is above a threshold value, the melanoma tumor will not respond to ICI treatment) (para 13).
Regarding claim 29, Jerby does not teach verbatim converting the deconvoluted scRNA-seq sequence data to a single readout; wherein when the value of the single readout is positive, the melanoma tumor will not respond to ICI treatment; or wherein when the value of the single readout is negative, the melanoma tumor will respond to ICI treatment.
However, Jerby teaches deconvolution using multiple gene signatures from transcriptomes (paras 178 and 19), calculating a high ICR score and low ICR score (see for example para 17), and oncogenic ICR scores (see for example Fig. 2B). Jerby further teaches the method comprises administering an immunotherapy if an ICR signature is not detected (i.e. if an ICR score is not positive, the melanoma tumor will respond to ICI treatment) (para 48), and administering a CDK4/6 inhibitor (an alternative non-ICI therapy) if an ICR signature is detected (i.e. if an ICR score is positive, the melanoma tumor will not respond to ICI treatment) (para 13). Jerby states that ICR in patients is unpredictable, hampering appropriate selection of patients for therapies and rational enrollment to clinical trials (para 5).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jerby to arrive at the instantly claimed invention. One would have been motivated to do so for the stated goal of improving predictability of ICR. It would have been obvious to try, as shown in Jerby, different calculations for ICR scores. Determining a deconvolution scoring system would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success since Jerby calculated multiple scoring systems for determining ICR and applied those scores to the determination of treatment responsiveness. There would further have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 30, Jerby teaches treatment with pembrolizumab (para 132).
Regarding claim 31, Jerby teaches IL2 as a non-ICI immunotherapy (para 631).
Regarding claims 33, 34, and 35, Jerby teaches a gene signature comprising NTRK2 (p. 366, Table 29) but does not teach its use for stratifying melanoma subtypes (claim 33); or the expression of the claimed genes is associated with a volar-like (claim 34) or non-volar cutaneous-like (claim 35) melanocyte-derived melanoma subtype.
Regarding claim 33, Belote teaches a gene signature that includes NTRK2 and HPGD (Fig. 1D and Table S1).
Regarding claim 34, Belote teaches upregulated expression of NTRK2 is associated with volar-like melanocytes. (Fig. 1D and Table S1).
Regarding claim 35, Belote teaches upregulated expression of HPGD is associated with non-volar cutaneous-like melanocytes HPGD (Fig. 1D and Table S1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jerby and Belote to arrive at the instantly claimed invention. The modification would have entailed using the gene signature of Belote in the method of Jerby. One would have been motivated by the benefits of a gene signature capable of stratifying melanoma samples by subtype, a stated goal of Jerby. Jerby teaches the use of multiple gene signatures towards the goal of identifying tumor samples resistant to ICI treatment and further recognized that different melanoma subtypes had different immunotherapy resistance (para 460). Similarly, Belote stated their motivation to use their resource for discovery of melanoma diagnostics and therapeutics (p. 8). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 36, Jerby teaches an immune checkpoint inhibitor resistance (ICR) gene signature in a tumor comprising SERPINF1 (para 19).
Response to Arguments against Claim Rejections - 35 U.S. C § 103
Claims 1, 4, 12-16, 18, 22, and 29 over Jerby
Applicant’s arguments, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn in view of the amendments to the claims. However, upon further consideration, a new ground(s) of rejection is made over Jerby in view of Belote as described above.
Claims 1, 9-10, 12, 26, and 33-35 over Jerby in view of Weiss
Applicant’s arguments, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn in view of the amendments to the claims. However, upon further consideration, a new ground(s) of rejection is made over Jerby in view of Belote as described above.
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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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682