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 .
Election/Restrictions
Applicant’s election without traverse of species “RNA”, “BCC” and “same area” in the reply filed on 08/24/2026 is acknowledged.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/24/2026.
Claim 2, though directed to a non-elected species, is rejoined.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 7-9, 12, 18-21, 29, 30, 90 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dobak (WO 2019/161126 A1, IDS reference) as evidenced by Sawant (Scientific Reports 6:33123 (2016)).
Dobak taught:
Regarding claim 1:
A method for non-invasive gene expression analysis of one or more target genes,
Abstract: “Described herein are methods, systems, and compositions for non-invasively diagnosing or detecting a skin disease or disorder. Diagnosing or detecting a non-melanoma skin cancer as provided herein comprises detecting gene expression levels of a set of identified genes…”.
comprising: receiving or obtaining data comprising measurements of RNA
Para 0003: “…a method of detecting gene expression levels of at least two of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, and SPP1…”.
Para 0003: “…the nucleic acids comprise RNA…the RNA is mRNA.”
obtained from a skin sample using a non-invasive sampling method,
Para 0003: “…isolating nucleic acids from a biological sample obtained from the subject…”.
Para 0003: “…the biological sample comprises a skin sample…”.
Para 0003: “…the skin sample is obtained by applying a plurality of adhesive patches to the skin sample in a manner sufficient to adhere the skin sample to the adhesive patch, and removing the adhesive patch from the skin in a manner sufficient to retain the adhered skin sample to the adhesive patch…”.
the skin sample having been obtained from a subject suspected of having BCC (basal cell carcinoma)
Para 0003: “…the skin sample comprises a lesion, and wherein the lesion is suspected to be…basal cell carcinoma or squamous cell carcinoma…”.
and applying one or more classifiers to the measurements to analyze gene expression of the one or more target genes in the skin sample
See title.
See also para 0045: “…the gene expression levels of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, SPP1, or a combination thereof are used to differentiate cancer samples from non-cancer samples…the gene expression levels of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, SPP1, or a combination thereof in cancer samples and non-cancer samples are analyzed using various algorithmic models. In some instances, the algorithmic model is random forest (rf) model…”.
Para 0046: “In some instances, the cancer samples comprise basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or a combination thereof. In some instances, the cancer samples comprise BCC and SCC. In some instances, the non-cancer samples comprise actinic keratosis (AK), seborrheic keratosis (SK), normal samples, or a combination thereof. In some instances, the non-cancer samples comprise actinic keratosis (AK), seborrheic keratosis (SK), and normal samples.”
Regarding claim 2:
Para 0034: “In some instances, SCC is further classified into subtypes and the subtypes comprises squamous cell carcinoma in situ (also known as Bowen’s disease), invasive squamous cell carcinoma (SCCI), clear cell SCC, spindle cell (sarcomatoid) SCC, SCC with single cell infiltrates, de novo SCC, verrucous carcinoma (VC), and lymphoepithelioma-like carcinoma of the skin. In some instances, the SCC subtype also comprises keratoacanthomas.”
Regarding claim 3:
Para 0003: “…the skin sample is obtained by applying a plurality of adhesive patches to the skin sample in a manner sufficient to adhere the skin sample to the adhesive patch, and removing the adhesive patch from the skin in a manner sufficient to retain the adhered skin sample to the adhesive patch…”.
Regarding claim 7:
Para 0096: “In some embodiments, the skin sample is obtained from a skin lesion.”
Para 0125: “The patch stripping method, devices, and systems described herein are useful for the collection of a skin sample from a skin lesion.”
Regarding claim 8:
Para 0003: “…the nucleic acids comprise RNA…the RNA is mRNA.”
Regarding claim 9:
Para 0003: “…detecting the expression levels comprise quantitative polymerase chain reaction (qPCR), sequencing, or microarray analysis.”
Para 0133: “In some embodiments, isolated RNA from a collected skin sample is reverse transcribed into cDNA, for example for amplification by PCR to enrich for target genes. The expression levels of these target genes are quantified by quantitative PCR in a gene expression test.”
Regarding claim 12:
Para 0003: “…a method of detecting gene expression levels of at least two of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, and SPP1…”.
As evidenced by Sawant (first statement of abstract): “The chemokine CXCL1/MGSA plays a pivotal role in the host immune response by recruiting and activating neutrophils for microbial killing at the tissue site.” Therefore, at least CXCL1 plays a role in the innate immune system.
Regarding claim 18:
Para 0037: “Methods and compositions as described herein are used for detecting gene expression levels of a gene of interest. In some instances, the gene of interest is implicated in a skin disease. In some instances, the skin disease is a non-melanoma skin cancer (NMSC). In some instances, the NMSC is BCC or SCC. In some cases, the skin disease is melanoma. Exemplary genes associated with a skin disease (e.g., a NMSC such as BCC or SCC) and, in some instances, detected using methods described herein include, but are not limited to, MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, and SPP1.”
Regarding claims 19 and 20:
Para 0083: “In some instances, the expression level is at least or about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more than 95% increased as compared to control.” Note that a 50% increase in expression is the same as 1.5 fold increase.
Regarding claim 21:
Para 0174: “Cancer samples and non-cancer samples were differentiated on the different gene expression patterns of these target genes. Using a l3-target gene panel ( MMP1 , S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, and VEGFA), BCC and SCC samples were differentiated from AK and other non-cancerous skin lesions of similar appearance with a sensitivity of 91% (95% Cl 86% - 95%) and a specificity of 87% (95% Cl 80% - 92%) based on 160 non-invasively collected adhesive patch skin biopsies (p<0.00l)…”. Here, the non-cancer sample can be considered a “control”.
Regarding claim 29:
Para 0045: “…analyzed using various algorithmic models. In some instances, the algorithmic model is random forest (rf) model…”.
Regarding claim 30:
Para 0005: “An aspect described herein is a method of diagnosing and treating a disease or disorder in a subject, comprising: (a) isolating nucleic acids from a biological sample obtained from the subject; (b) detecting the expression levels of at least two genes selected from the group consisting of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24 , AADACL2, PTCH1 , CD68, PRKACA, and SPP1, and comparing the expression levels of the at least two genes to a control; (c) identifying the subject as having the disease or disorder if there is a change in the expression levels of the at least two genes relative to the control; and (d) administering an effective amount of a therapeutic agent to the diagnosed subject.”
Regarding claim 90:
See discussion above and especially:
Para 0045: “…the gene expression levels of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, SPP1, or a combination thereof are used to differentiate cancer samples from non-cancer samples…the gene expression levels of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, SPP1, or a combination thereof in cancer samples and non-cancer samples are analyzed using various algorithmic models. In some instances, the algorithmic model is random forest (rf) model…”.
Para 0046: “In some instances, the cancer samples comprise basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or a combination thereof. In some instances, the cancer samples comprise BCC and SCC. In some instances, the non-cancer samples comprise actinic keratosis (AK), seborrheic keratosis (SK), normal samples, or a combination thereof. In some instances, the non-cancer samples comprise actinic keratosis (AK), seborrheic keratosis (SK), and normal samples.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dobak (WO 2019/161126 A1, IDS reference).
The teachings of Dobak have been discussed. Dobak taught applying a plurality of adhesive patches to the skin (para 0003). Dobak also taught the skin sample comprised “a lesion” (para 0003, 0096, 0125), which by any reasonable interpretation constitutes “an area of skin”. Dobak also taught (para 0003) that the plurality of patches could be pooled.
While Dobak did not expressly indicate applying multiple patches to a “same area” of skin, it would have been prima facie obvious to one of ordinary skill in the art prior to the effect filing date of the application that when using “a plurality” of adhesive patches to collect a skin sample from “a lesion”, each patch would be applied to that same area of skin.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dobak (WO 2019/161126 A1, IDS reference) in view of Sampath (US 2019/0330625).
The teachings of Dobak have been discussed. Dobak did not disclose any of the genes recited in claim 13.
Sampath disclosed (para 0078): “At steady state, healthy epidermal keratinocytes express high levels of exonic miR-198, but no FSTL1 protein (FIG. 1a). On the contrary, similar to wound microenvironment, migrating and proliferating keratinocytes in cutaneous squamous cell carcinoma (SCC) tissue sections express high levels of FSTL1, and very little or no miR-198 (FIG. 1b).”
In this way, Sampath disclosed a two gene classifier that was indicative of SCC.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effect filing date of the application to modify the method of Dobak by including FSTL1 and miR-198 among the classifiers of Dobak for distinguishing SCC, because Sampath determined this gene pair could distinguish healthy epidermal keratinocytes from keratinocytes in squamous cell carcinoma. Therefore, this modification would have added to Dobak’s toolbox of gene classifiers for distinguishing cancer samples from non-cancer samples.
Claim(s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dobak (WO 2019/161126 A1, IDS reference) in view of Firnhaber (American Family Physician 86(2):161-168 (2012)).
The teachings of Dobak have been discussed. Dobak disclosed (para 0006): “In one feature, treatment for the basal cell carcinoma or squamous cell carcinoma comprises surgery. In one feature, treatment for actinic keratosis comprises a topical treatment.”
However, Dobak did not mention the specific types of surgery or topical treatment recited in claim 31.
Firnhaber taught with respect to basal cell and squamous cell carcinomas (see abstract): “Mohs micrographic surgery has the lowest recurrence rate among treatments, but is best considered for large, high-risk tumors. Smaller, lower-risk tumors may be treated with surgical excision, electrodesiccation and curettage, or cryotherapy.”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effect filing date of the application to select these standard treatments for SCC and BCC when practicing the method of diagnosing and treating these cancers disclosed by Dobak.
Claim(s) 91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dobak (WO 2019/161126 A1, IDS reference) in view of Hao (WO 2020/132520 A2).
The teachings of Dobak have been discussed. In addition, Dobak disclosed (para 0010): “An aspect described herein is a computer-implemented system comprising: (a) a first computing device comprising a processor, a memory module, an operating system, and a computer program including instructions executable by the processor to create a data acquisition application for receiving gene expression from a sample, the data acquisition application comprising: a data receiving module for receiving gene expression data of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, SPP1, or a combination thereof; and (b) a second computing device comprising a processor, a memory module, an operating system, and a computer program including instructions executable by the processor to create a data analysis application for differentiating a cancer sample from a non-cancer sample…”.
Dobak disclosed (para 0011): “…a non-transitory computer-readable medium with instructions stored thereon, that when executed by a processor, perform the steps comprising: (a) generating gene expression data of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, and SPP1 from a set of biological samples by a hybridizing method; (b) obtaining, by a processor, the gene expression data; (c) generating a plurality of pair-wise interactions between at least two genes of MMP1, S100A7, CMPK2, IRF7, IGFL1, CXCL1, UPP1, DEFB4A, FOS, OAS3, SCD5, RTP4, VEGFA, COL5A2, IL24, AADACL2, PTCH1, CD68, PRKACA, and SPP1; (d) analyzing the plurality of pair-wise interactions using a machine learning method to determine an area under a curve (AUC) value for each of the plurality of pair-wise interactions; and (e) differentiating the one or more cancer samples from the one or more non-cancer samples…”.
Dobak disclosed at para 0088 “computer-implemented methods for differentiating one or more cancer samples from one or more non-cancer samples… the set of samples comprises basal cell carcinoma, squamous cell carcinoma, actinic keratosis (AK)…”.
Dobak spoke of a “data receiving module” as noted above, but did not expressly disclose a “communication interface” that receives the data “over a communication network”.
Hao disclosed (para 0014, page 4): “a system comprising a communication interface that is configured to receive, over a communication network, data derived from assaying gene expression products of a sample, one or more computer processors in communication with said communication interface, wherein the one or more computer processors are individually or collectively programmed to implement a method comprising: (i) receiving, over the communication network, the data derived from assaying gene expression products of the sample, (ii) detecting the level of one or more gene fusions in the sample, to yield gene fusion data corresponding to the level(s) of said one or more gene fusions; (iii) inputting said gene fusion data into a programmed computer to classify the sample as positive or negative for lung cancer; and (iv) electronically outputting an electronic report comprising said classification of (iii) that identifies said classification of said sample as positive or negative for said lung cancer.”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effect filing date of the application to modify the system of Dobak by incorporating a communications network and interface by which the system could receive the gene expression data, as in the system of Hao, since this was a known means in the art for receiving gene expression data for analysis by a processor. This would have saved the effort (and avoided potential errors) of a human being manually entering gene expression data obtained by one component of the system into another component of the system for analysis.
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 1-5,7-9,12-13,18-21,29-30 and 90-91 rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) a natural correlation between cancer and amounts of certain RNA (i.e. expression levels of certain genes). This judicial exception is not integrated into a practical application because the additional elements recited in the claims, such as obtaining a sample with adhesive patches and measuring amounts of RNA (e.g. by reverse transcription qPCR) are insignificant extra-solution activity (MPEP 2106.05(g)). In addition, the computer elements recited in claims 90 and 91 are merely general purpose computer system components that do not integrate the judicial exceptions into a practical application of those judicial exceptions (MPEP 2106.05(f)). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements recited in the claims were well-known, routine and conventional as evidenced by the teachings of the references used for the rejections under 35 USC 102 and 103 above, which are hereby incorporated into this rejection by reference.
Conclusion
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/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681
