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 of the invention Group I, comprising claims 39-41, 44, 49-51, 56-72, 76, and 77, in the reply filed 11/07/2025 is acknowledged. Furthermore, Applicant’s election of the species comprising a subset of the recited genes comprising at least 47 genes is acknowledged. As such, claim 73 is withdrawn from consideration pursuant to 37 CFR 1.42(b) as being drawn to a nonelected invention.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims Status
Claims 1-38, 42, 43, 45-48, 52-55, 74, 75, and 78-80 are canceled.
Claims 39-41, 44, 49-51, 56-73, 76, and 77 are pending.
Claim 73 is withdrawn from consideration.
Claims 39-41, 44, 49-51, 56-72, 76, and 77 are examined.
Priority
The instant application claims priority to US Provisional Application No. 63/334,837, filed 04/26/2022. Therefore, the Effective Filing Date (EFD) assigned to each of the claims 39-41, 44, 49-51, 56-72, 76, and 77 is the provisional filing date of Application No. 63/334,837, filed 04/26/2022.
Information Disclosure Statement
The Information Disclosure Statements filed 10/05/2023, and 09/30/2025 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The drawings filed 04/25/2023 are accepted.
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 39-41, 44, 49-51, 76 and 77 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to an abstract idea of mental steps, mathematic concepts, or a natural law without significantly more.
Claims 56-72 are eligible because the judicial exceptions are integrated into a practical application through the administration of dupilumab to a subject having a disease or condition suitable for treatment.
The MPEP at MPEP 2106.03 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of
matter?
(2A)(1) Are the claims directed to a judicially recognized exception, i.e. a law of nature,
a natural phenomenon, or an abstract idea?
(2A)(2) If the claims are directed to a judicial exception under Prong One, then is the
judicial exception integrated into a practical application?
(2B) If the claims are directed to a judicial exception and do not integrate the judicial
exception, do the claims provide an inventive concept?
With respect to step (1): Yes, the claims are directed to processes.
With respect to step (2A)(1): The claims are directed to abstract ideas of mental processes and mathematical concepts. The claims are also directed to laws of nature.
“Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection” (MPEP 2106.04). Abstract ideas include mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (procedures for observing, evaluating, analyzing/judging and organizing information (MPEP 2106.04(a)(2)). Laws of nature or natural phenomena include naturally occurring principles/relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature (MPEP 2106(b)).
Laws of nature recited in claim 1:
A method of carrying out a clinical trial for dupilumab treatment of a disease or condition, the method comprising using a dupilumab core gene signature as a clinical endpoint for the clinical trial
Mental processes recited in claim 76:
detecting the presence or absence of the at least ten nucleic acid molecules
Dependent claims 40, 41, 44, 49, 50, 51, and 77 recite additional steps that either are directed to abstract ideas or further limit the judicial exceptions in independent claim 1, and as such, are further directed to abstract ideas. Hence, the claims explicitly recite numerous elements that individually and in combination constitute abstract ideas. The relevant recitations are:
Claim 40: “wherein the dupilumab treatment core gene signature is generated by determining differential gene expression of a dupilumab treatment group and a placebo treatment group for a plurality of treatment studies, and identifying a plurality of genes that are differentially expressed”
Claim 41: “wherein the plurality of treatment studies comprises eosinophilic esophagitis, atopic dermatitis, asthma, grass allergy, and chronic rhinosinusitis with nasal polyposis”
Claim 44: “wherein the differential gene expression for the eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis treatment studies are carried out by comparing the baseline gene expression before treatment with dupilumab to the gene expression after treatment with dupilumab”
Claim 49: “wherein the plurality of genes that are differentially expressed comprises […] or any subset thereof comprising at least 40 genes, at least 42 genes, at least 44 genes, at least 46 genes, or at least 47 genes”
Claim 50: “generating a normalized enrichment score (NES) for the dupilumab treatment core gene signature prior to initiation of treatment of a subject with dupilumab and at least one time after initiation of treatment of a subject with dupilumab”
Claim 51: “wherein when dupilumab treatment results in a decrease in the NES for the dupilumab treatment core gene signature to an acceptable value, the clinical endpoint has been achieved”
Claim 77: “wherein the amount of the at least ten nucleic acid molecules encoding […] is determined”
The abstract ideas in the claims are evaluated under Broadest Reasonable Interpretation (BRI) and determined herein to each cover mental processes and mathematic concepts because the claims recite no more than analyzing the levels of biomarkers in a sample, and thus utilize mental processes and mathematical concepts to evaluate laws of nature.
With respect to step (2A)(2): The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone or in combination to determine if the judicial exception is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exception, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
Claim 76 recites the following additional elements that are not abstract ideas:
contacting a biological sample from the subject with a plurality of nucleic acid molecules comprising nucleotide sequences that are complementary to at least ten of the nucleic acid molecules
The step of contacting a biological sample with nucleic acid molecules gathers the data from the user on which the judicial exceptions are performed, and is thus directed to a step of data gathering. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
None of the dependent claims recite additional elements.
Lastly, the claims have been evaluated with respect to step (2B): Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims lack a specific inventive concept. Under said analysis, Applicant is reminded that the judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements of data gathering described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP at 2106.05(d)(I), determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to claim 76: The additional element of contacting a biological sample from the subject with a plurality of nucleic acid molecules comprising nucleotide sequences that are complementary to at least ten of the nucleic acid molecules does not rise to the level of significantly more than the judicial exception. With respect to Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247, techniques of hybridizing a gene probe are well-understood, routine and conventional. Furthermore, with respect to Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157), detecting DNA in a sample is well-understood, routine, and conventional. As such, As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. Individually, the limitations of the claims and the claims as a whole have been found lacking.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 39, 40, 56, 57, 59, and 63 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dobak et al. (US 2021/0222246 A1, published 07/22/2021).
Regarding claim 39, Dobak et al. teaches a method of carrying out a clinical trial for treatment of a disease, including atopic dermatitis (Abstract), the treatment being dupilumab (paragraph [0257]; paragraph [0346]), the method comprising using a gene signature for the treatment as a clinical endpoint for the clinical trial (paragraph [0004]).
Regarding claim 40, the claim is directed to the dupilumab core gene signature being generated by determining differential gene expression of a dupilumab treatment group and a placebo treatment group for a plurality of treatment studies, and identifying a plurality of genes that are differentially expressed. Dobak et al. teaches the method of claim 39. Dobak et al. also teaches determining differential gene expression of a dupilumab treatment group and a placebo treatment group for atopic dermatitis (paragraphs [0018]; [0256]-[0258]), and other treatment studies such as psoriasis (paragraph [0252]).
Regarding claim 56, Dobak et al. teaches a method of treating a subject having a disease or condition suitable for treatment with dupilumab, comprising:
identifying the subject as having a disease or condition suitable for treatment (Abstract) with dupilumab (paragraph [0346]) comprising:
generating a dupilumab treatment core gene signature (paragraph [0089]);
screening the dupilumab core gene signature against a whole transcriptome profile from the subject (paragraph [0337]); and
determining whether the subject is suitable for dupilumab treatment (paragraph [0337]); and
administering dupilumab to the subject having a disease or condition suitable for treatment with dupilumab (paragraph [0346]).
Regarding claim 57, the claim is directed to generating the dupilumab treatment core gene signature comprising determining differential gene expression of a dupilumab treatment group and a placebo treatment group for a plurality of treatment studies, and identifying a plurality of genes that are differentially expressed. Dobak et al. teaches the method of claim 56. Dobak et al. also teaches determining differential gene expression of a dupilumab treatment group and a placebo treatment group for atopic dermatitis (paragraphs [0018]; [0256]-[0258]), and other treatment studies such as psoriasis (paragraph [0252]).
Regarding claim 59, the claim is directed to the genes in the core gene signature identified from the differential gene expression being selected as having a fold-change≥2, and/or a q<0.05 in ≥ 3 out of 5 treatment studies. Dobak et al. teaches the method of claim 57. Dobak et al. also teaches the genes in the core gene signature having greater than a 2 fold-change (paragraph [0075]).
Regarding claim 63, the claim is directed to the differential gene expression being analyzed by a microarray or RNAseq. Dobak et al. teaches the method of claim 57. Dobak et al. also teaches analyzing gene expression by a microarray (paragraph [0173]).
Claim Rejections - 35 USC § 103
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.
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.
Claims 41, 58, 60, 61, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Dobak et al., as applied to claims 39, 40, 56, 57, 59, and 63, in view of Abbas et al. (US 2020/0165679 A1, published May 2020).
Regarding claim 41, the claim is directed to the plurality of treatment studies comprising eosinophilic esophagitis, atopic dermatitis, asthma, grass allergy, and chronic rhinosinusitis with nasal polyposis. Dobak et al. teaches the method of claim 40. Dobak et al. teaches a plurality of treatment studies comprising atopic dermatitis (paragraph [0256]). Dobak et al. also teaches IL-31 being involved in the promotion of allergic skin disorder and in regulation other allergic diseases such as asthma (paragraph [0195]) and teaches IL-5 being related to pathogenesis of eosinophil-dependent inflammatory diseases (paragraph [0197]).
Dobak et al. does not teach the claim elements of the plurality of treatment studies comprising eosinophilic esophagitis, grass allergy, and chronic rhinosinusitis.
However, Abbas et al. teaches methods of diagnosis and treating eosinophilic disorders. Abbas et al. teaches identification of biomarkers that are effective for determining which patients suffering with asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and eosinophilic esophagitis will respond effectively to which treatment (paragraphs [0008]; [0111]).
Regarding claim 58, the claim is directed to the plurality of treatment studies comprising eosinophilic esophagitis, atopic dermatitis, atopic dermatitis, asthma, grass allergy, and chronic rhinosinusitis with nasal polyposis. Dobak et al. teaches the method of claim 57. Dobak et al. teaches a plurality of treatment studies comprising atopic dermatitis (paragraph [0256]). Dobak et al. also teaches IL-31 being involved in the promotion of allergic skin disorder and in regulation other allergic diseases such as asthma (paragraph [0195]) and teaches IL-5 being related to pathogenesis of eosinophil-dependent inflammatory diseases (paragraph [0197]).
Dobak et al. does not teach the claim elements of the plurality of treatment studies comprising eosinophilic esophagitis, grass allergy, and chronic rhinosinusitis.
However, Abbas et al. teaches methods of diagnosis and treating eosinophilic disorders. Abbas et al. teaches identification of biomarkers that are effective for determining which patients suffering with asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and eosinophilic esophagitis will respond effectively to which treatment (paragraphs [0008]; [0111]).
Regarding claim 60, the claim is directed to the fold-change comprising subtracting the changes in expression in the placebo treatment group from the dupilumab treatment group. Dobak et al. teaches the method of claim 59.
Dobak et al. does not explicitly teach the claim element of the fold-change comprising subtracting the changes in expression in the placebo treatment group from the dupilumab treatment group
However, Abbas et al. teaches the expression change comprising taking the difference in expression in the placebo group from the treatment group (paragraph [0384]).
Regarding claim 61, the claim is directed to the differential gene expression for eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis treatment studies being carried out by comparing the baseline gene expression before treatment with dupilumab to the gene expression after treatment with dupilumab. Dobak et al. teaches the method of claim 58 in view of Abbas et al. Dobak et al. teaches a plurality of treatment studies comprising atopic dermatitis (paragraph [0256]).
Dobak et al. does not teach the claim element of the differential gene expression for eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis treatment studies being carried out by comparing the baseline gene expression before treatment with dupilumab to the gene expression after treatment with dupilumab.
However, Abbas et al. teaches monitoring the efficacy of a therapy based on measurements of biomarkers in a sample obtained from a patient before and after the treatment (paragraphs [0100] and [0101]), wherein the conditions can comprise atopic dermatitis, allergic rhinitis, nasal polyposis, and eosinophilic esophagitis will respond effectively to which treatment (paragraphs [0008]; [0111]). Furthermore, Abbas et al. teaches the treatment comprising dupilumab (paragraph [0056]).
Regarding claim 65, the claim is directed to the differential gene expression for the atopic dermatitis and chronic rhinosinusitis with nasal polyposis treatment studies being analyzed by microarray. Dobak et al. teaches the method of claim 63. Dobak et al. also teaches an atopic dermatitis treatment study (paragraph [0256]) wherein the expression is analyzed by microarray (paragraph [0173]).
Dobak et al. does not teach the claim element of the treatment study for chronic rhinosinusitis with nasal polyposis.
However, Abbas et al. teaches determining the efficacy of a therapy based on measurements of biomarkers wherein the conditions can comprise atopic dermatitis, allergic rhinitis, nasal polyposis (paragraphs [0008]; [0111]) and teaches analyzing expression levels using a microarray (paragraph [0280]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the analysis steps and treatment studies of Abbas et al. to the method of Dobak et al. because Dobak et al. is directed to analyzing gene expression levels in atopic dermatitis (Abstract), and discloses IL-31 being involved in the promotion of allergic skin disorder and in regulation other allergic diseases such as asthma (paragraph [0195]). Abbas et al. is directed to methods of diagnosis and treating eosinophilic disorders, including atopic dermatitis and asthma, and teaches biomarkers that are effective for determining which patients suffering with asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and eosinophilic esophagitis will respond effectively to which treatment (paragraphs [0008]; [0111]). Thus, one of ordinary skill in the art would have a reasonable expectation of success of analyzing expression biomarkers to evaluate treatment effectiveness in atopic dermatitis by combining the prior art references.
Claims 50, 51, 64, 67, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Dobak et al., as applied to claims 39, 40, 56, 57, 59, and 63 in the 102 rejection above, in view of Hamilton et al. (US 2021/0363264 A1, filed 05/21/2021).
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claim 50, the claim is directed to the clinical trial comprising generating a normalized enrichment score (NES) for the dupilumab treatment core gene signature prior to initiation of treatment of a subject with dupilumab and at least one time point after initiation of treatment of a subject with dupilumab. Dobak et al. teaches the method of claim 39.
Dobak et al. does not teach the claim element of generating a normalized enrichment score.
However, Hamilton et al. teaches methods for treating eosinophilic esophagitis by administering an IL-4R inhibitor. Hamilton et al. teaches generating an NES for the genes prior to dupilumab treatment and at a time point after initiation of a subject (paragraph [0122]).
Regarding claim 51, the claim is directed to when dupilumab treatment results in a decrease in the NES for the dupilumab treatment core gene signature to an acceptable value, the clinical endpoint having been achieved. Dobak et al. teaches the method of claim 50 in view of Hamilton et al.
Dobak et al. does not teach the claim element of when dupilumab treatment results in a decrease in the NES for the dupilumab treatment core gene signature to an acceptable value, the clinical endpoint having been achieved.
However, Hamilton et al. teaches a result of the dupilumab treatment comprising a decrease in the NES (paragraph [0122]), and teaches an at least 30% decrease relative to baseline (paragraph [0016]).
Regarding claim 64, the claim is directed to the differential gene expression of the eosinophilic esophagitis, asthma, and grass allergy treatment studies being analyzed by RNAseq. Dobak et al. teaches the method of claim 63.
Dobak et al. does not teach the claim elements of the differential gene expression of the eosinophilic esophagitis, asthma, and grass allergy treatment studies being analyzed by RNAseq.
However, Hamilton et al. teaches performing differential gene expression analysis (paragraph [0121]) of eosinophilic esophagitis (paragraph [0002]), asthma, or allergic rhinitis (paragraph [0010]), with the allergy comprising a grass allergy (paragraph [0054]), analyzed using RNA sequencing data (paragraph [0158]).
Regarding claim 67, the claim is directed to screening the dupilumab core gene signature against a whole transcriptome profile from the subject comprising: i) transforming the whole transcriptome profile from the subject into z-scores; ii) ranking the z-scores; and iii) generating a normalized enrichment score (NES) for all ranked z-scores using the plurality of genes that are differentially expressed and are in the dupilumab treatment core gene signature, thereby representing the dupilumab signature enrichment for the subject. Dobak et al. teaches the method of claim 56.
Dobak et al. does not teach the claim elements of i) transforming the whole transcriptome profile from the subject into z-scores; ii) ranking the z-scores; and iii) generating a normalized enrichment score (NES) for all ranked z-scores using the plurality of genes that are differentially expressed and are in the dupilumab treatment core gene signature, thereby representing the dupilumab signature enrichment for the subject.
However, Hamilton et al. teaches transforming the whole transcriptome profile from the subject into z-scores, ranking the z-scores, and generating an NES for all ranked z-scores using the plurality of genes that are differentially expressed (paragraphs [0194]-[0196]).
Regarding claim 68, the claim is directed to the NES being generated using a gene set enrichment analysis tool that takes both positive and negative gene sets into consideration. Dobak et al. teaches the method of claim 67 in view of Hamilton et al.
Dobak et al. does not teach the claim element of the NES being generated using a gene set enrichment analysis tool that takes both positive and negative gene sets into consideration.
However, Hamilton et al. teaches calculating an NES using a gene set enrichment analysis tool that takes both positive and negative gene sets into consideration (paragraph [0194]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the differential expression analysis using an NES score of Hamilton et al. to the method of Dobak et al. because both Dobak et al. and Hamilton et al. are directed to analyzing gene expression levels with respect to inflammatory conditions (see Abstract of both), such as atopic dermatitis (see Abstract of Dobak et al. and Hamilton et al. [0005]). Thus, one of ordinary skill in the art would have a reasonable expectation of success of using an NES score of quantifying the gene enrichment of the biomarkers involved in atopic dermatitis.
Claims 69-72 are rejected under 35 U.S.C. 103 as being unpatentable over Dobak et al. in view of Hamilton et al., as applied to claims 50, 51, 64, 67, and 68 above, and further in view of Subramanian et al. (“Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles”, PNAS, published 2005).
Regarding claim 69, Dobak et al. teaches the method of claim 68 in view of Hamilton et al.
Dobak et al. does not teach the claim elements of generating the NES.
However, Hamilton et al. teaches a) transforming each gene expression within the plurality of genes into a z-score (paragraph [0194]), and ordering the plurality of genes that are differentially expressed from the most up-regulated to the most down-regulated (paragraphs [0194]; [0171]). Hamilton et al. teaches using a gene set enrichment tool that takes both positive and negative gene sets into consideration (paragraph [0194]).
Hamilton et al. does not explicitly teach the claim elements of identifying hits, and step d)-g).
However, Subramanian et al. teaches identifying hits for the independent gene sets and teaches computing a running score by walking down the ranking, wherein the score increases by the equation as limited by the claim if the ith gene is a hit, or decreases by 1/(2N-S), where S is the combined total number of genes (page 15550, column 1, Section “Enrichment Score (ES(S), 2.). Subramanian et al. also teaches determining an Enrichment Score as a maximum deviation from zero along the running score (page 15550, column 1, Section “Enrichment Score (ES(S)), repeating the steps with a random gene set for 1,000 times to compute the ES null distribution (page 15550, column 2, Section “Estimating Significance”), and generating the NES as the enrichment score divided by the mean of the enrichment score null distribution (page 15546, column 1, “Step 2”; ). Furthermore, Subramanian et al. also teaches performing multiple hypothesis testing using multiple gene sets (page 15546, column 1, Section “Step 3”).
Regarding claim 70, the claim is directed to computing the statistical significance by determining the 95th percentile NES from healthy control samples. Dobak et al. teaches the method of claim 69 in view of Hamilton et al. and further in view of Subramanian et al.
Dobak et al. does not teach the claim element of computing the statistical significance by determining the 95th percentile NES from healthy control samples.
However, Hamilton et al. teaches determining the 95th percentile NES from healthy control samples (Table 9; paragraph [0197]).
Regarding claim 71, the claim is directed to computing the NES for all disease studies using a ranked list for each disease study. Dobak et al. teaches the method of claim 69 in view of Hamilton et al. and further in view of Subramanian et al.
Dobak et al. does not teach the claim element of computing the NES for all disease studies using a ranked list for each disease study.
However, Hamilton et al. teaches calculating the NES for entire ranked lists of transcripts for the study groups (paragraph [0171]).
Furthermore, Subramanian et al. teaches the inputs to GSEA for calculating enrichment scores comprising a ranked gene list (page 15550, Section “Appendix: Mathematical Description of Methods”, Inputs to GSEA).
Regarding claim 72, the claim is directed to when the NES of the subject is higher than the NES of a healthy control, the subject being suitable for dupilumab treatment. Dobak et al. teaches the method of claim 56.
Dobak et al. does not teach the claim element of when the NES of the subject is higher than the NES of a healthy control, the subject is suitable for dupilumab treatment.
However, Hamilton et al. teaches the NES score being strongly correlated with histological severity, demonstrating a biological association of the molecular signature with the clinical measure (paragraph [0201]).
Furthermore, Subramanian et al. teaches the NES of the subjects being higher than the control and thus the treatment seeming applicable for the subject (page 15549, column 1 and column 2, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the calculation of the NES of Subramanian to the method of Dobak et al. in view of Hamilton et al., because Hamilton et al. discloses calculating the NES using this GSEA method as taught by Subramanian et al. for calculating it (Hamilton et al. paragraph [0171]). Thus, one of ordinary skill in the art would have a reasonable expectation of success and would find it obvious to do so because the prior art teaches using this method for calculating the NES.
Conclusion
No claims are allowed.
Claims 49, 62, 66, 76, and 77 appears to be free from the art because the prior art does not seem to teach or fairly suggest the limitations of “the differential gene expression for the asthma and grass allergy treatment studies are carried out by comparing the gene expression with allergen challenge to the gene expression without allergen challenge”, “A method of detecting a plurality of nucleic acid molecules in a subject after treatment with dupilumab […], comprising: contacting a biological sample from the subject with a plurality of nucleic acid molecules comprising nucleotide sequences that are complementary to at least ten of the nucleic acid molecules encoding ALOX15, CCL26, SLC26A4, POSTN, SLC9A3, CLC, DPP4, MMP12, CDH26, CD209, NTRK2, SOCS1, CH25H, TREM2, CPA3, SERPINB4, IL RL1, PDCD1LG2, F13A1, CDH3, TPSAB1, CMYA5, CD1B, HAS3, TPSB2, IGFBP3, ATF3, P2RY6, IGFBP5, TMC5, ADORA3, RAB44, EMR4P, SERPINB10, P2RY1, P2RY14, AURKA, CLEC1OA, CD1C, CD1E, CST1, NOS2, FAM19A2, ALDH5A1, CEACAM3, DGAT2, S100A8, and RNF103-CHMP3”, or “wherein the plurality of genes that are differentially expressed comprises ALOX15, CCL26, SLC26A4, POSTN, SLC9A3, CLC, DPP4, MMP12, CDH26, CD209, NTRK2, SOCS1, CH25H, TREM2, CPA3, SERPINB4, ILRL1, PDCD1LG2, F13A1, CDH3, TPSAB1, CMYA5, CD1B, HAS3, TPSB2, IGFBP3, ATF3, P2RY6, IGFBP5, TMC5, ADORA3, RAB44, EMR4P, SERPINB1O, P2RY1, P2RY14, AURKA, CLEC1OA,CD1C, CD1E, CST1, NOS2, FAM19A2, ALDH5A1, CEACAM3, DGAT2, S100A8, and RNF103-CHMP3, or any subset thereof comprising at least 47 genes” (as elected in the species requirement).
Claim 62 and 66 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/E.A.N./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686