DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 6, and 8-12 are pending. Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 4-5 and 7 are cancelled. Claims 1-3, 6, and 8-9 are currently under examination.
Response to Amendment
The Amendment filed 6/17/25 has been entered. Claims 1-3, 6, and 8-9 are currently pending. Applicant’s amendments to claims 1, 6, and 8, and cancellations of claims 4-5 and 7, have overcome and/or rendered moot the 112(a) and 101 rejections previously set forth in the Non-Final Office Action mailed 3/18/25.
Response to Arguments
Applicant’s arguments, see pages 10-13, filed 6/17/25, with respect to the rejections of claims 1-3, 6, and 8-9 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection necessitated by claim amendments is made in this Final Office Action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 6, and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Vermeire et al. (2020; WO 2020/104705 A9; FOR citation N in PTO-892 filed on 3/18/25) in view of Győrffy et al. (2014; NPL citation 24 in IDS filed on 2/4/25; “Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy”; Proteomics Bioinform 7:272-277; DOI: 10.4172/jpb.1000329), GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet (2017; NPL citation W in PTO-892 filed on 3/18/25), Affymetrix Human Genome U133 Plus 2.0 Array Probe Set (2014; NPL citation V in PTO-892 filed on 3/18/25), Haberman et al. (2019; “Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response”; Nat Commun 10, 38; https://doi.org/10.1038/s41467-018-07841-3), Haberman et al. Supplementary Dataset 1 excerpt (2019), and Hänzelmann et al. (2013; NPL citation 25 in IDS filed on 2/4/25; “GSVA: gene set variation analysis for microarray and RNA-Seq data”; BMC Bioinformatics 14:7; http://www.biomedcentral.com/1471-2105/14/7).
This new 103 rejection is necessitated by claim amendments filed on 06/17/2025.
(i) Vermeire et al. teaches limitations relevant to claims 1-3, 6, and 8-9.
Relevant to claim 1, Vermeire et al. teaches “a method for predicting the therapeutic outcome of a treatment of in inflammatory bowel disease for… anti-IL-12/23 agents” (Abstract).
This teaching reads on claim 1 A method of predicting a response to a treatment regimen for an inflammatory bowel disease (IBD) in a subject in need thereof.
Further relevant to claim 1, Vermeire et al. teaches “In this study, we prospectively collected serum (proteomics), inflamed mucosal tissue from both ileum and colon (transcriptomics), sorted CD14+ and CD4+ T-cells (transcriptomics) and DNA (genomics) in CD [Crohn’s disease] patients” (page 81, lines 14-16).
This teaching reads on claim 1 a. obtaining a sample of the subject.
Further relevant to claim 1, Vermeire et al. teaches “6. A method of predicting a response to a vedolizumab therapy in a patient, comprising: assigning a sensitivity score to vedolizumab based on genomic features… wherein the patient is predicted to respond to or not respond to vedolizumab therapy based on the assigned sensitivity score” (page 34, lines 18-23).
The Vermeire et al “sensitivity score” reads on the instant enrichment score, as both scores are determined following an analysis of a panel of the inventions’ biomarkers (“genomic features”). Thus, this teaching reads on claim 1 detecting a… enrichment score for the panel of biomarkers.
Further relevant to claim 1, Vermeire et al. teaches “In this study, we prospectively collected” samples from Crohn’s disease “patients with active endoscopic disease initiating ustekinumab therapy. Ustekinumab (Janssen Biotech, Inc.), a fully human IgGl monoclonal antibody targeting the IL-12/IL-23p40 subunit, has been the latest approved biological agent for CD. All different omic datasets were subsequently integrated, in order to better understand the mode of action and identify potential biomarkers predictive for therapeutic success” (page 81, lines 14-20).
This teaching reads on claim 1 thereby identifying the subject as likely to respond to a treatment regimen comprising administering to the subject an anti-IL12/23p40 antibody or fragment thereof… and d. administering the anti-IL12/23p40 antibody or fragment thereof to the identified subject.
Relevant to claims 2 and 3, Vermeire et al. teaches that their methods “included 54 active IBD [inflammatory bowel disease] patients (24CD [Crohn’s disease], 30UC [ulcerative colitis])” (page 6, line 6), reading on claim 2 the inflammatory bowel disease is selected from ulcerative colitis or Crohn’s disease; and claim 3 the inflammatory bowel disease is ulcerative colitis.
Relevant to claim 6, Vermeire et al. teaches “We prospectively collected serum (proteomics), inflamed mucosal tissue (transcriptomics)…in IBD patients with active endoscopic disease…” (page 4, lines 13-15). This reads on claim 6 the sample is a tissue sample or a blood sample.
Relevant to claims 8-9, Vermeire et al. teaches “In this study, we prospectively collected” samples from Crohn’s disease “patients with active endoscopic disease initiating ustekinumab therapy. Ustekinumab (Janssen Biotech, Inc.), a fully human IgGl monoclonal antibody targeting the IL-12/IL-23p40 subunit, has been the latest approved biological agent for CD. All different omic datasets were subsequently integrated, in order to better understand the mode of action and identify potential biomarkers predictive for therapeutic success” (page 81, lines 14-20).
The antibody fragment recited in claim 8 (b) an antibody comprising a heavy chain variable domain amino acid sequence of SEQ ID NO:7 and a light chain variable domain amino acid sequence of SEQ ID NO:8 have 100% BLASTp similarity to the heavy and light chains of ustekinumab (results below), and are thus embraced by the Vermeire et al. utilization of ustekinumab.
SEQ ID NO:7 Heavy Chain BLASTp Result
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media_image1.png
307
724
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Greyscale
SEQ ID NO:8 Light Chain BLASTp Result
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318
730
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Greyscale
Thus, these teachings read on claim 8 wherein the anti-IL12/23p40 antibody or fragment thereof is selected from the group consisting of…(b) an antibody comprising a heavy chain variable domain amino acid sequence of SEQ ID NO:7 and a light chain variable domain amino acid sequence of SEQ ID NO:8; and claim 9 wherein the anti-IL12/23p40 antibody is ustekinumab.
(ii) Although Vermeire et al. teaches a “sensitivity score” that reads on the instant enrichment score, Vermeire et al. is silent to the instant b. contacting the sample with a set of probes that binds to a panel of biomarkers relevant to claim 1. However, this limitation was known in the prior art and taught by Győrffy et al., GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet, and Affymetrix Human Genome U133 Plus 2.0 Array Probe Set.
Relevant to claim 1, Győrffy et al. includes 4 GEO datasets (3 obtained from colon biopsies, 1 from peripheral blood mononuclear cells [PBMC]) within Table 1 for the transcriptomic microarray analyses. One microarray within those cited datasets is the GPL570 microarray platform corresponding to the Affymetrix Human Genome U133 Plus 2.0 Array, which contains “1,300,000 unique oligonucleotide features covering over 47,000 transcripts and variants, which, in turn, represent approximately 39,000 of the best characterized human genes... Oligonucleotide probes are synthesized in situ complementary to each corresponding sequence” (GeneChip Product Information Sheet, page 1, paragraphs 1 and 3 of “Product use” section).
Further relevant to claim 1, the Affymetrix Probe Set ID document contains probes for:
transglutaminase 2 (TGM2) [page 3,038],
TRAF interacting protein with forkhead associated domain (TIFA) [page 15,870],
carbonic anhydrase 4 (CA4) [page 6,282],
2'-5'-oligoadenylate synthetase 2 (OAS2) [page 6,501],
fibroblast growth factor 17 (FGF17) [page 13,973],
tryptophanyl-tRNA synthetase (WARS) [page 2,757],
CD274 molecule (CD274) [page 14,969],
synaptic vesicle glycoprotein 2B (SV2B) [page 18,042],
defensin beta 1 (DEFB1) [page 8,834],
annexin A1 (ANXA1) [page 18,203],
interferon induced protein 44 like (IFI44L) [page 5,193],
interleukin 13 receptor subunit alpha 2 (IL13RA2) [page 6,267],
ubiquitin D (UBD) [page 6,097] and,
LY6/PLAUR domain containing 5 (LYPD5) [page 19,023].
Taken together, these teachings read on claim 1 b. contacting the sample with a set of probes that binds to a panel of biomarkers… wherein the panel of biomarkers comprises…
Vermeire et al. in view of Győrffy et al., GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet, and Affymetrix Human Genome U133 Plus 2.0 Array Probe Set teach a method of predicting a response to a treatment regimen for an inflammatory bowel disease (IBD) in a subject in need thereof.
It would have been prima facie obvious to the skilled artisan to include the Győrffy et al., GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet, Affymetrix Human Genome U133 Plus 2.0 Array Probe Set microarray within the Vermeire et al. methodology. It is noted that the disclosures are analogous to the instant invention within the field of detection of biomarker expression.
The skilled artisan would be motivated to use a large-scale microarray, such as the Affymetrix platform, to determine expression of biomarkers. Vermeire et al. teaches that “some patients never respond to a particular therapy… Both from a patient perspective as from a socio-economic perspective, identifying the most suitable therapy for a given patient is key… personalized medicine will become even more necessary in future” (page 70, lines 21-28). Therefore, the skilled artisan would be motivated to predict patients’ responses to inflammatory bowel disease regimens in order to provide more efficient, personalized treatments. The skilled artisan would be motivated to assess a multi-gene biomarker panel for this personalized approach, as success of predicting treatment response and identifying biomarkers was previously demonstrated within the three studies cited by Győrffy et al Table 1 using the Affymetrix Human Genome U133 Plus 2.0 Array.
Additionally, the skilled artisan would find it obvious to perform gene set variation analysis upon the microarray data in order to further refine the results into personalized treatment regimens. Notably, the majority of the instant biomarker panel has been identified within a “core rectal UC gene expression signature composed of 5296 genes (Fig. 1a) differentially expressed (FDR < 0.001 and fold change (FC) ≥ 1.5) in comparison to controls (Ctl, Fig. 1 and Supplementary Dataset 1)” (Haberman et al. page 2, column 2, paragraph 3). Haberman et al. further teaches gene set enrichment of the core genes and pathways within Fig. 1.
The associated Haberman et al. Supplementary Dataset 1 excerpt teaches that the majority of the instant biomarker panel (TGM2, page 42; TIFA, page 29; OAS2, page 41; WARS, page 42; CD274, page 42; DEFB1, page 8; ANXA1, page 42; IFI44L, page 37; IL13RA2, page 40; UBD, page 42; and LYPD5, page 102) belongs within the “core rectal UC gene expression signature,” indicating the biomarkers’ importance in the disease genotype.
Given the biomarker panel’s importance in the disease genotype and associated gene set enrichment analyses, the skilled artisan would be motivated to perform gene set variation analysis (GSVA) to expand beyond the Haberman et al. GSE analyses. Hänzelmann et al. Abstract teaches that “GSVA provides increased power to detect subtle pathway activity changes over a sample population in comparison to corresponding methods. While GSE methods are generally regarded as end points of a bioinformatic analysis, GSVA constitutes a starting point to build pathway-centric models of biology. Moreover, GSVA contributes to the current need of GSE methods for RNA-seq data.”
The skilled artisan would find it obvious to predict a response to a treatment regimen because Haberman et al. Abstract teaches “Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy… Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.”
The skilled artisan would have a reasonable expectation of success given the teachings of Vermeire et al. in view of Győrffy et al., GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet, Affymetrix Human Genome U133 Plus 2.0 Array Probe Set, Haberman et al., and Hänzelmann et al. as discussed in the preceding paragraphs.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682