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 .
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 Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 4-5, 7, and 13-18 are cancelled. Claim 1 is amended. Claims 1-3, 6, and 8-9 are under examination.
Response to Amendment
The Amendment filed 3/23/26 has been entered. Claims 1-3, 6, and 8-12 are pending. Applicant’s amendment of claim 1 and cancellations of claims 13-18 have overcome the objections previously set forth in the Non-Final Office Action mailed 12/23/25.
Response to Arguments
Applicant’s arguments, see pages 5-10, filed 3/23/26, with respect to the rejections of claims 1-3, 6, and 8-9 under 35 USC 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Non-Final mailed 12/23/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Final Office Action.
Claim Objections
Claim 3 is objected to because of the following informalities:
claim 3 should end in a period.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Indefiniteness
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 1-3, 6, and 8-9 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.
This new 112(b) rejection is necessitated by claim amendments filed 2/17/26.
Claim 1 recites the limitation “a decrease in the expression of the panel of biomarkers compared with overall expression in the sample”. It is unclear as to how this comparison is made, and what gene(s) within the transcriptome constitute the “overall expression in the sample”. For example, is this decreased panel expression compared to the remaining non-panel transcriptome genes that would represent the “overall expression in the sample”? The skilled artisan would find this limitation unclear, as differential expression is usually determined in comparison to a reference (un-induced “control” state, housekeeping genes, spike-in controls… etc.). The broadest reasonable interpretation of this limitation allows for the comparison of the biomarker gene panel expressions against any given gene within the transcriptome.
For purposes of compact prosecution, this limitation will be interpreted as “a decrease in the expression of the panel of biomarkers compared” to expression of housekeeping gene GAPDH (see below 103 rejection prior art reference Human Genome U133 Plus 2.0 Array Product Information Sheet (2017; NPL citation W in PTO-892 filed on 3/18/25) identification of GAPDH as a housekeeping control gene for a microarray).
Claims 2-3, 6, and 8-9 directly/indirectly depend from claim 1 and are similarly indefinite.
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 Arijs et al. (2009; “Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment”. PLoS One. 2009 Nov 24;4(11):e7984. doi: 10.1371/journal.pone.0007984; and associated GEO accession GSE16879), GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet (2017; NPL citation W in PTO-892 filed on 3/18/25), and Affymetrix Human Genome U133 Plus 2.0 Array Probe Set (2014; NPL citation V in PTO-892 filed on 3/18/25).
This new 103 rejection is necessitated by claim amendments filed 2/17/26.
(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 identifying a subject with inflammatory bowel disease (IBD) as likely to respond to a treatment regimen, wherein the treatment regimen comprises administering to the subject an anti-IL12/23p40 antibody or fragment thereof.
Relevant to claim 1 a), 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.
Relevant to claim 1 c), Vermeire et al. teaches “2. A method to predict the response of an immune bowel disorder patient to a drug that blocks or inhibits the IL-12/23 pathway comprising the steps of: (a) determining the expression or activity of genes in a biological sample taken from the patient prior to treatment with the drug that blocks or inhibits the IL-12/23 pathway, and (b) comparing the expression profile of genes in said biological samples of patient with the expression or activity of genes obtained from a control sample… wherein the genes comprise the group consisting of genes of table 4' and wherein a different level of gene expression or activity relative to the control sample is an indication of response to the treatment or a propensity thereto in the patient” (page 18, lines 14-24).
This teaching reads on claim 1 c) detecting a… in the expression of the panel of biomarkers compared with overall expression in the sample… wherein detecting a… in the expression of the panel of biomarkers compared with overall expression in the sample identifies the subject as likely to respond to a treatment regimen comprising administering to the subject an anti-IL12/23p40 antibody or fragment thereof.
Relevant to claim 1 d), 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 d) administering the anti-IL12/23p40 antibody or fragment thereof to the subject identified as having a… in the expression of the panel of biomarkers compared with overall expression in the sample.
Relevant to claims 2-3, 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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SEQ ID NO:8 Light Chain BLASTp Result
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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 detection of differential biomarker gene expression, Vermeire et al. is silent to the instant contacting the sample with a set of probes that binds to a panel of biomarkers relevant to claim 1 b) and decrease in the expression of the panel of biomarkers relevant to claim 1 c) – d). However, these limitations were known in the prior art and taught by Arijs et al. and associated GEO accession GSE16879, 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 b) – c), Arijs et al. teaches identification of responders and non-responders to inflammatory bowel disease treatment infliximab, biopsy collection, and RNA isolation and oligonucleotide array hybridization using the Affymetrix Human Genome U133 Plus 2.0 Array, with the data publicly available in the Gene Expression Omnibus accession GSE16879 (page 2, Methods sections “Patients and biopsy specimens” and “RNA isolation and oligonucleotide array hybridization”).
Further relevant to claim 1 b), 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].
The GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet discloses that GAPDH is a housekeeping control gene (page 1 “Critical specifications” Table).
The Arijs et al. GSE16879 submission includes the below expression data for GAPDH and the instantly claimed panel of biomarkers:
GAPDH
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TGM2
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TIFA
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CA4
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OAS2
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FGF17
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WARS
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CD274
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SV2B
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DEFB1
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ANXA1
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IFI44L
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IL13RA2
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UBD
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LYPD5
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All 14 of the instantly claimed biomarkers exhibit claim 1 c) – d) decrease in the expression of the panel of biomarkers compared to expression of housekeeping gene GAPDH within the Arijs et al. dataset.
(iii) It would have been prima facie obvious to the skilled artisan to include the Arijs et al. biomarker panel and probeset, 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 IBD treatment response and identifying biomarkers was previously demonstrated by Arijs et al. use of the Affymetrix Human Genome U133 Plus 2.0 Array.
Although Arijs et al. administers the inflammatory bowel disease treatment infliximab treatment instead of the instantly claimed anti-IL12/23p40 antibody treatment, the skilled artisan would find it obvious and be motivated to examine the biomarker panel within identifications of subjects likely to respond to the instantly claimed treatment.
Vermeire et al. teaches that infliximab has “become the cornerstone in the management of moderate-to-severe IBD over the past two decades” (page 3, lines 11-12) and has performed expression analyses of IBD patients initiating infliximab and ustekinumab treatments (pages 4-6), indicating that the skilled artisan would find it obvious to determine patient responsiveness to both treatments. Additionally, as demonstrated within the above excerpts of Arijs et al. GEO data, the instantly claimed panel of biomarkers demonstrate differential expression between identified infliximab responders and non-responders, indicating to the skilled artisan that the genes would be of interest in IBD treatment responsiveness.
The skilled artisan would have a reasonable expectation of success given the teachings of Vermeire et al. in view of Arijs et al., GeneChip Human Genome U133 Plus 2.0 Array Product Information Sheet, and Affymetrix Human Genome U133 Plus 2.0 Array Probe Set, 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah J Kennedy whose telephone number is (571)272-1816. The examiner can normally be reached Monday - Friday 8a - 5p.
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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