DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 27, 2025 has been entered. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn. This action is FINAL.
Applicant’s election without traverse of rs11564258 in the reply filed on January 7, 2025 is reiterated for the record.
Claims 1, 4-11, 14-19, and 22-25 are currently pending.
Claims 4, 14, and 22-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 7, 2025.
Non-Compliant Amendment
3. Applicants are reminded that the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn— currently amended.” See MPEP 714. In the instant case, withdrawn claims 4, 14, and 22-24 do not have the correct status identifier. While the claims filed on August 27, 2025 are technically non-compliant, they have been entered anyway in order to advance prosecution. In response to this Office Action Applicants should indicate the correct current status of each claim.
Claim Rejections - 35 USC § 103
4. 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, 5-11, and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Connelly (Surgery Vol 156 No 2 August 2014 pages 253-262) in view of Tigno-Aranjuez (Journal of Biological Chemistry October 24, 2014 Vol 289 No 43 pages 29651-29664). The rejections are further evidenced by the dbSNP record for rs11564258 found online at https://www.ncbi.nlm.nih.gov/snp/rs11564258 and accessed 2/18/2025.
Regarding Claims 1, 5, 9, 11, 15, and 19 Connelly teaches genotyping ulcerative colitis (UC) patients for 314 of the most commonly inflammatory bowel disease (IBD) associated SNPs by a custom SNP microarray. Connelly teaches that SNP rs11564258 is associated with Crohn’s disease (CD) and UC. As evidenced by the dbSNP record for rs11564258 it is a property of this SNP that is comprises a G or A allele. Further as evidenced by the dbSNP record for rs11564258, it is a property of the SNP that it is at position “N” within SEQ ID NO:1. Thus Connelly teaches detecting a genotype comprising an A or G allele at rs11564258 in a sample obtained from a subject with UC.
Connelly does not teach a method of treating inflammatory bowel diseases (such as UC or CD) by administering a modulator of RIPK2 activity or expression (clm 1). Connelly does not teach a method reducing or ablating activity or expression of RIPK2 in a subject by administering a modulator of RIPK2 to the subject (clm 11). Connelly does not teach a method wherein the modulator of RIPK2 activity or expression comprises an antagonist or a partial antagonist of RIPK2 (clms 6, 16). Connelly does not teach a methos wherein the antagonist or partial antagonist comprises ponatinib, sorafenib, regorafenib, gefitinib, or erlotinib (clms 7, 17). Connelly does not teach a method wherein the antagonist or partial antagonist comprises a structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X (clms 8, 18). Connelly does not teach a method wherein the Crohn's disease comprises ileal Crohn's disease (clm 10).
Tigno-Aranjuez teaches that Gefitinib is an FDA approved RIPK2 inhibitor. Tigno-Aranjuez teaches that they show that pharmacologic RIPK2 inhibition drastically improves disease in spontaneous model of CD-like ileitis (page 29651). Tigno-Aranjuez demonstrates that Gefitinib-mediated inhibition of RIPK2 is beneficial in vivo in the SAMP1/YitFc mouse, a spontaneous mouse model of Crohn’s Disease in which NOD2 is WT. They show that inflammatory cytokine secretion in macrophages from these mice was also markedly reduced upon inhibition of RIPK2 and pharmacologic inhibition of RIPK2 tyrosine phosphorylation correlated with improvement in disease (page 29652, col 2). Additionally Tigno-Aranjuez discloses two novel inhibitors of RIPK2, namely OD36 and OD38. These two compounds OD36 and OD38, were tested in dose-response assays against Gefitinib to determine their comparable ability to inhibit RIPK2. While all three compounds showed that nanomolar concentrations could inhibit NOD2- mediated RIPK2 tyrosine autophosphorylation in HEK293 cells, both OD36 and OD38 displayed a more potent activity against RIPK2 (See Fig 2 inset). It is noted that OD36 and OD38 are compounds of the Formula VI.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Connelly by administering a modulator of RIPK2, such as Gefitinib to any subject with inflammatory bowel disease, including those with an A or G allele at SNP rs115642. One of skill in the art would have been motivated to administer Gefitinib since it was an FDA-approved RIPK2 inhibitor and has been shown to drastically improve disease in spontaneous models of CD like ileitis (page 29651). Further it would have been obvious to try treating IBD with other RIPK2 inhibitors, such as those having Formula IV particularly since Tigno-Aranjuez discloses two compounds of Formula VI (OD36 and OD38) that have both been shown to have more potent activity against RIPK2.
Response To Arguments
5. In the response the Applicants traversed the rejection under 35 USC 103. The Applicants argue that the claims are nonobvious over the cited art, at least because a person of skill in the art would have no motivation to combine the cited references to arrive at the claimed subject matter with a reasonable expectation of success.
The Applicants argue that Connelly is relied on for disclosing that rs11564258 is associated with Crohn's disease and ulcerative colitis. Connelly is not directed to identifying a subject for treatment nor selecting said treatment, but is rather directed to highlighting the lack of correlation between well-known IBD associated SNPs and UC- neoplasia. Connelly discloses rs11564258 in a laundry list of over 300 SNPs associated with IBD.
Applicants arguments and the teachings of Connelly have been fully considered. The instant claims require administering a modulator of RIPK2 to a subject having an inflammatory disease provided that the subject is determined to have a genotype comprising an A or G allele at rs11564258. Thus the claims broadly encompass administering a modulator of RIPK2 to any subject with an inflammatory disease that has provided a sample which has been genotyped at SNP rs11564258. Connelly teaches detecting a genotype comprising an A or G allele at rs11564258 in a sample obtained from a subject with UC. The Examiner acknowledges that Connelly is not directed to identifying a subject for treatment or selecting a treatment. However this is not relevant because the claims do not require this.
The Applicants argue that Tigno-Aranjuez is relied on for disclosing that use of the "FDA-approved RIPK2 inhibitor Gefitinib ... pharmacologic RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis". The Applicants argue that Tigno-Aranjuez specifically identifies a means of selecting patients for treatment with RIPK2 inhibitors where such patients lack SNPs associated with disease. The Applicants argue that Tingo-Aranjuez does not disclose any SNP associated with IBD, much less a SNP likely to correlate to successful treatment with RIPK2 inhibition. Instead, Tigno-Aranjuez identifies a panel of 9 genes specifically regulated by RIPK2 inhibition (Fig 1). rs11564258 is present in the MUC19 gene, which is not one of the genes identified in Tigno-Aranjuez. MUC19 is not disclosed anywhere in Tigno-Aranjuez and indeed, there no disclosed association between the MUC19 gene and RIPK2 activity in any of the cited art references. As such, reading the disclosures of Tigno-Aranjuez, a skilled artist would have no motivation to select rs11564258 as a marker for identifying patients for treatment with RIPK2 inhibitors. Applicant’s respectfully submits the Office is using improper hindsight bias based on the disclosures of the instant application to arrive at the conclusion of obviousness.
These arguments have been fully considered but are not persuasive. The claims do NOT recite a correlation between SNP rs11564258 and response to treatment with an RIPK2 inhibitor and therefore the prior art is not required to teach this. The claims do NOT require identifying patients for treatment with RIPK2 inhibitors either. The claims require administering a modulator of RIPK2 to a subject having an inflammatory disease, wherein the subject at some point prior has been genotyped at rs11564258. Tigno-Aranjuez is being relied upon to teach administering a modulator of RIPK2 to a subject having an inflammatory disease. Motivation is present to treat any subject with IBD (including the subjects of Connelly) with Gefitinib because it is an FDA-approved RIPK2 inhibitor and has been shown to drastically improve disease in spontaneous models of CD like ileitis (page 29651). The rejection does not have to provide motivation to select rs11564258 as a marker for identifying patients for treatment with RIPK2 inhibitors because this is NOT a recited claim limitation. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
6. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682