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
Some of the rejections of record have been maintained below.
Applicant’s election without traverse of
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in the reply filed on 12/15/2025 is acknowledged.
The elected species reads on claims 1, 8, 17, 19, 21, 23, 25, 47, 48.
Claims 26, 28, 29, and 256-261 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/15/2025.
Current Status of 18/037,697
The amended claims of 7/1/2026 were used to write this Office Action.
Claims 1, 8, 17, 19, 21, 23, 25, 47, 48, and 263-266 are examined on the merits.
Claims 263-266 are new.
Priority
This application is a national stage entry of PCT/US21/59668, which claims priority to US provisional application 63/115,317.
The instant claims find support from the provisional application. Therefore, the instant application’s effective filing date is 11/18/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/10/2026 and 7/01/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicants’ claim amendments and Remarks of 7/1/2026 are acknowledged and have been considered.
Any rejection and/or objection not specifically addressed or modified below is herein withdrawn.
In regard to the first obviousness rejection over Booher in view of Espinosa, this rejection is withdrawn. Applicants’ remarks with Examiner’s reply are summarized below:
Applicants amended (now canceled) claim 6 into claim 1. Espinosa does not teach NK-KB p-p50.
In regard to the second obviousness rejection over Booher in view of Schmitt, this rejection is maintained. Applicants’ remarks with Examiner’s reply are summarized below:
Applicants amended (now canceled) claim 6 into claim 1.
Applicants submit that nothing teaches or suggests the identification and treatment of a subpopulation of patients whose cancers will have a superior response to IRAK4 inhibitors compared to the general population. Additionally, nothing teaches or suggests the increased expression of NF-KB p-p50 as a predictive biomarker.
Applicants point out Figure 12A, which shows that patients with an increased expression of NF-KB p-p50 before treatment were significantly more likely to respond to IRAK4 inhibitor treatment. The patients with positive/increased amount of NF-KB p-p50 had a statistically significant p-value correlated with stable disease.
Examiner is unsure how Figure 12A supports Applicants’ claim of unexpected results.
In the footnote (which does not seem to be supported in the specification), Applicants submit that there is a statistically significant p-value correlated with stable disease. Though Applicant states that unexpected results have been achieved, the instant specification does not provide any unexpected or surprising results. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See MPEP 716.01(c).
Additionally, Examiner is unsure if the data is unexpected. Figure 12A lists patients, whether or not they were positive NF-KB p-p50 levels, and the patient’s best response. There also seems to be a difference between progressive disease (PD) and stable disease (SD). Each of these designations has a percentage. Although the percentages for the patients who are positive for NF-KB p-p50 are lower compared to the negative patients, Examiner is unsure if and how the data is unexpected.
Examiner notes that MPEP 716.02 states that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
In regard to the double patenting rejection over US patent no 10,758,518, the rejection in combination with Schmitt is maintained. Applicants submit that the artisan would not have predicted the unexpected results; however, Examiner disagrees for the reasons above.
In regard to the double patenting rejection over US patent no 12,178,821, the rejection in combination with Schmitt is maintained. Applicants submit that the artisan would not have predicted the unexpected results; however, Examiner disagrees for the reasons above.
In regard to the double patenting rejection over US applicant No 18/019,400, the rejection in combination with Schmitt is maintained. Applicants submit that the artisan would not have predicted the unexpected results; however, Examiner disagrees for the reasons above.
Response to Amendment
Claim Rejections - 35 USC § 103 -- Maintained and updated in light of the amended claims
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.
Claim(s) 1, 8, 17, 19, 21, 23, 25, 47, 48, and 263-266 are rejected under 35 U.S.C. 103 as being unpatentable over Curis (WO 2019089580) in view of Schmitt (Schmitt et al,. “p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage”, Mol Cell, December 2011) in view of HERMAN (Herman et al., “Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL”, Blood, March 21, 2014) and in view of Younes (Younes et al., “Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study”, Lancet Haematol., January 11, 2019).
Curis teaches the elected species (CAS# 1801344-12-6 compound fourth compound on page 92). This teaches the compound from claims 1, 17, 19, 21, 23, 25, 47, and 48.
Curis teaches a method of treating of cancer using the elected species (ref. claim 35). This teaches the disease of claim 1. Curis teaches this cancer can specifically be chronic lymphocytic leukemia (CLL) (ref claim 99).
Curis teaches conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) (page 14). This helps teach claims 262 and 265-266.
Curis teaches administering a combination of venetoclax and the elected species (figure 1). This helps teach claims 263 and 264.
Curis does not teach obtaining a biological sample or measuring an expression level of a phosphorylated NF-KB.
Schmitt teaches that phosphorylation of p50 results in the inhibition of NF-κB DNA binding; Expression of an un-phosphorylateable p50 mutant blocks inhibition of NF-κB regulated anti-apoptotic gene expression and attenuates SN1-methylator-induced cytotoxicity (summary). This helps teaches that when p50 is phosphorylated, it shuts downs anti-apoptotic genes (pro-survival). Schmitt teaches p-p50 was from a nuclear extract (page 3). This helps teach p-p50 of claim 1 and claim 8.
An artisan would have been motivated to look for biomarkers before administering a treatment because elevated p-p50 shuts downs anti-apoptotic genes, which is pro-survival (Schmitt summary). The artisan would expect to be able to measure the expression level of a phosphorylated NF-KB, such as p-p50, in cancer cells (“nuclear extract” Schmitt page 3). The artisan would also be motivated and expected to administer a treatment of the elected species (Curis example 2 on page 69-70 ) for cancer (Curis ref. claim 35). This teaches claims 1, 8, 17, 19, 21, 23, 25, 47, and 48.
Curis and Schmitt do not teach a BTK inhibitor and/or PD-1 inhibitor.
Herman teaches ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with Chronic lymphocytic leukemia (CLL) (title).
Younes teaches that a combination of ibrutinib and nivolumab in patients with relapsed chronic lymphocytic leukemia has synergistic antitumor effects (title and abstract).
The artisan would have found it obvious to combine the elected species (from Curis) with the additional agents, venetoclax from Curis, ibrutinib from Herman and Younes, and nivolumab from Younes. All of these compounds are known to be useful in treating Chronic lymphocytic leukemia (CLL). It is prima facie obvious to combine CLL treatment with another in order to form a treatment to be used for the very same purpose (treating CLL), especially since Curis also teaches adding additional agents (page 14). In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06(I). This teaches claims 263-266.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 1, 8, 17, 19, 21, 23, 25, 47, 48, rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 1 of U.S. Patent No. US10758518 (CURIS) in view of Schmitt (Schmitt et al,. “p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage”, Mol Cell, December 2011).
Curis teaches the elected species (ref claim 1). This teaches the compound from claims 1, 17, 19, 21, 23, 25, 47, and 48.
Curis teaches a method of treating of cancer (DLBCL) using the elected species (ref. claim 1). This teaches the disease of claim 1.
Curis does not teach obtaining a biological sample or measuring an expression level of a phosphorylated NF-KB.
Schmitt teaches that phosphorylation of p50 results in the inhibition of NF-κB DNA binding; Expression of an un-phosphorylateable p50 mutant blocks inhibition of NF-κB regulated anti-apoptotic gene expression and attenuates SN1-methylator-induced cytotoxicity (summary). This helps teaches that when p50 is phosphorylated, it shuts downs anti-apoptotic genes (pro-survival). Schmitt teaches p-p50 was from a nuclear extract (page 3). This helps teach claim 8.
An artisan would have been motivated to look for biomarkers before administering a treatment because elevated p-p50 shuts downs anti-apoptotic genes, which is pro-survival (Schmitt summary). The artisan would expect to be able to measure the expression level of a phosphorylated NF-KB, such as p-p50, in cancer cells (“nuclear extract” Schmitt page 3). The artisan would also be motivated and expected to administer a treatment of the elected species (Curis ref claim 1) for cancer (Curis ref. claim 1). This teaches claims 1, 8, 17, 19, 21, 23, 25, 47, 48.
Claim(s) 1, 8, 17, 19, 21, 23, 25, 47, 48, rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 1 of U.S. Patent No. US12178821 (CURIS) in view of Schmitt (Schmitt et al,. “p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage”, Mol Cell, December 2011).
Curis teaches the elected species (ref claim 23). This teaches the compound from claims 1, 17, 19, 21, 23, 25, 47, and 48.
Curis teaches a method of treating of cancer (DLBCL) using the elected species (ref. claim 1). This teaches the disease of claim 1.
Curis does not teach obtaining a biological sample or measuring an expression level of a phosphorylated NF-KB.
Schmitt teaches that phosphorylation of p50 results in the inhibition of NF-κB DNA binding; Expression of an un-phosphorylateable p50 mutant blocks inhibition of NF-κB regulated anti-apoptotic gene expression and attenuates SN1-methylator-induced cytotoxicity (summary). This helps teaches that when p50 is phosphorylated, it shuts downs anti-apoptotic genes (pro-survival). Schmitt teaches p-p50 was from a nuclear extract (page 3). This helps teach claim 8.
An artisan would have been motivated to look for biomarkers before administering a treatment because elevated p-p50 shuts downs anti-apoptotic genes, which is pro-survival (Schmitt summary). The artisan would expect to be able to measure the expression level of a phosphorylated NF-KB, such as p-p50, in cancer cells (“nuclear extract” Schmitt page 3). The artisan would also be motivated and expected to administer a treatment of the elected species (Curis ref claim 23) for cancer (Curis ref. claim 1). This teaches claims 1, 8, 17, 19, 21, 23, 25, 47, 48.
Claim(s) 1, 8, 17, 19, 21, 23, 25, 47, 48, rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 1 of U.S. PG Pub 2023310444 (CURIS) in view of Schmitt (Schmitt et al,. “p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage”, Mol Cell, December 2011).
Curis teaches the elected species (ref claim 1). This teaches the compound from claims 1, 17, 19, 21, 23, 25, 47, and 48.
Curis teaches a method of treating of cancer (DLBCL) using the elected species (ref. claim 67). This teaches the disease of claim 1.
Curis does not teach obtaining a biological sample or measuring an expression level of a phosphorylated NF-KB.
Schmitt teaches that phosphorylation of p50 results in the inhibition of NF-κB DNA binding; Expression of an un-phosphorylateable p50 mutant blocks inhibition of NF-κB regulated anti-apoptotic gene expression and attenuates SN1-methylator-induced cytotoxicity (summary). This helps teaches that when p50 is phosphorylated, it shuts downs anti-apoptotic genes (pro-survival). Schmitt teaches p-p50 was from a nuclear extract (page 3). This helps teach claims 6 and 8.
An artisan would have been motivated to look for biomarkers before administering a treatment because elevated p-p50 shuts downs anti-apoptotic genes, which is pro-survival (Schmitt summary). The artisan would expect to be able to measure the expression level of a phosphorylated NF-KB, such as p-p50, in cancer cells (“nuclear extract” Schmitt page 3). The artisan would also be motivated and expected to administer a treatment of the elected species (Curis ref claim 1) for cancer (Curis ref. claim 67). This teaches claims 1, 8, 17, 19, 21, 23, 25, 47, 48.
Conclusion
No claims are allowed as currently written.
THIS ACTION IS MADE FINAL. 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 GILLIAN A HUTTER whose telephone number is (571)272-6323. The examiner can normally be reached M-F 7:30-5.
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
