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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 3-4, 6, 9-10, and 12-13 and species: KRAS G12D, IL-33, an inhibitory nucleic acid, etokimab, an inhibitory nucleic acid as a species of antibody inhibitor, sequential administration, ATAC-Seq as a detection method, and pancreatic cancer in the reply filed 01/03/2023 is acknowledged.
Claims 6, 14-15, 17, 20, 22, 24-28, 30, and 32 are withdrawn from consideration pursuant to 37 CFR1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 01/03/2024.
Upon amendments to the claims filed 05/13/2024, claim 6 is now withdrawn because it was amended to include a nonelected species of a Brd4 inhibitor which is not under consideration.
Claims 1, 3-4, 9-10, and 12 are now under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
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, 3-4, 9-10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Nanchahal et al. (US 2019/202907 A1, in PTO-892 filed 07/17/2024), in view of Oishi et al. (WO 2018/098352 A2, in IDS filed 01/12/2021), in further view of Andersson et al. 2018 (in PTO-892 filed 07/17/2024).
Nanchahal et al. teaches “a method of treating a patient suffering from a systemic fibrotic condition which comprises administering to the patient an amount of an IL-33 antagonist effective to treat the patient”, see Abstract. Nanchahal et al. discloses that the treatment of the condition comprises administering an antibody known as “etokimab” or “ANB020”, which works by “inhibit[ing] IL-33 cytokine function by blocking interaction with the IL-33 cytokine's receptor at low picomolar potency. The IL-33 antagonist may be a decoy receptor, such as soluble ST2 (sST2 or soluble IL-1R4) (Kakkar 2008, Martin 2016)”, see paragraph 0121 and meets the requirement of instant claim 1 wherein etokimab is used as an inhibitor for a treatment. The term “Type 2 cytokine signaling inhibitor monotherapy” is being interpreted as selecting one inhibitor from the list recited in instant claim 1 under the broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Nanchahal et al. also teaches how “in the present invention, the IL-33 antigen binding domain may (a) bind to the cytokine IL-33, preferably neutralizing biological function, (b) be an antibody to the cytokine IL-33, (c) be an antibody to IR-1R4, (d) be an antibody to IR-1R3 (e) is a IL-1R4 soluble receptor, or (f) be a IL-1R3 soluble receptor”, see paragraph 0440. This meets the limitations of instant claim 3 wherein the inhibitor etokimab inhibits the signal of IL-33, and instant claim 12 wherein IL-33 is elevated and is subject to being targeted by the inhibitor.
However, Nanchahal does not teach a KRAS mutant pancreatic cancer. Oishi et al. remedies this deficiency.
Oishi et al. describe a modulator that targets KRAS induced immune checkpoint expression and teaches a method “for increasing the therapeutic efficacy of existing anticancer treatments through the co-administration of a modulator of KRAS signaling” wherein “the modulator of KRAS signaling enhances the efficacy of the immune checkpoint inhibitor at treating a KRAS associated diseases”, see Abstract and pg. 3, lines 28-31 respectively.
Oishi et al. teaches a method of treating cancer wherein “an immunotherapeutic agent specifically binds to a specific cytokine, cytokine receptor, co-stimulatory molecule, co-inhibitory molecule, or immunomodulatory receptor that modulates the immune system”, see pg. 52, lines 27-30, and that “an immunotherapeutic agent can be a cytokine, for example, an interferon (IFN), interleukin, or the like… An immunotherapeutic agent can also be interleukin-1 (IL-1), interleukin-1α (IL-lα), interleukin-1β (IL-lβ), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-11 (IL-11), interleukin-12 (IL-12), interleukin-13 (IL-13), or interleukin-18 (IL-18), or the like”, see pg. 53, lines 1-7.
Oishi et al. also teaches how “the oncogenic KRAS comprises a mutation chosen from G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, GOV, G13C, G13S, G13D, G13V, G13P, S17G, P34S, Q61K, Q61L, Q61R, and/or Q61H”, see pg. 6, lines 26-29. This meets the limitations of instant claim 4 wherein the KRAS mutant pancreatic cancer comprises the G12D mutation.
Oishi et al. teaches “the immunotherapeutic agent targets and/or binds a cancer or tumor cell marker or component. Exemplary cancer or tumor cell markers or components include , but are not limited to, are not limited to, … p53 (TP53)…”, see pg. 53-54. This meets the limitations of instant claim 9 wherein the subject harbors a mutation in TP53. Oishi et al. also teaches that the modulator of KRAS signaling can be used to treat cancer where “the tumor can be, for example, a tumor caused by pancreatic ductal adenocarcinoma (PDAC)…”, see pg. 7, lines 24-25 . This meets the limitations of instant claim 10 wherein the pancreatic cancer comprises pancreatic ductal adenocarcinoma.
Nanchahal et al and Oishi et al. do not explicitly teach how interceding on IL-33 pathways would effectively treat pancreatic cancer. Andersson et al. remedies this deficiency.
Andersson et al. teaches that “in mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2, or MMP9 markedly blocked metastasis” and “the IL-33-NF-κB-MMP9-laminin axis that mediates the CAF-TAM–committed cancer metastasis. Thus, targeting the CAF-TAM-vessel axis provides an outstanding therapeutic opportunity for cancer treatment”, see Abstract.
It would be obvious at the time of the instant invention to use the invention of Nanchahal et al., which uses etokimab to inhibit Type 2 cytokine signaling as a treatment for cancer by inhibiting IL-33 expression with Oishi et al., which is a modulator that targets KRAS mutant induced immune checkpoint expression on tumor cells and retains a higher efficacy when co-administered with existing anticancer treatments such as etokimab, with the teachings of Andersson et al. which discloses the connection between IL-33 signaling and pancreatic cancers. Given the teachings disclosed by Andersson et al. which demonstrate that blocking the mechanisms of IL-33 serves as a therapeutic for pancreatic cancer, one would be motivated to combine the inventions with the expectation of using an antibody such as etokimab to inhibit IL-33 and Type 2 cytokine signaling to regulate the expression of various interleukins that promote the progression of cancer, with a modulator that localizes at KRAS mutated pancreatic cancers, to result in a targeted and effective treatment.
Therefore, claims 1, 3-4, 9-10, and 12 are rejected as obvious over Nanchahal et al., Oishi et al., and Andersson et al.
Response to Arguments
Applicant's arguments filed 08/25/2025 have been fully considered but they are not persuasive.
Applicant argues that the amendment in claim 1 to recite a “KRAS mutant primary pancreatic cancer” renders the obviousness rejection moot. This is not found persuasive.
The prior art references teach treatments for pancreatic cancers, specifically pancreatic ductal adenocarcinomas with G12D genetic mutations. The claim amendment to recite a “KRAS mutant primary pancreatic cancer” is included in these teachings as it is an obvious variant and therefore obvious to try.
Applicant's arguments filed 08/25/2025 have been fully considered but they are not persuasive.
Applicant argues “Nanchahal does not teach or suggest that monotherapy with an IL-33 antagonist (e.g. etokimab) is effective in treating KRAS mutant primary pancreatic cancer” and that the evidentiary reference Moral et al. (Exhibit A) teaches that “IL-33 blockade actually exacerbates primary pancreatic tumor growth compared to IL-33 wildtype mouse models implanted with KRAS mutant PDAC tumors.” This is not found persuasive.
As discussed above, Nanchahal et al. teaches “a method of treating a patient suffering from a systemic fibrotic condition which comprises administering to the patient an amount of an IL-33 antagonist effective to treat the patient”, see Abstract. Nanchahal et al. discloses that the treatment of the condition comprises administering an antibody known as “etokimab” or “ANB020”, which works by “inhibit[ing] IL-33 cytokine function by blocking interaction with the IL-33 cytokine's receptor at low picomolar potency. The IL-33 antagonist may be a decoy receptor, such as soluble ST2 (sST2 or soluble IL-1R4)”, see paragraph 0121. This reads on the instant limitations wherein an inhibitor or antagonist of IL-33 is used to block signaling, thereby treating pancreatic cancer caused and made worse by increased signaling. The evidentiary reference Alam et al. (in PTO-892 filed 02/26/2025) demonstrates how “oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression”, see Abstract. Given that Nanchahal teaches etokimab, which is an inhibitor of IL-33, one skilled in the art could reasonably expect that the IL-33 inhibitor when deployed to KRAS mutant pancreatic cancers would result in tumor regression from the time of administration due to its blockade of the IL-33 signaling.
Applicant refers to Moral et al. to demonstrate that IL-33 blockages actually exacerbate primary pancreatic tumor growth when compared to IL33 wildtype mouse models impacted with KRAS mutant PDAC tumors. This is not found persuasive as Moral et al. is conducting experimentation on knockout mice in which IL-33 functions are removed, and thus altering the immune system function of the model entirely from the outset. Additionally, the teachings of Moral et al. contradict both the prior art references used in the obviousness rejection and Figure 27B provided by Applicant. Figure 27B discloses that blocking or inhibiting IL-33 exhibited reduced fibrosis and delayed development of mutant KRAS-driven pancreatic intraepithelial neoplasia, which demonstrates that blocking IL-33 signaling is useful for the treatment of patients with KRAS mutant primary pancreatic cancer.
In the specific knock out models used by Moral et al., the mice may have a number of unknown, variable characteristics that are affected in the knocking out of the gene that may result in aberrant functions, such as blockages of IL-33 that actually result in increased tumorigenesis. The prior art and Applicant’s disclosure explains how inhibiting this pathway interrupts the signaling that is implicated in the growth of tumors, thus leading to a decrease in tumor growth, see Nanchahal et al. and Andersson et al. By comparing dissimilar models in Moral et al. and the instant disclosure, Applicant fails to acknowledge the lack of predictability when applying the teachings of Moral et al. to the instant invention as they are not applying the same set of circumstances to each treatment (i.e. one is applied to a knock out variant mouse, the other is applied to a mouse with PDAC). As such, using the same treatment on different models may result in different outcomes as multiple pathways would be impacted in the knock out mice.
Both the references used in the rejection and Figure 27B from the instant specification bolster the finding that when an antagonist for IL-33 is applied to PDAC, the tumors are expected to cease growth. It is unclear how Applicant claims that the references teach away from this, and instead purports the idea that tumorigenesis would actually be increased by such action (blockade). In the instant specification, Applicant discloses that a “blockade of IL-33 signaling may be useful in treating or preventing pancreatic cancer. Accordingly, the inhibitors of Type 2 cytokine signaling disclosed herein are useful in methods for treating or preventing pancreatic cancer in a subject in need thereof”, see paragraph 0268. Given that Nanchahal teaches a type 2 cytokine signaling inhibitor for IL-33, it alone would be useful in treating pancreatic cancer and the addition of the Oishi reference to disclose limitations regarding the specific type of cancer serves to provide a more refined and targeted approach that contributes to the anticancer therapeutic regimen. Therefore, the each of the references contain a reasonable expectation of success that becomes more pronounced when combined.
Applicant argues that “the combined teachings of Oishi, Nanchahal, and Andersson fail to render the pending claims obvious because they do not teach or suggest each and every element of the claims, and also fail to provide any rationale or motivation for a skilled artisan to combine or modify the teachings therein to arrive at the claimed subject matter with any reasonable expectation of success.” This is not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The references used in the above rejection are not anticipatory and thus, each individual reference is not required to teach every limitation of claim on its own. Rather, it is the combination of references, which all highlight the implicated IL-33 pathway and how antagonists can be used to intercede as a treatment for diseases, that are used together to teach the limitation of the instant invention.
Therefore, the obviousness rejection is maintained.
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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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675