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
Information Disclosure Statements
The information disclosure statements (IDS) submitted 12/03/2025 has been considered.
Election/Restrictions
In view of the declaration submitted under 37 CFR 1.130(a), the restriction requirement has been reconsidered. The restriction requirement is maintained in view of references cited below.
Status of claims
Claims currently pending are claims 1-12.
Claims currently withdrawn are claims 3-12.
Claims currently under examination are claims 1-2.
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.
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) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hoey (WO2017/040666) in view of Ho (Bioorganic & Medicinal Chemistry Letters, 25, 2015, 5472-5476) and Krishnamurthy (Cancer Treatment Reviews 62, 2018, 50-60).
Hoey throughout the disclosure and specifically on p. 4, para. [0014] contemplates the combination of an FZD antagonist or Wnt pathway inhibitor in combination with an immunotherapeutic agent.
Hoey on p. 10, para. [0042] contemplates embodiments where an immunotherapeutic agent is a PD-1 antagonist. Hoey in para. [0043] identifies Pembrolizumab as an antagonist of PD-1.
Hoey on p. 2, para. [0008] states “Activation of the Wnt pathway is also associated with colorectal cancer.”
Hoey discusses Wnt pathway inhibitors, and specifically FZD antagonists, but does not discuss the compound claimed in claim 1 (ETC-159).
This is addressed by the combination of Ho and Krishnamurthy.
Ho is drawn to the use of PORCN inhibitors to treat cancer (title).
Ho on p. 5475, Fig. 7 teaches the structure of PORCN inhibitor ETC-159 (shown below).
ETC-159 (Ho, Fig. 7)
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Ho on p. 5475, left col., para. 3 states “The authors have demonstrated that ETC-159 is orally bioavailable and inhibits the growth of MMTV-Wnt1 tumours effectively.” Ho continues and states “…ETC-159 was also shown to be remarkably efficacious in treating preclinical models of genetically defined cancers, in particular pancreatic cancer with RNF43 loss of function mutation and in colorectal cancers with RSPO translocation.”
Krishnamurthy is drawn broadly to effects of targeting the Wnt pathway in cancers (title). Krishnamurthy on p. 55, sec. Porcupine inhibitors states “Porcupine is a Wnt pathway target that is amenable to inhibition while sparing Wnt-dependent tissues.” Krishnamurthy in the same section identifies ETC-159 as a small molecule PORCN inhibitor with efficacy in preclinical models of RSPO-translocated colorectal cancer.”
While Hoey is largely drawn to FZD inhibitors, it contemplates other small molecule inhibitors of downstream targets within the Wnt pathway. Krishnamurthy identifies PORCN as a downstream target. Both Krishnamurthy and Ho teach ETC-159 as an effective PORCN inhibitor. One of ordinary skill in the art could easily modify the combination taught in Hoey by using the PORCN inhibitor ETC-159 in place of whichever FZD or Wnt pathway inhibitor taught by Hoey.
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have modified the combination taught in Hoey by using ETC-159 in place of the FZD inhibitor to arrive at the instant claims with a reasonable assumption of success. One of ordinary skill would have been motivated to make the modification as Krishnamurthy teaches PORCN inhibitors can inhibit the Wnt pathway without affecting tissue dependent on Wnt signaling.
Response to Arguments
The affidavit received 12/03/2025 which includes the testimony of Veronica Diermayr has been considered.
The synergistic effect when the compound ETCF-159 is combined with nivolumab is acknowledged. The following data has been provided:
Figure 1, Affidavit
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However, this data is not persuasive as claim 1 is drawn broadly to anti-PD-1 antibodies and claim 2 is drawn specifically to pembrolizumab, for which the instant specification does not show a synergistic effect.
Pembrolizumab is contemplated in possible combinations as an anti-PD-1 antibody. However, the instant specification does not disclose any working examples that would indicate that the synergistic effect shown when ETC-159 is combined with nivolumab is consistent when ETC-159 is combined with pembrolizumab. The specification in examples 3-4 (p. 20-24), only contemplates administering pembrolizumab. The spec. on p. 21, para. 1 states “A 3+3 dose escalation study of compound A with the standard dose of pembrolizumab will first be tested. In this study, compound A at different doses…will be administered simultaneously with pembrolizumab to…determine the recommended dose (RD) of compound A for dose expansion. Example 4 continues outlining primary objectives, patient population, groups to be tested, and study design. But the specification and affidavit do not disclose any data or evidence that would suggest the synergistic effect is seen with ETC-159 and pembrolizumab. Essentially, the scope of the claim does not reflect what has been shown to have a synergistic effect.
Regarding applicant arguments against Hoey, applicant states “Hoey, et al. broadly refers to the use of FZD (antibody) antagonists or small molecule inhibitors of downstream targets within the Wnt pathway (amongst an infinitely large number of possible small molecules) in combination with an immunotherapeutic agent. However, the examples in Hoey, et al. relate to the use of FZD antibody antagonists with an immunotherapeutic agent. Hoey, et al. does not demonstrate any small molecule inhibitor of FZD that can be effectively combined with an immunotherapeutic agent, such as pembrolizumab. Hence, Hoey et al. would not motivate a person of ordinary skill in the art to combine small molecule inhibitors of Wnt signaling with pembrolizumab.”
Applicant further argues that “PORCN inhibitors, such as ETC-159, act upstream of the Wnt pathway by prevent palmitoylation of Wnt ligands, preventing the release of Wnt ligands into the cytoplasm for binding to downstream FZD receptors. In contrast to FZD antagonists, PROCHN-inhibitors, such as ETC-159, act very differently from FZD receptors by blocking all Wnt pathways…”.
The common effect of inhibiting FZD, as in Ho, and inhibiting PORCN receptors, as in Hoey, is that the Wnt pathway itself is inhibited. Katoh (International Journal of Molecular Medicine, 40:587-606, 2017) discusses the efficacy of targeting either FZD, specifically FZD5, or PORCN where, on p. 592, Figure 4 shows that certain cancers are treated with either Anti-FZD5 compounds or PORCN inhibitors. Katoh specifically states “Loss-of-function RNF43 or ZNRF3 mutations, RSPO2/3 fusions and RSPO3 upregulation in colorectal cancer, breast cancer, pancreatic cancer and other cancers activate the WNT/β-catenin signaling cascade as well as β-catenin-independent WNT signaling cascades, such as WNT/STOP and WNT/PCP signaling cascades. This type of cancers can be treated with anti-FZD5 mAb, anti-RSPO3 mAb, or PORCN inhibitors.” Therefore, at least in those cancers mentioned, PORCN inhibition is an alternative to FZD inhibition.
Figure 4
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FZD5 is discussed in Hoey and Is contemplated as a target for in para. [00208]. Therefore, it isn’t unreasonable for one of ordinary skill to modify the combination taught in Hoey to use the PORCN inhibitor ETC-159 in place of the FZD antagonist as the effect is that Wnt signaling is blocked. Krishnamurthy provides motivation to make the modification where it teaches “Porcupine is a Wnt pathway target that is amenable to inhibition while sparing Wnt-dependent tissues.”
Additionally, small molecule inhibitors of Wnt signaling are discussed and incorporated in para. [00260] of Hoey.
Conclusion
No claims allowed.
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.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624