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
1. This application is a 371 of PCT/FI2022/050249 04/14/2022; FOREIGN APPLICATIONS FINLAND 20217071 04/16/2021.
Claims 1, 8-12, 32, 38-79 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, the compound 1, in the reply filed on February 16, 2026 is acknowledged. The election was made with traverse and the examiner finds the arguments unpersuasive. According to the argument, the explanation as in the requirement as to why the common structure is not a significant structural element is “without evidentiary support” and as such has not met the burden of MPRP 1893.03(d) at (2). There is no requirement that evidence be provided, only that an explanation be provided. According to applicants’ representative claims 1, 8-12, 32, 42, read on the elected species.
Reasons for the indication of allowable subject matter
3. The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art is Burckhardt US 4,748,178. Burckhardt teaches the barbituric acid compounds with a similar structure on column 1:
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The X-R3 can be considered the same as L-A. Examples include those with a 1,3-substiuttion pattern, an alkoxy group and a pyridine or phenyl as A/R3 in the Table 3 on col. 13-14:
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The closest example is:
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This compound differs by the identity of the Z group. The claims are drawn to amides of imidazolones (12) and pyrrolidinones (1a) while Burckhardt has a 6 membered ring in the barbituric acid amides. There is no teaching or suggestion to change the ring from the barbituric acid group since this is the course of their biological activity and nothing points to altering it.
Rejoinder
4. Claims 1, 8-12, 32, 42-79 are allowable. Claims 38-41, previously withdrawn from consideration as a result of a restriction requirement, now require all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between inventions I and II, as set forth in the Office action mailed on December 30, 2025, is hereby withdrawn and claims 38-41 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claim 38-41 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancer it does not reasonably provide enablement for treating “a condition where inhibition of TEAD is desired” or chronic pain. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to the following:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are broad encompassing an treating unknown list of diseases described only as “a condition where inhibition of TEAD is desired”. It is not clear which diseases embrace “where inhibition of TEAD is desired” and the specification does not explain it. Claim 39 lists cancer and chronic pain, while claim 40-41 lists specific types of chronic pain and cancers. The specification has three pages, 264-267, related to the biology/pharmacology of the compounds. There is a single screening assay for inhibition of TEAD with a Hippo pathway reporter, “which contains firefly lucerifase gene under the control of TEAD” in MCF-7cells. The compounds are grouped by their range of IC50 values.
While this assay shows that the compound Hippo dependent pathway, this is not the only pathway that involves TEAD activation. For example in cancer biology Huh “Regulation of TEAD Transcription Factors in Cancer Biology” Cells 2019, 8, 600, 1-22, explains that TEAD signaling involves Hippo independent signaling, including Wnt/β-catenin, and TGFB, “Canonical Wnt/β-catenin pathway regulates TEAD and YAP/TAZ via both Hippo-dependent and-independent mechanisms” [ page 5] “The TGFβ pathway regulates multiple biological processes including embryonic development, stem cell differentiation, immune regulation, wound healing, and inflammation. The crosstalk between the TGFβ and Hippopathway centers on Smad and TEAD transcription factors, respectively. TGFβ stimulation triggers TEAD-mediated biological responses in the context of cell fate determination, tumorigenesis, and fibrosis, which are either dependent or independent of Smads (Figure 2a). TGFβ increases the expression level and activity of TEAD, and vice versa, TEAD can also directly trigger TGFβ signaling. TGFβ induces TAZ expression via a Smad3-independent ,p38-mediated, andMRTF-mediated mechanism [84]. TGFβ also induces TEAD2 expression during epithelial-to-mesenchymal transition (EMT) [65]. Thus, TGFβ-induced TEAD target gene expression promotes EMT in mammary gland epithelial cells and malignant tumor phenotypes. Notably, the TGFBII ligand itself is a direct target gene of TEAD that evokes a positive feedback regulation [36,85].” [page 5] Figure 2b is shown below which also mention the EGFR pathway:
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Tang “The role of non-canonical Hippo pathway in regulating immune homeostasis” European Journal of Medical Research (2023) 28:498, discusses mechanisms of TEAD activation shown in the specification is discussed on page 1
In the canonical Hippo pathway, activated MST1/2-WW45 complex phosphorylates and activates the LATS1/2-MOB1A/B complex, activated LATS1/2 MOB1A/B complex then phosphorylates and inactivates YAP and TAZ, leading to YAP/TAZ cytoplasmic retention and degradation. While in nucleus, YAP/TAZ interact with the transcription factor TEAD (translationally enhanced-associated domain) to initiate downstream gene transcription (Fig. 1a). Numerous studies have demonstrated that the Hippo pathway plays a crucial role in tissue homeostasis, regeneration, and tumorigenesis [4–11]
He also shows that the non-canonical pathway does not involve TEAD and is shown in Fig 1. b,
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This means that TEAD is not entirely necessary for Hippo pathway biology either.
Fu “The Hippo signaling pathway and its implications in human health and diseases. Sig Transduct Target Ther 7, 376 (2022) reviews the Hippo signaling pathway, which involves maladaptive hyperactivation but also by under stimulation. The cartoon on page 8 shows the involvement of Hippo in health and human disease.
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“Fig. 5 The summary of diseases caused by the dysregulation of the Hippo pathway. Hippo pathway dysregulation has been found to be present in a variety of organs or systems diseases and involved in the regulation of occurrence or progression of these diseases. The specific diseases are shown in boxes” The dysregulation of Hippo in lung inflammatory diseases is complex and activation may offer a protective effect, “Second, the Hippo pathway could regulate the inflammatory response in the lung. In a bacterial pneumonia model, the relative levels of p-YAP and p-TAZ were decreased in alveolar epithelial type II cells (AECIIs). YAP/TAZ activation seemed to be a protective reaction. When YAP/TAZ was deleted in AECIIs, inflammation in the lung became more severe.208 Similarly, the deletion of YAP in lung endothelial cells could lead to inflammation in the lung.309 In summary, activation of the Hippo pathway may contribute to pulmonary inflammation. However, the connection between other Hippo components and pulmonary inflammation needs to be further studied.” [page 10, col. 1] The compounds of the instant claims inhibit Hippo and it is not entirely clear which subset of the conditions in Fig. 5 above would benefit from this mechanism. As discussed above, since TEAD inhibition is not limited to effects of TEAD by Hippo since it is activated by multiple signaling cascades, it is further unclear which diseases are to be treated.
Cancer is not a single disease. Cancer genomics has revealed that there are many more forms of cancer than is apparent by traditional classifications based on morphology and organ location. We recognize that there are more than a dozen forms of breast cancer and more than 50 forms of leukemia and lymphoma. Within each of these subtypes, there are individualized patterns of mutations (gene signatures). These often cross the boundaries of traditional classification schemes. For example, from the perspective of treatment, chronic myelogenous leukemia (CML) is more like gastrointestinal stromal tumor (GIST) sarcoma than it is like other forms of leukemia because CML and GIST share very similar molecular targets that make both susceptible to dramatic responses from the same drug (Figure 4).” [Benz “THE JEREMIAH METZGER LECTURE Cancer in the TWENTY-FIRST Century: An Inside View from an Outsider” TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 128, 2017, 275-297]. The existence of a single compound for the treatment of all the claimed cancers is beyond the skill of oncologists today. “Thus, we ask a simple, yet fundamental, question: why is it so difficult to cure cancer? Cancer is not a single disease that can be eradicated by a single drug. Cancer occurs for a variety of reasons and no two cancers are identical.” Bae, Cancer Targeted Drug Delivery, Springer: New York, 2013, Page v. “The failure of even cancer-targeted drugs can be explained by assuming that a single tumor can be composed of many different types of cancer cells, necessitating the determination of the diversity within a tumor and the need of different treatments. In other words, a cancerous tumor is not homogeneous. It is possible that cancerous cells continue to mutate, become more aggressive, move around, and resist therapeutic drugs. The implication is that a cancer patient may have multiple subtypes of a cancer. The initial mutation is common to all cancer cells in a tumor, but subsequently cancer diversifies.” Hayat, M.A. AUTOPHAGY CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING Volume 5 Academic Press: Sand Diego, 2015, page xxi. “[I]t has become clear both how fundamentally different most cancer is from infectious disease, and also how limited the magic bullet approach is against genetically unstable pathogenic cells. There is a scientific consensus that most cancer results from somatic cellular evolution [7- 11]. This makes cancer fundamentally different from other cellular pathogens. In most cases, it arises from endogenous parasitism by human cells (5), rather than arriving exogenously as a non-human pathogen species. Consequently, cancer cells are genetically heterogeneous but fundamentally human, as opposed to infectious cellular diseases that are homogenous and fundamentally non-human. Despite this consensus, the tendencies to think of cancer as a non-self entity, rather than as self cells behaving abnormally, and to think of cancer as a fixed entity rather than a dynamic process, continue to mislead in important ways (12). These conceptual errors encourage efforts to identify molecular targets that will characterize cancer cells in multiple patients with the same 'type' of cancer. This idea was very productive for infectious disease medicine, but has been markedly less so for cancer medicine.” [Carlo C. Maley and Mel Greaves Frontiers in Cancer Research Springer: 2016, pages 18-19].
Based upon the foregoing, treating even a single cancer is exceedingly difficult with chemotherapeutic drugs. Only a handful of drugs are useful, platinum agents, etoposide, bevacizumab, pemetrexed or erlotinib and they do not treat all cancers. Typically the pre-clinical approach involves cell line screening followed by xenograft models. Damia “Contemporary pre-clinical development of anticancer agents –What are the optimal preclinical models?” EUROPEAN JOURNAL OF CANCER 2009, 45, 2768-2781. Damia outlines a strategy to identify cancer drugs in The Fig. 1 “Preclinical development steps in the evaluation of new compounds” on page 2769. The National Cancer Institute Screening program NCI60 seems to be the most widely used model for an initial screen. Sharma “Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents” Nature Reviews Cancer April 2010, Volume 10, 241-253, also discusses various models for pre-clinical cancer screens. Table 3 “Cell line platforms for assessing anticancer therapeutics” summarizes some approaches. The NCI screening program is also listed here. Ocana, A. “Preclinical development of molecular targeted agents for cancer” Nat. Rev. Clin. Oncol. 2011, 8, 200–209 also discusses such approaches and describes the situation this way: “Preclinical testing of novel drugs usually involves a panel of cancer cell lines, such as those used by the US National Cancer Institute (NCI‑60). Only drugs with some activity against specific cell lines are then evaluated in tumor xenograft models (Figure 2).” Pg. 200 “While these techniques evaluate the preclinical activity of compounds, they do not provide information about molecular mechanisms or tumor selectivity, and have rarely guided subsequent clinical development.” Ocana Pg. 201 “Although the identification of new anti-tumour agents is mainly based on in vitro methodologies, the in vivo models are absolutely required to assess the pharmacological activity of a potential new drug in animal models in which the drug undergoes distribution in both neoplastic and normal tissues, is metabolised and eliminated.” “The preclinical experimental models that are currently used for the identification and selection of novel anticancer drugs, which were overviewed in the present paper, are far from being satisfactory in mimicking the complex biological features of human tumours.” (Damia Page 2778) Even if there were data for cell-lines like those in NCI-60, the data are sadly non-correlative.
The situation is so dire that the National Cancer Institute essentially abandoned the NCI-60, Ledford “US cancer institute overhauls cell lines” Nature February 25, 2016 Volume 530 page 391: “When the NCI-60 was established, researchers had a very different conception of cancer, says James Doroshow, director of the Division of Cancer Treatment and Diagnosis at the NCI in Bethesda, Maryland. “Thirty years ago, the idea was that if you found a drug that worked on six breast cancer cell lines, then you could use it to treat breast cancer,” he says. “Well, it doesn’t work that way.” Since then, breast cancer has been broken down into subcategories that are based on genetic mutations — and each category may respond differently to treatment.” The NCI is focusing its efforts on “developing hundreds of ‘patient-derived xenografts’ (PDXs) by implanting small chunks of human tumours in mice — an environment that better mimics the human body. The tumours can then be harvested and reimplanted in other mice, allowing researchers to study a given tumour in multiple animals.” While nothing is known about the predictive value of these PDX models being developed, a retrospective National Cancer Institute Study examined 39 known cancer drugs using transplantable human tumor cell lines and compared them to phase II clinical outcomes (Johnson, et. al. “Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.” British Journal of Cancer 2001, 84, 1424–1431). The data was not predictive of activity against the same human tumors. Breast cancer cell line data (like AU565) was not predictive, see Figure 1 pg. 1427 far left column. Neither was it predictive of tumors of different tissues, i.e. breast cancer cell line data did not lead to predictive outcomes of lung cancer, skin cancer, colon cancer, etc., see Figure 1 columns second thru sixth to the right of the far left column. “[T]he failure rate in anticancer drug development is higher than for other diseases; only about 5% of agents identified as potential anticancer compounds demonstrate sufficient clinical activity in phase III trials to eventually be licensed.” (Ocana pg. 200). This 95% failure rate is remarkable and speaks poorly of these assays.
As aforementioned there is an in vitro assay for the inhibition of the TEAD/Hippo pathway. There is evidence that the HIPPO pathway is involved in cancer. See Fu above and Cunningham “Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma” Life Science Alliance Published Online: 31 July, 2025 vol 8 | no 10 | e202503241 discusses the use and development of TEAD inhibitors in the treatment of many cancers
The Hippo pathway comprises an upstream kinase cascade module, which functions to regulate the activity of the cotranscriptional activators YAP and TAZ (11, 12). These, alongside the TEAD family of transcription factors (13, 14), represent the downstream transcriptional effectors of the Hippo pathway. Since the initial discovery of the signalling pathway as a core regulator of a variety of processes in development, differentiation, and regeneration (15, 16), YAP and TAZ have since been implicated as oncogenic drivers across a range of cancer types (17, 18, 19, 20, 21, 22, 23, 24). Strikingly, PM is defined by a relatively high frequency of mutations within the Hippo pathway relative to other cancer types (6, 7, 8, 9, 10). These mutations include frequent loss-of-function mutations within the upstream Hippo pathway kinase cascade, including most frequently in NF2, with more infrequent loss-of function mutations in SAV1, LATS1, and LATS2 (6, 7, 8, 9, 10). Although designing therapeutics against loss of tumour suppressors has been challenging historically, multiple inhibitors of the TEADs have recently been developed with the hopes to position for clinical use. The development of a range of varied direct inhibitors is an exciting advancement in cancer research, as hyperactive YAP/TAZ-TEAD activity is a widespread phenomenon across many cancers (25). Most of the inhibitors developed comprise small molecule disruptors of TEAD autopalmitoylation, a post-translational modification required for the interaction between these transcription factors and YAP/TAZ (26, 27, 28). After initial preclinical development, some of these promising inhibitors have now progressed to clinical trials, to be positioned as YAP/TAZ-TEAD inhibitors in PM patients.
Whether any cancer is treatable with the claimed compound will have to be determined in the clinic, however the USPTO is not the FDA. The fact that the prior art recognizes some reasonable mechanism for the treatment of cancer through the activity applicant has shown for the compounds weighs in favor of enablement. As per MPEP 2107.03 IV “Office personnel should not impose on applicants the unnecessary burden of providing evidence from human clinical trials.”
Beyond cancer, it is not clear what diseases are treatable by the TEAD-Hippo pathway. There does not appear to by any association between the TEAD-Hippo pathway and pain. Finding agents to treat pain is quite difficult. Prediction of pain treatment from animal tests is not very good. Le Bars, et. al. "Animal Models of Nociception" Pharmacological Reviews 2001, 53, 597-652, at pg. 634 column 2, paragraph "Predictiveness-in terms of clinical applicability-is an absolute requirement in nociceptive tests for two reasons. First because it is necessary when searching for new molecules with therapeutic value to avoid false positives and false negatives (Collier, 1964; Chau, 1989). For example, the writhing test, which is very sensitive but only weakly predictive, has to be reserved for initial pharmacodynamic screening so that potentially analgesic substances are not missed (Hendershot and Forsaith, 1959; Loux et al., 1978; Dubinsky et al., 1987)." Neuropathic pain in particular is very difficult to treat, See Costigan “Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage” Annu. Rev. Neurosci. 2009. 32:1–32. The instant specification has no data related to pain treatment.
Based upon the foregoing, the complexity of TEAD signaling, the lack of data regarding pathways beyond Hippo and the lack of any data outside the cell based assay for the Hippo pathway, it is not clear which diseases are those where inhibition of TEAD is desired besides cancer.
Conclusion
6. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621