DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed January 12, 2026.
Claims 9-11, 14-24, and 40-44 are pending.
Claim 24 remains withdrawn.
Claims 2-8, 12-13, and 25-39 were previously cancelled by Applicant.
Claim 1 previously withdrawn, is cancelled by Applicant.
Claims 12-13 were previously cancelled by Applicant.
Claims 40-44 are new.
Claims 9-11, 14-23, and 40-44 are under consideration in the instant office action as explained below in the Election/Restriction section
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 12, 2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 9-11 and 14-23, drawn to a method for treating cancer in a mammal comprising administering one more compounds listed in claim 1, in the reply filed on January 16, 2025 is acknowledged.
The examiner notes claims 12-13 are cancelled by Applicant.
Claims 40-44 are new and are directed towards the subject matter of Group II (i.e.: drawn to a method for treating cancer in a mammal comprising administering one more compounds listed in claim 1) ; therefore, are elected.
Applicant’s election of species without traverse, drawn to the species of rhabdomyosarcoma as a species of cancer.
The elected species is allowable; therefore, the search was expanded to the full scope of the claims. No prior art was found.
Claims 1 and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 30, 2024.
The examiner notes claim 1 is cancelled by Applicant.
Claims 9-11, 14-23 and 40-44 are currently under examination and are the subject of this office action.
Information Disclosure Statement
No additional information disclosure statements have been submitted.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 112(a)
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.
Claims 9-11, 14-23 and 40-44 are/remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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: (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 based on the content of the disclosure. See MPEP § 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors as these relate to the pending claims follows.
(A)(B) Breadth of Claims and Nature of the invention
Claims 9-11, 14-23 and 40-44 are drawn towards methods for treating cancer in a human comprising one of more compounds selected from the group recited in claim 9.
Claim 9 is drawn towards methods “wherein the cancer is… rhabdomyosarcoma, Ewing's sarcoma, colorectal cancer, ovarian cancer, prostate cancer, CNS cancer, melanoma, breast cancer, leukemia, non-small cell lung cancer, renal cancer, and osteosarcoma, and wherein the cancer is a transcription-driven cancer.”
New claims 40-44 are directed towards specific cancers as recited in claim 9: colorectal cancer, ovarian cancer, prostate cancer, melanoma and breast cancer.
On page 13, paragraph [0086], Applicant defines “transcription driven cancer” as “a cancer in which the primary oncogenic driver is one or more transcription factors, or a chromatin remodeler that have undergone mutations (e.g., translocations) that disrupt the activity of a gene, either by increasing or reducing activity that leads to epigenetic reprogramming of the cells and oncogenic activity.”
It is well-known in the art that although not all cancers may be directly transcription driven, they may be affected by transcription factors.
As Bradner explains “Various types of transcriptional addiction appear to operate in specific subsets of cancer. Thus, the majority of human cancers exhibit genetic amplification or transcriptional dysregulation of MYC, which is accompanied by an anabolic transcriptional response driving proliferation and metabolic adaptation (Bradner et al. "Transcriptional addiction in cancer." Cell 168, no. 4 (2017): 629-643).
Consequently, the claims remain broad pertaining cancers recited.
As mentioned previously, John Hopkins Medicine teaches that “There are more than 120 different types of brain tumors, lesions and cysts, which are differentiated by where they occur and what kinds of cells they are made of,” which does not even include all the possible types of CNS cancer (John Hopkins Medicine, “Brain Tumor Types,” https://www.hopkinsmedicine.org/health/conditions-and-diseases/brain-tumor/brain-tumor-types#:~:text=There%20are%20more%20than%20120,cells%20they%20are%20made%20of, Accessed: July 30, 2025).
In terms of considering Applicant’s definition, Dang teaches that “The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20–25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood…Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets (Dang, D.D., Rosenblum, J.S., Shah, A.H., Zhuang, Z. and Doucet-O’Hare, T.T., 2023. Epigenetic regulation in primary CNS tumors: an opportunity to bridge old and new WHO classifications. Cancers, 15(9), p.2511).”
Dang further teaches that “Fifty-three primary CNS tumors had documentation of twenty-eight distinct alternative genetic and/or epigenetic pathways that demonstrate direct protein-protein interaction with the mammalian SWI/SNF chromatin remodeling complex (Table 4). Thirteen entities also shared known primary SWI/SNF subunit variants. Commonly represented epigenetic interactions included histone point mutations affecting chromatin remodeling function via polycomb repressive complex (PRC), direct mutation of PRC2 subunit proteins (EZHIP, SUZ12, EED), transcriptional activators and/or repressors with intrinsic histone acetyltransferase activity (YAP, EP300), and regulators of small non-coding RNA molecules (LIN28A, DICER1). Genetic mutations with direct interaction with SWI/SNF subunits primarily emphasized either transcription factors critical to cell cycle regulation, cell differentiation, and development (TP53, MYC, RB1) and/or genes involved in developmental signal transduction (WNT, SHH, NOTCH). This cohort of tumors was also associated with many malignant phenotypes predominantly affecting younger populations, particularly within the glioma/glioneuronal/neuronal, embryonal, pineal, meningioma, and mesenchymal categories.”
Dang also teaches examples of CNS cancers which emphasize the importance of age. By example only, “ATRX (alpha thalassemia/mental retardation syndrome X-linked) is a chromatin remodeling protein contained within the SWI/SNF superfamily of chromatin remodeling proteins and acts as a histone chaperone protein that loads histones onto telomeres to maintain heterochromatin [150,151,152,153,154]. ATRX interacts and forms a complex with Death Domain-Associated Protein (DAXX) to deposit H3.3, a histone variant, at nucleosomes [152]. In a 2012 study of pediatric GBM, somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway were found in 44% (21/44) of tumors; however, under the new WHO CNS 5 criteria, two of the tumors included in this analysis would not be classified as glioblastoma due to IDH mutations [5,33]. Despite this distinction in classification, regardless of IDH mutation status, all these tumors had defects in the H3.3-ATRX-DAXX chromatin remodeling pathway. Considering this, this suggests that there may be differences in the chromatin landscape that we do not yet appreciate that may lead to alterations in ERV expression that have an impact on the behavior of these tumors. The study also screened 784 gliomas of various grades and histology and showed that H3F3A mutations were specific to GBM in children and young adults [33], again suggesting the importance of age distribution in reflecting tumor biology.”
Dang also teaches embryonal tumor prominent in infants under the age of three years, such as “ Embryonal tumors include AT/RT, medulloblastoma, neuroblastoma, cribriform neuroepithelial tumor (CRINET), and other rare entities [157,158]. In support of our hypothesis that dysfunction of chromatin remodeling pathways during development may lead to tumorigenesis through currently unrecognized pathways, it has recently been found that medulloblastoma tumors originate from a failure to eliminate a developmental cell population that expresses Sox2 and is derived from the external germinal layer [159]. There are multiple examples of embryonal tumors that contain LOF mutations in the SWI/SNF pathway, such as AT/RT, CRINET, and medulloblastoma; however, bi-allelic loss of SMARCB1 in AT/RT has been the most well-characterized example [10,51,160,161,162].”
Dang teaches that “Our systematic review of the literature, guided by the most recent WHO CNS classification schema, has highlighted the need to marry our current framework based on histopathologic morphology with the insights evolved by the use of new technologies in epigenetic investigations. We have elaborated on trends between chromatin remodeling defects and expression of ERVs in tumors with a high degree of heterogeneity and dichotomous clinical behavior, suggesting that prognostication and intervention in these tumors may benefit from further translational stratification.”
Regarding pediatric neoplasms, Roosen teaches “Pediatric CNS tumors comprise a vast and expanding spectrum of molecularly defined entities [137]. Histologically, these entities present with various morphological patterns that are not unique for a single entity, thus complicating an accurate diagnosis based on standard histopathology alone…. While adult neoplasms have high numbers of somatic mutations, these often lack in pediatric neoplasms [236]. In contrast, pediatric tumors show a higher frequency of germline alterations, copy number alterations, and structural alterations such as enhancer hijacking events and gene fusions as possible oncogenic drivers (Roosen, M., Odé, Z., Bunt, J. and Kool, M., 2022. The oncogenic fusion landscape in pediatric CNS neoplasms. Acta Neuropathologica, 143(4), pp.427-451).”
Roosen teaches furthermore that “Fusion proteins as oncogenic drivers are emerging in pediatric CNS neoplasms. Since the implication of NGS more of these drivers have been described in case studies as well as in big multi-center sequencing studies. However, the variety of these fusions, the range of tumor entities in which they can occur, and their molecular mechanism are for a large part still unknown. Transcription regulators now comprise the second biggest group of fusion proteins. These fusions are mainly seen in tumor entities that have been recently discovered or reclassified. With the discovery of these transcriptional regulator fusions probably more brain tumor entities can be reclassified based on their molecular mechanism. Although, this review did not identify the prevalence of these different fusions, the reclassification of the tumor entities based on the fusion that is present, as seen in many of the transcription regulator fusions, shows that the fusions play an important part in these entities. Future research should focus on the mechanism behind these fusions to identify targeted therapeutic options for the distinct tumor entities.”
Consequently, Roosen teaches the unpredictability associated with transcription-driven pediatric neoplasm.
Regarding glioblastomas, Myers teaches that “Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear (Myers, B.L., Brayer, K.J., Paez-Beltran, L.E., Villicana, E., Keith, M.S., Suzuki, H., Newville, J., Anderson, R.H., Lo, Y., Mertz, C.M. and Kollipara, R.K., 2024. Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration. Nature communications, 15(1), p.10363).”
Myers further teaches that “Glioblastoma (GBM) is the most common and malignant form of glioma, with a median survival below 18 months and a 5-year survival rate of less than 10%1. A major challenge in the treatment of GBM is that by the time of diagnosis, highly infiltrative tumor cells have already migrated long distances on major white matter tracts and/or the microvasculature to invade surrounding brain regions. Thus, despite the use of fluorescence-guided surgery for maximal resection of tumor tissues followed by concurrent chemotherapy with temozolomide (TMZ) and conformal radiation, recurrence is unavoidable since complete elimination of all malignant cells is not possible.”
Myers further teaches “A common feature of GBMs, including lower-grade gliomas, is the presence of multiple neurodevelopmental transcription factors that may be responsible for maintaining tumor cells in an undifferentiated, progenitor-like state.. These studies suggest that the combinatorial functions or differential levels of transcription factors are the direct mechanistic link between oncogenic driver mutations with downstream transcriptional programs that influence or determine the various cellular states and hierarchy of GBM cells. However, which transcription factors are responsible for which cellular states or cell types and how the initiation, proliferation, and migration of GBMs are altered following perturbations of specific sets of transcription factors in vivo remains to be determined.”
By example only, Balan teaches that “Ovarian cancer is a complex disease with significant heterogeneity because of the existence of diverse subtypes or variations within a particular cancer type… Tumor heterogeneity appears to be quite high among subtypes and within a single tumor, posing a significant risk of treatment failure in ovarian cancer (3). Aside from the many subtypes of ovarian cancer, tumor heterogeneity, which can be classified into inter-tumoral and intra-tumoral heterogeneity, adds to the disease’s complexity. Inter-tumoral heterogeneity refers to the genotypic and phenotypic differences identified between numerous tumors of the same type in different individuals. For example, ovarian tumors in two distinct people might have quite varied profiles in terms of genetic alterations, cellular makeup, and responsiveness to therapy (Balan, Dharvind, Nirmala Chandralega Kampan, Magdalena Plebanski, and Nor Haslinda Abd Aziz. "Unlocking ovarian cancer heterogeneity: advancing immunotherapy through single-cell transcriptomics." Frontiers in Oncology 14 (2024): 1388663).”
Consequently, it is reasonable to conclude that the types of cancers claimed are unpredictable and diverse in terms of types and heterogeneity within cancers.
Claim 14 is directed towards methods “wherein the cancer is Ewing’s sarcoma.”
Claim 15-17 are directed towards methods “wherein the cancer is rhabdomyosarcoma,” and “wherein the cancer is alveolar rhabdomyosarcoma.”
Claim 18 is directed towards “wherein a histone demethylase is inhibited by the compound in the mammal.”
At page 13, paragraph [00083], Applicant explains that “In still other embodiments, the mammal is a non-human primate or a human. In some embodiments, the mammal is a human. In some embodiments, the mammal is a human infant, child or adolescent.”
Consequently, the subject of treatment remains diverse across pertaining human demographics across a variable age range. As aforementioned, for many of the cancers recited, patient population and age are critical features.
At page 15, paragraph [0089], Applicant also explains that “The terms "treat" and "prevent," and the like, as used herein, do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.”
Consequently, it is reasonable to conclude that the claims are broad with respect to the subject, disease, and methods of treatment.
(C) The state of the prior art
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05 (a).
To the best knowledge of the examiner, there is no general method and/or pharmaceutical composition containing pharmacological agents for cancer treatment.
As aforementioned, the cancers claimed are diverse and variability based on types and heterogeneity as exemplified with brain tumors and ovarian cancer as stated above.
Additionally, rhabdomyosarcoma and many pediatric cancers are notably characterized by being heterogenous.
In terms of rhabdomyosarcoma, Chen explains that “a bulk solid tumor such as rhabdomyosarcoma is composed of a heterogeneous population of cells which evolves to be more genetically unstable and complex as selective pressure is applied during drug treatment (Chen, Celine, Heathcliff Dorado Garcia, Monika Scheer, and Anton G. Henssen. "Current and future treatment strategies for rhabdomyosarcoma." Frontiers in Oncology 9 (2019): 1458).”
Furthermore, Chen emphasizes that ““Pediatric cancers are characterized by dynamic chromosomal instability, which can result in loss of chromosomal segments or copy-number alterations, contributing to the genetic heterogeneity of the tumor mass. A small subpopulation of drug-resistant tumor cells (harboring a genetic alteration conferring a survival advantage) present at initial treatment may persist and expand, resulting in eventual failure to eliminate residual tumor mass.”
Rhabdomyosarcoma (RMS) is unpredictable, still not well-understood, and faces issues with drug resistance. Chen explains that “based on data from early clinical trials enrolling pediatric rhabdomyosarcoma patients, single-agent therapies do not appear to achieve durable responses. As with most targeted therapies, almost all cancers treated with a single-agent therapy will eventually acquire resistance and reduced sensitivity to subsequent lines of treatment. Of equal importance to identifying novel therapeutic targets, is the unequivocal need to better understand how RMS tumors develop resistance to these therapies.”
Chen also explains the current status for rhabdomyosarcoma and targeting PAX-FOXO1: “In reality, few drugs have been developed specifically for childhood cancers due to a small market for a rare childhood diseases, and the ability to directly target PAX-FOXO1 does not appear to be within reach for some time.”
It is also known that dosing and combination therapies are critical in developing viable treatment methods for pediatric cancers such as rhabdomyosarcoma. Chen explains that “Generally speaking, the two known strategies for overcoming drug resistance are intermittent dosing schedules and combination therapies.”
With respect to drug resistance, Chen explains that “The gap between the observed efficacy of targeted therapies in preclinical models of RMS and the marginal improvements in patient outcomes observed in clinical trials has forced a reconsideration of our approach. Only when the mechanisms of drug resistance are understood will these new treatments be effective for children with metastatic or recurrent RMS, for which intensive chemotherapeutic regimens have already been exhausted.”
Consequently, Chen explains the variations between preclinical and clinical results based on issues with drug resistances and lack of knowledge in the art to understand such mechanisms.
It is well-known in the art that multidisciplinary treatment is required for RMS. Shinji explains “Patients with RMS require multidisciplinary treatment, including chemotherapy, surgical resection and radiation therapy (RT). Multi-drug chemotherapy regimens significantly improved the outcome in patients with localized RMS, although no marked improvement has been observed in patients with metastatic RMS.”
In terms of PAX-FOXO1, although some in vitro and in vivo studies have been performed it is a target that is still not validated. As Shinji explains, “Further preclinical studies on PAX-FOXO1-targeting treatment are needed to assess the usefulness of PAX-FOXO1 as a therapeutic target for RMS (Miwa, Shinji, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Kentaro Igarashi, and Hiroyuki Tsuchiya. 2020. "Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma" Cancers 12, no. 7: 1758).”
It is also difficult to conduct clinical trials due to the unpredictable nature of RMS. Shinji explains that “It is difficult to conduct clinical trials of anticancer drugs for the treatment of RMS owing to the rarity of RMS, its various subtypes, and differences in gene mutations.”
In terms of KDM inhibitors, this field is also nascent in terms of understanding the targets and proof-of-concept in a clinical setting.
In terms of KDM3 inhibitors, Yoo explains that “Despite the increasing number of KDM inhibitors in development, only a few drugs have produced satisfactory results and exhibited sufficient specificity for consideration as principal structures for drug development. Consequently, no currently reported compounds are selective for KDM3 subfamily members or their isoforms. Several reasons challenge the development of KDM3-selective inhibitors. First, most, if not all, KDM3 crystal structures are undetermined… Thus, the structure of KDM3 proteins needs to be elucidated to better understand its molecular mechanisms and facilitate the development of potent, and selective KDM3 inhibitors. Second, most inhibitors are cofactors or substrate mimics with poorly understood mechanisms of action for specific KDM3s. Additionally, other inhibitors identified to date target the broad catalytic machinery of KDM and, therefore, have low specificity for KDM3. Thus, more research is needed to understand the biochemical selectivity of KDM3 to develop specific inhibitors. Third, no conclusive data have validated the efficacy of KDM inhibitors against specific cancer types. These issues have prevented KDM inhibitors from progressing beyond basic research to clinical research and medical applications (Yoo, Jung, Yu Hyun Jeon, Ha Young Cho, Sang Wu Lee, Go Woon Kim, Dong Hoon Lee, and So Hee Kwon. "Advances in histone demethylase KDM3A as a cancer therapeutic target." Cancers 12, no. 5 (2020): 1098).
Similar trends are noted for KDM4. Chin explains that “The status of KDM4 inhibitor development is still in the early stages with small numbers of patents and journal articles. Future KDM4 inhibitor development should focus on obtaining selectivity between KDM4 subtypes, development of small molecules with in vivo activity. Compounds presented in the patents described in this manuscript usually have activity in the demethylase assay and the cell-based assay. However, compounds with in vivo activity have not yet been reported. Literature search indicates that only one compound, JIB-04, was reported to have in vivo activity until now. JIB-04 was identified in the phenotypic screening system intended for the epigenetic activity. Next, a search for the molecular target was conducted for JIB-04 and several KDM family proteins were identified as JIB-04 targets. Among them, KDM4D protein was identified as the one with the highest sensitivity. The next step for the KDM4 inhibitor development area will be the identification of small molecules selectively inhibiting only one subtype with in vivo activity (Chin, Young-Won, and Sun-Young Han. "KDM4 histone demethylase inhibitors for anti-cancer agents: a patent review." Expert opinion on therapeutic patents 25, no. 2 (2015): 135-144).
In terms of KDM5A inhibitors, similar issues are noted. Yang explains that “There are several challenges that have to be overcome during development of KDM5A inhibitors. Firstly, the high similarity in the catalytic domain between KDM5A with other demethylases, especially the other members of the KDM5 family, which greatly increases the difficult in developing selective inhibitors. Secondly, KDM5A contributes to the heterogeneity of varieties of cancers via regulating transcriptional outputs in cell or cancer-dependent manner, which is one of the main reasons for KDM5A inhibitors failing in in cellulo and in vivo studies. Thus, the identification of the disease profiles of current KDM5A inhibitors is very important for advancing clinical applications. Thirdly, KDM5A inhibitors are also faced with the common challenges during drug design or optimization such as improving cell permeability and stability. Finally, only inhibiting KDM5A demethylase activity may be insufficient to decrease the expression of their target genes… although preclinical studies of KDM5A inhibitors for cancer therapy have been reported, no specific KDM5A inhibitor has been advanced into clinical trials (Yang, Guan-Jun, Ming-Hui Zhu, Xin-Jiang Lu, Yan-Jun Liu, Jian-Fei Lu, Chung-Hang Leung, Dik-Lung Ma, and Jiong Chen. "The emerging role of KDM5A in human cancer." Journal of hematology & oncology 14 (2021): 1-18).”
Punnia-Moorthy explains that “The most advanced KDM5 inhibitor is EPT-103182. This small molecule compound targets KDM5B which has been shown to have an anti-proliferative effect in hematological and solid cancer cell lines as well as inhibiting tumor growth in a dose-dependent manner in xenograft models (Hancock et al., 2015; Maes et al., 2015). This inhibitor has yet to be tested in clinical trials.”
“The role of KDMs in cancer have identified them as potential therapeutic targets and a wide range of pharmacological agents have been developed. Given the complex interactions of KDMs with other epigenetic regulators it is not surprising that drugs targeting KDMs are yet to enter clinical practice and this remains a focus of future research (Punnia-Moorthy, Gaya, Peter Hersey, Abdullah Al Emran, and Jessamy Tiffen. "Lysine demethylases: promising drug targets in melanoma and other cancers." Frontiers in Genetics 12 (2021): 680633).”
Consequently, there is no support from the prior art suggesting that the claimed invention can serve as a treatment method for all cancers and pediatric cancers such as rhabdomyosarcoma in humans. Applicant has only provided screening data; however, there is no in vivo data provided to suggest data would translate into humans, including pediatric patients.
Additionally, KDM inhibitors are still a relatively nascent field where there are still many questions regarding mechanism, efficacy, selectivity, resistance, in vivo studies, clinical studies, and more. For rare pediatric cancers such as rhabdomyosarcoma, this challenging condition is known to be especially heterogenous and faces challenges with drug resistance. It is well-known that dosing is key and combination therapy critical to manage resistance issues.
Consequently, the claimed invention is directed towards a rare disease that is difficult to diagnose understand, targets that have not be fully validated for efficacy, and inhibitor classes that are equally not validated in in vivo and/or clinical settings.
Therefore, it is reasonable to conclude that the current state of the art for the claimed invention is highly unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for the general treatment of cancer and rhabdomyosarcoma in all subject as claimed.
(D) The level of one of ordinary skill
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP § 2141.03 (I)
The invention described pertains to medicine and pharmacology. One of ordinary skill would be a person with training in oncology, veterinary medicine, medicine, pharmacology, biochemistry or a related technical discipline.
(E) The level of predictability in the art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. See MPEP § 2164.03.
Consequently, technologies involving physiological activity as opposed to mechanical or electrical inventions are generally regarded as being unpredictable sciences.
As aforementioned, cancer is an unpredictable, complex and heterogenous disease, and pediatric cancers such as rhabdomyosarcoma known to be especially dynamic and characterized by heterogeneity. Rhabdomyosarcoma is a disease that is still not well-understood and faces issues with drug resistance which is not well-understood. PAX-FOXO1 as a target has not been fully proven or shown to be useful. As aforementioned, KDM inhibitors are still being studied, there are few cases of in vivo studies, and few if any clinical studies and face many critical questions regarding mechanism, efficacy, selectivity, resistance and more.
Based on these culminative factors, it is reasonable to conclude that predictability in the art is extremely low.
Consequently, the applicant would need to provide more details, working examples and guidance in order for the claimed invention to be enabling based on the scope and nature of the claimed invention.
The existence of working examples
The applicants’ working examples are directed towards: In vitro studies using two derivatives of RH4 FR-RMS cells. A high throughput screen and hit confirmation of compounds to identify inhibitors of PAX3-FOXO1.
Cytotoxicity studies of PFI-63 and PFI-90 in RH4 and RH30 rhabdomyosarcoma cells (cell confluence study).
Characterization of PFI-63 and PFI-90 as a histone lysine demethylase inhibitor through comparison with JIB-04 and GSK-J4, known multi-histone lysine demethylase inhibitors.
Docking studies supporting PFI-63 and PFI-90 is a KDM inhibitor that binds KDM3B and possibly other KDMs.
PFI-inhibitory activity study using a histone lysine demethylase panel.
In vitro studies using RH4 and SCMC human rhabdomyosarcoma cells (apoptosis studies).
In vitro screen against NCI-60 panel (page 44, paragraph [0199]).
In vitro studies in Ewing’s sarcoma and osteosarcoma cells.
Applicant themselves note that “PFI-90 has the potential to treat a range of cancers” (page 44, paragraph [0198]; however, potential does not directly translate into methods for treating cancer in a pediatric subject.
Applicant has only conducted a high-throughput in vitro screen; however, no in vivo studies or clinical studies have been performed. This does not support that these results can be directly translated into any human patient for the broad classes of cancers listed, including rhabdomyosarcoma and pediatric patients.
As aforementioned, dosing and treatment regimen is key for rhabdomyosarcoma in particular based on known issues with drug-resistance; monotherapy is known to be insufficient. No details on determining dosing and treatment regiments have been provided, which for this disease is not known to be routine the art and is in fact highly critical.
On this basis and the prior discussion, the working examples are both not commensurate with the scope of protection sought and are not enabling. One ordinarily skilled in the art would unable to simply translate the evidence provided by the applicant for treating all humans and cancers claimed without undue experimentation particularly based on the scope of invention.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As aforementioned, the quantity of experimentation depends on the prior art, the predictability of the art, and the direction provided by the inventor, which are factors that were already discussed.
In order for one ordinarily skilled in the art to practice the invention as disclosed, some attributes one would require, but are not limited to:
In vivo studies or similar models to validate and demonstrate in vitro results would translate towards treating the broad range of cancers provided in human patients including pediatric patients and supporting that the compounds can actually treat CNS cancers. It is well-known that properties for drugs to target the CNS are different compared to other cancer targets. Applicant has not demonstrated such drug delivery would be effective.
Additional studies to address the limitations associated with KDM inhibitors such as efficacy, selectivity, and understanding drug-resistance, particularly in vivo studies and translational models to support predictability in the subjects claimed.
Development of a treatment regime including how to determine effective dosage, timing, monitoring plan and administration method for the diverse class of subjects, cancers and disease progression, including addressing drug resistance.
Consequently, the examiner concludes that one ordinarily skilled in the art would require undue experimentation in order to practice invention based on the details provided and scope of invention defined in Claims 9-11, 14-23 and 40-44.
Consequently, 9-11, 14-23 and 40-44 remain rejected for lacking enablement with respect to treating the broad and diverse lists of cancers in humans as claimed, including pediatric cancers such as rhabdomyosarcoma.
NEW REJECTIONS
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation "wherein a histone demethylase is inhibited by the compound in the mammal”" in claim 18, and there is no prior recitation of “mammal.”
Additionally, claim 9 recites “one or more compounds selected from the group consisting of; therefore, it is unclear which compound is “the compound,” recited in claim 18.
Similarly, claims 22 and 23 recite “wherein the function of the PAX3-FOX01 fusion transcription factor is disrupted by the compound in the mammal,” without prior recitation of “mammal,” and likewise, ambiguity as to which compound is being referenced from claim 9 as “the compound” recited in claims 22-23
As per MPEP 2173.05 (e): A claim is indefinite when it contains words or phrases whose meaning is unclear. In re Packard, 751 F.3d 1307, 1314, 110 USPQ2d 1785, 1789 (Fed. Cir. 2014). The lack of clarity could arise where a claim refers to "said lever" or "the lever," where the claim contains no earlier recitation or limitation of a lever and where it would be unclear as to what element the limitation was making reference. Similarly, if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended. A claim which refers to "said aluminum lever," but recites only "a lever" earlier in the claim, is indefinite because it is uncertain as to the lever to which reference is made.”
There is insufficient antecedent basis for this limitation in the claim.
Claims 19-21 depends on claim 18 and fails to remedy this deficiency; therefore, is likewise rejected.
The examiner suggests amending claim 18 to read as “the human” to remedy the issue and to clarify which compounds recited in claim 9 are being referenced.
Likewise, the examiner suggests amending claims 22-23 to read as “the human” to remedy the issue and to clarify which compounds recited in claim 9 are being referenced.
Therefore, claims 18-23 are rejected as being indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 18-23 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 recites the limitation "wherein a histone demethylase is inhibited by the compound in the mammal,” which broadens the subject matter of claim 9, which is limited to humans.
Claims 19-21 depends on claim 18 and fail to remedy the deficiency.
Similarly, claims 22 and 23 recite “wherein the function of the PAX3-FOX01 fusion transcription factor is disrupted by the compound in the mammal,” which broadens the subject matter of claim 9, which is limited to humans.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Therefore, claims 18-23 are rejected for failing to further limit the subject matter of the claim upon which they depend.
Response to Arguments
The Remarks of January 12, 2026 have been fully considered but are not fully persuasive for the reasons below. The Examiner notes that additional remarks from the previous office actions dated February 13, 2025 and August 12, 2025 are incorporated herein.
35 USC 112(a)
Applicant’s Arguments:
Claim 9 is directed to methods of treatment comprising administering an effective amount of one or more compounds selected from the group consisting of two compounds, or a pharmaceutically acceptable salt thereof, lists only 13 types of cancer, and is further limited to the treatment of only human subjects. Further, claim 9 is herein amended to require that "the cancer is a transcription driven cancer." At the time of filing of the application, it was well within the ability of one reasonably skilled in the art to make and use the claimed invention.
Examiner’s Response:
The Examiner appreciates Applicant’s narrowing of the scope of the claimed invention; however, Applicant has failed to address the points raised by the Examiner regarding the specific cancers claimed and points made regarding KDM inhibitors. Specifically, the Examiner has emphasized the key role of patient population and age and many of the cancers claimed by Applicant are known to specifically impact pediatric patients. It is well-known in the art that dosing and treatment of pediatric patients is not routine; moreover, that treating rhabdomyosarcoma is additionally more challenging.
As discussed above and restated here for clarity, rhabdomyosarcoma (RMS) is unpredictable, still not well-understood, and faces issues with drug resistance. Chen explains that “based on data from early clinical trials enrolling pediatric rhabdomyosarcoma patients, single-agent therapies do not appear to achieve durable responses. As with most targeted therapies, almost all cancers treated with a single-agent therapy will eventually acquire resistance and reduced sensitivity to subsequent lines of treatment. Of equal importance to identifying novel therapeutic targets, is the unequivocal need to better understand how RMS tumors develop resistance to these therapies.”
Chen also explains the current status for rhabdomyosarcoma and targeting PAX-FOXO1: “In reality, few drugs have been developed specifically for childhood cancers due to a small market for a rare childhood diseases, and the ability to directly target PAX-FOXO1 does not appear to be within reach for some time.”
Applicant is reminded that as per MPEP 2164.05, “Once the examiner has weighed all the evidence and established a reasonable basis to question the enablement provided for the claimed invention, the burden falls on applicant to present persuasive arguments, supported by suitable proofs where necessary, that one skilled in the art would be able to make and use the claimed invention using the application as a guide. In re Brandstadter, 484 F.2d 1395, 1406-07, 179 USPQ 286, 294 (CCPA 1973).”
Consequently, the burden falls on Applicant to fully address the Wands factors and provide appropriate arguments and/or evidence.
As per MPEP 2164.05: “To overcome a prima facie case of lack of enablement, applicant must present argument and/or evidence that the disclosure would have enabled one of ordinary skill in the art to make and use the claimed invention at the time of filing. This does not preclude applicant from providing a declaration after the filing date which demonstrates that the claimed invention works. However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art at the time of filing. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must reasonably enable the full scope of the claimed invention. See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).”
The Examiner once more invites Applicant to address these points raised by Chen and additional points provided above in the enablement rejection, reminding Applicant that such evidence and arguments must be commensurate with the scope of the claimed invention and that the burden falls upon applicant to demonstrate an ordinarily skilled artisan would be able to use the invention as claimed using the applicant as a guide. Presently, Applicant has failed to do so.
Applicant’s Arguments:
Recent advances in oncology allow for identification and selection of targets by understanding the molecular mechanisms of tumor growth. This has led to the ability to discover small molecules e.g., signal transduction inhibitors, with effective antitumor effects. For example, imatinib mesylate is considered to be effective against chronic myeloid leukemia and gastrointestinal stromal tumors. Also, osimertinib is considered to be effective against non-small cell lung cancer. Similarly, the claimed compounds have shown to be effective at targeting and inhibiting histone demethylases in transcription driven cancers. Using the knowledge at the time of filing and the disclosure in the patent application, one reasonably skilled in the art would have been able to identify the subjects with the claimed types of claimed cancers.
Examiner’s Response:
Applicant cites to compounds that are unrelated to the compounds of instant invention, which are KDM inhibitors that have only been tested in limited in vitro screens.
Imatinhib mesylate is an oral tyrosine kinase inhibitor approved by the FDA in 2001 and has undergone substantial experimentation and evidence supporting its use (Flynn JP, Gerriets V. Imatinib. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551676/).
Osimertinib is an EGFR inhibitor also approved by the FDA in 2015 (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Osimertinib. [Updated 2017 Jun 1]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548495/).
The only relationship between these examples and instant invention is that they are all allegedly targeted therapeutics; however, mechanism of action, target, structures, properties and established precedence in the prior art is vastly different.
It is one matter to identify subjects with the claimed types of cancer, but completely different to develop an effective treatment method and regimen based on the complexity of the cancers as claimed, many of which are heterogenous, subject to drug resistance, require non-routine optimization for dosing schedules and are genetically unstable as discussed above in the enablement rejection.
The Examiner carefully notes that FDA approval is not required for enablement. Applicant should not misconstrue that the enablement rejection is due to lack of FDA approval and should instead consult MPEP 2164.01 for further details and the comprehensive Wands factor analysis provided the Examiner as is the standard test of enablement.
Applicant’s Arguments:
The Office does not require data showing successful treatment of human subjects in order for a patent application to be granted. Further, there is no requirement for human in vivo data showing each and every claimed cancer type can be treated. The Application provides abundant data showing that the claimed compounds inhibit growth of cancer cells.
Examiner’s Response:
As aforementioned, the enablement rejection is based on comprehensive Wands factor analysis establishing undue burden of experimentation, not FDA approval.
As Applicant themselves has admitted, the Applicant show inhibition of cancer cell growth in cell lines, but just because a compound can kill cancer cells or stop growth in vitro, does not mean such a compound can be translated into a method of treatment for a complex cancer in a pediatric patient or human based on the multivariate factors involved in designing an effective treatment plan well-known in the art of oncology. To this aim, applicant has provided no arguments or support in favor that a person of ordinary skill in the art would be able to practice the full scope of the amended claims without undue experimentation or to address the points raised by the examiner regarding such tasks. Again, a person of ordinary skill in the art must be able to use the application as a guide.
Presently, Applicant has failed to provide persuasive arguments supported by evidence supporting that the claimed invention is enabled and to fully address the points raised by the Examiner. In the previous Office Action and reiterated in this Office Action, the examiner provided a detailed and thorough Wands factor analysis detailing the factors pertaining enablement as per MPEP 2164.01(a), and identifying key issues within Applicant’s disclosure pertaining enablement. Applicant has not sufficiently addressed the points previously raised.
Therefore, the Examiner once more invites Applicant to present persuasive arguments and/or evidence to support their claims of an enabled disclosure.
For these reasons, the arguments by Applicant are not persuasive, and the claims remain rejected. Additionally, new 112(b) and 112(d) rejection have been made based on claim amendments.
Conclusion
Claims 9-11, 14-23, and 40-44 are under consideration and remain rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
