DETAILED ACTION
Status of Claims
The amendment submitted January 5, 2026 has been entered.
Claims 2-10, 14, 16-20, 22-26, 29-35, 37-39, 42-46, 49-52, 54-55, 57, 59, 61-62, 64-65, 69-74, 77, 79-80, 85, 91, and 95-100 are cancelled by Applicant.
Claims 11, 15, 21, 27, 28, 36, 40, 41, 47, 48, 56, 58, 60, 63, 66, 67, 68, 75, 76, 78, 81, 82, 83, 84, 86, 87, 89, 90, 92, 93, and 94 are amended by Applicant.
Claims 1, 11-13, 15, 21, 27-28, 36, 40-41, 47-48, 53, 56, 58, 60, 63, 66-68, 75-76, 78, 81-84, 86-90, and 92-94 are pending and under consideration and the subject of this office action.
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 .
Priority
This application is a 371 National Phase Application of PCT/US2023/011661 filed January 26, 2023, which claims the benefit of US provisional applications 63/303,451, filed on January 26, 2022.
Information Disclosure Statement
In nonprovisional applications, applicants and other individuals substantively involved with the preparation and/or prosecution of the application have a duty to submit to the Office information which is material to patentability as defined in 37 CFR 1.56. The provisions of 37 CFR 1.97 and 37 CFR 1.98 provide a mechanism by which patent applicants may comply with the duty of disclosure provided in 37 CFR 1.56 using an IDS. The IDS may be filed using form PTO/SB/08. See MPEP 609.
No IDS has been received; therefore, it has not been considered. The applicant is reminded of their legal obligation to submit to the Office information which is material to patentability.
Claim Objections
Claims 1 and 21 are objected to because of the following informalities: At numbered page 4, line 1 there is a random period after “-iso-Bu)” and before “and,” and additionally, at numbered page 4, line 3, Claim 1 is missing a period at the end of the claim, and has a semi-colon instead.
For claim 21, numbered page 9, second to last line of claim 21, there is similarly a random period after “-iso-Bu)” and before “and.”
Appropriate correction is required.
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 89-90 and 92-94 are 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 claim 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 they relate to the pending claims follows.
Breadth of Claims and Nature of the Invention
Claim 89 is directed towards “a method for treating an MTAP-deficient and/or an MTA-accumulating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1.”
The compounds of claim 1 (Formula I, see below) encompass a diversity of options for Ring A, Ring B, X, R1 and R2, resulting in multiple classes of heterocycles varying in sterics and electronics and it is well-known in the pharmaceutical arts that such modifications to chemical structures can result in dramatic differences in activity, pharmacokinetics and physical properties.
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Therefore, it is reasonable to conclude the claim is broad with respect to pharmacological agent.
On page 41, paragraph [0090], Applicant defines “[0090] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment"). In one embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the discase, disorder or condition, or preventing the recurrence of the disease, disorder or condition.”
Therefore, it is reasonable to conclude the claims are broad with respect to the definition of treating, which is inclusive of preventing and prophylactic treatments.
On page 6, paragraph [0013], Applicant defines “An "MTAP-deficiency-related" or "MTAP-deficiency" or "MTAP deficient" disease (for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g., a cancer) 'associated with MTAP deficiency" or a disease (for example, a proliferating disease, e.g., a cancer) "characterized by MTAP deficiency" and the like refer to an ailment (for example, a proliferating disease, e.g., a cancer) wherein a significant number of cells are MTAP-deficient. For example, in a MTAP-deficiency-related disease, one or more disease cells can have a significantly reduced post-translational modification, production, expression, level, stability and/or activity of MTAP. Examples of MTAP-deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma (See FIG. 1).
The Examiner notes disease is not simply limited to cancer and inclusive of other proliferating diseases.
With regards to cancer as a proliferating disease, it is well known that cancer, including tumors is a broad class of heterogenous diseases for which there exists no general treatment or prevention.
Hanahan explains that “there are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs” (Hanahan, Douglas, and Robert A. Weinberg. "The Hallmarks of Cancer." Cell 100, no. 1 (2000): 57-70).
Hanahan further comments that “Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy (Hanahan, D., 2022. Hallmarks of cancer: new dimensions. Cancer discovery, 12(1), pp.31-46).”
Hanahan further teaches that “We noted as an ancillary proposition that tumors are more than insular masses of proliferating cancer cells. Instead, they are complex tissues composed of multiple distinct cell types that participate in heterotypic interactions with one another…Cancer cells are the foundation of the disease; they initiate tumors and drive tumor progression forward, carrying the oncogenic and tumor suppressor mutations that define cancer as a genetic disease. Traditionally, the cancer cells within tumors have been portrayed as reasonably homogeneous cell populations until relatively late in the course of tumor progression, when hyperproliferation combined with increased genetic instability spawn distinct clonal subpopulations. Reflecting such clonal heterogeneity, many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (Hanahan, D. and Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. cell, 144(5), pp.646-674).”
Consequently, Hanahan teaches the diversity, heterogeneity and complexity of cancer as a disease of which there remains no general treatment, despite years of research and improved understanding.
With respect to the various cancers claimed, many are equally broad and heterogenous.
Additionally, it is well-known that tumor heterogeneity is a challenge in cancer treatment.
El-Sayes teaches that “Despite great advances in cancer therapy, tumor heterogeneity continues to be a great barrier for the successful treatment of cancer. It has long been established that tumor heterogeneity is prevalent in most cancer patients and is a major driver of acquired resistance to all forms of cancer therapy (El-Sayes, Nader, Alyssa Vito, and Karen Mossman. "Tumor heterogeneity: a great barrier in the age of cancer immunotherapy." Cancers 13, no. 4 (2021): 806).”
El-Sayes also teaches that “Major challenges with universal cancer therapy have historically been attributed to the large number of subtypes of the disease and the biological differences associated with cancers arising in different parts of the body. While this locational diversity remains a challenge for unifying cancer treatment across various types, it has now become clear that even patients with phenotypically identical cancers often have dichotomous responses to treatment.”
El-Sayes further teaches that “Patients with the same type of malignancy may experience vastly different clinical outcomes, both before and after treatment. This interpatient heterogeneity is often seen in the clinic and is largely attributed to differences in somatic mutations acquired in the tumor.”
El-Sayes further teaches that “There is a plethora of innovative therapeutic approaches currently being developed for the treatment of cancer. Tumor heterogeneity acts as a major hurdle for treatment and a potentiator of acquired resistance regardless of the therapeutic approach or the type of cancer. Unlike primary resistance, acquired resistance can occur in patients that initially respond to therapy, resulting in a relapse after a period of tumor regression [33]. The mechanism of resistance caused by tumor heterogeneity is the same regardless of the treatment received. In a manner similar to that of natural selection, the composition of subpopulations in the tumor changes dynamically as a result of selective pressure exerted by therapeutic intervention and changes in the TME.”
By example only Marino teaches that “Molecular heterogeneity is a frequent event in cancer responsible of several critical issues in diagnosis and treatment of oncologic patients. Lung tumours are characterized by high degree of molecular heterogeneity associated to different mechanisms of origin including genetic, epigenetic and non-genetic source (Marino, Federica Zito, Roberto Bianco, Marina Accardo, Andrea Ronchi, Immacolata Cozzolino, Floriana Morgillo, Giulio Rossi, and Renato Franco. "Molecular heterogeneity in lung cancer: from mechanisms of origin to clinical implications." International journal of medical sciences 16, no. 7 (2019): 981).”
Marino further teaches that “Heterogeneity of molecular profile represents one of the most challenging issues in cancer, particularly in lung cancer, in the light of the resulting therapeutic implications. In lung cancer, different levels of molecular heterogeneity have been recognized including inter-patients, intra- and inter-tumour variability. Molecular heterogeneity between lung cancer patients with the same histotype represents a proven biological process resulting frequently in different treatment response for each individual patient.”
Marino teaches that “Tailored therapies based on the identification of molecular targets represent currently a well-established therapeutic scenario in the treatment of NSCLC patients, however short responses and development of resistance are frequently observed in daily clinical practice. Although the optimal efficacy of specific TKIs, a subset of NSCLC patients often shows a mixed response to treatment. Patient-specific response and resistance can originate not only from secondary aberrations induced by targeted therapy but also from intratumoral genetic heterogeneity.”
For breast cancer, Rivenbark teaches that “Breast cancer is noted for disparate clinical behaviors and patient outcomes, despite common histopathological features at diagnosis. Molecular pathogenesis studies suggest that breast cancer is a collection of diseases with variable molecular underpinnings that modulate therapeutic responses, disease-free intervals, and long-term survival. Traditional therapeutic strategies for individual patients are guided by the expression status of the estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor 2 (HER2). Although such methods for clinical classification have utility in selection of targeted therapies, short-term patient responses and long-term survival remain difficult to predict (Rivenbark, A.G., O’Connor, S.M. and Coleman, W.B., 2013. Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. The American journal of pathology, 183(4), pp.1113-1124).”
Rivenbark further explains that “If we accept the premise that every breast cancer is unique and reflects distinct qualitative and quantitative molecular traits, then knowledge of the entirety of molecular traits carried in any given breast cancer and patient is required for true personalized therapy to be realized…For current basic science, clinical, and translational researchers, the challenge is to evaluate large numbers of breast cancers (with known treatment and clinical response measures) to link specific qualitative or quantitative molecular traits with positive or negative responses to a variety of targeted and nontargeted drugs.”
Additionally, many cancers are also susceptible to resistance not noted until much later. By example only, for metastatic breast cancer, Lin explains that “Regardless of the advances in our ability to detect early and treat breast cancer, it is still one of the common types of malignancy worldwide, with the majority of patients decease upon metastatic disease (Lin, P.H. and Laliotis, G., 2022. The present and future of clinical management in metastatic breast cancer. Journal of clinical medicine, 11(19), p.5891).”
Particularly, Lin teaches that “Despite the recent advances in treatment, follow-up and targeted therapies, around 30% of breast cancer patients still eventually relapse with distant metastasis [5], which develops approximately 5–20 years after the initial diagnosis [6].”
Applicant is reminded that these teachings are by example only and the additional cancers recited by Applicant share similar attributes and challenges.
Therefore, it is reasonable to conclude the claims are broad with respect to type of disease and cancer, many of which are not preventable or curable diseases and subject to remission several years later.
Claim 90 is directed towards combination therapy.
Claim 92 is directed towards “wherein the disease is a proliferating disease.”
Claim 93 is directed towards “wherein the disease is an MTAP-deficient and/or MTA-accumulating cancer.”
Claim 94 is directed towards “wherein the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer (NSCLC), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.”
On page 41, paragraph [0088], Applicant defines subject as “[0088] A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomologus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.”
Consequently, it is reasonable to conclude the claims are broad with respect to subject in terms of species, patient population and is inclusive of a broad range of age groups including infants and pediatric subjects.
Therefore, it is reasonable to conclude that the claims are broad with respect to compound, disease or condition, treatment goal, and subject.
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).
Panome Bio teaches that “The PRMT5 inhibitor field is facing a patient selection crisis that’s quietly undermining billion-dollar drug development programs. While genomic biomarkers promised to revolutionize precision oncology, mounting evidence suggests that MTAP (S-methyl-5′-thioadenosine phosphorylase) deletion status, the primary biomarker used to identify patients for PRMT5 inhibitor trials, may not accurately predict clinical response. This disconnect between genomic theory and clinical reality is forcing pharmaceutical companies to reconsider their entire approach to PRMT5 patient stratification (Panome Bio, “Why MTAP Alone Falls Short for PRMT5 Patient Selection. https://panomebio.com/blog/why-mtap-alone-falls-short-for-prmt5-patient-selection/ Accessed July 29, 2026).”
Panome Bio additionally teaches that “However, recent clinical results have been more modest than expected. While some patients with MTAP-deleted tumors do respond to PRMT5 inhibitors, response rates remain in the 20-30% range rather than the dramatic effects seen in preclinical models. Even more concerning, some patients with confirmed MTAP deletions show no response whatsoever, while occasional patients with MTAP-intact tumors demonstrate unexpected sensitivity.”
Consequently, Panome Bio teaches issues in translating from preclinical models to the clinic and lack in predictability in determining patient response.
Panome Bio further teaches “Part of the problem stems from the limitations of preclinical model systems that guided biomarker development. Cell culture experiments, by definition, occur in MTAP-free environments where MTA accumulation proceeds unchecked. Xenograft models, while more physiologically relevant, typically contain fewer stromal cells than primary human tumors and may not accurately recapitulate the metabolic complexity of the tumor microenvironment.
These model system limitations explain why genomic biomarkers that work perfectly in the laboratory often fail to predict clinical outcomes. The metabolic phenotype that drives PRMT5 sensitivity depends not just on MTAP gene status, but on the complex interplay between tumor cells, stromal cells, and the broader tissue environment.”
Consequently, Panome Bio teaches the limitations associated with simply relying on preclinical models and in particular in vitro data and explains the complexity associated with PRMT5 and related pathways.
Li discusses current limitations in the field of PRMT5 inhibitors (Li, B., Yu, J.Q., Yang, Z. and Wang, Y., 2025. PRMT5: A Promising Synthetical Lethal Target for MTAP-Deleted Cancers. Journal of Medicinal Chemistry, 68(17), pp.18143-18163).
Particularly, Li teaches “Additionally, compound 24 was also granted Orphan Drug designation by the FDA for the treatment of malignant peripheral nerve sheath tumors and malignant gliomas, including the highly aggressive brain cancer glioblastoma (NCT05275478). Clinical evaluation revealed that no partial responses were observed among 23 patients with glioblastoma at active doses, with the median time on study lasting less than 2 months. Additionally, the concentration of compound 24 in cerebrospinal fluid was dramatically lower than that in plasma levels with a ratio of 30%, much below the threshold required to induce a therapeutic effect in the brain. Unfortunately, in November 2024, Tango Therapeutics announced that it would stop enrollment in the clinical trial of compound 24 following disappointing results for glioblastoma.”
Consequently, Li describes challenges in translation from preclinical to clinical outcomes based on common challenges associated with drug delivery to the brain.
Li further teaches “Consistent with its potent in vitro efficacy, compound 25 exhibited robust antitumor efficacy in the LU99 MTAP-del mouse xenograft model across multiple dosing regimens, with a TGI of 96% at a dose of 30 mg/kg BID, and 66 or 65% tumor regression at the doses of 60 mg/kg BID and 120 mg/kg QD, respectively. The robust activity profile supported the clinical potential of 25 in treating MTAP-deficient solid malignancies. (85) Notably, compound 25 has been advanced into Phase 1/2 clinical trials for the treatment of solid tumors with confirmed homozygous MTAP deletion (NCT05732831). The trials consist of two sequential sections: the Phase I dose-escalation portion evaluates the safety profile of compound 25 both as monotherapy and in combination with pembrolizumab in patients with MTAP-del solid tumors, while the Phase II expansion phase will enroll six parallel cohorts stratified by MTAP-del tumor types to assess the efficacy of both compound 25 monotherapy and combination therapy at the established recommended Phase II dose (RP2D). The dose-escalation study of compound 25 began in July 2023, and a total of 59 patients have been enrolled until 20 October 2024, 39 patients of which covered across 13 histologies and were evaluable for response at active doses (160–300 mg QD). Compound 25 exhibited broad-spectrum antitumor activity with favorable tolerability across multiple malignancies, including nonsmall cell lung cancer and pancreatic ductal adenocarcinoma. The current median duration of treatment has reached 24 weeks, which still increases with ongoing therapy. Progressive tumor shrinkage over extended treatment periods was observed in the responding patients. The median time to objective response was 16 weeks (range 8–32 weeks), with approximately 60% of partial responses emerging from patients with a stable disease. Notably, seven cholangiocarcinoma patients were enrolled, 3 of whom showed confirmed partial responses, and the other 4 patients are ongoing with a median time on study of 24 weeks. However, the current analysis was still limited by the small evaluable patient population and insufficient follow-up duration for precise ORR estimation across most tumor subtypes. (86, 87).”
Although both compounds differ from instant invention, they do highlight the challenges translating from preclinical to clinical trials.
Li further teaches “PRMT5 is a key enzyme involved in the regulation of gene expression and cellular processes through the methylation of arginine residues on histone and nonhistone proteins. Notably, both clinical investigations and preclinical studies have consistently demonstrated upregulated PRMT5 expression across multiple cancer types.”
Li further teaches “The clinical trials for most of the first-generation PRMT5 inhibitors have been terminated or suspended. Second-generation MTA-cooperative PRMT5 inhibitors were designed to stabilize the PRMT5·MTA complex and selectively inhibit PRMT5 activity in MTAP-del cancer cells while preserving PRMT5 activity in MTAP-WT cells, offering a potentially precise cancer treatment strategy.”
“For example, TNG908 was the first clinical candidate from Tango Therapeutics and showed robust antitumor efficacy in a LN18 MTAP-del mouse xenograft model with TGI of 100% at a dose of 60 mg/kg BID for 21 days. Unfortunately, TNG908 demonstrated inadequate blood–brain barrier (BBB) penetration in clinical trials, failing to achieve the anticipated therapeutic exposure levels in glioblastoma, and the compound was removed from the research and development pipelines by the company due to no observed partial responses among 23 patients with glioblastoma in the phase I/II trial.”
“It should be noted that the growth of MTAP-WT cells was still inhibited to some extent by the second-generation PRMT5 inhibitors, such as MRTX1719, having an IC50 value of 0.89 μM against MTAP-WT HCT116 cancer cells, which may lead to target-dependent hematological toxicity. Therefore, identification of the doses and conditions under which hematological toxicities do not occur matters a lot to the MTA-cooperative PRMT5 synthetic lethal inhibitors.”
Consequently, Li further highlights the challenges in developing PRMT5 inhibitors particularly in translation from preclinical to clinical trials.
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Consequently, in addition to the heterogeneity and challenges of treating and curing cancer, the prior art highlights that PRMT5 inhibitors are still nascent and possess many factors contributing to lack of predictability and translation from preclinical to clinical models.
Notably, Applicant has provided no specific guidelines or actual working examples directed towards methods of treatment for any particular disease or condition based on its deuterated analog. All data as presented are in vitro and based on knockouts, not any actual human lines screened.
Applicant has also failed to demonstrate any working examples or support suggesting preventative or curative effects as claimed.
Additionally, Applicant has failed to provide working examples pertaining to combination therapy and synergies.
Additionally, Mason-Osann teaches that “Combination therapy continues to be a valuable element of cancer treatment in the era of targeted therapies (1, 19, 20). Currently, preclinical strategies to identify new drug combinations often prioritize synergy (3–5); however, this approach may have drawbacks. First, synergy metrics do not assess absolute efficacy, therefore, synergy scores can prioritize combinations of drugs with little or no monotherapy activity, resulting in technically synergistic but weak treatments. This is a significant concern because synergy is most often observed among weak drugs (10). Second, synergy metrics are generally based on short-term assays and do not reveal response durability. Therefore, including other metrics, such as overall efficacy and durability of response may enhance the translational relevance of preclinical data (Mason-Osann, E., Pomeroy, A.E., Palmer, A.C. and Mettetal, J.T., 2024. Synergistic drug combinations promote the development of resistance in acute myeloid leukemia. Blood Cancer Discovery, 5(2), pp.95-105).”
Mason-Osann furthermore teaches that “The current data, supported by prior experiments and models (7, 11, 21, 22), suggest that combination strategies depending solely on synergy may compromise durability of response. In a synergistic combination, drugs depend on each other's activity to maximize effect; small losses in sensitivity to either component drug therefore produce a larger loss in sensitivity to the combination (Fig. 1A). This means that modest resistance to a single drug produces a large fitness benefit (Fig. 3D; Supplementary Fig. S5A), speeding the emergence of drug resistance…Together, these data have important implications for how to prioritize combinations in oncology. We have shown that synergistic drug combinations, while potentially useful to achieve high efficacy, contribute to the evolutionary pressure to develop drug resistance. Therefore, to identify regimens that produce durable clinical response, preclinical assessments of drug combinations should consider metrics beyond synergy, such as monotherapy activity, overall combination activity, and durability of response.”
Therefore, based on the prior art, it is reasonable to conclude that the current state of the art is unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed.
(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 medicine, oncology, veterinary 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, the cancers, diseases or conditions are heterogenous and highly variable pending on patient population, formulation, and various key dosing parameters. Additionally, the field of PRMT5 inhibitors is still nascent and faces challenges with predictability and translating from preclinical to clinical outcomes, in addition to still being a burgeoning field where issues with resistance are still not well-understood.
Based on these cumulative factors, it is reasonable to conclude that predictability in the art is 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’ examples are directed towards:
Synthesis and preparation of compounds of formula (I).
Cellular assay and viability assay using HAP1 MTAP-isogenic cell line (Examples 119-120, page 469-471 and Table 1, column 4-6 and 8).
Prophetic examples for combination viability assay (Example 121, page 471).
Suggestions for combination therapies (no data provided).
However, there are no actual human cell lines screened, animal models, biological tissue studies (i.e.: preclinical and/or clinical data) encompassing the broad range of cancers and/or proliferative disorders as claimed.
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 be unable to simply translate the evidence provided by the applicant without undue experimentation across the full scope of the instant invention in terms of disease, subject, and aim of treating and/or preventing.
Based on the lack of experimental data, unknowns, unpredictability in the art, no actual working examples or guidelines regarding specific diseases and key parameters, an ordinarily-skilled artisan would be required to undertake a heavy burden of experimentation in order to practice the instant invention as presently claimed.
(F) 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:
Studies supporting that the method is effective for the diseases or conditions as claimed and in treating the symptoms as claimed. All examples are cellular assays not directed towards any particular disease or condition. Cellular assays are using MTAP-knockout to assess sensitivity; however, not actual studies are done directed toward actual cancer and/or proliferating diseases.
Studies encompassing the wide range of subjects in terms of species, patient populations, including providing guidance on formulations, dosing parameters, and treatment plan based on disease or conditions.
Studies regarding pharmacokinetics, particularly for treating cancers and/or diseases where drug delivery is critical and based on present challenges with translating from preclinical to clinical models (i.e: brain cancers).
Long-term studies verifying effectiveness of the treatment and demonstrating prevention and/or prophylaxis. Many cancers and/or proliferative diseases experience drug resistance and remission after longer durations. Presently, issues with resistance are still not well-understood.
Particularly, the presence of actual data and evidence supporting the compounds and methods of treatment as claimed.
Studies demonstrating combination therapies as it cannot be assumed that simply combining therapeutic agents would result in a synergistic effect or effective treatment regimen.
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 89-90, 92-94.
Therefore, Claims 89-90, 92-94 are rejected for lacking enablement.
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 1, 11-13, 15, and 21 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.
Regarding claim 1, page 3, paragraph 1, line 8, the parentheses and phrase " (e.g., a ring that together with the morpholine or piperazine ring of Structure I can form a bridged, fused or spiro bicyclic heterocyclic ring) and page 3, paragraph 3, line 6" (e.g., substituted with 0, 1, 2 or 3 instances of R⁵, wherein each R⁵ is independently selected from the group consisting of =0, halo, -CN, -C1-C₆ alkyl, -C1-C₆ heteroalkyl, -C1-C₆ hydroxyalkyl….) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
As per MPEP § 2173.05(d): “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.”
Claims 11-13 are likewise rejected for failing to remedy the ambiguity.
Similarly, regarding claim 15, numbered page 6, paragraph 2, the phrases “ (e.g., substituted with 0, 1, 2 or 3 instances of R⁵, wherein each R⁵ is independently selected from the group consisting of =0, halo, -CN, -C₁-C₆ alkyl, - C1-C₆ heteroalkyl, -C1-C₆ haloalkyl, -C₃-C₉ cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -ORᵇ, -N(Rᵇ)₂, -C(=0)Rᵇ, -C(=0)ORᵇ, -NRᵇC(=0)Rᵇ, - NRᵇC(=0)ORᵇ, -C(=O)N(Rᵇ)₂, -OC(=O)N(Rᵇ)₂, -S(=O)Rᵇ, -S(=O)₂Rᵇ, -SRᵇ, - S(=O)(=NRb)Rᵇ, -NRᵇS(=O)₂Rᵇ and -S(=O)2N(Rᵇ)₂, wherein each Rᵇ is independently selected from the group consisting of H, -C1-C₆ alkyl (e.g., -Me, -Et, -Pr, -‘Pr,-“Bu, - ‘Bu, -sec-Bu, -iso-Bu)), and C₃-C₉ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); and” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Likewise, regarding claim 21, page 8, last paragraph, the phrases “(e.g., substituted with 0…” and page 9, paragraph 1, second last line ((e.g., -Me, -Et, -Pr, -ⁱPr,-“Bu, -Bu, -sec-Bu, -iso-Bu) and last line “(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl),”renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Therefore, Claims 1, 11-13, 15, and 21 are rejected on grounds of indefiniteness.
Examiner Interview
The Examiner notes that Ioana Davies, Attorney of Record was contacted to discuss possible Examiner’s Amendments. The Attorney informed the Examiner that Applicant preferred to receive a written office action; hence, the office action provided herein.
Allowable Subject Matter
Claims 27-28, 36, 40-41, 47-48, 53, 56, 58, 60, 63, 66-68, 75-76, 78, 81-84, 86-88 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1, 11-13, 15, 21, 89-90, and 92-94 are rejected.
Claims 27-28, 36, 40-41, 47-48, 53, 56, 58, 60, 63, 66-68, 75-76, 78, 81-84, and 86-88 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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