DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed January 20, 2026 and February 2, 2026.
Claims 248-291 and 294-299 are pending and under consideration.
Claims 292-293 were previously cancelled by Applicant.
Claims 248 and 279 are amended.
Claims 250, 253, 255, 257, 259, 261, 267, 269-270, 273, 276-278, 281-289, 294-296, and 299 previously withdrawn, are now rejoined as explained below in the Election/Restriction section.
Claims 248-280, 290-291, 294-295, and 297-298 are allowed.
Claims 248-291 and 294-299 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 .
Information Disclosure Statement
One additional information disclosure statements (IDS) submitted on January 20, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 248-280, 290-295, and 297-298, drawn to compounds and pharmaceutical compositions of Formula (I) in the reply filed on August 6, 2025 is acknowledged.
The examiner notes claims 292-293 were cancelled by Applicant.
Applicant’s election without traverse of Example 39 as a species of Formula (I) of in the reply filed on August 6, 2025 is acknowledged.
PNG
media_image1.png
208
153
media_image1.png
Greyscale
PNG
media_image2.png
160
584
media_image2.png
Greyscale
Example 39 reads on claims 248-249, 251-252, 254, 256, 258, 260, 262-266, 268, 271-272, 274-275, 279-280, 290-291, 297-298.
The compound was found free of the prior art; therefore, the search was expanded.
Claim 248-280, 290-291, 294-295, 297-298 are allowable. Claims 281-289, 296, and 299 previously withdrawn from consideration as a result of a restriction requirement, require all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between inventions Groups I-V, as set forth in the Office action mailed on May 7, 2025, is hereby withdrawn and claims 281-289, 296, and 299 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 248-291 and 294-299 are currently under examination and are the subject of this office action.
WITHDRAWN OBJECTIONS
The examiner withdraws objections to the specifications based on the revisions completed by Applicant to the specification and claims and cancellation of claims 8-9, 13-14, and 19 by Applicant.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to claim 279 under 35 U.S.C. 112(b) based on claim amendments made by Applicant.
The examiner withdraws rejections to Claims 248, 254, 256, 258, and 280 under 35 U.S.C. 102(a)(1) based on persuasive arguments by Applicant regarding Forbes’ requirement for a methyl substituent on the aromatic nitrogen atom of the tricyclic ring (see page 34 of Applicant’s Remarks, January 20, 2026).
NEW REJECTIONS
Rejoining and consideration of claims 281-289, 296, and 299 have necessitated new grounds of rejection. The Examiner notes that an interview was conducted on March 9, 2026 with Steven M. Sturlis, Agent of Record in an effort to mitigate 112(a) issues with the remaining claims; however, no agreement was reached and Applicant decided to instead proceed with the next Office Action as provided herein (see interview summary).
Claim Rejections - 35 USC § 112(b)
Claims 296 and 299 are rejected on the basis that they contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of claims 296 and 299 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 296 recites the following: “A method of treating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), macroglobulinemia, extranodal marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma, primary central nervous system lymphoma, T-cell lymphoma, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), or chronic graft versus host disease (cGVHD) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 294.”
Claim 299 recites the following: “A method of treating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), macroglobulinemia, extranodal marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma, primary central nervous system lymphoma, T-cell lymphoma, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), or chronic graft versus host disease (cGVHD) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 297.”
In both cases, the alternatives listed differ substantially as they are part of three different type of disease classes: cancer, autoimmune, and inflammatory disorders, which encompass vastly different etiologies, diagnosis, patient populations, treatment plans, and disease progression.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 281-289, 296, and 299 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(s) 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 would be unable to practice the invention as disclosed without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors in relation to the pending claims follows.
The breadth of the claims and nature of invention
Claim 281 is directed towards treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 248.
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.
Claim 248 encompasses a broad class of compounds varying in electronic and steric diversity.
Claim 282 is directed towards further administering a broad range of combination therapies, including “radiotherapy, cytotoxic chemotherapeutics, protease-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, and angiogenesis- targeted therapies,” which also comprises a broad range of combination therapies in terms of type (i.e.: small molecule, peptide, antibodies, etc.), structure, mechanism, dosing, administration, etc.
Claim 283 is directed towards “wherein the cancer is leukemia or a lymphoma,” which is an equally broad class of cancer type.
Chennamadhavuni teaches that “Leukemia is a heterogeneous group of hematologic malignancies that arise from the dysfunctional proliferation of developing leukocytes. It is classified as either acute or chronic based on the rapidity of proliferation and as myelocytic or lymphocytic based on the cell of origin (Chennamadhavuni A, Iyengar V, Mukkamalla SKR, et al. Leukemia. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560490/).”
Chennamadhavuni further teaches that “Patients with leukemia should be referred to a hematologist-oncologist to initiate treatment. Therapy varies significantly based on the leukemia subtype and patient factors (eg, age, comorbid conditions).”
Claim 284 is directed towards non-Hodgkin’s lymphoma.
Claim 284 is directed towards specific lymphomas and leukemias including “diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), macroglobulinemia, extranodal marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma, primary central nervous system lymphoma, and T-cell lymphoma.”
Claim 286 is directed towards treating an autoimmune disorder using the broad classes of compounds as per claim 248.
Cho teaches that “It is now apparent that many chronic inflammatory and destructive diseases are autoimmune, including rheumatoid arthritis, Graves' disease, Hashimoto's thyroiditis, and Sjogren's syndrome, which each affect about 1% of the world's population. In addition, autoimmune diseases also comprise less-common diseases such as type 1 diabetes, multiple sclerosis, Crohn's disease, vitiligo, pernicious anemia, primary biliary cirrhosis, systemic lupus erythematosus, and ankylosing spondylitis. Over 80 autoimmune diseases have now been identified. These diseases are distinguished by their primary target organ (joints, skin—psoriasis; central nervous system—multiple sclerosis; intestine—inflammatory bowel disease (IBD); pancreas—type 1 diabetes mellitus), time course of disease presentation relative to tissue damage and major genetic associations (Table 1) (Cho, J.H. and Feldman, M., 2015. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nature medicine, 21(7), pp.730-738).”
Cho additionally teaches challenges for specific diseases using rheumatoid arthritis as an example: “Within a single disease, there is considerable variation in clinical manifestations and severity. For example, in rheumatoid arthritis, there is marked heterogeneity in the age of onset. Furthermore, as a person with this disease ages, there is heterogeneity in the number of affected joints and their distribution; in some more severe cases, people develop extra-articular complications, such as nodules and lung fibrosis. There is considerable heterogeneity in the speed of progression and in the extent of joint damage, with the degree of cartilage and bone damage varying. Some, but not all, phenotypic heterogeneity is related to known factors, such as 'seropositivity', with rheumatoid factor (RF) and anti-citrullinated antibody (ACPA) often being associated with more severe disease than seronegative arthritis; seropositive disease also has different human leukocyte antigen (HLA) associations.”
Claim 287 is directed towards “wherein the autoimmune disorder is selected from
rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE).”
Claim 288 is directed towards treating an inflammatory disorder using the broad classes of compounds as per claim 248.
Monteleone teaches that “The term “Immune-mediated inflammatory diseases (IMIDs)” refers to a large and heterogenous group of disorders involving, either simultaneously or sequentially, more organs. The spectrum of IMIDs is broad even though those involving the gut [e.g., Crohn's disease (CD) and ulcerative colitis (UC), two inflammatory bowel diseases (IBD)], the joints [e.g., psoriatic arthritis, rheumatoid arthritis (RA), and axial spondyloarthritis], and the skin (e.g., psoriasis) are common, probably reflecting the major exposure of such organs to different stimuli [[1], [2], [3]]. Other frequent IMIDs are multiple sclerosis, systemic lupus, type 1 diabetes, and asthma. IMIDs must be differentiated from the paradoxical manifestations (i.e., cutaneous and/or articular lesions) occurring among persons with immune-mediated pathologies following the use of biologics (e.g., anti-TNF), which tend to disappear after the discontinuation of the implicated drug [4] (Monteleone, G., Moscardelli, A., Colella, A., Marafini, I. and Salvatori, S., 2023. Immune-mediated inflammatory diseases: common and different pathogenic and clinical features. Autoimmunity reviews, 22(10), p.103410).”
Monteleone further teaches that: “The etiologies of IMIDs are unknown but it is thought that these pathologies arise in genetically predisposed individuals for the action of multiple environment factors that boost an abnormal tissue-damaging immunoinflammatory reaction and different clinical manifestations [1]. Dissecting the biological pathways that sustain pathological inflammation has contributed to developing powerful pharmaceutical compounds, which have helped to better manage IMIDs, thus improving the patients' quality of life.”
Claim 289 is directed towards “wherein the inflammatory disorder is chronic graft
versus host disease (cGVHD).”
Claim 296 is directed towards a mix of specific cancers, autoimmune disorders and inflammatory disorders as aforementioned using specific compound as claimed in claim 294.
Claim 299 is directed towards a mix of specific cancers, autoimmune disorders and inflammatory disorders as aforementioned using specific compound as claimed in claim 297.
On page 11 of Applicant’s specification, “treating” is defined as “As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.”
Therefore, “treatment” is inclusive of curing and is broad with respect to what encompasses “treating.”
On page 11 of Applicant’s specification, “As used herein, the term "subject" refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.”
Therefore, it is reasonable to conclude the claims are broad with respect to subject which includes all animals, including mammals and humans.
The Examiner emphasizes Applicant’s listing of diseases is broad and inclusive of a wide-range of heterogenous diseases and conditions varying in etiology, pathology, and treatment options.
Consequently, it is reasonable to conclude that the claims are broad with respect to subject, small molecule, disease, and aim of “treating,” which includes curing.
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 compound and/or general treatment known to treat the wide range of diseases and/or disorders claimed including cancer, autoimmune disorder and inflammatory disorders. Many of the diseases recited are still not well-understood.
In terms of MALT1 and cancer, O’Neil teaches of the potential yet remaining challenges for this nascent field: “While six trials focus on the use of MALT1 inhibitors to treat NHL and CLL, one trial explores opportunities for modulating the TME to enhance anti-tumor immunity through MALT1 inhibition. The assessment of the safety of MALT1 inhibition will be critical for these early clinical studies. Preclinical data indicate that MALT1 targeting represents a double-edged sword that can induce tumor cell killing, but also loss of peripheral immune tolerance. In preclinical models, the long-term administration of highly potent MALT1 inhibitors provokes a systemic reduction of peripheral Treg cells, yielding an IPEX-like (immunodysregulation polyendocrinopathy enteropathy X-linked) autoimmune pathology (O'Neill, T.J., Tofaute, M.J. and Krappmann, D., 2023. Function and targeting of MALT1 paracaspase in cancer. Cancer treatment reviews, 117, p.102568).”
“Other preclinical studies indicate that the chemical nature of the MALT1 inhibitor and the dosing scheme will be critical to achieve optimal therapeutic effects while minimizing safety risks [8], [114]. Taken together, there is good evidence for a therapeutic window of MALT1 inhibition in cancer therapy. However, clinical data must also consider potential risks from combinatorial treatments, for instance simultaneous MALT1 and BTK inhibition for lymphoma therapy or MALT1 inhibitors together with ICI such as anti-PD-1 for augmenting anti-tumor immunity.”
Consequently, O’Neil teaches the importance of guidance pertaining dosing, challenges with combination therapies and MALT1, and issues with causing autoimmune pathologies.
In terms of MALT1 and autoimmune and inflammatory disorders, studies teach that there is a lack of consistency in terms of MALT1 protease activity.
Specifically, Yu teaches that “ By comparing mice homozygous for either null or catalytically inactive mutations in MALT1, we found that many, but not all MALT1 functions were dependent upon its protease activity, and that MALT1 protease activity plays a crucial role that complements its scaffolding activity across multiple immune cell types and in immune responses in vivo. In the absence of MALT1 protease activity, CD4+ and CD8+ T cells displayed decreased activation-induced proliferation and IL-2 production while B cell receptor stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle CLRs was also found to be partially dependent upon protease activity. Protease-dead mice displayed reduced basal immunoglobulin levels, and defective T-dependent and T-independent antibody responses. Despite these generally decreased responses, Malt1PD/PD mice, but not Malt1-/- mice, progressively developed inflammatory cell infiltrates in multiple organs, ultimately leading to morbidity due to hind limb paresis. These findings demonstrate the importance of MALT1 protease activity in mounting effective immune responses and in maintaining immune homeostasis in vivo (Yu, J.W., Hoffman, S., Beal, A.M., Dykon, A., Ringenberg, M.A., Hughes, A.C., Dare, L., Anderson, A.D., Finger, J., Kasparcova, V. and Rickard, D., 2015. MALT1 protease activity is required for innate and adaptive immune responses. PloS one, 10(5), p.e0127083).”
Additionally, Yu teaches about unpredictability pertaining MALT1 and cell types “However, it is apparent that the relative importance of MALT1 scaffolding and protease activities can vary substantially between different receptors and cell types…However, this does suggest that MALT1 scaffolding and protease activities must be in balance to support normal immune homeostasis in vivo. Given the growing interest in developing selective MALT1 inhibitors for treatment of autoimmune disorders and other diseases [2,3,36–38], it will be important to further explore this potential negative consequence of inhibiting MALT1 protease activity.”
“This work, along with two papers published during our review process [39,40], represent a key step in uncovering the physiological contributions of MALT1 scaffolding and protease activities in innate and adaptive immunity. Collectively, we and others identify MALT1 protease activity as a critical determinant for development of MZ and B1 B cells and control of autoimmune inflammation [39,40]. Surprisingly the role of MALT1 protease activity in lymphocyte activation is not consistent across all studies; however, work from our group and Thome’s group [39] strongly support the notion that MALT1 protease activity is critical for adaptive and innate immune cell responses. As outlined above, these results reinforce our view that MALT1 protease activity does not merely adjust IKK mediated NF-κB activation, but contributes significantly at the cellular and organism level to maintain normal systemic immunity. A key remaining question revolves around the mechanism by which MALT1 scaffolding and protease activities integrate signaling downstream of different receptors in different cell types… In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.”
Consequently, Yu demonstrates the unpredictability associated with MALT1 and how it can actually impair immune response and the importance of in vivo data.
Furthermore, Bornancin teaches that: “In conclusion, this work revealed a previously unappreciated role for the MALT1 protease activity in finely regulating immune function and homeostasis. The defective Th17 and B cell responses observed in Malt1PD/PD mice highlight the therapeutic potential of drugs targeting MALT1 protease function. In line with this, treatment with mepazine, which inhibits MALT1 protease activity in a micromolar range, was recently reported to attenuate EAE symptoms (44). However, the reduced Treg compartment and multiorgan pathology occurring in Malt1PD/PD mice provide a warning for the potential risks associated with sustained abrogation of MALT1’s enzymatic activity. Development of inducible PD mice or selective MALT1 inhibitors will help clarify whether chronic inhibition of MALT1 activity in autoimmune pathologies is of therapeutic value. The spontaneous pathology and the complexity of the immune alterations identified in this study open new exciting questions that deserve further investigation. In particular, it is still unclear which Ags and pathways drive the accumulation of TEM and TCM cells and the IgG1/IgE-skewed B cell responses in Malt1PD/PD mice, and what is their contribution to the overall pathology. More importantly, what is the relevance of MALT1 protease activity in humans? Polymorphisms in the Malt1 gene have been associated with combined immunodeficiency (45–47). However, in all cases the mutations resulted in a complete deficiency of the protein or very low MALT1 levels because of protein instability. Further work is required to assess whether specific mutations in the catalytic function of MALT1 contribute to multiorgan inflammatory disorders (Bornancin et al. 2015. Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. The Journal of Immunology, 194(8), pp.3723-3734).”
Consequently, the function of MALT1 remains unknown and unpredictable in humans, and inhibition may contribute to inflammatory and/or autoimmune disorders.
Additionally, the importance of in vivo models is also emphasized based on the unpredictability regarding MALT1 activity and therapeutic effects.
Additionally, Applicant has provided no support for combination therapies. Applicant has not demonstrated such data can be extrapolated across the combination of broad and chemically diverse pharmacological agents cited.
To this aim, 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, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for all types of cancer, autoimmune disorders and inflammatory disorders, and combination therapies in all subjects as claimed.
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 the biomedical and pharmaceutical arts. One of ordinary skill would be a person with considerable training in medicine, veterinary medicine, pharmacology, oncology, medicinal chemistry, biochemistry or a related technical discipline.
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 forementioned, cancer, autoimmune and inflammatory disorders each encompasses highly heterogenous classes of diseases and disorders additionally known to be highly unpredictable. In terms of the MALT1, many challenges and unknowns are still ongoing investigation within the field in terms as aforementioned. Additionally, there are well-known challenges translating from in vitro to in vivo to humans and lack of understanding regarding the complex role of MALT1. Consequently, this field is also highly unpredictable.
In this context, based on assessing the fields of study, the predictability in the art is very 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 amount of direction provided by the inventor
As aforementioned, the amount of direction provided depends on the prior art and predictability of in the art. Based on the scope of protection sought by the applicant and the discussion aforementioned, the inventor has failed to provide sufficient direction for one ordinarily skilled in the art to practice the disclosed invention as claimed.
The existence of working examples
The applicants’ working examples are directed towards:
MALT1 Protease assays (IC50)( (page 674, Table A)
Human IL10 Secretion Assays for Human Diffuse Large B Lymphoma Cells (OCI-LY10) (IC50) (page 674, Table A)
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 cancer, autoimmune and inflammatory disorders claimed. There are also no working examples supporting the broad range of combination therapies as per claim 282.
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 into methods encompassing the broad scope of subjects, diseases, compounds and aim of treatment as claimed without undue experimentation.
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 vitro & in vivo studies (i.e.: actual preclinical data or clinical data) encompassing the diverse class of subjects listed (i.e.: humans, mammals, and other animals) and broad range of cancer, autoimmune and inflammatory disorders as claimed.
Support demonstrating curative effects (i.e.: remission) as claimed.
Additional details on development of a treatment regime including how to determine effective dosage, timing, monitoring plan and administration method for the diverse class of subjects, diseases and disease progression.
Based on the preponderance of evidence and rationale put forth, 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 281-289, 296, and 299
Consequently, claims 281-289, 296, and 299 are rejected for lacking enablement.
Allowable Subject Matter
Claims 248-280, 290-291, 294-295, 297-298 are allowed.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art is Forbes et al. (Forbes, I.T., Dabbs, S., Duckworth, D.M., Ham, P., Jones, G.E., King, F.D., Saunders, D.V., Blaney, F.E., Naylor, C.B., Baxter, G.S. and Blackburn, T.P., 1996. Synthesis, Biological activity, and molecular modeling studies of selective 5-HT2C/2B receptor antagonists. Journal of medicinal chemistry, 39(25), pp.4966-4977) and Ersmark et al. (WO 2018/226150 A1, Information Disclosure Statement No. 1, June 11, 2025, Foreign Patent Documents No. 43).
Forbes discloses similar compounds as claimed in the instant invention; however, Forbes’ compounds are 5-HT2C/2B receptor antagonists. Forbes does not provide sufficient guidance to motivate an ordinary skilled artisan to modify Forbes’ compounds into MALT1 inhibitors containing the complex substitution patterns as claimed in the elected species and instant claims as indicated.
Ersmark discloses similar compounds to formula I that are MALT1 inhibitors as shown below; however, Ersmark’s compounds lack an additional ring motif and contain differing substitution patterns compared to the instantly claimed invention. Ersmark does not provide any suggestion to incorporate a tricyclic scaffold as in the instantly claimed invention, nor does Ersmark suggest the substitution patterns claimed in the elected species and instant claims as indicated.
PNG
media_image3.png
98
205
media_image3.png
Greyscale
PNG
media_image4.png
116
196
media_image4.png
Greyscale
Consequently, it would not be obvious to a person of ordinary skill in the art based on the effective filing date of the claimed invention to access instant compounds as a predictable result with a reasonable expectation of results.
Therefore, the disclosed invention is non-obvious and allowable.
Conclusion
Claims 248-280, 290-291, 294-295, and 297-298 are allowed. Claims 281-289, 296, and 299 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights