DETAILED 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 .
Election/Restrictions
Applicant’s election of brain cancer as the elected cell proliferative disease or disorder and NS1643 as the elected one or more therapeutic agent in the reply filed on 08/06/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
During a telephone conversation with Therese Finan on 09/24/2026 a provisional election was made to elect NS1643 as one or more therapeutic agent without specifying traverse instead of the election of NS1643 and the one or more therapeutic agent as set forth in the response to election requirement submitted on 08/05/2026
Claims 17, 19-20, 23, 25-26, 29-30, 32-33, 35-36, 40, 49, and 53-54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Priority
This application is the national stage entry of PCT/US22/81589, filed December 14, 2022, which is based on, and claims priority to U.S. Provisional Application No. 63/265,403, filed on December 14, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/22/2024 has been considered by the examiner.
Status of Claims
Claims 1-3, 15, 17, 19-20, 23, 25-26, 29-30, 32-33, 35-36, 40, 49, and 53-54 are pending. Claims 4-14, 16, 18, 21-22, 24, 27-28, 31, 34, 37-39, 41-48, 50-52, and 55-62 are canceled. Claims 17, 19-20, 23, 25-26, 29-30, 32-33, 35-36, 40, 49, and 53-54 are withdrawn. Claims 1-3 and 15 are examined in accordance to the elected species.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for selected therapeutic agents and combinations under the disclosed cell-culture, and tumor-tissue conditions, including inhibition of U87-cell proliferation and modulation of membrane potential by NS1643, does not reasonably provide enablement for the full scope of the claimed methods for treating a cell proliferative disease or disorder in a subject by administering an effective amount of the recited poloarity-modulating therapeutic agent (the elected NS1643) without experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The deficiency concerns the guidance for selecting and using therapeutically operative agent–disease combinations across the claimed scope. In particular, the claims extend beyond the identified compounds, cell systems, tumor tissues, and treatment conditions studied in the disclosure, while retaining functional requirements of channel activation or inhibition, cancer-cell polarity modulation, and effective treatment in a subject. The disclosed experimental findings and general administration guidance do not establish a sufficiently predictive relationship among these functions across that breadth. The following analysis explains the basis for this conclusion and accounts for evidence supporting enablement.
Applicable standard
Enablement is assessed from the disclosure and knowledge of a person of ordinary skill at the relevant filing date. Reasonable experimentation is permitted. The relevant factors include claim breadth, the nature of the invention, the state of the art, skill level, predictability, guidance, working examples, and the quantity of experimentation. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988); MPEP §§ 2164.01(a), 2164.04, and 2164.08. Functional limitations define the scope that must be enabled; they do not automatically supply instructions for obtaining the required results. Amgen Inc. v. Sanofi, 598 U.S. 594, 610–13 (2023). An example for every embodiment, clinical approval, and universal patient response are not required. In vitro evidence may support a therapeutic use through a reasonable correlation; an absence of in vivo experiments is not, by itself, dispositive. MPEP §§ 2164.01(c) and 2164.02. The Office must explain its reasonable basis for finding undue experimentation rather than merely demand further proof of efficacy.
Claim construction and functional scope
Claim 1 requires treatment of a cell proliferative disease or disorder in a subject in need thereof, administration of an effective amount of one or more therapeutic agents, and the functional property that the therapeutic agent modulates the polarity of a cancer cell. The recited alternatives are potassium-channel activators, sodium-channel inhibitors, calcium-channel inhibitors, proton-pump inhibitors, and combinations thereof. The construction used here treats the agent, rather than the cancer cell, as selected from those pharmacological classes.
Channel activation or inhibition and proton-pump inhibition describe pharmacological functions, not a closed list of chemical structures in claim 1. Thus, the claim is not confined to the particular agents tested. Nevertheless, a compound falls within the claimed therapeutic method only when the remaining limitations are also satisfied. A channel-active compound that cannot meet the polarity or treatment requirements is not treated as an operative embodiment merely because it belongs to one listed class.
The polarity limitation is understood in the context of the disclosed membrane-potential experiments. The claim says modulates, rather than requiring a particular magnitude, duration, or direction of membrane-potential change. It does not expressly require permanent hyperpolarization, terminal differentiation, senescence, a particular YAP response, or a cure. These experimental endpoints may support the therapeutic rationale, but they are not added as claim requirements. Nor does the claim expressly require that polarity modulation be the exclusive causal mechanism of treatment. The pertinent question is whether the required properties and therapeutic result can be obtained together across the claimed scope.
The effective-amount limitation requires a therapeutically meaningful pharmacological response, not merely an amount that can be formulated or changes an assay signal. Paragraph [073] expressly recognizes that an effective dosage need not work in every patient. Accordingly, occasional nonresponse and patient heterogeneity are not themselves grounds for rejection. Their significance is whether the disclosure and art provide a practical way to identify and implement operative uses without undue experimentation.
The method uses comprising and permits one or more agents. It therefore encompasses qualifying single-agent and combination treatments and does not require NS1643 to be the sole active ingredient. Conversely, a promising combination does not necessarily establish how to perform a claimed single-agent treatment. The analysis does not demand that every possible added ingredient, ineffective dose, or antagonistic mixture work.
Claim 2 depends from claim 1 and specifies potassium channels selected from KCNQ/Kv7, K(ATP), hERG, KCNK3, BK, and SK. Its additional restriction narrows the channel targets but does not select a single disease, compound, or therapeutically operative treatment condition. The analysis concerns the potassium-activator branch identified by this dependent claim; it does not assume that every other pharmacological class must activate these channels.
Claim 3 depends directly from claim 1 and specifies one or more of retigabine, minoxidil, NS1643, ONO-RS-082, and chlorzoxazone as potassium-channel activators. The named alternatives substantially narrow compound selection, which favors enablement. However, claim 3 retains the disease and functional treatment breadth inherited from claim 1. The rejection of claim 3 therefore cannot rest solely on the structurally open genus in claim 1.
Claim 15 also depends directly from claim 1. It identifies brain, prostate, breast, lung, colorectal, bladder, kidney, uterine, pancreatic, ovarian, liver and intrahepatic bile duct, oral cavity, and esophageal cancers, as well as melanoma, lymphoma, and leukemia. It retains claim 1’s agent alternatives. Claim 15 does not inherit claim 3’s compound list, and claim 3 does not inherit claim 15’s cancer list. The election of brain cancer and NS1643 does not rewrite these separate claim dependencies.
Disclosure and evidence favorable to enablement
The specification provides an experimental screening approach rather than only a proposed therapeutic hypothesis. Paragraphs [163]–[166] describe investigation of hyperpolarizing drugs, individually and with other agents, using cell-proliferation and recovery experiments. The methods provide concrete tools for evaluating candidates. This guidance reduces the work needed to reproduce the reported experiments and must be credited in assessing the experimentation remaining.
Most importantly for the elected species, paragraph [190] and Figure 4 report that NS1643 alone at 50 micromolar significantly decreased proliferation of human U87 glioblastoma cells after six days, with a reported 1.7-fold decrease relative to control. The same paragraph reports stronger effects with pantoprazole, rapamycin, or temozolomide. Paragraph [203] and Figure 16 report significant U87 hyperpolarization with NS1643 alone and with pantoprazole. These findings support both a relevant cellular therapeutic response and the polarity-modulating property; the Office does not characterize the single-agent evidence as absent.
Paragraphs [204]–[205] and Figure 17 describe testing in human neuronal cells. This adds information relevant to selectivity and tolerability, although a short cell-based assessment does not resolve exposure and response across the claimed treatments. The significance assigned to this evidence is proportionate to what was tested; it is not dismissed merely because it is not a whole-animal experiment.
Example 4, paragraphs [432]–[436], Table 3, and Figures 21–51 additionally describe breast- and colorectal-tumor tissue testing, including NS1643 alone and selected combinations. The tissue platform preserves microenvironmental features and is presented as clinically predictive. Responses varied; rapamycin–minoxidil showed favorable population trends. This is substantive evidence and a potential selection method, not merely a list of desired results. However, its demonstrated reach does not by itself encompass all claimed channel classes, agents, and diseases. Its routine applicability across that broader scope is a material issue in assessing the proposed rejection.
Paragraphs [141]–[153] provide pharmaceutical formulations, broad dosage ranges, schedules, and administration routes. Paragraph [141], for example, provides composition amounts and daily dose ranges, and paragraph [151] identifies oral, intravenous, intramuscular, subcutaneous, topical, and pulmonary administration. Therefore, the concern is not a complete absence of dosage or route instructions. The concern is the extent to which these general choices teach effective use for the claimed agent–disease pairings.
Fukushiro-Lopes et al., Oncotarget 9:3321–3337 (2018) cited in the IDS, Results, Figure 3, and Materials and Methods, reports reduced breast-tumor growth with NS1643 at 6 mg/kg intraperitoneally every two days in a mouse flank xenograft model. Its Discussion links channel stimulation to hyperpolarization and downstream growth suppression. This supports known administration and antitumor activity. The lower-dose result does not prove nonenablement because the claims require an effective amount. The study does not establish intracranial exposure or brain-tumor efficacy. Nevertheless, it weighs against any allegation that animal administration of NS1643 was unavailable or wholly speculative.
Ben-Hamo et al., Nature Communications 11:3296 (2020), Results and Figure 5, supplies concrete support for ex vivo organ-culture methods. It studies vinorelbine and ABT-263 in lung-cancer tissue, including explanted xenografts and fresh human tumor tissue. Its Methods describe preparation, treatment, and viability scoring. This supports the availability of a meaningful screening technique. It does not itself validate NS1643 or the claimed polarity-based therapeutic classes across brain cancers. The distinction concerns the demonstrated reach of the assay, not a categorical requirement for in vivo confirmation.
Technical basis for the scope concern
First, a common pharmacological label does not supply a demonstrated common therapeutic response. Paragraph [195] reports that agents which individually hyperpolarized NG108-15 cells produced different electrical responses in certain combinations: pantoprazole with retigabine or rapamycin produced depolarization, while combinations with lamotrigine or NS1643 did not observably change membrane potential relative to control. Paragraph [221] discusses reduced proliferation in combinations without the expected hyperpolarization. These observations show that the electrical response to a regimen cannot simply be inferred by adding the known responses of its ingredients.
These results do not prove that the active combinations are outside the claims, and do not establish that a therapeutic mechanism must be fully understood. They do bear on whether polarity modulation supplies a reliable general rule for extending the disclosed findings to the claimed functional classes. Paragraph [203] further distinguishes NS1643-alone effects from combination-associated YAP changes. The data therefore support selected responses under defined conditions, while leaving the extent of their generalization dependent on additional empirical assessment.
Second, the relevant channel can participate differently in different tumor contexts. Staudacher et al., PLoS ONE 9:e88164 (2014), Abstract and Introduction, reports glioblastoma-cell apoptosis associated with reduced hERG protein and reproduces the effect through hERG knockdown. Fukushiro-Lopes reports benefit from hERG stimulation in breast cancer. These are different interventions, not evidence that NS1643 is a blocker. Their contrast cautions against inferring a uniform treatment rule merely from hERG expression. It does not prove activation cannot treat glioblastoma or negate Applicant’s positive U87 results.
Third, extending the particular glioblastoma culture findings to the claimed brain-cancer scope raises specific questions of model representativeness. Lenting et al., Acta Neuropathologica 133:263–282 (2017), p. 269, under Human glioma cell lines: conventional cell cultures, discusses culture-associated genetic changes and drift in U87 and related lines. The reference also expressly recognizes their usefulness for reproducible pathway studies and drug prescreening. The appropriate inference is that U87 provides meaningful but bounded evidence; neither U87 nor NG108-15 is categorically rejected as incapable of supporting a therapeutic use.
Lenting, p. 267, addresses features relevant to preclinical model selection, including genetic background, heterogeneity, and the tumor environment. At p. 275, in its discussion of antiangiogenic studies, it contrasts the bulky, demarcated tumors and disrupted blood–brain barrier often obtained with orthotopic U87 models with diffuse infiltrative glioma. That passage illustrates a model-dependent exposure and growth-pattern concern. It is not an NS1643 experiment and is not relied upon as proof that NS1643 cannot cross the blood–brain barrier.
Additional evidence of the influence of the tumor environment is provided by Camphausen et al. (PNAS 102 (23):8287-8192 (2005)) compared U87 and U251 cell growth in vitro with subcutaneous and intracerebral xenografts and found significant differences in gene-expression profiles among those conditions. See p. 8287, Abstract. These findings support the concern that a response observed in cultured U87 cells cannot be assumed to remain unchanged in the intracranial environment.
For the presently claimed methods, the relevant question is whether the disclosure and knowledge in the art permit the required polarity-modulating activity and therapeutic response to be obtained together across the claimed scope through reasonable experimentation. Camphusen supplies evidence of environment-dependent biological differences but does not establish NS1643 is ineffective in vivo. Considered with the specification’s treatment-dependent polarity and proliferation findings, the reference supports examining whether the disclosed screening results provide sufficiently predictive guidance for the broader therapeutic uses. It is relied upon as a factor bearing on predictability, rather, that as an independent, rather than as an independent showing of undue experimentation or a categorical requirement for animal testing.
Fourth, the general dose and formulation teaching must be considered together with therapeutic selection. Reproducing a culture concentration is not itself an instruction for achieving a therapeutically useful concentration and duration in the relevant tumor tissue. However, routine pharmacokinetic and dose-finding work is not automatically undue. The scope concern arises where the artisan must first establish which of the broadly recited agents, disease settings, and functional responses produce treatment, and then develop conditions for obtaining that response in a subject. The repeated need to resolve that therapeutic relationship is more significant than an omitted numerical dose by itself.
Experimentation implicated by the claims
For an agent–disease pairing beyond the supported experimental settings, the remaining inquiry can include determining whether the agent produces the claimed cancer-cell polarity effect in the relevant tumor context; whether an exposure producing that effect also provides treatment; whether the effect is retained or altered in the proposed combination; and whether effective tumor exposure can be achieved with a suitable regimen. These are connected inquiries. A positive target-activity assay does not necessarily resolve cell-level polarity, and a cell-level polarity result does not necessarily resolve therapeutic response or exposure in a subject.
The proposed undue-experimentation inference rests on the need to establish these relationships repeatedly across heterogeneous functional classes and disease settings, without a sufficiently established rule connecting the screening result to the claimed therapeutic use throughout that scope. It does not rest on counting all conceivable drug–cancer combinations or requiring tests on every patient. Nor is the mere use of screening objectionable. The issue is whether the disclosed screening and tissue assays permit reasonable selection and implementation across the claim, or instead leave a substantial program of discovering which therapeutic uses can be performed.
Application of the Wands factors
Breadth of the claims. Claim 1 encompasses multiple functionally defined pharmacological classes, individual and combination regimens, and a broad therapeutic indication. Claim 2 restricts channel families but retains broad therapeutic use. Claim 3 substantially restricts compound identity but does not confine use to the supported disease settings. Claim 15 restricts diseases to an enumerated group while retaining the broad agent classes. These differences must be weighed; the narrower dependent claims are not rejected merely because claim 1 is broad.
Nature of the invention. The methods require pharmacological activity, cancer-cell polarity modulation, and effective treatment in a subject. The evidence discussed above shows that these properties are not interchangeable measurements and that combinations can alter electrical and biological responses. The scope issue concerns their practical conjunction, without imposing a requirement to prove one exclusive mechanism.
State of the prior art. The art provides known agents, channel assays, experimental cancer models, and some animal antitumor evidence. Those teachings assist practice and weigh in favor of enablement. The target-dependent and model-dependent findings discussed above nevertheless limit a simple extrapolation from channel classification or expression to therapeutic effect across the claims.
Level of skill. A person skilled in cancer pharmacology, with access to electrophysiological, cell-based, formulation, and preclinical techniques, would be capable of performing substantial routine work. The proposed rejection does not rely on inability to operate those techniques. Skill in performing an assay, however, must be distinguished from possessing sufficient guidance to identify and implement the claimed therapeutic uses across the functional breadth.
Predictability. The specification’s different responses to individual agents and combinations, together with the context-dependent hERG and glioma-model evidence, support reduced predictability of extrapolation. Camphausen further supports this concern by demonstrating that growth environment affects U87 gene expression, although that finding does not itself establish a change in NS1643 sensitivity. See p. 8287, Abstract, They do not establish absolute unpredictability. The positive single-agent and tissue results remain evidence favoring particular applications.
Direction and guidance. The disclosure provides concentrations, screening procedures, markers, formulation options, and administration choices. Its guidance is strongest for reproducing the experimental systems. The deficiency asserted is the lack of a sufficiently predictive selection and translation rule for the broader therapeutic scope, rather than an absence of any procedural teaching.
Working examples. The NG108-15, U87, neuronal-cell, and tumor-tissue studies provide substantial experimental support. The appropriate weight depends on the reasonable correlation of those systems with the use asserted. They are not disregarded for lack of animal testing, and their success is not treated as proof that all claimed classes and disease settings can be reached through routine extension.
Quantity of experimentation. No unsupported numerical estimate of experiments, years, or expense is asserted. The burden derives from the kinds of questions left open and their recurrence across the claimed scope. The proposed conclusion is that the artisan must perform more than confirmation or adjustment of a reliably taught treatment principle: the artisan must establish which functional agent–disease relationships can deliver the claimed treatment and then determine workable conditions for those relationships. This conclusion must be evaluated against the disclosed assays’ practical ability to reduce that burden.
Application to the dependent claims and conclusion
Claim 2’s identification of channel families does not itself explain which activators produce the required polarity and therapeutic responses in the broad disease scope. The record does not justify treating findings for hERG activation as a uniform treatment rule for KCNQ/Kv7, K(ATP), KCNK3, BK, and SK. The rejection concerns that functional extension, not the mere existence of multiple channel names.
For claim 3, known compound identity reduces the selection burden. The remaining asserted deficiency is the extension of those named agents to the inherited therapeutic scope, including the broad brain-cancer uses encompassing the elected species. Positive NS1643 findings do not automatically teach the corresponding uses of every named activator. Conversely, the Office does not conclude that all five agents lack enabled uses or that a nonresponsive candidate alone defeats the claim.
For claim 15, the listed cancers narrow the disease genus but still encompass distinct therapeutic settings. The breast- and colorectal-tissue evidence must be credited alongside the U87 results. The asserted deficiency concerns extending the functionally defined agent classes across the remaining scope without sufficient therapeutic selection guidance, rather than the absence of an example for every listed cancer.
Considering the foregoing factors together, the proposed rejection concludes that the specification provides meaningful experimental support for selected agents and regimens but does not provide commensurate guidance for identifying and implementing treatments across the full functional scope of claims 1–3 and 15 without undue experimentation. No particular in-subject treatment is affirmatively designated as an enabled subset, and no conclusion of universal inoperability is made. Applicant may address this rejection through an explanation of how the disclosure and filing-date knowledge permit the claimed scope to be practiced through reasonable experimentation, supporting evidence, or an appropriate amendment; new clinical or animal experiments are not categorically required.
Conclusion
Claims 1-3 and 15 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
