DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
2. The preliminary amendment filed 06/05/2024, that cancelled claims 1-129, amended claims 130, 132-141, and added claims 142-149, is acknowledged. There are no claims withdrawn.
Claims 130-149 are pending in the application and will be examined on the merits.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 02/23/2024 and 01/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
4. Claim149 is objected to because of the following informalities:
- In claim 149, the abbreviation/acronym; RANO is not spelled out.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
5. 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.
Claim 130-139, 141 and 146-149 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while describing ONC-206 and providing limited animal and early-phase human data does not reasonably provide enablement for a person of ordinary skill in the art of how to use/practice the full scope of the claimed methods of treating “one or more CNS neoplasms” with the numerous dosing regimens (e.g., twice daily for one or more days followed by drug holidays of varying length, wide dose ranges, combinations, and monitoring schemes) so as to achieve the broad set of functional clinical outcomes (e.g., progression free survival, overall survival, disease-free survival, disease control rate) across the entire class of CNS tumors, without undue experimentation.
The claims are extremely broad in both disease scope and dosing scope, whereas the disclosure teaches only a narrow set of human clinical regimens. In fact, neither the independent claims (claims 130 and 148) nor the instant specification define the term “subject in need thereof”. Similarly, neither the instant specification nor the instant claims provide a definition of “CNS cancer”. Thus, the claims are construed as referring to any subject animal, human and non-human. The pharmacokinetic (PK) data is determined in a limited animal (e.g., rodents, dogs) population. 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. Claims 130-147 are drawn to a dosing regimen of administering ONC-206 to a subject in need thereof. As noted in paragraph [0013] of applicant’s specification filed on 11/9/2023, ONC-206 has a known utility of treating CNS neoplasms. Thus, the examiner has interpreted the dosing regimen to encompass administration of ONC-206 to a subject having a CNS neoplasm.
It should be noted that claim 141 is directed towards a dosing regimen comprising ultrasound imaging. Although ultrasound imaging is an effective diagnostic tool used to assess a patient’s health/cancer status, it is not a treatment for cancer itself. Therefore, it cannot be a part of a dosing regimen.
Furthermore, instant claims 148-149 are drawn to a method for the treatment of one or more CNS neoplasms/cancers. Independent claim 148 is directed towards a method of treating one or more CNS cancer in a subject in need thereof where the administration of ONC-206 may provide “other objective response”. Dependent claim 149 includes all the limitations of claim 148, which encompasses treatments that yield one or more of the recited outcomes. The limitations of claim 149 limit what is considered for an “objective response” but doesn’t exclude that other outcomes would also be achieved, e.g., any of the other outcomes recited in independent claim 148.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the invention:
The instant invention concerns systemic therapy for recurrent or advanced CNS tumors, an area recognized as complex, heterogeneous, and clinically challenging; treatment response depends on tumor histology, molecular markers, blood-brain barrier penetration, and prior therapies (surgery, radiation, chemotherapy). The majority of recurrent CNS tumors lack effective systemic therapy options following surgical resection and adjuvant radiotherapy (Applicant’s Specification filed 11/09/2023-paragraphs [0002]-[0003], [0008] and [0031]).
Achieving endpoints like progression-free survival and overall survival, as recited in the claims 148-149, requires long-term disease control and reduction of radiographically defined tumor burden accepted criteria (e.g., ≥25% change in enhancing area under RANO or similar thresholds), which are not inherently predictable from in vitro sensitivity or limited single-agent PK data (Wen, Patrick Y et al. “Response Assessment in Neuro-Oncology Clinical Trials.” Journal of clinical oncology: official journal of the American Society of Clinical Oncology vol. 35,21 (2017): 2439-2449-High-Grade Gliomas, paragraph 3 and Pseudoprogression, paragraph 2).
The state of the prior art:
The prior art indicates that ONC-206 was, at the time of filing, in early phase clinical development, with ongoing dose escalation and schedule-finding trials exploring once-weekly and multi-day-per-week oral dosing in selected recurrent CNS tumors (Jazz et al. (Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms; Published: September 1 2020)-Detailed Description paragraph 1-3).
These clinical protocols show that the optimal dose, schedule, and effective tumor types were still being determined through phase I/II experimentation, and that clinicians considered variables such as maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and combination with radiation therapy, underscoring that efficacy across the full breadth of CNS neoplasms and dosing regimens was not established or routine in the art (“Oncology 206: Clinical Trial.” Cancer.gov (2021)).
The relative skill of those in the art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The predictability or lack thereof in the art:
Cancer therapy, particularly for heterogeneous CNS neoplasms, is widely recognized as a relatively unpredictable art; agents effective in one tumor type or line of therapy frequently fail in others, and responses vary widely even within a histological subgroup (Wen, Patrick Y et al. RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults. J Clin Oncol 41, 5187-5199(2023) and Jazz et al. Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms; Published: September 1 2020).
The cited literature on RANO criteria emphasizes variability in tumor measurement and progression assessment, highlighting that even evaluation of response is not straight forward or highly predictable, further underscoring the difficulty of reliably achieving progression-free survival, overall survival, and disease control rate improvements across the many tumor types recited in the claims (Wen, Patrick Y et al. “Response Assessment in Neuro-Oncology Clinical Trials.” Journal of clinical oncology: official journal of the American Society of Clinical Oncology vol. 35,21 (2017): 2439-2449, Abstract and Pseudoprogression paragraph 2).
The breadth of the claims:
The pending claims encompass:
The entire 2021 WHO classification of CNS tumors, including diverse gliomas, embryonal tumors, lymphomas, germ cell tumors, mesenchymal and metastatic tumors (Louis, David N et al. “The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.” Neuro-oncology vol. 23,8 (2021): 1231-1251. Table 1).
Very broad dose ranges (e.g., 5-150 mg; 5-100 mg/kg/day; oral, IV, and other routes) and many different frequencies (multiple times per day through monthly; complex BID-for-X-days followed by Y-day drug holidays).
Functional endpoints such as reduction in tumor size, progression-free survival, overall survival, disease-free survival, disease control rate, objective response and complete response, all measured by criteria such as RANO and RECIST (Raman, Fabio et al. “Evaluation of RANO Criteria for the Assessment of Tumor Progression for Lower-Grade Gliomas.” Cancers vol. 15,13 3274. 21 Jun. 2023, and Wen, Patrick Y et al. “Response Assessment in Neuro-Oncology Clinical Trials.” Journal of clinical oncology: official journal of the American Society of Clinical Oncology vol. 35,21 (2017)).
The breadth of these claims, spanning numerous unrelated CNS malignancies with different biology and standard-of-care therapies, and requiring successful achievement of stringent long-term efficacy endpoints, far exceeds the limited examples and data actually provided, which focus on pharmacokinetic modeling, rodent xenograft studies, and early-phase clinical projections for selected tumor types. The examples disclosed within the specification include specific cancer cell type like H4 glioma cells [0027], astrocytoma cells [Fig. 8], myc-overexpressing CNS tumors [00175], recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas [00176], and neuroblastoma, pheochromocytoma, Ewing sarcoma, high-grade glioma, cholangiocarcinoma and medulloblastoma [00180].
As such, the breadth of the claims is great.
The amount of direction or guidance presented:
The specification provides:
Structural and formulation information for ONC-206 and its salts, including general dosage form and route-of-administration guidance.
Preclinical rat PK and tissue distribution data, in vitro cytotoxicity data, and modeling of plasma concentrations for certain BID regimens.
Limited human PK data (e.g., plasma concentration profiles and projected plasma concentrations following BID dosing for three consecutive days) but not full outcome data demonstrating clinical benefit in the broad range of CNS neoplasms listed. The examples disclosed within the specification include specific cancer cell type like H4 glioma cells [0027], astrocytoma cells [Fig. 8], myc-overexpressing CNS tumors [00175], recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas [00176], and neuroblastoma, pheochromocytoma, Ewing sarcoma, high-grade glioma, cholangiocarcinoma and medulloblastoma [00180].
The disclosure does not, however, provide guidance enabling the skilled person to select, for each CNS tumor type and clinical setting (newly diagnosed vs recurrent, post-radiation timing, combination with other therapies), which of the many claimed doses (mg vs mg/kg), frequencies (from multiple times daily to monthly), drug holiday patterns, and monitoring schemes will reliably yield the claimed outcomes for one or more specific CNS neoplasms in terms of RANO- or RECIST-defined responses, survival endpoints, or disease control rates (Raman, Fabio et al. “Evaluation of RANO Criteria for the Assessment of Tumor Progression for Lower-Grade Gliomas.” Cancers vol. 15,13 3274. 21 Jun. 2023).
Furthermore, the efficacy and toxicity data obtained from pre-clinical in vitro and in vivo studies form the basis for clinical trials. However, limited data obtained from in vitro studies, immortalized cell lines, primary cells isolated from animal/human tissues, for only a few BID regimens is not helpful in enabling the broad scope of treatment/dosing regimen being claimed as it only provides prediction of human pharmacokinetics and pharmacodynamics and not optimal dosing regimens.
The presence or absence of working examples:
The working examples in the specification are primarily:
Animal studies (Sprague Dawley rat PK; xenograft models showing once-weekly dosing without body-weight loss).Applicant’s own data limits predictability of successful treatment as the NOAEL following single-dose administration of ONC206 to Sprague-Dawley rats by oral gavage was determined to be less than or equal to 102.2 mg/kg [00228]. These limitations are disclosed as “overall decrease of food consumption values and body weights over the course of the study” [00233], “hematology and serum chemistry values were outside of normal historical limits” [00234], and “(Animal 2686), there was widespread autolysis of multiple organs to include stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, liver, spleen, mesenteric lymph node, and bone marrow (sternum)” [00235].
In vitro cell-line (pulmonary, Functional Observational Battery (CNS), and cardiovascular readouts [00196] sensitivity panels and mechanistic studies (DRD2 antagonism, ClpP activation, ATF4/CHOP induction).
Projections and limited early clinical PK data, not full-scale clinical outcome data for the claimed regimens and endpoints across all CNS neoplasms.
No specific example demonstrates that administering ONC-206 according to the broad BID-plus-drug-holiday regimens claimed (e.g., twice daily for three or more consecutive days followed by holidays of varying length) actually produces the claimed objective responses, progression-free survival, disease-free survival, or disease control rate in any CNS tumor, much less across the entire WHO classification (Louis, David N et al. “The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.” Neuro-oncology vol. 23,8 (2021): 1231-1251. Table 1).
Note that lack of a working example, is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 130-149.
Consequently, claims 130-139, 141 and 146-149 are rejected for lacking enablement.
Claim Rejections - 35 USC § 102
7. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 130-139, 145, and 146 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jazz et al. (Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms; Published: September 1 2020) herein referred as Jazz.
Regarding claim 130, Jazz teaches a dosing regimen comprising administering to a subject in need thereof a dose of ONC-206: 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4- e]pyrimidin-5(1H)-one (Study Overview, Brief Summary, lines 3-4: “single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms.”), or a salt thereof,
Jazz further teaches twice daily dosing for at least one day followed by a drug holiday of at least one day (What is the study measuring-table replicated below, Maximum Tolerated Dose was determined to be twice daily for 3 days followed by 4 days off, thus meeting at the required twice daily for at least one day followed by a holiday of at least one day).
Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) of single-agent, oral ONC206
MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.
MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in >33% of participants. DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria defined in the subsequent Primary Outcome Measure using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE 5.0).
28 Days
Regarding claim 131, Jazz teaches dosing regimen of claim 130, wherein ONC-206 is administered twice daily for two or more consecutive days followed by a drug holiday of at least one day (What is the study measuring-table included in the rejection of claim 130. Primary Outcome Measures Measure Description, lines 1-2: “MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.” Thus, the drug is administered twice daily for at least two days and off for the rest of the week satisfying the at least one drug holiday condition.)
Regarding claim 132, Jazz teaches a dosing regimen of claim 130, wherein ONC-206 is administered twice daily for two or more consecutive days followed by a drug holiday of at least two consecutive days (What is the study measuring-table included in the rejection of claim 130. Primary Outcome Measures Measure Description, lines 1-2: “MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.” Thus, the drug is administered twice daily for at least two days and off for the rest of the week satisfying the at least two consecutive drug holiday condition.).
Regarding claim 133, Jazz teaches the dosing regimen of claim 130, wherein ONC-206 is administered twice daily for three or more consecutive days followed by a drug holiday of at least two consecutive days (What is the study measuring-table included in the rejection of claim 130. Primary Outcome Measures Measure Description, lines 1-2: “MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.” Thus, the drug is administered twice daily for at least three days and off for the rest of the week satisfying the at least two days drug holiday condition).
Regarding claim 134, Jazz teaches the dosing regimen of claim130, wherein ONC-206 is administered twice daily for three or more consecutive days followed by a drug holiday of at least three consecutive days (What is the study measuring-table included in the rejection of claim 130. Primary Outcome Measures Measure Description, lines 1-2: “MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.” Thus, the drug is administered twice daily for at least three days and off for the rest of the week satisfying the at least three days drug holiday condition.)
Regarding claim 135, Jazz teaches the dosing regimen of claim130, wherein ONC-206 is administered twice daily for three or more consecutive days followed by a drug holiday of at least four consecutive days (What is the study measuring-table included in the rejection of claim 130. Primary Outcome Measures Measure Description, lines 1-2: “MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.” Thus, the drug is administered twice daily for at least three days and off for the rest of the week satisfying the at least four days drug holiday condition).
Regarding claim 136, Jazz teaches the dosing regimen of claim 130, wherein the dose of ONC-206 is from about 5 mg to about 150 mg (What is the study measuring-table, Measure Description, line 2: “increasing doses up to 200 mg”, Detailed description, Para 1, line 1: “dose escalation” and Para 3, lines 3-6: “Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6.”).
It should be noted that claim 136 recites “about” which extends both endpoints of the recited dosage range and thus the range provided by Jazz is within a reasonable range of the dosage required. For claim 136 and claims 137-139 below, although Jazz may not explicitly indicate the dose range between from about 5 mg to about 150 mg of ONC-206, Jazz does indicate 11 Dose Levels increasing dose up to 200 mg without having patient(s) experience DLT (Dose Limiting Toxicity), “If no DLT is reported at a dose level, that dose level will be considered safe, and patient(s) will be enrolled at the next dose level. Toxicity information will continue to be evaluated from the time of the first protocol specific intervention, until 30 days from the last dose of study drug.” (Detailed Description, para. 4, first bullet point) "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II)
Regarding claim 137, Jazz teaches the dosing regimen of claim 130, wherein the dose of ONC-206 is from about 25 mg to about 100 mg (What is the study measuring-table, Measure Description, line 2: “increasing doses up to 200 mg”, Detailed description, Para 1, line 1: “dose escalation” and Para 3, lines 3-6: “Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6.”).
Regarding claim 138, Jazz teaches the dosing regimen of claim 130, wherein the dose of ONC-206 is one of 25 mg, 50 mg, 75 mg, or 100 mg (What is the study measuring-table, Measure Description, line 2: “increasing doses up to 200 mg”, Detailed description, Para 1, line 1: “dose escalation” and Para 3, lines 3-6: “Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6.”).
Regarding claim 139, Jazz teaches the dosing regimen of claim 130, wherein the dose of ONC-206 is 50 mg (What is the study measuring-table, Measure Description, line 2: “increasing doses up to 200 mg”, Detailed description, Para 1, line 1: “dose escalation” and Para 3, lines 3-6: “Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6.”).
Regarding claim 145, Jazz teaches the method of claim 130. While Jazz does not explicitly indicate a value of the target tissue distribution relative to plasma concentrations. It is reasonable to infer that any effective treatment such as one for CNS tumors using ONC-206 would inherently have the property of at least a target tissue distribution relative to plasma concentration of at least 2-fold higher.
Regarding claim 146, Jazz teaches the dosing regimen of claim 130, wherein the treatment relates to a recurrent neoplasm (Title, and Brief Summary, lines 3-4; “recurrent, primary central nervous system (CNS) neoplasms”).
Therefore, claims 131-139 and 145-146 are rejected as being anticipated by Jazz.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 140 and 142-144 are rejected under 35 U.S.C. 103 as being unpatentable over Jazz et al. (Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms; Published: September 1 2020) in view of Mueller et al. (ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC023) Published: January 29 2021); provided by applicant in the IDS submitted on January 17, 2025) herein referred as Mueller.
As to claim 140, Jazz teaches the dosing regimen of claim 130 as discussed above. However, Jazz does not explicitly indicate wherein the regimen further comprises administration of one or more additional therapeutic agent.
Mueller teaches wherein the regimen further comprises administration of one or more additional therapeutic agent (Brief Summary, lines 1-2; “in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the additional (radiation) therapy of Mueller to complement the dosing regimen (of ONC-206) of Jazz. One of ordinary skill in the art would have been motivated to do so in order to achieve optimal results for the treatment of CNS neoplasms by combining known treatments for cancer with ONC-206.
As to claim 142, Jazz teaches the dosing regimen of claim 130 as discussed above. However, Jazz does not explicitly indicate wherein the regimen further comprises radiation treatment, either concomitantly or sequentially in any order.
Mueller teaches wherein the regimen further comprises radiation treatment, either concomitantly or sequentially in any order (Brief Summary, lines 6-8; “in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent primary malignant CNS tumors.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to incorporate the additional (radiation) therapy of Mueller to the dosing regimen (of ONC-206) of Jazz. One of ordinary skill in the art would have been motivated to do so in order to achieve the best possible outcome for the treatment of CNS tumors by combining known treatments for cancer with ONC-206.
As to claim 143, Jazz teaches the dosing regimen of claim 142 as discussed above. However, Jazz does not explicitly disclose wherein the dose of ONC-206 is administered according to one of: a) at least 30 days post-radiation; b) at least 60 days post-radiation; and c) at least 90 days post-radiation.
Mueller teaches wherein the regimen further comprises administration of ONC-206 after four weeks from cytotoxic therapy or 6 weeks from nitrosoureas, a known drug used in chemotherapy and radiation therapy (Eligibility Criteria-inclusion criteria for ARM D).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to incorporate the delay in treatment as taught by Mueller into the teachings of Jazz in order to provide more effective therapy. One of ordinary skill in the art would have been motivated to do so in order to minimize pharmacokinetic interaction.
As to claim 144, Jazz teaches the dosing regimen of claim 130 as discussed above. However, Jazz does not explicitly indicate wherein the dose of ONC-206 is administered according to one of before surgical resection or after surgical resection.
Mueller teaches wherein the dose of ONC-206 is administered according to one of before surgical resection or after surgical resection (Eligibility Criteria, Description, Inclusion Criteria: ARM D, lines 3-4; “Participants who received a surgical resection for that progression are eligible if surgery has no curative intent.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to incorporate the timing of surgical resection component of Mueller’s study to accompany the dosing regimen (of ONC-206) of Jazz. One of ordinary skill in the art would have been motivated to do so in order to provide an ideal timing of administering ONC-206 to the patients and eventually achieve optimal results for the treatment of CNS neoplasms.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bastin et al. (Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities; 2020), which is relevant prior art establishing the reasons and motivations PHOSITA would select or evaluate various salt forms of a potential drug candidate during the drug discovery process.
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/S.I./
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622