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 .
Status of Claims
Claims 1, 4-22, 26-30 are pending.
Priority
Instant application 18/185,225, filed 07/28/2025 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 03/16/2023 and 10/22/2024 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 12/08/2025 has been entered. Claim 30 is amended.
Claim 30 was previously objected to. In view of the amendment to claim 30, applicant has overcome the previous objection. Therefore, the objection to claim 30 is withdrawn.
Claim Rejections - 35 USC § 103
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 1, 4-12, 17-19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Walter et al. (Stem Cells International, vol. 2019, June 2019, pp. 1–11) in view of Weiss (Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, vol. 39, no. 7, Mar. 2021, pp. 797–806).
Walter discloses a method of treating pancreatic ductal adenocarcinoma (PDAC) comprising administering PD-0325901 (mirdametinib) to PDAC cells derived from mice (see abstract, discussion sections):
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Additionally, Walter demonstrated that MEK inhibitors administered to mice significantly reduced the number of circulating tumor cells (“CTCs”) in vivo (page 9, section 3.5 “MEK Inhibitors Prevent Organoid Formation and Decrease CTCs In Vivo”). Further, Walter teaches administering mirdametinib as a monotherapy (see pg. 2, “Materials and Methods”, PD0325901 was used at 0.5 μM (5493 cells) or 5 μM (8926 and 9228 cells).
With respect to claim 1 and 4-12, Walter fails to teach administering mirdametinib to a human patient or a dose/dosing regimen for administering mirdametinib to human patients.
However, administration of mirdametinib to human patients and dosing regimens for the same were previously known in the prior art. For example, Weiss discloses results from a Phase II clinical trial of mirdametinib in adolescents and adults with NF1-related neurofibromas. The proposed mechanism of action is inhibition of the MAPK/ERK (MEK) pathway (see pg. 797, “Introduction”). Patients received mirdametinib orally twice a day at 2 mg/m2/dose (maximum dose of 4 mg BID) in a three-week on/one-week off sequence (see pg. 798, “Therapy”). Treatment with mirdametinib at this dosing regimen was demonstrated to be active and safe, and achieved a 42% partial response rate (see pg. 798, “Knowledge Generated”).
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter with the dosing regimen disclosed by Weiss to arrive at the method of instant claims 1 and 4-12. A skilled artisan would have enjoyed a reasonable expectation that the dosing regimen for mirdametinib taught by Weiss would result in treatment of a human patient having PDAC when administered to said patient in view of Walter’s teachings.
Claims 4, 6, 8, 10, and 12 recite a different dose of mirdametinib or a different daily dosing frequency than the dose and daily dosing frequency disclosed by Weiss (2 mg/m2/dose twice daily). However, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the daily dose of mirdametinib and the daily dosing frequency are result-effective variables that impact, for example, the amount of tumor shrinkage, or the occurrence of side effects as taught by Weiss. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization. Further, Weiss discloses adjusted doses (see Table A2).
With respect to claim 17, Weiss teaches administering mirdametinib in a 3-week on/1-week off sequence (see pg. 798, “Methods”).
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter with the dosing regimen disclosed by Weiss to arrive at the method of instant claim 17. A skilled artisan would have reasonably predicted that the dosing regimen for mirdametinib taught by Weiss would result in treatment of a patient having PDAC when administered to said patient in view of Walter’s teachings. .
With respect to claim 18, Weiss teaches administering mirdametinib to patients at ages in the range of 16 to 39 years old (see Table 1), which overlaps with the recited age range of ≥2 and< 25. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP 2144.05.
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter with the patient age range disclosed by Weiss to arrive at the method of instant claim 18. A skilled artisan would have reasonably predicted that patients having PDAC in the age range taught by Weiss would be treated when administered mirdametinib in view of Walter’s teachings.
With respect to claim 19, Weiss teaches administering mirdametinib to patients having no prior exposure to MEK inhibitors (see Table A1; Exclusion criteria – prior treatment with any MEKi).
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter with patients having no prior exposure to MEK inhibitors disclosed by Weiss to arrive at the method of instant claim 19. A skilled artisan would have reasonably predicted that PDAC patients having no prior exposure to MEK inhibitors taught by Weiss would be treated when administered mirdametinib in view of Walter’s teachings.
With respect to claim 22, Weiss teaches administering mirdametinib orally (see pg. 798, “Methods”).
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter with the mode of administration (oral) disclosed by Weiss to arrive at the method of instant claim 22. A skilled artisan would have reasonably predicted that PDAC patients would be treated when orally administered mirdametinib as taught by Walter in view of Weiss.
Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Walter in view of Weiss as applied to claims 1, 4-12, 17-19, and 22 above, and further in view of Georgiev ("Body Surface Area Calculator", www.gigacalculator.com/calculators/bsa-calculator.php).
The teachings of Walter in view of Weiss are disclosed above and at least those teachings are incorporated herein by reference.
With respect to claims 13-14, Walter in view of Weiss teaches the method of claim 1 but fails to teach a specific body surface area (BSA) of the patient receiving the dose (2 mg/m2 BID).
However, accounting for patient BSA in chemotherapy dosing regimens is known in the prior art. For example, Georgiev discloses mean BSA values by age and gender (see Tables).
A person having ordinary skill would have recognized that based on the average BSA values taught by Georgiev for the patient ages of Weiss (16-39 years; see Table 1), Weiss teaches that for patients having a BSA in the range of 1.74 m2 to 2.07 m2, the patients were initially orally administered between 3.5 to 4.1 mg mirdametinib twice daily. These BSA and dose ranges overlaps with the amounts in the limitation: for a patient having a body surface area of at least 1.5 m2, the patient is initially orally administered 4 mg mirdametinib twice daily of instant claim 13. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP 2144.05.
Instant claims 13-14 recite a different dose of mirdametinib for different BSA ranges from the dose and BSA range taught by Weiss in view of Georgiev. However, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the dose of mirdametinib administered to a patient having a particular BSA is a result-effective variable that impact, for example, the amount of tumor shrinkage, or the occurrence of side effects as taught by Weiss. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
With respect to claims 15-16, Weiss teaches reducing the dose due to an adverse event, and teaches acneiform as an adverse event. Table A2 of Weiss teaches the dose reduction protocols recited in (b), (c), and (d) of instant claim 15; Table 3 teaches acneiform.
Applying KSR example rationale (A), it would have been prima facie obvious to combine the method of treating PDAC taught by Walter in view of Weiss and Georgiev with the dose reduction after an adverse event, wherein the adverse event is acneiform taught by Weiss to arrive at the method of instant claims 15-16. A skilled artisan would have reasonably predicted that PDAC patients having an adverse reaction to mirdametinib would be more effectively treated by reducing the dose in response to the adverse event.
Dose reduction protocol (a) in instant claim 15 recites different initial and reduced doses from the doses taught by Weiss. However, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the initial and reduced doses of mirdametinib administered to a patient after an adverse event are result-effective variables that impact, for example, the recurrence of the adverse event and/or reduction of tumor size. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
Claims 20-21, 26, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Walter in view of Weiss as applied to claims 1, 4-12, 17-19, and 22 above, and further in view of Xu (WO 2021051135 A1; effectively filed September 12, 2019).
The teachings of Walter in view of Weiss are disclosed above and at least those teachings are incorporated by reference herein.
With respect to claims 26 and 29-30, Walter in view of Weiss teaches the method of claim 1, but fails to teach administering mirdametinib in combination with one or more autophagy inhibitors or PIKfyve inhibitors.
However, co-administration of MEK inhibitors and autophagy inhibitors was previously known in the prior art. For example, Xu teaches a method of treating cancer comprising administering a pharmaceutical composition comprising a PIKfyve inhibitor (apilimod), which is an autophagy inhibitor, and PD-0325901, which is mirdametinib (see claims 1, 4, 9, 11, and 22; and para. [117]). Xu also teaches the other PIKfyve inhibitors vacuolin-1, APY-0201, and YM201636 as recited in instant claim 30.
Applying KSR example rationale (G), it would have been prima facie obvious to co-administer a PIKfyve inhibitor, such as apilimod taught by Xu, with mirdametinib in the method of treating PDAC taught by Walter and Weiss. A person having ordinary skill in the art would have been motivated to co-administer an autophagy inhibitor with mirdametinib because, as taught by Xu, autophagy is one mechanism by which cancer cells may enhance their survival (see para. [25]). Further, Xu teaches that the combination of apilimod with MEK inhibitors has a synergistic effect for treating cancer (see, e.g. para. [127], Table 5).
With respect to claims 20-21, Walter in view of Weiss teaches the method of claim 1, but fails to teach administering mirdametinib to a patient having one or more KRAS mutations.
However, Xu teaches (see e.g. para. [43]) treating cancers characterized by an activating KRAS mutation, including KRAS mutations selected from KRAS G12(V, C, S, R, D, N, A), G13(D, C, R), Q22K, Q61(H, L, R), K117N and A146(T/V). In some embodiments, the activating KRAS mutation is selected from KRAS G12S, G12D, and G12C.
Applying KSR example rationale (G), it would have been prima facie obvious to co-administer a PIKFyve inhibitor, such as apilimod, with mirdametinib to a patient having an activating KRAS mutation in the method of treating PDAC taught by Walter and Weiss. A person having ordinary skill in the art would have been motivated to co-administer a PIKFyve inhibitor with mirdametinib to a patient having an activating KRAS mutation because point mutations in KRAS are known oncogenic drivers in PDAC.
Claims 20-21 and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Walter in view of Weiss as applied to claims 1, 4-12, 17-19, and 22 above, and further in view of Bryant (Nature Medicine, vol. 25, no. 4, Apr. 2019, pp. 628–40).
The teachings of Walter in view of Weiss are disclosed above and at least those teachings are incorporated herein by reference.
With respect to claims 27-28, Walter in view of Weiss teaches the method of claim 1, but fails to teach administering mirdametinib in combination with one or more autophagy inhibitors or ULK inhibitors.
However, co-administration of MEK inhibitors and ULK inhibitors to treat PDAC was previously known in the prior art. Bryant teaches that co-administering the MEK inhibitor binimetinib with the autophagy inhibitor hydroxychloroquine synergizes to reduce proliferation in human PDAC cells (see Fig. 7 and pg. 634, “ERK inhibition enhances dependence on autophagy”). Additionally, Bryant teaches autophagy inhibitors SBI-0206965 and MRT68921, which are ULK inhibitors, as equivalents as chloroquine for reducing proliferation of PDAC cell lines (see pg. 636, para. 1):
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Applying KSR example rationale (G), it would have been obvious to co-administer an autophagy inhibitor (such as hydroxychloroquine, or the ULK inhibitors MRT or SBI) taught by Bryant, with mirdametinib in the method of treating PDAC taught by Walter and Weiss. A person having ordinary skill in the art would have been motivated to co-administer an autophagy inhibitor with mirdametinib because, as taught by Bryant, autophagy inhibitors synergized with MEK inhibitors to inhibit PDAC tumor growth.
With respect to claims 20-21, Walter in view of Weiss teaches the method of claim 1, but fails to teach administering mirdametinib to a patient having one or more KRAS mutations.
However, Bryant teaches (page 629, left side, “Results”) that basal levels of autophagy are very high in KRAS-mutant PDAC, including KRAS G12C; and that suppression of KRAS increased autophagic flux in KRAS-mutant PDAC cell lines.
Applying KSR example rationale (G), it would have been prima facie obvious to co-administer an autophagy inhibitor with mirdametinib to a patient having an activating KRAS mutation in the method of treating PDAC taught by Walter and Weiss. A person having ordinary skill in the art would have been motivated to co-administer an autophagy inhibitor with mirdametinib to a patient having an activating KRAS mutation because Bryant teaches synergistic antitumor activity when MEK inhibitors are administered in combination with autophagy inhibitors to mutant KRAS mouse models of PDAC.
Response to Arguments
In response to the rejection of the instant claims as obvious over Walter in view of Weiss, Applicant traverses the rejection and argues the following (see Remarks 12/08/2025, page 11):
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In summary, Applicant argues that because Weiss is drawn to treating NF-1 related plexiform neurofibromas with mirdametinib, which is a different disease from PDAC, a person having ordinary skill in the art would not have applied the dosing regimen of Weiss to the method of treating PDAC taught by Walter. Applicant's arguments have been fully considered but they are not persuasive.
Walter demonstrated that MEK inhibitors administered to mice significantly reduced the number of circulating tumor cells (“CTCs”) in vivo (page 9, section 3.5 “MEK Inhibitors Prevent Organoid Formation and Decrease CTCs In Vivo”). Further, Walter disclosed that mirdametinib-mediated MEK inhibition in vitro impaired the invasion and migration capacities of PDAC cells; and compromised the growth and survival of the cells.
A skilled artisan could have identified suitable prior art dosing regimens of mirdametinib in humans as a starting point for optimization. A skilled artisan would have identified Weiss, which discloses that “Mirdametinib was safe and tolerable at the doses used in this clinical trial” (page 804, col. 2, 3rd para.). While the disease treated in Weiss is not PDAC, a skilled artisan would have recognized that the dose was safe and tolerable, and therefore could be a useful starting point in optimizing the dose based on surface area to treat PDAC in view of Walter’s teachings.
Differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the dose/dosing regimen of mirdametinib is a result-effective variable that impacts, for example, the occurrence adverse side effects in a patient. See, for example, Weiss (page 804, col. 2, 3rd para.) which states that dose reductions occurred in 26% of patients for non-severe side effects like grade 1 rash. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
Please note that the instant application (see Example 1) only provides in vitro data evaluating the synergy of mirdametinib + apilimod against a panel of PDAC cell lines. No evidence is presented in the instant specification for administering mirdametinib based on a dose adjusted to the body surface area of a human patient.
Applicant additionally argues that the study described in Weiss specifies exclusion criteria including impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of mirdametinib; and alleges that PDAC is a disease which “can affect absorption from the GI tract” (Remarks, page 8, second paragraph). In summary applicant appears to be arguing that Weiss teaches away from administering mirdametinib to a patient having PDAC based on the exclusion criteria in Weiss.
Applicants’ arguments have been fully considered but are not found persuasive. Please note that the Remarks referenced a Table A1 in Weiss, which could not be identified in the copy of Weiss cited in the current record. Additionally, Applicant references a Murray et al., which is also not present in the current record. Further, based on the citation provided by applicant, Murray published after the filing date of the instant application (published 2024).
See MPEP 2145(I) in this regard: “Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (‘An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.’).”
Moreover, the quoted passage merely reads “PDAC commonly leads to reduced exocrine pancreatic function and may impair absorption of nutrients.” The teaching that PDAC may impair absorption of certain nutrients is not objective evidence that PDAC was known by the person of ordinary skill to impair absorption of mirdametinib before the earliest priority date of the instant application. The quoted passage is not persuasive evidence that a person having ordinary skill, reading Weiss alone or in combination with Murray, would have been dissuaded from pursuing treating a human patient having PDAC with mirdametinib as taught by the combination of references cited in the rejection.
Conclusion
Claims 1, 4-22, and 26-30 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 Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621