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 .
DETAILED ACTION
Claim status
Claims 35-64 are pending. Claims 40, 45, 59 and 64 are withdrawn. Therefore, Claims 35-39, 41-44, 46-58 and 60-63 are examined on the merits.
Election/Restrictions
Applicant’s election of (i) adult patients with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas and a body surface area of at least 1.5 m2 as the patient population and (ii) initially administering 4 mg mirdametinib twice daily as the treatment regimen in the reply filed on 12/12/2025 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)).
Claims 40, 45, 59 and 64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2025.
Therefore, Claims 35-39, 41-44, 46-58, and 60-63 are examined on the merits.
Priority
The present application claims the benefit of U.S. Provisional Application Nos. 63/663,853, filed June 25, 2024, and 63/754,168, filed February 5, 2025.
Information Disclosure Statement
The Information Disclosure Statements filed 6/13/2025, 7/24/2025 and 12/15/2025 have been considered by the Examiner. The submissions are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Rejections - 35 USC § 112 – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 35, 47, and 54 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 35 and 54 contain limitations in parentheses; however, it is unclear whether the parenthetical content is intended to be limitations or merely examples. Further, the actual phrase inside the parentheses - “e.g., a patient with NFl who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection” - renders the claim indefinite because the text “e.g.,” makes it unclear whether the limitations following it are part of the claimed invention. See MPEP § 2173.05(d).
Claim 47 is objected to as being unclear in form because multiple lesion types and associated functional characteristics are recited in a single clause in a manner that renders the scope difficult to ascertain on the first reading. The claim is otherwise definite. Applicant is advised to amend the claim to separately recite the different lesion categories and their associated characteristics for clarity.
Claim Rejections - 35 USC § 112 – Scope of enablement
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 35-39, 41-44, 46-58, and 60-63 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 slowing down or lessening plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), does not reasonably provide enablement for treating NF1-PN. 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 test of enablement requires a determination of whether the disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Claim 1 broadly recites:
“a method of treating plexiform neurofibromas associated with neurofibromatosis type 1 by administering mirdametinib”
However, at 0232 of US PG-Pub 2025/0387356 A1 (instant application’s publication), the terms “treat,” “treated,” and “treating” are define to mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Thus, the claims are broadly drawn to treating – defined to encompass prophylactically preventing – NF1-PN by administering mirdametinib. This is claimed despite the lack of sufficient support for prevention/prophylaxis of NF1-PN whether in vitro or in vivo.
The state of the art does not support the capability to prevent or prophylactically treat NF1-PN as contemplated by the specification and the claims.
The nature of the invention:
The invention relates to a method of treating (as defined broadly) NF1-PN mirdametinib. Treatment is defined broadly to include not only therapeutic intervention, but also prophylaxis and prevention, i.e., inhibiting or stopping NF1-PN before it arises. The invention is not particularly based on a specifically identified mechanism of action that has been predictively demonstrated preventative/prophylactic intervention of NF1-PN as contemplated. Thus, the claims encompass embodiments that are not enabled by the as-filed specification.
Breadth of claim:
The breadth of the claims is broad insofar as encompassing embodiments purported to prevent NF1-PN from arising.
State and predictability of the art:
Neurofibromatosis 1-associated plexiform neurofibromas (NF1-PN) is caused by a genetic mutation that is either inherited or occurs spontaneously at conception. There is currently no known method to prevent this genetic change from happening. See Boston Children’s Hospital (Neurofibromatosis. © 2005-2026 Boston Children’s Hospital. All rights reserved. https://www.childrenshospital.org/conditions-treatments/neurofibromatosis#:~:text=Around%20half%20of%20all%20individuals,mutation%20of%20the%20NF1%20gene. Accessed 1/9/2026 – particularly p. 4 and p. 7)
Relative skill level:
One of ordinary skill in the art is one with access to reagents, tools and equipment used for diagnosing disease, performing tests and/or administering treatment to individuals. The skilled artisan also has many years of training and experience in either the clinical or laboratory environment or both. Therefore, it is clear that the level of skill of one in the art is high. However, this high level of skill is overcome in view of the limited teachings provided by the specification and the unpredictable state of the art, it would require the skilled artisan undue experimentation to make and use the invention commensurate to the scope of the claims.
The amount of direction or guidance provided and the presence or absence of working examples:
The specification fails to provide substantive guidance to treat (i.e., prevent) the claimed disease. While it provides a prophetic plan for a clinical trial to treat NF1-PN with mirdametinib, the specification does not demonstrate the prevention of NF1-PN as claimed.
The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agent could be predictably used for treating the claimed disease as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 102
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 35-39, 41-44, 46-58, and 60-63 are rejected under 35 U.S.C. 102a1 as being anticipated by Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Claimed invention
Independent Claim 35 is drawn to a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has symptomatic plexiform neurofibromas (PN) comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
for a patient having a body surface area (BSA) of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, and
wherein the method further comprises one or more of the following (conditional toxicity-management steps):
(a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline;
(b) upon the patient exhibiting at least grade 3 ocular toxicity, withholding the mirdametinib or pharmaceutically acceptable salt thereof until recovery to Grade 1 or lower or baseline and (1) if recovery occurs in no more than 14 days, resuming mirdametinib at a reduced dose or (2) if recovery occurs in more than 14 days, considering permanently discontinuing administration of mirdametinib;
(c) upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at the same dose; and
(d) upon the patient exhibiting retinal vein occlusion, permanently discontinuing administration of mirdametinib,
wherein the reduced dose is 3 mg in the morning and 3 mg in the evening for a patient having a body surface area (BSA) greater than or equal to 1.5 m2.
Independent Claim 54 is similar to Claim 35 but with only one toxicity level (grade ≥ 3) management step and the further recitation of “wherein (A) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL”.
Prior art
Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Claims 35-39, 41-44, 46-58, and 60-63 are rejected under 35 U.S.C. 103 as being unpatentable over Iloeje et al. (US Pat. 11,883,375) in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Claimed invention
A method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has symptomatic plexiform neurofibromas (PN) comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
for a patient having a body surface area (BSA) of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, and
wherein the method further comprises one or more of the following (conditional toxicity-management steps):
(a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline;
(b) upon the patient exhibiting at least grade 3 ocular toxicity, withholding the mirdametinib or pharmaceutically acceptable salt thereof until recovery to Grade 1 or lower or baseline and (1) if recovery occurs in no more than 14 days, resuming mirdametinib at a reduced dose or (2) if recovery occurs in more than 14 days, considering permanently discontinuing administration of mirdametinib;
(c) upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at the same dose; and
(d) upon the patient exhibiting retinal vein occlusion, permanently discontinuing administration of mirdametinib,
wherein the reduced dose is 3 mg in the morning and 3 mg in the evening for a patient having a body surface area (BSA) greater than or equal to 1.5 m2.
Independent Claim 54 is similar to Claim 35 but with only one toxicity level (grade ≥ 3) management step and the further recitation of “wherein (A) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL”.
Prior art
Iloeje teaches methods of treating patients 2 years or older with neurofibromatosis type 1 (NF1) having symptomatic plexiform neurofibromas (PN) by orally administering mirdametinib, as a MEK inhibitor (Iloeje, col. 1:24-25), according to body surface area (BSA)-based dosing regimens (Iloeje, abstract; col. 1:12-17; Claims 1-3). For a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily (BID) (Iloeje, col. 4:39-41,46-48), wherein the interval between dosages can be up to 12 hours (Iloeje, col. 7:40-41). Apparently, one dose is in the morning and the other in the evening (Iloeje, col. 13:34-47). Dosing is on a 28-day cycle (4-week course) with a 3 week on/1 week off (i.e., 21 days on/7 days off) schedule (see Iloeje, col. 22:9-12; Claim 12). In one embodiment of any of the methods described, the initial dosage regimen is continued to be used unless a severe adverse event occurs requiring reduction in the dosage regimen (Iloeje, col. 4:42-45). If the dose at the time of an adverse event is 4 mg mirdametinib twice daily, then the reduced daily dose is 3 mg administered twice daily (Iloeje, col. 5:8-12).
Thus, Iloeje therefore establishes the core treatment regimen, patient population, drug, route of administration and initial dose recited in Claim 35.
Although Iloeje teaches the treatment of NF1-PN with oral MEK inhibitor (mirdametinib) administration at a dose of 4 mg BID for a patient with a BSA of ≥1.5 m2 and either continuing administration, withholding administration or discontinuing administration of mirdametinib based on adverse effects from drug administration, Iloeje does not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because Iloeje (the primary reference) teaches a patient with NF1-PN (including NF1 with symptomatic PN) and a BSA of 1.5 mg/m2 can be initially treated with 4 mg of mirdametinib as a MEK inhibitor and continued to be used unless a severe adverse event occurs requiring reduction in the dosage regimen to 3 mg mirdametinib while Rosen teaches when mirdametinib causes toxicity, including ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates to MEK inhibition treatment of NF1-PN with mirdametinib and toxicity was a known adverse effect. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of Iloeje for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib to the method described by Iloeje, given that both references teach the use of mirdametinib for treating NF1-PN and that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. U.S. Patent No. 11,883,375 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of 1.05 to 1.49 m2 initially administered 3 mg mirdametinib.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
B. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-30 of U.S. Patent No. U.S. Patent No. 12,029,711 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 12 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.6 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
C. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. U.S. Patent No. 12,220,390 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 12 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.6 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
D. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. U.S. Patent No. 12,257,215 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 12 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.6 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
E. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. U.S. Patent No. 12,295,925 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2-15 years who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
F. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-25 of U.S. Patent No. U.S. Patent No. 12,383,517 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 12 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
G. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-15 of U.S. Patent No. U.S. Patent No. 12,390,430 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 12 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), including symptomatic disease, comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
H. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. U.S. Patent No. 12,357,597 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN), comprising orally administering an effective amount of mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
I. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. U.S. Patent No. 11,839,595 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
J. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. U.S. Patent No. 11,819,487 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2-15 years old who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
K. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. U.S. Patent No. 11,806,322 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
L. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. U.S. Patent No. 11,806,321 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
M. Claims 35-39, 41-44, 46-58 and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. U.S. Patent No. 11,571,402 in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
N. Claims 35-39, 41-44, 46-58 and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 90-96, 98-100, and 104-107 of copending Application No. 19/237,500 (U.S. PG-PUB 2025/0387358) in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
This is a provisional nonstatutory double patenting rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily.
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
O. Claims 35-39, 41-44, 46-58 and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 72-89 of copending Application No. 19/237,465 (U.S. PG-PUB 2025/0387357) in view of Rosen, E. ( “A Phase 1b/2a, Open-label Platform Study to Evaluate Mirdametinib as Monotherapy or in Combination with Other Anticancer Agents in Patients with Advanced Solid Cancers Harboring MAPK-activating Mutations.” Early Drug Development, Department of Medicine (Aug 29, 2022); Memorial Sloan Kettering Cancer Center (MSKCC); IRB Number: 21-288 A(5)) as evidenced by Drugbank (“Mirdametinib.” DrugBank ID: DB07101. https://go.drugbank.com/data_packages/trial. Accessed 1/9/2026).
This is a provisional nonstatutory double patenting rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily. And upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at the same dose (reference claims) or a reduced dose (instant claims).
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
P. Claims 35-39, 41-44, 46-58 and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-9, 11, 12, 14-22, 24, 34, 42-45 of copending Application No. 19/299,614.
This is a provisional nonstatutory double patenting rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method of treating a patient 2 years or older who has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib, wherein the amount is based on the body surface area (BSA) of the patient, including for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily. And upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at the same dose (reference claims) or a reduced dose (instant claims).
The reference claims do not expressly teach one of the claimed toxicity-grade-based decision tree options toxicity recited in Claim 35 (e.g., (a) upon the patient exhibiting grade ≤ 2 ocular toxicity, continuing mirdametinib administration and performing ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or less or baseline or (d) upon the patient exhibiting retinal vein occlusion (RVO), permanently discontinuing mirdametinib administration).
However, it was known that grade-based ophthalmic toxicity can be used for determining adjustments of MEK inhibitor, mirdametinib, dosage amounts as recited in Claim 35, Rosen teaches the use of 2 mg/m2 twice daily – which translates to 4 mg BID in a 2 m2-BSA (body surface area) adult (Rosen, p. 20, ‘Dose selection’ section) – mirdametinib as an oral MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) adult patients with plexiform neurofibromas (PN), including symptomatic disease. See Rosen, p. 8, 3rd full paragraph; see also p. 11. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Id. Rosen further teaches mirdametinib in a dose-adjustable regimen based on adverse effects of mirdametinib-induced ocular toxicity. See Rosen, pp. 66-67, Table 4. For example, upon an ocular toxicity-inducing adverse effect at a grade of ≤ 2, the patient receives ophthalmic exams monthly and mirdametinib administration can be continued at the same dose. Toxicity may cause administration interruption until resolution and continued at a reduced dose. See Id. For Grade ≥ 3 retinal vein occlusion (RVO) or retinal detachment, permanently discontinue mirdametinib. See Rosen, Id.
A person of ordinary skill in the art (POSA) would have found it obvious to base dosage amounts used for treating NF1-PN (including NF1 with symptomatic PN) on the grade of ophthalmic toxicity as recited in Claim 35, because the reference claims teach a patient with NF1-PN while Rosen teaches 4 mg BID mirdametinib administration to treat NF1-PN (including symptomatic disease) in an adult with a BSA of 2 m2 and when mirdametinib causes ophthalmic toxicity, the dosage of the inhibitor can be 1) continued with monthly ophthalmic monitoring until toxicity resolves, 2) interrupted, 3) reduced or 4) discontinued based on the level of ocular toxicity. Thus, each reference relates treatment of NF1-PN with mirdametinib while Rosen specifically teaches toxicity as a known adverse effect of mirdametinib. Applying the clinically used toxicity-management framework from described by Rosen to the teachings of the reference claims for the treatment of NF1-PN would have been a reasonably predictable and routine modification intended to improve patient safety. The POSA would have had a reasonable expectation of success of applying a known clinical management practice for mirdametinib taught be Rosen to the method described by the reference claims, given that both references teach the use of mirdametinib for treating NF1 and Rosen teaches that mirdametinib should be managed with consideration of its known toxicities, including known ocular toxicities explicitly disclosed by Rosen.
Regarding the limitation of Independent Claim 54 wherein the patient exhibits a Cmax of about 95 to about 280 ng/mL at steady state exposure, it is noted that this is a feature of administration of mirdametinib as evidenced by Drugbank, which states “The mean Cmax (%CV) at steady-state is 188 (52%) ng/mL in adults”. Thus, the limitations of Independent Claim 54 are met.
Claim 36 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food. Because the claim scope reads on both “with or without food”, it encompasses any disclosure of oral administration, which is expressly taught by the prior art as outlined above. Nonetheless, Rosen teaches administration of mirdametinib without regard for food. See p. 11, last paragraph. This also meets the limitations of Claim 55.
Claim 37 limits claim 35, wherein if a patient misses a dose of mirdametinib, the patient skips that dose and resumes administration at the next scheduled dose. Rosen teaches the MEK inhibitor can be skipped if a dose is missed (and >6 hours has elapsed since time of scheduled dose) and then taken the next dose at the normal time. See Rosen, p. 37, section 10.1. This also meets the limitations of Claim 56.
Claim 38 limits claim 35, wherein if vomiting occurs after administering a dose of mirdametinib, the patient does not administer an additional dose of mirdametinib, but continues with administration at the next scheduled dose. Rosen teaches if a subject vomits any time after taking a dose, then they must be instructed not to take another dose to “make up” for vomiting, but rather, to resume subsequent doses as prescribed. This also meets the limitations of Claim 57.
Claim 39 limits claim 35, wherein the patient is an adult patient. Rosen teaches treating adult patients. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 58.
Claim 41 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle. It is administered on a 3 weeks on / 1 week off (21 day on / 7 days off) schedule. See Rosen, p. 8, 3rd full paragraph. This also meets the limitations of Claim 60.
Claim 42 limits claim 35, wherein the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity. As outlined above, Rosen teaches when RVO occurs, toxicity is unacceptable and administration of administration should be discontinued. See Rosen, pp. 66-67, Table 4. This also meets the limitations of Claim 61.
Claim 43 limits claim 35, wherein an ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes. Rosen teaches ocular screening prior to inclusion in clinical treatment and monthly regular assessment. See p. 31 and see also Table 4 at p. 67. This also meets the limitations of Claim 62.
Claim 44 limits claim 35, wherein the patient has symptomatic plexiform neurofibromas. Rosen teaches mirdametinib as a MEK inhibitor used for the treatment of NF1-PN, including symptomatic PN. See Rosen, p. 11. This also meets the limitations of Claim 63.
Claim 46 limits claim 35, wherein the patient has plexiform neurofibromas that cause significant morbidity. Rosen teaches patients must have NF1-PN that is causing significant morbidity, such as head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus (i.e., paraspinal) lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. See p. 11. Thus, the PN-related morbidities are embraced by Claims 47-49.
Claims 50-53 - prior art need not teach PK values
Claims 50-53 depends on claim 35 but does not necessarily require the prior art to teach more than what is recited by Claim 35. Exemplary of the claimed limitations is Claim 50 which recites:
“…wherein the patient exhibits a Cmax of mirdametinib of from about 100 to about 500 ng/mL, prior to withholding the mirdametinib…”.
The PK values in Claims 50-53 are not required by the construction of the claimed method because they rely on the constructure of Claim 35 wherein withholding mirdametinib administration is not a requirement but a conditional scenario based on whether enough ocular toxicity occurs. Claim 35 states only one of the scenarios of (a)-(d) is required including (a) wherein mirdametinib is continued, not withheld, if ocular toxicity is low, i.e., grade ≤ 2. As such, if the triggering condition for withholding mirdametinib – ocular toxicity of grade ≥ 3 – does not occur, the PK limitation never comes into play. Therefore, the claimed method is met by the prior art because the PK values need not be taught since the prior art teaches continued mirdametinib administration with regular assessments for the low toxicity scenario; thus, meeting the limitations of Claims 50-53.
Conclusion
No claims allowed.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622