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
The office acknowledges Applicants filing of the claim amendments on 8/27/2024. Claims 5-30 has been amended. Claims 1-30 are pending and are examined based on the merits herein.
Application Priority
This application filed 08/27/2024 is a National Stage entry of PCT/US2023/ 064572, International Filing Date: 03/16/2023, PCT/US2023/064572 Claims Priority from Provisional Application 63321036, filed 03/17/2022, PCT/US2023/064572 Claims Priority from Provisional Application 63321046, filed 03/17/2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 8/27/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
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.
Claims 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (IDS: J Clin Oncol 2021 797-806) and Neurofibromatosis (NF) Consortium Protocol (NF Protocol 106 2018 1-89) in view of Chamseddin (Neuro-Oncology Advances 2019, i107-i116).
The Weiss and the NF Consortium Protocol publications disclose the findings and study protocol for the phase 2 NIH National Library of Medicine Trial (NCT02096471) of the oral administration of PD-0325901 (mirdametinib) to adolescent and adult humans with neurofibromatosis type 1 (NF1) and plexiform neurofibromas.
Weiss teaches a method for treating plexiform neurofibromas (PNs) comprising administering mirdametinib, a MAPK/ERK (MEK) kinase inhibitor, to adolescent and adult humans with neurofibromatosis type 1 (NF1) (Title and Abstract). Weiss further teaches that loss of the NF1 gene leads to hyperactivation of MEK and evidence suggests that inhibition of the MEK pathway can lead to significant shrinkage of PN and clinical benefit (page 797, introduction). Weiss teaches administration of a 2 mg/m2 or maximum dose of 4 mg twice per day that is therapeutically effective wherein during the course of a 4-week period, mirdametinib is administered for the first three weeks and discontinued for the last one week (page 798, Therapy and results in Fig 1)
Weiss teaches that a larger study of mirdametinib in children with NF1 and plexiform neurofibromas is in progress (page 805, Conclusion). Weiss teaches that future trials may consider testing MEK inhibition (mirdametinib, a MEK inhibitor) in combination with other agents to find therapies that will increase response rate (page 805, conclusion), thus suggesting a combination therapy as claimed. The reference teaches that mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in 42% partial response rate with preliminary evidence of reduction in pain (Abstract).
NF Consortium Protocol (NF Protocol 106) teaches that patients enrolled in the NIH National Library of Medicine Trial (NCT02096471) had a clinical diagnosis of NF1 using the NIH Consensus Conference or a constitutional NF1 mutation documented in a Clinical Laboratory Improvements Amendments/College of American Pathologists (CLIA/CAP) certified lab, and patients with NF1 may have an optic glioma (Patient Eligibility on page 25, 4.1.1.; Background and Rationale on page 12, 2.1); patients involved in the trial had no prior exposure to MEK inhibitors (Exclusion Criteria on page 28, final bullet).
Weiss and the NF Consortium Protocol do not teach treatment of cutaneous neurofibromas (cNFs).
Chamseddin discloses that cNFs are also regarded in the art as dermal neurofibromas (page i107, introduction). Furthermore, dermal neurofibromas (cNFs) and PNs are tumors associated with NF1 wherein both tumor types arise from the loss of the NF1 gene (page i108, introduction, paragraph 2). Dermal neurofibromas (cNFs) in particular are considered the most burdensome feature of the disease and at present there are no effective drug treatments (Abstract). However, the MEK pathway is linked to the pathology associated with cNF, and the MEK inhibitor, selumitinib, which had previously been shown to treat plexiform neurofibromas (page i112, col 2, paragraph 2), is currently undergoing investigation in a phase II clinical trial for treatment of NF1 and cNF (page i112, col 2, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to combine the teachings of Weiss and the NF Consortium Protocol with Chamseddin in order to treat cNF with mirdametinib for the following reasons: (i) Cutaneous and plexiform neurofibromas were known in the art to be common to NF1, and both tumor types were known to be related to dysregulation of the MEK pathway (ii) MEK inhibition with selumitinib and mirdametinib was already known as a strategy for treating PN, and selumitinib was already being evaluated as a treatment for cNF. (iii) the NF Consortium Protocol and Weiss teach the method of using mirdametinib to treat NF1 and PN, and the protocol specifically states that dermal neurofibromas are an expected target of the therapy owing to dermal and PNs being indistinguishable on the cellular level. Finally, Chamseddin elaborates on the similarities between cNF and PN and discloses that cNF is known in the art as dermal neurofibroma which was taught as a likely target of mirdametinib in the NF Consortium Protocol. A person of ordinary skill in the art would have found it obvious to arrive at the claimed method from the prior art teachings. One of ordinary skill in the art would be motivated to apply the above teachings to treat cNF because at the time there were no known drug treatments for cNF and these tumors were considered in the art to be the most burdensome feature of NF1. It was known that MEK inhibitors (mirdametinib and selumitinib) treated plexiform neurofibromas, and that both cutaneous and plexiform neurofibromas arise in NF1 patients, have a common origin, and result from dysregulation of the same cellular pathway. Moreover, due to these similarities there was speculation that MEK inhibition may treat both tumor types and a clinical trial was already underway studying the treatment of cNF in NF1 patients with selumitinib. Finally, the supporting protocol (NF Consortium Protocol) for Weiss specifically taught that cNFs were expected to respond to MEK inhibition. Accordingly, a person of ordinary skill would have been motivated to combine the teachings to treat cNF in NF1 patients as claimed and would have also had a reasonable expectation of success. Also, one would have a reasonable expectation of success because mirdametinib was already shown to be effective in a Phase II clinical trial for treating plexiform neurofibromas associated with NF1. Because both cutaneous and plexiform neurofibromas arise from dysregulation of the MEK pathway, it would be reasonable to expect that treating cutaneous neurofibromas with a MEK inhibitor (in adult and adolescent human patients) would likely also be effective. In fact, the NF Consortium Protocol expected that mirdametinib may also treat cNF. Finally, Weiss teaches a method that includes a dosing regimen (e.g. dose amount, frequency, and course of treatment) that could be used as a starting point for further optimization as would be routine in the art. Accordingly, the claimed invention would have been prima facie obvious to one of ordinary skill in the art prior to the filing date of the instant application. This addresses claims 1, 2 and 27. As to claim 5 from the prior art a skilled artisan would have found it obvious to administer a therapeutically effective amount of mirdametinib to derive therapeutic benefits treating cutaneous neurofibromas in subjects. Regarding claims 3-4, and 28-29, the NF Consortium Protocol (NF Protocol 106) teaches that patients enrolled in the NIH trial (NCT02096471) had a clinical diagnosis of NF1 using the NIH Consensus Conference or a constitutional NF1 mutation documented in a Clinical Laboratory Improvements Amendments/College of American Pathologists (CLIA/CAP) certified lab, and patients with NF1 may have an optic glioma (Patient Eligibility on page 25, 4.1.1.; Background and Rationale on page 12, 2.1). Moreover, patients involved in the trial had no prior exposure to MEK inhibitors (Exclusion Criteria on page 28, final bullet: Prior treatment with a MEK inhibitor of an any kind) and mirdametinib was the only therapy for NF1 investigated in the trial (See Page 26, 4.1.7. Prior Therapy; page 36 Concurrent Anticancer Therapy). The protocol further elaborates that ERK (MAPK/ERK or MEK) phosphorylation was optionally monitored in dermal neurofibromas as a marker of the effects of PD-0325901 (mirdametinib). The “cellular composition of dermal neurofibromas is indistinguishable from that of plexiform neurofibromas; therefore, dermal neurofibromas may be useful as an accessible surrogate tissue for analysis of therapeutic efficacy” (Pharmacodynamic Analysis on page 41, 9.1).
As to claims 6-21, Weiss teaches administration of a 2 mg/m2 or maximum dose of 4 mg twice per day that is therapeutically effective wherein during the course of a 4-week period, mirdametinib is administered for the first three weeks and discontinued for the last one week. It is noted that dosage depends on various factors including age, condition, body surface, weight, other diseases, type of administration etc. Dosage amount or dosage regimen in general is a parameter that is routinely optimized and is within the skill of an artisan (e.g. clinician). “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Ap-plied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012) (citing In re Aller, 220 F.2d 454, 456 (1955)).
As to claims 22-23, Weiss teaches that patients were removed from therapy for adverse events (page 798, col 1, Therapy section) wherein if the starting dose of mirdametinib was 4 mg twice per day, then the reduced daily dose is 3 mg administered twice per day (Table A2. Dose Reductions for Toxicity). Moreover, adverse events observed included acneiform (Table 3, Skin and subcutaneous tissue disorders).
As to claims 24-25, Weiss teaches mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain in plexiform neurofibromas patients. This teaching shows that treatment selectivity is based on response rates. It would have been obvious to a skilled artisan to routinely use this in treatment methods to attain therapeutic benefits in select patient population.
Regarding claim 26, Weiss teaches that a larger study of mirdametinib in children with NF1 and plexiform neurofibromas is in progress.
Regarding claim 30, Weiss teaches that future trials may consider testing MEK inhibition (mirdametinib is a MEK inhibitor) in combination with other agents to find therapies that will increase response rate (page 805, conclusion), thus suggesting a combination therapy as claimed.
Claims 1-3, 5, 7-9, 11-21, 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Irdam (US Pat. No. 11,453,641).
Regarding claims 1-2, Irdam teaches that neurofibromatosis Type 1 (NF1) is taught to be associated with tumors including cutaneous neurofibromas (col 5, line 1-5). Irdam teaches a method of treating neurofibromatosis in a patient comprising administering a solid form of mirdametinib to patient in need thereof (claim 1). Therefore, the treatment of neurofibromatosis includes treatments of cutaneous neurofibromas associated with NF1. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the application to treat cutaneous neurofibromas associated with Neurofibromatosis Type 1 (NF1) with mirdametinib. The treatment of NF1 is clearly within the scope of the method and may be associated with tumors including cutaneous neurofibromas. One of ordinary skill in the art would be motivated because there is an art recognized need for new cancer therapies and Irdam teaches a drug, mirdametinib, that is effective for treating tumors, including cutaneous neurofibromas, associated with NF1. A person skilled in the art would have had a reasonable expectation of success because Irdam teaches that mirdametinib treats cutaneous neurofibromas and provides sample dosing regimens (e.g. dose amount, frequency, treatment duration) as a starting point for further optimization. It would have only required routine experimentation to modify the teachings (e.g. dosages of the drug and frequency of treatment) of Irdam into a method of treatment as claimed.
Regarding claim 3, Irdam teaches that mirdametinib may also be used to treat a tumor including plexiform neurofibroma and optic pathway glioma (col 5, lines 1-5). The method of Irdam thus includes patients with a clinical NF1 diagnosis using the NIH Consensus Conference and one or more of the following (optic glioma) as instantly claimed.
Regarding claims 5, Irdam teaches wherein a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered (col 8, lines 1-5).
Regarding claims 7, 8, and 11-14, Irdam teaches wherein the mirdametinib, or a pharmaceutically acceptable salt thereof, is orally administered (col 13, line 11) daily at a dose of about 0.1 mg to about 20 mg (col 17, lines 36-67).
Regarding claims 9 and 15-18, Irdam teaches wherein the mirdametinib, or a pharmaceutically acceptable salt thereof, is orally administered twice daily at a dose from about 0.1 mg to about 10 mg (col 18, lines 29-36).
Regarding claim 20, Irdam teaches a maximum daily dose of 4 mg of mirdametinib administered twice daily in equal doses (col 18 , line 4-16).
Regarding claim 21, Irdam teaches (col 21, lines 6-12) wherein over each 4-week period (28-day dosing cycle), the mirdametinib is administered for the first three weeks (21 days in which the dose is administered) and discontinued for the last one week (7 days in which no dose is administered).
Regarding claims 6, 9-10, 19, It is noted that dosage depends on various factors including age, condition, body surface, weight, other diseases, type of administration etc. Dosage amount or dosage regimen in general is a parameter that is routinely optimized and is within the skill of an artisan (e.g. clinician). “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Ap-plied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012) (citing In re Aller, 220 F.2d 454, 456 (1955)). Hence a skilled artisan would have found it obvious from Irdam to optimize the dosage amount and the regimen and arrive at the claims.
As to claim 28, it would have been obvious to administer subjects who have had no prior experience of MEK inhibitor(s) to provide therapeutic treatment.
As to claim 29, Irdam’s method is to the administration of mirdametinib for the treatment of CN is monotherapy.
Claims 26-27, 30 are rejected under 35 U.S.C. 103 as being unpatentable over Irdam (US Pat. No. 11,453,641) as applied to claims 1-3, 5, 7-9, 11-21, 28-29 in view of Solares (ESMO Open. 2021 Aug 10;6(4):100223).
Irdam teachings as above. The above rejection is incorporated herein.
Irdam is not explicit in teaching the limitations of claims 26-30.
Solares disclose that patients with neurofibromatosis type 1 (NF1) frequently develop different types of peripheral nerve sheath tumors. The most common type is cutaneous neurofibroma, which is a benign peripheral nerve tumor that tends to increase in size and number with age but does not carry a risk of malignant transformation (see p 1, col. 1, para 1, Introduction). It is taught that plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible (Abstract). Table 1 list the various clinical trials for treatment of NF-1 associated with PN, the subjects include children 3-18 years (See Dombi, NCT01362803); and adults >18 years (see O’Sullivan, NCT02407405) with drug, selumetinib (p 4). Selumetinib is an oral, highly potent and selective inhibitor of MEK1/235 that has been studied in several malignancies. In the first trial 24 children and adolescents (3-18 years) with NF1 and inoperable PNs received selumetinib (b.i.d.; 20-30 mg/m2 continuously) in 28-day cycles (See p 3, col. 2, last para; p 5, col. 1, lines 1-3).
From Solares a skilled artisan would have found it obvious that cutaneous neurofibroma and plexiform neurofibromas are associated with NF1, the human subjects of NF1 include adult and children (3-18 years) and MEK inhibitor such as selumetinib has been used in the treatment of NF-1 associated PN. A skilled artisan would have found it obvious that patients of CN include adult and children (3-18 y) and hence administer mirdametinib to CN patients. A skilled artisan would have been motivated to administer to select CN patients as claimed with a reasonable amount of success and to provide therapeutic benefits. Thus claims 26-27 are addressed. As to claim 30, from Solares a skilled artisan would have found it obvious to add selumetinib in the treatment of NC to derive synergistic or additive therapeutic benefits as the drug has been shown to treat NF-1 and in patients with PN.
Claim Rejections - 35 USC § 112
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 24-25, 30 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.
Claim 24 depends from claim 1 wherein the method is further drawn to determining whether to select mirdametinib as a treatment for the patient. The recitation “wherein the method further comprises prior to treatment” implies that the method steps (i) and (ii) should take place prior to treating the patient with mirdametinib; however, step (ii) of the method requires assessing the response rate to mirdametinib. This claim is indefinite because it is unclear if the patient is treated with mirdametinib in order to select mirdametinib as a treatment for the patient. Appropriate clarification is requested. Claim 25 depends on claim 24 and is therefore also indefinite. Claims 24-25 have been examined based on the interpretation that based on the response rate further treatment with mirdametinib is continued with select patient population (who had a response rate as recited in the claims).
Claim 30 recites a limitation of ‘combination with another active ingredient’. There are hundreds of active ingredients available for treating a myriad of diseases. Applicants have not listed or defined what active ingredients are to be administered in the combination therapy. The limitation is indefinite and the metes and bounds of patent protection sought have not been defined. It is suggested that Applicants list specific active ingredients (in the claim) that is administered in the combination therapy.
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.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-19, 21-23, 25-26 of 19/082462 (‘462) or claims 1-21 of US 11819487 (‘487) or claims 1-28 of US 11839595 (‘595) or claims 1-24 of US 11806321 (‘321) or claims 1-30 of US 11883375 (‘375) or 1-26 of US 11806322 (‘322) or claims 1-30 of US 12220390 (‘390) or claims 1-22 of US 12257215 (‘215) or claims 1-25 of US 12295925 (‘925) or claims 1-21 of 11819487 (‘487).or claims 1-22 of US 12,661330 (‘330) in view of Chamseddin (Neuro-Oncology Advances 2019, i107-i116).
The instant claims are directed to:
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The dependent claims are limited to the subject additionally having neurofibromatosis 1, NF1, clinical diagnosis of NFI, the subject has NF1 mutation, oral administration, amounts of mirdametinib administered, dosage regimen, dosage amount based on body surface, adverse event, dose reduction, population selection, patient age, adult human patient, human patient has no prior exposure to MEK inhibitors, monotherapy or combination therapy with another active ingredient and/or surgery.
‘462 reference claims are to a method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) and a body surface area of 0.7 to 1.04 m2, the method comprising orally administering to the patient 2 mg mirdametinib twice daily; patient has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN); wherein the patient has head and neck lesions; wherein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following: (a) six or more caf6-au-lait macules with a diameter > 5 mm in prepubertal and > 15 mm in post-pubertal individuals; (b) freckling in axilla or inguinal regions; (c) optic glioma etc. (See claim 10); adverse event resulting in the dose reduction is acneiform and specific dosage regimens.
‘487 reference claims are directed to a method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein (a) for a patient having a body surface area no more than 0.69 m.sup.2, the patient is initially administered 1 mg mirdametinib twice daily, (b) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is initially administered 2 mg mirdametinib twice daily, (c) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is initially administered 3 mg mirdametinib twice daily, and (d) for a patient having a body surface area of at least 1.5 m.sup.2, the patient is initially administered 4 mg mirdametinib twice daily. The dependent claims are limited to dosage regimen, the patient diagnosed with two or more criteria including optic pathway glioma, Lisch nodules etc. (claim 13);
the adverse event resulting in the dose reduction is acneiform.
‘595 reference claims are directed to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein an amount of mirdametinib is administered on the first day of treatment; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has head and neck lesions; herein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 11), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘321 reference claims are to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein (a) for a patient having a body surface area no more than 0.69 m.sup.2, the patient is initially administered 1 mg mirdametinib twice daily, (b) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is initially administered 2 mg mirdametinib twice daily, (c) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is initially administered 3 mg mirdametinib twice daily, and (d) for a patient having a body surface area of at least 1.5 m.sup.2, the patient is initially administered 4 mg mirdametinib twice daily; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has head and neck lesions; herein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 11), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘375 reference claims are to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein (I) an amount of mirdametinib is administered on the first day of treatment to provide an AUC.sub.0-tau less than 300 ng.Math.h/mL; and (II) (a) for a patient having a body surface area no more than 0.69 m.sup.2, the patient is initially administered 1 mg mirdametinib, (b) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is initially administered 2 mg mirdametinib, or (c) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is initially administered 3 mg mirdametinib; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has head and neck lesions; herein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 10), the dependent claims are limited to age and specific dosage regimen.
‘322 reference claims are to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient; method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) that is progressing or causing significant morbidity comprising orally administering an effective amount of mirdametinib to the patient; wherein the patient has progressive PN; wherein the patient has head and neck lesions; herein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 11), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘390 reference claims are to a method of treating a human patient 2 years to less than 12 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient; wherein the patient has symptomatic, inoperable plexiform neurofibromas; herein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 16), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘215 reference claims are directed to a method of treating a human patient diagnosed with neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient wherein (a) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is administered 2 mg mirdametinib twice daily, or (b) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is administered 3 mg mirdametinib twice daily; wherein the patient is 12 years or older; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 16), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘925 reference claims method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein the patient has had no prior exposure to MEK inhibitors; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 16), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘487 reference claims are directed to a method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein (a) for a patient having a body surface area no more than 0.69 m.sup.2, the patient is initially administered 1 mg mirdametinib twice daily, (b) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is initially administered 2 mg mirdametinib twice daily, (c) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is initially administered 3 mg mirdametinib twice daily, and (d) for a patient having a body surface area of at least 1.5 m.sup.2, the patient is initially administered 4 mg mirdametinib twice daily. The dependent claims are limited to dosage regimen, the patient diagnosed with two or more criteria including optic pathway glioma, Lisch nodules etc. (claim 13); the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
‘330 reference claims are directed to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) and a body surface area of at least 1.5 m2 comprising orally administering 4 mg of mirdametinib twice daily; wherein the patient is 12 years or older; wherein the patient has symptomatic, inoperable plexiform neurofibromas; wherein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference, and one or more of the following: optic glioma (claim 16), wherein the adverse event resulting in the dose reduction is acneiform; mirdametinib is selected based on a response rate of at least 70%.
The reference claims are not explicit in teaching the cutaneous neurofibromas (cNF) as claimed.
Chamseddin teachings as discussed above.
From Chamseddin a person skilled in the art would have found it obvious that cNFs (dermal neurofibromas) and PNs are tumors associated with NF1 wherein both tumor types arise from the loss of the NF1 gene. Hence a skilled artisan would have found it obvious to use mirdametinib to treat cNFs with a reasonable expectation of success. A person of ordinary skill in the art would have found it obvious that the invention of the instant claim is an obvious variation of the subject matter claimed in the reference application. Further it would have been obvious to a skilled artisan to routinely optimize the dosage regimen, amount and arrive at the claimed method. Thus the claimed invention would have been obvious over the reference claims and the prior art.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23, 25-32 of co-pending application 19/053783 (‘783) or claims 1-15 of US 12263146 or claims 1-6 of US 12011424 or claims 1-2 of US 12324791 or claims 1-18 of US 12390430 or claims 90-96, 98-100, 104-107 of co-pending application 19/237500 (’500) or claims 35-46, 48-64 of co-pending application 19/237417 (‘417) or claims 1-6 of U.S. 11427534 (‘534) or claims 1-14 of U.S. 11084780 (‘780) or claims 1-30 of US 12029711 (‘711) or claims 1-22 of US 12383517 (‘517) or claims 1-2, 4-13, 15, 17-18, 22, 27-30, 42-44, 49-50 of co-pending application, 19/267096 (‘096) in view of Weiss (IDS: J Clin Oncol 2021 797-806) and Neurofibromatosis (NF) Consortium Protocol (NF Protocol 106 2018 1-89) and further in view of Chamseddin (Neuro-Oncology Advances 2019, i107-i116).
The instant claims as discussed above.
‘783 reference claims are directed to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) and a body surface area of 1.05 to 1.24 m2 comprising orally administering 3 mg mirdametinib twice daily to the patient, wherein over each four week period, the mirdametinib is administered for the first three weeks and discontinued for the last one week, wherein the patient is 2 to 15 years of age, wherein the patient has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) that is progressing, wherein the patient has head and neck lesions, wherein the dose is reduced to 2 mg of mirdametinib administered twice daily due to an adverse event.
‘146 reference claims are to a method of treating a human patient 2 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) and a body surface area of 1.5 to 1.74 m.sup.2 comprising orally administering an effective amount of mirdametinib to the patient, wherein the patient is initially administered 4 mg mirdametinib twice daily; mirdametinib is selected based on a response rate of at least 70%.
‘424 reference claims are to a method of treating a pediatric human patient 2 to 10 years of age who has neurofibromatosis type 1 NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering to the patient 1 mg mirdametinib twice daily; wherein the patient has symptomatic, inoperable plexiform neurofibromas.
‘791 reference claims are to a method of treating a human patient 8 years or older who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein an amount of mirdametinib is administered on the first day of treatment to provide (i) an AUC.sub.0-tau less than 400 ng.h/mL, (ii) a C.sub.max no more than 40 ng/mL, or (iii) both, wherein, during treatment, the patient suffers from acneiform rash.
‘430 reference claims are to a method of administering mirdametinib to a human patient in need thereof comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) for a patient having a body surface area of 0.4 to 0.69 m.sup.2, the patient is initially administered 1 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, (ii) for a patient having a body surface area of 0.7 to 1.04 m.sup.2, the patient is initially administered 2 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, (iii) for a patient having a body surface area of 1.05 to 1.49 m.sup.2, the patient is initially administered 3 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, and (iv) for a patient having a body surface area of at least 1.5 m.sup.2, the patient is initially administered 4 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, wherein the patient has symptomatic or progressive plexiform neurofibromas.
‘500 reference claims are directed to method of therapeutic treatment of a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN), wherein (i) the patient has been comprising orally treated with administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof and (ii) the patient exhibits symptomatic retinal pigment epithelium detachment (RPED),the method comprises withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution of the RPED to Grade 1 or less or baseline and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at the same dose, wherein (i) for a patient having a body surface area of 0.4 to 0.69 m2, the patient [[is]] was initially administered 1 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, (ii) for a patient having a body surface area of 0.7 to 1.04 m2, the patient was initially administered 2 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, (iii) for a patient having a body surface area of 1.05 to 1.49 m2, the patient was initially administered 3 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, and (iv) for a patient having a body surface area of at least 1.5 m2, the patient was initially administered 4 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily. The dependent claims are limited to dosage regimen, adult, pediatric population, the patient has symptomatic or progressive plexiform neurofibromas.
‘417 reference claims are to a method of treating therapeutic treatment of a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, with specific dosage regimen based on body surface area. The dependent claims are limited to dosage regimen, food regimen, adult or pediatric patient, the patient has symptomatic or progressive plexiform neurofibromas, paraspinal lesions.
‘534 reference claim(s) are drawn to a method of treating neurofibromatosis in a patient in need thereof comprising administering to the patient (defined in the specification as including humans, see col 31, lines 14-18) a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 1 mg to 4 mg N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-pheny !amino)benzamide (a compound of Formula (I), mirdametinib).
’780 reference claim(s) are drawn to a crystalline form of N- ((R)-2,3-dihydroxypropoxy)- 653 ,4-difluoro-2-(2-fluoro-4-iodo-pheny !amino )-benzamide of Formula (I) (mirdametinib).
‘711 reference claims are directed to an oral capsule comprising (a) about 1 mg mirdametinib having a d90 no more than 250 microns and (b) one or more pharmaceutically acceptable excipients and to a method of treating a human patient who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of one or more oral capsules. The method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis; wherein in step (i), mirdametinib is selected based on a response rate of at least 70%.
‘517 reference claims are directed to an oral capsule comprising (a) about 1 mg mirdametinib having a d90 no more than 250 microns and (b) one or more pharmaceutically acceptable excipients and to a method of treating a human patient who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of one or more oral capsules; the method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis.
‘096 reference claims are directed to an oral dosage form comprising (a) 0.5, 1, or 2 mg mirdametinib having a d50 of 1 to 30 microns and a d90 of 50 to 150 microns and (b) one or more pharmaceutically acceptable excipients; method of treating a human patient who has neurofibromatosis type 1 (NF1) comprising orally administering an effective amount of one or more oral dosage forms; wherein the method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis; wherein in step (i), mirdametinib is selected based on a response rate of at least 70%.
The reference claims teach treating NF1 with mirdametinib but do not teach treating cutaneous neurofibromas or the clinical diagnosis as claimed.
Weiss, Consortium Protocol and Chamseddin as discussed above.
From the teachings of the prior art a skilled artisan would have found it obvious that cutaneous and plexiform neurofibromas were known in the art to be common to NF1, and both tumor types were known to be related to dysregulation of the MEK pathway; MEK inhibition with selumitinib and mirdametinib was already known as a strategy for treating PN, and selumitinib was already being evaluated as a treatment for cNF and the NF Consortium Protocol and Weiss teach the method of using mirdametinib to treat NF1 and PN, and the protocol specifically states that dermal neurofibromas are an expected target of the therapy owing to dermal and PNs being indistinguishable on the cellular level. Finally, Chamseddin elaborates on the similarities between cNF and PN and discloses that cNF is known in the art as dermal neurofibroma which was taught as a likely target of mirdametinib in the NF Consortium Protocol. Hence a skilled artisan would have found it obvious to arrive at the claimed method from the reference claims with a reasonable amount of success. NF Consortium Protocol teaches the clinical diagnosis and the mutation as in instant claims 3-4. One would have found it obvious to treat cutaneous neurofibromas from the reference because there is an art recognized need for new cancer therapies, and the reference application is drawn to a method of treating cancer associated with NF1, which includes cutaneous neurofibromas. One of ordinary skill in the art would have a reasonable expectation of success in applying the method because cutaneous neurofibromas are clearly within the scope of cancers for which the method is applicable. A person of ordinary skill in the art would have found it obvious that the invention of the instant claim is an obvious variation of the subject matter claimed in the reference application. Further it would have been obvious to a skilled artisan to routinely optimize the dosage regimen, amount and arrive at the claimed method. Thus the claimed invention would have been obvious over the reference claims and the prior art.
Note: In regards to co-pending applications, this is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627
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