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 .
Claim Status
Claims 15-30 are pending and under examination. No new amendments were made to the claims.
Priority
This application is a U.S. national stage application under 35 U.S.C. 371 of international application no. PCT/EP2021/054164, filed 02/19/2021, which claims priority of foreign application no. EP20305163.6, filed 02/20/2020.
Information Disclosure Statement
The Information Disclosure Statement filed 10/16/2025 has been considered by the Examiner. The submission is 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.
Summary of Invention
Prior art already recognizes the use of masitinib in treatment of multiple sclerosis (MS) generally. However, Applicant has identified a specific subpopulation of (those with later-stage progressive MS defined by timing threshold of treatment initiation), particularly, Applicant provided evidence that initiating treatment with masitinib in patients with longer disease duration (>2-5 years) showed meaningful reduction in disability vs. placebo, whereas those receiving initial masitinib treatment with shorter disease duration did not.
However, prior art exists that anticipates the administration of masitinib to the subpopulation of those with longer disease duration as outlined below.
Specification
Maintained
The following guidelines illustrate the preferred layout for the specification of a utility application. Specifically, the first paragraph after the title should identify the CROSS-REFERENCE TO RELATED APPLICATIONS. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
Response to arguments:
Applicant argues that the specification meets all requirements of 37 CFR 1.77(b). However, it is recommended that Applicant insert a statement for the cross reference to related applications immediately following the title.
Claim Rejections - 35 USC § 102
Maintained
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 15-24 and 26-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moussy et al. (US PG-PUB 2013/0202555 A1).
Claimed invention
Independent Claim 15 reads on a method for treating progressive multiple sclerosis (MS) in a patient in need thereof, comprising initiating administration of masitinib, or a pharmaceutically acceptable salt or solvate thereof, more than 2 years after diagnosis or more than 5 years after onset of progressive MS.
Prior art
Moussy teaches administering masitinib to patients diagnosed with progressive multiple sclerosis, including those with primary progressive MS (PPMS) and relapse-free secondary progressive multiple sclerosis (rfSPMS), i.e., non-active SPMS. As stated by Moussy, the patients in the rfSPMS subgroups had a reported average disease duration of 12.3 years and those in the PPMS subgroup had a reported average disease duration of 2.3 years at the time of enrollment. See 0070; see also Table 2. Since this reflects the number of years between initial diagnosis and the start of treatment, it follows that these individuals received masitinib therapy more than 5 years – and certainly after 2 years – after diagnosis or onset. Therefore, the timing requirement of the claim is met by the treatment population disclosed in the reference, even though the reference does not label this delay in treatment as a distinct variable. The structure and timing of the clinical protocol necessarily involved initiating therapy in individuals who had been diagnosed with the claimed MS well beyond the 2- and 5-year threshold recited in the claim.
Claim 16 limits claim 15, wherein said patient has a time from diagnosis to treatment initiation greater than 2 years. Claim 17 limits claim 15, wherein said patient has a time from onset to treatment initiation greater than 5 years. Claim 18 limits claim 15, wherein said patient has a time from diagnosis to treatment initiation greater than 2 years and has a time from onset to treatment initiation greater than 5 years. These limitations are met because Moussy teaches the mean duration in the rfSPMS was 12.3 years and the mean duration in the PPMS population was 2.3 years. See 0069-0070; see also Table 2. Treatment necessarily began after diagnosis had been established for at least the amount of time claimed.
Claim 19 limits claim 15, wherein progressive MS is primary progressive multiple sclerosis (PPMS). Claim 20 limits claim 15, wherein progressive MS is non-active secondary progressive multiple sclerosis (non-active SPMS). As outlined above, Moussy teaches the mean duration in the rfSPMS (i.e., non-active SPMS) was 12.3 years and the mean duration in the PPMS population was 2.3 years. See 0069-0070; see also Table 2. Moussy further teaches the patients suffering from PPMS or rfSPMS were diagnosed by the `McDonald criteria` and having an Expanded Disability Status Scale (EDSS) score between 2 to 6.5 with a progression (which include symptoms) greater or less than 1 within 2 years prior to inclusion, were eligible for this study. See 0064.
Claim 21 limits claim 15, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesilate. Moussy teaches the mesylate salt form of masitinib as the preferred salt, which is orally available. See 0048,0050,0054,0059. Thus, the oral limitations of Claim 22 is met.
Claim 23 limits claim 15, wherein said masitinib is administered at a dose ranging from about 1 mg/kg/day to about 12 mg/kg/day. Moussy teaches patients were treated orally with 3 or mg/k/day masitinib, including escalating to 6 mg/kg/day. See 0069; 0076.
Claim 24 limits claim 15, wherein said masitinib is administered at a dose of about 4.5 mg/kg/day. While 3.0 mg/kg/day is disclosed, Moussy teaches the dose is preferably 4.5 to 6.0 +-1.5 mg/kg/day. See 0026,0027; see also Claims 25-26. That’s a dose selected from a very limited number of options that include 3.0, 4.5, 6.0, and 7.5 mg/kg. Thus, the claimed does is anticipated.
Claim 26 limits claim 15, wherein said masitinib, or the pharmaceutically acceptable salt or solvate thereof, is administered as a second-line treatment. Moussy discloses patients previously received physical therapy. See 0064. Thus, the initiation of masitinib therapy afterwards is a second-line therapy.
Claim 27 limits claim 15, wherein said patient failed to respond to a previously administered first-line treatment for multiple sclerosis or showed irreversible progression of the disease despite previous administration of a first-line treatment for multiple sclerosis. Moussy teaches the invention meets an unmet need that includes treatment of relapsing MS patients who were treated earlier. See 0009.
Claim 28 limits claim 15, wherein said masitinib is administered with at least one further pharmaceutically active agent. Claim 29 limits claim 28, wherein the at least one further pharmaceutically active agent is, inter alia, interferon. Claim 30 limits claim 29, wherein interferon is selected from, inter alia, interferon beta-lb interferon beta-la. Moussy teaches an additional disease modifying drug may be used in combination with masitinib including interferon beta-1a; an interferon beta-1b. See claim 36.
Response to arguments
Applicant’s arguments regarding the claimed temporal limitations (time period between diagnosis (or after onset) and treatment initiation) have been fully considered but are not persuasive. The specification defines “time from diagnosis to treatment” as the elapsed “time between the first clinically definite diagnosis of MS, in particular progressive MS, and initiation of treatment” (last par. of p. 10), and defines “time from onset to treatment initiation” as the elapsed time between the date of the first MS-related symptoms and treatment initiation” (first full par. p. 11). Notably, the specification does not require the first MS-related symptoms be limited to progressive MS, or a prospective determination of disease course at onset as suggested by Applicant’s arguments. Moussy expressly discloses treatment of patient populations classified as PPMS and SPMS and reports mean disease durations for those progressive MS populations at the time of masitinib initiation that exceed five years (as indicated in the rejection). Because progressive MS classification and disease duration in Moussy are determined retrospectively through patient history, the reported disease durations correspond to the elapsed time from MS symptom onset and/or diagnosis to treatment initiation as defined in the specification. Accordingly, Moussy discloses treatment of patients meeting the claimed temporal limitations and anticipates the claims.
Claim Rejections - 35 USC § 103
Maintained
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.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Moussy et al. (US PG-PUB 2013/0202555 A1).
Claimed invention
Claim 25 limits claim 15, wherein said masitinib is administered at an initial dose of about 4.5 mg/kg/day during at least 12 weeks, and then at a dose of about 6 mg/kg/day thereafter, with each dose escalation being subjected to toxicity controls.
Prior art
Moussy teaches the initial dose is preferably 4.5 to 6.0 +-1.5 mg/kg/day. See 0026,0027; see also Claims 25-26. Moussy further discloses the incremental changes in dose is 1.5 mg/kg/day. See 0048; Claim 26. Dose adjustment can be considered a dynamic process, with a patient undergoing multiple increases and/or decreases to optimize the balance between response and toxicity throughout treatment, both of which are likely to vary over time and duration of drug exposure. See 0051. Indeed, depending on age, individual condition, mode of administration, and the clinical setting, effective doses of said tyrosine kinase inhibitor or MC inhibitor, and in particular masitinib or a pharmaceutically acceptable salt thereof, in human patients with MS are 3.0 to 6.0 mg/kg/day per os, preferably in two daily intakes. For adult human patients with PPMS or rISPMS, a starting dose of said tyrosine kinase inhibitor or MC inhibitor, and in particular masitinib or a pharmaceutically acceptable salt thereof of, 4.5 to 6.0 mg/kg/day has been found to be the preferred embodiment according to the invention. For patients with an inadequate response after an assessment of response to therapy and in the absence of limiting toxicities, dose escalation of said tyrosine kinase inhibitor or MC inhibitor, and in particular masitinib or a pharmaceutically acceptable salt thereof to a maximum of 9.0 mg/kg/day can be safely considered and patients may be treated as long as they benefit from treatment and in the absence of limiting toxicities. See 0049.
While Moussy teaches masitinib administered at a preferred dose of about 4.5 to 6.0 mg/kg/day and incremental increases by 1.5 mg/kg/day depending on response and toxicity to treatment with masitinib, Moussy does not expressly teach administration of 4.5 mg/kg/day for at least 12 weeks followed by 6.0 mg/kg/day thereafter.
However, disease remission in MS is known to last for months or even years. Occasional relapses and minor remissions may occur. PPMS is characterized by slowly worsening neurologic function from the outset with no distinct relapses or remissions. See 0004. Given that Moussy teaches treatment of MS with 4.5 mg/kg/day and further given MS is a chronic disease with slowly progressive symptoms and dose titration may be guided by response and tolerability, a POSA would have found it obvious to treat a subject with MS with a dose of 4.5 for at least 12 weeks and then increasing the dose by 1.5 mg/kg/day to arrive at a dose of 6.0 mg/kg/day. The artisan would have understood from the Moussy disclosure that the dose may be maintained (at 4.5) for months or years while symptoms either remain in remission or have not become intolerable. If the disorder relapses and/or symptoms worsen, the artisan would reasonably seek to increase the dose by the disclosed 1.5 increment to 6.0 mg/kg/day for maximum therapeutic response while remaining within the fully disclosed dosing range and titration framework.
Response to argument
Applicant’s arguments regarding alleged improvements in disability outcomes have been fully considered but have not been found to be persuasive. As indicated above, the rejection is based on a POSA finding it obvious to treat a subject with MS with a dose of 4.5 for at least 12 weeks and then increasing the dose by 1.5 mg/kg/day to arrive at a dose of 6.0 mg/kg/day. Applicant has not established that the claimed dose increase or timing thereof is critical, nor has Applicant provided comparable evidence showing unexpected results attributable to the specific stepwise escalation. Accordingly, the claimed dosing regimen represents routine optimization of a known treatment and remains obvious over Moussy.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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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