DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claim listing filed on March 12, 2026 is pending. Claim 1 is canceled. Claims 2-15 are amended. Claims 19-25 are new. Claims 2-25 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on March 12, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because not all copies of foreign patent literature and non-patent literature documents are included in the instant application or the direct parent application (U.S. App. No. 16/782,094). MPEP § 609.02II.B.2 states “if the IDS submitted in the parent application complies with 37 CFR 1.98(a) to (c), copies of the patents, publications, pending U.S. applications, or other information submitted in the parent application need not be resubmitted in the continuing application” [emphasis added]. All documents have been considered except those marked by strikethrough (see attached IDS). Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Withdrawn Objections and Rejections
Applicant’s amendments to the specification and claims overcome all objections of record, and the specification objections and claim objections are withdrawn.
The rejection of Claims 2-14 and 16-18 under 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of Applicant’s amendments to the claims. Specifically, removing the indefinite terms “about” and “MS” overcome the rejection.
The rejection of Claims 2-18 under 35 U.S.C. 103(a) as being obvious over De Luca WO 2006/067141 (of record) in view of Rieckmann et al. J Neurol 2004 (of record) is withdrawn in view of the statement of common ownership filed by Applicant on 03/12/2026. Applicant states that De Luca WO 2006/067141 does not qualify as prior art, because WO 2006/067141 and the instant application were subject to an obligation of assignment to the same entity at the time the invention was made.
Claim Objections (New, necessitated by amendment)
Applicant is advised that should claim 2 be found allowable, claims 7 and 12 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claim 15 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 is maintained.
Applicant's arguments filed March 12, 2026 have been fully considered but they are not persuasive. Applicant argues that the amendments have rendered the indefinite issues moot. Examiner maintains that Claim 15 still recites the indefinite term “about” in line 3 that states “about 2 years.” “About” is indefinite for the reasons of record in the non-final office action filed 12/12/2025, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 2 and 7-25 are rejected under 35 U.S.C. 103(a) as being obvious over Grieb et al. Arch Immunol Ther Exp. 1995 in view of Bodor et al. WO 2004/087101.
The claims are drawn to a method of treating patients suffering from multiple sclerosis (MS) and who are refractory to a conventional therapy, comprising orally administering cladribine, following the steps of: (i) an induction period that lasts up to 4 months wherein a total dose of cladribine reached at the end of the period is from 1.7 mg/kg to 3.5 mg/kg and said cladribine is administered daily at a daily dose of 10 to 20 mg for 1 to 7 days of each month; (ii) a cladribine-free period of at least 8 months; (iii) a maintenance period that lasts up to 4 months, wherein the total dose of cladribine reached is equal to or less than the total dose reached at the end of the induction period and said cladribine is administered daily at a daily dose of 10 to 20 mg for 1 to 7 days of each month; (iv) a cladribine-free period of at least 8 months (Claim 2). Note, “for 1 to 7 days” is interpreted with the broadest reasonable interpretation to comprise 1, 2, 3, 4, 5, 6, or 7 days. Dependent claims recite: wherein the conventional therapy is beta interferon or glatiramer acetate (claims 3-4); refractory patients have experienced 1-5 relapses in the year prior to the beginning of cladribine treatment (Claim 6); the combined duration of periods (i) and (ii) is 1 year (Claims 14 and 19); the combined duration of the periods (i)-(iv) is about 2 years (Claims 15 and 20); the cladribine is orally administered as tablets or capsules (Claim 16); wherein the tablets or capsules contain 10 mg of cladribine (Claim 17); wherein said cladribine is orally administered 1-3 times a day (Claim 18); and wherein the induction and maintenance periods last up to 2 months (Claims 22 and 24) or 3 months (Claims 23 and 25).
Grieb teaches administering cladribine to treat remitting-relapsing multiple sclerosis patients in 6 monthly courses wherein each course comprises 5 once-daily doses of either 10 mg oral or 5 mg subcutaneous cladribine (Materials and Methods and page 326, paragraph 3). Oral administration of 10 mg cladribine reads on Claims 16-17 as it is understood in the art that oral administration is routinely by tablet or capsule. The oral bioavailability of cladribine is about 50% (page 325, paragraph 2), and the average body weight of the patients was 62 kg (Materials and Methods) which means that the patients received a total dose of cladribine of about 2.4 mg/kg after the 6-month induction period ((5 mg X 5 days X 6 months) / 62 kg = 2.4 mg/kg). The 6-month induction period was followed by a 3-month cladribine-free period and 1-month maintenance cladribine courses at 9, 12, and 15 months (Materials and Methods). Grieb references a separate study wherein multiple sclerosis patients were treated with 4 to 6 monthly courses of cladribine dosed at 0.1 mg/kg/day for 7 days (page 326, paragraph 2), teaching that the induction period could last up to 4 months.
Grieb teaches a cladribine-free period of 3 months after induction and maintenance periods, not at least 8 months as required by Claim 2. Further, the shortest induction period taught by Grieb is 4 months.
Bodor teaches that cladribine can be administered to treat multiple sclerosis (paragraph spanning pages 1-2). The therapeutically effective amount described in the literature includes but is not limited to about 0.04 to about 1.0 mg/kg/day (page 22, paragraph 4). Bodor teaches administering 10 mg of cladribine in solid form once per day for a period of 5 to 7 days in the first month, repeated for another period of 5 to 7 days in the second month, followed by ten months of no treatment (page 23, paragraph 2). This regimen reads on a 2-month induction period followed by a 10-month cladribine-free period. Alternatively, the patient could be treated with 10 mg of cladribine in solid form once per day for 5 to 7 days per month for a total of six months, followed by eighteen months of no treatment (page 23, paragraph 2). Importantly, Bodor teaches that one of skill will appreciate that the therapeutically effective amount of cladribine can be lowered or increased by fine tuning and can be tailored to the needs of the patient (page 24, paragraph 1). Therapeutically effective amounts can be easily determined empirically by starting at relatively low amounts and making step-wise increments with concurrent evaluation of beneficial effect (page 24, paragraph 1). Further, the compositions, dosage forms, and methods are used in concomitance with continuous clinical evaluations by a skilled practitioner (physician or veterinarian) to determine subsequent therapy and inform whether to increase, reduce, or continue a particular treatment dose and/or alter the mode of administration (page 26, paragraph 1). In summary, Bodor teaches that induction periods can be as short as two months and cladribine-free periods can be as long as ten or eighteen months. Most importantly, Bodor teaches that cladribine form, dose, and treatment schedule are all results-effective variables which are routinely optimized by practitioners.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the method of treating refractory multiple sclerosis as taught by Grieb by shortening the induction periods and lengthening the cladribine-free periods as taught by Bodor. Additionally, Bodor teaches that dosages and administration periods are results-effective variables which can be optimized. In the case of administering cladribine, one of skill in the art would clearly recognize that doses must be timed sufficiently to maintain the efficacy of the drug in vivo and that the timing of dosages can be variable and could easily be optimized by a treating physician based on the needs and physiology of an individual patient. As such, the duration of treatment and the dosages would amount to nothing more than routine experimentation that can be optimized on an individual patient basis (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977); and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)). "Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." Further, MPEP § 2144.05.II states "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." As dosage optimization is routine in the art of medicine and pharmacology, the claims are considered to be prima facie obvious over the teachings of Grieb and Bodor.
Claims 2-25 are rejected under 35 U.S.C. 103(a) as being obvious over Grieb et al. Arch Immunol Ther Exp. 1995 in view of Bodor et al. WO 2004/087101 as applied to Claims 2 and 7-25 above, and further in view of Rieckmann et al. J Neurol 2004 (of record).
The teachings of Grieb and Bodor are outlined in the rejection above and teach a method of treating remitting-relapsing multiple sclerosis but do not explicitly teach that the patient population is refractory to a conventional therapy comprising interferon beta or glatiramer acetate (Claims 3-5) or wherein the patients have had at least one relapse during the year prior to the beginning of treatment (Claim 6).
Rieckmann teaches that escalating therapy or switching therapies in patients who do not respond to standard basic therapy (i.e., are refractory to conventional therapy), can be considered as alternative therapeutic protocols (page 1333, paragraph 3 and Fig. 2). Specifically, the baseline immunomodulatory treatments for multiple sclerosis (i.e., conventional therapies) can comprise interferon beta or glatiramer acetate (page 1333, paragraph 3). Drugs and therapy combinations still under experimentation should only be considered after failure of licensed monotherapies (page 1335, paragraph 2). For example, mitoxantrone is indicated for patients with progressive relapsing or secondary progressive courses of MS who failed on “basic” immunotherapy (page 1334, paragraph 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the method of treating remitting-relapsing multiple sclerosis as taught by Grieb and Bodor by specifically treating patients who are refractory to a conventional therapy as taught by Rieckmann. From the teachings of Rieckmann, it would be obvious to the person of ordinary skill to apply new experimental drugs and treatment regimens to multiple sclerosis patients who experience relapse or treatment failure on the frontline standard treatment options (such as interferon beta or glatiramer acetate). Administering a new treatment to patients within a year of relapse is obvious as the patients are in need of a treatment that has efficacy. The motivation to apply the ‘new’ treatment regimen taught by Grieb and Bodor to refractory patients is because switching treatment to another therapeutic or combination therapy for non-responders was part of a routine optimization protocol in multiple sclerosis therapy (Rieckmann et al. page 1335, col 1, para 3) at the time the instant invention was made. Therefore, the claimed invention as a whole is prima facie obvious over the prior art.
Double Patenting (Maintained)
1. Claims 2-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 15, 17-18, 20, 27-30, and 36 of US Patent 9,925,151 (of record). Note, the original rejection applied to Claims 2-18 and now applies to Claims 2-25 due to Applicant’s amendments.
2. Claims 2 and 7-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of US Patent 10,555,913 (of record). Note, the original rejection applied to Claims 2 and 7-18 and now applies to Claims 2 and 7-25 due to Applicant’s amendments.
3. Claims 2-25 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-16 of US Patent 7,713,947 (of record) in view of Rieckmann et al. J Neurol 2004 (of record). Note, the original rejection applied to Claims 2-18 and now applies to Claims 2-25 due to Applicant’s amendments.
4. Claims 2-25 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of US patent 8,377,903 (of record) in view of Rieckmann et al. J Neurol 2004 (of record). Note, the original rejection applied to Claims 2-18 and now applies to Claims 2-25 due to Applicant’s amendments.
5. Claims 2, 5-16, and 19-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of US Patent 12,377,056 (of record). Note, the original rejection applied to Claims 2 and 5-16 and now applies to Claims 2, 5-16, and 19-25 due to Applicant’s amendments.
Applicant's arguments filed March 12, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims as amended are not obvious over the claims of the cited patents but does not distinctly point out how the instant claims are distinct from the patented claims. Examiner maintains that the instant claims are obvious over the patented claims, especially considering that that dosages and administration periods are results-effective variables which can be optimized. One of skill in the art would clearly recognize that doses must be timed sufficiently to maintain the efficacy of the drug in vivo and that the timing of dosages can be variable and could easily be optimized by a treating physician based on the needs and physiology of an individual patient. As such, minor differences in duration of treatment (2 months vs 3 months) and dosages (1.5 mg/kg vs 1.75 mg/kg) would amount to nothing more than routine experimentation that can be optimized on an individual patient basis. The rejections are maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675