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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/29/2025 has been entered.
Election/Restrictions
Applicant’s election of Group II in the paper filed 3/03/23 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 § 818.03(a)).
In view of applicant’s amendment and upon reconsideration the restriction requirement has been withdrawn.
Claims 87, 89, 95, 96, 98, 100-103, 106-115 and new claims 116-117 are under consideration in the instant Office Action.
Information Disclosure Statement
The information disclosure statement filed 6/30/206 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. There is no English abstract submitted with the non-English foreign document. It has been placed in the application file, but the information referred to therein has not been considered.
Withdrawn Rejections
The rejection of claims 87, 89, 95, 96, 98, 100-103, and 106-115 under 35 U.S.C. 103(a) as being unpatentable over De Luca et al., U.S. Patent No. 8,377,903 (IDS) is withdrawn in view of the newly amended claims with the new requirements.
The rejection of claims 87, 89, 95, 96, 98, 100-103 and 106-115 under 35 U.S.C. 103(a) as being unpatentable over Mitosek-Szewczyk et al. (2013) in view of Clinicaltrials.gov (2013, IDS), Montalban et al. (2016, IDS), and Alvorez-Gonzalez et al. (May, 2017, IDS) is withdrawn in view of the newly amended claims with the new requirements.
New Rejections Necessitated by Amendment
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 87, 89, 95, 96, 98, 100-103, and 106-115 and new claims 116-117 are rejected under 35 U.S.C. 103(a) as being unpatentable over De Luca et al., U.S. Patent No. 8,377,903 (IDS) in view of Alvorez-Gonzalez et al. (May, 2017, IDS) and Kalincik et al., 2014 (instant PTO-892).
The new claim amendment of claim 87 “…wherein said cladribine is to be orally administered to patients also receiving or having received one or more disease modifying drugs other than cladribine, selected from the group consisting of alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and teriflunomide.” Reads as administering cladribine after having stopped the administration of one of the disease modifying drugs which include fingolimod and natalizumab.
The ‘903 patent teaches the treatment of ESPMS (a type of SPMS), said treatment comprising the oral administration of a yearly dose of about 1.75 mg/kg bodyweight cladribine. A 10 month cladribine-free period between administration is also taught (see particularly, column 3, line 49 – column 4, line 13 and column 8, line 12 – column 9, line 54). The ‘903 patent teaches definitions of total dose, total effective dose, bioavailability of cladribine from about 30%-90%, a week , a month and treatment comprises 2 to 4 years (see column 4, lines 19-65), as required in the instant claims 87, 89, 95, 96, 98, 100, 10, 107-111. The ‘903 patent teaches patients include 18-55 years old (see column 8, lines 11-15) as in instant claims 113-115. The ‘903 patent teaches relapsing-remitting multiple sclerosis (see ‘903 patent claim 17) as required in instant claims 101, 103 and 106. The ‘903 patent teaches the formulation of claim 112 (see column 14, Table 2 and lines 28-35).
Note that the optimization of dosages/concentrations/timing of administration would have been prima facie obvious to one of ordinary skill in the art at the time of filing, see MPEP 2144.05.I:
“[W]here 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 Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
As set forth in MPEP 2144.05 II.A.:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Claims 87, 95, 102 and 111 are included in the rejection because the bioavailability of the claims is a property inherent to the administration of oral cladribine.
The ‘903 fails to teach prior disease modifying drugs which include fingolimod and natalizumab, before switching to cladribine treatment.
Alvorez-Gonzalez et al. teach the treatment of PPMS through the administration of 60 mg subcutaneous (s.c.) cladribine. The dosage was chosen because:
“…60 mg cladribine/year in an individual weighing less than 90 kg resembles bio-equivalence with the oral 3.5 mg/kg dose used in the pivotal CLARITY MS study,” (page 4, column 2).
The reference further teaches:
“Whilst progressive MS, particularly PPMS is often characterized by a relative quiescence in terms of lesion activity detected on MRI, there are many exceptions from this rule, and PPMS should therefore be considered as one end of the spectrum of MS presentations (the other being relapsing MS with a high relapse rate), rather than an altogether distinct subtype. This view is supported by the revised classification of MS into active and non-active (1) relapsing and (2) progressive disease, and a lesser emphasis on “primary” versus “secondary” progression,” (page 2, column 2).
Treatment was considered “successful” and the drug was referred to as a “promising candidate” for the treatment of PPMS (page 4).
Alvorez-Gonzalez et al. teaches that MS subjects were previously treated with fingolimod 6 months before switching to cladribine treatment (see abstract) as now required in instant claim 87 and new claim 116.
Kalincik teaches both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis which are the disease modifying drugs as in instant claims 87 and 116-117.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘903, Alvorez-Gonzalez and Kalincik. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Kalincik teaches that both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis and are disease modifying drugs and Alvorez-Gonzalez teaches to administer cladribine after having stopped the administration of one of the disease modifying drugs. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 87, 89, 95, 96, 98, 100-103 and 106-115 and new claims 116-117 are rejected under 35 U.S.C. 103(a) as being unpatentable over Mitosek-Szewczyk et al. (2013) in view of Clinicaltrials.gov (2013, IDS), Montalban et al. (2016, IDS), and Alvorez-Gonzalez et al. (May, 2017, IDS) and Kalincik et al., 2014 (instant PTO-892).
Mitosek-Szewczyk et al. teach the treatment of SPMS through the administration of cladribine (see particularly, Materials and Methods). Said administration caused a reduction in the number of B cells, a reduction in the ratio of CD4+ T cells to CD8+ T cells, and an increase in the number of plasmacytoid dendritic cells (pDCs) in the patients (see particularly Results). The reference further teaches that pDCs “…favor the induction of Treg[s]” in patients (see particularly page 39).
Note that CD4+ T cells are considered to be the major proinflammatory T cell population in MS patients.
Alvorez-Gonzalez et al. teach the treatment of PPMS through the administration of 60 mg subcutaneous (s.c.) cladribine. The dosage was chosen because:
“…60 mg cladribine/year in an individual weighing less than 90 kg resembles bio-equivalence with the oral 3.5 mg/kg dose used in the pivotal CLARITY MS study,” (page 4, column 2).
The reference further teaches:
“Whilst progressive MS, particularly PPMS is often characterized by a relative quiescence in terms of lesion activity detected on MRI, there are many exceptions from this rule, and PPMS should therefore be considered as one end of the spectrum of MS presentations (the other being relapsing MS with a high relapse rate), rather than an altogether distinct subtype. This view is supported by the revised classification of MS into active and non-active (1) relapsing and (2) progressive disease, and a lesser emphasis on “primary” versus “secondary” progression,” (page 2, column 2).
Treatment was considered “successful” and the drug was referred to as a “promising candidate” for the treatment of PPMS (page 4).
Alvorez-Gonzalez et al. teaches that MS subjects were previously treated with fingolimod 6 months before switching to cladribine treatment (see abstract) as now required in instant claim 87 and new claim 116.
Clinicaltrials.gov (ONWARD trial) teaches the treatment of SPMS patients through the oral administration of 3.5 mg/kg body weight cladribine over the course of 2 years (see particularly, Intervention, page 6).
Montalban et al. teach the results of the ONWARD trial, i.e., a 13.5% reduction in relapses, a 63% less likelihood of having a relapse, and a reduced number of new T1-Gd+ lesions (see the entire document).
In view of the combined references it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to treat progressive forms of MS, e.g., PPMS and SPMS through the administration of cladribine. Both Mitosek-Szewczyk et al. and Alvorez-Gonzalez et al. teach successful treatment thereof. Regarding oral versus s.c. administration, oral administration is clearly superior if for no other reason than higher expected compliance (it was known at the time of filing that patients would have been more likely to swallow a tablet than inject themselves). Regardless, the ONWARD trial comprised oral treatment of SPMS patients at the dosage of the CLARITY trial and of the instant claims (3.5 mg/kg body weight cladribine over the course of 2 years).
Further note that the optimization of dosages/concentrations/timing of administration would have been prima facie obvious to one of ordinary skill in the art at the time of filing, see MPEP 2144.05.I:
“[W]here 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 Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
As set forth in MPEP 2144.05 II.A.:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Claims 88, 99, and 105 are included in the rejection because the bioavailability of the claims is a property inherent to oral cladribine. Finally note the teachings Alvorez-Gonzalez et al. that RRMS and SPMS/PPMS are not really different diseases, but rather merely different ends of the MS disease spectrum. Accordingly, the ordinarily skilled artisan at the time of filing would have had a reasonable expectation of success.
Further, Alvorez-Gonzalez et al. teaches that MS subjects were previously treated with fingolimod 6 months before switching to cladribine treatment (see abstract) as now required in instant claim 87 and new claim 116.
Kalincik teaches both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis which are the disease modifying drugs as in instant claims 87 and 116-117.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Mitosek-Szewczyk, Clinicaltrials.gov, Montalban, Alvorez-Gonzalez and Kalincik. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Kalincik teaches that both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis and are disease modifying drugs and Alvorez-Gonzalez teaches to administer cladribine after having stopped the administration of one of the disease modifying drugs. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
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 87, 89, 95, 96, 98, 100-103, and 106-115 and new claims 116-117 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 10,849,919 in view of Alvorez-Gonzalez et al. (May, 2017, IDS) and Kalincik et al., 2014 (instant PTO-892).
The claims of the ‘919 patent recite the treatment of SPMS (Claims 1, 3, 9, 18, 27, and 34) through the administration of oral cladribine (Claims 1, 14, 27) at a dosage of 1.75 mg/kg +/-0.2 mg/kg per year (Claims 2 and 9) for 2 adjacent months (Claim 4) over 4 to 5 days/week (Claim 6) for 2 treatment year (Claim 11) with 10 months between treatments (Claim 8). The bodyweight dosages of Claims 24 and 27 correspond to the bodyweight dosages of instant Claim 95. ‘919 does not teach previously treating with the disease modifying drugs, fingolimod and natalizumab, as now required in instant claims 87 and 116-117.
Alvorez-Gonzalez et al. teaches that MS subjects were previously treated with fingolimod 6 months before switching to cladribine treatment (see abstract) as now required in instant claim 87 and new claim 116.
Kalincik teaches both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis which are the disease modifying drugs as in instant claims 87 and 116-117.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘919, Alvorez-Gonzalez and Kalincik. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Kalincik teaches that both fingolimod and natalizumab are treatments for subjects with active relapsing-remitting multiple sclerosis and are disease modifying drugs and Alvorez-Gonzalez teaches to administer cladribine after having stopped the administration of one of the disease modifying drugs. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Response to Arguments
Applicant's arguments filed 8/29/2025 have been fully considered but they are not persuasive. Applicant argues that their cladribine has some sort of unexplainable bioavailability power, apparently, not available in other cladribines.
A review of the specification shows that the inventors used off-the-shelf 10 mg Mavenclad® tablets (see paragraph [0561] of the pre-grant publication). urning to the manufacturers website (mavenclad.com) we see that the drug comes in 1 strength only (10 mg) and no special characteristics are claimed. Also note that the composition further comprises the inactive ingredients that applicant argues against, e.g., sorbitol, magnesium stearate, hydroxypropyl betide, etc. Regardless, whatever properties Mavenclad® comprises are inherent and cannot be separated from the composition. Also note that even if Mavenclad® has some unexplainable bioavailability power applicant's claims would clearly require limitation to the use of Mavenclad® only.
Applicant simply reviews a claim followed by arguing against the references individually. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is the combined references that render the claimed method obvious. Also note that the motivation to combine the references need not come from the references themselves and it need not be applicant's motivation for designing the claimed method.
"The claims of U.S. Patent No. 10,849,919 do not disclose or suggest the specific method of treating a patient diagnosed as suffering from secondary progressive multiple sclerosis, with the specific cumulative administered fixed dose and course of treatment. Thus, the rejection should be withdrawn.
As set forth above:
"See MPEP 2144.05.I:
“[W]here 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 Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)."
Further, as set forth in MPEP 2144.05 II.A.:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Applicant argues that the ranges of the claims are not routine optimization.
The cladribine dosages of the claims clearly encompass a range and further note that the limitations of the claims include ranges of timing and patient body weight as well. Thus, the claims require routine optimization. Also note that the actual drug dosages within the claimed ranges are not firmly constant because the bioavailability varies, and is only defined in claims 87, 95, 102 and 111.
Further, in regards to the IDS references being lined through and not being considered is due to issue of how the applicant cited the references in the IDS. While the reference copies are mostly present, the format of the way the refence is cited does not meet the requirements of the MPEP 609 for the requirements of an IDS. Therefore, the references were lined through and not considered by the Office. For example, Applicant cites references as “Publisher’s record of Montalban…” ; “PubMed Record of Alvarez-Gonzalez…”; or “Order of motion of Stay…”. Applicant’s own example on page 19 of their remarks shows the issue of multiple document numbers, (both foreign and US PGPub number) being set forth in the Foreign Patent Documents for a foreign reference. One citation per provided reference that matches the specifically provided copy to the office. These are incorrect citations and it is not how the MPEP sets forth how prior art or foreign refences need to be cited in the IDS and that is the reason why the Examiner did not consider the references as previously indicated.
Conclusion
No claims are allowed.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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