DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 03/23/2026, in which claims 32 and 41 are amended and claims 1-31 and 34-36 are canceled.
Claims 32-33 and 37-45 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/GB2021/053182 filed on 12/06/2021, which claims foreign priority to UNITED KINGDOM 2019460.1 filed on 12/10/2020.
Information Disclosure Statement
The information disclosure statement (IDS) dated 03/04/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Objections and Rejections Withdrawn
Applicant’s amendment and remarks, filed 03/23/2026, with respect that claims 35 and 41 are objected to as lacking a period has been fully considered and is persuasive, as claim 41 has been amended to include a period, and claim 35 has been canceled. This objection has been withdrawn.
Applicant’s amendment and remarks, filed 03/23/2026, with respect that claim 36 is rejected under 35 U.S.C. 112(d) has been fully considered and is persuasive, as claim 36 is canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/23/2026, with respect that claims 32-33 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Freeman in view of Varadkar has been fully considered and is persuasive, as claim 36 is canceled, and the scope of claim 32 has been amended to limit that the patient is known to have antibodies to NMDA receptor. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/23/2026, with respect that claims 37-45 are rejected under 35 U.S.C. 103 as being unpatentable over Freeman in view of Varadkar as applied to claim 32, further in view of Costello has been fully considered and is persuasive, as the scope of claim 32 has been amended to limit that the patient is known to have antibodies to NMDA receptor. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/23/2026, with respect that claims 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Dale in view of Ceronie has been fully considered and is persuasive, as claims 34-36 are canceled. This rejection has been withdrawn.
The following are maintained or new grounds of rejection necessitated by Applicant’s amendment, in which claim 32 is amended to incorporate the limitation of canceled claim 35 to now recite wherein the patient is known to have antibodies to NMDA receptor.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 32-33 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Dale et al. (Developmental Medicine & Child Neurology, 2012; PTO-892 09/23/2025) in view of Ceronie et al. (Journal of Neurology, 2018; PTO-892 09/23/2025).
Dale discusses the pathology and treatment of N-methyl-D-aspartate receptor (NMDAR) encephalitis (abstract). Dale teaches NMDAR encephalitis is an autoimmune encephalitis defined by the presence of autoantibodies that bind to the NMDAR (abstract). The instant specification defines antibodies to the NMDA receptor as anti-brain antibodies (Specification page 5, paragraph 4). Cerebrospinal fluid immunophenotyping has demonstrated B-cell expansion in opsoclonus–myoclonus and neuromyelitis optica, and has been used to support the humoral autoimmune hypothesis, and the use of drugs that deplete B-cell populations such as rituximab (page 191, paragraph 3). In particular, Dale discloses a study of NMDAR encephalitis patients observed to have very significant B-cell expansion (page 192, paragraph 3), and teaches that these B-cells are CD19+ B-cells (page 192, paragraphs 1-2). Dale teaches that this finding supports the use of drugs, such as rituximab, that deplete B-cells in severe or refractory cases of NMDAR encephalitis (abstract).
The teachings of Dale differ from that of the instantly claimed invention in that Dale does not teach administration of cladribine.
Ceronie discloses the mechanism of action of oral cladribine (abstract). Ceronie teaches that immunophenotyping data demonstrated that effective doses of oral cladribine induced marked (80–85%) CD19+ B cell depletion (page 1200, paragraph 4). Cladribine therefore behaves as a chemical CD19-depleter (paragraph bridging pages page 1207-1208).
It would have been prima facie obvious to administer the cladribine of Ceronie to the NMDAR encephalitis patients of Dale before the effective filing date of the claimed invention to arrive at the instantly claimed invention because the NMDAR encephalitis patients of Dale demonstrated B-cell expansion of CD19+ B-cells, and Ceronie teaches that cladribine therefore behaves as a chemical CD19-depleter. One of ordinary skill in the art would have a reasonable expectation of success because Dale suggests that drugs that deplete B-cells should be used in severe or refractory cases of NMDAR encephalitis.
Regarding instant claim 33, one of ordinary skill in the art would have been motivated to treat a patent with refractory AE using the cladribine if Ceronie because Dale teaches that drugs that deplete B-cells may be useful in the treatment of severe or refractory cases of NMDAR encephalitis (abstract).
Claims 37-38 and 40-45 are rejected under 35 U.S.C. 103 as being unpatentable over Dale et al. (Developmental Medicine & Child Neurology, 2012; PTO-892 09/23/2025) in view of Ceronie et al. (Journal of Neurology, 2018; PTO-892 09/23/2025), as applied to claim 32, further in view of Costello et al. (Journal of Neuroscience Nursing, 2008; IDS 06/09/2023).
The combined teachings of Dale and Ceronie teach the method of claim 32, as discussed in detail above. Furthermore, Ceronie discusses the mechanism of action for oral cladribine, which had been recently licensed for relapsing multiple sclerosis (abstract: background).
The combined teachings of Dale and Ceronie differ from that of the instantly claimed invention in that they do not teach the dose form of the cladribine.
Costello discusses the formulation of cladribine in the treatment of MS (abstract). Costello teaches that cladribine targets both T and B lymphocytes (page 276, paragraph 1). Costello discloses an oral formulation of cladribine with improved safety profiles and improved routes of administration (abstract). Costello teaches that this formulation is in the form of a 10 mg tablet of oral cladribine. The number of tablets administered is standardized based on patient weight (page 278, paragraph 2). One treatment course with cladribine tablets is defined as once-daily therapy (page 278, paragraph 4). Costello teaches that oral formulations can be of great benefit to patients in terms of convenience, quality of life, and improved adherence (page 276, paragraph 1).
One of ordinary skill in the art would have been motivated to administer the cladribine in the method of Dale and Ceronie in the form of the oral cladribine tablets taught by Costello because Costello teaches that oral formulations can be of great benefit to patients in terms of convenience, quality of life, and improved adherence. One of ordinary skill in the art would have had a reasonable expectation of success because Costello teaches that this oral formulation is used in the treatment of MS and Ceronie teaches the mechanism of action for the administration of oral cladribine for the treatment of relapsing multiple sclerosis.
Response to Arguments
Applicant's arguments filed 03/23/2026 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that, as Dale teaches that the B-cell expansion in NMDAR encephalitis is observed in the CSF, but not the peripheral blood, and Ceronie is silent on the effect of cladribine on B-cells in CSF, therefore one of ordinary skill in the art would not have been motivated to treat the patients of Dale using the cladribine of Ceronie (Remarks, paragraph bridging pages 9-10 to page 10, paragraph 2). Applicant states that Ceronie does not broadly disclose cladribine as a chemical CD19-depleter, but instead explicitly refers to the peripheral blood context (Remarks, page 10, paragraph 1). This is not persuasive.
Ceronie teaches that Cladribine behaves as a chemical CD19-depleter because the germinal centres of B cells are particularly vulnerable to inhibition by cladribine due to the high level of proliferation and DCK expression (paragraph bridging pages 1207-1208), and that this, coupled with the slow repopulation kinetics of B cells, results in the memory B cell depletion by cladribine (abstract: conclusions). Thus Ceronie teaches a mechanism of cladribine action that is not limited to B cells in the peripheral blood, but would instead be expected to have an effect on B cells regardless of B cell location.
Applicant further argues that one of ordinary skill in the art would not have a reasonable expectation of success in treating the patients of Dale using the cladribine of Ceronie because Ceronie only provides data regarding administration to the peripheral blood, and not directly to the CSF (cerebrospinal fluid). This is not persuasive.
Applicant is arguing that Ceronie teaches only administration to the peripheral blood and thus the orally administered cladribine of Ceronie would not be expected to affect the CSF. However, the instant rejection is based on the obviousness of substitution of the B-cell depleting drugs of Dale for the B-cell depleting drug of Ceronie in a method of treating encephalitis. The instant rejection is not necessarily limited to a method comprising oral administration. It would be prima facie obvious for one of ordinary skill in the art to administer cladribine by the most effective route. In addition, the instant claim is not limited to any particular route of administration.
Furthermore, Applicant's argument amounts to an argument that because Ceronie does not describe the complete pharmacokinetics of orally administered cladribine one of ordinary skill in the art would have no way of knowing whether orally administered cladribine was capable of effecting B-cells inside the blood brain barrier. However, establishing the pharmacokinetics of a drug is routine and conventional in the pharmaceutic arts. Ceronie teaches that an oral-cladribine prodrug was shown to be very effective at controlling relapsing MS and was first licensed in 2011 (page 1200, paragraph 3). Ceronie cites articles on cladribine published as early as 1993, including "The treatment of chronic progressive multiple sclerosis with cladribine" published by Beutler et al. in 1996 (references 17 and 32, found on page 1209). Thus Ceronie teaches that cladribine is a long established drug that has passed clinical trials, and thus one of ordinary skill in the art would have known that studies of the pharmacokinetics of cladribine were readily available. To give a further example and not necessary for the case of obviousness, the abstract of Liliemark's "The Clinical Pharmacokinetics of Cladribine", published 1997, states that the concentration of orally administered cladribine in the cerebrospinal fluid is 25% of that in plasma in patients without central nervous system disease; in patients with meningeal disease, the cladribine concentration in the cerebrospinal fluid exceeds that in plasma.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 03/23/2026.
Conclusion
No claims are 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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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