DETAILED ACTION
This action contains rejections not necessitated by amendment and is therefore non-final.
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 .
Status of Claims
The amendment filed 03/06/26 is acknowledged. Claims 1-10, 17, 19, 21, 23, and 25-27 are cancelled. Claims 11, 18, 22, 24, and 28 are amended. No restriction is imposed in this case. Claims 11-16, 18, 20, 22, 24, and 28 are pending and under review.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is the national
stage entry of PCT/US2021/023611 filed on March 23, 2021 and claiming the benefit of US
Provisional Application No. 62/993,645, filed on March 23, 2020. Claims 11-16, 18, 20, 22, 24, and 28 are given an earliest effective filing date of March 23, 2020.
Withdrawn Rejections
The rejection of claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of claim 18 now being dependent upon claim 11 and the clarification of the members of the grouping within claim 18 as symptoms of MOG-AAD.
The rejection of claims 11-16, 18, and 20-28 under 35 U.S.C. 101 for being directed to a natural phenomenon judicial exception without significantly more is withdrawn for incorporating the judicial exception into a practical application.
Claim Rejections - 35 USC § 112 (New)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11-16, 18, 20, 22, 24, and 28 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for diagnosing a subject for relapse of MOG-AAD, does not reasonably provide enablement for diagnosing a subject as having MOG-AAD. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Claim 11 recites detecting a level of TNFAIP3 in a sample, comparing said sample to a reference, and diagnosing a subject for MOG-AAD or relapse if the level is lower than the reference. The examples demonstrate an association between TNFAIP3 levels and disease activity in subjects already identified as having MOG-AAD and the ability to distinguish between remission and relapse status in this group based on the level of TNFAIP3 compared to a reference sample. However, the examples do not demonstrate how to use TNFAIP3 to establish an initial diagnosis. In fact, all examples are disclosed in reference to relapse status and at no point is a diagnosis of MOG-AAD made in a subject of unknown disease status. This gap is significant because the art recognizes that low expression of TNFAIP3 is also seen in other diseases such as multiple sclerosis (MS) [see Das et al., p. 6, col. 1, par. 3, lines 1-7; see Navone et al., p. 101, col. 1, discussion, par. 1, lines 8-10], yet neither the claims nor the specification teaches how to distinguish MOG-AAD from these other diseases based on TNFAIP3 expression alone. For example, the specification broadly defines a reference value as essentially any predetermined threshold, range, percentile, etc. [see instant specification p. 14, par. 1-2], and further discloses a decreased TNFAIP3 level as encompassing reductions ranges from 1-500% or more below the reference value [see instant specification, p. 15, par. 4]. Further, the instant drawings and specification depict about a 3-fold decrease in TNFAIP3 expression as indicative of relapse [see instant FIGs 3A-C and 5F]. The prior art likewise teaches that TNFAIP3 is decreased 2-3-fold in MS patients relative to healthy controls [see Gilli et al., FIGs 2B and 3B]. In view of the lack of specificity of TNFAIP3 to MOG-AAD, a person having ordinary skill in the art would be required to engage in undue experimentation to determine how to use a lower level of TNFAIP3 to specifically generate an initial diagnosis MOG-AAD over a different condition in which TNFAIP3 is similarly altered.
Therefore, claims 11-16, 18, 20, 22, 24, and 28 are rejected under 35 U.S.C. 112(a) for lack of enablement.
Claim Rejections - 35 USC § 103 (New)
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 11-16, 18, and 20-28 are rejected under 35 U.S.C. 103 as being unpatentable over Gilli et al., in view of Navone et al., and in further view Jarius et al., Das et al., Soloman et al., and dos Passos et al.
Claims 11-16, 18, and 20-28 are drawn to a method of treating MOG-AAD comprising detecting a level of TNFAIP3 in a sample, comparing it to a reference sample, and administering a treatment.
Gilli et al. discloses collecting a blood sample (instant claims 11 and 16) from a human subject [see p.2, study design, lines 1-2] (instant claim 20), detecting the level of TNFAIP3 in said sample using RT-PCR [see p. 4, col. 2, validation of selected transcripts, lines 1-3] (instant claims 11, 14, and 15) and western blot (a type of immunoblotting assay) [see p. 6, col. 1, protein expression, lines 1-3] (instant claims 11-13), comparing the level to a reference sample [see citations above for RTPCR and western blot], and diagnosing the subject with relapse of MS when the level is lower than the reference level [see fig. 2B; see abstract, conclusions, lines 1-2]. Navone et al. likewise teaches that TNFAIP3 is under-expressed in MS patients compared to healthy controls [see p. 101, col. 1, discussion, par. 1, lines 8-10), confirming TNFAIP3 as a disease associated biomarker measurable by conventional molecular biology techniques [see p. 102, col. 1, par. 4, lines 1-3].
The combination of Gilli et al. and Navone et al. do not teach or suggest measuring TNFAIP3 in MOG-AAD nor administering a treatment.
Jarious et al. teaches that MS and MOG-AAD (formerly MOG-IgG positive disease and MOG-EM) are inflammatory demyelinating autoimmune diseases of the central nervous system that share overlapping clinical manifestations, including optic neuritis, transverse myelitis [see abstract, lines 1-3], and inflammatory white matter lesions [see p. 7, col. 1, diagnostic criteria, lines 2-4), such that misdiagnosis frequently occurred [see abstract, lines 6-7]. Jarius et al. discloses a method of screening for MOG-EM based on expert consensus prior to MOG-IgG antibody testing. Examples of such criteria that support a diagnosis of MOG-EM include a good response to plasma exchange [see p. 6, col. 1, bullet “a”] (instant claim 11) and rituximab [see p. 6, col. 1, bullet “b”] (instant claim 22), good response to intravenous immunoglobulin (IVIG) [see p. 6, col. 1, par. 1, lines 5-9], and monophasic or relapsing acute optic neuritis and encephalitis [see p. 7, col. 2, bullet “1”] (instant claim 18). Additionally, Jarius et al. teaches that frequent flare ups after administration of methylprednisolone (also called IVMP, methylprednisolone is a prednisone derivative, immunosuppressant, and corticosteroid) for acute attacks are indicative of MOG-EM [see p. 3, table 1, bullet “x”], and that such steroids must be monitored and tapered off properly to prevent these negative side effects [see p. 2, col. 1, par. 1, lines 13-16] (instant claim 24). Of note, Jarius et al. does not exclude it’s use but instead suggests proper supervision.
The combination of these references does not teach or suggest measuring TNFAIP3 in MOG-AAD specifically or administering TNFAIP3 as a treatment.
Das et al. teaches that single nucleotide polymorphisms (SNP) near the TNFAIP3 gene are associated with a spectrum of chronic systemic inflammatory diseases and that mice with the TNFAIP3 gene deleted spontaneously develop autoimmune diseases [see Das et al., abstract, lines 7-11]. Das et al. notes that TNFAIP3 is one of the few genes that have been linked to multiple immune diseases [see Das et al., p. 6, col. 1, par. 3, lines 1-7], and TNFAIP3 heterozygous mice have increased susceptibility to psoriasis and atherosclerosis [see Das et al., p. 6, col. 2, par. 1, lines 14-15]. Furthermore, as discussed above, TNFAIP3 was known to be altered in MS, and it was also known in the art that MS and MOG-AAD were inflammatory demyelinating autoimmune diseases of the central nervous system that shared overlapping clinical manifestations, including optic neuritis, transverse myelitis, and inflammatory white matter lesions, such that misdiagnosis frequently occurred [See Solomon et al., p. 27, par. 5; also see Jarius et al., abstract]. Before the effective filing date of the instant application, both were known to involve immune-mediated demyelination and activation of common inflammatory pathways such as T-cell involvement, macrophage infiltration, and complement deposition [see dos Passos et al., p. 3, col. 1, par. 1, lines 7-14]. Taken together, because TNFAIP3 is demonstrated as a marker for autoimmune diseases broadly, is shown to be reduced in MS, and MS exhibits largely similar clinical and biological features as those associated with MOG-AAD, a person having ordinary skill in the art would have reasonably expected that TNFAIP3 would be altered in MOG-AAD, and it would have been similarly obvious to use TNFAIP3 associated MS literature in studies of MOG-AAD, with a reasonable expectation that it would provide similar information on disease status, given the analogous pathways and clinical features shared between MOG-AAD and MS.
Regarding the administration of TNFAIP3 as a treatment for MOG-AAD, given that TNFAIP3 is known to mediate inflammation, and that low levels of TNFAIP3 are known to induce relapse of autoimmune disease, it is prima facie obvious to administer TNFAIP3 to restore its levels and thereby modulate the underlying disease process with a reasonable expectation of success.
Therefore, claims 11-16, 18, 20, 22, 24, and 28 are rejected under 35 U.S.C. 103.
Response to Arguments
Applicant’s arguments filed 03/06/2026 have been fully considered but they are not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Applicant argues that the cited references all relate to MS and are completely silent to MOG-AAD as required in the present claims, and accordingly do not teach every limitation of the instant claims. This is not found persuasive as newly cited references Soloman et al., Jarius et al., and dos Passos et al. individually and collectively disclose the biological mechanisms and treatments that are shared in both MS and MOG-AAD pathology. In line with this, the rejection asserts that the prior art provides sufficient information that a person having ordinary skill in the art would have been motivated to explore TNFAIP3 in a disease context closely related to MS with a reasonable expectation of success. The biological mechanisms that support this rationale are expanded upon below.
Applicant argues that because Multiple Sclerosis (MS) and MOG-AAD have distinct clinical features and varied response to treatments, a person of ordinary skill in the art would have had no reason to believe that a gene that was found to be under-expressed in MS patients could be associated with MOG-AAD. This is not found persuasive because the rejection does not rely on the assumption that all therapies effective in MS will necessarily be effective in MOG-AAD, but instead relies upon the recognition that MS and MOG-AAD are related inflammatory demyelinating disorders sharing pathogenic mechanisms, including the inflammatory mechanisms discussed above. That is, TNFAIP3 existed as a biomarker for autoimmune diseases broadly, it was known as a biomarker for MS, and it was known that MS shared many biological indicators and pathways associated with MOG-AAD. More specifically, both diseases were known to involve immune mediated demyelination and activation of common inflammatory mechanisms, including T-cell mediated responses, macrophage infiltration, and complement associated pathology as discussed previously [see dos Passos et al., p. 3, col. 1, par. 1, lines 7-14]. The prior art teaches that TNFAIP3 negatively regulates NF-kB and TNF receptor driven inflammatory pathways, thereby reducing inflammatory activation of immune cells such as macrophages, dendritic cells, T cells, and B cells, and subsequently reducing autoimmune responses like autoantibody production and immune complex associated disease phenotypes that lead to complement activation [see Das et al., p. 4-5]. Given that MOG-AAD and MS share immunopathological mechanisms as described above, and TNFAIP3 functions as a regulator of the upstream autoimmune and inflammatory pathways common to both conditions, a person having ordinary skill in the art would have understood TNFAIP3 to be a relevant and therapeutic target for both conditions with predictable anti-inflammatory effects common to many autoimmune diseases.
Regarding Applicant’s argument that certain therapies used in MS provide incomplete control of MOG-AAD, this does not demonstrate that the diseases lack biological overlap and instead acknowledges that such therapies exert some level of therapeutic effect. Furthermore, these outcomes reflect drug-specific mechanisms and not shared upstream immune regulation similar to the modulatory effects of TNFAIP3.
Applicant argues that a person of ordinary skill in the art would have had no reason or motivation to use these references as guidance for treating MOG-AAD. This is not found persuasive because Jarius et al. specifically teaches that immunosuppressive agents such as methylprednisolone and rituximab can be used to treat MOG-AAD as discussed above. Further, as discussed above, the prior art teaches that TNFAIP3 negatively regulates NF-kB and TNF receptor driven inflammatory pathways, thereby reducing inflammatory activation of immune cells such as macrophages, dendritic cells, T cells, and B cells, and subsequently reducing autoimmune responses like autoantibody production and immune complex associated disease phenotypes that lead to complement activation [see Das et al., p. 4-5]. Given that MOG-AAD and MS share immunopathological mechanisms, and TNFAIP3 functions as a regulator of the upstream autoimmune and inflammatory pathways common to both conditions, increasing TNFAIP3 would provide predictable anti-inflammatory effects.
Applicant argues that a person of ordinary skill in the art would have had no reasonable expectation of success in using the cited references to treat MOG-AAD or arrive at the claimed invention. This is not found persuasive for the reasons discussed above. Additionally, the claimed treatment methods for MOG-AAD of an immunosuppressive agent, IVIG, rituximab, and prednisone derivatives, were known at the time of the invention and were also used in the treatment of MS as discussed above.
Applicant argues that it is the present inventors who shows for the first time the association of TNFAIP3 levels with MOG-AAD. This is not found persuasive because TNFAIP3 existed as a biomarker for autoimmune diseases broadly, it was known as a biomarker for MS, and it was known that MS shared many biological indicators and pathways associated with MOG-AAD. Accordingly, it would have been obvious to explore TNFAIP3 as a biomarker in MOG-AAD because TNFAIP3 would have been expected to function as a critical upstream regulator of immune responses in both conditions.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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/TIRONE D. JOHNSON/Examiner, Art Unit 1675
/Adam Weidner/Primary Examiner, Art Unit 1675
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