DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 04 February 2026 have been entered. Claims 1-2, 7, 20-23, 25, 27-33, and 35-38 were previously pending in the application. No claims have been cancelled and no new claims have been added by Applicant. Claims 1-2, 7, 20-23, 25, 27-33, and 35-38 are currently pending in the application. Claims 1 and 2 are independent claims.
The election of Group I, drawn to a method of treating a human subject having a condition mediated by a deficiency in myelin, remains in effect in the instant application.
The following election of species remains in effect in the instant application:
genes: TCF7L2;
Modulators: Trichostatin A;
Glial progenitor cells source: derived from embryonic cells; and
Conditions: multiple sclerosis.
Claims 2 and 35-38 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 23, 25, 31, and 33 remain withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 7, 20-22, 27-30, and 32 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/017737, filed 11 February 2020, which claims priority to U.S. Provisional Application No. 62/805,202, filed 13 February 2019.
Thus, the earliest possible priority for the instant application is 13 February 2019.
Specification
The objection to the specification of the disclosure for reciting trade names and/or marks without the appropriate symbols and/or generic terminology is withdrawn in view of the amendment to the specification.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
**The following new rejection is necessitated by amendments to the claims.
Amended, previously presented, and original claims 1, 7, 20-22, 27-30, and 32 are rejected 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. Claims 7, 20-22, 27-30, and 32 are included in this rejection due to their dependence on independent claim 1.
Amended claim 1 newly recites “resident” in line 9 to modify “glial progenitor cells in the subject”, which is indefinite because it is unclear whether Applicant intends for “resident glial progenitor cells” to mean anything other than its broadest reasonable interpretation, wherein “resident glial progenitor cells” are glial progenitor cells which are in the subject. The specification does not provide a limiting definition for the term “resident” which would indicate any scope other than merely present within the subject. However, by reciting “resident glial progenitor cells in the subject”, it is unclear whether Applicant intended to use the term “resident” redundantly with “in the subject” or whether Applicant intends for “resident” to encompass a more limited scope. As such, the metes and bounds of the claim cannot be determined.
Original claim 32 recites the term “the glial progenitor cells” in line 1. There is insufficient antecedent basis for this limitation in the claims. Claim 32 is dependent on claim 28, which is dependent on claim 1. Amended claim 1 newly recites “resident glial progenitor cells” in line 9. Claim 28 recites, “human glial progenitor cells” in line 2. Therefore, it is unclear to which glial progenitor cells claim 32 is referring. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(a)- Enablement
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.
**The following new rejection is necessitated by amendments to the claims.
Amended, previously presented, and original claims 1, 7, 20-22, 27-30, and 32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to a method of treating a human subject having a condition mediated by a deficiency in myelin. The method comprises administering a modulator of a cell signaling pathway under conditions effective to treat the condition, wherein the modulator is trichostatin A (TSA) and the signaling pathway is transcription factor 7 like 2 (TCF7L2) signaling pathway, and wherein the treatment is through inducing differentiation of resident glial progenitor cells (GPCs) in the subject into oligodendrocytes via the one or more modulators, wherein said administering is carried out using intracerebral delivery, intrathecal delivery, intranasal delivery, oral delivery, or via direct infusion into brain ventricles (claims 1, 7, 20, 21, 22, and 27, as elected). The claims additionally recite wherein the method further comprises administering to the selected subject a preparation of human glial progenitor cells derived from embryonic stem cells (claims 28 and 32, as elected).
This rejection addresses the absence of an enabling disclosure for treating multiple sclerosis by administration of TSA to induce differentiation of resident glial progenitor cells (GPCs) in the subject into oligodendrocytes via the TSA.
This issues were identified by the Office after analysis of the disclosure provided by the specification. The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the instant methods. The Wands analysis and supporting specific evidence are presented below for the identified issue.
The specification generically teaches TSA as an exemplary modulator of Notch signaling [0058], an exemplary modulator of cAMP signaling [0061], and an exemplary modulator of TCF7L2 signaling [0070]. The specification also generically teaches to administer modulators of TCF7L2 signaling to treat a human subject having a condition mediated by a deficiency in myelin [0006, 0016, 0068]. The specification further teaches that TCF7L2 signaling is a major driver of myelination [0120].
Additionally, the working examples teach a remyelination model system wherein human GPCs (hGPCs) are neonatally engrafted, followed by treatment with cuprizone to induce demyelination, and removal of cuprizone to allow remyelination, wherein engrafted hGPCs generate new oligodendrocytes and remyelinate demyelinated axons following cuprizone removal [0009, 0104]. The specification teaches a transcriptomic analysis comparing gene expression in post-cuprizone hGPCs compared to control hGPCs engrafted into mice without cuprizone treatment, wherein TCF7L2 signaling is strongly upregulated in remyelinating neonatally-transplanted hGPCs following removal of cuprizone compared to neonatally-transplanted hGPCs in mice without cuprizone treatment [0107, 0120, 0131]. As such, the specification merely identifies TCF7L2 signaling as a pathway differentially expressed between hGPCs in a mouse recovering from cuprizone-induced demyelination vs hGPCs in a mouse not treated with cuprizone, and subsequently extrapolates prophetically to assume a beneficial effect of modulating the TCF7L2 signaling pathway sufficient for both inducing differentiation of hGPCs into oligodendrocytes and promoting remyelination to treat multiple sclerosis.
The specification does not provide any data or experiments teaching any administration of any modulators to any subjects. The specification does not provide any data for any treatment of any condition mediated by a deficiency in myelin. Specifically, the specification does not provide any data for any TSA administration, any data for any administration modulating TCF7L2 signaling in any subject, nor any data for the treatment of multiple sclerosis (MS). Further, the specification does not provide any data showing that TSA can induce differentiation of resident glial progenitor cells into oligodendrocytes either in vitro or in vivo. As such, the working examples do not exemplify the administration of TSA to modulate TCF72L signaling to treat multiple sclerosis in a subject having MS.
Applicant filed a declaration of the inventor, Dr. Steven A. Goldman, under 37 C.F.R. 1.132 (“Goldman Declaration”) stating, “even if mere treatment of astrocytes with TSA could convert them [astrocytes] into oligodendrocyte progenitor cells, such treatment would result in unwarranted effects” [page 4 ¶ 2] and “TSA is a non-specific HDAC inhibitor, so use of TSA itself would have unintended consequences” [page 4 ¶ 4]. As such, the Goldman Declaration asserts the unpredictability of TSA as a modulator for promoting differentiation of oligodendrocytes.
Additionally, the art at the time of filing teaches that the broad HDAC inhibitor TSA was used to show that HDAC activity is necessary for the differentiation of OPCs in culture, and that HDAC activity is critical for the induction of myelination in the rat corpus callosum [Jacob et al. 2011, Mol. Neurobiol., 44, 303-312, column 9 ¶ 2]. Jacob also teaches that TSA is able to reprogram OPCs into neural stem-like cells capable of neurogenesis by activating re-expression of the stem cell marker Sox2, and that HDAC inhibition by TSA correlated with the reactivation of a dozen other genes that mark the stem cell state with silencing of oligodendrocyte lineage-specific genes [column 9 ¶ 3]. Further, Jacob teaches that HDACs promote differentiation into OPCs in complex ways [column 10 ¶ 1]. Additionally, Jacob teaches that three proteins which prevent oligodendrocyte differentiation (i.e., Id2, Egr1, and Sox11), and thus need to be silenced for induction of the differentiation process, are TSA-sensitive early targets of HDACs [column 10 ¶ 2]. Jacob teaches that in summary, the use of pharmacological HDAC inhibitors provided proof of concept that histone deacetylation is crucial for oligodendrocyte differentiation [column 10 ¶ 3]. Jacob further teaches that silencing of HDAC1 and HDAC2 in a cuprizone-mediated demyelination-remyelination model prevented the expression of oligodendrocyte differentiation markers [column 12 ¶ 1].
Neither the specification nor the art at the time of filing teaches treating multiple sclerosis by administration of TSA to induce differentiation of resident glial progenitor cells (GPCs)/OPCs in a subject into oligodendrocytes by the action of the HDAC inhibitor TSA. Thus, in view of the teachings of Jacob that treatment with the HDAC inhibitor TSA prevents the differentiation of OPCs into oligodendrocytes, the further teachings of Jacob that HDACs are critical for promoting the differentiation of oligodendrocytes, Applicant’s complete lack of teachings for TSA inducing differentiation of oligodendrocytes, Applicant’s complete lack of data for administering TSA to any subject, Applicant’s complete lack of data for any treatment of multiple sclerosis, and the breadth of the claims, the ordinarily skilled artisan would have considered treating multiple sclerosis by inducing differentiation of OPCs/GPCs into oligodendrocytes by administration of TSA as highly unpredictable. As such, it would have required undue experimentation to practice Applicant’s invention as claimed.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and original claims 1, 7, 20-22, 27-30, and 32 under 35 U.S.C. 103 as being unpatentable over Jayaraman et al. [2017, Neurobiology of Disease, Vol. 108, 1-12, cited in a prior action]; in view of Plemel et al. [2017, Nature Review Drug Discovery, Vol. 16, 617-634, cited in a prior action]; Kennedy et al. [2016, Cell Reports, Vol. 169100, 2666-2685, cited in a prior action]; Ross et al. [2004, Journal of Neuroimmunology, Vol. 151, 66-77, cited in a prior action]; Goldman et al. [2012, Science, Vol. 338, 491-495, cited in a prior action]; Windrem et al. [2008, Cell Stem Cell, Vol. 2, 553-565, cited in a prior action]; Franklin & ffrench-Constant [2008, Nature Reviews Neuroscience, Vol. 9, 839-855, cited in a prior action]; Zare et al. [2018, Regenerative Medicine, 13(7), 803-819]; and Zare et al. [2019, Iranian Journal of Pharmaceutical Research, 18(1), 286-295, published online 11 February 2019 (e.g., 1397/11/22 in the Persian calendar)], is withdrawn in view of Applicant’s claims which now recite wherein the treatment is through inducing differentiation of resident glial progenitor cells in independent claim 1.
Examiner’s Note
As indicated in the previous action, note that U.S. Patent No. 12,303,549, hereafter referred to as the ‘549 patent, claims recite a method of treating or inhibiting onset of Huntington’s disease, which is a condition mediated by a deficiency in myelin, comprising administering to the selected subject one or more modulators of a gene or protein encoded thereof involved in the NKX2.2-OLIG2-SOX10-MYRF regulatory cascade, including the TCF7L2 gene, wherein the method results in an increase in myelination in the subject (claims 1 and 2). Therefore, the ‘549 patent claims encompass the instant claims in that the modulator is broadly recited, and the disease is a species of the broadly recited conditions of the instant application claims. However, the ‘549 claims do not recite the instantly elected disease multiple sclerosis nor the instantly elected modulator trichostatin A. As such, instant application is not subject to a double patenting rejection over the ‘549 patent claims at this time.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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