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 .
Applicant’s amendments and remarks filed 11-20-25 have been considered.
The prior rejection under 35 U.S.C. 112(d) has been withdrawn in view of applicant’s claim amendments.
Claims 1-5, 25, 26, 34 and 36 are pending.
Claims 1-5 and 25 are under examination.
Claims 26, 34 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the replies filed on 10-10-23 and 1-26-24.
The prior rejections under 35 U.S.C. 112(b) and 35 U.S.C. 112(a) have been withdrawn in view of applicant’s claim amendments.
Claims 1-5 and 25 stand under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an engineered human CD8+ T cell derived from a human CD8+ T cell isolated from a human subject with multiple sclerosis (MS), the engineered CD8+ T cell comprising a heterologous nucleic acid encoding a T cell receptor (TCR) that binds to a self-antigen bound to a major histocompatibility complex (MHC) class II, wherein the heterologous nucleic acid encoding the TCR is from the heterologous nucleic acid encoding the B8 TCR, only insofar as the B8 TCR sequence is obtainable by the skilled artisan and only insofar as the murine B8 TCR is capable of binding the human MOG35-55 peptide; additionally, neither the instant specification nor the teachings of the art reasonably provide enablement for the breadth of claim 1 and dependent claims thereof as they read on the breadth of any engineered human CD8+ T cell derived from any human CD8+ T cell isolated from any human subject with multiple sclerosis (MS), wherein the engineered human CD8+ T cell comprises a heterologous nucleic acid encoding any TCR derived from any CD4+ T cell isolated from a human subject with MS. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Applicant has amended claim 1 to specify that the engineered human CD8+ T cell “derived from a human CD8+ T cell isolated from a human subject with multiple sclerosis (MS), the engineered CD8+ T cell comprising a heterologous nucleic acid encoding a T cell receptor (TCR) that binds to a self- antigen bound to a major histocompatibility complex (MHC) class II, wherein the heterologous nucleic acid encoding the TCR is derived from a CD4+ T cell isolated from the human subject with MS,” is able to bind to a self-antigen which “…is an antigenic peptide of or derived from myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), or myelin associated glycoprotein (MAG).”
Applicant argues: “The claims do not allow for any TCR from any CD4+ T cell from any human subject with MS. Rather, claim 1 makes clear that the CD4+ T cell and the TCR must be from the same subject whose CD8+ T cell is being engineered. In other words, the engineering relies on autologous engineering; NOT mixing cells/TCRs from any given subject. Moreover, claim 1 has now been amended to recite that the TCR ‘binds to a self-antigen bound to a major
histocompatibility complex (MHC) class II ... wherein the self-antigen is an antigenic peptide of
or derived from myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), or
myelin associated glycoprotein (MAG).’
Example 1 of the present application ‘demonstrate[s] that the underlying concept of the
engineered CD8+ T cell approach is sound as adoptive transfer of myelin specific engineered
CD8+ T cells can ameliorate established neuroinflammatory disease.’ Specifically, this Example
shows that engineered CD8+ T cells that express an anti-MOG TCR from CD4+ T cells
demonstrate antigen-specific lysis both in vitro and in vivo….Thus, the specification provides clear basis for the concept of using MOG-targeting TCRs from an MS model to treat the disease.”
Applicant further points to the teachings of Martinsen et al. (2022, provided by applicant as “Exhibit 1”) and Quarles (2007, provided applicant as “Exhibit 2”) as support for the proposition that “MBP and MAG are likewise both known to be associated with the pathogenesis of
multiple sclerosis,” and concludes “Because MOG, MBP, and MAG are all associated with pathogenesis of multiple sclerosis and CD8+ T cells targeting MOG can attenuate MS in an in vivo model (see Example 1), a skilled person would reasonably expect that engineering human a CD8+ T cell derived from a human CD8+ T cell isolated from a human subject with multiple sclerosis (MS) to express a heterologous nucleic acid encoding a T cell receptor (TCR) that binds to MOG, MBP, or MAG could be used to treat MS.”
(see Remarks at pages 5-6).
Applicant’s remarks have been considered but have not been found convincing essentially for the reasons of record.
As set forth in the prior Office Action, reviewing the teachings of the instant specification it appears that the only potential use of the engineered human CD8+ T cells of the instant claims is for the treatment of the autoimmune, neuroinflammatory disease which is multiple sclerosis. Moreover, as asserted by applicant the claimed engineered human CD8+ T cell “must be from the same subject whose CD8+ T cell is being engineered…the engineering relies on autologous engineering; NOT mixing cells/TCRs from any given subject.” Thus, the engineered human CD8+ T cells of the instant claims cannot comprise the murine CD4+ B8 TCR which was featured in Example 1 of the specification.
As further described in the prior Office Action at page 8, 1st and 2nd full paragraphs, “while…the teachings of the instant specification focus on the murine CD4 T-cell derived 2D2 and B8 TCRs as example of TCRs that could potentially be used to make as a CHASE-type cell capable of recognizing and eliminating APCs displaying self-antigen bound to MHC class II, and presumably, in turn, treating multiple sclerosis, the skilled artisan considering the teachings of Lees would have tremendous uncertainty as to how to identify a TCR from a human CD4 T cell that will function like the murine B8 TCR rather than 2D2 TCR which, when transferred to a murine CD8 T-cell and administered to an EAE mouse model, exacerbates rather than ameliorates disease.”
Moreover, expanding beyond the teachings of “Lees 2016” (showing 2D2 TCR (MOG35-55 specific) transduced CD8+ T cell exacerbate murine EAE); the prior Office Action at page 9 also pointed to “Anderson 2012” (showing 1C6 TCR (MOG35-55 specific) transduced CD8+ T cell also exacerbate murine EAE); and “Ford 1996” (showing CNS resident microglia commonly express MHC class II which may play role in suppressing MBP reactive CD4 T-cells that would otherwise be encephalitogenic – suggesting genetically modified CD8 T cells may be doing more harm than good by eliminating CNS resident microglia that would otherwise be terminating MBP-reactive CD4 T cells via apoptosis induction) to illustrate the tremendous uncertainty / unpredictability the skilled artisan would have to address in attempting to make and use the engineered human CD8+ T cells for the treatment of multiple sclerosis.
Applicant’s argument fails to establish how, in the face of the uncertainty / unpredictability in the art described above, the ordinarily skilled artisan would be able to make and use the engineered human CD8+ T cells of the instant claims. For example, given a single example in a mouse EAE model system based on the murine B8 CD4+ TCR, which appears to be uniquely able to engineer a murine CD8+ T cell into an EAE suppressive cell, and further given the teachings of Lees B6 and Anderson in which other murine CD4+ TCRs (2D2 and 1C6, also MOG35-55 specific) transferred to a murine CD8+ T cells were shown to exacerbate EAE, it is unclear how the ordinarily skilled artisan would be able to make and use the engineered human CD8+ T cells of the instant claims without having to resort to undue experimentation to identify if such cells having the required ability to treat multiple sclerosis can be produced.
While applicant points to Example 1 of the instant specification, and further points to the newly provided teachings of Exhibits 1 and 2 of Martinsen et al. (2022) and Quarles (2007) as support for the proposition that beyond MOG, “MBP and MAG are likewise both known to be associated with the pathogenesis of multiple sclerosis;” none of the above address the tremendous uncertainty that the skilled artisan would for making the claimed cells.
Indeed, in reviewing the teachings of Martinsen et al. (2022) the following teaching was noted at page 11733, right col.,, 2nd full paragraph:
“There are two forms of EAE, active and adoptive-transfer (AT), caused by different methods of induction. Active EAE is induced by immunizing with an array of tissue and myelin peptides. Among these are MBP and peptides derived from it. AT EAE is induced by immunization of a model animal with myelin-specific CD4+ T cells from a donor animal (Stromnes and Goverman
2006b).”
Stromnes et al. (Nat Protoc 1:1952–1960, 2006, cited herewith solely in response to applicant’s argument and provision of the teachings of Martinsen) teaches the following at page 1954, col. bridging paragraph, “…the induction of EAE by immunization of antigens emulsified in adjuvant is optimal for eliciting MHC class II-restricted CD4+ T cells but not MHC class I-restricted CD8+ T cells. This is an important limitation, as the potential role of CD8+ T cells in contributing to the pathogenesis of MS has been increasingly recognized25–28. ”
Thus, this teaching of Stromnes provides yet another reason the skilled artisan would have tremendous uncertainty for making the claimed cells because it raises the possibility that some CD8+ T cells may themselves contribute to the pathogenesis of MS.
Indeed, considering the references cited by Stromnes, in particular citation 27 of Stromnes which was readily available to the undersigned, leads to the teachings of Friese et al. (Brain (2005), 128, 1747–1763, cited herewith solely in response to applicant’s argument and provision of the teachings of Martinsen), which suggests, inter alia, that CD8+ T cells are clonally expanded in the blood and brain of MS patients, and that these clonally expanded T cells “…most probably recognize local target structures and cause damage to CNS tissue.” (see page 1753-54 bridging paragraph – 1st full paragraph; see also Friese Table 3).
Given the likely role for CD8+ T cells in MS pathogenesis as detailed by Friese, yet another uncertainty the skilled artisan would need to somehow address in attempting to produce the claimed engineered human CD8+ T cell that can be used for the treatment of MS is that some engineered human CD8+ T cells derived from a human subject with MS may comprise an endogenous TCR that is itself capable of recognizing local target structures and causing damage to CNS tissue, and, in turn, such cells may be net pathogenic in an MS patient.
In sum, in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trial and error experimentation to make and use the engineered human CD8+ T cells of the instant claims.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644