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 the Claims
Claims 1,7-14 and 16-17 are currently pending in the Application and examined on the merits below.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7-14 are rejected under 35 U.S.C. 103 as being unpatentable over Eshhar (WO2008095141, of record) and further in view of June (WO2014012001A2, of record), Lim (Journal of Immunology, 2005 pp. 4180-4183, of record), and Nakasone (International Journal of Hematology 2015, 101:438-451, of record).
Instant claim 1 describes a method of improving pulmonary function in a human subject suffering from GVHD through administration of human Treg cells modified to express a CD19 directed chimeric antigen receptor.
In regards to the claim 1 the disclosure of Eshhar describes methods of treatment of autoimmune or alloimmune disease such as GVH (graft versus host disease-GVHD) through administration of Treg cell which have been genetically modified to express a chimeric receptor molecules (“T-body” chimeric fusion protein-p20, 3-11). The disclosure of Eshhar describes that the chimeric signalling molecules introduced to the Treg cells may comprise a leader sequence (L) an antigen binding domain (VL-VH), hinge (H-CD28 derived) a transmembrane domain (TM-CD28 derived), and intracellular signalling domains (FcRgamma+CD28 costimulatory)(figure 1). The chimeric receptor is comprised of scFv binding moiety (derived from an antibody)(p20, 16-23). The disclosure of Eshhar describes that pathogenic cells of autoimmune disease pathology commonly manifest as inflammation at the disease site/target organ caused by release of inflammatory (“proinflammatory”) cytokine by T cells and other cells that contribute to the activation steps and effector pathways of immune/inflammatory processes (p7, 7-16). Specifically the disclosure indicates that B lymphocytes and plasma cells are among this type of cell, and may provide for processes which lead to destruction of target cells and tissue damage (p7, 7-16). Thus the disclosure of Eshhar indicates that chimeric receptor Treg of the invention may be targeted to antigen such as MHC which is an antigen found on B cells (claim 27) and the disease which may be treated is GVH (p31, 18-25). GVH is described as a common occurrence in human organ transplant and allogeneic bone marrow transplant situations.
With respect to the particular B cell antigen which is targeted by a CAR modified Treg cell the disclosure of Eshhar recognizes that CD19 is a target antigen that is previously utilized in CAR-T cell preparations for the in-vitro pre-clinical validation of cytotoxicity directed to B cell derived acute lymphoblastic leukemia target cells (p38, 11-19). Eshar does not specifically indicated that Treg may be directed to CD19 which may be found on B lineage cells. Furthermore the disclosure of Eshhar does not describe that chronic GVH as a subspecies of GVH may be treated by the disclosed method. Eshhar does however describe that Treg cells can be specific for effector cells of cells of hematopoietic lineage that participate in inflammation in order to suppress an inflammatory condition or undesired immune response (Eshhar p16-17) of which B cells are considered as producers of auto-antibodies which important in particular manifestations of “chronic” GVH.
However the further disclosure of Nakasone describes that effector immune B cells are implicated in the pathophysiology of cGVHD (p440) and that inhibiting B cell function through outright deletion of pathological B cells or more importantly for the present consideration “modulation “ of B cell immune response through influencing pathological B effector cells is an effective interventional treatment for chronic GVHD (p441-442). Additionally the further supporting disclosure of Lim presents data supporting a direct role for Treg cells in the suppression of B cell humoral responses through direct inhibition of Ig class switch recombination in germinal centers (typically lymph nodes) (introduction). This characteristic of Treg cells is described as important in maintaining immune tolerance in the immune globulin (antibody) response (discussion, p4183) as such important in preventing certain types of autoimmunity from occurring. The further disclosure of June provides a previously clinically validated CD19 antigen targeted chimeric antigen receptor that are disclosed as useful in the treatment of GVHD (p3, 10-15). It would therefore be obvious to utilize the well characterized CD19 antigen targeted CAR (B cell targeted) described by June and Eshhar, comprised in Treg cells as in the reference of Eshhar, for the purposes of beneficially targeting pathogenic B cells in a chronic GVHD disease setting as would be effectively disclosed by Lim described above to achieve the effect of inhibiting B cell effector cell responses directly, inhibiting downstream autoantibody production implicated in the pathology of the cGVHD as described by Nakasone.
With regards to the further added limitation of persistence of modified cells in the subject as previously described for the claim 9, The disclosure of June investigates the persistence of CD19 transduced T cells in patients infused with said cells for purposes of treating B cell cancers. The disclosure of June et al, as previously described would include Treg cells and these cells were found to persist in the subject for up to 18 months (p28, 30-34; p29, 1-5; figure2; fig8). The disclosure of June therefore offers support for the indication that the persistence of cells in subjects is an expected latent property of method made obvious by the combined disclosure above.
In regards to claims 7 and 8 the disclosure of Eshhar describes that it is known in the art that engagement of antigen (in this case the chimeric receptor) and delivery of intracellular signals that include for example CD3zeta and CD28 and or 4-1BB signals results in enhanced survival of said engaged cells thereby resulting in strong antigen specific CD4+ T cell memory (p37-38, last paragraph-first paragraph). Additionally, for example with respect to in-vivo proliferation of modified Treg cells the disclosure of Eshhar additionally describes that (p57 example IV), TNP-redirected (comprising a CAR) Treg cells illustrated in-vivo proliferation when exposed to activation by antigen. It would be therefore be obvious to expect that similarly activated (through the B cell targeted T cell receptor) chimeric antigen receptor comprising T cells would similarly proliferate and form memory Treg cells upon continued exposure to antigen (on resident B cells such as MHC antigen) in-vivo in human patients.
With respect to claim 9 as indicated above Eshhar is silent with respect to persistence of chimeric antigen receptor transduced Treg cells in humans that may be infused with said cells, in the time frame of 12 months to 3 years after infusion. It would therefore be obvious to expect that cells derived from a “purified” population of modified Treg cells would similarly survive at some level in the subject, even at low levels as the instant claim does not particularly require any limitation of specific percentages, or numbers.
In regards to the claims 10 and 11 the disclosure of Eshhar et al further describes that the typical effective dose is between 10^6 and 10^11 (p42 23-26) Treg cells per injection or intravenous (p43, 11) infusion. If one would assume a weight of a human to range from 10kg-100kg for instance one would find that these ranges encompass the instantly claimed ranges in claims 10 and 11 on a cells/kg basis. Eshhar further describes that the dose regimens for such therapeutically effective numbers of modified Treg cells may be modified to individual needs and effective amounts may be obviously modified empirically by those of ordinary skill in the art without undue experimentation (p42, 13-23).
With respect to the claims 12-14 the disclosure of Eshhar describes the particular parameters of the antigen binding domain of the chimeric antigen receptor and preferred route of administration as described above.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Eshhar, June, Lim and Nakasone as applied to claim 1 above, and further in view of Srinivasan et al (Blood, 9 February 2012 Volume 119, Number 6; of record IDS). The aforementioned disclosure do not describe the particular measurement of pulmonary dysfunction are improved upon administration of CAR modified Treg cells. However as indicated above the provided references make obvious utilization of CAR-modified Treg cells directed to pathological B cells/pathological tissue sites for purposes of abrogating B cell mediated pathophysiology of chronic GVHD. Thus the combined disclosure above make obvious the claimed method, and the improvement of the lung function is considered therefore a result that naturally follows from the claimed method. Furthermore evidence provided by the disclosure of Nakasone for instance indicates that chronic GVHD may be manifested through lung involvement (p439) with fibrosis may develop in cGVHD subjects which is associated with B cell infiltration and alloantibody deposition at the site of pathology (lung, liver). Thus allo-antibody production by B cells is implicated in the pathophysiology of the lung dysfunction involved in cGVHD, with down regulation provided by T-regulatory cells directed to B cells at pathological sites and lymphoid organs such as germinal centers offering a method of down-regulating the response of the B cell to allow antigen thus ameliorating the downstream symptomatic disease. Additional support for the improvement of lung function such as for example reducing elastance, resistance and or/increasing compliance is provided by the disclosure of Srinivasan. The disclosure of Srinivasan is concerned with etiology of cGVHD in mouse model , as manifested by germinal center formation and subsequent alloantibody secretion and deposition in lung tissue. Lung involvement in cGVHD was manifested as increased elastance, decreased compliance and increase in airway resistance (p1572, reference 16). The disclosure further characterizes that disruption of pathogenic B cell germinal center formation by targeted depletion/inhibition of B cells with LT-beta-R-Ig ameliorates the lung pathology in model cGVHD animals (figure 7). It would thus be a latent property of the claimed method that markers of lung function would be improved as detected by measurement of the known read-out parameters as indicated by Srinivasan for example.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Eshhar (WO2008095141, of record) and further in view of June (WO2014012001A2, of record), Lim (Journal of Immunology, 2005 pp. 4180-4183, of record), and Nakasone (International Journal of Hematology 2015, 101:438-451, of record).
The claim 17 describes a method of treating a patient suffering from GVHD that is similarly made obvious by the disclosure of the reference patents as indicated and explained for the instant claim 1 as above.
Response to Arguments- Claim Rejections - 35 USC § 103
Applicant amends claims 1, 17 to incorporate elements previously presented in the claim 9 regarding the persistence of modified cells in the subject after administration to a human subject. Claim 9 is amended further limiting the persistence of modified cells in the subject to extend at least two years or at least three years after administration to the human subject. Applicant primarily argues that the disclosure of “Eshhar cannot make obvious the extended persistence of the modified Treg cells” at least 12 months after administration as required by the pending claims.
In reply, as previously presented, the disclosure of Eshhar describes Treg cells modified with chimeric antigen receptors which may be targeted to a B cell antigen. The disclosure describes that such cells are useful for the purposes of treating graft versus host disease (abstract, p1, p31 18-25). The examples of Eshhar are concerned with murine models of disease and do not investigate the persistence of modified Treg cells in human subjects. Treatment of human subjects with modified human Treg is contemplated by Eshhar. However the disclosure of June as previously indicated describes treatment of human subjects with CD19 directed chimeric antigen receptor modified T cells which comprise CD4+ CD25+ T cells which were found to persist in the subject for up to 18 months (p28, 30-34; p29, 1-5; figure2; fig8). The disclosure of June therefore further supports a finding that the persistence of cells in the subject is an inherent property of the claimed method made obvious by the combined disclosure of Eshhar, June and further supported by Lim and Nakasone.
Conclusion
Summary: 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.
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/BRIAN HARTNETT/Examiner, Art Unit 1644
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671