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 1-29-26 amendment and remarks are acknowledged.
Claims 1, 6, 7, 10-15, 27-31, 36-47 and 50 are pending.
Claims 1, 6, 7, 10, 12, 13, 27-31, 36-47 and 50 are under examination as they read on:
the species which is “an agent which selectively expands δ1 T cells but does not selectively expand δ2 or δ3 T cells;”
the sub-species of “agent which selectively expands δ1 T cells but does not selectively expand δ2 or δ3 T cells” is an agent which “binds a Bin 4 δ1 epitope”;
the sub-sub-species of “agent which selectively expands δ1 T cells but does not selectively expand δ2 or δ3 T cells, and which binds a Bin 4 δ1 epitope” is the “δ1-35 antibody;”
the species of engineered γδ T cells to be administered in the method of claim 31 is “the administered population of engineered and/or non-engineered γδ T cells is a population comprising at least 60% γδ T cells;”
the species of cytokine secreted from the δ1 T cells of claim 40 is “IL-2;” and
the species of disease to be treated in claim 47 is “cancer.”
Claims 11, 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6-24-25.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The prior rejection under 35 U.S.C. 112(a), written description, has been withdrawn in view of applicant’s amendments and remarks.
Claims 1, 6, 7, 10, 12, 13, 27-31, 36-47 and 50 stand 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 a method of treating cancer in a subject in need thereof comprising administering to the subject (i) an effective amount of γδ T cells engineered to comprise a chimeric antigen receptor (CAR) comprising an scFv that specifically binds a tumor associated antigen expressed on a cancer cell surface, wherein the CAR further comprises a transmembrane domain, a co-stimulatory signaling domain, and a CD3-zeta signaling domain and (ii) an effective amount of an antibody having the CDRs of the δ1-35 antibody, wherein said antibody further comprises a constant domain recognized by Fc receptors (FcR) found on certain types of cells, and wherein the δ1-35 antibody has the ability to activate, expand, and/or maintain the γδ T cells of part (i) in said cancer subject in need thereof, thereby treating cancer, does not reasonably provide enablement for practicing the breadth of the methods of claims encompassing, e.g., an in vivo method for activating, expanding, and/or maintaining a population of γδ T cells in a subject, the method comprising administering to the subject an effective amount of one or more agents which selectively expand δ1 T cells…wherein the one or more agents that selectively expand δ1 T cells bind to an activating epitope specific of a δ1 TCR…thereby activating, expanding and/or maintaining the population of γδ T cells in the subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Applicant argues the claimed methods are enabled for various reasons, but applicant’s arguments have not been found convincing essentially for the reasons of record. Each of applicant’s arguments will be addressed below in turn.
Applicant argues the following at page 9, 1st paragraph of their remarks (emphasis added):
‘‘Applicant respectfully submits that the Office's analysis fails to give the claims their broadest reasonable interpretation and improperly imports limitations into claim 1. Claim 1 recites ‘an in vivo method for activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject.’ Although the method can be used in treating diseases, e.g., as recited in claim 47, the scope of claim 1 should not be limited to a method of treatment. δ1 γδ T cells play a role in maintaining innate immunity and immunosurveillance (see, e.g., Percival S et al., Bioactive Food Components that Enhance γδ T Cell Function May Play a Role in Cancer Prevention, J Nutr. 2008 Jan;138(1):l-4), and thus a skilled artisan would understand that expanding and activating and/or maintaining δ1 γδ T cells in vivo can regulate (e.g., enhance) such functions of δ1 γδ T cells even in healthy subjects. Consistently, the specification states ‘administration of a composition of the disclosure to a subject modulates the activity of endogenous lymphocytes in a subject's body. In some cases, administration of the composition of the disclosure to a subject provides an antigen to an endogenous T-cell and may boost an immune response.’ Specification as filed at p. 73. Such embodiments are not necessarily limited to disease treatment. Further, the method in claim 1 can also be used in animal studies of δ1 γδ T cell function, not necessarily related to a disease treatment.’”
The undersigned disagrees with application’s assertion that “…the Office's analysis fails to give the claims their broadest reasonable interpretation and improperly imports limitations into claim 1.”
Claims 1 and 47 as amended recite,
“An in vivo method for activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject, the method comprising administering to the subject an effective amount of one or more agents which selectively expand δ1 γδ T cells… wherein the agent that selectively expands γδ T-cells is an antibody comprising the complementarity determination regions (CDRs) of an antibody selected from the group consisting of…δ1-35… thereby activating, expanding and/or maintaining the population of γδ T cells in the subject” (claim 1),
and
“A method of treating a cancer, infectious disease, inflammatory disease, or an autoimmune disease in a subject in need thereof by performing the method according to claim 1” (claim 47).
With respect to treating, e.g., inflammatory or autoimmune disease in a subject in need thereof, at page 72-73 bridging paragraph the specification teaches the following about treating inflammatory, including autoimmune diseases, as claimed:
“In some cases, a composition of the disclosure may be used to treat an immune disease, such as an autoimmune disease. Inflammatory diseases, including autoimmune diseases are also a class of diseases associated with B-cell disorders. Examples of immune diseases or conditions, including autoimmune conditions, include: rheumatoid arthritis, rheumatic fever, multiple sclerosis, experimental autoimmune encephalomyelitis, psoriasis, uveitis, diabetes mellitus, systemic lupus erythematosus (SLE), lupus nephritis, eczema, scleroderma, polymyositis/scleroderma, polymyositis/dermatomyositis, ulcerative proctitis, ulcerative colitis, severe combined immunodeficiency (SCID), DiGeorge syndrome, ataxia-telangiectasia, seasonal allergies, perennial allergies, food allergies, anaphylaxis, mastocytosis, allergic rhinitis, atopic dermatitis, Parkinson's, Alzheimer's, hypersplenism, leukocyte adhesion deficiency, X-linked lymphoproliferative disease, X-linked agammaglobulinemia, selective immunoglobulin A deficiency, hyper IgM syndrome, HIV, autoimmune lymphoproliferative syndrome, Wiskott-Aldrich syndrome, chronic granulomatous disease, common variable immunodeficiency (CVID), hyperimmunoglobulin E syndrome, Hashimoto's thyroiditis, acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenia purpura, dermatomyositis, Sydenham' a chorea, myasthenia gravis, polyglandular syndromes, bullous pemphigoid, Henoch-Schonlein purpura, poststreptococcalnephritis, erythema nodosum, erythema multiforme, gA nephropathy, Takayasu's arteritis, Addison's disease, sarcoidosis, ulcerative colitis, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitisubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, chronic active hepatitis, polychondritis, pamphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis, /polymyalgia, peraiciousanemia, rapidly progressive glomerulonephritis, psoriasis, fibrosing alveolitis, and cancer.”
However, by contrast to applicant’s argument, nowhere does the specification describe which particular heathy subjects would want to be treated with, or would need to be treated with an anti-δ1 antibody (as applicant asserts),
(i) for the purpose of “maintaining innate immunity and immunosurveillance,” or
(ii) for the purpose of “expanding and activating and/or maintaining δ1 γδ T cells in vivo [so as to] regulate (e.g., enhance) such functions of δ1 γδ T cells even in healthy subjects.”
In other words, according to applicant’s logic the claimed “in vivo method for activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject…” should be considered enabled so long as the administered antibody does indeed activate, expand, and/or maintain a population of δ1 γδ T cells in a subject.
The flaw in applicant’s argument is that nowhere does the specification describe any setting / any particular group or species of healthy patients who are not suffering from a cancer, an infectious disease, an inflammatory disease or an autoimmune disease and who would benefit from / would be in need of a treatment which will activate, expand, and/or maintain a population of δ1 γδ T cells in said otherwise healthy subject.
For example, nowhere does the instant specification describe how, e.g., a hypothetical deficiency in δ1 γδ T-cells in otherwise healthy patients can be addressed via the claimed method and how doing so will presumably prevent some undisclosed disease.
Rather, under the heading “Methods of Treatment” at page 67 the specification simply states:
“Pharmaceutical compositions containing a non-engineered, enriched γδ T-cell population, an engineered, enriched γδ T-cell population, and/or admixtures thereof, as described herein may be administered for prophylactic and/or therapeutic treatments. Additionally or alternatively, pharmaceutical compositions containing one or more agents that selectively expand a γδ T-cell population, as described herein, may be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions can be administered to a subject already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The compositions, can also be administered to lessen a likelihood of developing, contracting, or worsening a condition. Effective amounts of a population of a nonengineered, enriched γδ T-cell population, an engineered, enriched γδ T-cell population, admixtures thereof, and/or one or more agents that selectively expand a γδ T-cell population for therapeutic use can vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and/or response to the drugs, and/or the judgment of the treating physician.”
However, merely asserting that “pharmaceutical compositions containing one or more agents that selectively expand a γδ T-cell population, as described herein, may be administered for prophylactic and/or therapeutic treatments,” wherein said “prophylactic and/or therapeutic treatments” presumably proceed by “activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject” still does not describe any setting / any particular group / species of healthy patients who are not suffering from a cancer, an infectious disease, an inflammatory disease or an autoimmune disease and who would benefit from / would be in need of a treatment which will activate, expand, and/or maintain a population of δ1 γδ T cells in said otherwise healthy subject.
Indeed the idea that the elected species of anti-δ1 γδ antibody, i.e., the δ1-35 anti-δ1 γδ antibody, can be used to both activate, expand, and/or maintain δ1 γδ T cells, e.g., in a cancer subject in a way that exerts a pro-inflammatory, anti-cancer effect, and furthermore the same antibody can activate, expand, and/or maintain δ1 γδ T cells in an autoimmune or inflammatory disease sufferer in a way that lessens inflammation is on its face non-sensical.
The ordinarily skilled artisan would not understand how diseases with such pathologically distinct, and in numerous ways opposing etiologies, such as the vast genus of cancers as compared to the vast genus of inflammatory / autoimmune diseases, could be treated merely by “activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject,” by “administering to the subject an effective amount of one or more agents which selectively expand δ1 γδ T cells…wherein the agent that selectively expands γδ T-cells is an antibody comprising the complementarity determination regions (CDRs) of an antibody selected from the group consisting of…δ1-35….”
Likewise, it was well known in the art prior to applicant’s first filed application that immune checkpoint inhibition for the treatment of cancer, which is a pro-inflammatory, anti-cancer treatment, often also induces autoimmunity and/or pathogenic inflammation in the treated patient (a so-called “immune-related adverse even” / “irAE”). This illustrates the opposing pathologies of these diseases and in turn why it would be a priori unclear to the ordinarily skilled artisan which subjects will benefit from having their δ1 γδ T-cells activated, expanded, and/or maintained by administration of a δ1-37 antibody versus which subjects will be harmed by such a treatment.
With respect to treating a subject having cancer, e.g., a solid cancer that occurs in a certain organ such as pancreatic cancer, by grossly activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject, without also equipping said δ1 γδ T cells with a CAR that specifically binds a tumor associated antigen expressed on a cancer cell of interest, as described by Fleming at Fig. 1 some γδ T cells have protumor effects, e.g., by “[d]irect inhibition of αβ effector T cell function via PD-1/PD-L1 axis.” Moreover, as further descried by Fleming at page 568, 1st paragraph, the murine model of pancreatic adenocarcinoma (PDA) taught in Daley et al. showed that “…PD-L1 blockade failed to induce tumor protection in TCR-δ-deficient mice, with no enhanced CD4+ or CD8+ T cell infiltration. Therefore, via cell-to-cell contact through PD-L1, tumor-infiltrating γδ T cells are capable of restraining αβ T cell activation thereby promoting tumor progression.”
At page 9-10 bridging paragraph – 1st paragraph, applicant further argues (emphasis in the original):
“…using the in vivo method for treating diseases are fully enabled by the specification and knowledge in prior art. ‘The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation.’ MPEP 2164.01, emphasis added. ‘A patent need not teach, and preferably omits, what is well known in the art.’ Id. As discussed above, the effects of γδ T cell activation, including treatment of diseases such as cancer, are known in the art. See e.g., Silva-Santos et al., γδ T cells in cancer, Nature Reviews Immunology volume 15, pages683-691 (2015); Percival Set al., Bioactive Food Components that Enhance γδ T Cell Function May Play a Role in Cancer Prevention, J Nutr. 2008 Jan; 138(1): 1-4. The claimed method is a novel and non-obvious way to activate γδ T cells in vivo that can be applied to various conditions based on the knowledge in the art.
Further, ‘if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition.’ MPEP 2164.02, emphasis added. ‘The Supreme Court clarified that the specification does not always need to 'describe with particularity how to make and use every single embodiment within a claimed class ' ... Rather, the specification may require a reasonable amount of experimentation to make and use the invention.’ Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., effective January 10, 2024 (‘Guidelines’), emphasis added. Here, the working examples provides methods and results of the in vivo activation/expansion of δ1 γδ T cells in various cell and animal models, including various cancer cell lines (see Specification as filed Example 1 at pp. 82-83) and a non-tumor bearing mouse model (see Specification as filed Example 3 at pp. 85-87). The cells and animals used in the working examples are commonly used models correlated to various diseases and conditions. Further, the specification provides detailed disclosures on exemplary methods of treatment and conditions that can be treated. See e.g., Specification as filed at pp. 67-81. Thus, combination of the Specification as filed together with the general knowledge in the art fully enables using the claimed method for treating various diseases and regulating immunity status in a subject.”
With respect to Example 1 at pp. 82-83, by contrast to applicant’s argument this is not a “working example” but rather a prophetic example, in other words Example 1 does not show any actual results displaying “methods and results of the in vivo activation/expansion of δ1 γδ T cells in various cell and animal models, including various cancer cell lines;” rather it merely sets forth a plan for doing such experiments.
With respect to Example 3 at pp. 85-86, as a preliminary matter note that according to Example 3 the mice “were inoculated with Vδ1, Vδ2, or Vδ3 γδ CAR-T cells expanded as described in WO 2017/197347 or WO 2019/099744” but Figs. 6-8 of the instant specification do not seem to indicate which subset(s) of γδ cells were being measured in this experiments.
Moreover, even if the ordinarily skilled artisan were to assume that the data of Figs. 6-8 must display an assessment of Vδ1 γδ CAR-T cells, the experiments of this Example were performed with “NOG non-tumor bearing mice that express an hIL-15 transgene” and thus are drawn to a particular embodiment (non-tumor, hIL-15 express mice), but this example cannot be reasonably understood as applicant asserts to be one where “[t]he cells and animals used in the working examples are commonly used models correlated to various diseases and conditions.” How does measuring the amount of human γδ T-cells in various mouse tissues “correlate[] to various diseases and conditions”? What conclusion could the ordinarily skilled artisan drawn from the results of Example 3 about the effect of non-CAR comprising, endogenous δ1 γδ T cells on “various diseases and conditions”? The ordinarily skilled artisan would not know how the presence of human γδ CAR T-cells in various mouse tissues correlates to various diseases and conditions, and the claims are not even drawn to the administration of CAR T-cells that have been engineered to express IL-15.
Notably, throughout their remarks applicant points to various scientific publications – Chui et al. (2016); Silva-Santos et al. (2015); Percival et al. (2008) – but these references have not been made of record and thus cannot be evaluated for their significance with respect to applicant’s arguments.
As set forth in MPEP § 2164.05 (emphasis added):
“Once the examiner has weighed all the evidence and established a reasonable basis to question the enablement provided for the claimed invention, the burden falls on applicant to present persuasive arguments, supported by suitable proofs where necessary, that one skilled in the art would be able to make and use the claimed invention using the application as a guide. In re Brandstadter, 484 F.2d 1395, 1406-07, 179 USPQ 286, 294 (CCPA 1973). The evidence provided by applicant need not be absolute but merely convincing to one skilled in the art, based on a preponderance of the evidence standard.
Applicant may submit factual affidavits under 37 CFR 1.132 or cite references to show what one skilled in the art knew at the time of filing the application….
The examiner must then weigh all the evidence of record, including the specification, any new evidence supplied by applicant, and any evidence and scientific reasoning previously presented in the rejection and then decide whether the claimed invention is enabled, based on a preponderance of the evidence standard. The examiner should never make this determination based on personal opinion. The determination should always be based on the weight of all the evidence of record.”
With respect to applicant’s argument that the δ1-34 antibody which is administered according to the method of claim 1 can potentially have any Fc isotype, and since various Fc isotypes were known in the art, pointing to the non-supplied publication of Chui et al. (2016), the skilled artisan could make and use various versions of the “δ1-34 antibody,” each having a different Fc isotype, in the claimed method. However, how is the ordinarily skilled artisan to know if they are actually making and using the δ1-34 antibody, which would be understood by the ordinarily skilled artisan to be a naturally occurring murine antibody having specific heavy and light chain sequences (said heavy and light chain sequences comprising heavy and light chain variable domains and heavy and light chain Fc domains), without knowing which particular Fc isoform is present in this particular antibody?
Note in this regard that the teachings of the instant specification at page 2, 4th paragraph suggest that certain antibody Fc regions may favor ADCC mediated γδ T-cell lysis over γδ T-cell expansion (emphasis added):
“Selective expansion of γδ T-cell sub-types has been demonstrated ex vivo and in vivo by the use of known ligands of Vγ9Vδ2. For example, Pressey et al., Medicine (Baltimore). 2016 September; 95(39): e4909, reports in vivo expansion of Vγ9Vδ2 using intravenous zoledronate, a synthetic pyrophosphate mimic, and subcutaneous IL-2. Selective expansion of other γδ T-cell sub-types has been demonstrated ex vivo using immobilized antibodies that selectively bind and cross-link, e.g., δ1, δ2, and δ3 sub-types. See, WO 2016/081518; WO 2017/197347; and WO 2019/099744, the contents of which are incorporated in the entirety. Unfortunately, however, in vivo immobilization is typically performed by binding the antibody to an Fc receptor on the surface of a cell, which would generally be expected to induce an antibody-dependent cell-mediated cytotoxicity (ADCC) effect and thereby reduce the population of γδ T-cells recognized by the antibody. Similarly, methods of reducing the interaction between Fc receptor and the antibody also reduce immobilization and therefore would also not be expected to achieve robust in vivo expansion. Accordingly, clinically-relevant methods of expanding specific γδ T cell subsets in vivo, and the cells produced thereby, are greatly needed.”
Furthermore, as taught at page 86, last paragraph of the instant specification, at least one antibody Fc isoform (hIgG4) can significantly impair the ability of an antibody having the δ1-34 variable domains to induce cell (δ1 γδ cell?) proliferation.
Thus, by contrast to applicant’s argument the skilled artisan needs to know, e.g., the particular Fc isoform of the δ1-34 antibody, to be enabled to use the δ1-34 antibody in the claimed method.
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie unpatentability of the instant claims under 35 USC § 112(a), the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 2163.05.
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