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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8-26-26 has been entered.
Upon further consideration the species of disease to treated via the 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 each of the one or more agents that selectively expands δ1 T cells is an antibody comprising… thereby activating, expanding and/or maintaining the population of γδ T cells in the subject has been expanded to include “infectious disease,” “inflammatory disease,” and “autoimmune disease.”
Claims 1, 6, 7, 10, 12, 13, 27-31, 38-47, 50 and 52-56 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,” “infectious disease,” “inflammatory disease,” or “autoimmune disease.”
Claims 11, 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim.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.
Claims 1, 6, 7, 10, 12, 13, 27-31, 38-47, 50 and 52-56 are 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 tumor recognition moiety, and (ii) an effective amount of an antibody having the CDRs of the δ1-35 antibody, wherein said 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, or for
a method of treating an infectious disease in a subject in need thereof comprising administering an effective amount of an antibody having the CDRs of the δ1-35 antibody, wherein said antibody has the ability to activate, expand, and/or maintain the δ1 γδ T cells in said infectious disease subject in need thereof,
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 δ1 γδ T cells in a subject, such as a subject having an inflammatory or autoimmune disease, 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.
As a preliminary matter note the following guidance set forth in MPEP § 2111:
“The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005) expressly recognized that the USPTO employs the ‘broadest reasonable interpretation’ standard:
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The Patent and Trademark Office (‘PTO’) determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must ‘conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description.’ 37 CFR 1.75(d)(1).”
Likewise, MPEP § 2164.08 instructs:
“All questions of enablement are evaluated against the claimed subject matter. The focus of the examination inquiry is whether everything within the scope of the claim is enabled. Accordingly, the first analytical step requires that the examiner determine exactly what subject matter is encompassed by the claims.”
(emphasis added).
Claim 1 recites the following (emphasis added):
“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 T cells wherein each of the one or more agents that selectively expand δ1 T cells is an antibody comprising the complementarity determining regions (CDRs) of an antibody selected from the group consisting of…δ1-35…thereby activating, expanding and/or maintaining the population of δ1 γδ T cells in the subject.”
Dependent claim 47 recites “[a] method of treating cancer or an infectious disease in a subject in need thereof by performing the method of claim 1.”
At page 9, 1st full paragraph the specification states:
“In a third aspect, the present invention provides a use of an agent that selectively expands δ1
T cells, δ2 T cells, or δ3 T cells in the manufacture of a medicament for the in vivo expansion of γδ T cells in a subject in need thereof. In some embodiments, the in vivo expansion of γδ T cells in a subject comprises treating a cancer, infectious disease, inflammatory disease, or an autoimmune disease in the subject.”
Note that 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 (emphasis added):
“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.”
Considering the guidance set forth above, the utility of the claimed “in vivo methods for activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject” of the instant claims would be understood by the skilled artisan to lie in treating a particular disease, such as cancer, infectious disease, inflammatory disease or an autoimmune disease in a subject in need thereof, said method “comprising administering to said subject an effective amount of one or more agents which selectively expand δ1 T cells wherein each of the one or more agents that selectively expand δ1 T cells is an antibody comprising the complementarity determining regions (CDRs) of an antibody selected from the group consisting of…δ1-35…thereby activating, expanding and/or maintaining the population of δ1 γδ T cells in the subject.”
By contrast, the skilled artisan knowledgeable of the prior art and the teachings of the instant specification would not be interested in “activating, expanding, and/or maintaining a population of γδ T cells in any given subject, e.g., in a healthy human adult, merely for the sake of doing so.
That established, when the teachings of the instant specification are considered in the context of the knowledge in the prior art, it remains the opinion of the undersigned that the skilled artisan would not have been enabled to practice the breadth of the claimed invention in the absence of undue experimentation, essentially for the reasons of record as described further below.
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.
Prior to applicant’s first filing date, the ordinarily skilled artisan would have been aware of several inflammatory and/or autoimmune diseases where it would be very unclear how “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….” would be helpful.
For example, at page 7, 1st full paragraph Singh taught, “Thus, our broad analysis of functional attributes of T cells in new-MS peripheral blood could identify that Vδ1 T cells uniquely had a significantly increased capacity to produce IFN-γ, implicating Vδ1 cells in the etiology of MS disease,” and at page 8-9 bridging paragraph “Thus, the level of IFN-γ production in Vδ1 T cells correlated positively with biomarkers of axonal damage and disease activity, and taken together, these data suggest that Vδ1 cells may have a disease-promoting function in early MS.” (see Singh et al., Front. Immunol. 8:260, 2017, cited herewith).
The Discussion section of Singh summarizes their finding and conclusions, emphasizing the diverse functions of γδ cells in different immune responses, dependent on a variety of factors, such as the tissue in which δ1 γδ T-cells accumulate and if said tissue does or does not comprise a δ1 γδ T-cell trigger (emphasis added):
“…The results demonstrate that activation of Th1-like Vδ1 cells correlates with disease activity and neuronal destruction early in MS pathogenesis and imply that Vδ1 cells may contribute to disease progression by the production of the proinflammatory cytokine IFN-γ….
…The IFN-γ-producing Vδ1 cells that we demonstrate in new-MS patients also produced TNF-α and to some extent GrB, but very low levels of IL-10 and IL-17. Consistent with this, Th1-like cytokine expression pattern, new-MS Vδ1 cells (like HD Vδ1 cells) were positive for Th1-associated T-bet and CXCR3, but were negative for RORγt expressed by Th17 cells…. Taken together, published data provide substantial evidence for a pathogenic role for IFN-γ in EAE/MS. The fact that we find an elevation of IFN-γ-producing Vδ1 cells in new-MS patient PBMC, therefore, implicate that these cells may contribute to disease pathogenesis. Future studies will be important to further characterize Vδ1 cells in CSF to strengthen this notion.
In further support of a causal role of Vδ1 cells in MS disease etiology, we found that the frequency of IFN-γ producing Vδ1 cells demonstrated a high correlation with clinical data and biomarkers of disease activity and axonal damage such as numbers of MRI lesions and levels of NFL in CSF. The association was particularly strong with NFL, a marker of axonal damage. The concentration of NFL is shown to be increased in CSF at all stages of MS, it is elevated with the presence of active MRI lesions, and the highest concentrations are found during acute relapses (43). Importantly, long-term follow-up studies have demonstrated that the NFL concentrations found at initial diagnosis of MS were predictive of disease severity and advancement to secondary progressive disease (44). Thus, our findings suggest that the Th1-skewed activation of Vδ1 cells is related to axonal damage….
The most predominant location of Vδ1 cells is in the intestinal epithelium where they comprise around 70% of γδ lymphocytes (46). Intraepithelial T lymphocytes maintain tolerance and integrity of the epithelial barrier under homeostatic conditions and promote immune protection from pathogens. Vδ1 cells that express IFN-γ and IL-17 are expanded in the periphery during some infections (47–49). Vδ1 cells are also implicated in the immune response against cancers (50), and intestinal Vδ1 cells were found to be the major source of tumor-promoting IL-17 in human colorectal cancer (51). This is in stark contrast to healthy individuals, in which Vδ1 cells are described as having more of regulatory characteristics and less inflammatory functions compared to Vδ2 γδ cells (31, 32). Interestingly, intestinal Vδ1 cells are expanded in celiac disease, and Vδ1 cells with gut-homing potential appeared in peripheral blood following gluten challenge of celiac patients on gluten-free diet (46, 52). This illustrates the diverse functions that can be expressed by γδ cells in different immune responses (8) and establishes that Vδ1 cells in new-MS patients have a functional phenotype, expressing IFN-γ, but not IL-17, clearly distinct from these situations. It also points to a possible connection between activated systemic Vδ1 cells and an immune trigger at a mucosal site. Evidence is accumulating that alterations in the intestinal microflora can mediate an increased risk for autoimmune disease, including EAE and MS (1, 53–55). It is evident from animal experiments that effects of the gut flora on T lymphocytes residing in intestinal mucosal tissues influence autoimmune responses in remote tissues. In this perspective, Vδ1 cells residing in the intestinal epithelium, thus located at the first tissue barrier in contact with gut bacteria and being sentinels of microbial alterations, should be considered in the interplay between microbiota and the immune system leading to autoimmune disease such as MS. Our finding that new-MS patients have a significant increase in IFN-γ-producing circulating Vδ1 cells reinforces this notion.”
In another study, Vavassori et al. (Blood Adv (2017) 1 (15): 1101–1106, cited herewith) describes the pathogenic role of TCR-Vγ8Vδ1 T-cell expansion in FAS-related autoimmune lymphoproliferative syndrome.
As taught in the Introductory paragraph of Vavassori, “Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disease characterized by chronic nonmalignant, noninfectious lymphadenopathy, splenomegaly, and an increased likelihood of developing lymphoma or autoimmunity.1,2”
Moreover, as concluded by Vavassori, “Our findings show that lymphadenopathy in ALPS-FAS patients can be driven by the expansion of TCR Vγ8Vδ1 T lymphocytes. Our study is the first to demonstrate that Vδ1 T cells are sensitive to activation- induced cell death via FAS/FASL interaction. The biological relevance of these findings is evidenced by the report of 2 unrelated patients, each with a different germ line heterozygous FAS mutation, suffering from refractory ALPS with massive infiltration of γδT cells in secondary lymphoid organs. Remarkably, both patients underwent a special treatment program to induce remission from anemia and organomegaly. Thus, treatment failure, especially with regard to organomegaly in patients with ALPS should prompt clinicians to look for Vδ1 T cell proliferation.” (see page 1104-05 bridging paragraph, emphasis added)
Likewise, Hua et al. (Clinical and Experimental Immunology, 186: 347–355, cited herewith) studied patients having primary biliary cholangitis (PBC), hitherto called primary biliary cirrhosis, which is a cholestatic liver disease of unclear aetiology with autoimmune features.
The teachings of Hua conclude that the evidence tends to indicate that δ1 γδ T-cells will be involved in the immunopathogenesis of PBC, but more needs to be done to be “fully conclusive” as to this matter:
“In conclusion, in this study we observed changes in the proportions and the absolute numbers of Vδ1 T cells that are associated with disease status of PBC. The phenotypes of Vδ1 T cells in our study indicate that Vδ1 T cells may participate in the immunopathogenesis of PBC and potentially perform cytotoxic activity. Therefore, the proportions of circulating Vδ1 T cells may be used to monitor PBC clinically. To our knowledge, this is the first report concerning increased circulating Vδ1 T cells in PBC. However, the results obtained in our study are not fully conclusive at present. Further definitions of the Vδ1 T cells involved in chronic cholangitis, as well as their effector cytokines. might uncover whether interference with Vδ1 T cells could be a useful target for the treatment of PBC.”
In conclusion, the above examples illustrate how, prior to applicant’s first filing date, the ordinarily skilled artisan would have been quite uncertain which, if any, inflammatory and/or autoimmune diseases would favorably respond to “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….”
Finally, as set forth in the Final Office Action, the skilled artisan would be highly uncertain as their ability to have an ameliorative effect in a subject having cancer, such as a solid cancer that occurs in an organ like the pancreas, by grossly activating, expanding, and/or maintaining a population of δ1 γδ T cells in said 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.
The reason the ordinarily skilled artisan would be highly uncertain about their ability to treat cancer according by grossly activating, expanding, and/or maintaining a population of δ1 γδ T cells in a cancer subject without more was because, as described by Fleming at Fig. 1, some γδ T cells were known to have protumor effects, e.g., by “[d]irect inhibition of αβ effector T cell function via PD-1/PD-L1 axis.”
Along these same lines, as further descried by Fleming at page 568, 1st paragraph, the murine model of pancreatic adenocarcinoma (PDA) taught in Daley et al. showed that:
“…PDA is a useful model for studies of the tumor-associated effects of γδ T cells because up to 75% of all CD3+ cells in human PDA tissue are γδ T cells…. Depletion of these cells resulted in reduced ductal dysplasia and fibrosis along with a massive influx of CD4+ and CD8+ cells with restored functionality as assessed by increased TNF-α and IFN-γ production. In vitro studies suggested that tumor-infiltrating γδ T cells inhibited αβ T cell activation via PD-1/PD-L1 ligation. Addition of a-PD-L1 antibody to the wild-type (WT) model system restored CD4+ and CD8+ T cell functionality in a manner similar to γδ T cell ablation. However, 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.”
Thus, the ordinarily skilled artisan would be quite uncertain about their ability to treat cancer by performing the method as currently recited in claim 1.
Applicant’s Arguments
At section III of their remarks filed 8-26-26, applicant argues the specification provides guidance as to one IgG constant domain (IgG4) that cannot be used with an antibody comprising the δ1-35 CDRs to activate, expand and/or maintain a population of δ1 γδ T cells in a subject, and that this guidance is sufficient to enable the claimed invention.
Applicant’s arguments are acknowledged but they fail to convincingly address this aspect of the rejection of record.
This aspect of the rejection is only applicable to claim 10 which recites that “the agent that selectively expands δ1 T-cells is…δ1-35….”
As described in the prior non-final Office Action mailed 8-29-25,
“[f]urthermore, as to claim 10 which specifies that the method of claim 2 is to be performed with the δ1-35 antibody, according to Examples 39 and 40 of WO2017197347, the δ1-35 antibody was isolated from a murine B-cell and has certain heavy and light chains as displayed in Figs. 33 and 34 of the ‘347. However, nowhere in Examples 39 and 40 or in Figs. 33 and 34 does the ‘347 teach the Fc isotype / subtype for the δ1-35 antibody. For example, is the δ1-35 antibody an IgG antibody, an IgD antibody or some other isotype? Likewise, if the δ1-35 antibody is an IgG type antibody, is it an IgG1, IgG2A, IgG2B, IgG2C or IgG3 isotype? Moreover, even within the IgG1 isotype there are yet different allotypes.
In the absence of such information the skilled artisan would not know how to make full length δ1-35 antibody since it would be unclear to the skilled artisan which Fc isotype, subtype and allotype should be used.”
To further illustrate why the skilled artisan would not know how to make the exact δ1-35 antibody first disclosed in WO2017197347, consider the teachings of the ’347 as set forth in Example 39, 1st paragraph:
“Example 39. Generation of specific γδ T cell activators
γδ T cell activators in the form of murine antibodies were produced by immunization of recombinant soluble human γδ TCR….[t]hree strains of mice (Balb/c, CD-1 and FVB) were inoculated with human recombinant γδTCR to provide hybridomas that secrete high affinity, murine monoclonal antibody activators….”
However, nowhere does ‘347 describe which mouse strain the δ1-35 antibody was isolated from.
Assume arguendo that it were to be isolated from the CD-1 strain. According to the Abstract of Aldinger et al (PLoS ONE 4(3): e4729, 2009, cited herewith), this “outbred” strain was “…drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies…. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities.”
Thus, even if the ordinarily skilled artisan were to make an antibody comprising the murine δ1-35 variable domains attached to certain select IgG1, IgG2A, IgG2B, IgG2C or IgG3 murine Fc isotypes, the ordinarily skilled artisan would have no way of knowing if they have successfully reproduced the δ1-35 antibody as it was hypothetically cloned from some outbred CD-1 mouse, and whichever CD-1 mouse the δ1-35 antibody was cloned from may have an IgG1, IgG2A, IgG2B, IgG2C or IgG3 isotype different from the “select” isotypes mentioned above.
Beginning at Section IV of the Remarks, Applicant further argues:
“IV. Claim I Does Not Recite Disease Treatment
The Examiner's rationale is inconsistent with the subject matter actually recited in claim 1. Claim 1 is directed to an in vivo method for activating, expanding, and/or maintaining a population of δ1 γδ T cells in a subject. Claim 1 does not require treatment or prevention of a disease, tumor regression, clinical response, correction of a δ1 T-cell deficiency, or selection of a subject expected to obtain a particular therapeutic benefit. Those requirements should not be imported into claim 1 when evaluating whether the specification enables a person of ordinary skill in the art to perform the cellular method actually claimed. Rather, the relevant inquiry is whether the specification enables a skilled artisan to administer the recited antibody and obtain the claimed in vivo cellular response….”
Applicant's arguments have been considered but have not been found convincing essentially for the reasons of record as described below.
Firstly, as evidenced by dependent claim 47, in some embodiments the subject of claim 1 is a subject having a cancer or an infectious disease. Thus, at least in the particular embodiment of claim 47 the subject receiving the one or more agents that selectively expand δ1 T-cells is a subject that desires a particular therapeutic benefit, i.e., treating their cancer or infectious disease.
Secondly, as set forth in the prior Final Office Action at beginning at page 6,
“…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….’”
Indeed, with respect to the final two paragraphs reproduced above, see Singh et al., Vavassori et al. and Hua et al. (as set forth above and cited herewith) illustrate how, prior to applicant’s first filing date, the ordinarily skilled artisan would have been quite uncertain which, if any, inflammatory and/or autoimmune diseases would favorably respond to “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….”
As to applicant’s assertion that “[c]onsistent with the scope of claim 1, the specification…defines an effective amount by reference to ascertainable expansion or maintenance of the target population…,” this assertion is inconsistent with how claim 1 would be understood when given broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art (see MPEP § 2111).
As set forth at page 14-15 bridging paragraph of the specification (emphasis added),
“An ‘effective amount’ in the context of an in vivo method of expanding or maintaining an in vivo population of γδ T cells in a subject refers to a dose that produces an ascertainable increase in expansion or maintenance of the in vivo population of γδ T cells in a subject. As an example, the effective dose may selectively expand a target population of administered γδ T cells by a detectable amount (e.g., at least 1%, at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 2-fold, or from about 1% to about 10%, or from about 10% to about 2-fold). As another example, the effective dose may selectively expand a target population of endogenous in vivo γδ T cells by a detectable amount (e.g., at least 1%, at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 2-fold, or from about 1% to about 10%, or from about 10% to about 2-fold). As another example, the effective dose may maintain a larger number of viable target γδ T cells in the subject or in a tissue of the subject (e.g., a tumor tissue) as compared to a control subject that is not administered the one or more agents that selectively expand γδ T cells.”
Thus, the “effective amount” recited in claim 1 and dependent claims thereof, such as claim 47, is taught by the specification to encompass in its breadth, e.g., maintaining a larger number of viable target γδ T cells in a tissue of the subject, wherein said tissue is a tumor tissue, i.e., wherein said subject is a cancer subject.
With respect to applicant’s assertions about “Thiebaut et al.” which is allegedly found “…in the Information Disclosure Statement filed herewith as contemporaneous evidence of the state of the art,” no such IDS or teaching appears to have been submitted with applicant’s remarks filed 8-26-26.
With respect to applicant’s assertion that “[a]mended claim 47 expressly recites treatment of a cancer or an infectious disease by performing the method of claim 1. Disease treatment is therefore an expressly recited additional feature in claim 47, rather than an inherent or required feature of claim 1,” it is the opinion of the undersigned that independent claim 1 necessarily encompasses the subject matter of dependent claim 47 in its breadth, consistent with the guidance set forth in in MPEP 608.01(n)(III), "The test as to whether a claim is a proper dependent claim is that it shall include every limitation of the claim from which it depends ( 35 U.S.C. 112, fourth paragraph) or in other words that it shall not conceivably be infringed by anything which would not also infringe the basic claim." (emphasis added).
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. §§ 716.01(d) and 2142.
No claims are allowed.
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
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