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 amendment filed on 2/10/2026 is acknowledged.
Election/Restrictions
Claims 1-20 are pending.
Upon further consideration, the Examiner has decided to add claims 13-20 to Group I. Group I of the Restriction Requirement mailed on 12/11/2025 encompasses claims 1-10 and 13-20 and Group II encompasses claims 11-12.
Applicant’s election without traverse of Group I directed towards a method of inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype, a method for treating an autoimmune disease, and a method for enriching Tregs in a subject in the reply filed on 2/10/2026 is acknowledged.
Claims 11- withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/10/2026.
Claims 1-10 and 13-20 are currently under consideration for their full scope.
Claim Rejections - 35 USC § 112
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.
Written Description
Claims 1-10 and 13-20 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering an effective amount of GC7 to a subject, administering an effective amount of an anti-DLL4 antibody, and administering GAD65-specific CAR Tregs as a treatment for type 1 diabetes; a method for treating type 1 diabetes comprising administering GC7 to inhibit eIF5A signaling, administering anti-DLL4 antibody to inhibit Notch signaling , and administering GAD65-specific CAR Tregs; and a method for enriching Tregs cells in a subject comprising simultaneously inhibiting eIF5A signaling with GC7 and Notch signaling with an anti-DLL4-antibody wherein the subject is being prepared for an organ transplant.
Applicant is not in possession of: a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering an effective amount of an eIF5A inhibitor to a subject, administering an effective amount of a Notch signaling inhibitor, and administering CAR Tregs as a treatment for type 1 diabetes; a method for treating an autoimmune disease comprising simultaneously inhibiting eIF5A and Notch signaling and administering a treatment for the autoimmune disease; and a method for enriching Tregs cells in a subject comprising simultaneously inhibiting eIF5A signaling and Notch signaling wherein the subject is being prepared for an organ transplant.
The claims encompass all inhibitors capable of inhibiting eIF5A signaling (directly or indirectly), all inhibitors capable of inhibiting Notch signaling (directly or indirectly), any CAR Tregs, and all autoimmune diseases.
The skilled artisan cannot envision all of the eIF5A inhibitors, Notch signaling inhibitors, and CAR Treg possibilities recited in the instant claims.
Regarding eIF5A inhibitors, the specification discloses (pages 8-9, [0043]; page 10, [0049]) hypusinated eIF5A is significantly overexpressed in diabetogenic CD4 T cells and inhibiting hypusinated eIF5A leads to enrichment of Treg cells. Deoxyhypusine synthase (DHS) catalyzes hypusination of eIF5A with the most potent DHS inhibitor being GC7 where it inhibits overexpression of eIF5A without affecting basal expression resulting in improved glucose tolerance, greater insulin secretion, etc. Other eIF5A inhibits include anti-eIF5A neutralizing antibodies, L-mimosine, ciclopirox, deferiprone, and combinations thereof. The specification discloses in Examples I-III the use of only one eIF5A inhibitor, GC7, for use in the treatment for type 1 diabetes in combination with anti-DLL4 and GAD65-CAR Tregs.
The specification does not reasonably convey possession of the full scope of eIF5A inhibitors encompassed by the claims. Absent a limiting species for “eIF5A inhibitor”, the genus opens up the claimed invention to all eIF5A inhibitors including those that indirectly target the eIF5A signaling pathway.
The art of Guo et al (PTO-892; page 1, reference W; “Guo”) teaches strategies for inhibiting eIF5A activation by inhibiting hypusination directly with DHPS inhibitors such as classical inhibitors/SPD analogs (GC-7, CNI-1493, etc) and allosteric inhibitors (compounds 11g and 8m) or DOHH inhibitors (ciclopirox, deferiprone, and mimosine) (Guo; Table 1; pages 6-8, Section 3). Guo teaches each inhibitor has a different mechanism of action either by inhibiting DHPS, an essential enzyme regulating the hypusination of eIF5A, directly through binding to the protein’s active site or binding to an allosteric site (i.e. NAD binding site); or inhibiting DOHH, an enzyme essential for hydroxylating an intermediate to form hypusine eIF5A (Guo; Figure 1, page 6, section 3.1).
Regarding Notch signaling inhibitors, the specification discloses (pages 9-10, [0044]-[0048]) Notch signaling to regulate immune cell maturation and the activation and differentiation of naïve CD8+ T cells into cytotoxic T-cells (CTLs) and that in type 1 diabetes, beta cells are specifically killed by CTLs. The specification discloses a non-limiting example Notch signaling inhibitor to include anti-DLL4 antibodies which help reduce the expansion of antigen-specific CTLs and help enrich antigen-specific Treg cells and enhance glucose-stimulated insulin secretion from islets. The specification additionally discloses in Examples I-III the use of only one anti-DLL4 antibody, anti-DLL4, for use in the treatment for type 1 diabetes in combination with GC7 and GAD65 CAR Tregs.
The specification does not reasonably convey possession of the full scope of Notch signaling inhibitors encompassed by the claims. Absent a limiting species for “Notch signaling inhibitor”, the genus opens up the claimed invention to all Notch signaling inhibitors including those that indirectly target the Notch signaling pathway.
The art of Christopoulos et al (PTO-892; page 1, reference V; “Christopoulos”) teaches that there are four Notch receptors each with their own structural differences contributing to their unique function within cells (page 2, right column, paragraph 2; page 3, left column, paragraph 2). Additionally, Christopoulos teaches there are multiple ways to inhibit Notch signaling such as inhibiting ligand binding and Notch receptor activation, inhibiting receptor endocytosis, inhibiting cleavage, and inhibiting NICD release with each inhibitory mechanism encompassing a variety of antibodies and compounds (Christopoulos; Figure 2; page 5, “Rationale for Therapeutic Targeting of the Notch Pathway”).
Regarding the term CAR Tregs, the specification discloses (page 15, [0065]) GAD65 auto-antigen expression on beta-cells as being a factor contributing to the spontaneous development of type 1 diabetes in mice which resembles the human disease. The specification (page 29, [00141]) discloses in Example II that GAD65 specific CAR Tregs treatment after priming the islet microenvironment with GC7 and anti-DLL4 antibody will induce complex anergy to activated CTLs and reconstitute the pancreatic islets to preserve the proper functioning of beta-islet cells. However, the specification does not disclose any other CAR Tregs or examples disclosing the efficacy of CAR Treg treatment for autoimmune diseases and type 1 diabetes.
The specification does not reasonably convey possession of the full scope of CAR Tregs encompassed by the claims. Absent a limiting species “CAR Tregs”, the genus opens up the claimed invention to any CAR Tregs. The art of Mishra et al (PTO-892; page 2, reference X; “Mishra”) teaches that CAR-Tregs employ a targeted immune modulation through antigen-specific suppression thereby circumventing the systemic immunosuppression and adverse effects commonly associated with conventional therapies (Mishra; page 1, left column, paragraph 1). Mishra teaches that equipping Tregs with synthetic CARS that target disease-relevant autoantigens, the CAR Tregs can home to sites of inflammation and re-establish immune tolerance in a high localized and antigen-specific manner (Mishra; page 3, right column).
Regarding the term “autoimmune diseases”, the specification discloses (page 15; [0065]; page 17, [0069]) the compositions are useful or priming the immune system in preparation for undergoing a treatment for an autoimmune disease such as type 1 diabetes where the combined eIF5A and Notch signaling inhibition can be useful any time during the course of an autoimmune disease to temporarily ameliorate the effects of the autoimmune disease as it can enrich Treg cells in vivo, in some embodiments by 3-4 fold, which is beneficial for any autoimmune disease. The specification discloses in Examples I-III the combined GC7 and anti-DLL4 treatment as a way to prevent or treat type 1 diabetes. However, the specification does not disclose any other autoimmune diseases or provide examples of treating other autoimmune diseases.
The specification does not reasonably convey possession of the full scope of autoimmune diseases encompassed by the claims. Absent a limiting species for the term “autoimmune disease”, the genus opens up the claimed invention to all autoimmune diseases.
The art of Mishra (see above) additionally teaches autoimmune diseases have different mechanisms of action and require disease specific treatments in order to effectively reduce and/or eliminate disease specific inflammation (Mishra; Figure 3; pages 6-9). For example, in type 1 diabetes mellitus (T1DM) Tregs cause the immune system to attack and destroy pancreatic beta-cells, so therapies are designed to suppress diabetogenic T cells and support the function of pancreatic β-cells such as insulin specific CAR Tregs (Mishra; Figure 3; pages 6-7). In rheumatoid arthritis, compromised Treg function results in elevated levels of proinflammatory cytokines like IFN-γ and TNF-α, intensifying inflammation and promoting joint deterioration so therapies such as Ovalbumin or citrullinated vimentin (CV) specific CAR Tregs can help localize immune suppression and protect joint integrity (Mishra; Figure 3; page 7, left column). In Crohn’s disease, proinflammatory Th17 cells are key contributors to pathogenesis and IFN-γ drives intestinal inflammation and tissue destruction, so therapies such as IL-23R specific CAR Tregs offer a targeted approach to modulate this immune dysregulation by suppressing Th17-mediated responses and downregulate proinflammatory cytokine release (Mishra; Figure 3; pages 7-8).
As such, claims 1-10 and 13-20 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims 1-10 and 13-20 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.
While being enabled for: a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering an effective amount of GC7 and administering an effective amount of anti-DLL4 antibody simultaneously and further administering GAD65-specific CAR Tregs; a method for treating type 1 diabetes comprising administering GC7 to inhibit eIF5A signaling in a subject having type 1 diabetes, simultaneously inhibiting Notch signaling with an anti-DLL4 antibody, and subsequently administering GAD65 Car Tregs as a treatment for type 1 diabetes; and a method for enriching Treg cells in a subject comprising simultaneously inhibiting eIF5A with GC7 and Notching signaling with anti-DLL4 antibody.
The specification does not reasonably provide enablement for: a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering an effective amount of an eIF5A inhibitor and administering an effective amount of a Notch signaling inhibitor simultaneously and further administering a treatment for type 1 diabetes comprising CAR-Tregs; a method for treating an autoimmune disease comprising: inhibiting eIF5A in a subject having an autoimmune disease, simultaneously inhibiting Notch signaling in a subject, and subsequently administering a treatment for the autoimmune disease to the subject; and a method for enriching Tregs in a subject comprising simultaneously inhibiting eIF5A and Notch signaling in a 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 use the invention commensurate in scope with these claims. The specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The breadth of claims 1-9 and 13-20 encompass all eIF5A inhibitors, all Notch signaling inhibitors, all treatments for type 1 diabetes, all CAR Tregs, and all autoimmune diseases. eIF5A inhibitors, Notch signaling inhibitors, and CAR Tregs all have different mechanisms of action and can be used to treat a variety of diseases. Autoimmune diseases all have different causes, affect different physiological processes, and are treated with different agents.
It is well established in the art that inhibiting eIF5A and Notch signaling is highly unpredictable and the effects of each are disease and tissue subtype specific. The art of Nakanishi et al (PTO-892; page 3, reference U; “Nakanishi”) teaches that loss of hypusinated eIF5a is associated with profound phenotypes in different tissues and cell types likely due to the pleiotropic effects of hypusinated eIF5A inhibition (Nakanishi; page 10, paragraph 5). Nakanishi teaches that inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis is associated with reduced levels of DHPS and hypusinated eIF5A and hypusinated eIF5A is shown to prevent chronic inflammation and carcinogenesis (Nakanishi; page 3, Section 2.1.1.). Nakanishi even teaches that GC7 has several off-target effects, so there is clearly a need for developing improved small molecules that efficiently block hypusinated eIF5A function (Nakanishi; page 10, paragraph 5). However, in type 1 diabetes, inhibiting hypusinated eIF5A with GC7 delayed the onset of disease and enriched Tregs (Nakanishi; page 7, paragraph 3). The art of Ma et al (PTO-892; page 2, reference V; “Ma”) teaches that systemic inhibition of Notch signaling may have multiple effects in different cell types (i.e. context dependent) implicating that effects of Notch manipulations need to be investigated without preestablished assumptions (Ma; page 556; left column, paragraph 3). In autoimmune diseases such as MS, SLE, RA, ITP, and T1D, Ma teaches inhibiting Notch signaling can be an efficacious treatment (Ma; pages 559-561; section 4.2). However, for other autoimmune diseases such as IBD, Notch signaling was identified as a key intracellular molecular pathway for the proper reconstruction of the intestinal epithelia (Ma; page 560, right column, paragraph 2). Additionally, sone studies have shown that Notch homologous may have opposite effects in the same disease while Notch inhibitors are non-selective and may inhibit all Notch homologous, producing unexpected side effects (Ma; page 561, right column, paragraph 2).
It is well established in the art the CAR Tregs are designed to be autoantigen specific for a specific disease. Any CAR Treg cannot treat any disease and it is unpredictable in the art as to whether the CAR Treg could have potential negative side effects or produce an unintended result worsening the disease in a patient. The art of Mishra (see above) teaches that CAR-Tregs employ a targeted immune modulation through antigen-specific suppression thereby circumventing the systemic immunosuppression and adverse effects commonly associated with conventional therapies (Mishra; page 1, left column, paragraph 1). Mishra teaches that equipping Tregs with synthetic CARS that target disease-relevant autoantigens, the CAR Tregs can home to sites of inflammation and re-establish immune tolerance in a high localized and antigen-specific manner (Mishra; page 3, right column). Mishra teaches examples of various CAR Tregs that are disease subtype specific (Mishra; Figure 3, pages 6-7). Taken from these examples, it is unpredictable as to whether an IL-23R specific Treg would offer the same therapeutic benefit to type 1 diabetes patients as it does to a patient with Crohn’s disease.
The prior art does not appear to provide any evidence as to treatment of the full scope of the claims of any as such, not any autoimmune disease can be treated with any eIF5A inhibitor, any Notch signaling inhibitor, and any treatment for type 1 diabetes including any CAR Tregs without undue experimentation.
The specification discloses (pages 9-11) various examples of eIF5A inhibitors and Notch signaling inhibitors with GC7 , anti-DLL4 antibody, and GAD65-specific CAR Tregs as preferred embodiments. However, the specification discloses in Examples I-III only GC7, anti-DLL4 antibody, and GAD65-specific CAR Tregs as efficacious treatment options in combination for patients with type 1 diabetes with no other type 1 diabetes treatments discussed. No other eIF5A inhibitors, Notch signaling inhibitors, and CAR Tregs are shown in combination to successfully induce plasticity in effector T cells to a Treg phenotype and enrich Tregs to improve the pancreatic immune microenvironment and improve β-islet cell function. Additionally, no other examples of autoimmune diseases are disclosed in the specification or if they can be treated effectively with inhibiting eIF5A and Notch signaling to prime the immune microenvironment for GAD65 CAR Treg treatment.
As such the claims are not enabled for the genus of eIF5A inhibitors, Notch signaling inhibitors, type 1 diabetes treatments including CAR Tregs, and autoimmune diseases. One of ordinary skill in the art cannot use the combination of the genus of eIF5A inhibitors, Notch signaling inhibitors, type 1 diabetes treatments, and CAR Tregs with unpredictable functions to treat the genus of autoimmune diseases and perform the recited function of enriching Tregs and inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype.
In view of the quantity of experimentation necessary, the lack of working
examples, the unpredictability in the art, the lack of sufficient guidance in the
specification, and the breadth of the claims, it would take undue trials and errors to
make and use the encompassed eIF5A inhibitors, Notch signaling inhibitors, type 1 diabetes treatments, CAR Tregs recited in the claims for predictable function of treating autoimmune diseases, inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype, and enrich Tregs.
Reasonable correlation must exist between the scope of the claims and scope of
the enablement set forth. In view of experimentation necessary the limited working
examples, the nature of the invention, the state of the prior art, the unpredictability of the
art and the breadth of the claims, it would take undue trials and errors to practice the
claimed invention.
Priority
This application claims domestic benefit to U.S. Provisional Application 63/389,391 effectively filed on 7/15/2022.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Imam et al (PTO-892; page 1, reference X; "Imam_2019") in view of Billiard et al (PTO-892; page 1, reference U; "Billiard").
Imam_2019 teaches the hallmark of type 1 diabetes is immune mediated destruction of insulin secreting β-cells of the pancreatic islets of Langerhans resulting in hyperglycemia and lifelong dependency on exogenous insulin and that T cell dynamics in the islet microenvironment is characterized by T helper (Th) 1 and Th17 cell bias and a Treg cell defect that ultimately culminates into cytotoxic T lymphocyte (CTL) mediated destruction of the β-cells (Imam_2019; page 1, paragraph 1). Imam_2019 teaches the effects of eIF5A inhibition via GC7 on T cell dynamics (i.e. T cell differentiation and plasticity) in the pancreas and local lymph nodes in mouse models expressing human GAD65, an antigen that initiates activation of T-cells and the onset of diabetes (Imam_2019; Summary; page 2, paragraph 4). In vivo GC7 inhibition enriched Treg population in the pancreas, IGLN, PPLN, and spleen and reduces Th1 and Th17 cells which in turn helped to significantly increase the total pancreatic insulin content in humanized T1D mice (Imam_2019; page 12, paragraphs 4, 7-8). Imam_2019 further teaches that although Tregs were enriched upon GC7 treatment resulting in increased Treg/Th17 and Treg/Th1 ratios, there was no reduction in cytotoxic CD8+ T cells in the islets (Imam_2019; Figure 2C and 3E; page 7, paragraphs 4-5 and 8; page 13, paragraph 1). Imam_2019 teaches that inhibition of eIF5A also reduced anti-GAD65 antibody production which may help to decease disease severity and help manage T1D in early stages of disease (Imam_2019; Figure 6C; Summary; page 11, paragraphs 1-2).
However, Imam_2019 does not teach instant claim 1 wherein the method comprises administering an effective amount of a Notching signaling inhibitor to a subject so as to inhibit Notch signaling in the subject; wherein eIF5A and Notch signaling in the subject are inhibited simultaneously so as to induce plasticity in effector T cells in a subject to exhibit a regulatory T cell phenotype (instant claim 1); wherein the Notch signaling inhibitor comprises an anti-Dll4 antibody; wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered sequentially; wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously; the method further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject; wherein the treatment comprises GAD65-specific CAR-Tregs. Imam_2019 also does not teach instant claim 13 wherein the method of treating an autoimmune disease comprises simultaneously inhibiting Notch signaling in a subject, and subsequently, administering a treatment for the autoimmune disease to the subject, wherein the simultaneous inhibition of eIF5A and Notch signaling in the subject enriches Treg cells in the subject so as to prime the subject's immune system for the treatment; wherein Notch signaling is inhibited with an anti-DLL4 antibody; wherein the treatment comprises GAD65-specific CAR-Tregs. Imam_2019 additionally does not teach instant claim 17 wherein the method comprises simultaneously inhibiting eIF5A and Notching signaling to enrich Treg cells in a subject; wherein Notch signaling is inhibited with an anti-DLL4 antibody; wherein the subject is being prepared for an organ transplant.
Billiard does teach Delta-like ligand 4 (Dll4)-Notch signaling being essential for T cell development and is necessary to inhibit the potential of early T cell progenitors to generate alternative lineages (Billiard; Summary; page 1011, left column, paragraph 1). Billiard teaches that anti-Dll4 antibody treatment prevents type 1 diabetes via a Treg cell-mediated mechanism of inducing a de novo generation of thymic nTreg cells (Billiard; page 1020, paragraph 1; Figure 3C). Additionally, Billiard teaches that anti-Dll4 antibody treatment fully prevented type 1 diabetes disease development in nonobese diabetic mice which was correlated with high ratio (i.e. enrichment) of Treg cell frequency, reduction in the expansion of antigen-specific cytotoxic T lymphocytes (CTLs) in pancreatic islets cells, and lack of CD8+ cell infiltration into the pancreatic islets cells (Billiard; Figure 7A-B; page 1020; right column, paragraph 2). Sustained Dll4-Notch signaling blockade is required to maintain alternative DC development in the thymus, promote early DC and Treg cell expansion followed by an enrichment of Treg cells in thymus, and induce Treg cell expansion in the periphery upon immune stimulation (Billiard; page 1023, left column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill, in the art before
the effective filing date, to combine the GC7-eIF5A inhibitor treatment in GAD65 expressing diabetic mice of Imam_2019 with the anti-Dll4 antibody capable of reducing expansion and proliferation of CD8+ T cells of Billiard with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine GC7-eIF5A of Imam_2019 with the anti-Dll4 antibody of Billiard before the effective filing date of the instant invention since the GC7-eIF5A inhibitor of Imam_2019 is capable of enriching Treg/Th17 and Treg/Th1 ratios to significantly increase the total pancreatic insulin content although not significantly impacting CTL function and decrease GAD65 antibodies; and the Notching signaling inhibitor, anti-Dll4 antibody, of Billiard is capable of reducing the expansion of CTLs and CD8+ cell infiltration in pancreatic islets cells.
Therefore, it would have been obvious to combine the GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4 antibody of Billiard to yield predictable results to more effectively treat type 1 diabetes by of inducing plasticity in effector T cells to enrich Treg cells in pancreatic β-islet cells to improve their functionality and increase insulin production while also depleting CD8+ T cell subset in the pancreatic microenvironment.
Regarding the simultaneous and sequential administration as recited in instant claims 1, 4-5, and 17, the timing of drug administration is considered a results effective variable, so a person of ordinary skill in the art would have been motivated to optimize the timing of eIF5A inhibitor and Notch signaling inhibitor administration in order to achieve the desired result of enriching Treg cells in type 1 diabetes. Therefore, it would be obvious to try the simultaneous and/or sequential administration of the eIF5A inhibitor and Notch signaling inhibitor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claims 6-10 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Imam_2019 (see above) and Billiard (see above) as applied to claims 1-5 and 17-19 above, and further in view of Imam et al (PTO-892; page 2, reference U; "Imam_2021”).
Imam_2019 and Billiard teach methods for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering an effective amount of eIF5A inhibitor and Notch signaling inhibitor to simultaneously inhibiting eIF5A and Notch signaling in a subject so as to induce plasticity in effector T cells in a subject; method of treating an autoimmune disease comprising inhibiting eIF5A in a subject having an autoimmune disease and simultaneously inhibiting Notch signaling in a subject wherein the simultaneous inhibition of eIF5A and Notch signaling in the subject enriches Treg cells in a subject so as to prime the subject’s immune system for treatment; and method for enriching Tregs in a subject comprising simultaneously inhibiting eIF5A and Notch signaling in a subject to enrich Tregs cells in the subject.
Imam_2019 and Billiard do not teach wherein the method of claim 1 further comprises administering a treatment for type 1 diabetes while eIF5 and Notch signaling ae inhibited in a subject; wherein the treatment comprises GAD65-specific CAR-Tregs; wherein the eIF5A inhibitor comprises GC7 and the Notching signaling inhibitor comprises an anti-DLL4 antibody. Imam_2019 and Billiard also do not teach the method of claim 13 comprising administering a treatment for the autoimmune disease; wherein the treatment comprises GAD65-specific CAR-Tregs.
However, Imam_2021 does teach the therapeutic application of pancreatic β-cell-GAD65-specific CAR Tregs for treatment of Type 1 Diabetes (Imam_2021; page 4, paragraphs 2-3; pages 11-12). Imam_2021 teaches the homing of the GAD65-CAR Tregs to the islets of Langerhans providing in vivo evidence for antigen specificity and the reduction of the number of functionally active effector T cells (Teff) in GAD65-CAR Treg treated animals providing evidence for T cell suppression (Imam_2021; page 22, paragraph 2). Imam_2021 additionally teaches the CAR-N Tregs appeared more efficacious in downregulating Teff cells than CAR-M Tregs and the antigen-specific proliferative capacity of GAD65-CAR-N/M-Tregs was 4-5 times higher than of antigen-specific unmodified (normal) Tregs. This provides evidence for the superiority of GAD65-CAR-Treg over normal Tregs on their diabetes reversal capacity observed in the GAD65-CAR-Treg treated groups (Imam_2021; page 22, paragraph 2).
It would have been prima facie obvious to one of ordinary skill, in the art before
the effective filing date, to combine the GC7-eIF5A inhibitor in GAD65 expressing diabetic mice of Imam_2019 with the anti-Dll4 antibody of Billiard with the GAD65-specific CAR Tregs of Imam_2021 with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine GC7-eIF5A of Imam_2019 with the anti-Dll4 antibody of Billiard with the GAD65-specific CAR Tregs of Imam_2021 before the effective filing date of the instant invention since the GC7-eIF5A inhibitor of Imam_2019 is capable of enriching Treg/Th17 and Treg/Th1 ratios to significantly increase the total pancreatic insulin content although not significantly impacting CTL function and decrease GAD65 antibodies; and the Notching signaling inhibitor, anti-Dll4 antibody, of Billiard is capable of reducing the expansion of CTLs and CD8+ cell infiltration in pancreatic islets cells. Additionally, Imam_2021 teaches GAD65-specific CAR Tregs is an efficacious treatment option for type 1 diabetes in the GAD65-specific CAR Tregs ability to downregulate Teff cells and suppress T cell functioning.
Therefore, it would have been obvious to combine the GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4 antibody of Billiard with the GAD65-specific CAR Tregs of Imam_2021 to yield predictable results of more effectively treating type 1 diabetes by increasing the specificity of treatment and promote the reduction of effector T cell functioning in the β-islet cells in the pancreas.
Regarding the timing of administration of the eIF5A inhibitor, Notch signaling inhibitor, and treatment for the autoimmune disease as recited in instant claim 13 the timing of drug administration is considered a results effective variable, so a person of ordinary skill in the art would have been motivated to optimize the timing of eIF5A inhibitor and Notch signaling inhibitor administration in order to achieve the desired result of enriching Treg cells in type 1 diabetes. Therefore, it would be obvious to try the simultaneous administration of the eIF5A inhibitor and Notch signaling inhibitor and subsequent administration of the treatment for the autoimmune disease.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Imam_2019 and Billiard as applied to claims 17-19 above, and further in view of Van Belle et al (PTO-892; page 3, Reference V; “Van Belle”) and Magee et al (PTO-892; page 2, reference W; “Magee”).
Imam_2019 and Billiard teach a method for enriching Tregs, the method comprising simultaneously inhibiting eIF5A with GC7 and Notching signaling with anti-DLL4 antibody in a subject to enrich Treg cells in the subject (see above). Imam_2019 and Billiard do not teach the method wherein the subject is being prepared for an organ transplant.
However, Van Belle teaches β-islet cell transplantation can temporarily cure type 1 diabetes mellitus but requires simultaneous immunosuppression to avoid allograft rejection (Van Belle; Abstract). Van Belle teaches the Edmonton protocol as a method for transplanting pancreatic islets from cadaveric donors into patients with type 1 diabetes where immunosuppression begins immediately before transplantation with an anti-IL-2 receptor α mAb and maintained for several months (Van Belle; page 1626, left – middle column, paragraph 2). However, with this immunosuppression, insulin independence is not sustained and graft function is lost in most patients after 5 years due to elevated levels of homeostatic cytokines and expansion of the population of autoreactive CD8+ T cells and immunosuppression via induction of islet antigen-specific Tregs can be a better option in this context (Van Belle; page 1626, middle column, paragraphs 1-2; right column, paragraph 1; Figure 1). Treg expansion itself is an important safeguard to limit autoimmune reactivity during lymphopenia and antigen specific induction of Tregs can warrant a long-term maintenance of tolerance without immunosuppression (Van Belle; page 1627; left column, paragraph 1; right column, paragraph 1).
Magee teaches transplantation as a treatment choice for many patients with end-stage organ disease and therapies that promote regulation while suppressing effector immunity function is imperative to improve graft survival and minimize conventional immunosuppression (Magee; Abstract; page 847, left column, paragraph 1). Magee teaches that Notch signaling is involved in the differentiation of naïve CD4+ T cells into various T helper subsets and that blocking Notch ligands such as DLL-1 and DLL-4 can prolong graft survival, ameliorate graft-versus-host disease (GVHD), and reduced severity of the disease (Magee; page 847, right column, paragraph 1). Additionally, Magee teaches Tregs are critical to the enhanced graft survival achieved with Notch-1 blockade because depletion of Tregs pretransplant in mice subsequently treated with aNotch-1 abrogated the survival advantage previously seen in aNotch-1 alone (Magee; page 860, left column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill, in the art before
the effective filing date, to combine the GC7-eIF5A inhibitor treatment of Imam_2019 with the anti-Dll4 antibody capable of reducing expansion and proliferation of CD8+ T cells of Billiard with the motivation to suppress the immune system prior to pancreatic islet cell transplantation of Van Belle and the motivation to prime the immune system using a Notch inhibitor prior to organ transplantation of Magee with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine GC7-eIF5A of Imam_2019 with the anti-Dll4 antibody of Billiard with the motivation to suppress the immune system prior to pancreatic islet cell transplantation of Van Belle and the motivation to prime the immune system using a Notch inhibitor prior to organ transplantation of Magee before the effective filing date of the instant invention since the GC7-eIF5A inhibitor of Imam_2019 is capable of enriching Treg/Th17 and Treg/Th1; and the Notching signaling inhibitor, anti-Dll4 antibody, of Billiard is capable of reducing the expansion of CTLs and CD8+ cell infiltration. Additionally, Van Belle teaches patients receiving an Islet cell transplant require immunosuppression prior to transplantation to minimize graft rejection and Magee teaches modulating the immune system (suppressing CTL function and increasing Treg function) with a Notch signaling inhibitor can prolong the graft’s survival and ameliorate GVHD.
Therefore, it would have been obvious to combine the GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4 antibody of Billiard with the motivation to suppress the immune system prior to pancreatic islet cell transplantation of Van Belle and the motivation to prime the immune system using a Notch inhibitor prior to organ transplantation of Magee to yield predictable results of priming the immune system prior to organ transplant by decreasing CTL expansion and presence and enriching Treg function to improve graft survival and ameliorate GVHD.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-3 and 5-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-12 and 14-15 of copending Application No. 18/670,112 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because '112 teaches in reference claim 8 a method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype wherein the method comprises administering an effective amount of an eIF5A inhibitor to a subject so as to inhibit eIF5A in a subject and administering an effective amount of a Notch signaling inhibitor to the subject as to inhibit Notch signaling in the subject wherein eIF5A and Notch signaling in the subject are inhibited simultaneously so as to induce plasticity in intermediate Tregs in the subject to exhibit a regulatory T cell phenotype; wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody; wherein the eIF5A and Notch signaling inhibitor are administered simultaneously; wherein the method further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject.
Therefore, ‘112 anticipate instant claims 1-3 and 5-7. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 8-10, and 13-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 12, and 14 of copending Application No. 18/670,112 in view of Imam_2019 (see above), Billiard (see above), and Imam_2021 (see above).
'112 has been discussed above. The claimed invention differs from '112 with respect to instant claims 4 and 8-10, wherein the treatment for type 1 diabetes comprises CAR Tregs; wherein the CAR Tregs are GAD65-specific CAR-Tregs; wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody; and instant claims 13-16 for a method of treating an autoimmune disease, the method comprising inhibiting eIF5A in a subject having an autoimmune disease, simultaneously inhibiting Notch signaling in the subject, and subsequently, administering a treatment for the autoimmune disease to the subject; wherein the simultaneous inhibition of eIF5A and Notch signaling in the subject enriches Treg cells in the subject so as to prime the subject's immune system for the treatment; wherein eIF5A is inhibited with GC7, and Notch signaling is inhibited with an anti-DLL4 antibody; wherein the autoimmune disease is type 1 diabetes (TID); wherein the treatment comprises GAD65-specific CAR-Tregs; and instant claims 17-19 for a method for enriching Treg cells in a subject, the method comprising simultaneously inhibiting eIF5A and Notch signaling in a subject to enrich Treg cells in the subject; wherein eIF5 A is inhibited with GC7; wherein Notch signaling is inhibited with an anti-Dll4 antibody.
However, Imam_2019 does teach the hallmark of type 1 diabetes is immune mediated destruction of insulin secreting β-cells of the pancreatic islets of Langerhans resulting in hyperglycemia and lifelong dependency on exogenous insulin and that T cell dynamics in the islet microenvironment is characterized by T helper (Th) 1 and Th17 cell bias and a Treg cell defect that ultimately culminates into CTL mediated destruction of the β-cells (Imam_2019; page 1, paragraph 1). Imam_2019 teaches the effects of eIF5A inhibition via GC7 on T cell dynamics (i.e. T cell differentiation and plasticity) in the pancreas and local lymph nodes in mouse models expressing human GAD65, an antigen that initiates activation of T-cells and the onset of diabetes (Imam_2019; Summary; page 2, paragraph 4). In vivo GC7 inhibition enriched Treg population in the pancreas, IGLN, PPLN, and spleen and reduces Th1 and Th17 cells which in turn helped to significantly increase the total pancreatic insulin content in humanized T1D mice (Imam_2019; page 12, paragraphs 4, 7-8). Imam_2019 further teaches that although Tregs were enriched upon GC7 treatment resulting in increased Treg/Th17 and Treg/Th1 ratios, there was no reduction in cytotoxic CD8 T cells in the islets (Imam_2019; Figure 2C and 3E; page 7, paragraphs 4-5 and 8; page 13, paragraph 1). Imam_2019 teaches that inhibition of eIF5A also reduced anti-GAD65 antibody production which may help to decease disease severity and help manage T1D in early stages of disease (Imam_2019; Figure 6C; Summary; page 11, paragraphs 1-2).
Billiard teaches Delta-like ligand 4 (Dll4)-Notch signaling being essential for T cell development and is necessary to inhibit the potential of early T cell progenitors to generate alternative lineages (Billiard; Summary; page 1011, left column, paragraph 1). Billiard teaches that anti-Dll4 antibody treatment prevents type 1 diabetes via a Treg cell-mediated mechanism of inducing a de novo generation of thymic nTreg cells (Billiard; page 1020, paragraph 1; Figure 3C). Additionally, Billiard teaches that anti-Dll4 antibody treatment fully prevented type 1 diabetes disease development in nonobese diabetic mice which was correlated with high ratio (i.e. enrichment) of Treg cell frequency, reduction in the expansion of antigen-specific cytotoxic T lymphocytes (CTLs) in pancreatic islets cells, and lack of CD8+ cell infiltration into the pancreatic islets cells (Billiard; Figure 7A-B; page 1020; right column, paragraph 2). Sustained Dll4-Notch signaling blockade is required to maintain alternative DC development in the thymus, promote early DC and Treg cell expansion followed by an enrichment of Treg cells in thymus, and induce Treg cell expansion in the periphery upon immune stimulation (Billiard; page 1023, left column, paragraph 1).
Imam_2021 does teach the therapeutic application of pancreatic β-cell-GAD65-specific CAR Tregs for treatment of Type 1 Diabetes (Imam_2021; page 4, paragraphs 2-3; pages 11-12). Imam_2021 teaches the homing of the GAD65-CAR Tregs to the islets of Langerhans providing in vivo evidence for antigen specificity and the reduction of the number of functionally active effector T cells (Teff) in GAD65-CAR Treg treated animals providing evidence for T cell suppression (Imam_2021; page 22, paragraph 2). Imam_2021 additionally teaches the CAR-N Tregs appeared more efficacious in downregulating Teff cells than CAR-M Tregs and the antigen-specific proliferative capacity of GAD65-CAR-N/M-Tregs was 4-5 times higher than of antigen-specific unmodified (normal) Tregs. This provides evidence for the superiority of GAD65-CAR-Treg over normal Tregs on their diabetes reversal capacity observed in the GAD65-CAR-Treg treated groups (Imam_2021; page 22, paragraph 2).
It would have been prima facie obvious to one of ordinary skill, in the art before
the effective filing date, to combine the method of inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype of ‘217 with GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4 antibody of Billiard with the GAD65-specific CAR Tregs of Imam_2021 with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine the method of ‘217 with the GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4-Notching signaling inhibitor of Billiard with the GAD65 specific CAR Tregs of Imam_2021 before the effective filing date of the instant invention since the GC7-eIF5A inhibitor of Imam_2019 is capable of enriching Treg/Th17 and Treg/Th1 ratios to significantly increase the total pancreatic insulin content although not significantly impacting CTL function and decrease GAD65 antibodies; and the Notching signaling inhibitor, anti-Dll4 antibody, of Billiard is capable of reducing the expansion of CTLs and CD8+ cell infiltration in pancreatic islets cells. Additionally, Imam_2021 teaches GAD65-specific CAR Tregs is an efficacious treatment option for type 1 diabetes in the GAD65-specific CAR Tregs ability to downregulate Teff cells and suppress T cell functioning.
Therefore, it would have been obvious to combine method of inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype of ‘217 with the anti-Dll4 antibody of Billiard with GC7-eIF5A inhibitor of Imam_2019 with the GAD65-specific CAR Tregs of Imam_2021 according to known methods to yield predictable results to improve specificity of type 1 diabetes treatments and increase/preserve the functionality of the pancreatic β-islet cells to produce insulin.
Regarding instant claim 4 wherein the eIF5A inhibitor and Notch signaling inhibitor are administered sequentially, the timing of drug administration is considered a results effective variable, so a person of ordinary skill in the art would have been motivated to optimize the timing of eIF5A inhibitor and Notch signaling inhibitor administration in order to achieve the desired result of enriching Treg cells in type 1 diabetes. Therefore, it would be obvious to try the sequential administration of the eIF5A inhibitor and Notch signaling inhibitor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 5-7, 13-15, and 17-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-12, 14-15, and 17-19 of copending Application No. 18/674,217 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because '217 teaches in reference claim 8 a method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype wherein the method comprises administering an effective amount of an eIF5A inhibitor to a subject so as to inhibit eIF5A in a subject and administering an effective amount of a Notch signaling inhibitor to the subject as to inhibit Notch signaling in the subject wherein eIF5A and Notch signaling in the subject are inhibited simultaneously so as to induce plasticity in intermediate Tregs in the subject to exhibit a regulatory T cell phenotype; wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody; wherein the eIF5A and Notch signaling inhibitor are administered simultaneously; wherein the method further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject; wherein the inhibition of eIF5A and Notch signaling is used to enrich T regulatory cells in vivo or in vitro prior to an adoptive T cell therapy for treating autoimmune disease; wherein the eIF5A and Notching signaling is used to induce tolerance for host versus graft injections or transplants.
Therefore, ‘217 anticipate instant claims 1-3, 5-7, 13-15, and 17-20. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 8-10, and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 12, and 14 of copending Application No. 18/670,112 in view of Imam_2019 (see above), Billiard (see above) and Imam_2021 (see above).
‘217 has been discussed above. The claimed invention differs from '217 with respect to instant claims 4, 8-10, and 16, wherein the treatment for type 1 diabetes comprises CAR Tregs; wherein the CAR Tregs are GAD65-specific CAR-Tregs; wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
However, Imam_2019 does teach the hallmark of type 1 diabetes is immune mediated destruction of insulin secreting β-cells of the pancreatic islets of Langerhans resulting in hyperglycemia and lifelong dependency on exogenous insulin and that T cell dynamics in the islet microenvironment is characterized by T helper (Th) 1 and Th17 cell bias and a Treg cell defect that ultimately culminates into CTL mediated destruction of the β-cells (Imam_2019; page 1, paragraph 1). Imam_2019 teaches the effects of eIF5A inhibition via GC7 on T cell dynamics (i.e. T cell differentiation and plasticity) in the pancreas and local lymph nodes in mouse models expressing human GAD65, an antigen that initiates activation of T-cells and the onset of diabetes (Imam_2019; Summary; page 2, paragraph 4). In vivo GC7 inhibition enriched Treg population in the pancreas, IGLN, PPLN, and spleen and reduces Th1 and Th17 cells which in turn helped to significantly increase the total pancreatic insulin content in humanized T1D mice (Imam_2019; page 12, paragraphs 4, 7-8). Imam_2019 further teaches that although Tregs were enriched upon GC7 treatment resulting in increased Treg/Th17 and Treg/Th1 ratios, there was no reduction in cytotoxic CD8 T cells in the islets (Imam_2019; Figure 2C and 3E; page 7, paragraphs 4-5 and 8; page 13, paragraph 1). Imam_2019 teaches that inhibition of eIF5A also reduced anti-GAD65 antibody production which may help to decease disease severity and help manage T1D in early stages of disease (Imam_2019; Figure 6C; Summary; page 11, paragraphs 1-2).
Billiard teaches Delta-like ligand 4 (Dll4)-Notch signaling being essential for T cell development and is necessary to inhibit the potential of early T cell progenitors to generate alternative lineages (Billiard; Summary; page 1011, left column, paragraph 1). Billiard teaches that anti-Dll4 antibody treatment prevents type 1 diabetes via a Treg cell-mediated mechanism of inducing a de novo generation of thymic nTreg cells (Billiard; page 1020, paragraph 1; Figure 3C). Additionally, Billiard teaches that anti-Dll4 antibody treatment fully prevented type 1 diabetes disease development in nonobese diabetic mice which was correlated with high ratio (i.e. enrichment) of Treg cell frequency, reduction in the expansion of antigen-specific cytotoxic T lymphocytes (CTLs) in pancreatic islets cells, and lack of CD8+ cell infiltration into the pancreatic islets cells (Billiard; Figure 7A-B; page 1020; right column, paragraph 2). Sustained Dll4-Notch signaling blockade is required to maintain alternative DC development in the thymus, promote early DC and Treg cell expansion followed by an enrichment of Treg cells in thymus, and induce Treg cell expansion in the periphery upon immune stimulation (Billiard; page 1023, left column, paragraph 1).
Imam_2021 does teach the therapeutic application of pancreatic β-cell-GAD65-specific CAR Tregs for treatment of Type 1 Diabetes (Imam_2021; page 4, paragraphs 2-3; pages 11-12). Imam_2021 teaches the homing of the GAD65-CAR Tregs to the islets of Langerhans providing in vivo evidence for antigen specificity and the reduction of the number of functionally active effector T cells (Teff) in GAD65-CAR Treg treated animals providing evidence for T cell suppression (Imam_2021; page 22, paragraph 2). Imam_2021 additionally teaches the CAR-N Tregs appeared more efficacious in downregulating Teff cells than CAR-M Tregs and the antigen-specific proliferative capacity of GAD65-CAR-N/M-Tregs was 4-5 times higher than of antigen-specific unmodified (normal) Tregs. This provides evidence for the superiority of GAD65-CAR-Treg over normal Tregs on their diabetes reversal capacity observed in the GAD65-CAR-Treg treated groups (Imam_2021; page 22, paragraph 2).
It would have been prima facie obvious to one of ordinary skill, in the art before
the effective filing date, to combine the method of inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype of ‘217 with GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4 antibody of Billiard with the GAD65-specific CAR Tregs of Imam_2021 with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine the method of ‘217 with the GC7-eIF5A inhibitor of Imam_2019 with the anti-Dll4-Notching signaling inhibitor of Billiard with the GAD65 specific CAR Tregs of Imam_2021 before the effective filing date of the instant invention since the GC7-eIF5A inhibitor of Imam_2019 is capable of enriching Treg/Th17 and Treg/Th1 ratios to significantly increase the total pancreatic insulin content although not significantly impacting CTL function and decrease GAD65 antibodies; and the Notching signaling inhibitor, anti-Dll4 antibody, of Billiard is capable of reducing the expansion of CTLs and CD8+ cell infiltration in pancreatic islets cells. Additionally, Imam_2021 teaches GAD65-specific CAR Tregs is an efficacious treatment option for type 1 diabetes in the GAD65-specific CAR Tregs ability to downregulate Teff cells and suppress T cell functioning.
Therefore, it would have been obvious to combine method of inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype of ‘217 with the anti-Dll4 antibody of Billiard with GC7-eIF5A inhibitor of Imam_2019 with the GAD65-specific CAR Tregs of Imam_2021 according to known methods to yield predictable results to improve specificity of type 1 diabetes treatments and increase/preserve the functionality of the pancreatic β-islet cells to produce insulin.
Regarding instant claim 4 wherein the eIF5A inhibitor and Notch signaling inhibitor are administered sequentially, the timing of drug administration is considered a results effective variable, so a person of ordinary skill in the art would have been motivated to optimize the timing of eIF5A inhibitor and Notch signaling inhibitor administration in order to achieve the desired result of enriching Treg cells in type 1 diabetes. Therefore, it would be obvious to try the sequential administration of the eIF5A inhibitor and Notch signaling inhibitor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/ Primary Examiner, Art Unit 1641