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 .
Claims 1-22 are pending.
Applicant’s election of Group I that read on (A) GC7 as the species of eIF5A inhibitor, (B) anti-DLL4 antibody as the species of Notch signaling inhibitor, (C) CD4+IFNg+IL17+FOXP3+ T cells as the species of intermediate regulatory T cell, (D) type I diabetic as the species of patient population in the reply filed on July 2, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 20-22 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-19, drawn to a method for inducing plasticity in intermediate Treg cells that read on (A) GC7 as the species of eIF5A inhibitor, (B) anti-DLL4 antibody as the species of Notch signaling inhibitor, (C) CD4+IFNg+IL17+FOXP3+ T cells as the species of intermediate regulatory T cell, (D) type I diabetic as the species of patient population, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/389,391, filed July 15, 2022, is acknowledged.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim objection
Claim 2 is objected to because of the following informality: the claim uses theabbreviation GC7 without first defining it. To clarify the claim, applicant should first spell out thefull term before using an abbreviation. Given the subject matter of the specification, theexaminer presumes that "GC7" stands for "N1-guanyl-1,7-diaminoheptane (GC7)". Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 17 recites the limitation "in vitro" in base claim 8. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "in vitro" in base claim 8. There is insufficient antecedent basis for this limitation in the claim.
Claim rejections under - 35 U.S.C. 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.
Claims 1-19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses a method for inducing plasticity in intermediate Treg cells, the method comprising: contacting intermediate Treg cells with an effective amount of any eIF5A inhibitor and an effective amount of any Notch signaling inhibitor so as to induce plasticity in the intermediate Treg cells to exhibit a regulatory T cell phenotype.
Claim 2 encompasses the method of claim 1, wherein the eIF5A inhibitor comprises GC7.
Claim 3 encompasses the method of claim 1, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 4 encompasses the method of claim 1, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 5 encompasses the method of claim 1, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 6 encompasses the method of claim 1, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 7 encompasses the method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 8 encompasses a method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype, the method comprising: administering an effective amount of any eIF5A inhibitor to a subject so as to inhibit eIF5A in the subject; and administering an effective amount of any Notch signaling inhibitor to the 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 intermediate Treg cells in the subject to exhibit a regulatory T cell phenotype.
Claim 9 encompasses the method of claim 8, wherein the eIF5A inhibitor comprises GC7.
Claim 10 encompasses the method of claim 8, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 11 encompasses the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 12 encompasses the method of claim 8, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 13 encompasses the method of claim 8, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 14 encompasses the method of claim 8, further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject.
Claim 15 encompasses the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 16 encompasses the method of claim 8, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 17 encompasses the method of claim 8, 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.
Claim 18 encompasses the method of claim 8, wherein the inhibition of eIF5A and Notch signaling is used to induce tolerance for host versus graft rejections or transplants.
Claim 19 encompasses the method of claim 8, wherein the inhibition of eIF5A and Notch signaling is used to generate T regulatory cells from T effector cells (CD4+CD25- and CD8 cells) or to enrich T regulatory cells in vitro for adoptive T regulatory cell therapy.
The specification discloses:
[0065] eIF5A, or eukaryotic translation initiation factor 5A, is a protein in humans encoded by the EIF5A gene. eIFSA is a 17kDA highly conserved protein expressed only in actively dividing (5%) mammalian cells (lymphocytes). eIFSA is believed to catalyze peptide bond formation and help resolve ribosomal stalls, making it an elongation factor despite the “initiation factor” name. eIF5A also regulates the protein translation processes associated with tumor proliferation. eIF5A is overexpressed in diabetes. Hypusinated eIFSA is involved in immune cell differentiation and maturation of dendritic cells (DCs). Hypusinated eIF5A is significantly overexpressed in diabetogenic CD4 T cells; inhibiting hypusinated eIF5A leads to the enrichment of Treg cells. Deoxyhypusine synthase (DHS) is known to catalyze hypusination of eIF5A. The spermidine analogue N1-guanyl-1,7-diaminoheptane (also known as GC7 or N1-carbamimidoyl-1,7-diamineoheptane) is the most potent DHS inhibitor. GC7 inhibits overexpression of eIFSA, without affecting the basal expression, and results in improved glucose tolerance, greater insulin secretion, decreased immune infiltration of islets, and delay of diabetes onset/amelioration in NOD mice, and humanized TID mice. eIFSA inhibitors other than GC7 include, but are not limited to, anti-eIF5A neutralizing antibodies, L-mimosine, ciclopirox (also known as CPX or Batrafen), deferiprone (also known as DEF), and combinations thereof. As one non-limiting example, GC7 has the following structure:
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[0066] As another non-limiting example, CPX has the following structure:
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[0067] As another non-limiting example, DEF has the following structure:
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Regarding Notch signaling inhibitor, the specification discloses:
[0069] Notch signaling inhibitors include, but are not limited to, gamma-secretase inhibitors (GSIs), alpha-secretase inhibitors, delta-like protein inhibitors, jagged protein inhibitors, small molecule blockers, endosomal acidification inhibitors, blocking or negative regulatory region antibodies, stapled peptides, Notch inhibiting genes, or Notch inhibiting siRNAs, shRNAs, or microRNAs, or combinations thereof. Non-limiting examples of Notch signaling inhibitors include anti-DLL4 antibodies; anti-DLL1 antibodies; MK-0752 (also known as cis-4- [(4-chlorophenyl) sulfonyl]-4-(2,5-difluorophenyl) cyclohexanepropanoic acid); N-[N-(3,5-difluorophenylacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (also known as DAPT); L685,458 (also known as (5S)-(t-butoxycarbonylamino)-6-phenyl-(4R) hydroxy-(2R) benzylhexanoyl)-L-leu-L-phe-amide); (S)-2-(2-(3,5-difluorophenyl) acetamido)-N- ((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e][1,4]diazepin-3-yl) propanamide (also known as Compound E or (s,s)-2-[2-(3,5-difluorophenyl)-acetylamino]-n-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1h-benzo [e][1,4]diazepin-3-yl)-propionamide); dibenzazepine (also known as DBZ); 7-amino-4-chloro-3-methoxyisocoumarin (also known as JLK6); [11-endo]-N-(5,6,7,8,9,10-hexahydro-6,9-methano benzo [9] [8] annulen-11-yl)-thiophene-2-sulfonamide; LY 2886721 hydrochloride (also known as N-[3- [(4aS,7aS)-2-Amino-4a,5-dihydro-4H-furo [3,4-d][1,3]thiazin-7a (7H)-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide hydrochloride); and combinations thereof.
The specification discloses the use of just GC7, an eIF5A inhibitor, in combination with just anti-DLL4 antibody, a Notch signaling inhibitor to induce plasticity in intermediate regulatory T cells that express (CD4+IFNg+IL17+FOXP3+) to functional regulatory T cells that express CD4+CD25+FOXP3+ in vitro.
However, the specification does not describe the chemical structures of any and all “eIF5A inhibitor” and “Notch signaling inhibitor” encompassed by the claimed methods.
The specification does not describe a representative number of species of eIF5A inhibitors and Notch signaling inhibitors falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual eIF5A inhibitor and Notch signaling inhibitor themselves encompassed by the claimed methods for inducing plasticity in intermediate Treg cells (claims 1, 5-7, 811, 13-16, 19) or for treating type 1 diabetes (claim 14), any and all autoimmune diseases (claim 17) or host versus graft rejections or transplants (claim 18) for adaptive T regulatory cell therapy (claim 19).
Regarding eIF5A inhibitors, Guo et al (Biomed Pharmacother 167: 115440, 2023; PTO 892) 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, Christopoulos et al (Front Immunol 12: 668207, 2021; PTO 892) 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”).
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
Regarding eIF5A and Notch signaling in the subject are inhibited simultaneously (claim 8), this is a reach through claim. The specification discloses administering eIF5A inhibitor, namely GC7, in combination with anti-DLL4 antibody simultaneously in vitro.
However, there is no objective evidence of inhibiting eIF5A and Notch signaling simultaneously in the subject.
Regarding enriching T regulatory cells in vivo or in vitro prior to an adoptive T cell therapy for treating any and all autoimmune disease, the specification discloses antigen specific GAD65 for generating GAD65 specific Treg cells for treating type 1 diabetes.
However, the specification does not teach the claimed Treg cells can be used to induce tolerance to any and all potential antigens associated with any and all autoimmune diseases or transplant by adoptive T regulatory cell therapy.
At the time the invention was made, it is well established in the art that inhibiting eIF5A and Notch signaling are highly unpredictable and the effects of each are disease and tissue subtype specific.
Mishra (Nature Cell ad Science 3(3): e00022, 2025; PTO 892) 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 (see 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).
Nakanishi et al (Int J Mol Sci 25(15): 8171, 2024; PTO 892) 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).
Ma et al (Expert Opinion on Therapeutic Targets 14(5): 553-565, 2010; PTO 892) 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 (see 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).
There are no in vivo working examples. It is unpredictable which undisclosed eIF5A inhibitor and Notch signaling inhibitor is effective for the claimed method for inducing plasticity of any intermediate regulator T cells (Treg) to exhibit any regulatory T cell phenotype for treating any and all potential autoimmune diseases, transplantation, host versus graft rejection.
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a method for inducing plasticity in intermediate regulatory T cells (iTreg) that express CD4+IFNγ+IL17+FOXP3+ to regulatory T cell (Treg) phenotype, the method comprising contacting the iTreg cells with an effective amount of an eIF5A inhibitor and an effective amount of a Notch signaling inhibitor thereby induce plasticity in the iTreg cells to exhibits a regulatory T cell phenotype CD4+CD25+FOXP3+, wherein the eIF5A inhibitor comprises N1-guanyl-1,7-diaminoheptane (GC7) and wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody, (2) a method for inducing plasticity in intermediate regulatory T cells (iTreg) that express CD4+IFNγ+IL17+FOXP3+ to regulatory T cell (Treg) phenotype CD4+CD25+FOXP3+, the method comprising: administering simultaneously an effective amount of an eIF5A inhibitor and an effective amount of a Notch signaling inhibitor to a subject, wherein the eIF5A inhibitor comprises N1-guanyl-1,7-diaminoheptane (GC7) and the Notch signaling inhibitor comprises an anti-DLL4 antibody, thereby induce plasticity in the iTreg cells to exhibits a regulatory T cell phenotype CD4+CD25+FOXP3+, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-19 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 (1) a method for inducing plasticity in intermediate regulatory T cells (iTreg) that express CD4+IFNγ+IL17+FOXP3+ to regulatory T cell (Treg) phenotype, the method comprising contacting the iTreg cells with an effective amount of an eIF5A inhibitor and an effective amount of a Notch signaling inhibitor thereby induce plasticity in the iTreg cells to exhibits a regulatory T cell phenotype CD4+CD25+FOXP3+, wherein the eIF5A inhibitor comprises N1-guanyl-1,7-diaminoheptane (GC7) and wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody, (2) a method for inducing plasticity in intermediate regulatory T cells (iTreg) that express CD4+IFNγ+IL17+FOXP3+ to regulatory T cell (Treg) phenotype CD4+CD25+FOXP3+, the method comprising: administering simultaneously an effective amount of an eIF5A inhibitor and an effective amount of a Notch signaling inhibitor to a subject, wherein the eIF5A inhibitor comprises N1-guanyl-1,7-diaminoheptane (GC7) and the Notch signaling inhibitor comprises an anti-DLL4 antibody, thereby induce plasticity in the iTreg cells to exhibits a regulatory T cell phenotype CD4+CD25+FOXP3+, does not reasonably provide enablement for any and all eIF5A inhibitor and Notch signaling inhibitor encompassed by the claimed methods as set forth in claims 1-19. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses a method for inducing plasticity in intermediate Treg cells, the method comprising: contacting intermediate Treg cells with an effective amount of any eIF5A inhibitor and an effective amount of any Notch signaling inhibitor so as to induce plasticity in the intermediate Treg cells to exhibit a regulatory T cell phenotype.
Claim 2 encompasses the method of claim 1, wherein the eIF5A inhibitor comprises GC7.
Claim 3 encompasses the method of claim 1, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 4 encompasses the method of claim 1, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 5 encompasses the method of claim 1, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 6 encompasses the method of claim 1, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 7 encompasses the method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 8 encompasses a method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype, the method comprising: administering an effective amount of any eIF5A inhibitor to a subject so as to inhibit eIF5A in the subject; and administering an effective amount of any Notch signaling inhibitor to the 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 intermediate Treg cells in the subject to exhibit a regulatory T cell phenotype.
Claim 9 encompasses the method of claim 8, wherein the eIF5A inhibitor comprises GC7.
Claim 10 encompasses the method of claim 8, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 11 encompasses the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 12 encompasses the method of claim 8, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 13 encompasses the method of claim 8, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 14 encompasses the method of claim 8, further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject.
Claim 15 encompasses the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 16 encompasses the method of claim 8, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 17 encompasses the method of claim 8, 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.
Claim 18 encompasses the method of claim 8, wherein the inhibition of eIF5A and Notch signaling is used to induce tolerance for host versus graft rejections or transplants.
Claim 19 encompasses the method of claim 8, wherein the inhibition of eIF5A and Notch signaling is used to generate T regulatory cells from T effector cells (CD4+CD25- and CD8 cells) or to enrich T regulatory cells in vitro for adoptive T regulatory cell therapy.
The specification discloses:
[0065] eIF5A, or eukaryotic translation initiation factor 5A, is a protein in humans encoded by the EIF5A gene. eIFSA is a 17kDA highly conserved protein expressed only in actively dividing (5%) mammalian cells (lymphocytes). eIFSA is believed to catalyze peptide bond formation and help resolve ribosomal stalls, making it an elongation factor despite the “initiation factor” name. eIF5A also regulates the protein translation processes associated with tumor proliferation. eIF5A is overexpressed in diabetes. Hypusinated eIFSA is involved in immune cell differentiation and maturation of dendritic cells (DCs). Hypusinated eIF5A is significantly overexpressed in diabetogenic CD4 T cells; inhibiting hypusinated eIF5A leads to the enrichment of Treg cells. Deoxyhypusine synthase (DHS) is known to catalyze hypusination of eIF5A. The spermidine analogue N1-guanyl-1,7-diaminoheptane (also known as GC7 or N1-carbamimidoyl-1,7-diamineoheptane) is the most potent DHS inhibitor. GC7 inhibits overexpression of eIFSA, without affecting the basal expression, and results in improved glucose tolerance, greater insulin secretion, decreased immune infiltration of islets, and delay of diabetes onset/amelioration in NOD mice, and humanized TID mice. eIFSA inhibitors other than GC7 include, but are not limited to, anti-eIF5A neutralizing antibodies, L-mimosine, ciclopirox (also known as CPX or Batrafen), deferiprone (also known as DEF), and combinations thereof. As one non-limiting example, GC7 has the following structure:
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[0066] As another non-limiting example, CPX has the following structure:
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[0067] As another non-limiting example, DEF has the following structure:
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Regarding Notch signaling inhibitor, the specification discloses:
[0069] Notch signaling inhibitors include, but are not limited to, gamma-secretase inhibitors (GSIs), alpha-secretase inhibitors, delta-like protein inhibitors, jagged protein inhibitors, small molecule blockers, endosomal acidification inhibitors, blocking or negative regulatory region antibodies, stapled peptides, Notch inhibiting genes, or Notch inhibiting siRNAs, shRNAs, or microRNAs, or combinations thereof. Non-limiting examples of Notch signaling inhibitors include anti-DLL4 antibodies; anti-DLL1 antibodies; MK-0752 (also known as cis-4- [(4-chlorophenyl) sulfonyl]-4-(2,5-difluorophenyl) cyclohexanepropanoic acid); N-[N-(3,5-difluorophenylacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (also known as DAPT); L685,458 (also known as (5S)-(t-butoxycarbonylamino)-6-phenyl-(4R) hydroxy-(2R) benzylhexanoyl)-L-leu-L-phe-amide); (S)-2-(2-(3,5-difluorophenyl) acetamido)-N- ((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e][1,4]diazepin-3-yl) propanamide (also known as Compound E or (s,s)-2-[2-(3,5-difluorophenyl)-acetylamino]-n-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1h-benzo [e][1,4]diazepin-3-yl)-propionamide); dibenzazepine (also known as DBZ); 7-amino-4-chloro-3-methoxyisocoumarin (also known as JLK6); [11-endo]-N-(5,6,7,8,9,10-hexahydro-6,9-methano benzo [9] [8] annulen-11-yl)-thiophene-2-sulfonamide; LY 2886721 hydrochloride (also known as N-[3- [(4aS,7aS)-2-Amino-4a,5-dihydro-4H-furo [3,4-d][1,3]thiazin-7a (7H)-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide hydrochloride); and combinations thereof.
The specification discloses the use of just GC7, an eIF5A inhibitor, in combination with just anti-DLL4 antibody, a Notch signaling inhibitor to induce plasticity in intermediate regulatory T cells that express (CD4+IFNg+IL17+FOXP3+) to functional regulatory T cells that express CD4+CD25+FOXP3+ in vitro.
However, the specification does not teach a representative number of species of eIF5A inhibitors and Notch signaling inhibitors falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use the claimed methods for inducing plasticity in intermediate Treg cells (claims 1, 5-7, 811, 13-16, 19) or for treating type 1 diabetes (claim 14), any and all autoimmune diseases (claim 17) or host versus graft rejections or transplants (claim 18) for adaptive T regulatory cell therapy (claim 19).
Regarding eIF5A inhibitors, Guo et al (Biomed Pharmacother 167: 115440, 2023; PTO 892) 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, Christopoulos et al (Front Immunol 12: 668207, 2021; PTO 892) 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 (see Figure 2; page 5, “Rationale for Therapeutic Targeting of the Notch Pathway”).
Regarding eIF5A and Notch signaling in the subject are inhibited simultaneously (claim 8), this is a reach through claim. The specification discloses administering eIF5A inhibitor, namely GC7, in combination with anti-DLL4 antibody simultaneously either in vitro.
However, there is no objective evidence of inhibiting eIF5A and Notch signaling simultaneously in the subject.
Regarding enriching T regulatory cells in vivo or in vitro prior to an adoptive T cell therapy for treating any and all autoimmune disease, the specification discloses antigen specific GAD65 for generating GAD65 specific Treg cells for treating type 1 diabetes.
However, the specification does not teach the claimed Treg cells can be used to induce tolerance to any and all potential antigens associated with any and all autoimmune diseases or transplant by adoptive T regulatory cell therapy.
At the time the invention was made, 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.
Mishra (Nature Cell ad Science 3(3): e00022, 2025; PTO 892) 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 (see 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).
Nakanishi et al (Int J Mol Sci 25(15): 8171, 2024; PTO 892) 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).
Ma et al (Expert Opinion on Therapeutic Targets 14(5): 553-565, 2010; PTO 892) 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 (see 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).
There are no in vivo working examples. It is unpredictable which undisclosed eIF5A inhibitor and Notch signaling inhibitor is effective for the claimed method for inducing plasticity of any intermediate regulator T cells (Treg) to exhibit any regulatory T cell phenotype for treating any and all potential autoimmune diseases, transplantation, host versus graft rejection.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-13, 15, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Iman et al (Scientific Report 9: 1533, 2019; PTO 892) in view of Billiard et al (J Exp Med 209(5): 1011-1028, 2012; PTO 892).
Claim 1 recites a method for inducing plasticity in intermediate Treg cells, the method comprising: contacting intermediate Treg cells with an effective amount of any eIF5A inhibitor and an effective amount of any Notch signaling inhibitor so as to induce plasticity in the intermediate Treg cells to exhibit a regulatory T cell phenotype.
Claim 2 recites the method of claim 1, wherein the eIF5A inhibitor comprises GC7.
Claim 3 recites the method of claim 1, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 4 recites the method of claim 1, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 5 recites the method of claim 1, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 6 recites the method of claim 1, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 7 recites the method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 8 recites a method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype, the method comprising: administering an effective amount of any eIF5A inhibitor to a subject so as to inhibit eIF5A in the subject; and administering an effective amount of any Notch signaling inhibitor to the 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 intermediate Treg cells in the subject to exhibit a regulatory T cell phenotype.
Claim 9 recites the method of claim 8, wherein the eIF5A inhibitor comprises GC7.
Claim 10 recites the method of claim 8, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 11 recites the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 12 recites the method of claim 8, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody.
Claim 13 recites the method of claim 8, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells.
Claim 15 recites the method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously.
Claim 16 recites the method of claim 8, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+.
Claim 17 recites the method of claim 8, 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.
Regarding claims 1, 2, 8, 9, Iman teaches a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering (aka contacting) an effective amount of eIF5A inhibitor, e.g., GC7 to a subject, e.g., humanized mouse model of T1D; Iman teaches that eIF5A inhibition enriches Treg population, see entire document, p. 6-7, 9, in particular. In male, the ratio of Treg/Th17 were significantly increased in IGLN, PPLN, and IGLN as measured by the IFNγ+IL17+CD4+ phenotype (p. 9-10, Fig. 5C. Iman teaches that eIF5A inhibition reduced the pro-inflammatory bias in the pancreatic microenvironment by reducing Th1 and Th17 cells and enriching Tregs, thereby deplaning the onset of Type 1 diabetes (T1D), see p. 11-12. Iman teaches modulating the cytokines milieu by inhibiting EIF5A which may have a role in inducing plasticity of different helper T subsets towards Tregs.
Claims 5 and 13 are included because Iman’s regulatory T cells (Treg) express IFNγ+IL17+CD4+ and all Treg cells naturally express FOXP3+.
Imam does not teach administering an effective amount of Notch singling inhibitor such as anti-DLL4 antibody as per claims 3-4, 8, 10 and 12.
However, Billiard teaches a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype comprising administering (aka contacting) an effective amount of an anti-DLL4 antibody to a subject, e.g., nonobese diabetic (NOD) mice in blocking a spontaneous autoimmune disease, e.g., type 1 diabetes (T1D), resulting higher T reg cell frequency, see entire document, p. 1020, right col. Billiard teaches that Notch signaling inhibition induced CD25+, FoxP3+ regulatory T cells (Tregs), see p. 1202, left col. Anti-DLL4 treatment of NOD mice at diabetes onset induces a significant increase in Treg cell number in the periphery (aka intermediate regulatory T cells that develop in the periphery rather than in the thymus) as opposed to under steady-state conditions. This Treg cell expansion directly correlates with T1D remission, see p. 1022, right col., in particular.
Regarding claims 6 and 16, Billiard teaches CD4+CD25+FoxP3+ regulatory T cells (Treg cells), see abstract, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the GC7-eIF5A inhibitor in diabetic mice of Imam_2019 with the anti-Dll4 antibody-Notch signaling inhibitor in diabetic mice of Billiard to arrive at the claimed invention with a reasonable expectation of success, e.g., increased regulatory T cell phenotype, e.g., CD4+CD25+FOXP3+.
One of ordinary skill in the art would have been motivated to combine Imam’s GC7-eIF5A inhibitor with Billiard’s anti-Dll4 antibody because each of which taught in the art to be useful for expanding T regulatory cell population for treating inflammatory type 1 diabetes. In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two modes of treatment, each of which is taught by the prior art to be useful for the same purpose in order to make a protocol that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art.
Applying the same logic to the instant method as claimed, given the teaching of the prior art of method using any of eIF5A inhibitor GC7 and Notch signaling inhibitor anti-DLL4 antibody in the method of inducing plasticity of Treg cells for treating autoimmune inflammatory type 1 diabetes, it would have been obvious to treat type 1 diabetes by increasing the number of regulatory T cells with GC7 and anti-DLL4 antibody because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful as agents for the same purpose of treating type 1 diabetes.
Claims 7, 11 and 15 are included because it is within the purview of one of ordinary skill in the pharmaceutical to administer eIF5A inhibitor GC7 and Notch signaling inhibitor anti-DLL4 antibody simultaneously (aka at the same time) for convenience.
Claim 17 is included as administering eIF5A inhibitor GC7 and Notch signaling inhibitor anti-DLL4 antibody to a subject is expected to generate or enrich regulatory T cells in vivo to induce tolerance for treating autoimmune disease such as type I diabetes. The term “or” does not require in vitro prior to an adoptive T cell therapy for treating autoimmune disease.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Iman et al (Scientific Report 9: 1533, 2019; PTO 892) in view of Billiard et al (J Exp Med 209(5): 1011-1028, 2012; PTO 892) as applied to claims 1-4, 6-12, 15, 16 and 17 mentioned above and further in view of Mirmira et al (US20120196918, published August 2, 2012; PTO 892).
The combine teachings of Iman and Billiard have been discussed supra.
The references do not teach that the method further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject as per claim 14.
However, Mirmira teaches a method of treating type 1 and type 2 diabetes (see entire document, para. [0010]) by administering to a subject with a therapeutic effective amount of eIF5A inhibitor such as GC7 (para. [0011], [0013]) or si-eIF5A nucleotide sequence 5'-AACGGAAUGACUUCCAGCUGA-3 (SEQ ID NO: 2) capable of interfering with the mRNA translating iNOS to prevent death of islets, lowers blood glucose levels, avoid insulin resistance and inflammatory response in islets associated with type 1 and type 2 diabetes, see entire document, para. [0019], reference claims in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to treat type 1 diabetes by administering to a subject a combination of GC7-eIF5A inhibitor of Imam with the anti-Dll4 antibody-Notch signaling inhibitor of Billiard to generate regulatory T cells and si-eIF5A includes a nucleotide having the sequence 5'-AACGGAAUGACUUCCAGCUGA-3 (SEQ ID NO: 2) as taught by Grassi with a reasonable expectation of success, e.g., treating type 1 diabetes that include insulin resistance, see para. [0019].
One of ordinary skill in the art would have been motivated to so because Mirmira teaches that that depletion of eIF5A Protects Mice Against Multiple Low-Dose Streptozotocin (STZ)-Induced Hyperglycemia and Islet Loss, see para. [0085] to [0086] and inhibition of hypusination protects against cytokine-induced beta cell dysfunction in vitro. GC7 treatment protects mice against Streptozotocin (STZ)-induced hyperglycemia and islet loss, see para. [0100].
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to combine Mirmira’s method of controlling EIF5A and its hypusination with si-RNA comprises the nucleotide synthesis 5'-AACGGAAUGACUUCCAGCUGA-3 (SEQ ID NO: 2) to treat type 1 diabetes and the method of Iman and Billiard because each of which taught in the art to be useful for treating inflammatory type 1 diabetes. In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two modes of treatment, each of which is taught by the prior art to be useful for the same purpose in order to make a protocol that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Iman et al (Scientific Report 9: 1533, 2019; PTO 892) in view of Billiard et al (J Exp Med 209(5): 1011-1028, 2012; PTO 892) as applied to claims 1-4, 6-12, 15, 16 and 17 mentioned above and further in view of Grassi et al (US20110076258 (published March 31, 2011; PTO 892).
The combine teachings of Iman and Billiard have been discussed supra.
The references do not teach that the method is used to induce tolerance for transplant or host versus graft rejection as per claim 18 or to enrich T regulatory cells in vitro for adoptive T regulatory T cell therapy as per claim 19.
However, Grassi teaches the importance of Treg cells in establishing and maintaining T cell tolerance has generated significant interest in methods for expanding Treg cells in vitro for therapeutic purposes, e.g., adoptive Treg cell therapy. Expanded Treg cell infusions can be used, e.g., to modulate the immune response; induced tolerance to cell, tissue and organ transplants; and treat autoimmune conditions. However, such clinical applications have been delayed by the challenge of successfully expanding Treg subpopulations without significant contamination from effector cells, e.g., Th17 cells, that may emerge from Foxp3.sup.+ selection. Such contaminating cells may outgrow Treg cells. Further, Treg cells may lose suppressive activity after repetitive stimulation in vitro, see para. [0009].
Regarding claim 19, Grassi teaches enrichment and/or isolation of specific subpopulations of T cells, e.g., naive CD4.sup.+ cells and/or Treg cells, may be performed using positive and negative selection techniques known in the art, including but not limited to: fluorescence activated cell sorting (FACS), magnetic separation using antibody-coated magnetic beads, affinity chromatography, cytotoxic agents joined to a monoclonal antibody or used in conjunction with a monoclonal antibody, e.g. complement and cytotoxins, and "panning" with antibody attached to a solid matrix, e.g., plate, or other convenient technique. Positive selection may be combined with negative selection against T cells comprising surface makers specific to non-desired T cell types, see para. [0156].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to induce tolerance for transplant or graft versus host disease (GVHD) by administering to a subject a combination of GC7-eIF5A inhibitor of Imam with the anti-Dll4 antibody-Notch signaling inhibitor of Billiard to generate regulatory T cells and enriching said regulatory T cells in vitro for adoptive Treg cell therapy as taught by Grassi with a reasonable expectation of success, e.g., modulating T cell-dependent immune responses.
One of ordinary skill in the art would have been motivated to so because Grassi teaches that Treg cells have been established as importance in maintain T cell tolerance for therapeutic purposes, e.g., adoptive Treg cell therapy since expanded Treg cell infusion can be used to modulate immune response by inducing tolerance to cell, tissue, and organ transplant and Treg cells.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify the method of Iman and Billiard in view of Grassi et al because Grassi teaches that regulatory T cells may be enriched using positive and negative selection techniques known in the art, including but not limited to: fluorescence activated cell sorting (FACS), magnetic separation using antibody-coated magnetic beads, affinity chromatography, cytotoxic agents joined to a monoclonal antibody or used in conjunction with a monoclonal antibody, e.g. complement and cytotoxins, and "panning" with antibody attached to a solid matrix, e.g., plate, or other convenient technique.
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007)
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Statutory Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-19 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1-16 of copending Application No.18/670,112 (reference application).
Copending claims are as follow:
1. A method for inducing plasticity in intermediate Treg cells, the method comprising: contacting intermediate Treg cells with an effective amount of an eIF5A inhibitor and an effective amount of a Notch signaling inhibitor so as to induce plasticity in the intermediate Treg cells to exhibit a regulatory T cell phenotype, which corresponds to instant claim 1.
2. The method of claim 1, wherein the eIF5A inhibitor comprises GC7, which corresponds to instant claim 2.
3. The method of claim 1, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claim 2.
4. The method of claim 1, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claim 4.
5. The method of claim 1, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells, which corresponds to instant claim 5.
6. The method of claim 1, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+, which corresponds to instant claim 6.
7. The method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously, which corresponds to instant claim 7.
8. A method for inducing plasticity in intermediate Treg cells to exhibit a regulatory T cell phenotype, the method comprising: administering an effective amount of an eIF5A inhibitor to a subject so as to inhibit eIF5A in the subject; and administering an effective amount of a Notch signaling inhibitor to the 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 intermediate Treg cells in the subject to exhibit a regulatory T cell phenotype, which corresponds to instant claim 8.
9. The method of claim 8, wherein the eIF5A inhibitor comprises GC7, which corresponds to instant claim 9.
10. The method of claim 8, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claim 10.
11. The method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously, which corresponds to instant claim 11.
12. The method of claim 8, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claim 12.
13. The method of claim 8, wherein the intermediate Treg cells are CD4+IFNg+IL17+FOXP3+ T cells, which corresponds to instant claim13.
14. The method of claim 8, further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject, which corresponds to instant claim 14.
15. The method of claim 8, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously, which corresponds to instant claim 15.
16. The method of claim 8, wherein the regulatory T cell phenotype is CD4+CD25+FOXP3+, which corresponds to instant claim 16.
This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Nonstatutory 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10, 13-15, 17-20 of copending Application No. 18/353,183 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because
Copending claim 1 recites a method for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype, the method comprising: administering an effective amount of an eIF5A inhibitor to a subject so as to inhibit eIF5A in the subject; and administering an effective amount of a Notch signaling inhibitor to the 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 the subject to exhibit a regulatory T cell phenotype, which corresponds to instant claims 1, 8.
2. The method of claim 1, wherein the eIF5A inhibitor comprises GC7, which corresponds to instant claims 2, 9.
3. The method of claim 1, wherein the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claims 3, 10.
4. The method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered sequentially.
5. The method of claim 1, wherein the eIF5A inhibitor and the Notch signaling inhibitor are administered simultaneously, which corresponds to instant claims 7, 11, 15.
6. The method of claim 1, further comprising administering a treatment for type 1 diabetes to the subject while eIF5A and Notch signaling are inhibited in the subject, which corresponds to instant claim 14.
7. The method of claim 6, wherein the eIF5A inhibitor comprises GC7 and the Notch signaling inhibitor comprises an anti-DLL4 antibody, which corresponds to instant claims 2-3, 9-10, .
13. 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, which corresponds to instant claim 17.
14. The method of claim 13, wherein eIF5A is inhibited with GC7, and Notch signaling is inhibited with an anti-DLL4 antibody, which corresponds to instant claims 2-3, 9-10.
15. The method of claim 13, wherein the autoimmune disease is type 1 diabetes (T1D), which corresponds to instant claim 14.
17. 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, which corresponds to instant claim 17.
18. The method of claim 17, wherein eIF5A is inhibited with GC7, which corresponds to instant claim 9.
19. The method of claim 17, wherein Notch signaling is inhibited with an anti-DLL4 antibody, which corresponds to instant claim 10.
20. The method of claim 17, w herein the subject is being prepared for an organ transplant, which corresponds to instant claim 18.
Therefore, ‘183 copending application anticipates instant claims 1-19.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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