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, 4-6, 8, 13, 16-17 and 20 are pending and being acted upon in this Office Action.
Priority
This application claims domestic benefit to U.S. Provisional Application 63/389,391 effectively filed on 7/15/2022.
Rejection Withdrawn
The written description and enablement rejections of claims 8, 16, 17 and 20 is 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement are withdrawn in view of the claim amendment.
Applicant’s arguments, see p. 5-6, filed July 23, 2026, with respect to the rejection(s) of claim(s)
1-5 and 17-19 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") have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
The rejection of claims 6-10 and 13-16 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applied to claims 1-5 and 17-19 above, and further in view of Imam et al (PTO-892; page 2, reference U; "Imam_2021”) is withdrawn because the addition of Imam_2021 does not render the unexpected results obvious.
The rejection of claim 20 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Van Belle et al (PTO-892; page 3, Reference V; “Van Belle”) and Magee et al (PTO-892; page 2, reference W; “Magee”) is withdrawn because the addition of Van Belle et al and Magee does not cure the deficiency of Imam_2019 and Billiard. .
Rejection Maintained
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, 4-6 and 13 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 N1-guanyl-1,7-diaminoheptane (GC7) to a subject in need thereof, 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 N1-guanyl-1,7-diaminoheptane (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 N1-guanyl-1,7-diaminoheptane (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 comprising GC7 to a subject, e.g., healthy subject, administering an effective amount of a Notch signaling inhibitor comprising an anti-DLL4 antibody (claims 1, 4-5), and administering any treatment for type 1 diabetes (claims 6, 13).
The claims encompass administering eIF5A inhibitor comprising GC7 to any subject, including healthy subject.
The specification discloses in Examples I-III the use of only one eIF5A inhibitor, GC7, in combination with anti-DLL4 and GAD65-CAR Tregs to treat a subject with type 1 diabetes.
However, the specification does not disclose treating healthy subject by administering GC7, an eIF4A inhibitor, in combination with an anti-DLL4 antibody to the subject.
Even assuming the subject has type diabetes, the specification does not describe any treatment for type 1 diabetes (claims 6, 13), other than administering GAD65-specific CAR-Tregs.
The specification does not reasonably convey possession of the full scope of the claimed methods.
As such, claims 1, 4-6 and 13 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that Claim 1 has been amended to recite the eIF5A inhibitor comprises GC7 and to recite the Notch signaling inhibitor comprises an anti-DLL4 antibody. No new matter has been added.
Claim 8 has been amended to recite the treatment comprises CAR-Tregs which are GAD65- specific CAR-Tregs. No new matter has been added.
Claim 13 has been amended to recite administering to the subject an eIF5A inhibitor comprising GC7, to recite administering to the subject a Notch signaling inhibitor comprising an anti-DLL4 antibody, and to recite the autoimmune disease is type 1 diabetes (T1D). No new matter has been added.
Claim 17 has been amended to recite administering an eIF5A inhibitor comprising GC7 to the subject and to recite administering a Notch signaling inhibitor comprising an anti-DLL4 antibody to the subject. No new matter has been added.
In view of the above amendments, this rejection is untenable. The Office Action admits, on page 3, that Applicant is in possession of the subject matter defined in the amended claims. Therefore, Applicant respectfully requests withdrawal of this rejection.
In response, the amendment to claims 1, 8, 13 and 17 is acknowledged.
The amended claim 1 still recites a subject (claim 1), and any treatment for type 1 diabetes (claim 6) and any treatment for autoimmune disease to the subject (claim 13). The term “subject” encompasses healthy subject as well as subject with type I diabetes.
The claims encompass administering eIF5A inhibitor comprising GC7 to any subject, including healthy subject.
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 comprising GC7 to a subject, e.g., healthy subject, administering an effective amount of a Notch signaling inhibitor comprising an anti-DLL4 antibody (claims 1, 4-5), and administering any treatment for type 1 diabetes (claims 6, 13).
The specification discloses in Examples I-III the use of only one eIF5A inhibitor, GC7, in combination with anti-DLL4 and GAD65-CAR Tregs to treat a subject with type 1 diabetes.
However, the specification does not disclose treating healthy subject by administering GC7, an eIF4A inhibitor, in combination with an anti-DLL4 antibody to the subject. Amending claim 1 to recite a subject in need thereof would obviate this rejection.
Even assuming the subject has type diabetes, the specification does not describe any treatment for type 1 diabetes (claims 6, 13), other than administering GAD65-specific CAR-Tregs.
The specification does not reasonably convey possession of the full scope of the claimed methods.
As such, claims 1, 4-6 and 13 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
For these reasons, the rejection is maintained.
Enablement
Claims 1, 4-6 and 13 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 N1-guanyl-1,7-diaminoheptane (GC7) to a subject in need thereof, 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 N1-guanyl-1,7-diaminoheptane (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 N1-guanyl-1,7-diaminoheptane (GC7) and Notch signaling with an anti-DLL4-antibody wherein the subject is being prepared for an organ transplant.
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 comprising GC7 to a subject, e.g., healthy subject, administering an effective amount of a Notch signaling inhibitor comprising an anti-DLL4 antibody (claims 1, 4-5), and administering any treatment for type 1 diabetes (claims 6, 13).
The claims encompass administering eIF5A inhibitor comprising GC7 to any subject, including healthy subject.
The specification discloses in Examples I-III the use of only one eIF5A inhibitor, GC7, in combination with anti-DLL4 and GAD65-CAR Tregs to treat a subject with type 1 diabetes.
However, the specification does not disclose treating healthy subject by administering GC7, an eIF4A inhibitor, in combination with an anti-DLL4 antibody to the subject. There are no in vivo working example of treating healthy subject.
Even assuming the subject has type diabetes, the specification does not teach treating the subject with any treatment for type 1 diabetes (claims 6, 13), other than administering GAD65-specific CAR-Tregs.
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.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that this rejection is untenable in view of the amendments discussed above.
In response, the amendment to claims 1, 8, 13 and 17 is acknowledged.
The amended claim 1 still recites a subject (claim 1), and any treatment for type 1 diabetes (claim 6) and any treatment for autoimmune disease to the subject (claim 13). The term “subject” encompasses healthy subject as well as subject with type I diabetes.
The claims encompass administering eIF5A inhibitor comprising GC7 to any subject, including healthy subject.
Enablement is not commensurate with treating healthy subject by administering eIF5A inhibitor comprising GC7 and anti-DLL4 antibody to the subject. Amending claim 1 to recite a subject in need thereof would obviate this rejection.
Even assuming the subject has type diabetes, the specification does not teach any treatment for type 1 diabetes (claims 6, 13), other than administering GAD65-specific CAR-Tregs. There are no objective evidence of treating healthy subject or subject with type 1 diabetes with any and all possible treatment. It is unpredictable which undisclosed treatment is effective for type 1 diabetes.
For these reasons, the rejection is maintained.
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, 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.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant respectfully declines to comment on the merits of this provisional double patenting rejection given its provisional nature. Applicant notes that the present application has a patent term filing date of July 17, 2023, and copending application no. 18/670,112 has a patent term filing date of May 24, 2024. Therefore, the present application has an earlier patent term filing date than copending application no. 18/670,112. Accordingly, if this is the only rejection remaining in the application, it should be withdrawn and this application should be permitted to issue. See MPEP § 1490(VI)(D)(2)(a).
In response, the present application has an earlier patent term filing date than copending application no. 18/670,112 is acknowledged. The rejection is maintained because other rejections are still pending in this application and ready for allowance.
Claims 1, 4, 8, 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.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant respectfully declines to comment on the merits of this provisional double patenting rejection given its provisional nature. Applicant notes that the present application has a patent term filing date of July 17, 2023, and copending application no. 18/670,112 has a patent term filing date of May 24, 2024. Therefore, the present application has an earlier patent term filing date than copending application no. 18/670,112. Accordingly, if this is the only rejection remaining in the application, it should be withdrawn and this application should be permitted to issue. See MPEP § 1490(VI)(D)(2)(a).
In response, the present application has an earlier patent term filing date than copending application no. 18/674,217 is acknowledged. The rejection is maintained because other rejections are still pending in this application and ready for allowance.
Claims 1, 13, 17 and 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.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant respectfully declines to comment on the merits of this provisional double patenting rejection given its provisional nature. Applicant notes that the present application has a patent term filing date of July 17, 2023, and copending application no. 18/674,217 has a patent term filing date of May 24, 2024. Therefore, the present application has an earlier patent term filing date than copending application no. 18/670,112. Accordingly, if this is the only rejection remaining in the application, it should be withdrawn and this application should be permitted to issue. See MPEP § 1490(VI)(D)(2)(a).
In response, the present application has an earlier patent term filing date than copending application no. 18/674,217 is acknowledged. The rejection is maintained because other rejections are still pending in this application and ready for allowance.
Claims 1, 4, 8 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.
Applicants’ arguments filed July 23, 2026 have been fully considered but are not found persuasive.
Applicant respectfully declines to comment on the merits of this provisional double patenting rejection given its provisional nature. Applicant notes that the present application has a patent term filing date of July 17, 2023, and copending application no. 18/674,217 has a patent term filing date of May 24, 2024. Therefore, the present application has an earlier patent term filing date than copending application no. 18/670,112. Accordingly, if this is the only rejection remaining in the application, it should be withdrawn and this application should be permitted to issue. See MPEP § 1490(VI)(D)(2)(a).
In response, the present application has an earlier patent term filing date than copending application no. 18/674,217 is acknowledged. The rejection is maintained because other rejections are still pending in this application and ready for allowance.
Claim Objection
Claim 1 is objected to because of the following informality: The claim uses the abbreviation GC7 without first defining it. To clarify the claim, applicant should first spell out the full term before using an abbreviation. Given the subject matter of the specification, the examiner presumes that "GC7" stands for "N1-guanyl-1,7-diaminoheptane (GC7)". Appropriate correction is required.
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 13, 16, 17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mirmira et a (US20120196918, published August 2, 2012; PTO 892) in view of Skokos et al (US Patent No. 8,889,133, issued November 18, 2014; PTO 892) and Jaume et al (US20220008522, published Jan 13, 2022; PTO 892).
Regarding claim 13, Mirmira teaches a method of treating autoimmune inflammatory disease, e.g., diabetes type 1 by administering to a human subject (see para. [0010]) or mice (para. [0116]) an EIF5A inhibitor, e.g., GC7, see entire document, abstract, para. [0014], [0018], [0019], [0063], in particular.
Mirmira does not teach administering to the subject a Notch signaling inhibitor comprising an anti-DLL4 antibody and subsequently administering a treatment for type 1 diabetes (T1D) as per claim 13 and wherein the treatment comprises GAD65-specific CAR-Tregs as per claims 16 and 20.
However, Skokos teaches a method of treating diabetes type 1 with DLL4 antagonist, e.g., anti-DLL4 Ab that binds DLL4 with high affinity and blocks the binding of Dll4 to the Notch receptors and/or blocks the Dll4-Notch signal pathways, thereby increasing the number of regulatory T cells (Treg cells or Tregs) in the subject (aka enriching Treg cells in a subject as per claim 17), see entire document, col. 1, lines 15-36, col. 2, lines 8-30. Examples of antibodies include polyclonal, monoclonal (mAb), chimeric, humanized, or a wholly human antibody or fragment thereof. The antibody fragment may be a single chain antibody, an Fab, or an (Fab').sub.2, see col. 2, lines 41-50, in particular.
Skokos teaches that the method wherein the Dll4 antagonist is co-administered concurrently or sequentially with at least one additional therapeutic agent, for example, a blood glucose lowering agent (e.g., insulin, insulin analogues, and the like), immunosuppressive agent or immunosuppressant, anti-inflammatory agent, analgesic agent, and the like, see col. 3, line 66 through col. 4, lines 21, combination therapies, in particular. Skokos teaches that Dll4 antagonists exhibit protective effects on pancreatic islets, lower blood glucose levels, and block the production of auto-antibodies, including those against insulin and glutamic acid decarboxylase 65 (GAD65), via the expansion of regulatory T cells (Tregs), see abstract, in particular.
Neither Mirmira nor Skokos teaches the treatment comprises GAD65-specific CAR-Tregs as per claim 16.
However, Jaume teaches GAD65 antigen-specific CAR-Tregs that can prevent the development of autoimmune diabetes or T1D, autoimmune tolerance and transplantation tolerance as per claim 16, see entire document, para [0012], [0022], [0023], Summary of the invention, in particular. Jaume teaches a method of treating autoimmune disease such as diabetes type 1 disease (T1D) by administering to a human subject an effective amount of the immunoresponsive cell, e.g., GAD65 antigen-specific CAR-Tregs, thereby treating Type 1 diabetes (T1D), see entire document, para. [0151], reference claims 9-10, 40, 46-50, in particular.
Regarding claim 20, Jaume teaches that subject is an organ transplant recipient, see para. [0014].
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 a subject diagnosed with diabetes type 1 disease (T1D) by simultaneously administering to the subject the GC7-eIF5A inhibitor of Mirmira with the anti-Dll4 antibody-Notch signaling inhibitor of Skokos by increasing the number of regulatory T cells (Tregs) within the thymus of the subject and then administering the GAD65 antigen-specific CAR-Tregs of Jaume to arrive at the claimed invention with a reasonable expectation of success, e.g., treating autoimmune type 1 diabetes (T1D) in a subject by increasing autoimmune tolerance.
One of ordinary skill in the art would have been motivated to combine Mirmira’s GC7-eIF5A inhibitor with Skokos’s anti-Dll4 antibody and Jaume’s GAD65 antigen-specific CAR-Tregs 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 or three 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.
One of ordinary skill in the art would have been motivated to do so because Mirmira teaches that eIF5A is also expressed in pancreatic islets, and has now been shown to promote the inflammatory response in islets during the development of diabetes and treatment with eIF5A inhibitor such as GC7 can protect islets from inflammatory cytokine-induced dysfunction and block iNOS, see para. [0094] to [0095].
One of ordinary skill in the art would have been motivated to do so because Skokos teaches that Dll4 antagonists exhibit protective effects on pancreatic islets, lower blood glucose levels, and block the production of auto-antibodies, including those against insulin and glutamic acid decarboxylase 65 (GAD65), via the expansion of regulatory T cells (Tregs), see abstract, in particular.
One of ordinary skill in the art would have been motivated to do so because Jaume teaches GAD65 antigen-specific CAR-Tregs can induce alloimmune transplant tolerance and lengthening survival of organ transplanted in the subject, see para. [0033].
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.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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