DETAILED ACTION
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 .
Priority
The instant application is a 35 U.S.C. 371 national phase application and claims priority to International Application No. PCT/JP2021/032566 (filing date 08/31/2021), which claims the benefit of the prior-filed Japanese Provisional Patent Application Nos. 63/231,471 (filing date 08/10/2021) and 63/073,208 (filing date 09/01/2020).
Status of Application/Claims
The amendment, filed 12/17/2025, is acknowledged. Claims 2-11 are canceled. Claim 1 is currently amended. Claims 12-29 are new. Claims 1 and 12-29 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/2025 has been fully considered by the examiner.
Withdrawn Objections & Rejections
Regarding the Specification objection for trade names and/or trademark compliance issues, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the Claim 3 objection for minor informalities, applicant amendment has addressed the issue and claim 3 is canceled. Thus, the objection is withdrawn.
Regarding the rejections for claim 10 under 35 U.S.C. 101 for eligibility, applicant amendment has addressed the issue and claim 10 is canceled. Thus, the rejection is withdrawn.
Regarding the rejections for claim 10 under 35 U.S.C. 112(b) for indefiniteness, applicant amendment has addressed the issue and claim 10 is canceled. Thus, the rejection is withdrawn.
Regarding the rejection for claims 1-2 and 10 under 35 U.S.C. 102 for novelty, applicant amendment has addressed the issue. Claims 2 and 10 are canceled. Thus, the rejection is withdrawn. Claim 1 is amended and newly rejected under 35 U.S.C. 103 for obviousness (see below rejection).
Regarding the rejections for claims 1, 3-6, and 8-10 under 35 U.S.C. 103 for obviousness: Claims 2-6 and 8-10 are canceled and the rejections are withdrawn for claims 2-6 and 8-10. Claim 1 is amended and has resulted in a new 35 U.S.C. 103 obviousness rejection; thus, the rejection for claim 1 is maintained in modified form (see below rejection).
Regarding the non-statutory double patenting rejections for claims 1-11: Claims 2-6 and 8-11 are canceled and the rejections are withdrawn for claims 2-6 and 8-11. Claim 1 is amended and has resulted in a new double patenting rejection; thus, the rejection for claim 1 is maintained in modified form (see below rejection).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 18-19, 21-22, 24, and 27-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Karow et al. – WO2020069398A1 (published 04/02/2020; effective filing date: 09/27/2018; herein referred to as Karow); as evidenced by Norris, et al. Type 1 diabetes—early life origins and changing epidemiology. Lancet Diabetes Endocrinology (March 2020), 8:3, p.1-27 (herein referred to as Norris).
Karow teaches that IL-2 is approved for treatment of cancer but has a short half-life and that high doses of IL-2 can cause adverse side effects associated with systemic immune activation (p.3-4, [0005]). Karow teaches engineered masked cytokines comprising human IL-2, wherein IL-2 can comprise amino acid substitutions wherein position C125 contains a C125A substitution that contributes to stabilization of the [AltContent: textbox (Instant SEQ ID NO: 1 (WT) vs Karow SEQ ID NO: 1 (C125A)
[img-media_image1.png])]cytokine (p.180, #15-16; see Karow amino acid IL-2 SEQ ID NO: 1).
Karow further teaches an E62A mutation that results in a variant capable of binding IL-Rα but that has reduced binding to IL-2Rα (p.5, [0012]; p.44, [0210]; p.45-46, [0211-0212]; p.47, [0213]; p.179, #7-8). Karow also teaches engineered masked cytokines with half-life extension domains that can be comprised of an IgG1 Fc domain (i.e., an “IgG Fc”) or fragment thereof (p.107, [0341]). Karow also teaches (poly)nucleotide sequences encoding polypeptide components of masked cytokines, including IL-2 variants fused to IgG Fc domain half-life extension domains, using standard recombinant techniques (p.143, [0459]; p.166, [0542]). Karow further teaches compositions and therapeutic formulations comprising IL-2 variants and IL-2 fusion proteins (i.e., “masked cytokines”; p.153, [0505 – 0506]). Karow teaches the use of the IL-2 cytokines for treatment or prevention of autoimmune disease (p. 166, [0542]) and that the IL-2 treatment can comprise pharmaceutically acceptable carriers that including salt-forming counterions such as sodium (p.177, [0580]). Karow further teaches treatment via administration of the masked cytokine comprising an IL-2 variant to a subject that is mammalian (p.166, [0542]; p.178, [0587]). Karow teaches that the method of treatment for autoimmune disease can include treatment of various inflammatory diseases and forms of arthritis, Crohn’s disease, ulcerative colitis, type I diabetes, multiple sclerosis, lupus, and ankylosing spondylitis (among others; p.166, [0543]). As Karow teaches treatment of autoimmune disease and type I diabetes, which is an autoimmune disease characterized by hyperglycemia (as evidenced by Norris, p.1 Introduction), Karow necessarily also teaches treatment of “autoimmune hyperglycemia” (p.166, [0543]).
Regarding instant claims 1, 18-19, 22, 24, and 27: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Karow by modifying the engineered IL-2 variant of SEQ ID NO: 1 taught by Karow to also contain an E62A substitution (also taught by Karow), to arrive at the claimed IL-2 variant of instant claim 1, in order to receive the expected benefit that the E62A mutation provides for reduced binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the exact position substitutions for achieving these results. It would have further been obvious to combine the teachings of Karow to additionally fuse the IL-2 variant to an IgG Fc domain (also taught by Karow), to arrive at the instantly claimed invention in order to receive the expected benefit that the IgG Fc domain would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow teaches the amino acid sequence for Fc domains. It would have further been obvious to one of ordinary skill in the art before the effective filing date to include the IL-2 variant of Karow into a pharmaceutical composition/therapeutic formulation (also taught by Karow) in order to administer the composition to subjects for treatment of autoimmune disease (also taught by Karow) because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Karow teaches compositions and formulations for treating various autoimmune disease.
Regarding instant claim 21: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Karow by using standard recombinant techniques to obtain a nucleotide encoding the amino acid sequence for the IL-2 variant (as taught by as taught by Karow) to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Karow teaches that recombinant methods for obtaining nucleotide sequences for known amino acid sequences is a standard technique used in the field.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claim 1; and further in view of Kang, et al.—WO2020057646A1, Novel interleukin 2 and use thereof (published 03/26/2020; herein referred to as Kang).
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
Karow does not teach the IL-2 substitution T37Y.
Kang teaches IL-2 muteins that comprise a mutation T37Y for the beneifit of reducing or eliminating binding affinity for the IL-2Rα receptor (p.40, para.4; p.43, para.3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Karow with the teachings of Kang by modifying the engineered E62A/C125A IL-2 variant taught by Karow to also contain an T37Y substitution (taught by Kang), to arrive at the claimed IL-2 variant of instant claim 13, in order to receive the expected benefit that the T37A mutation provides for further reducing binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Kang teaches the exact position substitution for the T37Y substitution.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claim 1; and further in view of Piaggio, et al.—WO2020201095A1 (effective filing date: 03/27/2020; herein referred to as Piaggio).
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
Karow does not teach the IL-2 substitution M23L.
Piaggio teaches IL-2 muteins for treatment of immune disorders including autoimmune and inflammatory disorders (title; abstract). Piaggio teaches IL-2 mutants that comprise a mutation M23L for the benefit of preferentially stimulating Tregs (p.4, last paragraph).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Karow with the teachings of Piaggio by modifying the engineered E62A/C125A IL-2 variant taught by Karow to also contain an M23L substitution (taught by Piaggio), to arrive at the claimed IL-2 variant of instant claim 15, in order to receive the expected benefit that the M23L mutation provides for preferential activation of Tregs. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Piaggio teaches the exact position substitution for the M23L substitution.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claim 1; further in view of Long, et al.—US20080254026A1 (published 10/16/2008; effective filing date 11/04/2003; herein referred to as Long); and, further in view of Barnes and Gray. Bioinformatics for geneticists. John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England. 2003, p.1-411 (herein referred to as Barnes).
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
Karow does not teach the IL-2 substitution P34F.
Long teaches “improved” IL-2 muteins for reduced toxicities by lowering natural killer cell pro-inflammatory cytokine production while maintaining cell proliferation, which includes an IL-2 muteins harboring a P34V substitution (p.121, [0882]).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Karow with the teachings of Long by modifying the engineered E62A/C125A IL-2 variant taught by Karow to also contain an P34 substitution that is P34V (taught by Long), to arrive at the claimed IL-2 variant of instant claim 16, in order to receive the expected benefit that the P34V mutation provides for reduced toxicity. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Long teaches the exact position substitution for the P34V substitution.
Long does not teach that the P34 substitution is specifically to a phenylalanine/F (i.e., P34F).
Barnes teaches the nature of mutations and the properties of amino acids in a variety of different protein contexts to provide for anticipating or interpreting the effect that a particular amino acid change will have on protein structure and function (p.292, para.2). Barnes teaches that valine/V is a hydrophobic amino acid (p.297, Fig.14.3); and, teaches that valine/V can be substituted by other hydrophobic amino acids such as phenylalanine/F (p.300, section 14.5; Fig.14.3).
It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of Karow/Long with the teachings of Barnes by modifying the IL-2 mutein comprising a P34 mutation to specifically comprise an P34F substitution, in order to arrive at the instantly claimed IL-2 variant of instant claim 16, because the combination of prior art elements results in a predictable result of producing an IL-2 variant harboring a P34F substitution. One of ordinary skill would be motivated to do so because Long teaches that introducing a P34V mutation provides for reduced toxicity. It would have further been obvious to modify the P34V mutation to be a P34F mutation by substituting the valine/V modification (taught by Long) to a phenylalanine/F modification (taught by Barnes), to arrive at the instantly claimed invention, because this would be a simple substitution of one known element for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Long teaches that the P34 position can be mutated to the hydrophobic amino acid valine for reduced toxicity, and Barnes teaches that valine/V can be substituted to other hydrophobic amino acids.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claim 1; and further in view of Li, et al.—WO2020252418A2 (effective filing date: 06/14/2019; herein referred to as Li).
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
Karow does not teach the IL-2 substitution E68F.
Li teaches IL-2 variants including IL-2 mutants that comprise a mutation E68F for the benefit of enhanced binding to IL-2Rα (p.80, [0225]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Karow with the teachings of Li by modifying the engineered E62A/C125A IL-2 variant taught by Karow to also contain an E68F substitution (taught by Li), to arrive at the claimed IL-2 variant of instant claim 17, in order to receive the expected benefit that the E68F mutation provides for enhanced IL-2 binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Li teaches the exact position substitution for the E68F substitution.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claim 1; and further in view of Askgene Pharma, Inc., WO2019173832A2, Novel cytokine prodrugs (herein referred to as Askgene).
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1. Karow further teaches that the IL-2 variant can be fused to IgG Fc domains, and more broadly, antibodies and antibody derivatives (p.92, [0311]; p.115, [0368]).
Karow does not explicitly teach that the IL-2 variant is fused to an anti-CTLA4 antibody (instant claim 20).
Askgene teaches bioactivatable “prodrugs” wherein the prodrug comprises “bioactivatable domains” comprising cytokines IL-2 or IL-15 which are fused to “carrier moieties” that can comprise an Fc domain that is an IgG and an antigen-binding fragment that can bind CTLA-4 (paragraphs [0017], [0067]-[0068], [0088]-[0089]). Askgene teaches that the carrier may improve the pharmacokinetic profile such as serum half-life of the cytokine and may target the cytokine to a target site (p.14, [0061]-[0063]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Karow with the teachings of Askgene by modifying the fusion protein comprising the IL-2 variant to fuse an anti-CTLA4 antibody to the cytokine (as taught by Askgene), to arrive at the instantly claimed invention in order to receive the expected benefit that the anti-CTLA4 antibody would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow and Askgene both teach IL-2 fusion proteins comprising IL-2 and antibodies, and Askgene specifically teaches fusion of the anti-CTLA4 antibody to IL-2.
Claims 23, 25-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Karow as applied to claims 1, 19, and 24 above; and further in view of Chinen et al. An essential role for IL-2 receptor in regulatory T cell function. Nature Immunology (2016), 17: 11, p.1322-1333 (herein referred to as Chinen); and further in view of Gasteiger et al. Foxp3+ regulatory T-cells and IL-2: the Moirai of T-cell fates? Frontiers in Immunology (2012), 3:179, p.1-4 (herein referred to as Gasteiger).
The combination of teachings by Karow teaches an IL-2 fusion protein that is fused to an IgG Fc domain for treating autoimmune disease, as applied to instant claims 1, 19, and 24 above.
Karow does not teach a method of proliferation of Tregs in a subject via administration of the IL-2 fusion protein (instant claim 23); that administration of the IL-2 fusion protein increases levels of phosphorylated STAT5 (instant claim 25); that administration of the IL-2 fusion protein increases Tregs (instant claim 26); or, proliferation via contacting the population of Tregs with the IL-2 fusion protein (instant claim 29).
Chinen teaches that Tregs express abundant amounts IL-2 receptor alpha but are unable to produce IL-2 and rely on IL-2 produced by other T cells (abstract; p.2, para.1). Chinen further teaches that the repression of IL-2 in Tregs is required to maintain the constitutive expression of IL-2Rα on Tregs; and that this level of Treg IL 2Rα expression plays a key role in Treg cell-mediated suppression of T effector cells by depriving T effector cells of IL-2 (p.2, para.3). Chinen also teaches the significance of IL-2R signaling in Tregs (i.e., activation due to binding/contact of a functional IL-2; instant claim 11), including their maintenance, proliferation, and function due to activation of JAK STAT5, PI3K-Akt, and Ras-ERK signaling pathways, including via phosphorylation of STAT5 (p.2, para.2-3; Figs.1- 2). Chinen teaches that STAT5 is a downstream target of IL-2/IL-2R signaling and that STAT5 activity in Tregs correlates with their proliferative capacity and expression of IL 2Rα (p.2, para.1; p.8, para.2).
Gasteiger teaches that IL-2 binds a trimeric complex comprising IL-2R α, β, and γ subunits (p.1, para.4). Gasteiger teaches that the α/β-heterodimer facilitates IL-2 capture with high affinity (p.1, para.4). Gasteiger teaches that Tregs constitutively express IL-2Rα whereas other T cells express IL-2Rα (i.e., CD25) after undergoing cell division; and that this allows Tregs to sense IL-2 early during an immune responses by restricting cytokine availability to other T cells to balance the effector T cell differentiation and expansion (p.2, para.4, Fig.1).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Karow with the teachings of Chinen and Gasteiger by using the IL-2 fusion protein for treatment of autoimmune disease (as taught by Karow) to also increase the levels of phosphorylated STAT5 by inducing proliferation of T cells in order to increase Tregs (as taught by Chinen) to arrive at the instantly claimed invention because the combination of prior art elements results in a predictable result of IL-2 variant-mediated STAT5 activation and Treg proliferation. One of ordinary skill in the art would have a reasonable expectation of success because Gasteiger teaches that IL-2 binds the α/β-heterodimer with high affinity and Tregs constitutively express IL-2Rα . The recitations “of proliferating T cells (Treg cells), comprising contacting the population of T cells with…IL-2 variant of claim 1 or … IL-2 fusion protein of claim 19” are merely mechanisms of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. /n re Omeprazole Patent Litigation, 483 F.3d
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.
19/016,709
Claims 1 and 12-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 14, 19, 21, 22, 87, 91, and 94 of copending Application No. 19/016/709 (herein referred to as App’709); in view of Karow et al. – WO2020069398A1 (published 04/02/2020; herein referred to as Karow); in further view of Kang, et al.—WO2020057646A1, Novel interleukin 2 and use thereof (published 03/26/2020; herein referred to as Kang); in further view of Piaggio, et al.—WO2020201095A1 (effective filing date: 03/27/2020; herein referred to as Piaggio); in further view of Long, et al.—US20080254026A1 (published 10/16/2008; effective filing date 11/04/2003; herein referred to as Long); in further view of Barnes and Gray. Bioinformatics for geneticists. John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England. 2003, p.1-411 (herein referred to as Barnes); in further view of Li, et al.—WO2020252418A2 (effective filing date: 06/14/2019; herein referred to as Li); in further view of Askgene Pharma, Inc., WO2019173832A2, Novel cytokine prodrugs (herein referred to as Askgene); in further view of Chinen et al. An essential role for IL-2 receptor in regulatory T cell function. Nature Immunology (2016), 17: 11, p.1322-1333 (herein referred to as Chinen); and further in view of Gasteiger et al. Foxp3+ regulatory T-cells and IL-2: the Moirai of T-cell fates? Frontiers in Immunology (2012), 3:179, p.1-4 (herein referred to as Gasteiger); and, as evidenced by Norris, et al. Type 1 diabetes—early life origins and changing epidemiology. Lancet Diabetes Endocrinology (March 2020), 8:3, p.1-27 (herein referred to as Norris).
App’709 teaches masked cytokines comprising IL-2 polypeptides (App’709 claims 1-2; instant claim 1) and attenuated IL-2 polypeptides (App’709 claim 3; instant claim 1) with E62A and or C125A mutations (App’709 claims 14, 19, and 21-22; instant claims 1 and 18); and wherein the masked cytokine also comprises an Fc domain (App’709 claim 1; instant claim 19). App’709 also teaches nucleic acids encoding the IL-2 cytokines (App’709 claim 87; instant claim 21); and pharmaceutical compositions of the IL-2 cytokine that further comprise a pharmaceutically acceptable carrier (App’709 claim 91; instant claim 22). App’709 also teaches a method of treating or preventing autoimmune disease via administration of IL-2 (App’709 claim 94; instant claim 24).
App’709 does not teach that the IL-2 variant comprises a T37Y substitution (instant claim 13); that the IL-2 variant comprises a M23L substitution (instant claim 15); that the IL-2 variant comprises a P34F substitution (instant claim 16); that the IL-2 variant comprises a E68F substitution (instant claim 17); that the Fc domain of the fusion protein is an IgG Fc (instant claim 19); that the IL-2 fusion protein is fused to an anti-CTLA4 antibody (instant claim 20); a method of proliferation of Tregs via administration of the IL-2 fusion protein (instant claim 23); that administration of the IL-2 fusion protein increases levels of pSTAT5 (instant claim 25) or Tregs (instant claim 26); or, proliferation via contacting the population of Tregs with the IL-2 fusion protein (instant claim 29).
[AltContent: textbox (Instant SEQ ID NO: 1 (WT) vs Karow SEQ ID NO: 1 (C125A)
[img-media_image1.png])]Karow also teaches that IL-2 is approved for treatment of cancer but has a short half-life and that high doses of IL-2 can cause adverse side effects associated with systemic immune activation (p.3-4, [0005]). Karow teaches engineered masked cytokines comprising human IL-2, wherein IL-2 can comprise amino acid substitutions wherein position C125 contains a C125A substitution that contributes to stabilization of the cytokine (p.180, #15-16; see Karow amino acid IL-2 SEQ ID NO: 1).
Karow also teaches an E62A mutation that results in a variant capable of binding IL-Rα but that has reduced binding to IL-2Rα (p.5, [0012]; p.44, [0210]; p.45-46, [0211-0212]; p.47, [0213]; p.179, #7-8). Karow also teaches engineered masked cytokines with half-life extension domains that can be comprised of an IgG1 Fc domain (i.e., an “IgG Fc”) or fragment thereof (p.107, [0341]). Karow also teaches (poly)nucleotide sequences encoding polypeptide components of masked cytokines, including IL-2 variants fused to IgG Fc domain half-life extension domains, using standard recombinant techniques (p.143, [0459]; p.166, [0542]). Karow further teaches compositions and therapeutic formulations comprising IL-2 variants and IL-2 fusion proteins (i.e., “masked cytokines”; p.153, [0505 – 0506]). Karow teaches the use of the IL-2 cytokines for treatment or prevention of autoimmune disease (p. 166, [0542]) and that the IL-2 treatment can comprise pharmaceutically acceptable carriers that including salt-forming counterions such as sodium (p.177, [0580]). Karow further teaches treatment via administration of the masked cytokine comprising an IL-2 variant to a subject that is mammalian (p.166, [0542]; p.178, [0587]). Karow teaches that the method of treatment for autoimmune disease can include treatment of various inflammatory diseases and forms of arthritis, Crohn’s disease, ulcerative colitis, type I diabetes, multiple sclerosis, lupus, and ankylosing spondylitis (among others; p.166, [0543]). As Karow teaches treatment of autoimmune disease and type I diabetes, which is an autoimmune disease characterized by hyperglycemia (as evidenced by Norris, p.1 Introduction), Karow necessarily also teaches treatment of “autoimmune hyperglycemia” (p.166, [0543]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of App’709 with the teachings of Karow by modifying the engineered IL-2 variant of App’709 by adding an IgG Fc domain (taught by Karow), to arrive at the claimed IL-2 fusion protein, in order to receive the expected benefit that the IgG Fc domain would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow teaches the amino acid sequence for Fc domains.
App’709 and Karow do not teach the IL-2 substitution T37Y.
Kang teaches IL-2 muteins that comprise a mutation T37Y for the benefit of reducing or eliminating binding affinity for the IL-2Rα receptor (p.40, para.4; p.43, para.3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’709/Karow with the teachings of Kang by modifying the engineered E62A/C125A IL-2 variant taught by App’709/Karow to also contain an T37Y substitution (taught by Kang), to arrive at the claimed IL-2 variant of instant claim 13, in order to receive the expected benefit that the T37A mutation provides for further reducing binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Kang teaches the exact position substitution for the T37Y substitution.
The combination of teachings by App’709/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’709/Karow does not teach the IL-2 substitution M23L.
Piaggio teaches IL-2 muteins for treatment of immune disorders including autoimmune and inflammatory disorders (title; abstract). Piaggio teaches IL-2 mutants that comprise a mutation M23L for the benefit of preferentially stimulating Tregs (p.4, last paragraph).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’709/Karow with the teachings of Piaggio by modifying the engineered E62A/C125A IL-2 variant taught by App’709/Karow to also contain an M23L substitution (taught by Piaggio), to arrive at the claimed IL-2 variant of instant claim 15, in order to receive the expected benefit that the M23L mutation provides for preferential activation of Tregs. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Piaggio teaches the exact position substitution for the M23L substitution.
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’709/Karow does not teach the IL-2 substitution P34F.
Long teaches “improved” IL-2 muteins for reduced toxicities by lowering natural killer cell pro-inflammatory cytokine production while maintaining cell proliferation, which includes an IL-2 muteins harboring a P34V substitution (p.121, [0882]).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’709/Karow with the teachings of Long by modifying the engineered E62A/C125A IL-2 variant taught by App’709/Karow to also contain an P34 substitution that is P34V (taught by Long), to arrive at the claimed IL-2 variant of instant claim 16, in order to receive the expected benefit that the P34V mutation provides for reduced toxicity. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Long teaches the exact position substitution for the P34V substitution.
Long does not teach that the P34 substitution is specifically to a phenylalanine/F (i.e., P34F).
Barnes teaches the nature of mutations and the properties of amino acids in a variety of different protein contexts to provide for anticipating or interpreting the effect that a particular amino acid change will have on protein structure and function (p.292, para.2). Barnes teaches that valine/V is a hydrophobic amino acid (p.297, Fig.14.3); and, teaches that valine/V can be substituted by other hydrophobic amino acids such as phenylalanine/F (p.300, section 14.5; Fig.14.3).
It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’709/Karow/Long with the teachings of Barnes by modifying the IL-2 mutein comprising a P34 mutation to specifically comprise an P34F substitution, in order to arrive at the instantly claimed IL-2 variant of instant claim 16, because the combination of prior art elements results in a predictable result of producing an IL-2 variant harboring a P34F substitution. One of ordinary skill would be motivated to do so because Long teaches that introducing a P34V mutation provides for reduced toxicity. It would have further been obvious to modify the P34V mutation to be a P34F mutation by substituting the valine/V modification (taught by Long) to a phenylalanine/F modification (taught by Barnes), to arrive at the instantly claimed invention, because this would be a simple substitution of one known element for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Long teaches that the P34 position can be mutated to the hydrophobic amino acid valine for reduced toxicity, and Barnes teaches that valine/V can be substituted to other hydrophobic amino acids.
The combination of teachings by App’709/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’709/Karow does not teach the IL-2 substitution E68F.
Li teaches IL-2 variants including IL-2 mutants that comprise a mutation E68F for the benefit of enhanced binding to IL-2Rα (p.80, [0225]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’709/Karow with the teachings of Li by modifying the engineered E62A/C125A IL-2 variant taught by App’709/Karow to also contain an E68F substitution (taught by Li), to arrive at the claimed IL-2 variant of instant claim 17, in order to receive the expected benefit that the E68F mutation provides for enhanced IL-2 binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Li teaches the exact position substitution for the E68F substitution.
The combination of teachings by App’709/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1. Karow further teaches that the IL-2 variant can be fused to IgG Fc domains, and more broadly, antibodies and antibody derivatives (p.92, [0311]; p.115, [0368]).
App’709/Karow does not explicitly teach that the IL-2 variant is fused to an anti-CTLA4 antibody (instant claim 20).
Askgene teaches bioactivatable “prodrugs” wherein the prodrug comprises “bioactivatable domains” comprising cytokines IL-2 or IL-15 which are fused to “carrier moieties” that can comprise an Fc domain that is an IgG and an antigen-binding fragment that can bind CTLA-4 (paragraphs [0017], [0067]-[0068], [0088]-[0089]). Askgene teaches that the carrier may improve the pharmacokinetic profile such as serum half-life of the cytokine and may target the cytokine to a target site (p.14, [0061]-[0063]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’709/Karow with the teachings of Askgene by modifying the fusion protein comprising the IL-2 variant to fuse an anti-CTLA4 antibody to the cytokine (as taught by Askgene), to arrive at the instantly claimed invention in order to receive the expected benefit that the anti-CTLA4 antibody would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow and Askgene both teach IL-2 fusion proteins comprising IL-2 and antibodies, and Askgene specifically teaches fusion of the anti-CTLA4 antibody to IL-2.
The combination of teachings by App’709/Karow teaches an IL-2 fusion protein that is fused to an IgG Fc domain for treating autoimmune disease, as applied to instant claims 1, 19, and 24 above.
App’709/Karow does not teach a method of proliferation of Tregs in a subject via administration of the IL-2 fusion protein (instant claim 23); that administration of the IL-2 fusion protein increases levels of phosphorylated STAT5 (instant claim 25); that administration of the IL-2 fusion protein increases Tregs (instant claim 26); or, proliferation via contacting the population of Tregs with the IL-2 fusion protein (instant claim 29).
Chinen teaches that Tregs express abundant amounts IL-2 receptor alpha but are unable to produce IL-2 and rely on IL-2 produced by other T cells (abstract; p.2, para.1). Chinen further teaches that the repression of IL-2 in Tregs is required to maintain the constitutive expression of IL-2Rα on Tregs; and that this level of Treg IL 2Rα expression plays a key role in Treg cell-mediated suppression of T effector cells by depriving T effector cells of IL-2 (p.2, para.3). Chinen also teaches the significance of IL-2R signaling in Tregs (i.e., activation due to binding/contact of a functional IL-2; instant claim 11), including their maintenance, proliferation, and function due to activation of JAK STAT5, PI3K-Akt, and Ras-ERK signaling pathways, including via phosphorylation of STAT5 (p.2, para.2-3; Figs.1- 2). Chinen teaches that STAT5 is a downstream target of IL-2/IL-2R signaling and that STAT5 activity in Tregs correlates with their proliferative capacity and expression of IL 2Rα (p.2, para.1; p.8, para.2).
Gasteiger teaches that IL-2 binds a trimeric complex comprising IL-2R α, β, and γ subunits (p.1, para.4). Gasteiger teaches that the α/β-heterodimer facilitates IL-2 capture with high affinity (p.1, para.4). Gasteiger teaches that Tregs constitutively express IL-2Rα whereas other T cells express IL-2Rα (i.e., CD25) after undergoing cell division; and that this allows Tregs to sense IL-2 early during an immune responses by restricting cytokine availability to other T cells to balance the effector T cell differentiation and expansion (p.2, para.4, Fig.1).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’709/Karow with the teachings of Chinen and Gasteiger by using the IL-2 fusion protein for treatment of autoimmune disease (as taught by Karow) to also increase the levels of phosphorylated STAT5 by inducing proliferation of T cells in order to increase Tregs (as taught by Chinen) to arrive at the instantly claimed invention because the combination of prior art elements results in a predictable result of IL-2 variant-mediated STAT5 activation and Treg proliferation. One of ordinary skill in the art would have a reasonable expectation of success because Gasteiger teaches that IL-2 binds the α/β-heterodimer with high affinity and Tregs constitutively express IL-2Rα . The recitations “of proliferating T cells (Treg cells), comprising contacting the population of T cells with…IL-2 variant of claim 1 or … IL-2 fusion protein of claim 19” are merely mechanisms of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. /n re Omeprazole Patent Litigation, 483 F.3d
18/821,234
Claims 1 and 12-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 40, 61, 65, 91, and 94 of copending Application No. 18/821,234 (herein referred to as App’234); in view of Karow et al. – WO2020069398A1 (published 04/02/2020; herein referred to as Karow); in further view of Kang, et al.—WO2020057646A1, Novel interleukin 2 and use thereof (published 03/26/2020; herein referred to as Kang); in further view of Piaggio, et al.—WO2020201095A1 (effective filing date: 03/27/2020; herein referred to as Piaggio); in further view of Long, et al.—US20080254026A1 (published 10/16/2008; effective filing date 11/04/2003; herein referred to as Long); in further view of Barnes and Gray. Bioinformatics for geneticists. John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England. 2003, p.1-411 (herein referred to as Barnes); in further view of Li, et al.—WO2020252418A2 (effective filing date: 06/14/2019; herein referred to as Li); in further view of Askgene Pharma, Inc., WO2019173832A2, Novel cytokine prodrugs (herein referred to as Askgene); in further view of Chinen et al. An essential role for IL-2 receptor in regulatory T cell function. Nature Immunology (2016), 17: 11, p.1322-1333 (herein referred to as Chinen); and further in view of Gasteiger et al. Foxp3+ regulatory T-cells and IL-2: the Moirai of T-cell fates? Frontiers in Immunology (2012), 3:179, p.1-4 (herein referred to as Gasteiger); and, as evidenced by Norris, et al. Type 1 diabetes—early life origins and changing epidemiology. Lancet Diabetes Endocrinology (March 2020), 8:3, p.1-27 (herein referred to as Norris).
App’234 teaches masked cytokines comprising IL-2 polypeptides (App’234 claims 1-2; instant claim 1) and attenuated IL-2 polypeptides (App’234 claim 3; instant claim 1) with E62 and or C125A mutations (App’234 claims 1-2 and 40; instant claim 1); and wherein the masked cytokine also comprises an Fc domain (App’234 claim 27; instant claim 19). App’234 also teaches nucleic acids encoding the IL-2 cytokines (App’234 claim 61; instant claim 21); and pharmaceutical compositions of the IL-2 cytokine that further comprise a pharmaceutically acceptable carrier (App’234 claim 65; instant claim 22). App’234 also teaches a method of treating or preventing autoimmune disease via administration of IL-2 (App’234 claim 68; instant claim 24).
App’234 does not teach that the IL-2 variant specifically comprises an E62A substitution (instant claims 1 and 18); that the IL-2 variant comprises a T37Y substitution (instant claim 13); that the IL-2 variant comprises a M23L substitution (instant claim 15); that the IL-2 variant comprises a P34F substitution (instant claim 16); that the IL-2 variant comprises a E68F substitution (instant claim 17); that the Fc domain of the fusion protein is an IgG Fc (instant claim 19); that the IL-2 fusion protein is fused to an anti-CTLA4 antibody (instant claim 20); a method of proliferation of Tregs via administration of the IL-2 fusion protein (instant claim 23); that administration of the IL-2 fusion protein increases levels of pSTAT5 (instant claim 25) or Tregs (instant claim 26); or, proliferation via contacting the population of Tregs with the IL-2 fusion protein (instant claim 29).
[AltContent: textbox (Instant SEQ ID NO: 1 (WT) vs Karow SEQ ID NO: 1 (C125A)
[img-media_image1.png])]Karow also teaches that IL-2 is approved for treatment of cancer but has a short half-life and that high doses of IL-2 can cause adverse side effects associated with systemic immune activation (p.3-4, [0005]). Karow teaches engineered masked cytokines comprising human IL-2, wherein IL-2 can comprise amino acid substitutions wherein position C125 contains a C125A substitution that contributes to stabilization of the cytokine (p.180, #15-16; see Karow amino acid IL-2 SEQ ID NO: 1).
Karow also teaches an E62A mutation that results in a variant capable of binding IL-Rα but that has reduced binding to IL-2Rα (p.5, [0012]; p.44, [0210]; p.45-46, [0211-0212]; p.47, [0213]; p.179, #7-8). Karow also teaches engineered masked cytokines with half-life extension domains that can be comprised of an IgG1 Fc domain (i.e., an “IgG Fc”) or fragment thereof (p.107, [0341]). Karow also teaches (poly)nucleotide sequences encoding polypeptide components of masked cytokines, including IL-2 variants fused to IgG Fc domain half-life extension domains, using standard recombinant techniques (p.143, [0459]; p.166, [0542]). Karow further teaches compositions and therapeutic formulations comprising IL-2 variants and IL-2 fusion proteins (i.e., “masked cytokines”; p.153, [0505 – 0506]). Karow teaches the use of the IL-2 cytokines for treatment or prevention of autoimmune disease (p. 166, [0542]) and that the IL-2 treatment can comprise pharmaceutically acceptable carriers that including salt-forming counterions such as sodium (p.177, [0580]). Karow further teaches treatment via administration of the masked cytokine comprising an IL-2 variant to a subject that is mammalian (p.166, [0542]; p.178, [0587]). Karow teaches that the method of treatment for autoimmune disease can include treatment of various inflammatory diseases and forms of arthritis, Crohn’s disease, ulcerative colitis, type I diabetes, multiple sclerosis, lupus, and ankylosing spondylitis (among others; p.166, [0543]). As Karow teaches treatment of autoimmune disease and type I diabetes, which is an autoimmune disease characterized by hyperglycemia (as evidenced by Norris, p.1 Introduction), Karow necessarily also teaches treatment of “autoimmune hyperglycemia” (p.166, [0543]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of App’234 with the teachings of Karow by modifying the engineered IL-2 variant of App’234 by adding an IgG Fc domain (taught by Karow), to arrive at the claimed IL-2 fusion protein, in order to receive the expected benefit that the IgG Fc domain would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow teaches the amino acid sequence for Fc domains.
App’234 and Karow do not teach the IL-2 substitution T37Y.
Kang teaches IL-2 muteins that comprise a mutation T37Y for the beneifit of reducing or eliminating binding affinity for the IL-2Rα receptor (p.40, para.4; p.43, para.3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’234/Karow with the teachings of Kang by modifying the engineered E62A/C125A IL-2 variant taught by App’234/Karow to also contain an T37Y substitution (taught by Kang), to arrive at the claimed IL-2 variant of instant claim 13, in order to receive the expected benefit that the T37A mutation provides for further reducing binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Kang teaches the exact position substitution for the T37Y substitution.
The combination of teachings by App’234/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’234/Karow does not teach the IL-2 substitution M23L.
Piaggio teaches IL-2 muteins for treatment of immune disorders including autoimmune and inflammatory disorders (title; abstract). Piaggio teaches IL-2 mutants that comprise a mutation M23L for the benefit of preferentially stimulating Tregs (p.4, last paragraph).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’234/Karow with the teachings of Piaggio by modifying the engineered E62A/C125A IL-2 variant taught by App’234/Karow to also contain an M23L substitution (taught by Piaggio), to arrive at the claimed IL-2 variant of instant claim 15, in order to receive the expected benefit that the M23L mutation provides for preferential activation of Tregs. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Piaggio teaches the exact position substitution for the M23L substitution.
The combination of teachings by Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’234/Karow does not teach the IL-2 substitution P34F.
Long teaches “improved” IL-2 muteins for reduced toxicities by lowering natural killer cell pro-inflammatory cytokine production while maintaining cell proliferation, which includes an IL-2 muteins harboring a P34V substitution (p.121, [0882]).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’234/Karow with the teachings of Long by modifying the engineered E62A/C125A IL-2 variant taught by App’234/Karow to also contain an P34 substitution that is P34V (taught by Long), to arrive at the claimed IL-2 variant of instant claim 16, in order to receive the expected benefit that the P34V mutation provides for reduced toxicity. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Long teaches the exact position substitution for the P34V substitution.
Long does not teach that the P34 substitution is specifically to a phenylalanine/F (i.e., P34F).
Barnes teaches the nature of mutations and the properties of amino acids in a variety of different protein contexts to provide for anticipating or interpreting the effect that a particular amino acid change will have on protein structure and function (p.292, para.2). Barnes teaches that valine/V is a hydrophobic amino acid (p.297, Fig.14.3); and, teaches that valine/V can be substituted by other hydrophobic amino acids such as phenylalanine/F (p.300, section 14.5; Fig.14.3).
It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’234/Karow/Long with the teachings of Barnes by modifying the IL-2 mutein comprising a P34 mutation to specifically comprise an P34F substitution, in order to arrive at the instantly claimed IL-2 variant of instant claim 16, because the combination of prior art elements results in a predictable result of producing an IL-2 variant harboring a P34F substitution. One of ordinary skill would be motivated to do so because Long teaches that introducing a P34V mutation provides for reduced toxicity. It would have further been obvious to modify the P34V mutation to be a P34F mutation by substituting the valine/V modification (taught by Long) to a phenylalanine/F modification (taught by Barnes), to arrive at the instantly claimed invention, because this would be a simple substitution of one known element for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Long teaches that the P34 position can be mutated to the hydrophobic amino acid valine for reduced toxicity, and Barnes teaches that valine/V can be substituted to other hydrophobic amino acids.
The combination of teachings by App’234/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1.
App’234/Karow does not teach the IL-2 substitution E68F.
Li teaches IL-2 variants including IL-2 mutants that comprise a mutation E68F for the benefit of enhanced binding to IL-2Rα (p.80, [0225]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’234/Karow with the teachings of Li by modifying the engineered E62A/C125A IL-2 variant taught by App’234/Karow to also contain an E68F substitution (taught by Li), to arrive at the claimed IL-2 variant of instant claim 17, in order to receive the expected benefit that the E68F mutation provides for enhanced IL-2 binding to IL-2Rα. One of ordinary skill would have a reasonable expectation of success because Karow teaches the sequence for IL-2 and the E62A and C125A mutations, and Li teaches the exact position substitution for the E68F substitution.
The combination of teachings by App’234/Karow teaches an E62A/C125A IL-2 variant as described above for instant claim 1. Karow further teaches that the IL-2 variant can be fused to IgG Fc domains, and more broadly, antibodies and antibody derivatives (p.92, [0311]; p.115, [0368]).
App’234/Karow does not explicitly teach that the IL-2 variant is fused to an anti-CTLA4 antibody (instant claim 20).
Askgene teaches bioactivatable “prodrugs” wherein the prodrug comprises “bioactivatable domains” comprising cytokines IL-2 or IL-15 which are fused to “carrier moieties” that can comprise an Fc domain that is an IgG and an antigen-binding fragment that can bind CTLA-4 (paragraphs [0017], [0067]-[0068], [0088]-[0089]). Askgene teaches that the carrier may improve the pharmacokinetic profile such as serum half-life of the cytokine and may target the cytokine to a target site (p.14, [0061]-[0063]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’234/Karow with the teachings of Askgene by modifying the fusion protein comprising the IL-2 variant to fuse an anti-CTLA4 antibody to the cytokine (as taught by Askgene), to arrive at the instantly claimed invention in order to receive the expected benefit that the anti-CTLA4 antibody would provide for extending the half-life of IL-2. One of ordinary skill would have a reasonable expectation of success because Karow and Askgene both teach IL-2 fusion proteins comprising IL-2 and antibodies, and Askgene specifically teaches fusion of the anti-CTLA4 antibody to IL-2.
The combination of teachings by App’234/Karow teaches an IL-2 fusion protein that is fused to an IgG Fc domain for treating autoimmune disease, as applied to instant claims 1, 19, and 24 above.
App’234/Karow does not teach a method of proliferation of Tregs in a subject via administration of the IL-2 fusion protein (instant claim 23); that administration of the IL-2 fusion protein increases levels of phosphorylated STAT5 (instant claim 25); that administration of the IL-2 fusion protein increases Tregs (instant claim 26); or, proliferation via contacting the population of Tregs with the IL-2 fusion protein (instant claim 29).
Chinen teaches that Tregs express abundant amounts IL-2 receptor alpha but are unable to produce IL-2 and rely on IL-2 produced by other T cells (abstract; p.2, para.1). Chinen further teaches that the repression of IL-2 in Tregs is required to maintain the constitutive expression of IL-2Rα on Tregs; and that this level of Treg IL 2Rα expression plays a key role in Treg cell-mediated suppression of T effector cells by depriving T effector cells of IL-2 (p.2, para.3). Chinen also teaches the significance of IL-2R signaling in Tregs (i.e., activation due to binding/contact of a functional IL-2; instant claim 11), including their maintenance, proliferation, and function due to activation of JAK STAT5, PI3K-Akt, and Ras-ERK signaling pathways, including via phosphorylation of STAT5 (p.2, para.2-3; Figs.1- 2). Chinen teaches that STAT5 is a downstream target of IL-2/IL-2R signaling and that STAT5 activity in Tregs correlates with their proliferative capacity and expression of IL 2Rα (p.2, para.1; p.8, para.2).
Gasteiger teaches that IL-2 binds a trimeric complex comprising IL-2R α, β, and γ subunits (p.1, para.4). Gasteiger teaches that the α/β-heterodimer facilitates IL-2 capture with high affinity (p.1, para.4). Gasteiger teaches that Tregs constitutively express IL-2Rα whereas other T cells express IL-2Rα (i.e., CD25) after undergoing cell division; and that this allows Tregs to sense IL-2 early during an immune responses by restricting cytokine availability to other T cells to balance the effector T cell differentiation and expansion (p.2, para.4, Fig.1).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’234/Karow with the teachings of Chinen and Gasteiger by using the IL-2 fusion protein for treatment of autoimmune disease (as taught by Karow) to also increase the levels of phosphorylated STAT5 by inducing proliferation of T cells in order to increase Tregs (as taught by Chinen) to arrive at the instantly claimed invention because the combination of prior art elements results in a predictable result of IL-2 variant-mediated STAT5 activation and Treg proliferation. One of ordinary skill in the art would have a reasonable expectation of success because Gasteiger teaches that IL-2 binds the α/β-heterodimer with high affinity and Tregs constitutively express IL-2Rα . The recitations “of proliferating T cells (Treg cells), comprising contacting the population of T cells with…IL-2 variant of claim 1 or … IL-2 fusion protein of claim 19” are merely mechanisms of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. /n re Omeprazole Patent Litigation, 483 F.3d.
Response to Arguments
Regarding the claim 1 rejections under 35 U.S.C. 103 and for double patenting over the reference of Karow, applicant claims that because Karow discusses mutants with at least four substitutions, claim 1 was not obvious over Karow (see applicant arguments submitted 12/17/2025, p.4, para.2). The rejection in the non-final office action filed 09/18/2025 was correct as claim 1 previously recited “at least one amino acid substitution” wherein Karow’s teachings read on claim 1. Claim 1 has been amended wherein the claimed engineered human IL-2 variant comprises C125A and E62A. Karow teaches IL-2 muteins for the purpose of treating autoimmune disease and also teaches the specific E62A and C125A mutations, as well as the motivations for incorporating these mutations, which is all that is required for a read on the amended claim. Thus, applicant arguments are not found to be persuasive, and the new obviousness rejection for claim 1, as well as the double patenting rejections for claim 1, are maintained in modified form over Karow above.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
An IL-2 variant comprising the specific amino acid substitutions T111H and/or E15T is novel.
Regarding the T111H substitution: Ptacin, et al.—TWI906467B (published 12/01/2025; herein referred to as Ptacin) teaches an IL-2 variant with a mutation at the T111 position for the purpose of modifying hydrophobic IL-2 residues that interact with the IL-2Rα subunit (p.16, para.4). However, Ptacin does not specifically teach the T111H substitution and was published after applicant’s effective filing date.
Regarding the E15T substitution: Chartier-Courtaud and Fardis. WO2020131547A1 (published: 09/25/2020; effective filing date: 12/19/2018) herein referred to as Chartier-Courtaud) teaches methods of expanding tumor infiltrating lymphocytes using engineered cytokine receptor pairs and teaches “orthogonal IL-2 variants” wherein the IL-2 variant is orthogonal to an IL-2 receptor. While Chartier-Courtaud teaches IL-2 variants with the mutation E15T and discusses the IL-2 α, β, and γ subunits, Chartier-Courtaud does not specify the motivation for this specific mutation or the effect of the IL-2 mutation on receptor binding or any other motivation for the E15T substitution (p.261, [001274])
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647