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 claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US20/64651, filing date 12/11/2020, which claims the benefit of the prior-filed United States Provisional Patent Application No. 62/947,749, filing date 12/13/2019.
Status of Application/Claims
The amendment, filed 01/14/2026, is acknowledged. Claims 1-47, 50-54, 56-57, 61, and 65-67 are canceled. Claims48-49, 55, and 58-60 are currently amended. Claims 48-49, 55, 58-60, and 62-64 are currently pending and examined on the merits herein.
Information Disclosure Statement
The IDS was filed on 10/08/2022. The information disclosure statement (IDS) filed on 09/05/2025 lists a reference (i.e., #6 Xencor, Inc. WO2019204665 for which there is no attached pdf. Thus, this reference was not considered by the examiner. The other references listed on the IDS filed 09/05/2025 were otherwise fully considered by the examiner.
Withdrawn Objections & Rejections
Regarding the abstract objection for exceeding word limit requirements, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
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 Thus, the objection is withdrawn.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 objection for claim 49 for minor informalities, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the rejections for claim 59 under 35 U.S.C. 112(b) for indefiniteness: Applicant amendment has addressed the issue and the rejection is withdrawn.
Regarding the rejection for claims 48-54, 56-59, 62-63, and 65-67 under 35 U.S.C. 102 for novelty, applicant amendment has overcome the rejection and the rejection is withdrawn. (See new obviousness rejection below.)
Regarding the rejections for claims 52 and 60 under 35 U.S.C. 103 for obviousness: Claim 52 is canceled. Applicant amendment has addressed the obviousness rejection for claim 60. Thus, the rejections for claims 52 and 60 are withdrawn. (See new obviousness rejection below).
Regarding the rejection for claim 61 under 35 U.S.C. 103 for obviousness: Applicant amendment has addressed the issue and claim 61 is canceled. Thus, the rejection for claim 61 is withdrawn. (See new obviousness rejection below).
Regarding the rejection for claim 64 under 35 U.S.C. 103 for obviousness: Applicant amendment has addressed the issue and the rejection for claim 64 is withdrawn. (See new obviousness rejection below.).
Regarding the non-statutory double patenting rejections for claims 48-53 and 55-62: No arguments are submitted in the “Applicant Remarks” document filed 01/14/2026. Claims 50-53, 56-57 and 61 are canceled. Applicant amendment has resulted in a double patenting rejection that is maintained in modified form for claims 48-49, 55, 58-60, and 62-64.
Claim Rejections - 35 USC § 103
(New Rejections)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 48-49, 55, 58-59, and 62-64 are rejected under 35 U.S.C. 103 as being unpatentable over Xencor, Inc. – WO2020077276A2 (effective filing date: 10/12/2018; herein referred to as Xencor); further in view of UniProt. P0DOX5: IGG1_HUMAN, 07/18/2018, p.8 (herein referred to as UP-IgG1); further in view of Jong, et al.—US20210238296A1 (effective filing date: 05/03/2019; herein referred to as Jong); and, further in view of Pfizer, Inc.—US20190263877A1 (publication date: 08/29/2019; effective filing date: 02/28/2018; herein referred to as Pfizer); and, as evidenced by Chen, et al. Fusion protein linkers: Property, design and functionality. Adv Drug Deliv Rev. (2013), 65:10, p.1357-1369 (herein referred to as Chen).
Xencor teaches PD-1 targeted IL-15/IL15Rα Fc fusion proteins for administration for cancer treatment (title; abstract). Xencor teaches use of the fusion protein formulated optionally with pharmaceutically acceptable carriers, excipients, or stabilizers (p.105, [00482]); and, in combination therapies with other (secondary) therapeutics, include checkpoint blockade inhibitors (p.96, [00439]). Xencor teaches that IL-15 aids in proliferation and differentiation of B cells, T cells, and NK cells, and is potentially valuable as a cancer therapeutic, but that IL-15 cytokine therapy suffers from low half-life and systemic toxicity (p.1, [0003]). Xencor teaches fusion proteins comprising an Fc domain, IL-15 domain, and an IL-15Rα domain that can be in various formats, including “Fc-single-chain IL-15/Rα fusion or “Fc-scIL-15/Rα” (Figure 13G comprises IL-15 fused to IL-15Rα(sushi) complex or “scIL-15Rα) which is then fused to the C-terminus of a heterodimeric Fc region…” (p.11, [0046]; Fig.13G). Xencor teaches that the presence of the IL-15/IL-15Rα complex allows for binding to the common gamma chain and/or the IL-2 receptor β-chain (p.48, [00220]). Xencor teaches various formats for therapeutic antibody molecules including formats wherein the molecule consists of a dimeric antibody wherein the IL-15 cytokine and IL-15Rα are on the same chain joined by a linker or different chains, (see Fig.28A, C, E-F, and H versus Fig.28G for example); wherein the Fc molecule(s) is/are fused directly with a linker to one or both of IL-15 and IL-15Rα (see Fig.28C(IL-15), Fig.28D(IL-15Rα) and Fig.28G for example; also see Fig1A-G and Fig.28A-H in full). Additionally, Xencor teaches formats wherein IL-2Rα and IL-15 cytokine are expressed as different proteins and are thus separated to facilitate a non-covalent IL-15/Rα complex (p.75, [00346]; Fig.13F for example). Further, Xencor teaches amino acid SEQ ID NO: 12, which encodes the full IL-15Rα sushi domain that includes the N-terminal signal sequence, and overlaps 100% with instant amino acid SEQ ID NO: 4. Thus, Xencor SEQ ID NO: 12 also comprises and teaches [AltContent: textbox (Instant SEQ ID NO: 4 vs Xencor SEQ ID NO: 12 IL-15Rα (Instant SEQ ID NO: 5 also underlined)
[img-media_image1.png])]instant SEQ ID NOs: 5.
Xencor also teaches several linkers that can be used to join the different domains, including several variable length GS linkers (Fig.8 table) that includes “(GGGGS)1-7” that can be used to link the IL-15 and IL-15Rα together and/or to the Fc domain (p.7, [0034]). Xencor states that these variable length linkers can be used for joining the domains of various formats, including the format represented by Fig.13G wherein the IL-15Rα and IL-15 cytokine are fused to the C-terminus of the antibody molecule. Xencor further states that “as will be appreciated, the linkers can be replaced by other linkers, some of which are depicted in Figures 8 and 9” (p.12, [0045-0047], [0051-0052], [0059-0062], [0073], [0079-0080]; [0099-100], [00151]). As evidenced by Chen, the linkers of Xencor Fig.8 that includes the GS linkers are “non-cleavable linkers.” Regarding the Fc domain, Xencor teaches constructs wherein the antibody or Fc region originates from IgG1, and also states that the antibodies can be designed with other IgG “backbones” including IgG2, IgG3, and IgG4 (p.40, [00184]). Regarding the IL-15 cytokine, Xencor teaches various mutants including a substitution mutation Q108E, which provides the benefit of reduced potency (p.12, [0048]; Fig.18).
Xencor does not teach the Fc domain of instant SEQ ID NO: 14 (instant claim 48); an IL-15 Q108 variant that is specifically Q108S and encoded by instant SEQ ID NO: 208 (instant claim 48); or, the specific order of the therapeutic cytokine molecule that is in the order of, from N- to C-terminus, Fc—IL-15 variant—IL-15Rα (instant claim 48).
Regarding the order of the domains: It would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to combine the teachings of Xencor by modifying a therapeutic cytokine molecule comprising an Fc domain, IL-15 variant domain, and IL-15Rα domain wherein the domains are joined via linkers (taught by Xencor), by rearranging the single chain construct of Fc—IL-15Rα—IL-15 to be Fc—IL-15 variant—IL-15Rα, in order to arrive at the instantly claimed invention because the combination of prior art teachings by Xencor teaches various formats wherein an IL-15/Rα dimer can be attached at either the N- or C-terminus of an Fc-only antibody, full-length antibody, and bivalent antibodies. One would have a reasonable expectation of success because it would be obvious to try a format wherein the IL-15 variant is linked to the C-terminus of the Fc region followed by the IL-15Rα because Xencor also teaches that IL-15 can be directly linked to the Fc domain and still interact with an IL-15Rα that is encoded by Xencor SEQ ID NO: 12 (i.e., instant SEQ ID NO: 4/5).
[AltContent: textbox (Instant SEQ ID NO: 14 vs UP-IgG1 P0DOX5
[img-media_image2.png])] Regarding the Fc domain of instant SEQ ID NO: 14: The Fc domain of instant SEQ ID NO: 14 encodes an IgG1 Fc domain with the following mutations: L14A, L15A, and G17A. UP-IgG1 teaches the IgG1 amino acid sequence comprising the Fc domain, but does not teach the mutations (see alignment below). Jong teaches that one or more substitutions that include L234A and L235A (which correspond to instant positions L14A and L15A, respectively) can impart reduced effector function (p.4, [0058]). Jong also teaches the G237A substitution (which corresponds to instant position G17A) for the benefit of Fc-gamma receptor modulation (p.4, [0061]).
Regarding the IL-15 Q108S variant of instant SEQ ID NO: 208: Pfizer teaches IL-15 variants for treating disorders, including cancer (title; abstract); and, also teaches the problem of IL-15 toxicity with current immune-oncology therapeutic approaches (p.1, [0004-0005]). Pfizer specifically teaches variants I68H, I68F, I68K, Q108S, and Q108A, to reduce IL-2Rβ binding (p.41, Table 2).
It would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to combine the teachings of Xencor with the teachings of UP-IgG1, Jong, and Pfizer by modifying the therapeutic IL-15 cytokine molecule of format Fc—IL-15 variant—IL-15Rα by using the IgG1 amino acid sequence (taught by UP-IgG1) and incorporating L14A, L15A, and G17A substitutions (taught by Jong), because the combination of prior art teaching leads to a predictable result and benefit of producing an IgG1 Fc molecule with reduced/modified effector function (also taught by Jong). One would have a reasonable expectation of success because Xencor teaches that the antibody fragment can be an Fc domain and that the Fc domain can be derived from IgG1. It would also have been obvious to modify the IL-15 variant of the therapeutic cytokine molecule (taught by Xencor) by using Pfizer’s Q108A substituted IL-15 as the IL-15 variant domain, to arrive at the instantly claimed invention, in order to receive the benefit that the Q108A mutation allows for reduced IL-2Rβ binding and reduced toxicity.
Claims 48-49, 55, 58-59, and 62-64 are rejected under 35 U.S.C. 103 as being unpatentable over Xencor, UP-IgG1, Jong, and Pfizer; further in view of Chen; and, further in view of Lu and Yu—US20210163452A1 (effective filing date: 07/25/2018; herein referred to as Lu).
The combination of Xencor/UP-IgG1/Jong/Pfizer (as evidenced by Chen) teaches a therapeutic IL-15 cytokine molecule, and pharmaceutical composition thereof, with the format of instant claim 48 wherein the C-terminal Fc domain (instant “D1”) is linked to the IL-15 Q108S variant (instant “D2”) followed by the IL-15Rα domain (instant “D3”), wherein two separate flexible GS linkers are used to join D1 to D2, and D2 to D3, respectively, for combination therapies for the treatment of cancer (instant claims 48-49, 55, 58-59, and 62-64).
The combination of Xencor/UP-IgG1/Jong/Pfizer does not teach that the D2/IL-15 domain is linked to the D3/IL-15Rα domain via a protease cleavable linker (instant claims 48, 58-59, and 60); or, wherein the construct is encoded by instant amino acid SEQ ID NO: 230 (instant claim 60).
Instant SEQ ID NO: 230 encodes the cytokine construct wherein the Fc/D1 domain is linked to the IL-15 variant/D2 domain via a non-cleavable peptide linker, and the IL-15 variant/D2 domain is linked to the IL-15Rα/D3 domain via a protease cleavable peptide linker. Further, the Fc domain of instant SEQ ID NO: 230 encodes for the IgG1 L14A/L15A/G15A mutant, which is taught by the combination of UP-IgG1 and Jong above. The IL-15 variant of instant SEQ ID NO: 230 encodes for the IL-15 Q108S variant which is taught by Pfizer above. The IL-15Rα domain of instant SEQ ID NO: 230 encodes for the IL-15Rα sushi domain, which is taught by Xencor above.
Regarding the “L1” linker that joins D1 and D2, instant SEQ ID NO: 230 encodes a flexible non-cleavable GS linker of the sequence “GGGGSGGGGSGGGGS” (see Xencor Fig.8 table; as evidenced by Chen). Xencor teaches constructs wherein the peptide linkers are comprised of flexible GS linkers (as evidenced by Chen).
The combination of Xencor/UP-IgG1/Jong/Pfizer does not teach that the specific linker of sequence “GGGGSGGGGSGGGGS” connects the D1 and D2 domains.
Chen teaches property, design, and functionality rationales for the use of different types of linkers for fusion proteins (title; abstract). Chen teaches that flexible and rigid linkers are generally used for linking functional domains of proteins together while cleavable linkers are generally used to release a free functional domain in vivo (abstract). Chen teaches that linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles (abstract). Additionally, Chen teaches that direct fusion of functional domains without a linker may lead to many undesirable outcomes, including misfolding of the fusion protein, low yield in protein production, or impaired bioactivity; and, that contributing linker properties include length, hydrophobicity, and secondary structure (p2, para.2). Chen teaches that flexible linkers allow for mobility of the connecting functional domains and usually incorporate Glycine/G and Serine/S or Threonine/T; and, that these linkers primarily consist of stretches of (GGGGS)n, whereby adjusting the copy number “n”, the length can be optimized to achieve appropriate separation (p.1359, col.2, para.5; p.1360, col.1, para.1).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Xencor/UP-IgG1/Jong/Pfizer with the teachings of Chen by modifying the therapeutic cytokine molecule (taught by the combination of Xencor/UP-IgG1/Jong/Pfizer) by modifying the “L1” linker connecting the D1 and D2 domains (taught by Xencor) by using a linker of “GGGGSGGGGSGGGGS” (taught by the combination of Xencor/Chen) because the combination of prior art teachings results from a flexible GS linker of format (GGGGS)n (taught by Chen) which is commonly used to link domains of fusion proteins and provides benefits that include for increased mobility. It would have been obvious to try a linker of (GGGGS)3 because Xencor teaches formats of (GGGGS)1-7. One of ordinary skill in the art would have a reasonable expectation of success because Xencor teaches that the linkers can be replaced by other linkers, and Chen teaches that the (GGGGS)n copy number can be adjusted and optimized.
Regarding the “L2” linker that joins D2 and D3, instant SEQ ID NO: 230 encodes the amino acid sequence “GGPLGMLSQS.” Xencor teaches that the linkers of the therapeutic cytokine molecule can be replaced by other linkers. Additionally, Xencor teaches formats wherein the IL-15 cytokine is expressed separately for non-covalent binding to IL-15Rα, producing separate IL-15 and IL-15Rα products. As described above, Chen teaches the benefits of flexible, rigid, and protease cleavable linkers. Chen teaches that protease cleavable linkers can be used in fusion protein design for the benefit of retaining an extended half-life while releasing free functional domains in vivo (p.1361, col.2, para.3).
Xencor/UP-IgG1/Jong/Pfizer/Chen do not teach the proteolytically cleavable sequence of “GGPLGMLSQS” links the D2/IL-15 and D3/IL-15Rα domains.
Lu also teaches “prodrugs” that comprise Fc domains, IL-15, and IL-15 “masking domains” of IL-15Rα sushi polypeptide for treatment of cancer (abstract; p.3, [0028]; p.9, [0096]; ). Notably, Lu also teaches several cleavable linkers, including SEQ ID NO: 17 which is the same sequence as the “L2” linker “GGPLGMLSQS” of instantly claimed construct SEQ ID NO: 230 (p.15, SEQ ID NO: 17); and, teaches a specific embodiment wherein, when the prodrug comprises IL-15 and IL-15Rα, the IL-15Rα binds to IL-15 and inhibits biological activity of the cytokine, and wherein the “masking moiety”/IL-15Rα is fused to the cytokine through a cleavable peptide linker (p.93-94, claims 9-10)
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Xencor/UP-IgG1/Jong/Pfizer/Chen with the additional teachings of Chen as well as the teachings of Lu by modifying the therapeutic cytokine molecule (taught by the combination of Xencor/UP-IgG1/Jong/Pfizer/Chen) by modifying the “L2” linker connecting the D2 and D3 domains (taught by Xencor) by replacing the flexible linker (taught by the combination of Xencor/Chen) with a protease cleavable linker of sequence “GGPLGMLSQS” (taught by Lu), in order to arrive at the instantly claimed invention, because the combination of prior art teachings results in the predictable result of producing a construct in the format of instant SEQ ID NO: 230 wherein the L2 linker is encoded by the “GGPLGMLSQS” linker. It would have been obvious to try a cleavable linker because Chen teaches the benefit of retaining increased half-life by covalently linking domains of fusion proteins and Xencor that linkers can be replaced with other linkers, and because Xencor teaches constructs wherein the IL-15 and IL-15Rα are ultimately separate from one another. One of ordinary skill in the art would have a reasonable expectation of success because Xencor and Lu teach therapeutic cytokine constructs comprising Fc, IL-15, and IL-15Rα, Lu teaches the specific cleavable linker sequence of SEQ ID NO: 17/ “GGPLGMLSQS,” and, Lu specifically teaches IL-15 linkage to IL-15Rα via cleavable linkers.
Double Patenting
(Rejections Maintained in Modified Form)
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.
US11634467
Claims 48-49, 55, 58-60, and 62-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-9 of U.S. Patent No. 11634467 (herein referred to as Pat’467); further in view of Xencor; further in view of Pfizer; further in view of Chen; and, further in view of Lu.
Pat’467 teaches the D1-D2-D3 bioactivatable polypeptide drug wherein: D1 is a functional moiety that is an Fc domain comprised of one of amino acid SEQ ID NOs: 14-16, 156, or 166-168; D2 is bioactivatable moiety IL-15; and D3 is a concealing moiety that is a receptor/binding partner comprised one of SEQ ID NOs: 4-5 (Pat’467 claim 1; instant claim 48). Pat.467 also teaches that the domains can be in the form or monomer, dimer, or combination thereof (Pat’467 claim 3; instant claim 49); and, wherein the construct can be in a pharmaceutical composition with an acceptable carrier (Pat.467 claim 9; instant claim 62). Pat’467 also teaches that linkers L1 (joining D1 to D2) and L2 (joining D2 to D3) can each be non-cleavable or cleavable peptide linkers (Pat’467 claim 2; instant claim 59); wherein L1 and L2 can be any one of instant SEQ ID NOs: 71-96, 157-161, or 107-127 (Pat’467 claim 5; instant claims 55 and 58).
While Pat’467 teaches the WT IL-15 SEQ ID NO: 2, Pat’467 does not teach that D2 has the amino acid sequence of one of instant SEQ ID NOs: 182-192 or 199-215 (instant claim 48); that the construct can be used for a method of cancer treatment (instant claim 63); or, that the construct is administered as a pharmaceutical composition in combination with another therapeutic agent (instant claim 64).
Xencor teaches PD-1 targeted IL-15/IL15Rα Fc fusion proteins for administration for cancer treatment (title; abstract). Xencor teaches use of the fusion protein formulated optionally with pharmaceutically acceptable carriers, excipients, or stabilizers (p.105, [00482]); and, in combination therapies with other (secondary) therapeutics, include checkpoint blockade inhibitors (p.96, [00439]). Xencor teaches that IL-15 aids in proliferation and differentiation of B cells, T cells, and NK cells, and is potentially valuable as a cancer therapeutic, but that IL-15 cytokine therapy suffers from low half-life and systemic toxicity (p.1, [0003]). Xencor teaches fusion proteins comprising an Fc domain, IL-15 domain, and an IL-15Rα domain that can be in various formats, including “Fc-single-chain IL-15/Rα fusion or “Fc-scIL-15/Rα” (Figure 13G comprises IL-15 fused to IL-15Rα(sushi) complex or “scIL-15Rα) which is then fused to the C-terminus of a heterodimeric Fc region…” (p.11, [0046]; Fig.13G). Xencor teaches that the presence of the IL-15/IL-15Rα complex allows for binding to the common gamma chain and/or the IL-2 receptor β-chain (p.48, [00220]). Xencor teaches various formats for therapeutic antibody molecules including formats wherein the molecule consists of a dimeric antibody wherein the IL-15 cytokine and IL-15Rα are on the same chain joined by a linker or different chains, (see Fig.28A, C, E-F, and H versus Fig.28G for example); wherein the Fc molecule(s) is/are fused directly with a linker to one or both of IL-15 and IL-15Rα (see Fig.28C(IL-15), Fig.28D(IL-15Rα) and Fig.28G for example; also see Fig1A-G and Fig.28A-H in full). Additionally, Xencor teaches formats wherein IL-2Rα and IL-15 cytokine are expressed as different proteins and are thus separated to facilitate a non-covalent IL-15/Rα complex (p.75, [00346]; Fig.13F for example). Further, Xencor teaches amino acid SEQ ID NO: 12, which encodes the full IL-15Rα sushi domain that includes the N-terminal signal sequence, and overlaps 100% with instant amino acid SEQ ID NO: 4. Thus, Xencor [AltContent: textbox (Instant SEQ ID NO: 4 vs Xencor SEQ ID NO: 12 IL-15Rα (Instant SEQ ID NO: 5 also underlined)
[img-media_image1.png])]SEQ ID NO: 12 also comprises and teaches instant SEQ ID NOs: 5.
Xencor also teaches several linkers that can be used to join the different domains, including several variable length GS linkers (Fig.8 table) that includes “(GGGGS)1-7” that can be used to link the IL-15 and IL-15Rα together and/or to the Fc domain (p.7, [0034]). Xencor states that these variable length linkers can be used for joining the domains of various formats, including the format represented by Fig.13G wherein the IL-15Rα and IL-15 cytokine are fused to the C-terminus of the antibody molecule. Xencor further states that “as will be appreciated, the linkers can be replaced by other linkers, some of which are depicted in Figures 8 and 9” (p.12, [0045-0047], [0051-0052], [0059-0062], [0073], [0079-0080]; [0099-100], [00151]). As evidenced by Chen, the linkers of Xencor Fig.8 that includes the GS linkers are “non-cleavable linkers.” Regarding the Fc domain, Xencor teaches constructs wherein the antibody or Fc region originates from IgG1, and also states that the antibodies can be designed with other IgG “backbones” including IgG2, IgG3, and IgG4 (p.40, [00184]). Regarding the IL-15 cytokine, Xencor teaches various mutants including a substitution mutation Q108E, which provides the benefit of reduced potency (p.12, [0048]; Fig.18).
Xencor does not teach the Fc domain of instant SEQ ID NO: 14 (instant claim 48); an IL-15 Q108 variant that is specifically Q108S and encoded by instant SEQ ID NO: 208 (instant claim 48); or, the specific order of the therapeutic cytokine molecule that is in the order of, from N- to C-terminus, Fc—IL-15 variant—IL-15Rα (instant claim 48).
Regarding the IL-15 Q108S variant of instant SEQ ID NO: 208: Pfizer teaches IL-15 variants for treating disorders, including cancer (title; abstract); and, also teaches the problem of IL-15 toxicity with current immune-oncology therapeutic approaches (p.1, [0004-0005]). Pfizer specifically teaches variants I68H, I68F, I68K, Q108S, and Q108A, to reduce IL-2Rβ binding (p.41, Table 2).
Regarding instant claims 48, 63, and 64: It would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to combine the teachings of Pat’467 with the teachings of Xencor and Pfizer by modifying the therapeutic IL-15 cytokine molecule of format Fc—IL-15—IL-15Rα (taught by Pat’467) by using Pfizer’s Q108A substituted IL-15 as the IL-15 variant domain, to arrive at the instantly claimed invention, in order to receive the benefit that the Q108A mutation allows for reduced IL-2Rβ binding and reduced toxicity for a combination cancer treatment comprising the therapeutic cytokine molecule, a pharmaceutically acceptable excipient, and a second therapeutic agent.
Regarding instant claim 60: Instant SEQ ID NO: 230 encodes the cytokine construct wherein the Fc/D1 domain is linked to the IL-15 variant/D2 domain via a non-cleavable peptide linker, and the IL-15 variant/D2 domain is linked to the IL-15Rα/D3 domain via a protease cleavable peptide linker. Further, the Fc domain of instant SEQ ID NO: 230 encodes for the IgG1 L14A/L15A/G15A mutant, which is taught by Pat’468 above. The IL-15 variant of instant SEQ ID NO: 230 encodes for the IL-15 Q108S variant which is taught by Pfizer above. The IL-15Rα domain of instant SEQ ID NO: 230 encodes for the IL-15Rα sushi domain, which is taught by Pat’468 above.
Regarding the “L1” linker that joins D1 and D2, instant SEQ ID NO: 230 encodes a flexible non-cleavable GS linker of the sequence “GGGGSGGGGSGGGGS” (see Xencor Fig.8 table; as evidenced by Chen). Xencor teaches constructs wherein the peptide linkers are comprised of flexible GS linkers (as evidenced by Chen).
The combination of Pat’468/Xencor/Pfizer does not teach that the specific linker of sequence “GGGGSGGGGSGGGGS” connects the D1 and D2 domains.
Chen teaches property, design, and functionality rationales for the use of different types of linkers for fusion proteins (title; abstract). Chen teaches that flexible and rigid linkers are generally used for linking functional domains of proteins together while cleavable linkers are generally used to release a free functional domain in vivo (abstract). Chen teaches that linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles (abstract). Additionally, Chen teaches that direct fusion of functional domains without a linker may lead to many undesirable outcomes, including misfolding of the fusion protein, low yield in protein production, or impaired bioactivity; and, that contributing linker properties include length, hydrophobicity, and secondary structure (p2, para.2). Chen teaches that flexible linkers allow for mobility of the connecting functional domains and usually incorporate Glycine/G and Serine/S or Threonine/T; and, that these linkers primarily consist of stretches of (GGGGS)n, whereby adjusting the copy number “n”, the length can be optimized to achieve appropriate separation (p.1359, col.2, para.5; p.1360, col.1, para.1).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Pat’468/Xencor/Pfizer with the teachings of Chen by modifying the therapeutic cytokine molecule (taught by the combination of Pat’468 Xencor/Pfizer) by modifying the “L1” linker connecting the D1 and D2 domains (taught by Xencor) by using a linker of “GGGGSGGGGSGGGGS” (taught by the combination of Xencor/Chen) because the combination of prior art teachings results from a flexible GS linker of format (GGGGS)n (taught by Chen) which is commonly used to link domains of fusion proteins and provides benefits that include for increased mobility. It would have been obvious to try a linker of (GGGGS)3 because Xencor teaches formats of (GGGGS)1-7. One of ordinary skill in the art would have a reasonable expectation of success because Xencor teaches that the linkers can be replaced by other linkers, and Chen teaches that the (GGGGS)n copy number can be adjusted and optimized.
Regarding the “L2” linker that joins D2 and D3, instant SEQ ID NO: 230 encodes the amino acid sequence “GGPLGMLSQS.” Xencor teaches that the linkers of the therapeutic cytokine molecule can be replaced by other linkers. Additionally, Xencor teaches formats wherein the IL-15 cytokine is expressed separately for non-covalent binding to IL-15Rα, producing separate IL-15 and IL-15Rα products. As described above, Chen teaches the benefits of flexible, rigid, and protease cleavable linkers. Chen teaches that protease cleavable linkers can be used in fusion protein design for the benefit of retaining an extended half-life while releasing free functional domains in vivo (p.1361, col.2, para.3).
Pat’468/Xencor/Pfizer/Chen do not teach the proteolytically cleavable sequence of “GGPLGMLSQS” links the D2/IL-15 and D3/IL-15Rα domains.
Lu also teaches “prodrugs” that comprise Fc domains, IL-15, and IL-15 “masking domains” of IL-15Rα sushi polypeptide for treatment of cancer (abstract; p.3, [0028]; p.9, [0096]; ). Notably, Lu also teaches several cleavable linkers, including SEQ ID NO: 17 which is the same sequence as the “L2” linker “GGPLGMLSQS” of instantly claimed construct SEQ ID NO: 230 (p.15, SEQ ID NO: 17); and, teaches a specific embodiment wherein, when the prodrug comprises IL-15 and IL-15Rα, the IL-15Rα binds to IL-15 and inhibits biological activity of the cytokine, and wherein the “masking moiety”/IL-15Rα is fused to the cytokine through a cleavable peptide linker (p.93-94, claims 9-10)
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Pat’468/Xencor/Pfizer/Chen with the additional teachings of Chen as well as the teachings of Lu by modifying the therapeutic cytokine molecule (taught by the combination of Pat’468/Xencor/Pfizer/Chen) by modifying the “L2” linker connecting the D2 and D3 domains (taught by Xencor) by replacing the flexible linker (taught by the combination of Xencor/Chen) with a protease cleavable linker of sequence “GGPLGMLSQS” (taught by Lu), in order to arrive at the instantly claimed invention, because the combination of prior art teachings results in the predictable result of producing a construct in the format of instant SEQ ID NO: 230 wherein the L2 linker is encoded by the “GGPLGMLSQS” linker. It would have been obvious to try a cleavable linker because Chen teaches the benefit of retaining increased half-life by covalently linking domains of fusion proteins and Xencor that linkers can be replaced with other linkers, and because Xencor teaches constructs wherein the IL-15 and IL-15Rα are ultimately separate from one another. One of ordinary skill in the art would have a reasonable expectation of success because Xencor and Lu teach therapeutic cytokine constructs comprising Fc, IL-15, and IL-15Rα, Lu teaches the specific cleavable linker sequence of SEQ ID NO: 17/ “GGPLGMLSQS,” and, Lu specifically teaches IL-15 linkage to IL-15Rα via cleavable linkers.
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