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
This application claims priority to U.S. provisional applications 63/328697, filed on 07
April 2022, 63/358799, filed on 06 July 2022, and 63/408059, filed on 19 September 2022. The effective filing date is 07 April 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 24 July 2025 and 07 November 2023 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 24-28 are pending and the subject of this office action.
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.
Claims 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0352362 A1 (herein Bernett) in view of US 2021/0230243 A1 (herein Desjarlais).
In regard to claim 24, Bernett teaches a LAG-3 targeted fusion protein containing IL-15/IL-15RA FC fusion proteins and LAG-3 antigen binding domains (abstract). More specifically, Bernett teaches a multimeric protein complex comprising: a) a first monomer comprising, from N-to C-terminal: i) an IL-15Ra(sushi) domain; ii) a first domain linker; iii) an IL-15 variant; iv) a hinge; v) a first variant Fc domain comprising CH2-CH3; b) a second monomer comprising, from N-to C-terminal, VH-CHl-hinge-CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain; and c) a third monomer comprising a VL-CL ([0012]). The VH and VL are a variable heavy domain and a variable light domain, respectively, that form a human LAG-3 antigen binding domain. This disclosed embodiment effectively describes the invention set forth in instant claim 24 of the instant invention, which describes a multimeric LAG-3-targeted IL-15/Rα-FC fusion protein complex comprised of three components: (a) a first monomer comprising the amino acid sequence set forth in SEQ ID NO: 168; (b) a second monomer comprising the amino acid sequence set forth in SEQ ID NO: 169; (c) a third monomer comprising the amino acid sequence set forth in SEQ ID NO: 170.
In regard to claim 24(a), the monomer comprising SEQ ID NO: 168 is a fusion protein comprising the following from N-to C-terminal: a VH region of an antigen binding domain specific to LAG-3 - a CH1 region - a hinge region - CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain. This fusion is taught by Bernett, SEQ ID NO: 326, and shares 100% sequence identity with SEQ ID NO: 168 of the instant application, as shown below:
326 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDAWMSWVRQAPGKGLEWVAEISTKANNHAT 60
Instant168 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDAWMSWVRQAPGKGLEWVAEISTKANNHAT 60
************************************************************
326 YYAESVKGRFTISRDDSKSSVYLQMNSLRAEDTAVYYCTRLATWDWYFDVWGQGTTVTVS 120
Instant168 YYAESVKGRFTISRDDSKSSVYLQMNSLRAEDTAVYYCTRLATWDWYFDVWGQGTTVTVS 120
************************************************************
326 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
Instant168 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
************************************************************
326 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAG 240
Instant168 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAG 240
************************************************************
326 PSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 300
Instant168 PSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 300
************************************************************
326 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREQ 360
Instant168 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREQ 360
************************************************************
326 MTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
Instant168 MTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
************************************************************
326 QQGNVFSCSVLHEALHSHYTQKSLSLSPGK 450
Instant168 QQGNVFSCSVLHEALHSHYTQKSLSLSPGK 450
******************************
In regard to claim 24(c), the monomer comprising SEQ ID NO: 170 is a fusion protein comprising the following from N-to C-terminal: a VL region of an antigen binding domain specific to LAG-3 - a VL region. This fusion is taught by Bernett, SEQ ID NO: 327, and shares 100% sequence identity with SEQ ID NO: 170 of the instant application, as shown below:
327 DIVLTQSPSSLSASVGDRVTITCRASQSVDYDGDSYMNWYQQKPGKPPKLLIYAASELES 60
170 DIVLTQSPSSLSASVGDRVTITCRASQSVDYDGDSYMNWYQQKPGKPPKLLIYAASELES 60
************************************************************
327 GIPARFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPFTFGSGTKLEIKRTVAAPSVF 120
170 GIPARFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPFTFGSGTKLEIKRTVAAPSVF 120
************************************************************
327 IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 180
170 IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 180
************************************************************
327 STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 218
170 STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 218
**************************************
In regard to claim 24(b), the monomer comprising SEQ ID NO: 169 is a fusion protein comprising the following from N-to C-terminal: an IL-15Ra(sushi) domain - a first domain linker - an IL-15 variant - a hinge - a first variant Fc domain comprising CH2-CH3. A similar fusion is taught by Bernett, SEQ ID NO: 325, but Bernett is deficient in teaching this specific sequence (i.e. amino acid substitutions within the IL-15 variant and differences in the linker sequence). These deficiencies are taught by Desjarlais.
Desjarlais teaches a similar multimeric complex (claims 190 and 218):
a) a first monomer comprising, from N- to C-terminal:
i) a IL-15 Ra sushi domain protein;
ii) a first domain linker;
iii) a variant IL-15 protein comprising an amino acid substitution selected from the group consisting of N71Q, N79Q, N112Q, S114del and S114A; and
iv) a first variant Fc domain; and
b) a second monomer comprising a heavy chain comprising VH-CHl-hinge-CH2-CH3, wherein said CH2-CH3 is a second variant Fc domain;
c) a third monomer comprising a light chain comprising VL-CL;
wherein said VH and VL domains form an antigen binding domain that binds to human PD-I.
Claim 218 teaches a targeted IL-15/Ra heterodimeric Fc fusion protein, SEQ ID NO: 225, that shares 100% sequence identity with SEQ ID NO: 170 of the instant application, as shown below:
225 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS 60
169 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS 60
************************************************************
225 LKCIRGGGGAGGGGAGGGGAGGGGAGGGGANWVNVISDLKKIEDLIQSMHIDATLYTESN 120
169 LKCIRGGGGAGGGGAGGGGAGGGGAGGGGANWVNVISDLKKIEDLIQSMHIDATLYTESN 120
************************************************************
225 VHPSCKVTAMKCFLLELQVISLESGDASIHDTVQDLIILAQNSLSSNGQVTESGCKECEE 180
169 VHPSCKVTAMKCFLLELQVISLESGDASIHDTVQDLIILAQNSLSSNGQVTESGCKECEE 180
************************************************************
225 LEEKNIKEFLQSFVHIVQMFIQTSEPKSSDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLM 240
169 LEEKNIKEFLQSFVHIVQMFIQTSEPKSSDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLM 240
************************************************************
225 ISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEEYNSTYRVVSVLTVLHQD 300
169 ISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEEYNSTYRVVSVLTVLHQD 300
************************************************************
225 WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGF 360
169 WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCDVSGF 360
************************************************************
225 YPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVLHEAL 420
169 YPSDIAVEWESDGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWEQGDVFSCSVLHEAL 420
************************************************************
225 HSHYTQKSLSLSPGK 435
169 HSHYTQKSLSLSPGK 435
***************
It would have been obvious to one skilled in the art to combine the teachings of Desjarlais (a modified IL-15/Rα heterodimeric Fc fusion protein) with the LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins and LAG-3 antigen binding domains by Bernett. One of ordinary skill in the art at the time of filing would have been motivated to incorporate the amino acid substitutions (N71Q, N79Q, and N112Q) within IL-15 and use of a Gly-Ala linker instead of a Gly-Ser linker, due to the recognized benefits (increased homogeneity and enhanced specificity towards effector memory T cells) associated with removal of N-linked glycosylation sites or O-linked glycosylation sites, respectively, as taught by Desjarlais ([1158-1159], [1167], and figures 120 and 121). Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
In regard to claim 25, Bernett and Desjarlais teach a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, as discussed for claim 24.
Bernett further teaches nucleic acids encoding any of the three monomers discussed in claim 24, allowing for necessary variation in composition to accommodate vector specific format requirements ([0056] and [0456]).
In regard to claim 26, Bernett and Desjarlais teach a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, as discussed for claim 24.
Bernett further teaches expression vectors for the expression of any of the three monomers, either alone or in combination, with the nature of the expression vector being dependent on the expression host cell ([0457] and [0458]).
In regard to claim 27, Bernett and Desjarlais teach a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, as discussed for claim 24.
Bernett further teaches expression of any of the three monomers, either alone or in combination, by culturing expression host cells comprising the expression vectors ([0143], [0459], [0461]).
In regard to claim 28, Bernett and Desjarlais teach a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, as discussed for claim 24.
Bernett further teaches a method for making LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, by culturing expression host cells comprising the expression vectors, as discussed for claim 28, and subsequently purified using ion exchange chromatography ([0461], claim 12).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 24-28 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 176, 225, 226, 227, 228, 229, and 230 of U.S. Patent No. 11932675 in view of 2019/0352362 A1 (herein Bernett) and US 2021/0230243 A1 (herein Desjarlais).
‘675, claim 176, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modification selected from a group consisting of N71Q, N79Q, N112Q, S114del, and S114A. This is relevant to the second monomer described in claim 24, which is comprised of N71Q/ N79Q/N112Q amino acid modifications.
‘675, claim 225, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modification selected from a group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E. This is relevant to the second monomer described in claim 24, which is comprised of D30N/E64Q/N65D amino acid modifications.
‘675, claim 226, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modification selected from a group consisting of N71Q/N79Q, N71Q/N79Q/N112Q, N71Q/N79Q/S114del, and N71Q/N79Q/S114A. This is relevant to the second monomer described in claim 24, which is comprised of N71Q/ N79Q/N112Q amino acid modifications.
‘675, claim 227, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modification selected from a group consisting of N1D/N4D/D8N, N1D/N4D/N65D, N1D/D30N, N1D/D61N, N1D/D61N/E64Q/Q108E, N1D/E64Q, N1D/N65D, N1D/Q108E, N4D/D30N, N4D/D61N, N4D/D61N/N65D, N4D/D61N/E64Q/Q108E, N4D/E64Q, N4D/N65D, D8N/D61N, D8N/E64Q, D30N/E64Q, D30N/N65D, D30N/E64Q/N65D, D30N/Q180E, D61N/E64Q/N65D, E64Q/N65D, E64Q/Q108E and N65D/Q108E. This is relevant to the second monomer described in claim 24, which is comprised of D30N/E64Q/N65D amino acid modifications.
‘675, claim 228, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modification N71Q/N79Q/N112Q. This is relevant to the second monomer described in claim 24, which is comprised of N71Q/ N79Q/N112Q amino acid modifications.
‘675, claim 229, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modifications N71Q/N79Q/N112Q and D30N/N65D. This is relevant to the second monomer described in claim 24, which is comprised of N71Q/ N79Q/N112Q and D30N/N65Q amino acid modifications.
‘675, claim 230, describes a pharmaceutical composition comprising a variant of IL-15 comprised of amino acid modifications N71Q/N79Q/N112Q and D30N/E64Q/N65D. This is relevant to the second monomer described in claim 24, which is comprised of N71Q/ N79Q/N112Q and D30N/E64Q/N65Q amino acid modifications.
However, ‘675 does not indicate a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion protein. Bernett teaches this deficiency, but does not teach an IL-15 variant comprised with N71Q/N79Q/N112Q amino acid modifications. Thus, one would have been motivated to combine the LAG-3 targeted multimeric complex, taught by Bernett ([0012], SEQ ID NO: 168, 169, and 170), with the IL-15 variant described in ‘675. One would also have been motivated to incorporate the modified IL-15 variant, described in ‘362, due to the increased homogeneity and enhanced specificity towards effector memory T cells, as taught by Desjarlais ([1158-1159], [1167], and figures 120 and 121). There would have been reasonable expectation of success based on the prior art describing each element individually.
In regard to instant claim 25, Bernett teaches nucleic acids encoding any of the three monomers discussed in claim 24, allowing for necessary variation in composition to accommodate vector specific format requirements ([0056] and [0456]).
In regard to instant claim 26, Bernett teaches expression vectors for the expression of any of the three monomers, either alone or in combination, with the nature of the expression vector being dependent on the expression host cell ([0457] and [0458]).
In regard to instant claim 27, Bernett teaches expression of any of the three monomers, either alone or in combination, by culturing expression host cells comprising the expression vectors ([0143], [0459], [0461]).
In regard to instant claim 28, Bernett teaches a method for making LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, by culturing expression host cells comprising the expression vectors, as discussed for claim 28, and subsequently purified using ion exchange chromatography ([0461], claim 12).
Claims 24-28 are rejected on the ground of non-statutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11505595 in view of 2019/0352362 A1 (herein Bernett) and US 2021/0230243 A1 (herein Desjarlais).
‘595, claim 1, describes a multimeric fusion protein complex comprising: a) a first monomer comprising, from N-to C-terminal: i) an IL-15Ra(sushi) domain; ii) a first domain linker; iii) an IL-15 variant; iv) a hinge; v) a first variant Fc domain comprising CH2-CH3; b) a second monomer comprising, from N-to C-terminal, VH-CH1-hinge-CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain; and c) a third monomer comprising a VL-CL. The VH and VL are a variable heavy domain and a variable light domain, respectively, that form a human T-cell immunoglobulin and mucin-domain containing (TIM3) antigen binding domain. Furthermore, the first variant Fc domain comprises skew variants L368D/K370S and pI variants Q295E/N384D/Q418E/N421D. The second variant contains skew variants S364K/E357Q. Both Fc variants comprise FcKO variants E233P/L234V/L235A/G236del/S267L. The overall architecture of this complex as well as the various Fc amino acid modifications are shared between the invention described in claim 1 of ‘595 and claim 24 of the instant application. ‘595 claim 1 is deficient in the IL-15 variant modifications, described in greater detail above, as well the incorporation of VL and VH regions forming the LAG-3 antigen binding fragment. These deficiencies are taught by Bernett and Desjarlais.
Bernett teaches a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion protein ([0012], SEQ ID NO: 168, 169, and 170). One would have been motivated to substitute the TIM-3-targeted antigen binding fragment, VH and VL, with LAG-3 targeted antigen binding fragment, taught by Bernett, due to previously identified role LAG-3 plays in T cell regulation via its roles in effector T cells, Treg and potentially Trl cells as noted by Anderson, et al. (2016) Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation. Immunity. May 17; 44(5): 989-1004. There would have been reasonable expectation of success based on the prior art describing each element individually, as the inventor is essentially substituting one previously defined element, VH and VL from an anti-TIM-3 antibody, with the corresponding regions of another immune checkpoint receptor-targeted antibody, LAG-3.
Desjarlais teaches a series of amino acid modification to limit the number of glycosylation sites on the IL-15 variant ([1158-1159], [1167], and figures 120 and 121). One would also have been motivated to incorporate the modified IL-15 variant with the complex, described in ‘362 claim 1, due to the increased homogeneity and enhanced specificity towards effector memory T cells cells gained by the Il-15 modifications, as taught by Desjarlais. There would have been reasonable expectation of success based on the prior art describing each element individually.
In regard to instant claim 25, Bernett teaches nucleic acids encoding any of the three monomers discussed in claim 24, allowing for necessary variation in composition to accommodate vector specific format requirements ([0056] and [0456]).
In regard to instant claim 26, Bernett teaches expression vectors for the expression of any of the three monomers, either alone or in combination, with the nature of the expression vector being dependent on the expression host cell ([0457] and [0458]).
In regard to instant claim 27, Bernett teaches expression of any of the three monomers, either alone or in combination, by culturing expression host cells comprising the expression vectors ([0143], [0459], [0461]).
In regard to instant claim 28, Bernett teaches a method for making LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, by culturing expression host cells comprising the expression vectors, as discussed for claim 28, and subsequently purified using ion exchange chromatography ([0461], claim 12).
Claims 24-28 are rejected on the ground of non-statutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11377477 in view of 2019/0352362 A1 (herein Bernett).
‘477, claim 1, describes a multimeric fusion protein complex comprising: a) a first monomer comprising, from N-to C-terminal: i) an IL-15Ra(sushi) domain; ii) a first domain linker; iii) an IL-15 variant; iv) a hinge; v) a first variant Fc domain comprising CH2-CH3; b) a second monomer comprising, from N-to C-terminal, VH-CH1-hinge-CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain; and c) a third monomer comprising a VL-CL ([0012]). The VH and VL are a variable heavy domain and a variable light domain, respectively, that form a PD-1 antigen binding domain. The overall architecture of this complex is shared between the invention described in claim 1 of ‘477 and claim 24 of the instant application. ‘477 claim 1 is deficient in regard to the incorporation of VL and VH regions forming the LAG-3 antigen binding fragment. These deficiencies are taught by Bernett.
Bernett teaches a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion protein ([0012], SEQ ID NO: 168, 169, and 170). One would have been motivated to substitute the TIM-3-targeted antigen binding fragment, VH and VL, with LAG-3 targeted antigen binding fragment, taught by Bernett, due to previously identified role LAG-3 plays in T cell regulation via its roles in effector T cells, Treg and potentially Trl cells as noted by Anderson, et al. (2016) Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation. Immunity. May 17; 44(5): 989-1004. There would have been reasonable expectation of success based on the prior art describing each element individually, as the inventor is essentially substituting one previously defined element, VH and VL from an anti-PD-1 antibody, with the corresponding regions of another immune checkpoint receptor-targeted antibody, LAG-3.
In regard to instant claim 25, Bernett teaches nucleic acids encoding any of the three monomers discussed in claim 24, allowing for necessary variation in composition to accommodate vector specific format requirements ([0056] and [0456]).
In regard to instant claim 26, Bernett teaches expression vectors for the expression of any of the three monomers, either alone or in combination, with the nature of the expression vector being dependent on the expression host cell ([0457] and [0458]).
In regard to instant claim 27, Bernett teaches expression of any of the three monomers, either alone or in combination, by culturing expression host cells comprising the expression vectors ([0143], [0459], [0461]).
In regard to instant claim 28, Bernett teaches a method for making LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, by culturing expression host cells comprising the expression vectors, as discussed for claim 28, and subsequently purified using ion exchange chromatography ([0461], claim 12).
Claims 24-28 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 11524991 in view of 2019/0352362 A1 (herein Bernett).
‘991, claim 1, describes a multimeric fusion protein complex comprising: a) a first monomer comprising, from N-to C-terminal: i) an IL-15Ra(sushi) domain; ii) a first domain linker; iii) an IL-15 variant; iv) a hinge; v) a first variant Fc domain comprising CH2-CH3; b) a second monomer comprising, from N-to C-terminal, VH-CH1-hinge-CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain; and c) a third monomer comprising a VL-CL. The VH and VL are a variable heavy domain and a variable light domain, respectively, that form a human PD-1 antigen binding domain. Furthermore, the first variant Fc domain comprises skew variants L368D/K370S and pI variants Q295E/N384D/Q418E/N421D. The second variant contains skew variants S364K/E357Q. Both Fc variants comprise FcKO variants E233P/L234V/L235A/G236del/S267L. The overall architecture of this complex as well as the various Fc amino acid modifications are shared between the invention described in claim 1 of ‘991 and claim 24 of the instant application. ‘991 claim 1 is deficient in the IL-15 variant modifications, described in greater detail above, as well the incorporation of VL and VH regions forming the LAG-3 antigen binding fragment. These deficiencies are taught by Bernett .
Bernett teaches a LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion protein ([0012], SEQ ID NO: 168, 169, and 170). One would have been motivated to substitute the PD-1-targeted antigen binding fragment, VH and VL, with LAG-3 targeted antigen binding fragment, taught by Bernett, due to previously identified role LAG-3 plays in T cell regulation via its roles in effector T cells, Treg and potentially Trl cells as noted by Anderson, et al. (2016) Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation. Immunity. May 17; 44(5): 989-1004. There would have been reasonable expectation of success based on the prior art describing each element individually, as the inventor is essentially substituting one previously defined element, VH and VL from an anti-PD-1 antibody, with the corresponding regions of another immune checkpoint receptor-targeted antibody, LAG-3.
Desjarlais teaches a series of amino acid modification to limit the number of glycosylation sites on the IL-15 variant ([1158-1159], [1167], and figures 120 and 121). One would also have been motivated to incorporate the modified IL-15 variant, to the complex described in ‘991 claim 1, due to the increased homogeneity and enhanced specificity towards effector memory T cells gained by the Il-15 modifications, as taught by Desjarlais. There would have been reasonable expectation of success based on the prior art describing each element individually.
In regard to instant claim 25, Bernett teaches nucleic acids encoding any of the three monomers discussed in claim 24, allowing for necessary variation in composition to accommodate vector specific format requirements ([0056] and [0456]).
In regard to instant claim 26, Bernett teaches expression vectors for the expression of any of the three monomers, either alone or in combination, with the nature of the expression vector being dependent on the expression host cell ([0457] and [0458]).
In regard to instant claim 27, Bernett teaches expression of any of the three monomers, either alone or in combination, by culturing expression host cells comprising the expression vectors ([0143], [0459], [0461]).
In regard to instant claim 28, Bernett teaches a method for making LAG-3 targeted fusion protein containing IL-15/IL-15Rα FC fusion proteins, by culturing expression host cells comprising the expression vectors, as discussed for claim 28, and subsequently purified using ion exchange chromatography ([0461], claim 12).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647