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 .
Election/Restriction
Applicant's election without traverse of Group I (Claims 16-22, 29, 46, and 61) and species election of:
First and second Fc domains having the substitutions S267K/L368D/K370S : S267K/S364K/E357Q
IL15 comprising D30N/E64Q/N65D and IL15Ra without any substitutions
Not applicable
Heterodimeric protein construct of Claim 29
in the reply filed on November 3, 2025 is acknowledged.
Claims 16-21, 23, 46, 61, 80-81, and 87-89 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 3, 2025.
Claim Status
Claim listing filed on November 3, 2025 is pending. Claims 1-15, 22, 24-28, 30-45, 47-60, and 62-79 are canceled. Claim 29 is amended. Claims 82-89 are new. Claims 16-21, 23, 46, 61, 80-81, and 87-89 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 29 and 82-86 are examined upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of US Application No. 16/660,028 filed October 22, 2019, which is a continuation of 15/785,401 filed October 16, 2017, which claims the benefit of US Provisional Application No. 62/443,465 filed January 6, 2017; US Provisional Application No. 62/447,926 filed March 28, 2017; US Provisional Application No. 62/416,087 filed November 1, 2016; and Provisional Application No. 62/408,655 filed October 14. 2016. All claims have been given an effective filing date of July X, 2018.
Claims 85-86 do not have support in US Provisional Application No. 62/408,655, because it does not teach the IL-15 mutations. Claims 85-86 do have support in US Provisional Application No. 62/447,926 and receive an effective filing date of March 28, 2017. Claims 29 and 82-84 receive an effective filing date of October 14, 2016.
Information Disclosure Statement
The information disclosure statements filed on November 25, 2022 and October 27, 2023 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because copies of all foreign patent documents and non-patent literature documents are not included in the instant application or the parent application (U.S. App. No. 16/660,028). The missing documents are marked on the attached IDS with a strikethrough. MPEP § 609.02II.B.2 states “if the IDS submitted in the parent application complies with 37 CFR 1.98(a) to (c), copies of the patents, publications, pending U.S. applications, or other information submitted in the parent application need not be resubmitted in the continuing application” [emphasis added]. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
All the other information disclosure statements (IDSs) submitted on December 15, 2023 and November 3, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: In paragraph [0006] line 6, “seconddomain” requires a space between “second” and “domain.” Appropriate correction is required.
Claim Objections
Claim 86 is objected to because of the following informalities: There is an unnecessary parenthesis at the end of claim that needs to be deleted. Specifically, the parenthesis in “SEQ ID NO: 335)” needs to be deleted. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 83 and 85 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 83 recites “an additional set of amino acid substitutions consisting of G236R/L328R… and E233P/L234V/L235A/G236del.” Claim 83 lists a Markush group of amino acid substitution sets but does not recite “selected from the group consisting of” as is required for proper Markush claim language (MPEP § 2117.I). An alternative interpretation of “consisting of” is that the heterodimeric protein is required to have all of the amino acid substitution sets listed in Claim 83. The claim language is indefinite, and the metes and bounds of what is being claimed cannot be determined. For the purpose of compact prosecution, Claim 83 is interpreted as “Fc domains have an additional set of amino acid substitutions selected from the group consisting of” wherein only one substitution set is required.
Claim 85 recites wherein said IL-15 protein has one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E. However, it is unclear what is represented by these substitutions because no reference IL-15 sequence is provided. For example, both SEQ ID NOs: 1 and 2 are IL-15 amino acid sequences (full-length versus truncated); however, the amino acid residues at position 1 in both sequences differ. Therefore, without an IL-15 reference sequence, the metes and bounds of the listed substitutions are indefinite. For the purpose of compact prosecution, it is interpreted that the substitutions are in reference to an IL-15 comprising SEQ ID NO: 2.
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 29 and 82-85 are rejected under 35 U.S.C. 103 as being unpatentable over Wong US 8,507,222 (published 2013) in view of Moore WO 2016/086196 (published June 2016 and not a prior art exception under 35 U.S.C. due to a different inventive entity).
In regard to Claim 1, Wong teaches a fusion protein comprising a dimer of two Fc domains wherein an IL-15Rα sushi receptor (IL-15RαSu) is bound to the N-terminals of each Fc domain by a linker (Claim 6, Fig. 64, and paragraph [0013]). The fusion protein further comprises two IL-15 polypeptides that are non-covalently bound to the IL-15RαSu (Claim 6, Fig. 64, paragraph [0141]). The IL-15/IL-15RαSu complex is linked to an Fc domain to extend the circulating half-life (paragraph [0181]). In regard to Claim 84, SEQ ID NO: 35 teaches the sequence of IL-15RαSu (residues 403-467) (paragraph [0080] and Fig. 4B) that is 100% identical to instant SEQ ID NO: 4. In regard to Claim 84, SEQ ID NO: 39 teaches the sequence of IL-15 with a N72D mutation (residues 399-512) (paragraph [0087] and Fig. 10B) that is 99.1% identical to instant SEQ ID NO: 2. It is obvious that the wild-type IL-15 amino acid sequence (without the N72D mutation) is 100% identical to instant SEQ ID NO: 2.
In regard to Claim 85, Wong teaches that mutations can be introduced into the IL-15 domain that increase or decrease its ability to interact with the IL-15Rβγ chains and affect its biological activities (paragraph [0338]). For example, the N72D mutation is known to increase IL-15 biological activity 5 to 10-fold (paragraph [0338]). Alternatively, D8N and N65D mutations showed a significant decrease in IL-15 biological activity (paragraph [0338]). IL-15 substitutions known to decrease activity such as N65D, D8N, I6S, D8A, D61A, N65A, N72R, V104P or Q108A are of particular interest because they are expected to provide better therapeutic activity and lower toxicity by optimizing the therapeutic index of IL-15 (paragraph [0346]).
Wong fails to teach wherein the fusion protein is a heterodimer comprising first and second Fc domains comprising the amino acid substitutions S267K/L368D/K370S : S267K/S364K/E357Q (Claim 29), wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D (Claim 82), and wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising G236R/L328R (Claim 83).
However, Moore teaches that for some therapeutic applications it is desirable to reduce or remove the normal binding of the Fc domain to the Fcγ receptors to eliminate or significantly reduce antigen-dependent cellular cytotoxicity (ADCC) activity (paragraph [00209]). A number of known substitutions can be made in one or both Fc domains to disrupt Fcγ receptor binding including S267K and/or G236R/L328R (paragraph [00209] and Fig. 31). The mutations ablate FcyR binding but generally not FcRn binding (paragraph [00209]).
Moore further teaches that heterodimeric mutations can be made in the Fc domains to skew the formation of dimers in certain orientations, increase stability, and promote self-assembly in cells (paragraphs [00142] and [00189]-[00194]). The mutations can comprise L368D/K370S in a first Fc domain and S364K/E357Q in a second Fc domain (paragraph [00194]). Moore also teaches mutations in the Fc domain that lower the isoelectric point (pI) which cause increased serum half-life and aid in purification (paragraph [00185]). A first Fc domain can comprise the mutations N208D/Q295E/N384D/Q418E/N421D to lower the pI of the Fc domain (Figure 30). Any of the Fc ablation variants, heterodimerization variants, and pI variants can be combined (paragraph [00212]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the Fc domain mutations taught by Moore to the IL-15 fusion protein taught by Wong. Wong specifically teaches that the IL-15/IL-15RαSu complex is linked to an Fc domain to extend the circulating half-life of the fusion protein. One of ordinary skill can appreciate that the Fc domain extends a protein’s half-life by binding the neonatal Fc receptor (FcRn) and binding other receptors such as Fcγ to stimulate ADCC is an off-target, unintended effect of the Fc domain in this therapeutic setting. The Fc domain mutations taught by Moore are understood to (1) disrupt Fcγ receptor binding but not FcRn binding which reduces off-target effects; (2) promote stable heterodimer formation that can be self-assembled in cells; and (3) lower the pI which causes increased serum half-life and aids in purification. Further, Moore specifically teaches that these known beneficial Fc domain mutations can be combined with one another. Thus, one of ordinary skill would have recognized that applying the known Fc mutations to the known IL-15 fusion protein would have yielded predictable results and resulted in an improved therapeutic protein.
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.
1. Claims 29 and 84-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7 of U.S. Patent No. 11,377,477.
The instant claims recite a heterodimeric protein comprising (1) a IL-15RαSu linked to the N-terminus of a first Fc domain wherein the IL-15Rα is bound to IL-15 and (2) a second Fc domain wherein the first and second Fc domains comprise the mutations L368D/K370S:S364K/E357Q (Claim 29). Dependent claims recite wherein the IL-15 is human wild-type IL-15 (SEQ ID NO: 1 is full-length and SEQ ID NO: 2 is truncated) and the IL-15Rα is human wild-type IL-15Rα (SEQ ID NO: 3 is full-length and SEQ ID NO: 4 is sushi domain) (Claim 84) and the IL-15 comprises one or more amino acid substitutions selected from D8N or N65D (Claim 85).
The patented claims recite a IL-15/Rα heterodimeric Fc fusion protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). Dependent claims recite: wherein the IL-15 protein comprises the amino acid substitutions D8N or N65D (Claim 5) and wherein the first and second Fc domains comprise the mutations L368D/K370S:S364K/E357Q (Claim 7).
The patented claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
2. Claims 29 and 82-85 are rejected on the ground of obvious-type nonstatutory double patenting as being unpatentable over claim 8 of U.S. Patent No. 11,584,794 in view of Moore WO 2016/086196.
Instant Claims 29 and 84-85 are recited above. Instant claims 82-83 recite wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D and G236R/L328R respectively.
The patented claims recite a heterodimeric protein comprising an IL-15Rα linked to the N-terminus of a first Fc domain and an IL-15 protein noncovalently attached to the IL-15Rα wherein the IL-15 protein comprises SEQ ID NO: 2 with the substitutions N4D/N65D (Claim 8). The heterodimeric protein further comprises a second Fc domain (Claim 8). Note, patented SEQ ID NO: 2 is 100% identical to instant SEQ ID NO: 2.
The patented claims do not teach wherein the first and second Fc domains comprise the amino acid substitutions L368D/K370S : S364K/E357Q (Claim 29), wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D (Claim 82), and wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising G236R/L328R (Claim 83).
However, Moore teaches that for some therapeutic applications it is desirable to reduce or remove the normal binding of the Fc domain to the Fcγ receptors to eliminate or significantly reduce antigen-dependent cellular cytotoxicity (ADCC) activity (paragraph [00209]). A number of known substitutions can be made in one or both Fc domains to disrupt Fcγ receptor binding including G236R/L328R (paragraph [00209] and Fig. 31). Moore teaches that heterodimeric mutations can be made in the Fc domains to skew the formation of dimers in certain orientations, increase stability, and promote self-assembly in cells (paragraphs [00142] and [00189]-[00194]) and can comprise L368D/K370S in a first Fc domain and S364K/E357Q in a second Fc domain (paragraph [00194]). Moore also teaches mutations in the Fc domain that lower the isoelectric point (pI) which cause increased serum half-life and aid in purification (paragraph [00185]). A first Fc domain can comprise the mutations N208D/Q295E/N384D/Q418E/N421D to lower the pI of the Fc domain (Figure 30). Any of the Fc ablation variants, heterodimerization variants, and pI variants can be combined (paragraph [00212]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the Fc domain mutations taught by Moore to the IL-15 fusion protein taught by the patented claims is order to favorably (1) disrupt Fcγ receptor binding but not FcRn binding which reduces off-target effects; (2) promote stable heterodimer formation that can be self-assembled in cells; and (3) lower the pI which cause increased serum half-life and aids in purification. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims in view of Moore.
3. Claims 29 and 82-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 5-6 of U.S. Patent No. 11,618,776.
The instant claims 29 and 82-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). The IL-15 comprises SEQ ID NO: 2 and one or more substitutions selected from D8N and N65D, and the first and second Fc domains comprise L368D/K370S:S364K/E357Q (Claim 1). Dependent claims recite: wherein the IL-15RαSu domain comprises SEQ ID NO: 4 (Claim 3) which is 100% identical to instant SEQ ID NO: 4; wherein the first and second Fc domains have additional amino acid substitutions comprising Q295E/N384D/Q418E/N421D and G236R/L328R (Claims 5 and 6 respectively).
The patented claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
4. Claims 29 and 82-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-7 of U.S. Patent No. 11,524,991.
The instant claims 29 and 82-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). The first and second Fc domains comprise L368D/K370S:S364K/E357Q (Claim 1). Dependent claims recite: wherein the first and second Fc domains have additional amino acid substitutions comprising Q295E/N384D/Q418E/N421D and G236R/L328R (Claims 2 and 3 respectively); wherein the IL-15 comprises SEQ ID NO: 2 and substitutions N4D/N65D (Claim 6); and wherein the IL-15RαSu domain comprises SEQ ID NO: 4 (Claim 7) which is 100% identical to instant SEQ ID NO: 4.
The patented claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
5. Claims 29 and 82-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 11,505,595.
The instant claims 29 and 82-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). The first and second Fc domains comprise L368D/K370S:S364K/E357Q; Q295E/N384D/Q418E/N421D; and E233P/L234V/L235A/G236del/S267K (Claim 1). Dependent claims recite wherein the IL-15 comprises SEQ ID NO: 2 and substitutions selected from N4D and/or N65D (Claim 4).
The patented claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
6. Claims 29 and 82-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 10 of U.S. Patent No. 10,550,185.
The instant claims 29 and 82-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). The first and second Fc domains comprise L368D/K370S:S364K/E357Q; Q295E/N384D/Q418E/N421D; and G236R/L328R (Claims 1-3 respectively). The IL-15 comprises SEQ ID NO: 2 and substitutions selected from N4D/N65D (Claim 1). The heterodimeric protein can have an alternative orientation wherein the IL-15RαSu is fused to the N-terminus of the first Fc domain with a linker and the IL-15 is noncovalently bound to the IL-15RαSu (Claim 10).
Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
7. Claims 29 and 83-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 7 of U.S. Patent No. 12,239,688.
The instant claims 29 and 83-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain and a first Fc domain, and a second monomer comprising, from N- to C-terminal, an IL-15 protein and a second Fc domain (Claim 1). The IL-15 comprises SEQ ID NO: 2 and substitutions N4D/N65D (Claim 1). Dependent claims recite: wherein the IL-15RαSu comprises SEQ ID NO: 4 (Claim 3) which is 100% identical to instant SEQ ID NO: 4; wherein the first and second Fc domains comprise L368D/K370S:S364K/E357Q (Claim 4); and wherein the first and second Fc domains comprise E233P/L234V/L235A/G236del/S267K (Claim 7).
The patented claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
8. Claims 29 and 82-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-6 of U.S. Patent No. 11,084,863.
The instant claims 29 and 82-85 are recited above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, an IL-15 protein, an IL-15Rα sushi domain, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 1). The first and second Fc domains comprise S267K/L368D/K370S : S267K/S364K/E357Q (Claim 1). The IL-15RαSu comprises SEQ ID NO: 4 and the IL-15 comprises SEQ ID NO: 2 (Claim 1) which are 100% identical to instant SEQ ID NOs: 4 and 2 respectively. The first and/or second Fc domains comprise Q295E/N384D/Q418E/N421D (Claim 2) and G236R/L328R (Claim 3). The IL-15 comprises substitutions N4D/N65D (Claims 5-6).
The patented claims teach all the components of the instant claims, just with IL-15 covalently bound to IL-15RαSu by a linker instead of noncovalently bound. This difference is not patentably distinct, and the instant claims are either anticipated and/or rendered obvious by the patented claims.
9. Claims 29 and 84-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,501,543.
Instant claims 29 and 84-85 are set forth above.
The patented claims recite a heterodimeric protein comprising a first monomer comprising SEQ ID NO: 1014 and a second monomer comprising SEQ ID NO: 1017 (Claim 1). SEQ ID NO: 1014 comprises in N- to C-terminal orientation a human IL-15 and an Fc domain wherein the IL-15 comprises substitutions D30N/E64Q/N65D and the Fc domain comprises substitutions S267K/L368D/K370S (as evidenced by Fig. 104AQ that defines the sequence). SEQ ID NO: 1017 comprises in N- to C-terminal orientation a IL-15RαSu and a second Fc domain wherein the Fc domain comprises substitutions S267K/S364K/E357Q (as evidenced by Fig. 104AQ that defines the sequence).
The patented claims teach all the components of the instant claims, just with the IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
10. Claims 29 and 84-85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,509,495.
Instant claims 29 and 84-85 are set forth above.
The patented claims recite a protein comprising a first monomer comprising SEQ ID NO: 367, a second monomer comprising SEQ ID NO: 368, and a third monomer comprising SEQ ID NO: 369 (Claim 1). SEQ ID NO: 367 comprises in N- to C-terminal orientation a human IL-15RαSu, a human IL-15, and an Fc domain wherein the IL-15 comprises substitutions D30N/E64Q/N65D and the Fc domain comprises substitutions S267K/L368D/K370S (as evidenced by Fig. 48C that defines the sequence). SEQ ID NO: 368 comprises a second Fc domain comprising substitutions S267K/S364K/E357Q (as evidenced by Fig. 48C that defines the sequence).
The patented claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the patented claims. Thus, the instant claims are either anticipated and/or rendered obvious by the patented claims.
11. Claims 29 and 82-85 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 4 of copending U.S. App. No. 19/010,767 in view of Moore WO 2016/086196.
The instant claims are set forth above.
The copending claim recites: a heterodimeric protein comprising (1) an IL-15 protein covalently attached to the N-terminus of a first Fc domain wherein the IL-15 protein comprises SEQ ID NO: 5 and (2) a IL-15Rα protein covalently attached to the N-terminus of a second Fc domain wherein the IL-15Rα comprises SEQ ID NO: 4 (Claim 4). Note, SEQ ID NO: 4 is 100% identical to instant SEQ ID NO: 4. SEQ ID NO: 5 is 100% identical to instant SEQ ID NO: 2 comprising mutations D30N/E64Q/N65D.
The copending claims do not teach wherein the first and second Fc domains comprise the amino acid substitutions L368D/K370S : S364K/E357Q (Claim 29), wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D (Claim 82), and wherein the first and/or second Fc domains have an additional set of amino acid substitutions comprising G236R/L328R (Claim 83).
However, Moore teaches that for some therapeutic applications it is desirable to reduce or remove the normal binding of the Fc domain to the Fcγ receptors to eliminate or significantly reduce antigen-dependent cellular cytotoxicity (ADCC) activity (paragraph [00209]). A number of known substitutions can be made in one or both Fc domains to disrupt Fcγ receptor binding including G236R/L328R (paragraph [00209] and Fig. 31). Moore teaches that heterodimeric mutations can be made in the Fc domains to skew the formation of dimers in certain orientations, increase stability, and promote self-assembly in cells (paragraphs [00142] and [00189]-[00194]) and can comprise L368D/K370S in a first Fc domain and S364K/E357Q in a second Fc domain (paragraph [00194]). Moore also teaches mutations in the Fc domain that lower the isoelectric point (pI) which cause increased serum half-life and aid in purification (paragraph [00185]). A first Fc domain can comprise the mutations N208D/Q295E/N384D/Q418E/N421D to lower the pI of the Fc domain (Figure 30). Any of the Fc ablation variants, heterodimerization variants, and pI variants can be combined (paragraph [00212]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the Fc domain mutations taught by Moore to the IL-15 fusion protein taught by the copending claims is order to favorably (1) disrupt Fcγ receptor binding but not FcRn binding which reduces off-target effects; (2) promote stable heterodimer formation that can be self-assembled in cells; and (3) lower the pI which cause increased serum half-life and aids in purification. Further, the copending claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Moore. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Claims 29 and 82-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 9, and 13-14 of copending U.S. App. No. 18/423,941.
The instant claims are set forth above.
The copending claim recites: a heterodimeric protein comprising (1) an IL-15 protein covalently attached to the N-terminus of a first Fc domain and (2) a IL-15Rα protein covalently attached to the N-terminus of a second Fc domain (Claim 1). Dependent claims recite: wherein the first and second Fc domains comprise E233P/L234V/L235A/G236del/S267K (Claim 6); wherein the first Fc domain comprises L368D/K370S and the second Fc domain comprises S364K/E357Q (Claim 7); the first and/or second Fc domain further comprise Q295E/N384D/Q418E/N421D (Claim 9); the IL-15 protein comprises SEQ ID NO: 5 (Claim 13); and the IL-15Rα comprises SEQ ID NO: 4 (Claim 14). Note, SEQ ID NO: 4 is 100% identical to instant SEQ ID NO: 4. SEQ ID NO: 5 is 100% identical to instant SEQ ID NO: 335 which is IL-15 comprising SEQ ID NO: 2 with mutations D30N/E64Q/N65D.
The copending claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 29 and 82-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14 and 19-21 of copending U.S. App. No. 17/965,593.
The instant claims are set forth above.
The copending claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain, an IL-15 protein, and a first Fc domain, and a second monomer comprising a second Fc domain (Claim 14). The IL-15 protein can comprise substitutions N4D and/or N65D (Claim 14). Dependent claims recite: wherein the first and second Fc domains comprise E233P/L234V/L235A/G236del/S267K (Claim 20); wherein the first Fc domain comprises L368D/K370S and the second Fc domain comprises S364K/E357Q (Claim 19); and the first Fc domain further comprise Q295E/N384D/Q418E/N421D (Claim 21).
The copending claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claims 29 and 83-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8, and 11 of copending U.S. App. No. 18/939,513.
Instant claims 29 and 83-85 are set forth above. Claim 86 recites wherein said fusion protein has a sequence of SEQ ID NO: 336, the second Fc domain has a sequence of SEQ ID NO: 339, and the second protein domain (IL-15) has a sequence of SEQ ID NO: 335. Note, “has a polypeptide sequence of SEQ ID NO: X” is interpreted as “comprises SEQ ID NO: X.”
The copending claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain and a first Fc domain, and a second monomer comprising, from N- to C-terminal, an IL-15 and a second Fc domain (Claim 1). The IL-15 protein can comprise SEQ ID NO: 2 with substitutions N4D/N65D (Claim 1). The first and second Fc domains comprise substitutions S267K/L368D/K370S : S267K/S364K/E357Q (Claim 1). Dependent claims recite: wherein the IL-15RαSu domain comprises SEQ ID NO: 4 (Claim 4) which is 100% identical to instant SEQ ID NO: 4; wherein the first and second Fc domains comprise E233P/L234V/L235A/G236del/S267K (Claim 8); and wherein the heterodimeric Fc fusion protein comprises the amino acid sequences of SEQ ID NOs: 204 and 205 (Claim 11). Note, SEQ ID NO: 204 comprises 100% identity to instant SEQ ID NOs: 335 and 336 (Fc portion from residues 66-296). SEQ ID NO: 205 comprises 100% identity to instant SEQ ID NOs: 339 and 336 (IL-15RαSu portion from residues 1-65).
The copending claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. Claims 29 and 83-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending U.S. App. No. 18/431,350.
Instant claims 29 and 83-85 are set forth above.
The copending claims recite a heterodimeric protein comprising a first monomer comprising, from N- to C-terminal, a IL-15Rα sushi domain and a first Fc domain, and a second monomer comprising, from N- to C-terminal, an IL-15 and a second Fc domain (Claim 3). The IL-15 protein can comprise SEQ ID NO: 5 (Claim 3) which is 100% identical to instant SEQ ID NO: 2 with mutations D30N/E64Q/N65D. The IL-15RαSu domain comprises SEQ ID NO: 4 (Claim 3) which is 100% identical to instant SEQ ID NO: 4. The first and second Fc domains comprise substitutions S267K/L368D/K370S : S267K/S364K/E357Q (Claim 3). The first and second Fc domains comprise E233P/L234V/L235A/G236del/S267K (Claim 3).
The copending claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Claims 29 and 84-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of copending U.S. App. No. 18/296,591.
Instant claims 29 and 84-85 are set forth above.
The copending claims recite a fusion protein comprising a first monomer comprising SEQ ID NO: 168, a second monomer comprising SEQ ID NO: 169, and a third monomer comprising SEQ ID NO: 170 (Claim 24). SEQ ID NO: 168 comprises in N- to C-terminal orientation a human IL-15RαSu, a human IL-15, and an Fc domain wherein the IL-15 comprises substitutions D30N/E64Q/N65D and the Fc domain comprises substitutions S267K/S364K/E357Q (as evidenced by copending Fig. 18A that defines the sequence). SEQ ID NO: 169 comprises a second Fc domain comprising substitutions S267K/L368D/K370S (as evidenced by copending Fig. 18A that defines the sequence).
The copending claims teach all the components of the instant claims, just with IL-15RαSu N-terminal to the IL-15. Switching the order of two protein domains is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
17. Claims 29 and 84-85 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of copending U.S. App. No. 17/814,456.
Instant claims 29 and 84-85 are set forth above.
The copending claims recite a fusion protein comprising a first monomer comprising SEQ ID NO: 9 and a second monomer comprising SEQ ID NO: 10 (Claim 24). SEQ ID NO: 9 comprises in N- to C-terminal orientation a human IL-15 and an Fc domain wherein the IL-15 comprises substitutions D30N/E64Q/N65D and the Fc domain comprises substitutions S267K/L368D/K370S (as evidenced by copending Fig. 9 that defines the sequence). SEQ ID NO: 10 comprises in N- to C-terminal orientation a IL-15RαSu and a second Fc domain wherein the Fc domain comprises substitutions S267K/S364K/E357Q (as evidenced by copending Fig. 9 that defines the sequence).
The copending claims teach all the components of the instant claims, just with IL-15RαSu and the IL-15 on separate Fc domains. This difference is a matter of orientation and the instant claims are not patentably distinct from the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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, Jeffrey Stucker can be reached at (571) 272-0911. 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.
/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675