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
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 371 of PCT/CA21/50872 filed on 06/24/2021, which claims the benefit of US Provisional Application Nos 63/165,738 filed 03/24/2021; 63/165,600 filed 03/24/2021; 63/094,322 filed 10/20/2020; 63/093,724 filed 10/19/2020; and 63/043,227 filed 06/24/2020. All claims have been given an effective filing date of June 24, 2020.
Election/Restriction
Applicant's election without traverse of Group I (Claims 1, 3-22, and 31-32) in the reply filed on December 22, 2025 is acknowledged.
Applicant’s species election of:
F42A
Table 2, SEQ ID NO: 6, H9-F42A
SEQ ID NOs: 148 and 213, MDNA-132-Fc-MDNA109 (1:1:1 KIH)
IL-13
SEQ ID NO: 115 "C11," Table 8
Colon cancer
in the reply filed on December 22, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the species election requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 4-7, 9, and 23-30 are withdrawn from further consideration pursuant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 December 22, 2025.
Claim Status
Claim listing filed on June 22, 2023 is pending. Claim 2 is canceled. Claims 1, 3-10, 12-23, 26, and 29-32 are amended. Claims 4-7, 9, and 23-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 1, 3, 8, 10-22, and 31-32 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 08/24/2024, 10/18/2024, 12/10/2024, and 07/23/2025 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:
The table on page 133 is labeled “Table 38” and should be labeled “Table 14” as it is the 14th table to appear in the specification. All other tables following the table on page 133 will need to be relabeled accordingly (Table 14 on page 158 becomes “Table 15”; Table 15 on page 158 becomes “Table 16”; etc.).
The drawings show Figure 1A and 1B, but the brief description of the drawings only refers to Figure 1. MPEP § 608.01(f) states “If the drawings show Figures 1A, 1B, and 1C and the brief description of the drawings refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.” Therefore, the brief description of Figure 1 on page 6 needs to be amended to describe Figures 1A and 1B.
Appropriate correction is required.
The disclosure is objected to because the title at the top of the specification recites “USES AND METHODS FOR IL-2 BISPECIFIC CYTOKINE FUSIONS” which is not consistent with the title listed on the Application Data Sheet filed on December 21, 2022 which recites “BIFUNCTIONAL SUPERKINES AND USES THEREOF.” 37 C.F.R. 1.72 states “Unless the title is supplied in an application data sheet, the title of the invention should appear as a heading on the first page of the specification.” It is unclear which title is the intended title due to the inconsistency between the Application Data Sheet and the specification.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there is a hyperlink in each of paragraphs [0365] and [0375]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Sequence Compliance in Drawings
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825. Specifically, no sequence identification has been provided for the amino acid sequences presented in Figures 1A and 1B of the drawings. MPEP § 2412.04 states that where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a)), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a)) in the Brief Description is clear.
Should Applicant choose to correct the drawings, corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant is reminded to comply with sequence rules as stated in MPEP§ 2422 and review the specification to ensure the application is in full sequence compliance in response to this action.
Claim Objections
Claims 8, 16, 19, and 21 objected to because of the following informalities:
Claim 19 recites “IL2Rα” in lines 2 and 3 wherein all other recitations of IL-2 use a hyphen. For consistency, “IL2Rα” should recite “IL-2Rα” in Claim 19.
Claims 8, 16, and 21 reference tables and figures. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience" (see MPEP § 2173.05(s)). Therefore, instead of referencing tables and figures, the appropriate SEQ ID NOs should be listed in the claims.
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 17-20 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 17 recites “increased binding capacity”; Claim 18 recites “greater binding affinity”; Claim 19 recites “abrogated IL-2Rα” which is further defined by “i.e., does not significantly bind to IL-2Rα”; and Claim 20 recites “decreased binding affinity.” All of these phrases are considered indefinite relative terminology (MPEP § 2173.05(b)). It is clear that binding capacity and binding affinity can be quantified by means understood in the art prior to filing, and the increases and decreases are relative to wild-type human IL-2. However, it is unclear what threshold of change is encompassed by the claims. What level of increase is encompassed by Claims 17-18 (e.g. a 10% increase? a 20% increase? a statistically non-significant increase?). Similarly, what level of binding is encompassed by “does not significantly bind” in Claim 19 (emphasis added)? It is unclear what is considered “significant” binding. The binding affinities for wild-type IL-2 to IL-2Rβ and IL-2α are understood in the art (Wang et al. Annu. Rev. Immunol. 2009, page 38 paragraph 1). However, the value of the binding capacity for wild-type human IL-2 to IL-2Rβ is unclear (Claim 17). For these reasons, the metes and bounds of Claims 17-20 are unclear. The specification defines that in some embodiments the binding affinity or binding capacity can change by 2-fold and in other embodiments can change by 100-fold (paragraphs [00164]-[00165]). These non-limiting examples do not adequately define the claimed relative terminology and instead exemplify how vastly the subject matter can differ when no threshold of change is defined. Due to indefinite relative terminology, Claims 17-20 are rejected.
Note, Claims 17-20 are considered inherent functional properties of the IL-2 mutein structure defined in Claim 1 (MPEP § 2112.01). Claims 8 and 16 are interpreted wherein the IL-2 mutein and the second cytokine “comprise” the sequences listed in the recited tables. An “Fc antibody fragment” (Claims 10-12) is interpreted as the Fc domain of an antibody comprising two heavy chain constant domains (CH2 and CH3) as understood in the art. Further, the N297A substitution on the Fc domain (Claim 12) is understood in the art with the Kabat numbering scheme. Based on specification Table 12, “MDNA132-Fc-MDNA109 (1:1:1 KIH)” in Claim 22 is interpreted as a bispecific IL-2 cytokine fusion protein comprising SEQ ID NOs: 148 and 213.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 8, 10-20, and 31-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
In regard to Claims 1, 3, 8, and 14-20, Fidai teaches an IL-2 mutein that has increased and/or enhanced IL-2Rβ binding that comprises substitutions L80F, R81D, L85V, I86V, and I92F numbered in accordance with wild-type human IL-1 of SEQ ID NO: 2 (paragraph [00104]). Note, Fidai SEQ ID NO: 2 is 100% identical to instant SEQ ID NO: 2. The IL-2 mutein can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to a wild-type IL-13 or IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein can comprise SEQ ID NO: 6 which further comprises a F42A substitution (paragraphs [00102] and [00117]). Note, Fidai SEQ ID NO: 6 is 100% identical to instant SEQ ID NO: 6 and reads on instant Claim 8. The IL-13 mutein can comprise SEQ ID NO: 115 (paragraph [00152] and Table 7) wherein Fidai SEQ ID NO: 115 is 100% identical to instant SEQ ID NO: 115 and reads on instant Claim 16. Note, the IL-2 mutein comprising substitutions L80F, R81D, L85V, I86V, and I92F and fused to a second cytokine taught by Fidai anticipates the inherent functional properties of Claims 17-20 (see MPEP § 2112.01 and above claim interpretation under 112(b)).
In regard to Claims 10-13, Fidai teaches that the IL-2 mutein fusion protein can comprise a human Fc antibody fragment and the Fc antibody fragment can comprise a N297A substitution (paragraph [0014]). The IL-2 mutein fusion protein can comprise an albumin (paragraph [0014]).
In regard to Claims 31-32, Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, Claims 1, 3, 8, 10-20, and 31-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fidai.
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 1, 3, 8, 10-22, and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025) in view of Zhong et al. US 11,692,020 (effectively filed Nov. 2019).
The teachings of Fidai as they apply to Claims 1, 3, 8, 10-20, and 31-32 are outlined in the 102(a)(1) rejection above. Specifically, Fidai teaches an IL-2 mutein (SEQ ID NO: 6) fused to an IL-13 mutein (SEQ ID NO: 115) and a human Fc antibody fragment. Alternatively, the IL-2 mutein can comprise SEQ ID NO: 9 (paragraph [00121]) which is 100% identical to instant SEQ ID NO: 9. Fidai further teaches wherein the IL-2 mutein is linked to the Fc region via a linker peptide such as (GGGGS)n wherein n is an integer between 1 and 10 (paragraph [00128]). The Fc region can be an IgG1 region (paragraph [00126]) and comprise various substitutions known to disrupt the high affinity Fc receptor binding site (non-lytic) (paragraph [00129]) and/or “knob-in-hole” mutations (Table 5). Fidai fails to teach wherein the bispecific IL-2 cytokine fusion comprises SEQ ID NOs: 148 and 213 (Claims 21-22).
SEQ ID NO: 148 comprises:
Residues 1-113: SEQ ID NO: 115 (IL-13 mutein)
Residues 114-128: (GGGGS)3 linker
Residues 129-353: Human IgG1 Fc region comprising various point substitutions
Residues 354-374: (GGGGS)4 linker
Residues 375-507: SEQ ID NO: 9 (IL-2 mutein)
SEQ ID NO: 213 comprises:
Residues 1-227: Human IgG1 Fc region comprising various point substitutions
Therefore, the only aspects of SEQ ID NOs: 148 and 213 not anticipated by Fidai are the human IgG1 Fc regions comprising various point substitutions (residues 129-353 of SEQ ID NO: 148 and residues 1-227 of SEQ ID NO: 213).
Zhong teaches fusion proteins comprising first and second cytokine domains fused together by an Fc antibody fragment (col. 3 lines 10-16, col. 4 lines 19-58, Figs. 4-6). The Fc domain can be a human IgG1 Fc domain or a mutein thereof (col. 25 lines 19-25). The Fc domain can comprise a pair of chains in a knobs-in-holes configuration and can specifically comprise SEQ ID NOs: 120 and 121 (col. 25 lines 29-46). SEQ ID NO: 120 is 100% identical to instant residues 129-353 of SEQ ID NO: 148, and SEQ ID NO: 121 is 100% identical to instant SEQ ID NO: 213.
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 substitute the Fc antibody domains taught by Fidai with the specific Fc antibody domains taught by Zhong. Zhong specifically teaches Fc antibody domains (SEQ ID NOs: 120 and 121) that can be used to fuse two cytokines into one fusion protein. Fidai teaches fusion proteins comprising two cytokines and an Fc antibody domain. Therefore, it would be obvious to substitute the known Fc antibody domains of Zhong into the fusion proteins of Fidai with predictable results. The motivation to use the Fc regions of Zhong is because they are specifically taught to fuse two cytokines together to form a fusion protein that can be used in pharmaceutical applications (Zhong col. 61 lines 50-67) which is the same product and application taught by Fidai. It is obvious to substitute equivalents known for the same purpose (MPEP § 2144.06.II).
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 1, 3, 8, 10-20, and 31-32 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,404,497 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims recite a bispecific IL-2 cytokine fusion comprising an IL-2 mutein fused to a second cytokine, wherein the IL-2 mutein comprises L80F, R81D, L85V, I86V, and I92F substitutions (Claims 1 and 17-20). Dependent claims recite: wherein the IL-2 mutein further comprises F42A substitution (Claim 3); wherein the IL-2 mutein comprises SEQ ID NO: 6 (Claim 8); wherein the fusion protein comprises a human Fc antibody fragment comprising a N297A substitution (Claims 10-12); wherein the fusion protein further comprises albumin (Claim 13); wherein the second cytokine is IL-13 (Claims 14-15), specifically comprising SEQ ID NO: 115 (Claim 16); and a pharmaceutical composition comprising the fusion protein, an anti-PD-1 antibody or inhibitor, and a pharmaceutically acceptable carrier (Claims 31-32).
The patented claims recite a modified oncolytic virus vector that encodes an IL-4 receptor targeted cargo protein and an IL-2 mutein (Claim 1). The IL-4 receptor targeted cargo protein comprises SEQ ID NO: 35 which is an IL-13 mutein (Claims 2 and 6). The IL-2 mutein comprises L80F, R81D, L85V, I86V, I92F, and F42A (Claims 3-4). The IL-2 mutein comprises SEQ ID NO: 82 (Claim 5). Note, patented SEQ ID NO: 35 is 100% identical to instant SEQ ID NO: 115, and patented SEQ ID NO: 82 is 100% identical to instant SEQ ID NO: 6. A viral vector that encodes proteins anticipates the proteins.
The patented claims do not teach wherein the IL-13 mutein is fused to the IL-2 mutein (instant Claim 1), wherein the fusion protein comprises a human Fc antibody fragment comprising a N297A substitution (instant Claims 10-12); wherein the fusion protein further comprises albumin (instant Claim 13); or a pharmaceutical composition comprising the fusion protein, an anti-PD-1 antibody or inhibitor, and a pharmaceutically acceptable carrier (instant Claims 31-32).
Fidai teaches an IL-2 mutein comprising substitutions L80F, R81D, L85V, I86V, and I92F (paragraph [00104]) that can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to a wild-type IL-13 or IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein fusion protein can comprise a human Fc antibody fragment and the Fc antibody fragment can comprise a N297A substitution (paragraph [0014]). The IL-2 mutein fusion protein can comprise an albumin (paragraph [0014]). Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to formulate the IL-13 mutein and the IL-2 mutein taught by the patented claims as a fusion protein with an Fc antibody domain. Fidai teaches that the motivation to formulate the two cytokine muteins as a fusion protein is to specifically target cancer cells as well as the immunosuppressive cells in the tumor microenvironment (paragraph [00151]). Thus, the instant claims are either anticipated and/or rendered obvious by the Patented claims in view of Fidai.
2. Claims 1, 3, 8, 10-20, and 31-32 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1 and 4-8 of U.S. Patent No. 11,542,312 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims are recited above.
The patented claims recite a method of treating cancer by administering an anti-PD-1 antibody and an IL-2 mutein comprising SEQ ID NO: 9 wherein SEQ ID NO: 9 comprises substitutions L80F, R81D, L85V, I86V, I92F, F42A, and E62A (Claim 1); the IL-2 mutein is a fusion protein (Claim 4); the fusion protein comprises the IL-2 mutein linked to an Fc antibody fragment (Claim 5); the Fc antibody fragment is human or comprises a N297A substitution (Claims 6-7); the fusion protein comprises said IL-2 mutein linked to an albumin (Claim 8). Note, instant SEQ ID NO: 6 is IL-2 comprising substitutions L80F, R81D, L85V, I86V, I92F, and F42A. Patented claim 1 reads on a pharmaceutical composition comprising an IL-2 mutein fusion protein, an anti-PD-1 antibody, and a pharmaceutically acceptable excipient by teaching a combination treatment that is pharmaceutically administered.
The patented claims do not teach wherein IL-13 is fused to the IL-2 mutein (instant Claims 1 and 14-15) or wherein the IL-13 is a mutein comprising SEQ ID NO: 115 (Claim 16).
Fidai teaches an IL-2 mutein comprising substitutions L80F, R81D, L85V, I86V, and I92F (paragraph [00104]) that can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to a wild-type IL-13 or IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein can further comprise substitutions F42A and/or E62A (paragraphs [00117]) and [00121]). The IL-13 mutein can comprise SEQ ID NO: 115 (paragraph [00152] and Table 7) wherein Fidai SEQ ID NO: 115 is 100% identical to instant SEQ ID NO: 115. The IL-2 mutein fusion protein can be administered in combination with an anti-PD-1 antibody to treat cancer (paragraphs [00307]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to adapt the method of treatment taught by the patented claims to comprise an IL-2 mutein fusion specifically comprising an IL-13 mutein as taught by Fidai. Fidai teaches that the motivation to formulate the IL-2 mutein as a fusion protein with an IL-13 mutein is to specifically target cancer cells as well as the immunosuppressive cells in the tumor microenvironment (paragraph [00151]). Thus, the instant claims are either anticipated and/or rendered obvious by the Patented claims in view of Fidai.
3. Claims 1, 3, 8, 10-20, and 31-32 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 10 of U.S. Patent No. 12,338,269 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims are recited above.
The patented claims recite a nucleic acid encoding a fusion protein wherein the fusion protein comprises an IL-2 mutein comprising SEQ ID NO: 9 linked to a heterologous polypeptide (Claim 1); the IL-2 mutein is linked to an Fc antibody fragment (Claim 4); the Fc antibody fragment is human and comprises a N297A substitution (Claims 5-6); and the IL-2 mutein is linked to an albumin (Claim 10). Note, patented SEQ ID NO: 9 is IL-2 comprising substitutions L80F, R81D, L85V, I86V, I92F, F42A, and E62A. A nucleic acid encoding a fusion protein anticipates the fusion protein.
The patented claims do not teach wherein IL-13 is fused to the IL-2 mutein (instant Claims 1 and 14-15); wherein the IL-13 is a mutein comprising SEQ ID NO: 115 (Claim 16); or a pharmaceutical composition comprising the fusion protein, an anti-PD-1 antibody or inhibitor, and a pharmaceutically acceptable carrier (instant Claims 31-32).
Fidai teaches an IL-2 mutein comprising substitutions L80F, R81D, L85V, I86V, and I92F (paragraph [00104]) that can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to a wild-type IL-13 or IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein can further comprise substitutions F42A and/or E62A (paragraphs [00117]) and [00121]). The IL-13 mutein can comprise SEQ ID NO: 115 (paragraph [00152] and Table 7) wherein Fidai SEQ ID NO: 115 is 100% identical to instant SEQ ID NO: 115. The IL-2 mutein fusion protein can be administered in combination with an anti-PD-1 antibody to treat cancer (paragraphs [00307]). Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to adapt the IL-2 mutein fusion protein taught by the patented claims to comprise an IL-2 mutein fusion specifically comprising an IL-13 mutein as taught by Fidai. Fidai teaches that the motivation to formulate the IL-2 mutein as a fusion protein with an IL-13 mutein is to specifically target cancer cells as well as the immunosuppressive cells in the tumor microenvironment (paragraph [00151]). Thus, the instant claims are either anticipated and/or rendered obvious by the Patented claims in view of Fidai.
4. Claims 1, 3, 8, 10-20, and 31-32 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 9-10, 12-13, and 16-17 of copending U.S. App. No. 19/110,294 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims are set forth above.
The copending claims recite: an IL-2 mutein comprising L80F, R81D, L85V, I86V, I92F, and F42A (Claims 1-3); wherein the IL-2 mutein is fused to an albumin, an Fc molecule, and/or another mutein, optionally wherein the other mutein is an IL-13 mutein (Claims 9-10 and 12); wherein the IL-2 mutein is fused to an Fc molecule and an IL-13 mutein (Claim 13); and wherein the IL-2 mutein has increased binding to CD122 and decreased binding to CD25 compared to wild-type IL-2 (Claims 16-17). Note, instant SEQ ID NO: 6 is IL-2 comprising substitutions L80F, R81D, L85V, I86V, I92F, and F42A.
The copending claims do not teach wherein the Fc molecule is a human Fc antibody fragment that comprises a N297A mutation (Claims 11-12); wherein the IL-13 mutein comprises SEQ ID NO: 115 (Claim 16); or a pharmaceutical composition comprising the fusion protein, an anti-PD-1 antibody or inhibitor, and a pharmaceutically acceptable carrier (instant Claims 31-32).
Fidai teaches an IL-2 mutein comprising substitutions L80F, R81D, L85V, I86V, and I92F (paragraph [00104]) that can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to a wild-type IL-13 or IL-13 mutein (paragraphs [00151]-[00152]). The IL-13 mutein can comprise SEQ ID NO: 115 (paragraph [00152] and Table 7) wherein Fidai SEQ ID NO: 115 is 100% identical to instant SEQ ID NO: 115. The IL-2 mutein fusion protein can comprise a human Fc antibody fragment comprising a N297A substitution (paragraph [0014]). Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to substitute the generic IL-13 mutein and Fc domain taught by the copending claims to specifically comprise SEQ ID NO: 115 and a human Fc domain comprising N297A, respectively, as taught by Fidai. Both the copending claims and Fidai teach a fusion protein comprising an IL-2 mutein, an IL-13 mutein, and an Fc domain. It would be obvious to use the specific sequences taught by Fidai in the fusion protein of the copening claims. One of ordinary skill would be motivated to use the known amino acid sequences to physically make the fusion protein described by the copending claims. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Fidai. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
5. Claims 1, 3, 8, 10-20, and 31-32 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 22, 25, 31, and 33-34 of copending U.S. App. No. 19/474,659 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims are set forth above.
The copending claims recite: a composition comprising an IL-13 mutein and an immunomodulatory agent (Claim 22); wherein the IL-13 mutein comprises SEQ ID NO: 89 (Claim 25); wherein the immunomodulatory agent is an IL-2 mutein or IL-2 mutein fusion protein (Claim 31); wherein the IL-2 mutein comprises SEQ ID NO: 2 (Claim 33); and wherein the IL-2 mutein fusion protein comprises SEQ ID NO: 31 which comprises a human Fc domain comprising a N297A substitution (Claim 34). Copending SEQ ID NOs: 89 and 2 are 100% identical to instant SEQ ID NOs: 115 and 6, respectively.
The copending claims do not teach wherein the IL-13 mutein is fused to the IL-2 mutein or IL-2 mutein fusion protein (instant Claims 1 and 14-15); wherein the fusion protein comprises albumin (Claim 13); and a pharmaceutical composition comprising the fusion protein, an anti-PD-1 antibody or inhibitor, and a pharmaceutically acceptable carrier (instant Claims 31-32).
Fidai teaches an IL-2 mutein that can be formatted as a fusion protein (paragraph [0014]) and can specifically be fused to an IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein fusion protein can comprise an albumin (paragraph [0014]). Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to formulate the IL-13 mutein and the IL-2 mutein (with or without the Fc domain) taught by the copending claims as a fusion protein. Fidai teaches that the motivation to formulate the two cytokine muteins as a fusion protein is to specifically target cancer cells as well as the immunosuppressive cells in the tumor microenvironment (paragraph [00151]). Further, administering one fusion protein is practically simpler than administering two separate cytokines. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Fidai. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
6. Claims 1, 3, 8, 10-20, and 31-32 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 5, 7, 10, and 24 of copending U.S. App. No. 19/496,152 in view of Fidai WO 2018/234862 (of record in the restriction filed 10/20/2025).
The instant claims are set forth above.
The copending claims recite: an IL-2 cytokine fusion protein comprising an IL-2 mutein and an IL-2 masking moiety (Claim 1) wherein the masking moiety comprises an IL-13 mutein (Claim 2); the IL-13 mutein comprises SEQ ID NO: 216 (Claims 3 and 5); the IL-2 mutein comprises SEQ ID NO: 6 (Claim 7); the IL-2 moiety further comprises an albumin or an Fc domain (Claim 10); and a pharmaceutical composition comprising the IL-2 cytokine fusion protein and a pharmaceutically acceptable carrier (Claim 24). Copending SEQ ID NOs: 216 and 6 are 100% identical to instant SEQ ID NOs: 115 and 6, respectively.
The copending claims do not teach wherein the Fc domain is a human Fc antibody fragment that comprises a N297A mutation (Claims 11-12) or wherein the pharmaceutical composition further comprises an anti-PD-1 antibody or inhibitor (instant Claim 32).
Fidai teaches a fusion protein comprising an IL-2 mutein (paragraph [0014]) fused to a an IL-13 mutein (paragraphs [00151]-[00152]). The IL-2 mutein fusion protein can comprise a human Fc antibody fragment comprising a N297A substitution (paragraph [0014]). Fidai teaches a pharmaceutical composition comprising the IL-2 mutein fusion protein and a pharmaceutically acceptable carrier (paragraph [0018]). The pharmaceutical composition can further comprise an anti-PD-1 antibody or inhibitor (paragraph [0019]).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the IL-2 mutein and IL-13 mutein fusion protein taught by the copending claims to specifically comprise a N297A mutation in the Fc domain and to be combined with an anti-PD-1 antibody as taught by Fidai. The N297A Fc domain substitution is well understood in the art to reduce off-target immune effects. It would be obvious to one of ordinary skill to apply this known mutation to the fusion protein of the copending claims, especially because Fidai teaches that the substitution is compatible with IL-2 mutein and IL-13 mutein fusion proteins. Fidai also makes obvious combining the fusion protein with an anti-PD-1 antibody, resulting in a pharmaceutical composition that has applications in treating cancer. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Fidai. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Note, no provisional double patenting rejection is made in view of U.S. App. Nos. 18/840,261 and 19/212,027 because the copending claims are directed to an IL-2 mutein fused to an anti-PD-1 antibody, and it is unclear if further appending a second cytokine would alter the function of the anti-PD1/IL-2 mutein fusion protein. Therefore, the copending claims are patentably distinct from the instant claims.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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