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 .
Claim Status
Claim listing filed on February 6, 2026 is pending. Claims 1-2, 4, 7-8, 21, and 24-25 are amended. Claims 10-20 and 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 1-9, 21, and 24-26 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 11/28/2025 and 12/24/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Objections and Rejections
The amendments to the specification and claims overcome all objections of record, and the specification objections and claim objections are withdrawn.
The rejection of Claims 1, 2-4, 7, 9, 21, and 25 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. In particular, Claim 1 no longer recites the indefinite phrase “a mutation at the binding interface of IL-2 to IL-2Rβγ that weakens the binding to an IL-2Rβγ receptor,” and Claims 2 and 25 no longer recite the indefinite term “preferably.”
The rejection of Claims 25-26 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. In particular, Claim 25 is no longer directed to a genus of possible B’C’ loop regions as it recites “substituting aa73 to aa83 in the B’C’ loop region with the sequence AGDASIH.” The residues 73 to 83 are interpreted in alignment with mature human wild-type IL-2 (instant SEQ ID NO: 3) and equivalents thereof. For example, it would be clear to one of ordinary skill that residues 73 to 83 of instant SEQ ID NO: 3 correspond to residues 93 to 103 of the full-length native human IL-2 sequence comprising a signal peptide (instant SEQ ID NO: 2).
The rejection of Claim 21 under 35 U.S.C. 102(a)(1) as being anticipated by Gavin WO 2014/153111 is withdrawn in view of Applicant’s amendments. Gavin fails to teach wherein the IL-2-Fc dimer protein comprises the IL-2 mutant protein of Claim 1 as required by amended Claim 21.
The provisional rejection of Claims 25-26 on the ground of nonstatutory double patenting as being unpatentable over claim 30 of App. No. 17/059,539 is withdrawn in view of Applicant’s amendments. Note, U.S. App. No. 17/059,539 was published as US Patent No. 12,551,531 on February 17, 2026. Amended Claims 25-26 are directed to a B’C’ loop region of AGDASIH which is not taught by the patented claims.
Claim Objections (New, necessitated by amendment)
Claim 25 is objected to because of the following informalities: Claim 25 requires a period at the end of the sentence. Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claim 24 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 is maintained.
It is of record in the non-final office action filed 11/06/2025 that the metes and bounds of what is encompassed by the “binding interface of IL-2 to IL-2Rβγ” is unclear. Specifically, the specification defines that “in some embodiments” the binding interface comprises residues 12-20, 84-95, and 126 (page 8) which means that in other embodiments, the mutations fall outside of these residues. Because Claim 24 recites “introducing one or more mutations into a binding interface of IL-2 to IL-2Rβγ” without further defining specific residues, mutations, or sequences, the indefiniteness is maintained.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive. Applicant argues that Claim 24 has been amended to address the Examiner’s rejections, but the claim still recites “mutations into a binding interface of IL-2 to IL-2Rβγ” which is indefinite for the reasons outlined above and of record.
The rejection of Claims 1-9, 21, and 24 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to a mutant IL-2 protein having at least 85% identity to wild-type IL-2 wherein the wild-type IL-2 comprises a sequence of SEQ ID NOs: 1, 2, or 3. SEQ ID NOs: 1 and 3 comprise 133 amino acid residues, and SEQ ID NO: 2 comprises 153 amino acid residues. 15% variation in these sequences means that 19 amino acids of SEQ ID NOs: 1 and 3 can be added, deleted, or substituted in any combination. Further, 22 amino acids of SEQ ID NO: 2 can be added, deleted, or substituted in any combination. Claim 1 defines wherein residues 73 to 83 are replaced with a 7 amino acid defined sequence and wherein the IL-2Rβγ binding interface mutation comprises 1-2 substitutions. These limitations account for variation in up to 13 amino acid residues. That leaves 6 to 9 amino acid residues that can be added, deleted, or substituted in any combination with no guidance on how possible amino acid variations affect protein function. Thus, independent Claim 1 is still directed to a genus of possible IL-2 mutant proteins. Similarly, Claim 8 is directed to a genus of IL-2 mutant proteins comprising at least 90% sequence identity to SEQ ID NOs: 148, 197, 489, or 513. Further, Claim 24 is directed to a method for obtaining an IL-2 mutant protein comprising introducing one or more mutations into a binding interface of IL-2 to IL-2Rβγ. Because the specification does not clearly define the binding interface, this limitation encompasses any number of mutations that could occur at any residue.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive.
Applicant argues that proper written description for the B’C’ loop region AGDASIH is provided in Table 6 in addition to the 5 species of B’C’ loops that Examiner acknowledges have proper written description (SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH; of record). Examiner finds the supporting data in Table 6 persuasive and agrees that there is proper written description for six species of B’C’ loop region (AGDASIH, SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH) that are understood to improve molecule expression yield and purity.
Applicant argues that “weakened IL-2Rβγ binding” is defined as relative to the corresponding IL-2 protein before introduction of the IL-2Rβγ binding-interface mutation, so the appropriate control molecule is Y144 – not wild-type IL-2 as Examiner had previously considered. Examiner finds this persuasive and in light of Table 9 and Figure 6 of the specification and page 16 of Applicant remarks, Examiner agrees that there is proper written description for the specific IL-2Rβγ binding interface mutations listed in Claim 1 (D20N, D84E, D84N, D84N+E95Q, D84N+Q126E, D84N+V91I, D84Q, D84T, D84T+H16T, D84T+Q126E, E15Q, E95N, E95Q, H16N, H16N+D84N, H16T, H16T+D84Q, H16T+V91I, N88D, N88R, N88Q, N88T, Q126E and V91I). Note, the E95Q mutation displayed reduced binding affinity to IL-2Rβ and was not evaluated for IL-2Rβγ, but it is reasonable for one of ordinary skill to understand that IL-2Rβ and Il-2Rγ bind in a cooperative manner, so reduced binding to IL-2Rβ will disrupt IL-2Rβγ binding with a reasonable expectation of success. Similarly, the mutation N88R showed reduced IL-2Rβγ binding in molecule 3082 which is not a direct comparison to the Y144 control, but given that other mutations at residue N88 consistently reduced IL-2Rβγ binding as compared to the proper Y144 control, one of ordinary skill would understand that N88R would disrupt IL-2Rβγ binding with a reasonable expectation of success. Therefore, Examiner agrees that there is proper written description for the specific IL-2Rβγ binding interface mutations listed in Claim 1.
Applicant argues that ordinarily skilled artisans would reasonably conclude that Applicant possessed the claimed invention on the basis of the explicit mutation descriptions. Examiner disagrees. While there is proper written description for the six species of B’C’ loop region defined in Claim 1 and the specific IL-2Rβγ binding interface mutations listed in Claim 1, Claim 1 encompasses further amino acid variation by reciting “at least 85%” identity to the wild-type IL-2. As outlined above, that leaves 6 to 9 amino acid residues that can be added, deleted, or substituted in any combination in addition to the defined mutations with no guidance provided in the specification. To overcome the written description rejection of record, Claim 1 could recite wherein the mutant IL-2 comprises SEQ ID NOs: 1, 2, or 3; and further comprises a shortened B’C’ loop region selected from the group consisting of AGDASIH, SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH between residues aa72 and aa84; and further comprises an IL-2Rβγ binding interface mutation selected from the group consisting of D20N, D84E, D84N, D84N+E95Q, D84N+Q126E, D84N+V91I, D84Q, D84T, D84T+H16T, D84T+Q126E, E15Q, E95N, E95Q, H16N, H16N+D84N, H16T, H16T+D84Q, H16T+V91I, N88D, N88R, N88Q, N88T, Q126E and V91I; wherein the amino acid positions are numbered according to SEQ ID NO: 1. This potential claim language would define the wild-type sequences and the specific mutations for which the specification provides proper written description and would remove the variation in sequence identity which is not supported by the specification. Claim 24 could potentially be amended to recite the specific IL-2Rβγ binding interface mutations as defined in Claim 1. Because the claims are still directed to a genus of possible IL-2 mutant proteins that lack proper written description, the rejection is maintained.
The rejection of Claims 1-9, 21, and 24 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification, while being enabling for the IL-2Rβγ binding interface mutations and B’C’ loop regions defined in Claim 1, does not reasonably provide enablement for the genus of IL-2 mutant proteins comprising at least 85% sequence identity to SEQ ID NOs: 1, 2, or 3 (Claim 1). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is explained in detail in the written description rejection above how Claims 1, 8, and 24 are directed to a genus of possible IL-2 mutant proteins with substantial structural variation.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive.
Applicant argues that the amended claims recite specific mutations, and the claimed invention can be practiced by one of ordinary skill in the art. Examiner agrees that there is proper enablement for the six species of shortened B’C’ loop region recited in Claim 1 (AGDASIH, SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH) and the specific IL-2Rβγ binding interface mutation recited in Claim 1 (D20N, D84E, D84N, D84N+E95Q, D84N+Q126E, D84N+V91I, D84Q, D84T, D84T+H16T, D84T+Q126E, E15Q, E95N, E95Q, H16N, H16N+D84N, H16T, H16T+D84Q, H16T+V91I, N88D, N88R, N88Q, N88T, Q126E and V91I). However, the specification provides no guidance for how 6 to 9 amino acid residues can be added, deleted, or substituted in any combination (in addition to the defined B’C’ loop regions and specific IL-2Rβγ binding interface mutations) such that the intended function of the IL-2 mutant proteins is maintained. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the thousands of IL-2 mutants encompassed by the claims (specifically varying amino acids in addition to the defined B’C’ loop regions and specific IL-2Rβγ binding interface mutations) and screen their characteristics in order to practice the invention commensurate with the scope of the claims. Further, the genus of IL-2 mutant proteins in Claim 24 is even broader as the method comprises “introducing one or more mutations into a binding interface of IL-2 to IL-2Rβγ” which encompasses any number of mutations that could occur at any residue. Therefore, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Applicant’s arguments have been considered, and the rejection is maintained.
Double Patenting (Maintained)
1. The provisional rejection of Claims 25-26 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 20 of copending U.S. App. No. 17/911,922 is maintained.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive. Applicant argues that the cited patent does not claim the IL-2 mutant proteins defined in the present claims. However, both the copending claims and the instant claims are directed to a method for engineering a B’C’ loop region of an IL-2 protein by substituting aa73 to aa83 with the sequence AGDASIH and the resulting mutant IL-2 protein thereof. Applicant’s arguments are not persuasive, and the rejection is maintained.
2. The provisional rejection of Claims 1-2, 4-9, 21, and 24-26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 17 of copending U.S. App. No. 18/693,453 is maintained.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive. Applicant argues that the cited patent does not claim the IL-2 mutant proteins defined in the present claims. However, both the copending claims and the instant claims are directed to an IL-2 mutant comprising a N88D mutation and a shortened B’C’ loop region sequence AGDASIH at positions 73-83. Note, copending SEQ ID NO: 4 is 100% identical to instant SEQ ID NO: 513. Applicant’s arguments are not persuasive, and the rejection is maintained.
3. The provisional rejection of Claims 1-2, 4-6, 8-9, 21, and 24-26 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of copending U.S. App. No. 19/166,754 is maintained.
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive. Applicant argues that the cited patent does not claim the IL-2 mutant proteins defined in the present claims. However, both the copending claims and the instant claims are directed to an IL-2 mutant comprising a N88R mutation and a shortened B’C’ loop region sequence AGDASIH. Note, copending SEQ ID NO: 4 is 98% identical to instant SEQ ID NO: 513. Applicant’s arguments are not persuasive, and the rejection is maintained.
Double Patenting (New, necessitated by amendment)
4. Claims 1-2, 4, 6, 8-9, 21, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22-26 and 39 of copending U.S. App. No. 19/376,374. Note, the previous double patenting search was performed on 10/30/2025 (as documented in the search report filed 11/06/2025), and U.S. App. No. 19/376,374 was filed 10/31/2025. Therefore, the new provisional nonstatutory double patenting rejection is a result of a newly submitted copending application.
The instant claims are of record.
The copending claims are directed to an immunoconjugate comprising an anti-PD-1 antibody and an IL-2 mutant wherein the IL-2 mutant comprises a N88R mutation and deletion of amino acids from positions 73 to 83 and replacement with an amino acid sequence of AGDASIH or AQSKNFH (Claims 22-24). The IL-2 mutant comprises the amino acid sequence set forth in SEQ ID NOs: 23 or 25 (Claims 25-26). A pharmaceutical composition comprising an immunoconjugate comprising an anti-PD-1 antibody fused to an IL-2 mutant wherein the IL-2 mutant comprises SEQ ID NO: 25 (Claim 39). Note, copending SEQ ID NOs: 23 and 25 are 98.8% and 98% identical to instant SEQ ID NO: 513, respectively.
Thus, the copending claims either anticipate and/or render obvious the instant 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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