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
Newly amended Claim 36 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 21, 2025.
Claim Status
Claim listing filed on August 19, 2025 is pending. Claims 1-34, 38, 40-51, and 54 are canceled. Claims 35-37 and 39 are amended. Claims 36 and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 35, 37, 39, and 52 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 42-43 and 51 have rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the claims have overcome the claim objections of record, and the claim objections are withdrawn.
The rejection of claims 35, 37, 39, and 52 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments to Claim 35. The claims are no longer directed to indefinite relative terminology or functional language.
The rejection of claims 37 and 39 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. Claim 37 recites wherein the IL-2 variant consists of a specific amino acid sequence, and Claim 39 recites wherein the fusion protein consists of a specific amino acid sequence, so the claims are no longer directed to a genus of fusion proteins. Note, “an IL-6R antibody” as defined in Claim 35 has proper written description and enablement because the anti-IL-6R antibody tocilizumab was known in the art prior to filing as evidenced by Sheng-Xiao et al., Annals of the Rheumatic Diseases 2017 (of record).
The rejection of Claims 35 and 52 under 35 U.S.C. 103 as being unpatentable over Gillies US 2003/0166163, and further in view of Sheng-Xiao et al., Annals of the Rheumatic Diseases 2017 is withdrawn in view of Applicant’s amendments. Gillies and Sheng-Xiao fail to teach wherein the IL-2 variant comprises the mutations D20Q and S125I which is a limitation of amended Claim 35.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 35 and 52 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 and enablement requirements is maintained. Note, the original 112(a) written description and enablement rejections applied to Claims 35-37, 39, 42-43, and 51-52, and now apply to Clams 35 and 52 due to Applicant’s amendments.
Claim 35 recites “wherein said IL-2 variant polypeptide is selected from the group consisting of an IL-2 variant polypeptide consisting of the amino acid sequence as set forth in SEQ ID NO: 3 having the amino acid substitutions L19H, S125I and Q126E and an IL-2 variant polypeptide consisting of the amino acid sequence as set forth in SEQ ID NO: 3 having the amino acid substitutions D20Q and S125I” (emphasis added). An amino acid sequence “as set forth in” SEQ ID NO: 3 encompasses any fragment of two or more amino acid residues within the recited sequence. Due to the language “as set forth in”, Claims 35 and 52 are still directed to a genus of possible IL-2 variants. Alternative claim language could recite “the amino acid sequence of SEQ ID NO: 3 having the amino acid substitutions…” This alternative claim language directs Claim 35 to two specific IL-2 variants which would overcome the 112(a) rejections of record.
Claim Rejections - 35 USC § 103 (Maintained)
Claims 35, 37, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Gillies US 2003/0166163 (of record) in view of Sheng-Xiao et al., Annals of the Rheumatic Diseases 2017 (of record), and further in view of Klein WO 2015/118016 A1 (of record) and Shanafelt US 6,955,807 (of record). Note, the original rejection applied to Claims 35-37, 39, 42-43, and 51-52, and now applies to Claims 35, 37, and 52 due to Applicant’s amendments.
Based on the teachings of Gillies, Sheng-Xiao, Klein, and Shanafelt, it would have been obvious to one of ordinary skill in the art before the effective filing date to make an isolated fusion protein comprising an IL-2 variant consisting of SEQ ID NO: 3 having the mutations D20Q and S125I fused to the anti-IL-6R antibody tocilizumab (of record).
Applicant's arguments filed August 19, 2025 have been fully considered but they are not persuasive.
Applicant directs Examiner to Examples 16 and 17 in the specification and states that the claimed fusion proteins exhibit enhanced Treg cell selectivity over alternative constructs, and these unexpected and beneficial effects were not taught or suggested by Gillies, Sheng-Xiao, or any other prior art. The fusion proteins comprising tocilizumab and IL-2 having D20Q/S125I mutations are termed P-0559 and P-0560 in the specification (Table 8). Example 16 teaches that P-0559 and P-0569 demonstrate selective activation of Treg cells over CD4+ Tconv cells in vitro (paragraph [0292] and Figs. 26A-B). From Figures 26A-B, it appears that P-0559 had about a 40-fold increase in %pStat5 preferential to Tregs (~40% in Treg and ~1% in Tconv cells). P-0560 had about a 30-fold increase in %pStat5 preferential to Tregs (~60% in Treg and ~2% in Tconv cells). Example 17 teaches similar trends but in vivo rather than in vitro. It is of record that Shanafelt teaches the D20Q mutation in human IL-2 increases selectivity for T cells over NK cells by 100-fold (Table 1 and column 20, lines 39-46), and that mutations in D20 of human IL-2 confer selectivity for the IL-2Rαβγ receptor (T cells) over the IL-2Rβγ receptor (NK cells) (column 4, lines 61-67 and column 5, line 1). Based on the teachings of Shanafelt, the results in Examples 16-17 (preferential Treg stimulation by 30 to 40-fold) are not unexpected.
Further, specification paragraph [0293] teaches “Additional IL-2 variant tocilizumab bifunctional fusion proteins, exemplified by P-0588 (D20S/S125l), P-0589 (D20N/S1251), and P-0590 (L19N/S1251/Q126E), demonstrated similar activity profile as P-0559, namely reduced potency in inducing STAT5 phosphorylation in Treg cells but a wider selectivity window over conventional CD4+ T cells (FIGS. 26C and 26D)” (emphasis added). Therefore, the specification teaches that P-0559 had a similar activity profile as compared to alternative constructs, not enhanced Treg cell selectivity over alternative constructs as argued by Applicant. Applicant’s arguments are not persuasive, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Gillies US 2003/0166163 (of record) in view of Sheng-Xiao et al., Annals of the Rheumatic Diseases 2017 (of record), Klein WO 2015/118016 A1 (of record), and Shanafelt US 6,955,807 (of record) as applied to Claims 35, 37, and 52 above, and further in view of Bedi US 2020/0140547 (filed May 2018) and Djuretic WO 2020/247843 (effectively filed June 5, 2019).
Gillies, Sheng-Xiao, Klein, and Shanafelt teach an isolated fusion protein comprising an IL-2 variant consisting of SEQ ID NO: 3 having the mutations D20Q and S125I fused to the anti-IL-6R antibody tocilizumab (of record). However, Gillies, Sheng-Xiao, Klein, and Shanafelt fail to teach wherein the isolated fusion protein consists of SEQ ID NOs: 253 and 265 (Claim 39). SEQ ID NO: 253 is the tocilizumab light chain (specification page 147), and SEQ ID NO: 265 is the tocilizumab heavy chain comprising mutations L236A, L237A, and G239A linked to the IL-2 variant comprising SEQ ID NO: 3 having mutations D20Q and S125I by a GGGSGGGS linker (specification pages 150-151).
Bedi teaches the amino acid sequences of tocilizumab light chain (SEQ ID NO: 214) and tocilizumab heavy chain (SEQ ID NO: 213) (paragraph [0172] and Figs. 116A-B). Bedi teaches wherein the tocilizumab is fused to TGFβRII extracellular domain (ECD) and PD-1 ECD (paragraph [0172]) which further exemplifies that tocilizumab is known to function as a fusion protein. Bedi SEQ ID NO: 214 (residues 1-214) is 100% identical to instant SEQ ID NO: 253 (residues 1-214) as shown in the sequence alignment below wherein the top line is instant SEQ ID NO: 253 and the bottom line is Bedi SEQ ID NO: 214:
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235
512
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Bedi SEQ ID NO: 213 (residues 1-448) is 99% identical to instant SEQ ID NO: 265 (residues 1-448) as shown in the sequence alignment below wherein the top line is instant SEQ ID NO: 265 and the bottom line is Bedi SEQ ID NO: 213:
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415
510
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51
254
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Instant SEQ ID NO: 265 (residues 1-448) only differs from Bedi SEQ ID NO: 213 by mutations L236A, L237A, and G239A. Note, both sequences have a G at position 448 even though the above sequence alignment misaligns the two residues.
Djuretic teaches fusion proteins comprising a mutant IL-2 polypeptide and an antigen binding molecule (abstract, title, and Fig. 4). Djuretic teaches that Fc domains that are null variants preferably have abolished effector functions such as disrupted binding to FcγRs and/or complement receptors, and an Fc null variant can comprise mutations L234A/L235A/G237A which is equivalent to L236A/L237A/G239A of the instant application wherein the alignment numbering is shifted by two residues (paragraph [0071]). It is well understood that an Fc null variant with abolished effector function (ie decreased binding to FcγRs) can be applied to antibody therapies to avoid unwanted immune responses and improve specificity. Djuretic further teaches that glycine/serine linkers can be used to connect two polypeptide chains, specifically a linker comprising GGGSGGGS (paragraph [0073] and SEQ ID NO: 5).
It would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to produce a fusion protein consisting of SEQ ID NOs: 253 and 265 as a result of combining prior art elements according to known methods to yield predictable results. Gillies, Sheng-Xiao, Klein, and Shanafelt teach an isolated fusion protein comprising an IL-2 variant consisting of SEQ ID NO: 3 having the mutations D20Q and S125I fused to the anti-IL-6R antibody tocilizumab, and Bedi teaches the amino acid sequence of tocilizumab and Djuretic teaches known Fc domain mutations and linkers that can be applied to mutant IL-2 fusion proteins. One of ordinary skill in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately (tocilizumab binds to IL-6R and comprises a Fc null variant domain that is linked with a standard linker to an IL-2 mutant that preferentially activates Treg cells). The motivation to apply the teachings of Bedi and Djuretic is to provide an amino acid sequence for tocilizumab for the purpose of producing the antibody and to mutate the Fc portion of tocilizumab to reduce effector function in order to avoid unwanted immune responses.
Double Patenting
1. The rejection of Claims 35, 39, and 52 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 6 of U.S. Patent No. 12,152,060 (of record) is maintained. Note, the original rejection applied to Claims 35-37, 42, and 52 and now applies to Claims 35, 39, and 52 due to Applicant’s amendments.
2. The provisional rejection of Claims 35, 39, and 52 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, and 7 of copending U.S. App. No. 18/593,486 is maintained. Note, the original rejection applied to Claims 35-37, 42, and 52 and now applies to Claims 35, 39, and 52 due to Applicant’s amendments.
Applicant's arguments filed August 19, 2025 have been fully considered but they are not persuasive. Applicant argues that it is appropriate to hold the double patenting rejections in abeyance until such time as there is otherwise allowable subject matter. This is not persuasive because MPEP § 804.I.B.1 states: “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.” Therefore, the double patenting rejections are maintained.
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.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675