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 .
Claims Status
The Amendment filed on 18Dec2025 is acknowledged in which claim(s) 2-4, 6, 8-16, 18, 20-25, 29-33, 38, 40-42, 46-50, and 53-66 were canceled by Applicant.
Claim(s) 1, 5, 7, 17, 19, 26, 28, 34-37, 39, 43-45, 51-52, and 67-68 is/are currently pending and presented for examination on the merits.
Response to Amendment and Arguments
All previous rejections and/or objections of claim(s) 6, 49 are moot in view of claim cancelation.
The objection(s) to claim(s) 51-52, 67-68, the drawings, and/or the specification have been withdrawn in view of the Amendment filed on 18Dec2025.
The rejection(s) of claim(s) 1, 5, 7, 17, 19, 39, 67 under 35 U.S.C. § 102, of claim(s) 51, 68 under 35 U.S.C. § 102/103, and of claim(s) 26, 28; 34-36, 52; 37, 43-44; 37, 43, 45 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 18Dec2025, which added new limitations to the base claim.
Amendments to the base claim and new IDS disclosures necessitate new rejections/objections. Only those Applicant arguments pertinent to new rejections/objections are addressed herein.
New Rejections Necessitated by Claim Amendments/New IDS Disclosure
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5, 7, 17, 19, 39, 51 and 67-68 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2024/0262880 A1 (hereinafter “US880”), as evidenced by Sigma Aldrich (Cleavage Enzymes for Fusion Protein Purification, website saved 05Sep2025; hereinafter “Sigma Aldrich”), in view of US 2002/0169291 A1 (hereinafter “US291”).
Regarding instant claims 1, 5, 51, 68, US880 teaches activatable cytokine polypeptides comprising an artificial terminal blocking moiety attached to a protease cleavage site, attached to a cytokine, that may be cleaved in the tumor microenvironment, and that the cytokine is activated when the cleavage site is cleaved, releasing the blocking moiety [e.g., title, abstract; paras 0019 0069; abstract fig; fig 1a]. US880 further teaches the cytokine is IL-18 [e.g., paras 0006, 0072, 0114, 0121, 0131-0132, 0159; claims 73-90].
Regarding instant claims 7, 17, 19, US880 teaches the protease is selected from (entire list not provided in this office action) Factor Xa, Enterokinase, Kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, granzyme M, uPA, a calpain, a MMP, an ADAM, a FAP, a matriptase, a plasminogen activator, a cathepsin, a caspase, a tryptase, and a tumor cell surface protease [e.g., table 1a; paras 0156, 0180; claim 78]. As evidenced by Sigma Aldrich, Factor Xa and Enterokinase proteases leave no additional residues on the fused protein [e.g., Factor Xa, Enterokinase], and thrombin cleavage leaves 2 residues attached to the fusion protein [e.g., Thrombin].
Regarding instant claim 39, US880 further teaches the cleaved, active form of the cytokine (e.g., IL-18) can bind to its receptor [e.g., abstract; figs 1A-4B; para 0006].
Regarding instant claim 67, US880 further teaches the protease cleavage site may be artificially engineered [e.g., para 0160]. US880 teaches that protein modifications can result in changes in the amino acid sequence to modify a restriction site, and that such modifications include N or C terminal fusion domains [e.g., para 0167]. Additionally, as discussed above (see 7, 17, 19 rejection), US880 discloses proteases that cleave without leaving additional residues (e.g., of the terminal moiety) on the fusion protein (e.g., IL-18).
US880 does not expressly teach the (I) activatable IL18 polypeptide (Act-IL18) comprises C38A, C76A, and C127A substitutions; (II) Act-IL18 C38A/C76A/C127A , further comprising (1) a protease cleavable site, wherein the protease (a) is selected from Factor Xa, Enterokinase, Kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, granzyme M, uPA, a calpain, a MMP, an ADAM, a FAP, a matriptase, a plasminogen activator, a cathepsin, a caspase, or a tryptase, (b) leaves no residues on the IL18 molecule, or (c) leaves residues on the IL18 molecule; and/or (III) Act-IL18 C38A/C76A/C127A, wherein (a) the active (cleaved) form of IL18 binds IL18R, or (b) the terminal IL18 residues are substituted such that the entirety of the artificial terminal moiety is cleaved from the IL18 molecule.
US291 teaches IL18 mutants, production, and uses thereof [e.g., title, abstract]. US291 further teaches C38, C76 and C127 substitutions to alanine increases IL18 stability relative to wild-type IL18 [e.g., ¶ 0016; fig. 1B].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the WT IL18 of the Act-IL18 as taught by US880, with the C38A/C76A/C127A IL18 as taught by US291, in the context of designing and developing an activatable IL18 therapeutic. A PHOSITA would have been motivated to substitute the WT IL18 of the Act-IL18 as taught by US880, with the C38A/C76A/C127A IL18 as taught by US291, because US291 teaches that the C38A/C76A/C127A substitutions, relative to WT IL18, increase IL18 variant stability. While US880 and US291 are silent on the activatable (masked) IL18 as well as the activated (cleaved) IL18 specific EC50 characteristics, these are considered a function of the activatable IL-18 composition itself. Therefore , the specific EC50 limitation(s) of activatable (e.g., claim 51) and activated (e.g., claim 68) IL18 are necessarily met by the recitation the activatable IL-18 C38A/C76A/C127A composition. There would have been a reasonable expectation of success for a PHOSITA to substitute the C38A/C76A/C127A, because US880 teaches the Act-IL18 structure, and US291 teaches an IL18 variant comprising C38A/C76A/C127A substitutions which increases IL18 variant stability. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified Act-IL18 C38A/C76A/C127A composition as taught by US880 and US291 (see above) to include that the (I) Act-IL18 C38A/C76A/C127A , further comprising (1) a protease cleavable site, wherein the protease (a) is selected from Factor Xa, Enterokinase, Kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, granzyme M, uPA, a calpain, a MMP, an ADAM, a FAP, a matriptase, a plasminogen activator, a cathepsin, a caspase, or a tryptase, (b) leaves no residues on the IL18 molecule, or (c) leaves residues on the IL18 molecule; and/or (II) Act-IL18 C38A/C76A/C127A, wherein (a) the active (cleaved) form of IL18 binds IL18R, or (b) the terminal IL18 residues are substituted such that the entirety of the artificial terminal moiety is cleaved from the IL18 molecule.as taught by US880, because US880 and US291 teach the Act-IL18 C38A/C76A/C127A, and US880 further teaches protease cleavable site compositions of the Act-IL18 variant compositions. There is an expectation of success for a PHOPSITA to substitute the modified Act-IL18 C38A/C76A/C127A composition taught by US880 and US291 with the protease cleavable site characteristics of US880, US880 and US291 teach the Act-IL18 C38A/C76A/C127A, and US880 further teaches specific protease cleavable site compositions of Act-IL18 variants. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 26, 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2024/0262880 A1 (hereinafter “US880”), as evidenced by Sigma Aldrich (Cleavage Enzymes for Fusion Protein Purification, website saved 05Sep2025; hereinafter “Sigma Aldrich”) and US 2002/0169291 A1 (hereinafter “US291”) as applied to claim 1 above, and further in view of WO 2021/028690 A1 (hereinafter “WO690”).
The teachings of US880 and US291 as recited above for claim 1.
US880 and US291 do not expressly teach the activatable IL-18 comprises (1) an N terminal artificial (blocking) moiety comprising an IL-18 propeptide, or (2) a propeptide having the amino acid sequence of instant SEQ ID NO: 89.
WO690 teaches a modified pro-IL-18 cytokine, wherein the pro-peptide is modified from a native pro-peptide of a pro-IL-18 propeptide and teaches that the prop-peptide is a polypeptide having SEQ ID: 25 [e.g., paras 0154-0156], which is the same as the instant claimed Act-IL-18 propeptide of instant SEQ ID NO: 89 (see alignment below). WO690 further teaches the propeptide is located at the N terminus of the activatable pro-IL-18 molecule [e.g., para 010, 031, 0122, 0152-0156].
Alignment of Act-IL-18 propeptide instant SEQ ID NO: 89 with WO690 IL-18 propeptide sequence SEQ ID: 25:
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It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the N-terminal blocking moiety of the modified Act-IL18 C38A/C76A/C127A polypeptide composition as taught by US880 and US291 (see above), with the IL-18 propeptide sequence taught by WO690, in the context of designing and developing an activatable IL-18 therapeutic. A PHOSITA would have been motivated to substitute the N-terminal blocking moiety of the Act-IL18 C38A/C76A/C127A polypeptide composition taught by US880 and US291, with the N-terminal IL-18 propeptide blocking moiety sequence taught by WO690, because US880 and US291 teach the base Act-IL18 C38A/C76A/C127A structure, US880 and WO690 teach activatable IL-18 cytokines with an N-terminal blocking moiety, and WO690 teaches a sequence for a modified IL-18 propeptide that was derived from the native IL-18 propeptide (e.g., inactive) sequence. There would have been a reasonable expectation of success for a PHOSITA to substitute the N-terminal blocking moiety of the Act-IL18 C38A/C76A/C127A polypeptide composition as taught by US880 and US291 with the N-terminal IL-18 propeptide blocking moiety sequence taught by WO690, because US880 and US291 teach the base Act-IL18 C38A/C76A/C127A structure, US880 and WO690 teach overlapping subject matter of activatable IL-18 polypeptides with N terminal blocking moieties, and WO690 teaches a native-derived modified IL-18 propeptide sequence functions as a blocking moiety for an activatable IL-18 polypeptide. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 34-36, and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2024/0262880 A1 (hereinafter “US880”), as evidenced by Sigma Aldrich (Cleavage Enzymes for Fusion Protein Purification, website saved 05Sep2025; hereinafter “Sigma Aldrich”) and US 2002/0169291 A1 (hereinafter “US291”) as applied to claim 1 above, and further in view of Wei et al. (FEBS Letters, 588 2014) 3838-3843; hereinafter “Wei”).and US 7,767,207 B2 (hereinafter “US207”)
The teachings of US880 and US291 as recited above for claim 1.
US880 further teaches the blocking moiety can be attached to the C terminus via a linker to a cytokine polypeptide [e.g., para 0155; fig 1A].
US880 and US291 do not expressly teach the C38A/C76A/C127A further comprises an artificial D3 blocking moiety of SEQ ID NO: 93, with an EC50 that is about 10-fold to about 100-fold greater than the activated IL-18 polypeptide.
Wei teaches the structural basis for the specific recognition of IL-18 by its alpha receptor [e.g., title and abstract]. Wei further teaches that the IL-18 binding protein (IL-18BP) binds IL-18 and inhibits its interaction with its receptor because IL-18BP adopts a single Ig-fold and interacts with IL-18 in a manner very similar to the D3 domain of the IL-18Ra, therefore directly blocking the binding site 2 between IL-18 and IL-18Ra [e.g., pg. 3840, “3.2 Interactions between IL-18 and IL-18Ra”].
US207 teaches methods of inhibiting IL-18 activity, and compounds capable of binding to human interleukin-18 useful for treating various diseases and/or disorders [e.g., title, abstract, cols 1-3]. US207 further teach teaches the Human interleukin-18 (IL-18) receptor fragment (SEQ ID: 7) [e.g., pg. 12, table 4], which is the same as the instant claimed D3 domain blocking moiety of SEQ ID NO: 93 (see alignment below).
Alignment of instant claimed D3 domain blocking moiety of SEQ ID NO: 93 with US207 SEQ ID: 7:
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Further, it would have been obvious to a PHOSITA to modify the modified Act-IL18 C38A/C76A/C127A polypeptide composition of US880 and US291 (see above) to include that the composition further comprises an artificial D3 blocking moiety of SEQ ID NO: 93, with an EC50 that is about 10-fold to about 100-fold greater than the activated IL-18 polypeptide as taught by Wei and US207, in the context of designing and developing an activatable IL-18 polypeptide therapeutic. A PHOSITA would have been motivated to substitute the blocking moiety of the Act-IL18 C38A/C76A/ C127A as taught by US880 and US291, with the IL-18Ra D3 fragment sequence taught by US207, because Wei teaches that the natural inhibitor of IL-18 known as IL-18BP interacts with IL-18 in a similar way to the IL-18Ra D3 domain, and therefore D3 would likely mimic that inhibitory effect on IL-18. The activatable IL-18 polypeptide comprising a C terminal D3 blocking moiety would necessarily possess the same EC50 characteristics of the instant claims (e.g., about 10-fold to about 100-fold higher than activated IL-18) as this is a function of the activatable cytokine composition itself. There would have been a reasonable expectation of success for a PHOSITA to substitute the blocking moiety of the modified Act-IL18 C38A/C76A/C127A polypeptide composition of US880 and US291 (see above), with the IL-18Ra D3 fragment sequence taught by US207 because Wei teaches that the natural inhibitor of IL-18 known as IL-18BP interacts with IL-18 in a similar way to the IL-18Ra D3 domain, and therefore a PHOSITA would reasonably expect the D3 sequence fragment taught by US207 to mimic the known inhibitory interactions of the IL-18BP relative to IL-18. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 37 and 43-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2024/0262880 A1 (hereinafter “US880”), as evidenced by Sigma Aldrich (Cleavage Enzymes for Fusion Protein Purification, website saved 05Sep2025; hereinafter “Sigma Aldrich”) and US 2002/0169291 A1 (hereinafter “US291”) as applied to claim 1 above, and further in view of US 2023/0355714 A1 (hereinafter “US714”).
The teachings of US880 and US291 as recited above for claim 1.
US880 and US291 do not expressly teach that (1) the active form of the IL18 polypeptide displays reduced binding to IL18 binding protein (IL-18BP) compared to WT IL-18, or (2) that the IL18 peptide further comprises E06A and K53A substitutions.
Regarding instant claims 37, US714 teaches there is a need for IL-18 variants to provide effective IL-18 signaling activity to treat cancer and other diseases and disorders [e.g., para 0004]. US714 further teaches IL-18 variants that specifically bind the IL-18R and also exhibit substantially reduced binding to the IL-18 binding protein (IL-18BP) [e.g., para 0005], and that IL-18BP neutralizes IL-18 (inhibits binding to WT IL-18 receptor) [e.g., paras 0021, 0069]. Regarding instant claims 43-44, US714 teaches an IL-18 protein variant with E06K and K53A amino acid substitutions [e.g., para 0044].
Further, it would have been obvious to a PHOSITA to modify the IL-18 portion of modified Act-IL18 C38A/C76A/C127A polypeptide composition as taught by US880 and US291 (see above), to include the IL-18 variant with E06A and K53A substitutions with reduced IL-18BP binding taught by US714, in the context of designing and developing an activatable IL-18 polypeptide with reduced IL-18BP binding. A PHOSITA would have been motivated to substitute the IL-18 portion of the Act-IL18 C38A/C76A/C127A taught by US880 and US291, with the IL-18 variant with E06A and K53A substitutions with reduced IL-18BP binding taught by US714, because US880 and US291 teach the base Act-IL18 structure, US880 further teaches an activatable IL-18 polypeptide that is cleavable in the tumor microenvironment, both US880 and US714 teach treating cancer with IL-18, and US714 teaches an IL-18 variant with E06A and K53A substitutions that displays reduced binding with IL-18BP as a cancer therapy. There would have been a reasonable expectation of success for a PHOSITA to substitute the IL-18 portion of the modified Act-IL18 C38A/C76A/C127A composition as taught by US880 and US291 (see above), with the E06A and K53A IL-18 variant with reduced IL-18BP binding taught by US714, because US880 and US291 teach the Act-IL18 C38A/C76A/C127A base structure, US880 teaches an activatable IL-18 polypeptide that is cleavable in the tumor microenvironment, and US714 teaches and an IL-18 variant comprising E06A and K53A substitutions that displays reduced binding with IL-18BP as a cancer therapy. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 37, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2024/0262880 A1 (hereinafter “US880”), as evidenced by Sigma Aldrich (Cleavage Enzymes for Fusion Protein Purification, website saved 05Sep2025; hereinafter “Sigma Aldrich”), US 2002/0169291 A1 (hereinafter “US291”) and US 2023/0355714 A1 (hereinafter “US714”) as applied to claims 1 and 44 above, and further in view of Swencki-Underwood (Cytokine 34 (2006) 114–124; hereinafter “Underwood”).
The teachings of US880, US291 and US714 as recited above apply for claims 1 and 44.
US880, US291 and US714 do not expressly teach the activatable IL-18 peptide further comprises T63A and V11I substitutions.
Underwood teaches engineering human IL-18 polypeptide to increase bioactivity and bioavailability, comprising V11I/T63A substitutions [e.g., title and abstract].
Further, it would have been obvious to a PHOSITA to modify the IL-18 polypeptide of the modified Act-IL18 C38A/C76A/C127A/E06A/K53A of US880, US291 and US714 (see above) to include the IL-18 polypeptide further comprises the V11I/T63A substitutions as taught by Underwood, because US880, US291, and US714 teach the Act-IL18 C38A/C76A/C127A/E06A/K53A base structure, US880 and US714 teach activatable IL-18 including embodiments comprising IL-18 variants to treat cancer, and Underwood teaches the IL-18 substitutions V11I/T63A results in increased IL-18 bioactivity, which would be desirable (post cleavage activation of the cytokine) for a therapeutic agent. There is an expectation of success for a PHOPSITA to further modify the modified IL-18 polypeptide of the Act-IL18 C38A/C76A/C127A/E06A/K53A polypeptide of US880, US291 and US714 (see above) with the V11I/T63A substitutions taught by Underwood, because underwood teaches these substitutions in IL-18 result in increased bioactivity. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that an Act-IL18 comprising C38A, C76A, and/or C127A substitutions was not taught by the collection of references in the Office Action mailed on 09/19/2025.
In response, Applicant Amendment filed on 18Dec2025 amended base claim 1 to require C38A, C76A, and/or C127A substitutions to the WT IL18 sequence. Further, Applicant IDS filed on 18Dec2025 disclosed US 2002/0169291 A1 (hereinafter “US291”), which teaches the recited IL18 substitutions. The base claim amendment and the new IDS disclosure necessitated new rejections. In the new rejections, the instant Office Action relies upon US880 to teach the base Act-IL18 structure and comprising parts thereof, and US291 was relied upon to teach the IL18 C38A/C76A/C127A substitutions (see rejections above for details), thereby meeting the new base claim limitations.
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 1, 5, 7, 17, 19, 26, 28, 34-37, 39, 43-45, 51-52, and 67-68 are maintained.
Conclusion
No claims are currently allowed.
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 18Dec2025 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643