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
The instant application claims the benefit of the prior-filed United States Provisional Patent Application Nos. 63/313,127 (filing date 02/23/2022), 63/313,210 (filing date 02/23/2022), 63/313,222 (filing date 02/23/2022), 63/313,248 (filing date 02/23/2022), 63/479,529 (filing date 01/11/2023).
Status of Application/Claims
The amendment, filed 12/19/2025, is acknowledged. Claims 1-4, 6-27, 29-30, 32-33, 36-46, 48-78 are canceled. Claims 5, 28, and 47 are currently amended. Claims 79-87 are new. Claims 5, 28, 31, 34-35, 47, and 79-87 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/2025 has been fully considered by the examiner.
Withdrawn Objections & Rejections
Regarding the Drawings objection for poor resolution and minor informalities, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the Specification objection for trade names and/or trademark compliance issues, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the claim objections to claims 8 and 73, applicant amendment has corrected the issue and the claims are canceled. Thus, the claim objections for claims 8 and 73 are withdrawn.
Regarding the rejections for claims 8-10 under 35 U.S.C. 112(a) for failing to comply with the written description requirement, applicant amendment has addressed the issue and claims 8-10 are canceled. Thus, the rejection for claims 8-10 is withdrawn.
Regarding the rejection for claims 5, 16-17, 24, and 34 under 35 U.S.C. 103 for obviousness: Claims 16-17 and 24 are canceled and the rejection of these claims is withdrawn. The rejection for amended claim 5 and previously presented claim 34 is maintained in modified form.
Regarding each of the rejections for claim 19, claim 21, and claims 26-27 and 29-30 under 35 U.S.C. 103 for obviousness: Claims 19, 21, 26-27, and 29-30 are canceled and the rejections for these claims are withdrawn.
Regarding the rejection for claims 25, 28, 35, 47, and 73 under 35 U.S.C. 103 for obviousness: Claims 25 and 73 are canceled and the rejection of these claims is withdrawn. The rejection for amended claims 28 and 47 and for previously presented claim 35 is maintained in modified form.
Regarding the rejection for claim 31 under 35 U.S.C. 103 for obviousness, the rejection is maintained in modified form.
Regarding the non-statutory double patenting rejections for claims 5, 8-9, 16-17, 19, 21, 24-31, 34-35, 47, and 73: Claims 8-9, 16-17, 19, 21, 24-27, 29-30, and 73 are canceled and the rejections for these claims are withdrawn. The double patenting rejections for amended claims 5, 28, and 47 and the double patenting rejections for previously presented claims 34-35 and 47 are maintained in modified form.
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.
Claims 5, 28, 34-35, 47 and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Swencki-Underwood, et al. Engineering human IL-18 with increased bioactivity and bioavailability. Cytokine (2006), 34, p.114-124 (herein referred to as Swencki-Underwood); further in view of Dinarello and Kim. US2002/0169291A1 (publication date: 11/14/2002; effective filing date: 03/08/2001; herein referred to as Dinarello); and, further in view of Kim et al., Identification of amino acid residues critical for biological activity in human interleukin-18. J. Biological Chemistry (2002), 277:13, p.10998-11003 (herein referred to as Kim).
Swencki-Underwood teaches that cytokines can act as adjuvants for enhancing the immune response (abstract). Swencki-Underwood teaches IL-18 variants with increased bioactivity and bioavailability, including the single mutant T63A and the double mutant V11I/T63A (WT IL-18 reference sequence shown in Fig.1). Swencki-Underwood, thus, teaches the V11I/T63A double mutant and a single T63A mutant, which exhibit higher IFNγ production than wild type (WT) IL-18 (p.121, Figs.8A-B).
Swencki-Underwood does not teach that the modified IL-18 also has an E6K substitution or a K53A substitution (instant claims 5, 34-35 and 47); or, that the modified IL-18 also comprises C38A, C76A, and C127A substitutions (instant claims 28 and 79).
Dinarello teaches the use of cytokines, including IL-18, used as adjuvants for increasing the effectivity of immunotherapy to cancer. Dinarello also teaches that for IL-18 to be used locally, neutralization by the inhibitory IL-18 binding protein (IL-18BP) must be overcome to maintain effectivity of IL-18 (p.9, [0014]). Dinarello teaches single and double mutants at positions E42 and K89 (i.e., E42A, K89A, and E42A/K89A mutants; based on unprocessed IL-18 that contains the signal sequence) which correspond to applicant’s mature IL-18 positions E6 and K53 (p.3, Fig.1B-mature E6 and K52 highlighted in black for Dinarello SEQ ID NO: 2). Thus, Dinarello teaches the instant IL-18 K53A mutation. Dinarello teaches that these mutants have lower affinity to the inhibitory IL-18BP (IL-18 binding protein). Dinarello further teaches that IL-18 contains 4 cysteines (at positions C38, C68, C76, and C127) and that one or all of these cysteines can be mutated to serine or alanine to provide higher stability of the molecule (p.3, Fig.1B; p.9, [0016]).
Kim also teaches an E42 mutant that is a E42K substituted mutant that exhibits increased biological activity with numbering based on the unprocessed IL-18 sequence (abstract; p.11000, Fig.1) which corresponds to the instant E6K mutant. Kim also teaches that the E6K mutant exhibits an EC50 for IFNγ production of approximately 600-fold compared to wild type (i.e., p.11001, Fig.3B shows E42K EC50 ~600pg/mL IFNγ at 3.1ng/mL compared to undetectable wild type levels at this concentration; i.e., a mutant with EC50 at least an 80-fold difference).
Regarding instant claim 5: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Swencki-Underwood with the teachings of Dinarello and Kim by modifying the IL-18 V11I/T63A double mutant taught by Swencki-Underwood that exhibits high IFNγ production to also comprise a K53A substitution (as taught by Dinarello) and an E6K substitution (as taught by Kim), in order to receive the expected benefits that the K53A substitution would provide for lower affinity of IL-18 to the inhibitory IL-18BP (as taught by Dinarello) and that the E6K substitution would provide for increased IFNγ production (as taught by Kim). One of ordinary skill in the art would have a reasonable expectation of success because Swencki-Underwood, Dinarello, and Kim all teach the exact substitutions and benefits of the claimed invention; and, both Dinarello and Kim teach substitutions at the E6 position for enhanced IL-18 activity.
Regarding instant claim 28: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further modify the combined teachings of Swencki-Underwood/Dinarello/Kim with further teachings from Dinarello by modifying the IL-18 E6K/V11I/K53A/T63A mutant to further comprise C38A, C76A, and C127A substitutions to arrive at the instantly claimed invention, in order to receive the expected benefit that the C[Wingdings font/0xE0]A substitution(s) would provide for higher stability of IL-18 (as taught by Dinarello). As Dinarello teaches that one or all of the cysteines can be mutated at positions C38, C68, C76, and/or C127 to receive this benefit, it would be obvious to try the combination of C38A/C76A/C127A from the finite number of identified, predictable solutions with a reasonable expectation of success and is a matter of routine optimization.
Regarding instant claims 34-35, 47, and 79: Instant SEQ ID NO: 30 differs from WT IL-18 in that SEQ ID NO: 30 harbors the following substitutions (see alignment below): E6K, V11I, C38A, K53A, C76A, and C127A.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 30[img-media_image1.png])]Thus, the combination of prior art teachings teaches an IL-18 mutant encoded by a sequence that consists of instant SEQ ID NO: 30 at 100% identity; thus, claims 34-35, 47, and 79 are rendered obvious via the above analysis.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Swencki-Underwood, Dinarello, and Kim as applied to claim 5 above; and, in further view of Purushottam, et al. Single-site glycine-specific labeling of proteins. Nature Communications (2019), 10:2539, p.1-10 (herein referred to as Purushottam).
The combination of teachings by Swencki-Underwood, Dinarello, and Kim teaches the E6K/V11I/K53A/T63A IL-18 mutant as described for instant claim 5 above.
The combination of Swencki-Underwood/Dinarello/Kim does not teach that the modified IL-18 comprises at least one glycine residue attached to the N-terminus (instant claim 31).
Purushottam teaches site-specific labeling of natural or easy-to-engineer N-terminal glycine in proteins for the purpose of making the N-terminal glycine a unique target for single-site N-terminal labeling amongst other proteinogenic amino acids that may be present in the protein (abstract). Purushottam also teaches that the method involving addition of N-terminal glycine generates a latent nucleophile from N-terminus imine that reacts with an aldehyde to deliver an aminoalcohol under physiological conditions and provides for late-stage tagging and purification of analytically pure protein that does not affect protein function (abstract; p.5, Fig.3a; Fig.4a). Purushottam teaches that this “user-friendly” N-terminal glycine-mediated labeling provides for improved overall yield (p.7, col.2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Swencki-Underwood/Dinarello/Kim with the teachings of Purushottam by modifying the IL-18 E6K/V11I/K53A/T63A mutant (as taught by the combination of Swencki-Underwood/Dinarello/Kim) with an N-terminal glycine (as taught by Purushottam) to arrive at the instantly claimed invention, in order to receive the benefit (as taught by Purushottam) that addition of N-terminal glycine allows for user-friendly single-site labeling and improved purification of analytically pure protein with retained function. One of ordinary skill in the art would have a reasonable expectation of success because the IL-18 sequence and mutations are taught by the prior art and Puroshottam teaches site-specific labeling of polypeptides with N-terminal glycine.
Claim 81 is rejected under 35 U.S.C. 103 as being unpatentable over Swencki-Underwood, Dinarello, and Kim as applied to claim 5 above; and, in further view of Nisthal, et al.—US20230146665A1 (effective filing date 7/27/2021; herein referred to as Nisthal).
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 8[img-media_image2.png])]Regarding instant claim 81, instant SEQ ID NO: 8 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, K53A, T63A, C68A, C76A, T95C, and C127A.
The combination of teachings by Swencki-Underwood, Dinarello, and Kim teaches the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant as described for instant claims 5, 28, and 34 above.
The combination of Swencki-Underwood/Dinarello/Kim does not teach that the modified IL-18 comprises the T95C of SEQ ID NO: 8 (instant claim 81).
Nisthal teaches polypeptides comprising modified IL-18, including variants with improved stability via cysteine engineering at position T95 (i.e., T95C substitution; abstract; p.18, [0174]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Swencki-Underwood/Dinarello/Kim with the teachings of Nisthal by modifying the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant (taught by the combination of Swencki-Underwood/Dinarello/Kim) further incorporating the T95C substitution taught by Nisthal, to arrive at the instantly claimed SEQ ID NO: 8, in order to receive the expected benefit that the T95C substitution provides for improved IL-18 stability (taught by Nisthal). One of ordinary skill in the art would have a reasonable expectation of success because Nisthal also teaches that combinations of mutations at E6, V11, C38, K53, T63, C68, and C127 can also be mutated with the T95 mutation to produce a functional IL-18 polypeptide (see p.18—19, [0174—0175]).
Claims 82-83 and 87 are rejected under 35 U.S.C. 103 as being unpatentable over Swencki-Underwood, Dinarello, and Kim as applied to claim 5 above; and, in further view of Barnes and Gray. Bioinformatics for geneticists. John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England. 2003, p.1-411 (herein referred to as Barnes).
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 232[img-media_image3.png])]Regarding instant claim 82, instant SEQ ID NO: 232 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, I49M, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that M/methionine is a sulfur-containing amino acid unlike the proper aliphatic amino acids isoleucine, valine, and leucine (p.301; p.297, Fig.14.3). Thus, the resulting I49M substitution would be a non-conservative substitution.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 233[img-media_image4.png])]Regarding instant claim 83, instant SEQ ID NO: 233 encodes an IL-18 mutant with the following substitutions compared to WT IL-18, which additionally comprises an I49R substitution (see alignment below): E6K, V11I, C38A, I49R, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]; and WT IL-18 SEQ ID NO: 2 vs IL-18 muteins SEQ ID NO: 3-5, for example). Dinarello further specifically teaches the substitution I49R.
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that R/arginine is a positively charged polar amino acid (p.297, Fig.14.3). Thus, the resulting I49R substitution would be a non-conservative substitution.
Regarding instant claims 82 and 83: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of Swencki-Underwood/Dinarello/Kim with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position I49 (taught by Dinarello) that is an I49M or I49R substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at I49 provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that I[Wingdings font/0xE0]M and I[Wingdings font/0xE0]R are non-conservative substitutions. Additionally, it would have been obvious to try mutating to M or R as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
Regarding instant claim 87, instant SEQ ID NO: 239 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, M51G, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Met-87,” which corresponds to instant position M51, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 239[img-media_image5.png])]Barnes teaches that M/methionine is a sulfur-containing amino acid; but, that G/glycine is a small/tiny hydrophobic amino acid (p.301; p.297, Fig.14.3). Thus, the resulting M51G substitution would be a non-conservative substitution.
Regarding instant claim 87: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of Swencki-Underwood/Dinarello/Kim with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position M51 (taught by Dinarello) that is an M51G substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at M51G provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that M[Wingdings font/0xE0]G are non-conservative substitutions. Additionally, it would have been obvious to try mutating to G as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
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.
18/113,399
Claims 5, 28, 31, 34-35, 47, and 79-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, 17, 19, 26, 28, 34-37, 39, 43-45, 51-52, and 67-68 of copending Application No. 18/113,399 (reference application; herein referred to as App’399); and, in further view of Dinarello, Puroshottam, Nisthal, and Barnes. Although the claims at issue are not identical, they are not patentably distinct from each other because App’399 teaches an activatable IL-18 that comprises V11I/T63A/E6K/K53A/C38A/C76A/C127A substitutions (App’399 claims 1, 44-45; instant claims 5, 28, 34-35, 47, and 79).
App’399 teaches the V11I/T63A/E6K/K53A/C38A/C76A/C127A IL-18 mutant as described for instant claims 5, 28, 34-35, 47, and 79 above.
App’399 does not teach that the modified IL-18 comprises at least one glycine residue attached to the N-terminus (instant claim 31).
Purushottam teaches site-specific labeling of natural or easy-to-engineer N-terminal glycine in proteins for the purpose of making the N-terminal glycine a unique target for single-site N-terminal labeling amongst other proteinogenic amino acids that may be present in the protein (abstract). Purushottam also teaches that the method involving addition of N-terminal glycine generates a latent nucleophile from N-terminus imine that reacts with an aldehyde to deliver an aminoalcohol under physiological conditions and provides for late-stage tagging and purification of analytically pure protein that does not affect protein function (abstract; p.5, Fig.3a; Fig.4a). Purushottam teaches that this “user-friendly” N-terminal glycine-mediated labeling provides for improved overall yield (p.7, col.2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’399 with the teachings of Purushottam by modifying the IL-18 E6K/V11I/K53A/T63A mutant (as taught by App’399) with an N-terminal glycine (as taught by Purushottam) to arrive at the instantly claimed invention, in order to receive the benefit (as taught by Purushottam) that addition of N-terminal glycine allows for user-friendly single-site labeling and improved purification of analytically pure protein with retained function. One of ordinary skill in the art would have a reasonable expectation of success because the IL-18 sequence and mutations are taught by the prior art and Puroshottam teaches site-specific labeling of polypeptides with N-terminal glycine.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 8[img-media_image2.png])]Regarding instant claim 81, instant SEQ ID NO: 8 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, K53A, T63A, C68A, C76A, T95C, and C127A.
App’399 teaches the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant as described for instant claims 5, 28, and 34 above.
App’399 does not teach that the modified IL-18 comprises the T95C of SEQ ID NO: 8 (instant claim 81).
Nisthal teaches polypeptides comprising modified IL-18, including variants with improved stability via cysteine engineering at position T95 (i.e., T95C substitution; abstract; p.18, [0174]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’399 with the teachings of Nisthal by modifying the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant (taught by App’399) further incorporating the T95C substitution taught by Nisthal, to arrive at the instantly claimed SEQ ID NO: 8, in order to receive the expected benefit that the T95C substitution provides for improved IL-18 stability (taught by Nisthal). One of ordinary skill in the art would have a reasonable expectation of success because Nisthal also teaches that combinations of mutations at E6, V11, C38, K53, T63, C68, and C127 can also be mutated with the T95 mutation to produce a functional IL-18 polypeptide (see p.18—19, [0174—0175]).
Regarding instant claim 82, instant SEQ ID NO: 232 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, I49M, K53A, T63A, C76A, and C127A.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 232[img-media_image3.png])]Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that M/methionine is a sulfur-containing amino acid unlike the proper aliphatic amino acids isoleucine, valine, and leucine (p.301; p.297, Fig.14.3). Thus, the resulting I49M substitution would be a non-conservative substitution.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 233[img-media_image4.png])]Regarding instant claim 83, instant SEQ ID NO: 233 encodes an IL-18 mutant with the following substitutions compared to WT IL-18, which additionally comprises an I49R substitution (see alignment below): E6K, V11I, C38A, I49R, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]; and WT IL-18 SEQ ID NO: 2 vs IL-18 muteins SEQ ID NO: 3-5, for example). Dinarello further specifically teaches the substitution I49R.
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that R/arginine is a positively charged polar amino acid (p.297, Fig.14.3). Thus, the resulting I49R substitution would be a non-conservative substitution.
Regarding instant claims 82 and 83: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’399 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position I49 (taught by Dinarello) that is an I49M or I49R substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at I49 provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that I[Wingdings font/0xE0]M and I[Wingdings font/0xE0]R are non-conservative substitutions. Additionally, it would have been obvious to try mutating to M or R as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 239[img-media_image5.png])]Regarding instant claim 87, instant SEQ ID NO: 239 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, M51G, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Met-87,” which corresponds to instant position M51, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that M/methionine is a sulfur-containing amino acid; but, that G/glycine is a small/tiny hydrophobic amino acid (p.301; p.297, Fig.14.3). Thus, the resulting M51G substitution would be a non-conservative substitution.
Regarding instant claim 87: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’399 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position M51 (taught by Dinarello) that is an M51G substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at M51G provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that M[Wingdings font/0xE0]G are non-conservative substitutions. Additionally, it would have been obvious to try mutating to G as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18/813,101
Claims 5, 28, 31, 34-35, 47, and 79-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6, 8, 13-14, 17, 19-20, 22, 29-30, 35, 43-44, 55-56, and 68-70 of copending Application No. 18/813,101 (herein referred to as App’101); and, in further view of Dinarello, Puroshottam, Nisthal, and Barnes. Although the claims at issue are not identical, they are not patentably distinct from each other because App’101 teaches an activatable IL-18 that comprises V11I/T63A/E6K/K53A/C38A/C76A/C127A substitutions (App’101 claims 1-2, 29-30, and 35; instant claims 5, 28, 34-35, 47, and 79).
App’101 teaches the V11I/T63A/E6K/K53A/C38A/C76A/C127A IL-18 mutant as described for instant claims 5, 28, 34-35, 47, and 79 above.
App’101 does not teach that the modified IL-18 comprises at least one glycine residue attached to the N-terminus (instant claim 31).
Purushottam teaches site-specific labeling of natural or easy-to-engineer N-terminal glycine in proteins for the purpose of making the N-terminal glycine a unique target for single-site N-terminal labeling amongst other proteinogenic amino acids that may be present in the protein (abstract). Purushottam also teaches that the method involving addition of N-terminal glycine generates a latent nucleophile from N-terminus imine that reacts with an aldehyde to deliver an aminoalcohol under physiological conditions and provides for late-stage tagging and purification of analytically pure protein that does not affect protein function (abstract; p.5, Fig.3a; Fig.4a). Purushottam teaches that this “user-friendly” N-terminal glycine-mediated labeling provides for improved overall yield (p.7, col.2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’101 with the teachings of Purushottam by modifying the IL-18 E6K/V11I/K53A/T63A mutant (as taught by App’101) with an N-terminal glycine (as taught by Purushottam) to arrive at the instantly claimed invention, in order to receive the benefit (as taught by Purushottam) that addition of N-terminal glycine allows for user-friendly single-site labeling and improved purification of analytically pure protein with retained function. One of ordinary skill in the art would have a reasonable expectation of success because the IL-18 sequence and mutations are taught by the prior art and Puroshottam teaches site-specific labeling of polypeptides with N-terminal glycine.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 8[img-media_image2.png])]Regarding instant claim 81, instant SEQ ID NO: 8 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, K53A, T63A, C68A, C76A, T95C, and C127A.
App’101 teaches the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant as described for instant claims 5, 28, and 34 above.
App’101 does not teach that the modified IL-18 comprises the T95C of SEQ ID NO: 8 (instant claim 81).
Nisthal teaches polypeptides comprising modified IL-18, including variants with improved stability via cysteine engineering at position T95 (i.e., T95C substitution; abstract; p.18, [0174]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’101 with the teachings of Nisthal by modifying the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant (taught by App’101) further incorporating the T95C substitution taught by Nisthal, to arrive at the instantly claimed SEQ ID NO: 8, in order to receive the expected benefit that the T95C substitution provides for improved IL-18 stability (taught by Nisthal). One of ordinary skill in the art would have a reasonable expectation of success because Nisthal also teaches that combinations of mutations at E6, V11, C38, K53, T63, C68, and C127 can also be mutated with the T95 mutation to produce a functional IL-18 polypeptide (see p.18—19, [0174—0175]).
Regarding instant claim 82, instant SEQ ID NO: 232 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, I49M, K53A, T63A, C76A, and C127A.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 232[img-media_image3.png])]Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that M/methionine is a sulfur-containing amino acid unlike the proper aliphatic amino acids isoleucine, valine, and leucine (p.301; p.297, Fig.14.3). Thus, the resulting I49M substitution would be a non-conservative substitution.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 233[img-media_image4.png])]Regarding instant claim 83, instant SEQ ID NO: 233 encodes an IL-18 mutant with the following substitutions compared to WT IL-18, which additionally comprises an I49R substitution (see alignment below): E6K, V11I, C38A, I49R, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]; and WT IL-18 SEQ ID NO: 2 vs IL-18 muteins SEQ ID NO: 3-5, for example). Dinarello further specifically teaches the substitution I49R.
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that R/arginine is a positively charged polar amino acid (p.297, Fig.14.3). Thus, the resulting I49R substitution would be a non-conservative substitution.
Regarding instant claims 82 and 83: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’101 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position I49 (taught by Dinarello) that is an I49M or I49R substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at I49 provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that I[Wingdings font/0xE0]M and I[Wingdings font/0xE0]R are non-conservative substitutions. Additionally, it would have been obvious to try mutating to M or R as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 239[img-media_image5.png])]Regarding instant claim 87, instant SEQ ID NO: 239 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, M51G, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Met-87,” which corresponds to instant position M51, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that M/methionine is a sulfur-containing amino acid; but, that G/glycine is a small/tiny hydrophobic amino acid (p.301; p.297, Fig.14.3). Thus, the resulting M51G substitution would be a non-conservative substitution.
Regarding instant claim 87: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’101 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position M51 (taught by Dinarello) that is an M51G substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at M51G provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that M[Wingdings font/0xE0]G are non-conservative substitutions. Additionally, it would have been obvious to try mutating to G as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18/813,358
Claims 5, 28, 31, 34-35, 47, and 79-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 18-22, 28, 33-35, 37-38, 43, 46, 49, 51, 53, 64, and 66 of copending Application No. 18/813,358 (herein referred to as App’358); and, in further view of Dinarello, Puroshottam, Nisthal, and Barnes. Although the claims at issue are not identical, they are not patentably distinct from each other because App’101 teaches an activatable IL-18 that comprises V11/T63/E6/K53/C38/C76/C127 substitutions (App’101 claims 38 and 43; instant claims 5, 28, 34-35, 47, and 79).
App’358 does not teach that the specific substitutions are V11I/T63A/E6K/ K53A/C38A/C76A/C127A (instant claims 5, 28, 34-35, 47, and 79).
Swencki-Underwood teaches that cytokines can act as adjuvants for enhancing the immune response (abstract). Swencki-Underwood teaches IL-18 variants with increased bioactivity and bioavailability, including the single mutant T63A and the double mutant V11I/T63A (WT IL-18 reference sequence shown in Fig.1). Swencki-Underwood, thus, teaches the V11I/T63A double mutant and a single T63A mutant, which exhibit higher IFNγ production than wild type (WT) IL-18 (p.121, Figs.8A-B).
Swencki-Underwood does not teach that the modified IL-18 also has an E6K substitution or a K53A substitution (instant claims 5, 34-35 and 47); or, that the modified IL-18 also comprises C38A, C76A, and C127A substitutions (instant claims 28 and 79).
Dinarello teaches the use of cytokines, including IL-18, used as adjuvants for increasing the effectivity of immunotherapy to cancer. Dinarello also teaches that for IL-18 to be used locally, neutralization by the inhibitory IL-18 binding protein (IL-18BP) must be overcome to maintain effectivity of IL-18 (p.9, [0014]). Dinarello teaches single and double mutants at positions E42 and K89 (i.e., E42A, K89A, and E42A/K89A mutants; based on unprocessed IL-18 that contains the signal sequence) which correspond to applicant’s mature IL-18 positions E6 and K53 (p.3, Fig.1B-mature E6 and K52 highlighted in black for Dinarello SEQ ID NO: 2). Thus, Dinarello teaches the instant IL-18 K53A mutation. Dinarello teaches that these mutants have lower affinity to the inhibitory IL-18BP (IL-18 binding protein). Dinarello further teaches that IL-18 contains 4 cysteines (at positions C38, C68, C76, and C127) and that one or all of these cysteines can be mutated to serine or alanine to provide higher stability of the molecule (p.3, Fig.1B; p.9, [0016]).
Kim also teaches an E42 mutant that is a E42K substituted mutant that exhibits increased biological activity with numbering based on the unprocessed IL-18 sequence (abstract; p.11000, Fig.1) which corresponds to the instant E6K mutant. Kim also teaches that the E6K mutant exhibits an EC50 for IFNγ production of approximately 600-fold compared to wild type (i.e., p.11001, Fig.3B shows E42K EC50 ~600pg/mL IFNγ at 3.1ng/mL compared to undetectable wild type levels at this concentration; i.e., a mutant with EC50 at least an 80-fold difference).
Regarding instant claim 5: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of App’358 with the teachings of Swencki-Underwood, Dinarello, and Kim by modifying the IL-18 V11/T63/E6/K53/C38/C76/C127 mutant to comprise V11I and T63A substitutions specifically as taught by Swencki-Underwood because the V11I/T63A double mutant exhibits high IFNγ production; and to also comprise a K53A substitution (as taught by Dinarello) and an E6K substitution (as taught by Kim), in order to receive the expected benefits that the K53A substitution would provide for lower affinity of IL-18 to the inhibitory IL-18BP (as taught by Dinarello) and that the E6K substitution would provide for increased IFNγ production (as taught by Kim). One of ordinary skill in the art would have a reasonable expectation of success because Swencki-Underwood, Dinarello, and Kim all teach the exact substitutions and benefits of the claimed invention; and, both Dinarello and Kim teach substitutions at the E6 position for enhanced IL-18 activity.
Regarding instant claim 28: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further modify the combined teachings of App’358/Swencki-Underwood/Dinarello/Kim with further teachings from Dinarello by modifying the IL-18 E6K/V11I/K53A/T63A mutant to further comprise C38A, C76A, and C127A substitutions to arrive at the instantly claimed invention, in order to receive the expected benefit that the C[Wingdings font/0xE0]A substitution(s) would provide for higher stability of IL-18 (as taught by Dinarello). As Dinarello teaches that one or all of the cysteines can be mutated at positions C38, C68, C76, and/or C127 to receive this benefit, it would be obvious to try the combination of C38A/C76A/C127A from the finite number of identified, predictable solutions with a reasonable expectation of success and is a matter of routine optimization.
Regarding instant claims 34-35, 47, and 79: Instant SEQ ID NO: 30 differs from WT IL-18 in that SEQ ID NO: 30 harbors the following substitutions (see alignment below): E6K, V11I, C38A, K53A, C76A, and C127A.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 30[img-media_image1.png])]Thus, the combination of prior art teachings teaches an IL-18 mutant encoded by a sequence that consists of instant SEQ ID NO: 30 at 100% identity; thus, claims 34-35, 47, and 79 are rendered obvious via the above analysis.
The combination of App’358/Swencki-Underwood/Dinarello/Kim teaches the V11I/T63A/E6K/K53A/C38A/C76A/C127A IL-18 mutant as described for instant claims 5, 28, 34-35, 47, and 79 above.
App’358 does not teach that the modified IL-18 comprises at least one glycine residue attached to the N-terminus (instant claim 31).
Purushottam teaches site-specific labeling of natural or easy-to-engineer N-terminal glycine in proteins for the purpose of making the N-terminal glycine a unique target for single-site N-terminal labeling amongst other proteinogenic amino acids that may be present in the protein (abstract). Purushottam also teaches that the method involving addition of N-terminal glycine generates a latent nucleophile from N-terminus imine that reacts with an aldehyde to deliver an aminoalcohol under physiological conditions and provides for late-stage tagging and purification of analytically pure protein that does not affect protein function (abstract; p.5, Fig.3a; Fig.4a). Purushottam teaches that this “user-friendly” N-terminal glycine-mediated labeling provides for improved overall yield (p.7, col.2, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’358 with the teachings of Purushottam by modifying the IL-18 E6K/V11I/K53A/T63A mutant (as taught by App’358) with an N-terminal glycine (as taught by Purushottam) to arrive at the instantly claimed invention, in order to receive the benefit (as taught by Purushottam) that addition of N-terminal glycine allows for user-friendly single-site labeling and improved purification of analytically pure protein with retained function. One of ordinary skill in the art would have a reasonable expectation of success because the IL-18 sequence and mutations are taught by the prior art and Puroshottam teaches site-specific labeling of polypeptides with N-terminal glycine.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 8[img-media_image2.png])]Regarding instant claim 81, instant SEQ ID NO: 8 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, K53A, T63A, C68A, C76A, T95C, and C127A.
App’358 teaches the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant as described for instant claims 5, 28, and 34 above.
App’358 does not teach that the modified IL-18 comprises the T95C of SEQ ID NO: 8 (instant claim 81).
Nisthal teaches polypeptides comprising modified IL-18, including variants with improved stability via cysteine engineering at position T95 (i.e., T95C substitution; abstract; p.18, [0174]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’358 with the teachings of Nisthal by modifying the E6K/V11I/C38A/K53A/T63A/C68A/C127A IL-18 mutant (taught by App’358) further incorporating the T95C substitution taught by Nisthal, to arrive at the instantly claimed SEQ ID NO: 8, in order to receive the expected benefit that the T95C substitution provides for improved IL-18 stability (taught by Nisthal). One of ordinary skill in the art would have a reasonable expectation of success because Nisthal also teaches that combinations of mutations at E6, V11, C38, K53, T63, C68, and C127 can also be mutated with the T95 mutation to produce a functional IL-18 polypeptide (see p.18—19, [0174—0175]).
Regarding instant claim 82, instant SEQ ID NO: 232 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, I49M, K53A, T63A, C76A, and C127A.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 232[img-media_image3.png])]Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that M/methionine is a sulfur-containing amino acid unlike the proper aliphatic amino acids isoleucine, valine, and leucine (p.301; p.297, Fig.14.3). Thus, the resulting I49M substitution would be a non-conservative substitution.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 233[img-media_image4.png])]Regarding instant claim 83, instant SEQ ID NO: 233 encodes an IL-18 mutant with the following substitutions compared to WT IL-18, which additionally comprises an I49R substitution (see alignment below): E6K, V11I, C38A, I49R, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Ile-85,” which corresponds to instant position I49, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]; and WT IL-18 SEQ ID NO: 2 vs IL-18 muteins SEQ ID NO: 3-5, for example). Dinarello further specifically teaches the substitution I49R.
Barnes teaches that I/isoleucine is an aliphatic hydrophobic amino acid similar to leucine; but, that R/arginine is a positively charged polar amino acid (p.297, Fig.14.3). Thus, the resulting I49R substitution would be a non-conservative substitution.
Regarding instant claims 82 and 83: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’358 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position I49 (taught by Dinarello) that is an I49M or I49R substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at I49 provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that I[Wingdings font/0xE0]M and I[Wingdings font/0xE0]R are non-conservative substitutions. Additionally, it would have been obvious to try mutating to M or R as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
[AltContent: textbox (WT IL-18 SEQ ID NO: 1 vs. Instant IL-18 mutant SEQ ID NO: 239[img-media_image5.png])]Regarding instant claim 87, instant SEQ ID NO: 239 encodes an IL-18 mutant with the following substitutions compared to WT IL-18 (see alignment below): E6K, V11I, C38A, M51G, K53A, T63A, C76A, and C127A.
Dinarello additionally teaches that amino acid “Met-87,” which corresponds to instant position M51, can be mutated via substitution to other amino acids, and preferably non-conservative amino acids, in order to make IL-18 less susceptible to neutralization by IL-18BP (see Dinarello p.2, [0018—[0020]; p.3, [0031]).
Barnes teaches that M/methionine is a sulfur-containing amino acid; but, that G/glycine is a small/tiny hydrophobic amino acid (p.301; p.297, Fig.14.3). Thus, the resulting M51G substitution would be a non-conservative substitution.
Regarding instant claim 87: It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of App’358 with additional teachings of Dinarello and the teachings of Barnes by modifying the IL-18 E6K/V11I/C38A/K53A/T63A/C76A/C127A mutant to further comprise a substitution at position M51 (taught by Dinarello) that is an M51G substitution (as taught by the combination of Dinarello and Barnes), in order to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Dinarello, that a substitution at M51G provides for less susceptibility of IL-18 to neutralization by IL-18BP. One of ordinary skill in the art would have a reasonable expectation of success because Dinarello teaches that non-conservative substitutions are preferred to elicit this effect and Barnes teaches that M[Wingdings font/0xE0]G are non-conservative substitutions. Additionally, it would have been obvious to try mutating to G as there is a finite, predictable number of non-conservative amino acids, which provides one of ordinary skill with a reasonable expectation of success via routine optimization.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Regarding the obviousness rejection of the IL-18 E6K/V11I/K53A/T63A mutant, applicant argues that a person of ordinary skill in the art would have no reason to select the instant combination of E6K, V11I, K53A, and T63A substitutions from the myriad of IL-18 substitutions known in the art at the time of filing” (see applicant arguments, 12/19/2025, p.2, para.2). Further, applicant submits that the claimed combination of substitutions possesses “uniquely high potency and resistance to inhibition by IL-18BP, far beyond that which would be predicted based on the teachings of Swencki-Underwood, Dinarello, and Kim” (see applicant arguments, 12/19/2025, p.2, para.3). The examiner respectfully disagrees as the prior art teaches specific motivations for each of the IL-18 substitutions, as well as the motivation for each substitution which are synergistic: Swencki-Underwood teaches the V11I/T63A mutant; Dinarello teaches the K53A mutant; and, Kim teaches the E6K mutant. Further, as the combination of prior art teachings resulting in the obviousness rejection of an IL-18 mutant that shares 100% identity to the instantly claimed structure, the IL-18 mutant taught by the combination of prior art references necessarily possesses the same properties of “uniquely high potency and resistance to inhibition by IL-18BP.” Thus, the combination of prior art teaches the IL-18 E6K/V11I/K53A/T63A mutant as well as the associated functions based on inherent structure/function properties. Thus, applicant arguments are not persuasive and the rejections are maintained in modified form above. By the same logic, the combination of prior art references also teaches the IL-18 mutants of instant SEQ ID NOs: 8, 232, 233, and 239, which arbor the following additional mutations, respectively: T95C, I49M, I49R, and M51G.
Allowable Subject Matter
A modified IL-18 polypeptide that comprises substitutions E6K, V11I, K53A, and T63A (of instant claim 5) as well as M86C and/or K8E, and/or V153E or V153Y is novel.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art is provided by Nisthal which teaches substitutions at Q103 that can include Q103C, Q103L, Q103I, and Q103E (p.18, [0174]); however, the prior art does not teach the specific Q103R substitution, K8E substitution of V153E/Y substitution, nor any motivations for incorporating these substitutions.
Conclusion
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.
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 Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647