DETAILED OFFICE ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment filed on 24 September 2025 is acknowledged and entered. Following the amendment, claims 3 and 154 are canceled, and claims 1, 4, 152, and 155 are amended.
Currently, claims Currently, claims 1, 2, 4, 24, 30, 47, 51, 91, 113, 152, 153 and 155-157 are pending, and claims 1, 2, 4, 24, 30, 47, 51, 152, 153 and 155-157 are under consideration. Claims 91 and 113 remain withdrawn from further consideration as being drawn to a non-elected invention.
Withdrawal of Objections and Rejections:
All objections and rejections of claims 3 and 154 are moot as the applicant has canceled the claim.
The rejection of claims 24 and 30 under 35 U.S.C. 112(b), as being indefinite is withdrawn in view of applicant’s amendment.
The prior art rejection of claims 152, 156 and 157 under 35 U.S.C. 103 as being unpatentable over Dinarello et al (US 2002/0169291A1, 11/14/2002; or its patent US 7,524,488 4/28/2009), and in view of Kim et al. (J Biol Chem. 2002 Mar 29; 277(13): 10998-11003) is withdrawn upon further consideration.
Formal Matters:
Information Disclosure Statement
Applicant's IDS submitted on 9/24/2025 is acknowledged and has been considered. A signed copy is attached hereto.
Claims
Claim 24 is objected to for the following reason, appropriate correction is required:
Claim 24 recites “comprises a polypeptide sequence as set forth in SEQ ID NO: 7”; the following is suggested: “comprises the polypeptide sequence as set forth in SEQ ID NO: 7”.
Rejections under 35 U.S.C. §112:
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4, 47 and 51 remain rejected, and claims 152, 153 and 155-157 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 remains indefinite for the recitation “wherein any additional modification to the polypeptide sequence … is selected from …” because it is unclear 1) what “any additional modification” is meant or encompasses, for example, is “any additional modification” required, or does “any” mean that the modified IL-18 polypeptide may or may not comprise additional modification (especially in view of the dependent claim 24, in which, the recited SEQ ID NO:7 only comprises E06K and K53A substitutions); and 2) does “modification” mean a single one amino acid substitution, or a combination of any number of amino acid substitutions selected from the recited residues? The metes and bounds of the claim, therefore, cannot be determined. The claim is further indefinite for the recitation “wherein the modified IL-18 polypeptide … with an EC50 which is at most 10-fold higher than that of the IL-18 polypeptide of SEQ ID NO: 1” because it is unclear what it is meant or encompasses. For example, does it mean that all encompassed variants have an EC50 which is at least higher than that of the IL-18 polypeptide of SEQ ID NO: 1 (which is not supported by the specification), but up to 10-fold higher? Or does it also encompass those with an EC50 lower than that of the IL-18 polypeptide of SEQ ID NO: 1, including no said functional activity? Does the claim try to claim a mixture of the IL-18 polypeptides with commonly defined structure but diverse functional activity (which functional limitation would be meaningless)? Such is confusing, and the claim fails to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor. The metes and bounds of the claim, therefore, cannot be determined. Claims 4, 152 and 155 are similarly indefinite for “any additional modification”.
Claim 2 is indefinite for the recitation “wherein the modified IL-18 polypeptide further comprises T63A” because it is unclear what “further comprises” is meant since “T63A” is already recited in claim 1, from which claim 2 is dependent.
The remaining claims are included in this rejection because they are dependent from the specifically mentioned claims without resolving the indefiniteness issue belonging thereto.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1, 2, 4, 47 and 51 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention, for the reasons of record set forth in the previous Office Actions mailed on 11/6/2024, and 4/24/2025.
Applicants argument filed on 24 September 2025 has been fully considered, but is not deemed persuasive for the reasons below.
At page 6 of the response, the applicant argues that at least SEQ ID NOs: 2, 7, 10, 18, and 22 all possess the modifications E06K and K53A and have EC50 values that are at most 10-fold higher than that of WT IL-18; that the Office Action appears to misconstrue the claim as instead requiring that the claimed IL-18 polypeptides are 10-fold more potent however, the limitation of claim 1 regarding the EC50 value instead encompasses IL-18 polypeptides which are not only more potent, but also the IL-18 polypeptides which have modestly reduced potency (e.g., modestly higher EC50 values), thus, nearly half of the variants having E06K and K53A substitutions meet the limitations; accordingly, the instant disclosure provides a sufficient description to show possession of the invention as claimed; that the claims have been amended to recite wherein any additional modification to the polypeptide sequence of the IL-18 polypeptide related to SEQ ID NO: 1 is selected from …, thus, the claims now recite sufficient structure to guide a person of ordinary skill in the art to those IL-18 polypeptides meeting the other limitations of the claims; and the claims now require that a substantial portion of the sequence matches that of WT IL-18 and recites only a few substitutions which can be introduced in combination with E06K and K53A substitutions.
This argument is not persuasive for the reasons of record. Note, SEQ ID NO: 7 only comprises E06K and K53A substitutions, and does not comprise “any additional modification” as required by the claims (claims 1 and 152, for example), therefore, SEQ ID NO: 7 does not meet the structural limitation of the claims. Further, according to applicant, claim 1 regarding the EC50 value instead encompasses IL-18 polypeptides which are not only more potent, but also the IL-18 polypeptides which have modestly reduced potency. However, the claim, as written (indefinite), seems encompassing variants with any EC50, including those with loss of said activity (not with “modestly reduced potency”), i.e., the recited functional limitation is not so meaningful. For example, the variant of SEQ ID NO: 3 comprises E06K and K53A substitutions plus additional 6 amino acid substitutions selected from those recited in claim 1, and meets the structural limitation of the claim. However, this variant exhibits no binding to IL-18Ra, no binding to IL-18Ra/b heterodimer, and no binding to IL-18BP (see Tables 5-7, for example), and loss of the potency to induce IFNγ production (pages 174-175, Table 9, for example). Similarly, the variant of SEQ ID NO: 12 is another example, which comprises E06K and K53A substitutions plus additional 2 amino acid substitutions (S55A and F02A) selected from those recited in claim 1, meeting the structural limitation of claim 1; however, these 4 amino acid substitutions of the variant resulted in losing the binding activity and the ability to induce IFNγ production. In contrast, the variant of SEQ ID NO: 10 comprises E06K and K53A substitutions plus additional 2 amino acid substitutions of S55A and T63A (difference in one amino acid as compared to SEQ ID NO: 12), meeting the structural limitation of claim 1, and exhibits higher potency/activity (lower EC50 value) in inducing IFNγ production as compared to SEQ ID NO: 1 (Table 9). In fact, the difference in the EC50 between SEQ ID NO: 10 and 12 is almost 7000 times (about 6923X), and SEQ ID NO: 11 (different in one residue (a different one) is in between. Clearly, there is no regularity between the “additional modification” in structure (the polypeptide sequence) and the recited functional activity (inducing IFNγ production); and the specification discloses very limited number of the variants (varying significantly in the activity), while claiming an extremely broad genus comprising countless number of species with or without said functional activity.
According to applicant, at least SEQ ID NOs: 2, 7, 10, 18, and 22 all possess the modifications E06K and K53A and have EC50 values that are at most 10-fold higher than that of WT IL-18 (such is indefinite and does not make sense), which is not the case, because: first, SEQ ID NO: 7 does not meet the structural limitation of the amended claims, thus, is excluded. Further, again, as discussed in the previous Office Actions, the specification discloses 11 variants meeting the structural limitation of the claims (claims 1 and 152, for example), which are derived from the IL-18 of SEQ ID NO: 1, and comprising E06K and K53A substitutions plus “additional modification”, wherein only 3 comprise T63A substitution (SEQ ID NO: 3, 10 and 18); only 2 in total (SEQ ID NO: 10 and 18) have an EC50 that is higher than that of the IL-18 polypeptide of SEQ ID NO: 1 (as claimed?); only 1 (SEQ ID NO: 18) has an EC50 that is 10-fold higher than that of the IL-18 polypeptide of SEQ ID NO: 1; and at least 4 variants (SEQ ID NO: 3, 12, 13 and 17) lost the recited functional activity (inducing IFNγ production) significantly or almost completely (Table 9, for example). Even according to applicants argument (seems claiming a mix of higher and lower EC50 as compared to that of SEQ ID NO: 1), only 4 species might meet the limitations of the claims, while claiming countless number of % variants of SEQ ID NO: 18 or 7, while the specification provides no sufficient teachings regarding the structure-function relationship of SEQ ID NO:18 or 7, such as identification of any particular portion of SEQ ID NO:18 or 7 that must be conserved, and which 5% of the sequence can be further altered while retaining the desired functional properties of the modified IL-18 polypeptide. In addition, the result shown in Table 9 indicates that the activity of the modified IL-18 variants varies significantly and unpredictable. Given the very limited number of species disclosed and the extremely broad genus claimed, one skilled in the art would not conclude that applicant was in possession of the claimed invention at the time the application was filed.
Therefore, again, only the modified IL-18 of SEQ ID NO: 18 and 10, but not the full breadth of the claims (“any additional modification” and “having at least 95% sequence identity …”) meet the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Enablement
Claims 152, 153 and 155-157 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention, for the reasons of record set forth in the last Office Action mailed on 4/24/2025.
Applicants argument filed on 24 September 2025 has been fully considered, but is not deemed persuasive for the reasons below.
At pages 7-8 of the response, the applicant argues that, regarding the Office Action's assertion that "the claims encompass countless IL-18 variants", the amendments to the claims submitted herein limiting the locations of allowed substitutions, which substantially restricts the number of IL-18 variants falling within the scope of the claim, accordingly, a person of ordinary skill in the art would be able to readily ascertain which of the claimed variants exhibit suitable activity by routine experimentation with a reasonable expectation of success as the number of variants encompassed is now smaller and the instant disclosure provides guidance on how to make such IL-18 polypeptides and their activity; that regarding the Office Action's assertion that it is unclear how the results of the data provide should be interpreted and how such IL-18s would be suitable for cancer treatment, the instant claims are not directed to a method of treating cancer (or any other indication), and thus reliance on this as a grounds for rejecting the enablement of the instant claims is misplaced (MPEP 2164.01(c)), such a factor would not be relevant to the instant claims; and that an enablement rejection on such grounds is erroneous.
This argument is not persuasive for the reasons of record and the following: first, the issue is not whether the claims limit the locations of allowed substitutions, and a person of ordinary skill in the art would be able to readily ascertain which of the claimed variants exhibit suitable activity by routine experimentation, rather, the issue is that, as discussed in the previous Office Action, the present claims are drawn to various variants (amino acid substitutions and % variant) without a functional limitation recited for the variants (the independent claim 152, for example). As such, the claims encompass inactive IL-18 variants, and the specification does not teach how to use such variants without a functional activity. In addition, while claim 156 recites “the modified IL-18 polypeptide exhibits a lower affinity for IL-18BP”; and claim 157 recites “wherein the modified IL-18 polypeptide binds to an IL-18Ra/b”, it is unclear what such variants can be used for, or it is unclear to one skilled in the art as to how to use these variants in the “real world”. As discussed in the last Office Action, the examiner tried to identify any use for the claimed variants in the specification, without a significant finding. Although the claims are not directed to a method, 35 U.S.C. 112(a) requires that the specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same. Such requirement applies to a claimed product as well. Further, the breadth of the claims is extremely broad, which encompasses countless IL-18 variants given all possible combinations of the recited amino acid substitutions and additional 5% sequence variations, and encompasses inactive IL-18 variants. As such, the large quantity of experimentation would be necessary to make and test the countless number of the IL-18 variants encompassed, and to determine how to use the variants without a functional activity (including % variants), and how to use the variants such as the IL-18 variants of SEQ ID NO: 7 and 10 in the “real world”. Therefore, it would require undue experimentation in order to make and use the claimed invention.
New ground of rejection
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 24 recites “wherein the modified IL- 18 polypeptide comprises a polypeptide sequence as set forth in SEQ ID NO: 7”, which SEQ ID NO: 7 comprises E06K and K53A only as compared to SEQ ID NO: 1, i.e., SEQ ID NO: 7 does not comprise “any additional modification” as that recited in claim 1, from which claim 24 is dependent. Note, here, “any additional modification” is interpretated as being required, i.e., the modified IL-18 polypeptide does comprise additional amino acid substitution(s) since claim 1 is indefinite for the reasons discussed above.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Rejections Over Prior Art:
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 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 of this title, 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.
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.
Claims 1, 24, 47 and 51 remain rejected under 35 U.S.C. 103 as being unpatentable over Dinarello et al (US 2002/0169291A1, 11/14/2002; or its patent US 7,524,488 4/28/2009; provided by applicant), and in view of Kim et al. (J Biol Chem. 2002 Mar 29; 277(13): 10998-11003; provided by applicant), for the reasons of record set forth in the last Office Action mailed on 4/24/2025.
Applicants argument filed on 24 September 2025 has been fully considered, but is not deemed persuasive for the reasons below.
At pages 9-11 of the response, the applicant argues that the combined mutations of E6K and K53A provide a surprising, unexpected synergy when combined in an IL-18 polypeptide as in the instant claims resulting in IL-18 polypeptides which possess greater activity and greatly reduced ability to be inhibited by IL-18BP compared to what would be expected based on the teachings of the prior art; that Kim and Dinarello both teach that the E6A and E6K modifications provide an IL-18 which is 2-fold more potent than WT IL-18, suggesting these modifications are substantially equivalent in enhancing potency, a person of ordinary skill in the art would surmise that the combination of E6K and K53A substitutions would be equivalent to one which has E6A and K53A substitutions; that in contrast, the applicant has identified that the E6K/K53A double mutant is over 14-fold more potent in inducing IFNγ production (Table 9) between WT IL-18 (0.276 nM) vs. the E6K/K53A double mutant (0.0192 nM)), nearly double the expected potency based on the teachings of the prior art; that this synergy in enhancing potency allows the incorporation of additional substitutions to impart other properties (which may individually negatively impact potency) and still retain a highly potent IL-18 polypeptide, for example, Table 9 shows that the addition of E6K and K53A modifications to a variant having a T63A modification results in a highly potent IL-18 polypeptide (EC50 0.0268 nM, about 10-fold more potent than WT IL-18) despite the T63A modification by itself lowering potency by about 2-fold (EC50 of the T63A-only mutant having an EC50 of 0.449 nM).
This argument is not persuasive for the following reasons: first, applicants comparison between WT IL-18 of SEQ ID NO: 1 (0.276 nM) vs. the E6K/K53A double mutant of SEQ ID NO: 7 (0.0192 nM) is not so relevant because the IL-18 variants of SEQ ID NO: 7 (E6K/K53A) does not comprise any additional modification as required by claim 1. Therefore, applicant’s argument based on such is outside of what being claimed. Further, out of the rest 11 variants tested and comprising E6K/K53A substitutions (Table 9), only one, the variant of SEQ ID NO: 18 (E6K/K53A/T63A) exhibits said synergy. The variant of SEQ ID NO: 10 (E6K/K53A/S55A/ T63A) exhibits improved EC50, but no synergy; and the remaining 9 variants (comprising E6K/K53A) exhibit either significantly reduced or almost diminished said functional activity. Clearly, E6K/K53A alone cannot control said functional activity when combined with the additional amino acid substitutions (as claimed). However, the present claims (claim 1, for example), as written, encompass countless number of the IL-18 variants (see discussion above), while only one variant, SEQ ID NO: 18 (E6K/K53A/T63A), meeting the limitations of the claims and exhibits said synergy. The present specification clearly demonstrates (in Table 9) that there is no way to predict that an IL-18 variant comprising E6K/K53A and “additional modification” as claimed would necessarily exhibit increase in said functional activity, let alone, synergy, especially in view of the fact that the majority of the variants in Table 9, which meet the structural limitation of claim 1, exhibit decrease in said functional activity. Thus, the evidence of said unexpected result is not commensurate in scope with the claims. According to MPEP, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support" (MPEP 716.02(d)).
At pages 13-15 of the response, the applicant argues that in addition to reliably enhancing potency of IL-18 polypeptides more than would be expected, the combination of E6K and K53A modifications frequently results in IL-18 polypeptides which display greatly reduced ability to be inhibited by IL-18BP, far beyond that which would be expected based on the prior art, as Table 9 shows that the E6K variant has an IC50 for inhibition by IL-18BP of 7.79 nM compared to the IC50 of 1.47 for WT IL-18, a reduction of inhibition of ~5.3-fold, that the IC50 for the K53A variant is 27.3 nM, reduction of inhibition about 18.5-fold, and that when the two modifications are combined, nearly all of the variants tested which still retained IL-18 IFNg stimulation activity comparable to that of WT IL-18 showed abolished or nearly abolished inhibition by IL-18 BP, specifically, variants 2 (E6K, K53A, S55A), 7 (E6K, K53A), 10 (E6K, K53A, S55A, T63A), and 18 (E6K, K53A, T63A); that such a reduced ability to be inhibited by IL-18BP is not expected in view of the prior art, which IL-18 variants show a modest reduction in inhibition by IL-18 BP compared to WT IL-18; accordingly, in view of the high degree of potency and extremely minimal inhibition by IL-1 8BP unexpectedly demonstrated by the IL- 18 polypeptides of the application, the instant claims are not obvious in view of Dinarello and Kim.
This argument is not persuasive for the following reasons: first, again, applicants comparison of IC50 between the IL-18 variants carrying a single amino acid substitution (E6K or K53A) and WT IL-18 is not so relevant because such are not encompassed by the claims, i.e., again, applicant is arguing that outside of what being claimed. Further, contrary to applicants argument that the combination of E6K and K53A modifications reliably enhancing potency of IL-18 polypeptides more than would be expected, as discussed above, the majority of the variants (9/11) in Table 9, which meet the structural limitation of claim 1, exhibit decreased or diminished potency (EC50), including SEQ ID NO: 2, 3, 11-14, 17, 22 and 71; and only two variants (2/11), SEQ ID NO: 10 and 18, exhibit the enhanced potency. Therefore, applicants further argument that the combination of E6K and K53A modifications frequently results in IL-18 polypeptides which display greatly reduced ability to be inhibited by IL-18BP is not meaningful or persuasive.
Conclusion:
No claim is allowed.
Claim 30 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Advisory Information:
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 extension fee 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 should be directed to Examiner DONG JIANG whose telephone number is 571-272-0872. The examiner can normally be reached on Monday - Friday from 9:30 AM to 7:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DONG JIANG/
Primary Examiner, Art Unit 1674
12/8/25