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 amendments and remarks filed 07/29/2026 are acknowledged.
Claims 1-15 and 29-33 are pending.
Claims 14-15 are amended.
Claims 16-28 are canceled.
Applicant’s election without traverse of the following species in the reply filed on 07/29/2026 is acknowledged: 4CS/S10C/K53T/M60K/Nl55C for the combination of amino acid substitutions for the variant human IL-18 protein, 3 monomers for the construct with the specific structure of: (a) a first monomer comprising from N-terminus to C-terminus: a first variable heavy domain (VH1), an scFv, and a first Fc domain; (b) a second monomer comprising from N-terminus to C-terminus: said variant human IL18 protein and a second Fc domain; and (c) a third monomer comprising from N-terminus to C-terminus: a first variable light domain (VL1) and a constant light domain, wherein the VH1 and the VL1 together form the first ABD that binds to the ECD of the human TTA and wherein the scFv comprises a second variable heavy domain (VH2), a scFv linker, and a second variable light domain (VL2), wherein the VH2 and the VL2 together form the second ABD that binds to the ECD of human CD3ɛ, GPC3 as the specific TTA, SEQ ID NOs: 2604 and 2606 for the sequences of the anti-GPC3 TTA, and SEQ ID NOs: 1620 and 1615 for the second ABD that binds to ECD of human CD3ɛ.
Claims 6-12 and 30-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/29/2026,
Therefore, claims 1-5, 13-15 and 29 are under examination.
Priority
The instant application claims priority to provisional applications 63/382,590, 63/387,650, 63/387,913, 63/478,652, 63/481,343, 63/502,279, 63/502,344, and 63/590,872. Priority is given with the earliest effective filing date of 11/07/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/29/2023, 04/17/2024, 07/17/2024, 01/06/2025, and 03/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because of the following:
(a) Figures 1A-B, 2A-B, 3A-B, 8, 9A-E, 10, 11, 13A-B, 14, 15A-B, 16A-C, 17-18, 19A-I, 20A-C, 21A-I, 22A-22DO, 41A-C, 42A-D, 43A-B, 44A-C, 80A-R, 88A-E, 119, 120A-F, 121A-B, 122A-K, 123A-M, 124A-F, 125A-G, 126-127, 128A-C, 129, 146-147, 148A-H, 149A-R, 150A-C, 151A-B, 152, 153A-C, 154A-B, 155, 156A-156FF, 157A-R, 158A0C, 159, 160A-C, and 161A-G list sequences of the sequence listing without any significant characteristics that could only be demonstrated by a figure. MPEP 2422.02 states “pursuant to 37 CFR 1.83(a), sequences that are included in sequence listings should not be duplicated in the drawings.”
(b) Figures 23A-B, 24A-B, 25A-B, 32-33, 83B-D, 84A-J, 85A-J, 109, 110B, 112A-B, 162, 163A-B, 164A-B165A-B, 166A-C, and 167A-B are of insufficient quality to read and/or interpret.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 14 are objected to because of the following informalities: Claims 1 and 14 recite an acronym (i.e. IL-18, IL-18BP, GPC3, EGFR, Trop2, CD20, B7H3, FLT3, CD19, CD123, CD22, CD38, CEA, MSLN, BCMA, CAIX, CLDN18.2, HER2, PD-1, ANO1). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction is required.
Claim 2 is rejected as being dependent upon a rejected base claim (i.e. claim 1) but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. If rewritten in independent form, the Examiner recommends amending the claim to recite the “variant human IL-18 protein comprises the combination of amino acid substitutions selected from the group consisting of 4CS/S10C/K53T/M60K/N155C and 4CS/S10C/K53T/V153K/N155C” for clarity and to mitigate any 112(b) issues.
Claim 4 is objected to because of the following informalities: Claim 4 recites “reduced binding to IL-BP”. The Examiner believes this was meant to recite “reduced binding to IL-18BP.” Appropriate correction is required.
Claims 15 and 29 are objected to because of the following informalities: Claims 15 and 29 recite reference to specific Figures. MPEP 2173.05(s) states "where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). Appropriate correction is required.
Improper Markush Grouping
Claims 1, 3, and 13 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a "single structural similarity" and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a "single structural similarity" and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of amino acid modifications for the variant human IL-18 protein, as set forth in instant claims 1 and 13, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives do not share both a substantial structural feature and a common use that flows from the substantial structural feature. For example, 4CS/S10C/K53T/M60K/Nl55C for the combination of amino acid substitutions for the variant human IL-18 protein, as elected, encompasses 8 substitutions. However, the claim also encompasses variant hIL-18 proteins with single amino acid substitutions, such as K8R or Q103Y, and various other combination of amino acid substitutions, such as E6Q/K53T/M60K/V153K, which comprise only one of the elected substitutions. Therefore, the alternatives listed do share both a substantial structural feature and a common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Note: 4CS/S10C/K53T/M60K/Nl55C for the combination of amino acid substitutions for the variant human IL-18 protein, as elected, was found to be novel and non-obvious. The Examiner did not search additional species because the non-elected species do not fall within a proper Markush group. See MPEP 803.02(III)(C)(2). However, any embodiment that comprises the combination of amino acid substitutions of 4CS/S10C/K53T/Nl55C would be a proper species of the elected embodiment.
Claim 3, which depends from claim 1, is therefore rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 112(b)
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.
Claim 15 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation “wherein said first ABD that binds to the ECD of human GPC3 comprises a variable heavy domain and variable light domain pair as depicted in Figure 123G and SEQ ID NOS: 2604 and 2606.” SEQ ID NO: 2604 comprises more than a variable heavy domain for GPC3 and appears to comprise a heavy chain (H1.1) and a light chain (L1.16) that are specific for GPC3. Therefore, it is unclear what is meant by a “variable heavy domain and variable light domain pair as depicted in SEQ ID NOS: 2604 and 2606” since SEQ ID NO: 2604 comprises more than a variable heavy domain sequence. Therefore, the scope of this claim is indefinite.
Further, claim 15 lacks antecedent basis. The lack of antecedent basis arises from claim 15’s dependence from claim 4 which does not recite “a first ABD that binds to the ECD of human GPC3”.
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.
Claims 4-5 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett (US20180127501; instant PTO-892) in view of Zhou et al., 2020 (12/19/2023 IDS), Jazayeri et al., 2012 (instant PTO-892), and Ishiguro et al., 2017 (instant PTO-892).
Regarding claims 4-5 and 14, Bernett teaches a bispecific antibody that can have a one-arm central-scFv format [see 0011, Figure 2C depicted below] for use in activating T cells for the treatment of cancer.
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Bernett teaches the structure of the one armed mAb (depicted in Figure 2N which
lacks the scFv of Figure 2C), comprising one monomer that comprises only an Fc
domain (a second monomer comprising a second Fc domain), and another monomer that is a heavy chain (i.e. a first monomer comprising a VH1 and a first Fc domain), and further has a variable light chain domain (VL) and a constant light (CL) domain that associate with the heavy chain to form a Fab (i.e. a third monomer) [0395]. Thus, the description of the structure of Figure 2N can be applied to Figure 2C, which depicts a first monomer comprising from N-terminus to C-terminus, a first VH1, an scFv comprising a second variable heavy domain, a scFv linker, and a second variable light domain, and a first Fc domain, a second monomer comprising a second Fc domain, and a third monomer comprising from N-terminus to C-terminus a first VL1 and a constant light domain.
However, Bernett does not specifically teach that the second monomer comprises a variant human IL18 protein that has reduced binding to IL-BP, that the first antigen binding domain (ABD) binds to the extracellular domain (ECD) of human GPC3, or that the second ABD binds to the ECD of human CD3ɛ.
Zhou teaches a ‘decoy-resistant’ IL-18 (i.e. hDR-18; variant IL-18) protein, which maintains signaling potential, but is impervious to inhibition by IL-18BP (i.e. reduced binding to IL-BP), and exhibits potent anti-tumor efficacy in mouse tumor models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells expressing TOX, expanding the pool of stem-like TCF1+ precursor CD8+ T cells, and enhancing NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression [pages 1-2, Summary; page 7, third paragraph].
Jazayeri teaches monomeric Fc-cytokines (one molecule of cytokine fused to a single Fc dimer) which have improved pharmacokinetics [see Abstract; Figure 5c; page 22, left column, fourth-fifth paragraphs].
Ishiguro teaches a bispecific antibody termed ERY974 that binds to membranous (i.e. extracellular domains) human GPC3 and CD3e [page 2, right column, first paragraph] that redirects they cytolytic active of T cells against tumor cells expressing the highly tumor-specific antigen GPC3 [page 8, left column, first paragraph]. Ishiguro further teaches that GPC3 is expressed in hepatocellular carcinomas, lung squamous cell carcinomas, lung small cell carcinomas, esophagus squamous cell carcinomas, cardiac adenocarcinomas, gastric cancers, and head and neck cancers, and was not detected in normal tissues, except for the endometrium and placenta [page 2, right column, second paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the construct for use in the treatment of cancer of Bernett to further comprise the variant human IL18 protein of Zhou attached to the N terminus of the second Fc domain. One would have been motivated to have modified the construct of Bernett to comprise the variant human IL-18 protein of Zhou attached to the N terminus of the second Fc domain because Zhou teaches a variant hIL-18 protein that maintains signaling potential, but is impervious to inhibition by IL-18BP, and exhibits potent anti-tumor (cancer) efficacy. This follows the logic of MPEP 2144.06 which states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the separate, anti-cancer therapeutics into a single construct for the same purpose of treating cancer. Further, one would have been motivated with a reasonable expectation of success to have modified the construct to comprise the variant human IL18 protein of Zhou attached to the N terminus of the second Fc domain because Jazayeri teaches that this is a known structure in the art and that monomeric Fc-cytokines have improved pharmacokinetics.
Additionally, one would have been motivated to have modified the Fab and scFv in the construct of Bernett to specifically bind to the ECD of GPC3 and to the ECD of human CD3e. One would have been motivated to have modified the Fab and scFv in the construct of Bernett to specifically bind to the extracellular domain of GPC3 and to the ECD of human CD3e because Ishiguro teaches a bispecific antibody termed ERY974 that binds to the ECDs of human GPC3 and CD3e which redirects the cytolytic activity of T cells against tumor cells expressing the highly tumor-specific antigen GPC3, which is expressed in various cancers, but not in normal tissues. Thus, one would want to create a construct with anti-tumor activity and various targets in order to have the highest chance of targeting and treating the tumor.
Claims 4-5, 14, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett (US20180127501; instant PTO-892) in view of Zhou et al., 2020 (12/19/2023 IDS), Jazayeri et al., 2012 (instant PTO-892), and Ishiguro et al., 2017 (instant PTO-892), as applied to claims 4-5 and 14 above, and further in view of Desjarlais (WO2014110601; instant PTO-892).
The teachings of Bernett, Zhou, Jazayeri, and Ishiguro are above.
However, Bernett, Zhou, Jazayeri, and Ishiguro do not specifically teach that the second ABD that binds to the ECD of human CD3e comprises a variable heavy domain of SEQ ID NO: 1620 and a variable light domain of SEQ ID NO: 1616.
Regarding claim 29, Desjarlais teaches SEQ ID NO: 398, a humanized anti-CD3 antibody light chain variable region [Figure 26XX], and SEQ ID NO: 253, a humanized anti-CD3 antibody heavy chain variable region [Figure 26FF].
SEQ ID NOs: 398 and 253 of Desjarlais have 100% sequence identity to SEQ ID NOs: 1616 and 1620, respectively, of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the second ABD that binds to the ECD of human CD3e in the construct as taught by Bernett, Zhou, Jazayeri, and Ishiguro to comprise the specific sequences of Desjarlais. One would have been motivated to have modified the second ABD that binds to the ECD of human CD3e to comprise the sequences as taught by Desjarlais because Desjarlais teaches that SEQ ID NO: 398 is a humanized anti-CD3 antibody light chain variable region and SEQ ID NO: 253 is a humanized anti-CD3 antibody heavy chain variable region. Further, one would have been motivated to use these sequences for the variable heavy domain and variable light domain of the second ABD that binds to the ECD of human CD3e because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Allowable Subject Matter
4CS/S10C/K53T/M60K/Nl55C for the combination of amino acid substitutions for the variant human IL-18 protein, as elected, and any embodiment that comprises the combination of amino acid substitutions of 4CS/S10C/K53T/Nl55C, was found to be novel and non-obvious. However, consistent with the improper markush rejection, the Examiner did not search the other species within the instant claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
