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 .
Claim Status
Claim listing filed on December 31, 2025 is pending. Claims 2-3, 6, 21-24, 28, 31-32, 35, 37, 40-41, and 46 are canceled. Claims 1, 15-18, 25-26, 29-30, 34, and 54-55 are amended. Claims 5, 7-8, 36, 38-39, 42, 45, and 47-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species. Claims 1, 4, 9-20, 25-27, 29-30, 33-34, 43-44, and 54-55 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 3 and 23 have rendered all previous rejections directed to these claims moot.
The amendments to the claims have overcome all objections of record, and the claim objections are withdrawn.
The rejection of claims 1, 4, 9-20, 25-27, 29-30, 33-34, 43-44, and 54-55 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 1, 4, 9-20, 25-27, 29-30, 33-34, 43-44, and 54-55 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 is maintained. The claims contain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Amended Claim 1 now defines the placement of the IL-15 within the ultralong CDR3 (“wherein the IL-15 cytokine sequence replaces the knob region or a portion of the knob region”); however, Claim 1 is directed to a genus of possible chimeric cytokine modified antibodies that vary in antibody structure and IL-15 structure. Specifically, the IL-15 sequence can comprise “at least at or about 85% sequence identity to SEQ ID NO: 1” (Claim 1), and based on the specification definition of “about”, this limitation is interpreted as “at least 65% sequence identity to SEQ ID NO: 1” (interpretation of record in the non-final action filed 07/02/2025, page 12). Considering SEQ ID NO: 1 is 114 amino acids long, any combination of 39 amino acids can be inserted, deleted, or substituted with any other amino acid (35% X 114). The disclosure does not provide proper written description for the substantial structural variation in the IL-15 cytokine.
Claim 11 recites wherein the antibody comprises a variable heavy chain encoded by the sequence set forth in SEQ ID NO: 5 and a variable light chain encoded by the sequence set forth in SEQ ID NO: 8. It is of record in the non-final action filed 07/02/2025 that a sequence “set forth in SEQ ID NO: X” reads on any segment of two or more amino acids within SEQ ID NO: X (page 12). Therefore, Claim 11 is directed to a genus of antibodies comprising variable heavy and light chain domains encoded by SEQ ID NOs: 5 and 8 respectively or any fragment thereof. Further, Claim 15 recites wherein the antibody comprises a heavy chain or portion thereof that is a human heavy chain germline sequence or a variant comprising one or more mutations and a light chain or a portion thereof that is a human light chain germline sequence or a variant comprising one or more mutations (underline added to emphasize structural variation encompassed by fragments and variants). It is well-understood in the art that antibody heavy and light variable domains each comprise three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The claims broadly encompass antibody heavy and light variable domain fragments and variants that can comprise any length and any combination of mutations. The disclosure does not provide proper written description for the substantial structural variation in the antibody domains.
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that amended Claim 1 recites a specific structural configuration in which a human IL-15 cytokine is incorporated within a bovine ultralong heavy-chain CDR3 architecture. While the placement of the IL-15 within the ultralong CDR3 is now defined, the claims are still directed to a genus of possible chimeric cytokine modified antibodies that vary in IL-15 structure and antibody structure as outlined above.
Applicant argues that the claims do not require the antibody to bind a target ligand. Applicant argues that the antibody (and corresponding CDRs) act as a scaffold for the IL-15 sequence and that the antibody binding capabilities are not the novelty of the claimed invention. No matter if the antibody binding function is or is not the point of novelty, the claims are still directed to a genus of antibodies with structural variation in their heavy and light domains, and it is unclear how this structural variation affects the function of the claimed chimeric cytokine. Even if the antibody is only used as a scaffold for the IL-15 cytokine, the antibody domains are required to have proper folding and structure to maintain a stable framework for the IL-15 cytokine. Specifically, the antibody is required to have an ascending stalk domain, a knob region, and a descending stalk domain in its ultralong CDR3 region (Claim 1) and it is unclear from the disclosure how mutations in this domain could disrupt this required architecture. Currently, substantial variation is claimed within the antibody domains and the disclosure offers no structure-to-function correlation for how these structural variations may affect antibody binding and/or scaffolding function. Applicant’s arguments have been considered but they are not persuasive, and the rejection is maintained.
The rejection of Claims 1, 4, 9-20, 25-27, 29-30, 33-34, 43-44, and 54-55 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification, while being enabling for the specific species of chimeric cytokine modified antibody B15 and those known in the art prior to filing, does not reasonably provide enablement for the genus of chimeric cytokine modified antibodies (Claim 1). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
As outlined in the written description rejection above, amended Claim 1 now defines the placement of the IL-15 within the ultralong CDR3; however, Claim 1 is still directed to a genus of possible chimeric cytokine modified antibodies that vary in antibody structure and IL-15 structure. A person having ordinary skill in the art would have to perform further experimentation to make the chimeric cytokine modified antibodies encompassed by the claims by varying the antibody domains and IL-15 structures and screen their characteristics in order to practice the invention commensurate with the scope of the claims.
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that amended Claim 1 recites a specific structural configuration in which a human IL-15 cytokine is incorporated within a bovine ultralong heavy-chain CDR3 architecture. Applicant argues that from the working examples, the recited replacement of the knob region with IL-15 between the stalk domains can be achieved using routine recombinant techniques without undue experimentation. While the placement of the IL-15 within the ultralong CDR3 is now defined and properly enabled, the claims are still directed to a genus of possible chimeric cytokine modified antibodies with substantial variation in IL-15 structure and antibody structure that lacks enablement.
Applicant argues that the claims do not require identifying antibodies with any particular antigen-binding function or “target ligand” binding, and the antibody provides a scaffold for positioning and presenting IL-15 within the modified ultralong CDR3. No matter what the antibody’s intended function is (ligand targeting or protein scaffolding), a genus of antibodies is claimed with substantial structural variation and the disclosure provides no guidance for how variation in the amino acids can affect function (ligand targeting and/or protein scaffolding). One of ordinary skill would have to make a representative number of antibody species (fragments and mutational variants) and screen their characteristics (ligand binding and/or protein scaffolding) in order to make and use the claimed genus of chimeric cytokine modified antibodies, and this level of experimentation is undue. Applicant’s arguments have been considered but they are not persuasive, and the rejection is maintained.
Claim Rejections - 35 USC § 102 (Modified, necessitated by amendment)
Claims 1, 4, 9-20, 34, and 43-44 under 35 U.S.C. 102(a)(1) are rejected as being anticipated by Smider et al WO 2013/106489 (of record) as evidenced by Bernett et al. WO 2018/071919 (of record) and Vadnais et al. Curr Opin Struct Biol. 2016.
Amended Claim 1 recites wherein the ultralong CDR3 region comprises an ascending stalk domain, a knob region, and a descending stalk domain wherein the IL-15 cytokine sequence replaces the knob region or a portion of the knob region. It is of record in the non-final rejection filed 07/02/2025 that Smider teaches inserting an IL-15 cytokine into an ultralong CDR3 of a bovine antibody wherein the bovine antibody is BLV1H12. Smider specifically teaches working examples of inserting cytokines into the ultralong CDR3 of BLV1H12 by replacing a “cysteine-rich portion” of the ultralong CDR3 (paragraph [00601]). Smider further teaches that the ultralong CDR3 comprises a cysteine motif and structural changes to the ultralong CDR3 are made in between one or more cysteine residues in the cysteine motif (paragraph [00150]). The “cysteine motif” and “cysteine-rich portion” of the ultralong CDR3 is synonymous with the knob region as evidenced by Vadnais. Vadnais teaches that the ultralong CDR3 of BLV1H12 comprises an ascending stalk, a knob region, and a descending stalk (Fig. 1A) wherein the knob region falls between the stalks, the knob region is encoded by DH, and the knob region is rich in cysteines (Fig. 1B and page 5 paragraph 2). The knob region itself is formed by the disulfide bonds in between cysteine residues (page 5 paragraph 2 and introduction paragraph 1). Therefore, Vadnais teaches that the BLV1H12 ultralong CDR3 taught by Smider inherently comprises an ascending stalk, a knob region, and a descending stalk wherein the cytokine is inserted in the knob region (aka cysteine motif). Although the terminology differs (knob region vs cysteine motif), it is clear that Smider reads on amended Claim 1.
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that Smider does not read on amended Claim 1 because it encompasses the limitations of canceled Claim 23, specifically wherein the cytokine is present between the ascending stalk domain and the descending stalk domain. As evidenced by Vadnais, the BLV1H12 ultralong CDR3 taught by Smider inherently comprises an ascending stalk, a knob region, and a descending stalk wherein the cytokine is inserted in the knob region (aka cysteine motif) between the stalks. The rejection is maintained.
Claims 1 and 25-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ekiert et al WO 2013/106485 (of record) as evidenced by Bernett et al. WO 2018/071919 (of record).
It is of record in the non-final rejection filed 07/02/2025 that Ekiert teaches humanized bovine antibodies comprising an ultralong CDR3 wherein an IL-15 cytokine can be inserted to replace the knob domain. Ekiert does not specifically teach the amino acid sequence of IL-15, but Bernett defines the sequence of mature human wild type IL-15 in SEQ ID NO: 6 (Fig. 2A) which shares 100% identity to instant SEQ ID NO: 1. Therefore, the teachings of Ekiert read on amended Claim 1, specifically wherein the IL-15 sequence comprises “at least at or about 85% sequence identity to SEQ ID NO: 1.”
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that Ekiert does not read on amended Claim 1 because it encompasses the limitations of canceled Claim 3, specifically wherein the IL-15 cytokine comprises at least at or about 85% sequence identity to SEQ ID NO: 1. As evidenced by Bernett, the IL-15 cytokine taught by Ekiert inherently comprises SEQ ID NO: 1 because it is the known sequence of mature human wild type IL-15. The rejection is maintained.
Claim Rejections - 35 USC § 103 (Modified, necessitated by amendment)
Claims 1, 4, 9-20, 29-30, 33-34, and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Smider et al WO 2013/106489 (of record) as applied to Claims 1, 4, 9-20, 34, and 43-44 as evidenced by Bernett et al. WO 2018/071919 (of record) and Vadnais et al. Curr Opin Struct Biol. 2016 above, and further in view of Bernett et al. WO 2018/071919 (of record).
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that Smider does not read on amended Claim 1 because it encompasses the limitations of canceled Claim 23, specifically wherein the cytokine is present between the ascending stalk domain and the descending stalk domain. As evidenced by Vadnais in the 102 rejection above, the BLV1H12 ultralong CDR3 taught by Smider inherently comprises an ascending stalk, a knob region, and a descending stalk wherein the cytokine is inserted in the knob region (aka cysteine motif) between the stalks. The rejection is maintained.
Claims 1, 4, 9-20, 34, 43-44, and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Smider et al WO 2013/106489 (of record) as applied to Claims 1, 4, 9-20, 34, and 43-44 as evidenced by Bernett et al. WO 2018/071919 (of record) and Vadnais et al. Curr Opin Struct Biol. 2016 above, and further in view of Bazirgan et al. WO 2015/010100 (of record).
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant argues that Smider does not read on amended Claim 1 because it encompasses the limitations of canceled Claim 23, specifically wherein the cytokine is present between the ascending stalk domain and the descending stalk domain. As evidenced by Vadnais in the 102 rejection above, the BLV1H12 ultralong CDR3 taught by Smider inherently comprises an ascending stalk, a knob region, and a descending stalk wherein the cytokine is inserted in the knob region (aka cysteine motif) between the stalks. The rejection is maintained.
Double Patenting (Maintained)
The provisional rejection of Claims 1, 4, 9-10, 14-15, 17, 25-27, 29, 33, and 43-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9, 25, 31, 33, 45, 48, and 61-62 of copending U.S. App. No. 18/557,470 as evidenced by Bernett et al. WO 2018/071919 (of record) is maintained.
Applicant's arguments filed December 31, 2025 have been fully considered but they are not persuasive. Applicant requests that this provisional double patenting rejection be held in abeyance until otherwise allowable subject matter is found. MPEP § 804.I.B.1 states that “as filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.” As no terminal disclaimer has been filed and no showing has been made that the claims are patentably distinct, the provisional double patenting rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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