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 March 5, 2026 is pending. Claims 1-2, 5-172, and 185-188 are canceled. Claims 3-4, 173-184 and 189-190 are amended. Claims 191-192 are new. Claims 178-184 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 3-4, 173-177, and 189-192 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on 03/05/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 1-2 and 185-188 have rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the abstract overcome all objections of record, and the specification objections are withdrawn.
The rejection of Claim 4 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. Claim 4 no longer recites the indefinite phrase “at least 100% sequence identity.”
The rejection of Claims 3-4, 173-177, and 189-190 under 35 U.S.C. 103 as being unpatentable over Penaflor WO 2021/207274 and Zhu et al. J Biol Chem. 1997 in view of Jin WO 2021/244486 and Ranasinghe et al. Cytokine Growth Factor Rev. 2014 as evidenced by UniProt IL13RA2 2020 is withdrawn in view of Applicant’s remarks filed 03/05/2026. It is persuasive that Penaflor teaches orthogonal receptors wherein the instantly claimed switch receptors are an improvement upon orthogonal receptors because the switch receptors do not require administration of an orthogonal cytokine (specification pages 49-50 and 233). It is also persuasive that the modification proposed by the Examiner would change the intended effect of the orthogonal receptors described in Penaflor. In light of the distinction between orthogonal and switch receptors, the rejection is withdrawn.
The provisional rejection of Claims 3-4, 173-175, and 189-190 on the ground of nonstatutory double patenting as being unpatentable over claims 34-37, 41, 47, 51-54, and 62 of copending U.S. App. No. 17/641,688 is withdrawn in view of the Notice of Abandonment filed in U.S. App. No. 17/641,688 on January 6, 2026.
Claim Rejections - 35 USC § 112 (Maintain)
The rejection of Claims 3, 173-177, and 189-192 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 is maintained.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive. Applicant argues that a person of ordinary skill would have recognized what is meant by a ligand-binding domain (LBD) of a receptor selected from IL13Ra2, IL2Rb, IL18Ra, and IL18Rb because the term “ligand-binding domain” was well understood by a person of ordinary skill in the art as evidenced by Zhukova et al. (Exhibit A) and Pletnev et al. (Exhibit B). Zhukova discloses the structural properties of IL1 receptors which are not currently claimed, and Pletnev discloses the structural properties of IL10 receptors which are not currently claimed. Therefore, neither Exhibit A nor Exhibit B provide evidence for the structural metes and bounds of the instantly claimed LBDs. Applicant remarks recite the LBD as being “the portion of a receptor that is responsible for recognizing and binding to a ligand” which further defines the LBD using indefinite functional language. It is still unclear what portions (e.g. what amino acid residues) of the cytokine receptors makeup the “ligand-binding domain.” For example, Lupardus et al. Structure. 2010 teaches that IL-13 binds IL-13Ra2 at two binding sites (Site II and Site III) spanning Domains 1, 2, and 3 of IL-13Ra2 (Figure 1C). It is unclear if a IL-13Ra2 LBD comprising just Domain 1 would be capable of ligand binding, if a IL-13Ra2 LBD comprising just Domain 3 would be capable of ligand binding, or if all 3 Domains are necessary for ligand binding. As such, the structural metes and bounds of what is encompassed by a IL-13Ra2 LBD are unclear due to the functional definition.
Applicant argues that the specification teaches the amino acid sequences for each of the LBDs recited in Claim 3 (SEQ ID NOs: 7-14 on pages67-70 and 97-99). However, it is of record in the non-final office action filed 12/05/2025 that the specification recites “in some embodiments” the LBD of human IL-13Rα2 has at least 80% identity to SEQ ID NO: 7 (page 97, lines 15-20), and the term “in some embodiments” makes the definition non-limiting in structure. In some embodiments, the IL-13Ra2 LBD comprises SEQ ID NO: 7, but in other embodiments, the IL-13Ra2 LBD could comprise a different structure as long as ligand binding function is maintained. The specification does not, for example, define that the IL-13Ra2 LBD comprises residues x to z of a defined sequence. Because the specification nor the art prior to filing clearly defines the structural metes and bounds (e.g. amino acid residues) that comprise the LBDs of the recited cytokine receptors, the indefinite functional language rejection is maintained.
Applicant argues that a person of ordinary would have recognized what is meant by an intracellular signaling domain of an IL9Ra because these receptors are well known as evidenced by Zhu et al. (Exhibit C). Zhu teaches that amino acid residues 295-338 of IL-9Ra are essential for IL-9-induced cell proliferation and phosphorylation of JAK kinases wherein amino acid residues 338-422 of IL-9Ra are critical for IL-9-induced cell growth, activation of STAT3, and up-regulation of c-myc and junB gene expression (page 21339, last paragraph). Therefore, different structures are responsible for different signaling functions. It is unclear what specific amino acid residues are encompassed by “a human IL9Ra intracellular signaling domain” as encompassed by the claims. For example, could a IL9Ra intracellular signaling domain solely comprise residues 295-338 or are residues 338-422 also necessary for sufficient functional signaling? The phrase is still defined by its function without clear structural metes and bounds.
Applicant argues that the specification provides amino acid sequences for the intracellular signaling domain (ICD) of an IL9Ra (SEQ ID NOs: 1, 2, and 73 pages 64-65), but as stated above, the specification recites “in some embodiments” the ICD of IL9Ra comprises SEQ ID NO: 1 (page 95) which is a non-limiitng example rather than a definition.
Applicant argues that a person of ordinary skill would understand what is meant by “an extracellular binding domain that binds to a tumor antigen” in Claim 175 because the antigen binding domain is capable of binding a tumor antigen. This definition solely defines the binding domain by its function rather than any sort of structure. Applicant further argues that the specification provides numerous examples of suitable tumor antigens to which the domains bind. Listing tumor antigens to which the domains bind provides no structural definition for the binding domains themselves. Specification page 163 defines that the antigen binding domains can include “any domain that binds to the antigen” and lists non-limiting examples of binding domain structures which do not provide clear structural boundaries for what is encompassed by the binding domains. The indefinite functional language rejection is maintained.
Note, “a human CD8 transmembrane domain, a human 4-1BB costimulatory domain, a human CD28 costimulatory domain, and a human CD3z signaling domain” as recited in Claim 175 are definite as they are standard domains used in CARs as evidenced by Jayaraman et al. EBioMedicine. 2020.
The rejection of Claims 3-4, 173-177, and 189-192 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.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive. Applicant argues that Claim 3 has been amended to recite the specific human chimeric cytokine receptors described in Table 1 of the specification, and as such, the specification conveys that Applicants were in possession of the invention. Table 1 teaches five human chimeric cytokine receptors comprising SEQ ID NOs: 15, 17, 19, 21, and 23. Instant claim 3 encompasses a much broader genus than the chimeric cytokine receptors comprising SEQ ID NOs: 15, 17, 19, 21, and 23. The broadest reasonable interpretation is that the domains recited in Claim 3 encompass functional truncations and structural variants. This interpretation is further supported by Claim 4 which recites wherein the chimeric cytokine receptor of Claim 3 comprises at least 95% identity to the sequence set forth in SEQ ID NOs: 15, 17, 19, 21, or 23. Note, the sequence “set forth in” encompasses any fragment of two or more amino acid residues within the recited sequences. Alternative claim language to encompass the recited sequences in their entirety could recite “at least 95% sequence identity to the sequence comprising SEQ ID NO: 15, 17, 19, 21, or 23.” Even if Claim 4 recited “comprising” rather than “set forth in,” the claim would still encompass a genus of possible chimeric cytokine receptors. As SEQ ID NO: 17 comprises 594 residues, 5% variation means that any combination of 29 amino acids can be inserted, deleted, or substituted which results in a genus of thousands of chimeric cytokine receptor variants. Importantly, Claim 3 encompasses an even broader genus of chimeric cytokine receptors than Claim 4 (as is proper for dependent claims). Therefore, the amended claims are still directed to a genus of chimeric cytokine receptors for which the specification lacks proper written description.
Applicant argues that there is proper written description for the CARs described in Claim 175 that comprise “an extracellular binding domain that binds to a tumor antigen” because the specification provides numerous examples of suitable tumor antigens to which the domains bind (page 163) and exemplary amino acid sequences for exemplary extracellular tumor antigen binding domains (pages 172-173 and 179-187). Examiner maintains that listing examples of tumor antigens to which the domains bind does not provide any examples of the binding domains themselves. Further, the exemplary binding domains outlined on pages 172-173 and 179-187 teach an anti-human mesothelin scFv, an anti-GD2 scFv, an anti-HER2 scFv, an anti-TnMuc1 scFv, an anti-CD70 scFv, an anti-PMSA scFv, an anti-EGFRvIII scFv, and an anti-EGFR_806 scFv. Eight scFvs do not adequately represent the substantial variation across the genus of CARs claimed. The CAR can bind any tumor antigen and thousands of tumor antigens have been identified in the art. Further, there are potentially thousands of binding domains that can bind each tumor antigen as the claimed CARs are not limited to scFv structure. Therefore, the amended claims are still directed to a genus of CARs for which the specification lacks proper written description.
The rejection of Claims 3-4, 173-177, and 189-192 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 CCRs in Table 1 and CARs known in the art prior to filling, does not reasonably provide enablement for the genus of CCRs and the genus of CARs encompassed by the claims. 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.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive. Applicant argues that Claim 3 has been amended to recite the specific human chimeric cytokine receptors described in Table 1 of the specification, and as such, the specification provides ample descriptions for each of the components of the chimeric cytokine receptors. It is outlined in the written description rejection above how the claims are still directed to a broad genus of chimeric cytokine receptors (CCRs), and a person having ordinary skill in the art would have to perform further experimentation to make the CCRs encompassed by the claims, express them in cells, and screen their characteristics in order to practice the invention commensurate with the scope of the claims. This level of experimentation is undue (of record in the non-final office action filed 12/05/2025).
Applicant argues that there is proper enablement for the CARs defined in Claim 175 because the specification provides numerous examples of suitable tumor antigens to which the domains bind (page 163) and exemplary amino acid sequences for exemplary extracellular tumor antigen binding domains (pages 172-173 and 179-187). It is outlined in the written description rejection above how the claims are still directed to a broad genus of CARs that can bind any tumor antigen and comprise any structural binding domain. Even the CARs known in the art prior to filing do not provide proper enablement for the claimed genus of CARs which comprises substantial structural variation.
Applicant argues that a person of ordinary skill would have understood that the activation of STAT1, STAT3, and STAT5 is achieved by the intracellular signaling domain of an IL9Ra and does not depend on the specific tumor antigen binding domain of the CAR. Examiner agrees with this statement; however, this argument does not apply to the instant enablement rejection. The test of enablement is whether the specification contains sufficient information to enable one skilled in the art to make and use the claimed invention without undue experimentation (MPEP § 2164.01). The present issue is that one of ordinary skill could not make and use a cell comprising a CAR comprising an extracellular binding domain that binds to any tumor antigen without undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make a representative number of extracellular binding domains that bind a representative number of tumor antigens, formulate the binding domains as CARs, express the CARs in cells in combination with the claimed CCRs, and screen their characteristics in order to practice the invention commensurate with the scope of the claims. This level of experimentation is undue, and the rejection is maintained.
Double Patenting (Maintained)
1. The rejection of Claims 3-4, 173-175, and 191-192 on the ground of obvious-type nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 12, and 14-20 of U.S. Patent No. 12,221,469 in view of Clancy et al. Nature Education 2008 is maintained.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive. Applicant argues that the Examiner has not provided any evidence or any other reasoning to support the conclusion that the claims of the ‘469 patnet would render obvious a claim comprising the specific components as recited in instant Claim 3. Instant Claim 3(b) is directed to a chimeric cytokine receptor comprising an extracellular domain comprising a human IL2Rb LBD, a human IL9Ra transmembrane domain, and an intracellular domain comprising a human IL9Ra intracellular signaling domain. It is of record in the non-final office action filed 12/05/2025 that the ‘469 patent teaches a chimeric receptor comprising an extracellular portion comprising a binding domain of IL-2Rb, a transmembrane domain of IL-9, and an intracellular portion comprising an endodomain of an IL-9 receptor that induces signaling (Patented Claims 1, 3, and 5). Because the patented claims teach the same chimeric cytokine receptor components as the instant claims, the patented claims anticipate and/or make obvious instant Claim 3, and the rejection is maintained. Note, the rejection applies to newly added Claims 191-192 because one of ordinary skill would understand the generic “chimeric antigen receptor” of patented Claim 12 to comprise a human CD8 transmembrane domain, a human 4-1BB costimulatory domain, a human CD28 costimulatory domain, and/or a human CD3z signaling domain as these are standard domains used in CARs as evidenced by Jayaraman et al. EBioMedicine. 2020.
2. The provisional rejection of Claims 1, 173, 175-176, and 191-192 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 13 of copending U.S. App. No. 18/549,503 is maintained.
3. The provisional rejection of Claims 3-4, 173-176, and 191-192 on the ground of nonstatutory double patenting as being unpatentable over claims 45, 73, and 83-88 of copending U.S. App. No. 17/017,522 is maintained.
4. The provisional rejection of Claims 3-4 and 173-174 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, and 7-14 of copending U.S. App. No. 19/003,599 is maintained.
Applicant's arguments filed March 5, 2026 pertaining to the provisional nonstatutory double patenting rejections #2-4 above have been fully considered but they are not persuasive. Applicant requests that this provisional double patenting rejections 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 rejections are maintained.
Allowable Subject Matter
No claim is allowed. However, a chimeric cytokine receptor comprising SEQ ID NOs: 17, 19, 21, or 23 is enabled and free of the prior art.
Conclusion
THIS ACTION IS MADE FINAL. 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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