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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2022/029915, filed 5/18/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/190480, filed 5/19/2021.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-8, 14-21 and 39, in the reply filed on 7/20/2026 is acknowledged. Claims 9 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/20/2026. Applicant’s election of species of an anti-BCMA scFv of SEQ ID NO: 10 and a CD19 VHH of SEQ ID NO: 3, in the reply of 7/20/2026, is acknowledged. Claims 5-6 are withdrawn from consideration as being drawn to non-elected species. Further, it is noted that of the species of SEQ ID NOs: 63-70, of claim 20, only SEQ ID NOs: 65-66 and 69-70, read on the elected species. Thus, claim 20 will be searched on the basis of SEQ ID NOs: 65-66 and 69-70.
Status of Claims
Claims 1-9, 14-21 and 39-40 are pending, claims 5-6, 9 and 40 are withdrawn, claims 1-4, 7-8, 14-21 and 39 are being examined on the merits.
Claim Objections
Claim 3 is objected to because of the following informalities: Claim 3 recites “the first tumor-associated antigen is CD19 and the second tumor antigen-associated is BCMA”. This is believed to be a typo, wherein it should read “the second tumor-associated antigen is BCMA”. Appropriate correction is required.
Claims 16-17 are objected to because of the following informalities: Claims 16-17 recite “CD3 z”. While it is understood to be referring to CD3zeta, the z should be part of the “CD3” and not a separate word. For example, applicants could use CD3ζ, CD3z, CD3zeta, CD3-zeta. In any instance the “z” should be part of “CD3” as the domain it is referring is one structure of CD3. Appropriate correction is required.
Claim Interpretation
The applicants use the phrase “optionally” in claims 1, 6, 8, 14 and 17-18. The claim terms, steps and elements that follow the word “optionally” are not required and do not carry patentable weight. While the claims are not ambiguous, a person skilled in the art would understand that none of the elements are part of the claimed invention; the inventions is only limited by those elements which proceed the word “optionally”. However, when limitations that follow “optionally” change the scope with regard to the claim’s preceding limitations, the claims may be rendered indefinite. The optional language should be made non-optional or removed for clarity. For example, claim 17 recites wherein the CD3 zeta signaling domain “optionally” comprises a STAT binding motif. The CD3 zeta domain was introduced in claim 16 and each of the polypeptides of claim 20 comprise a STAT binding motif. Thus, it is somewhat unclear if claim 17 is requiring a CD3zeta with a STAT binding motif. However, the claim will be interpreted as not requiring a STAT binding motif, and only limiting the CAR polypeptide by way of requiring a CD3zeta signaling domain without a STAT binding motif.
Claim Rejections - 35 USC § 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.
Claim 8 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 8 recites the CAR polypeptide of claim 7, wherein a) and b) comprises the amino acid sequence of SEQ ID NO: 12, 65, 66, 69, 70, 72, 78 or 80. Claim 7 depends from claim 4, which depends from claim 3, which depends from claim 1. Claim 1 recites a) and b) as the first and second binding moiety. However, each of SEQ ID NOs: 12, 65, 66, 69, 70, 72, 78 and 80 encode full CAR constructs with transmembrane and intracellular signaling domains, beyond just the binding moieties. Thus it is unclear how “a) and b) comprises”, for example, the amino acid sequence of SEQ ID NO: 65, which is far larger than just the binding motifs of a) and b). Thus, the metes and bounds of the claim are unclear, as it is unclear is claim 8 requires the full sequences as listed, or if the claim is limited to only the a) and b) domains of the full sequences. As the metes and bounds are unclear, claim 8 is rejected for indefiniteness.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 15-19, 21 and 39 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Pogson, (WO 2019/126724; published 6/27/2019).
Pogson teaches multivalent CAR constructs (title). Pogson teaches a CAR comprising a scFv antibody that binds a first antigen and a sdAb (i.e. VHH) that binds a second antigen, a transmembrane domain, one or more intracellular costimulatory signaling domains and a primary signaling domain (pg. 81, claim 1); wherein the first and second antigens are selected from BCMA, CD19 or CD20 (pg. 82, claims 6-12); wherein the one or more costimulatory domains are selected from 4-1BB or CD28 (pg. 85, claim 32); wherein the primary signaling domain (i.e. cytoplasmic signaling domain) comprises CD3zeta (pg. 86, claims 35-36); and wherein the CAR comprises a transmembrane domain from CD8α (pg. 85, claims 29-30). Pogson also teaches cells engineered to express the CAR (pg. 87, claim 56), which are immune cells (claim 58), as well as pharmaceutical compositions comprising the engineered cells (pg. 88, claim 65).
Specifically, Pogson teaches an embodiment of a sdCD19/CD20scFv tandem CAR; see Example 2 (pg. 78), as well the format of Fig. 3 (bottom), and results (Fig. 7).
Pogson teaches a multivalent CAR comprising a CD19 VHH and a CD20 scFv, with a CD8α transmembrane domain located between the antigen binding domain and the costimulatory domain, a 4-1BB costimulatory domain and a CD3zeta cytoplasmic signaling domain. Pogson also teaches immune cells comprising the construct and pharmaceutical compositions comprising the engineered immune cells. Thus, Pogson anticipates instant claims 1-3, 15-19, 21 and 39.
Claim Rejections - 35 USC § 103
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 1-4, 7, 14-19, 21 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Pogson, (WO 2019/126724; published 6/27/2019).
The reasons why Pogson anticipates instant claims 1, 2, 15-19, 21 and 39 is described above. However, Pogson does not exemplify an embodiment of a bi-specific CAR comprising a CD19 VHH domain and a BCMA scFv domain.
Nonetheless, Pogson teaches the first and second binding domains of the CAR are a VHH and a scFv, in either order; and wherein the antigens to which the VHH and scFv are directed are CD19 and BCMA. Pogson teaches the embodiment of a CD19-VHH/CD20-scFv CAR, of example 2. Further, in Example 1 (pg. 77), Pogson teaches an alternative embodiment of a multivalent CAR comprising an anti-EGFR VHH and an anti-BCMA scFv binding domains. Thus, Pogson teaches anti-CD19 VHH binding domains, anti-BCMA scFv binding domains, and multivalent CAR constructs comprising each of the binding domains with an alternative binder.
Importantly, the anti-CD19 VHH of Pogson is that of SEQ ID NO: 18 (pg. 78, para. 2). Pogson SEQ ID NO: 18 is 100% identical in amino acid sequence to the anti-CD19 VHH of instant SEQ ID NO: 3.
It would have been obvious to one of skill in the art to modify the CD19/CD20 bispecific CAR of Pogson, to instead be a CD19/BCMA bispecific CAR, wherein the anti-CD19 binding domain is a VHH and the anti-BCMA binding domain is a scFv. One would have been motivated to do so in order to target the CAR construct, and cells expressing the CAR, to CD19+ and BCMA+ tumor cells, as taught by Pogson. There would have been a reasonable expectation for success given that Pogson teaches the anti-CD19 VHH binding domain in multivariant CARs with an alternative scFv binding domain, as well as anti-BMSA scFv binding domains in multivariant CARs with an alternative VHH binding domain. Thus, the invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claims 1-4 and 7; an anti-CD19 VHH/anti-BMSA scFv multivalent CAR construct of Pogson makes obvious instant claims 1-4. As the anti-CD19 VHH of Pogson SEQ ID NO: 18 is 100% identical to that of instant SEQ ID NO: 3, Pogson makes obvious instant claim 7.
Regarding claim 14; Pogson teaches the linker between the VHH and the scFv binding domains may be a peptide linker, of about 1 to 25 amino acids (pg. 25, para. 1), including the GSTSGSGKPGSGEGSTKG linker of SEQ ID NO: 46 (pg. 26, para. 1). Thus, Pogson makes obvious instant claim 14. In addition, Pogson teaches (G4S)n linkers, as well as teaching that suitable linkers may be all or partially flexible, such that the linker includes a flexible linker as well as one or more portions that confer less flexible structure to provide for a desired CAR structure (pg. 10, para. 0196). Thus, as proline-alanine sequences are known in the art for imparting a degree of rigidity to a linker, Pogson makes obvious using a GGGGSPAG linker, such as that of instant SEQ ID NO: 57.
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Pogson, (WO 2019/126724; published 6/27/2019) as applied to claims 1-4, 7, 14-19, 21 and 39 above, and further in view of Kochenderfer, (WO 2013/154760; published 10/17/13).
The reasons why Pogson make obvious claims 1-4, 7, 14-19, 21 and 39 is described above. Specifically, Pogson contemplates a multivalent CAR comprising an anti-CD19 VHH, which is identical to that of instant SEQ ID NO: 3, and an anti-BCMA scFv. Pogson further teaches the TM and intracellular domains of the CAR, as well as using a peptide linker, as described above.
However, Pogson does not teach wherein the anti-BCMA scFv has an amino acid sequence of instant SEQ ID NO: 10.
Kochenderfer teaches CARs targeting BCMA (title, abstract). Kochenderfer teaches the CARs comprise the anti-BCMA binding moiety of an anti-BCMA monoclonal antibody, as disclosed in WO 2010/104949 (pg. 8, para. 0030), which may be an scFv binding domain (pg. 8, para. 0028), and which is embodied in the CAR of SEQ ID NO: 5 (pg. 12, para. 0046; pg. 39, claim 7). Kochenderfer teaches the CAR may comprise a CD8α signal sequence (pg. 8, para. 0031), a hinge sequence derived from CD8α (para. 0032), a transmembrane sequence derived from CD8α (para. 0033), and an intracellular signaling domain of either 4-1BB or CD3zeta (para. 0034).
The anti-BCMA CAR of Kochenderfer SEQ ID NO: 5 comprises the anti-BCMA scFv of instant SEQ ID NO: 10 with 100% sequence identity. The anti-BCMA CAR of Kochenderfer SEQ ID NO: 5, also comprises the CD8α signal sequence of instant SEQ ID NO: 45 with 100% sequence identity.
It would have been obvious to one of skill in the art to substitute the anti-BCMA scFv of Kochenderfer into the anti-CD19/anti-BCMA multivalent CAR of Pogson. One would have been motivated to do so in order to have an alternative anti-BCMA binding domain as desired. There would have been a reasonable expectation for success given that the anti-BCMA scFv binding domain of Kochenderfer may be incorporated into a CAR construct, as taught by Kochenderfer, and that anti-BCMA scFv binding domains may be incorporated into a multivalent CAR construct further comprising an anti-CD19 VHH binding domain, as taught by Pogson. Thus, the invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Section 2143 of the MPEP teaches examples of rationales which support a conclusion of obviousness include (B)- Simple substitution of one known element for another to obtain predictable results. In this case, as both anti-BCMA binding domains are in the same scFv format, and each was taught for use as an antigen binding domain of a CAR, including a multivalent CAR, it is obvious to substitute one version of an anti-BCMA scFv in place of an alternative version of an anti-BCMA scFv, to obtain predictable results with a reasonable expectation for success.
Regarding claim 7; claim 7 was made obvious over Pogson, as described above, in view of the claim language that the CAR comprises SEQ ID NO: 3 “and/or” SEQ ID NO: 10. However, in the case that the claim reads SEQ ID NO: 3 “and” SEQ ID NO: 10, the multivalent CD19/BCMA CAR construct of the combination of Pogson and Kochenderfer, comprising the anti-CD19 VHH of Pogson, which is 100% identical to instant SEQ ID NO: 3, and the anti-BCMA scFv of Kochenderfer, derived from SEQ ID NO: 5, which is 100% identical to instant SEQ ID NO: 10, makes obvious instant claim 7.
Regarding claim 8; instant SEQ ID NO: 65 encodes a CAR construct comprising a first binding moiety which is an anti-CD19 VHH and a second binding moiety which is an anti-BCMA scFv, in that order (specs., pg. 50). Pogson teaches an anti-CD19 VHH/anti-CD20 scFv and an anti-EGFR VHH/anti-BCMA scFv. Thus the anti-CD19 VHH/anti-BCMA scFv CAR, made obvious by Pogson, comprising the anti-BCMA scFv construct of Kochenderfer, makes obvious “wherein a) and b) comprises the amino acid sequence of SEQ ID NO: 65”, and thus makes obvious instant claim 8.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Pogson, (WO 2019/126724; published 6/27/2019) and Kochenderfer, (WO 2013/154760; published 10/17/13) as applied to claims 1-4, 7-8, 14-19, 21 and 39 above, and further in view of Xu et al., (US 2024/0115607; with priority to 1/26/2021) and Kagoya et al., (Nature Medicine, 2018).
The bispecific CAR polypeptide of, for example, instant SEQ ID NO: 65 encodes a) a CD8α signal peptide, b) an anti-CD19 VHH, c) a GS flexible linker, d) an anti-BCMA scFv, e) an CD8α hinge, f) a CD8α TM domain, g) a 4-1BB intracellular domain, h) an IL-2Rb signaling domain, and i) a modified CD3zeta signaling domain comprising a STAT binding motif (i.e. SEQ ID NO: 42, pg. 48).
As described above, the combination anti-CD19 VHH/anti-BCMA scFv CAR of Pogson and Kochenderfer makes obvious the CD8α signaling domain, the anti-CD19 VHH, the GGGGPAG linker, and the anti-BCMA scFv, and the GS linker, with 100% sequence identity to residues 1-394 of instant SEQ ID NO: 65, and whereby the multivalent CAR may further comprise a CD8 hinge/TM, one or more co-stimulatory domains such as 4-1BB, and a CD3zeta intracellular signaling domain.
However, the combination of Pogson and Kochenderfer do not teach wherein the CAR construct comprises the CD8 hinge/TM, the 4-1BB and IL-2RB co-stimulatory domains, and the modified CD3zeta domain comprising the STAT binding motif of residues 395-711 of instant SEQ ID NO: 65.
Xu et al. teaches various CAR constructs comprising a CD19 scFv binding domain (abstract, Fig. 15). Xu teaches that the CAR construct polypeptides comprise an extracellular binding domain, a transmembrane domain and an intracellular domain, and may also comprise co-stimulatory domains, spacers/hinge domain, or signal peptides; and that various combinations of the different domains can be used across embodiments (pg. 6, para. 0166; Fig. 7). For example, Xu teaches a signal peptide of SEQ IUD NO: 38 (pg. 2, para. 0039), which is identical to instant SEQ ID NO: 45. Xu teaches a spacer domain which comprises a CD8 hinge, of SEQ ID NO: 44 (pg. 2, para. 0047), which is identical to that of instant SEQ ID NO: 44. Xu teaches a transmembrane domain of CD8, of SEQ ID NO: 32 (pg. 4, para. 0095), which is identical to that of instant SEQ ID NO: 38. Xu teaches a costimulatory domain of 4-1BB and IL2Rb, of SEQ ID NOs: 15-16, respectively (pg. 3, para. 0085), which are identical to that of instant SEQ ID NOs: 39-40, respectively. Xu teaches a CD3zeta intracellular domain of SEQ ID NO: 11 (pg. 13, para. 0211), which is identical to that of instant SEQ ID NO: 43 (without STAT binding motif). Xu embodies the CD8 hinge/TM, 4-1BB and IL-2RB costimulatory domains and CD3zeta intracellular domain, of SEQ ID NOs: 44, 32, 15, 16 and 11 in construct CC013 of SEQ ID NO: 86 (pg. 36, para. 0353; pg. 31, Table 6). Thus, the amino acid sequence of the CAR of Xu, SEQ ID NO: 86 has an identical amino acid sequence of the CAR of instant SEQ ID NO: 65 from residues 395-711, comprising the CD8 hinge/TM, 4-1BB, IL2-RB, CD3zeta domains; with the exception of the STAT binding motif of the instant CD3zeta domain (see below).
It would have been obvious to one of skill in the art to utilize the CD8 hinge/TM, 4-1BB, IL-2RB and CD3zeta domains of the CAR constructs of Xu with the anti-CD19/anti-BCMA extracellular domains of Pogson and Kochenderfer. One would have been motivated to do so with reasonable expectation for success given that Pogson and Kochenderfer teach the CARs will comprise a hinge/TM domain, one or more co-stimulatory domains and a CD3zeta intracellular domain, and Xu teaches such domains were known in the art and used together in various CAR constructs. As each of the various non-binding domains of the CAR of SEQ ID NO: 65 were known in the art and taught in various combinations for use in CAR constructs, none of the domains, or their particular combination, provides a point of novelty to the instant CAR constructs. As Pogson and Kochenderfer teach multivalent extracellular binding domains, which comprise the anti-CD19 VHH of instant SEQ ID NO: 3 and the anti-BCMA scFv of instant SEQ ID NO: 10, with 100% sequence identity, as well as the signaling peptide of instant SEQ ID NO: 45, the extracellular domains of the CAR construct are also known and obvious to combine with the signaling domains of Xu et al. in a CAR construct polypeptide.
However, neither Pogson, Kochenderfer nor Xu teach a CD3zeta intracellular signaling domain which comprises a STAT binding motif; specifically, the “YRHQ” amino acid substitution of the CD3zeta domain of instant SEQ ID NO: 42 (pg. 48, underlined substitution).
Kagoya et al. teaches novel CARs containing a JAK-STAT signaling domain provides superior antitumor effects (title). Kagoya teaches this new-generation CD19 CAR encodes a truncated cytoplasmic domain from IL-2RB and a CD3z domain comprising a “YXXQ” STAT3-binding motif (abstract), whereby the YXXQ motif is at the C terminus of the CD3zeta (pg. 352, col. 2, para. 2). One such embodiment comprises a “LHMQ” to “YRHQ” substitution in the CD3zeta domain (Fig. 1a). The full sequence of example constructs comprising the “YRHQ” substitution are provided in Supplementary Table 1 of the Supplementary Data (pg. 19). Thus, Kagoya teaches CAR constructs comprising a CD3zeta intracellular signaling domain in which the amino acid residues “LHMQ” are substituted with “YRHQ” so as to impart a STAT binding motif, which binds STAT3 and improves the antitumor effects of the CAR construct.
It would have been obvious to one of skill in the art to modify the CD3zeta intracellular domain of the CD19/BCMA multivalent CAR constructs of Pogson, Kochenderfer and Xu, to comprise a “YRHQ” STAT binding motif. One would have been motivated to do so in order to improve the antitumor effects of CAR constructs, as taught by Kagoya et al. There would have been a reasonable expectation for success given that the “YRHQ” STAT motif may be substituted into the C-terminus of the CD3zeta intracellular domain of the CAR construct, and that Pogson, Kochenderfer and Xu teach CAR construct comprising a CD3zeta intracellular signaling domain. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 20; a CAR construct comprising a multivalent extracellular binding domain with a CD19 VHH and a anti-BCMA scFv of Pogson and Kochenderfer, and further comprising the signaling peptide, CD8 hinge/TM, 4-1BB, IL-2RB and CD3zeta domains of Xu, wherein the CD3zeta domain comprises the STAT binding motif of Kagoya, makes obvious the CAR construct of instant SEQ ID NO: 65. Thus, the combination construct of Pogson, Kochenderfer, Xu and Kagoya makes obvious instant claim 20.
MPEP section 2143 teaches examples of rationales which support a conclusion of obviousness including (A)- combining prior art elements according to known methods to yield predictable results; (B)- simple substitution of one known element for another to obtain predictable results; (E)- Obvious to try choosing from a finite number of identified, predictable solutions, with reasonable expectation of success; (F)- known work in one field of endeavor may prompt variations of it for use in the same field based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; and (G)- Some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill in the art to modify the prior art reference teachings to arrive at the claimed invention.
Here, the CAR construct of instant SEQ ID NO: 65 combines various CAR domains, whereby each domain was taught in the art as suitable for use in CAR constructs. No domain of the CAR polypeptide of instant SEQ ID NO: 65 is novel over the prior art domains, an combining them into various specific embodiments is well within the skill of the artisan in order to generate variant embodiments as desired, based on the teachings of the art.
Allowable Subject Matter
The anti-CD19 VHH of SEQ ID NOs: 1-2 have been searched and are free of the art. Thus, CAR constructs comprising the anti-CD19 VHH domains of SEQ ID NOs: 1 or 2 would therefore comprise allowable subject matter.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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