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 .
1. The Amendment filed April 13, 2026 in response to the Office Action of January 13, 2026 is acknowledged and has been entered. Claims 1-2, 5-6, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 86-89, 94, 102, 106, 111, 123, and 133 are pending. Applicant has canceled previous claims 27 and 184-189.
Claims 1-2, 5-6, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 86-89, 94, 102, 106, 111, 123, and 133 are currently being examined.
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on 4/13/2026 was filed after the mailing date of the Non-Final Office Action on 1/13/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Amendment
3. The amendments to the specification in response to the office action of 1/13/2026 is acknowledged and the objection to the specification is withdrawn.
4. The rejection of claim 187 under 35 USC 112(b) is withdrawn in light of the Applicant cancelling the claim.
5. The rejection of claims 27 and 184-187 under 35 USC 102(a)(1)(a)(2) as being anticipated by Sather are withdrawn in light of the Applicant cancelling these claims.
6. The rejection of claims 188-189 under 35 USC 103 as being unpatentable over Sather, et al (WO2020/092854 A2, cited in IDS from 1/4/2024) in view of Sather (WO/092854 A2, cited in IDS from 1/4/2024) was not acknowledged in the amendment remarks from 4/13/2026. However, Applicant cancelled claims 188-189 and in light of their cancellation, the rejection is withdrawn.
Maintained Rejection with New Arguments
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.
7. Claims 1-2, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 94, 102, 106, 111, 123, and 133, remain rejected under 35 U.S.C. 103 as being unpatentable over Sather, et al. (WO 2020/092854 A2, cited in IDS from 1/4/2024) in view of Brinkman, et al. (MABS
2017 9:2, 182-212).
In regard to claims 1-2, Sather discloses a bispecific CAR comprising an extracellular domain comprising a heavy chain and light chain region of a GPRC5D-binding domain and a heavy and light chain region of a BCMA-binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain (pg. 311, example 20).
Sather does not disclose an extracellular domain comprising from amino to carboxy terminus: a variable region of GPRC5D, the VH/VL regions of BCMA, and the other variable region of GPRC5D, or where GPRC5D and BCMA are swapped.
Sather does suggest, however, that the antibody format of the CAR binding domains can include diabody formats ([290]; [298]; [329]; [330]; [484]; [485]), and teaches the CAR is expressed in effector T cells, and administered to treat cancer ([518]; [553-554]; [585]; [825]; Example 13-23).
Brinkman teaches various bispecific constructs for use in therapeutic treatment. Particularly, Brinkman teaches a diabody bispecific construct of sandwiching the variable regions of one antigen binding domain between the variable regions of the other antigen binding domain, e.g. VH1-VL2-VH2-VL1 (See Fig. 2, box 3 and pg. 186). Brinkman suggests the diabody formats can be expressed by therapeutic effector cells and for various applications (p. 186, col. 1).
It would have been obvious to a person of ordinary skill in the art to apply the diabody bispecific antigen domain pattern taught in Brinkman to the bispecific CAR of Sather to make the disclosure of the claimed invention from claims 1-2. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Sather suggests their CAR bispecific binding domain format includes diabody format, and teaches expressing the CAR in therapeutic effector T cells, and (2) Brinkman teaches such diabody formats are known and established, and are expressed by effector cells for therapy.
In regard to claim 20, the limitations of claim 1 are disclosed as discussed above.
Brinkman further discloses the VH or VL regions of any domains being joined by a linker
sequence (pg. 185).
In regard to claim 37, the limitations of claim 1 are disclosed as discussed above.
Sather further discloses a bispecific CAR comprising the VH and VL regions of GPRC5D binding domains comprising the amino acid sequences of SEQ ID NOs:1, 2, 3, 4, 5, and 6 (SEQ ID NO:298, 301).
In regard to claim 40, the limitations of claim 1 are disclosed as discussed above.
Sather further discloses the VH and VL regions of GPRC5D binding domains comprising an amino acid sequence of at least 90% of SEQ ID NO:7 and 8, respectively (SEQ ID NO:298, 301).
In regard to claim 44, the limitations of claim 1 are disclosed as discussed above. Sather further discloses the VH and VL regions of BCMA binding domains comprising the amino acid sequences of SEQ ID NOs:9, 10, 11, 12, 13, and 14, respectively (SEQ ID NOs:298, 301).
In regard to claim 48, the limitations of claim 1 are disclosed as discussed above.
Sather further discloses the VH and VL regions of BCMA binding domains comprising the amino acid sequence of at least 90% of SEQ ID NOs: 15 and 16, respectively (SEQ ID NOs:298, 301).
In regard to claims 62-63, the limitations of claim 1 are disclosed as discussed above. Sather further discloses the spacer region comprising an immunoglobulin hinge region (pg. 311, example 20).
In regards to claim 71, the limitations of claim 1 are disclosed as discussed above. Sather further discloses a CD28-derived transmembrane domain (pg. 311, example 20).
In regards to claim 74, 77, and 80, the limitations of claim 1 are disclosed as discussed above. Sather further discloses an intracellular signaling domain of 4-1BB and CD3zeta (pg.311, example 20).
In regards to claim 83, the limitations of claim 1 are disclosed as discussed above. Sather further discloses the CAR sequence of the amino acid sequence of SEQ ID NO:37. While it is noted that at least 95% identity to the listed sequence could not be found, SEQ ID NO:37 corresponds to the functional sequences listed through claim 86 (see claim 86 rejection below). Additional amino acid sequences provide no further functional limitations and therefore do not overcome the nonobvious rejection.
In regards to claim 94, the limitations of claim 1 are disclosed as discussed above. Sather further discloses a polynucleotide encoding the CAR construct (pg.311, example 20).
In regards to claim 102, the limitations of claims 1 and 94 are disclosed as discussed above. Sather further discloses a vector comprising the polynucleotide of claim 94 (pg.311, example 20).
In regards to claim 106 and 111, the limitations of claim 1 are disclosed as discussed above. Sather further discloses using a T cell for the expression of the CAR construct (pg.311, example 20).
In regards to claims 123, the limitations of claim 1 and 106 are disclosed as discussed above. Sather further discloses the use of the CAR cell in a pharmaceutical composition (abstract).
In regards to claim 133, the limitations of claim 1 and 106 are disclosed as discussed above. Sather further discloses the method of using the CAR cells for the treatment of diseases (abstract).
Response to Arguments
9. Applicants argue that (1) the examiner has failed to establish a prima facie case of obviousness and (2) objective evidence of nonobviousness further rebuts any such prima facie case.
On the first point, the applicant argues that a prima facie case has not been established because Sather and Brinkman do not teach or suggest all claim limitations- including a “loop” configuration, there was no basis for combining the references of Sather and Brinkman, and that Brinkman teaches against rearrangement of VH and VL of different antibodies with a reasonable expectation of success.
On the second point, the applicant argues that objective evidence of nonobviousness rebuts a prima facie case because the cited references fail to provide any reasonable expectation of success that the claimed “loop” configuration would be functional or advantageous.
9. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive.
On page 13 of the response, Applicant asserts the present claims relate to a bispecific CAR format in which the extracellular domain includes a GPRC5D-binding domain and a BCMA-binding domain arranged in a “loop” configuration. Examiner respectfully disagrees.
Applicant cites Figure 2B of the drawing to support the assertion that the bispecific CAR is in a loop configuration. However, claim language is to be interpreted using the broadest reasonable interpretation (BRI) without incorporating limitations from the specification, "[t]hough understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment." Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004). See also Liebel-Flarsheim Co. v. Medrad Inc., 358 F.3d 898, 906, 69 USPQ2d 1801, 1807 (Fed. Cir. 2004).
Claim 1 recites:
A bispecific chimeric antigen receptor (CAR) comprising:
(a) an extracellular domain comprising a GPRC5D-binding domain that binds to GPRC5D comprising a heavy chain variable (VH) region and a light chain variable (VL) region; and a BCMA-binding domain that binds to BCMA comprising a VH region and a VL region, wherein the extracellular domain comprises, in order from amino to carboxy terminus:
(i) one of the VH region and the VL region of the GPRC5D-binding domain, one of the VH region and the VL region of the BCMA-binding domain, the other of the VH region and the VL region of the BCMA-binding domain, and the other of the VH region and the VL region of the GPRC5D-binding domain; or
(ii) one of the VH region and the VL region of the BCMA-binding domain, one of the VH region and the VL region of the GPRC5D-binding domain, the other of the VH region and the VL region of the GPRC5D-binding domain, and the other of the VH region and the VL region of the BCMA-binding domain;
(b) a spacer;(c) a transmembrane domain; and (d) an intracellular signaling domain.
The BRI of claim 1 is a bispecific CAR construct comprising a GPRC5D-binding domain comprising a VH and a VL region and a BCMA-binding domain region comprising a VH and a VL region, where the arrangement of the VH and VL regions may comprise a variety of configurations that are drawn to either GPRC5D(VH or VL)-BCMA(VH or VL)-BCMA(VH or VL not chosen in the second position)-GPRC5D(VH or VL not chosen in the first position) or BCMA(VH or VL)-GPRC5D(VH or VL)-GPRC5D(VH or VL not chosen in the second position)-GPRC5D(VH or VL not chosen in the first position). The BRI of the claim does not limit the claim to a “loop” configuration. The claim encompasses any configurations that allow the bispecific CAR to still function to bind GPRC5D and BCMA. Applicant argues that their working examples in the specification demonstrate that a loop configuration is advantageous over a linear confirmation. However, this is not relevant because applicant has not claimed a CAR protein that is limited to a loop configuration and Applicant has provided no evidence that a linear configuration is not possible by the BRI of the claim.
The Applicant provides no objective evidence that the claimed bispecific construct must be in a loop configuration. Therefore, an establishment of obviousness of the claim does not need to recite a reference that discloses, teaches, or suggests a loop configuration of the present claimed CAR to present a prima facie case of obviousness.
Second, Applicant argues that there is no basis for combining the CAR disclosed in Sather with the teachings of Brinkman because Brinkman is directed to soluble bispecific antibody formats that do not present distinct and structural features of CARs including- membrane anchoring, receptor signaling, and cellular activation.
In response, the rejection of record is updated with new arguments demonstrating the cited prior art provides both the motivation and reasonable expectation of success to modify the CAR binding domain of Sather. Sather suggests a bispecific diabody format for their CAR binding domain, and Brinkman teaching known, established bispecific diabody formats. The rejection states: One would have been motivated to, and have a reasonable expectation of success to, because: (1) Sather suggests their CAR bispecific binding domain format includes diabody format, and teaches expressing the CAR in therapeutic effector T cells, and (2) Brinkman teaches such diabody formats are known and established, and are expressed by effector cells for therapy.
Brinkman teaches different known bispecific diabody arrangements of VH and VL regions of two different antigen-binding domains that still allow for antigen binding of both targets. Further, as discussed above Brinkman teaches the design of VH and VL arrangements allows for compact dimers to be created for use in treatment that can be used to retarget effector cells and molecules.
Applicant argues that Brinkman does not teach the construct of a VH1-VL2-VH2-VL1, or its other iterations. However, on page 186, Brinkman teaches:
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295
639
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Therefore, it would have been reasonable for one of ordinary skill in the art to apply the teachings of Brinkman to Sather because Brinkman teaches VH and VL arrangements that can improve the extracellular antigen-binding domain of CAR proteins.
Third, Applicant argues that Brinkman teaches unpredictability of arrangements of the antibody binding formats in a manner that would discourage one of ordinary skill in the art from intermixing VH/VL domains of different antibodies. Examiner respectfully disagrees.
Applicant asserts that Brinkman concludes that there is not one best format for a desired molecule combination and this would discourage one of ordinary skill from intermixing the VH and VL domains. Regarding a prior art references suggestion of desirable alternatives, the court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. (MPEP 2143.01). In this case, Applicant has not provided objective evidence that Brinkman teaches away from the intermixing of VH and VL regions in bispecific antigen-binding domains. On the contrary, Brinkman teaches that bispecific antigen-binding domains are capable of functioning in a variety of different formats, particularly as diabodies. Further, as copied above Brinkman teaches the conversion of single VH and VL diabody arrangements into a single chain bispecific chain as being an improvement over the prior technology. Applicant provides no objective evidence that the arrangement taught in Brinkman, that is demonstrated through their claimed invention, would discourage a person of ordinary skill in the art to try to use the redesigned bispecific single chain with the CAR protein of Sather with a reasonable expectation of success.
New Rejections
(based on new considerations)
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.
10. Claims 1-2, 5-6, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 94, 102, 106, 111, 123, and 133 are rejected under 35 U.S.C. 103 as being unpatentable over Sather, et al. (WO 2020/092854 A2, cited in IDS from 1/4/2024); in view of Zhang (US Patent Application Publication 2022/0049004, filed May 2020, claiming priority to May 2019); and Xie (Cancers, pub. June 30, 2022, 14:3230).
Sather teaches a bispecific GPRC5D x BCMA CAR as set forth above.
Sather does not teach the bispecific CAR GPRC5D and BCMA binding domains are arranged in a bivalent loop structure.
Zhang teaches making a bispecific CAR that binds to BCMA and GPRC5D ([19]; [112]; [155]; [164]; claims 3 and 10), wherein the CAR is expressed in a T cell as a bispecific scFv loop structure ([37]; Table 1).
Xie teaches dual targeting CAR T cells have been developed as a way to overcome antigen escape from tumor cells exposed to previous single antigen CAR cell therapy, where the tumor cells evolved to express a low level of the antigen targeted on the previous single target CAR T cell. Xie also teaches that BCMA dual target CARs expressed with other antigens through a plasma cell have been successful in preclinical and clinical trials. (See Xie, page 2, paragraph 2). Xie further teaches that a common strategy for constructing dual target CAR cells is a bivalent loop CAR structure. (See Xie, page 4, section (v), also Fig. 1E below). Xie teaches that the bivalent loop structure provides the CAR with a higher potency over tandem CAR structures. (See Xie, page 4, Table 1).
Xie Figure 1E:
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420
341
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It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to combine the bispecific GPRC5D-BCMA CAR of Sather with the teachings of Zhang and Xie to produce the present claimed invention. It would have been obvious because Zhang teaches making a structure for binding to GPRC5D and BCMA in a loop structure and Xie teaches that bispecific CAR T cells help overcome antigen escape experienced with single CAR cells and the bivalent loop structure is a commonly known structure that provides for higher potency that a tandem bispecific CAR structure. It would have had a reasonable expectation of success because Xie teaches that BCMA has already been successfully used in bispecific CAR cells with other antigens expressed on plasma cells. Therefore, a person of ordinary skill in the art prior to the effective filing date would have been motivated to use the GPRC5D and BCMA binding domains disclosed in Sather with the bivalent loop structure taught in Zhang and Xie with a reasonable expectation at successfully developing the bispecific looped CAR structure of the present claimed invention.
11. Claims 86-89 are rejected under 35 U.S.C. 103 as being unpatentable over Sather, et al. (WO 2020/092854 A2, cited in IDS from 1/4/2024); in view of Zhang (US Patent Application Publication 2022/0049004, filed May 2020, claiming priority to May 2019); and Xie (Cancers, pub. June 30, 2022, 14:3230).
Sather teaches a bispecific GPRC5D-BCMA CAR as set forth above. Sather further teaches the linker sequences of SEQ ID NO: 21 and 17, the spacer in SEQ ID NO: 27, the transmembrane domain in SEQ ID NO: 28, the intracellular signaling domain in SEQ ID NOs: 29 and 30. (See alignments below).
Sather does not disclose the structure of the bispecific CAR in a loop structure with an extracellular binding domain of the amino acid structure of SEQ ID NO:83, or the entire CAR structure of the amino acid sequence of SEQ ID NO:37 and a nucleotide sequence of SEQ ID NO:119.
Sather does teach all of the functional sequences included in the bispecific GPRC5D-BCMA CAR extracellular binding domain and the entire CAR. (SEQ ID NO: 298, See alignment below). Additional amino acid structure provides no further functional limitations and does not overcome the nonobvious rejection regarding dependent claims 87-89 and the SEQ ID NOs: 83, 37, and 119.
Zhang teaches making a bispecific CAR that binds to BCMA and GPRC5D ([19]; [112]; [155]; [164]; claims 3 and 10), wherein the CAR is expressed in a T cell as a bispecific scFv loop structure ([37]; Table 1).
Xie teaches dual targeting CAR T cells have been developed as a way to overcome antigen escape from tumor cells exposed to previous single antigen CAR cell therapy, where the tumor cells evolved to express a low level of the antigen targeted on the previous single target CAR T cell. Xie also teaches that BCMA dual target CARs expressed with other antigens through a plasma cell have been successful in preclinical and clinical trials. (See Xie, page 2, paragraph 2). Xie further teaches that a common strategy for constructing dual target CAR cells is a bivalent loop CAR structure. (See Xie, page 4, section (v), also Fig. 1E above). Xie teaches that the bivalent loop structure provides the CAR with a higher potency over tandem CAR structures. (See Xie, page 4, Table 1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to combine the bispecific GPRC5D-BCMA CAR functional sequences of Sather with the teachings of Zhang and Xie to produce the structure of the present claimed invention. It would have been obvious because Sather teaches all of the functional amino acid sequences of the GPRC5D-BCMA CAR, Zhang teaches making a structure for binding to GPRC5D and BCMA in a loop structure and Xie teaches that bispecific CAR T cells help overcome antigen escape experienced with single CAR cells and the bivalent loop structure is a commonly known structure that provides for higher potency that a tandem bispecific CAR structure. It would have had a reasonable expectation of success because Sather teaches the amino acid sequences are successful at binding GPRC5D and BCMA and Xie teaches that BCMA has already been successfully used in bispecific CAR cells with other antigens expressed on plasma cells. Therefore, a person of ordinary skill in the art prior to the effective filing date would have been motivated to use the GPRC5D and BCMA binding domains disclosed in Sather with the bivalent loop structure taught in Zhang and Xie with a reasonable expectation of successfully developing the bispecific looped CAR structure of the present claimed invention.
SEQ ID NOs:1, 2, and 3 100% match in SEQ ID NO:298 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
XX
CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
XX
DR WPI; 2020-37638B/042.
Query Match 86.1%; Score 152.4; Length 1374;
Best Local Similarity 41.0%;
Matches 32; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 SHSMN--------------SISSDSTYTYYADSVKG------------------------ 22
||||| |||||||||||||||||
Db 876 SHSMNWVRQAPGKGLEWVSSISSDSTYTYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 935
Qy 23 --------SGGQWKYYDY 32
||||||||||
Db 936 TAVYYCARSGGQWKYYDY 953
SEQ ID NO: 21 100% match in SEQ ID NO: 50 (Sather):
PNG
media_image3.png
324
471
media_image3.png
Greyscale
PNG
media_image4.png
134
467
media_image4.png
Greyscale
SEQ ID NO: 17 100% match in SEQ ID NO: 47 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
XX
CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
XX
DR WPI; 2020-37638B/042.
XX
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 117 100.0 22 BGU58162 -- 14 Linker peptide, SEQ 196.
ALIGNMENT:
Query Match 100.0%; Score 117; Length 22;
Best Local Similarity 100.0%;
Matches 22; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GSRGGGGSGGGGSGGGGSLEMA 22
||||||||||||||||||||||
Db 1 GSRGGGGSGGGGSGGGGSLEMA 22
SEQ ID NOs:4, 5, and 6 100% match in SEQ ID NO:298 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
XX
CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
XX
DR WPI; 2020-37638B/042.
Query Match 84.4%; Score 133.3; Length 1374;
Best Local Similarity 39.0%;
Matches 30; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 QGDSLRSYYAS---------------GKNNRPS--------------------------- 18
||||||||||| |||||||
Db 737 QGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDE 796
Qy 19 -----NSRDSSGNPPVV 30
||||||||||||
Db 797 ADYYCNSRDSSGNPPVV 813
SEQ ID NOs:9, 10, and 11 100% match in SEQ ID NO:298 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
XX
CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
XX
DR WPI; 2020-37638B/042.
XX
Query Match 86.4%; Score 156.4; Length 1374;
Best Local Similarity 40.3%;
Matches 31; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 DYYVY--------------WINPNSGGTNYAQKFQG------------------------ 22
||||| |||||||||||||||||
Db 177 DYYVYWMRQAPGQGLESMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDD 236
Qy 23 --------SQRDGYMDY 31
|||||||||
Db 237 TAMYYCARSQRDGYMDY 253
SEQ ID NOs:12, 13, and 14 100% match in SEQ ID NO:298 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
XX
CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
XX
DR WPI; 2020-37638B/042.
XX
Query Match 79.6%; Score 96.3; Length 1374;
Best Local Similarity 34.7%;
Matches 25; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 TGTSSDVG---------------EDSKRPS------------------------------ 15
|||||||| |||||||
Db 43 TGTSSDVGWYQQHPGKAPKLMIYEDSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADY 102
Qy 16 --SSNTRSSTLV 25
||||||||||
Db 103 YCSSNTRSSTLV 114
SEQ ID NOs: 27, 28, 29, and 30 in SEQ ID NO: 298 (Sather):
WO2020092854-A2.
XX
CC PD 07-MAY-2020.
XX
CC PF 31-OCT-2019; 2019WO-US059285.
XX
PR 01-NOV-2018; 2018US-0754576P.
PR 30-NOV-2018; 2018US-0774159P.
PR 15-MAR-2019; 2019US-0819422P.
PR 23-SEP-2019; 2019US-0904187P.
PR 23-SEP-2019; 2019US-0904197P.
XX
CC PA (JUNO-) JUNO THERAPEUTICS INC.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
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CC PI Sather BD, Smith EL, De Imus C, Harrington K, Jones J, Chen A;
CC PI Tareen S, Hess E, Ponko S, Olshefsky A, Fernandez De Larrea C;
CC PI Brentjens R;
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DR WPI; 2020-37638B/042.
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Query Match 100.0%; Score 2203; Length 1374;
Best Local Similarity 100.0%;
Matches 410; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV 60
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Db 965 ESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV 1024
Qy 61 DGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1025 DGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA 1084
Qy 121 KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1085 KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 1144
Qy 181 SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1145 SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVL 1204
Qy 241 ACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRV 300
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Db 1205 ACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRV 1264
Qy 301 KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1265 KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL 1324
Qy 361 QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 410
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1325 QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 1374
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.
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.
12. Claims 1-2, 5, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 94, 102, 106, 111, 123, and 133 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites:
A bispecific chimeric antigen receptor (CAR) comprising:
(a) an extracellular domain comprising a GPRC5D-binding domain that binds to GPRC5D comprising a heavy chain variable (VH) region and a light chain variable (VL) region; and a BCMA-binding domain that binds to BCMA comprising a VH region and a VL region, wherein the extracellular domain comprises, in order from amino to carboxy terminus:
(i) one of the VH region and the VL region of the GPRC5D-binding domain, one of the VH region and the VL region of the BCMA-binding domain, the other of the VH region and the VL region of the BCMA-binding domain, and the other of the VH region and the VL region of the GPRC5D-binding domain; or
(ii) one of the VH region and the VL region of the BCMA-binding domain, one of the VH region and the VL region of the GPRC5D-binding domain, the other of the VH region and the VL region of the GPRC5D-binding domain, and the other of the VH region and the VL region of the BCMA-binding domain;
(b) a spacer;(c) a transmembrane domain; and (d) an intracellular signaling domain.
In section (a) the claim recites that both GPRC5D and BCMA comprise one VH and one VL region, but in both sections (i) and (ii) the use of “and” between “one of the VH region and the VL region” claims both VH and VL regions for the first part of the phrase, leaving no other VH or VL regions for the second part of sections (i) and (ii). It is unclear in the second phrase of sections (i) and (ii) what “the other of the VH region and the VL region” is referring to since both VH and VL regions are present in the first part of the phrase. The claim includes three variable regions for each of the GPRC5D and BCMA binding domains and it is unclear what the “other” VH and VL region is referring to in sections (i) and (ii).
Examiner Suggestion: To overcome this rejection, please amend claim 1 to recite “the VH region or the VL region” and “the other of the VH region or the VL region”.
For the sake of compact prosecution, the examiner is interpreting the claim with the amendment described above.
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.
13. Claims 1-2, 5-6, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 94, 102, 106, 111, 123, and 133 are 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 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a bispecific CAR comprising an extracellular domain comprising a GPRC5D-binding domain and a BCMA-binding domain with both binding domains comprising a VH region and a VL region with no accompanying amino acid structure.
Thus, the claims identify the CAR by the function of binding both GPRC5D and BCMA and no amino acid sequence structure. Thus, the claims encompass a vast genus of CAR variants comprising variable VH and VL regions required to bind GPRC5D and VH and VL regions required to bind BCMA.
Dependent claims 37, 40, 44, and 48 recite the sequence structure of one of the GPRC5D or BCMA binding domains, but not both.
Dependent claim 83 recites the CAR sequence structure has at least about 95% sequence identity to anyone of SEQ ID NOs:35-44, therefore encompasses a vast genus of variant CAR sequences having up to 5% sequence discrepancy from the recited SEQ ID NOs that can occur anywhere including the CDR regions critical to the claimed GPRC5D and BCMA binding functions.
The instant specification discloses fourteen different arrangements of CAR protein amino acid sequences all comprising the same GPRC5D VH amino acid structure of SEQ ID NO:7 which comprises the CDRH1, CDRH2, CDRH3 amino acid sequences of SEQ ID NOs:1, 2, and 3; the same GPRC5D VL amino acid structure of SEQ ID NO:8 which comprises the CDRL1, CDRL2, and CDRL3 amino acids sequences of SEQ ID NOs:4, 5, and 6; the same BCMA VH amino acid structure of SEQ ID NO:15 which comprises the CDRH1, CDRH2, CDRH3 amino acid sequences of SEQ ID NOs:9, 10, and 11; and the same BCMA VL amino acid structure of SEQ ID NO:16 which comprises the CDRL1, CDRL2, and CDRL3 amino acids sequences of SEQ ID NOs:12, 13, and 14.
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Thus, the instant specification identifies making CAR proteins that function to bind GPRC5D and BCMA comprising a structurally distinct VH comprising a specific CDRH1-3 amino acid sequence structure and a distinct VL comprising a specific CDRL1-3 amino acid sequence structure for both binding domains.
To provide adequate written description and evidence of possession of the claimed bispecific CAR genus, the instant specification can structurally describe representative bispecific CAR variants that function to bind both GPRC5D and BCMA, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the binding domains function “binds to GPRC5D” and “binds to BCMA” and no amino acid sequence structure. The instant specification fails to describe structural features common to the members of the bispecific CAR genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative bispecific CAR variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the amino acid sequences listed above, the specification fails to provide variant CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of GPRC5D and BCMA VH and VL region sequence variants for the genus of bispecific CARs that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed bispecific CAR.
The claims broadly encompass any VH region or VL region variant that functions to bind GPRC5D or BCMA. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain GPRC5D or BCMA binding function. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of bispecific CARs encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single bispecific CAR comprising GPRC5D VH and VL regions and BCMA VH and VL regions with no sequence structure as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for binding domains that bind GPRC5D or BCMA and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The GPRC5D or BCMA antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed bispecific CAR, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide GPRC5D or BCMA-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of bispecific CAR variants that bind GPRC5D and BCMA and comprise any VH or VL regions that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claims 1 and 6 to recite:
“A bispecific chimeric antigen receptor (CAR) comprising:
(a) an extracellular domain comprising a GPRC5D-binding domain that binds to GPRC5D comprising a heavy chain variable (VH) region, wherein the VH region and a light chain variable (VL) region, wherein the VL region comprises a CDR-1, a CDR-2, and a CDR-3 comprising the amino acid sequences set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and a BCMA-binding domain that binds to BCMA comprising a VH region, wherein the VH region comprises a CDR-1, a CDR-2, and a CDR-3 comprising the amino acid sequences set forth in SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively; and a VL region, wherein the VL region comprises a CDR-1, a CDR-2, and a CDR-3 comprising the amino acid sequences set forth in SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, respectively, wherein the extracellular domain comprises, in order from amino to carboxy terminus…”.
Conclusion
13. Claims 1-2, 5-6, 20, 37, 40, 44, 48, 62-63, 71, 74, 77, 80, 83, 86-89, 94, 102, 106, 111, 123, and 133 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642
Prosecution Insights