DETAILED ACTION
The claim amendments filed 1/6/2023 are acknowledged and entered into the record.
Accordingly, Claims 1, 10, 22, 23, 79 and 81 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
New Grounds of Rejection
(necessitated by amendment)
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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 10, 22, 23, 79 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al. (WO2015142675) in view of Raum et al. (US20170037149 the US equivalent of WO2017021362 (IDS)), Feldman (US20150031624) and Mukherjee (US Patent 9,845,362).
Loew teaches that chimeric antigen receptor (CAR) expressing immune cells can be used to treat a variety of cancers by tailoring the antigen-binding domain of the CAR to an antigen expressed on the particular cancer. See entire document, e.g., Abstract. Loew provides an extensive list of potential tumor target antigens at, e.g., [0030]. Methods of preparing nucleic acids encoding CAR polypeptides as well as vectors for introducing the CAR construct into immune cells such as T cells and NK cells are taught generally, and Loew exemplifies preparation of a CAR specific for tumor antigen EGFR and folate receptor alpha in the working examples. In many of Loew’s constructs, a leader peptide is linked to a scFv specific for the tumor antigen of interest, which is in turn linked via a hinge to a transmembrane region, that is linked to an intracellular signaling domain that comprises both a costimulatory domain and a primary signaling domain. E.g., [005], Figure 33A.
Loew teaches that CD28 can be used for both the transmembrane domain (e.g., [009]) and the costimulatory domain (e.g., [0016]).
The CD8 leader peptide taught by Loew in SEQ ID NO: 2 is “MALPVTALLLPLALLLHAARP”. That sequence is identical to the leader peptide found in instant SEQ ID NO: 64:
Qy 1 MALPVTALLLPLALLLHAARP 21
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Db 1 MALPVTALLLPLALLLHAARP 21 .
The CD3 zeta amino acid sequence taught by Loew in SEQ ID NO: 20 is identical to the CD3 zeta component of instant SEQ ID NO: 64 (residues 382-493) and is also identical to instant SEQ ID NO 10, recited in instant claims 10:
Qy 382 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 441
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Db 1 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 60
Qy 442 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 493
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Db 61 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 112 .
In Example 9 at [001133], Loew teaches that CD19 specific CAR-T cell therapy has been effective clinically for treating B-cell ALL, but that for acute leukemias such as AML, CD19 is not an appropriate target. Loew identifies in Example 9 a panel of limited panel of tumor antigens that would be suitable to target with CAR therapy of these acute leukemias. One of the antigens identified is FLT3. Accordingly, Loew teaches that in some embodiments, an antigen binding domain specific for FLT3 can be used as part of a chimeric antigen receptor to produce a CAR therapy that should be useful for treating a particular type of cancer, AML. [00365], [00720].
Loew does not prepare a chimeric antigen receptor comprising an antigen binding domain that binds FLT3 and Loew does not teach an antigen binding domain comprising a heavy chain variable region (VH) as set forth in SEQ ID NO: 16 (which comprises heavy chain complementarity determining regions (CDRs) 1, 2, and 3 as set forth in SEQ ID NOS: 17, 18, and 19, respectively) and a light chain variable region as set forth in SEQ ID NO: 21 (which comprises heavy chain complementarity determining regions (CDRs) 1, 2, and 3 as set forth in SEQ ID NOS: 17, 18, and 19, respectively), as recited in independent claim 1 and inherent in the VH and VL domains of clone 10E3 recited in independent claim 22, and present in the sequence of SEQ ID NO: 64 recited in independent claim 79. Loew does not teach the CD28 costimulatory domain consisting of SEQ ID NO:2.
Raum teaches a bispecific antibody that binds CD3 expressed on T cells and the target antigen FLT3. See entire document, e.g., Abstract. The encoding nucleic acids and vectors are also taught. Abstract, but see also
In one embodiment, the anti-FLT3 component is “FL-1”, which comprises the VH set forth in SEQ ID NO: 157 and the VL set forth in SEQ ID NO: 158. A scFv comprising that VH and VL linked by a G4S linker is set forth in SEQ ID NO: 159. An alignment of SEQ ID NO: 159 (“Db”) to residues 22-270 of instant SEQ ID NO: 62 (“Qy”) is shown below:
Qy 22 QVTLKESGPVLVKPTETLTLTCTVSGFSLINARMGVSWIRQPPGKALEWLAHIFSNAEKS 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVTLKESGPVLVKPTETLTLTCTVSGFSLINARMGVSWIRQPPGKALEWLAHIFSNAEKS 60
Qy 82 YRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCARIPGYGGNGDYHYYGMDVWGQG 141
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCARIPGYGGNGDYHYYGMDVWGQG 120
Qy 142 TTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITCRASQGIRNDLGWYQQ 201
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITCRASQGIRNDLGWYQQ 180
Qy 202 KPGKAPKRLIYASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNNFPWTF 261
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KPGKAPKRLIYASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNNFPWTF 240
Qy 262 GQGTKVEIK 270
|||||||||
Db 241 GQGTKVEIK 249
The scFv of SEQ ID NO: 159 is therefore a scFv that is specific for FLT3 and that comprises a heavy chain variable region (VH) as set forth in SEQ ID NO: 16 (which comprises heavy chain complementarity determining regions (CDRs) 1, 2, and 3 as set forth in SEQ ID NOS: 17, 18, and 19, respectively) and a light chain variable region as set forth in SEQ ID NO: 21 (which comprises heavy chain complementarity determining regions (CDRs) 1, 2, and 3 as set forth in SEQ ID NOS: 17, 18, and 19, respectively). These are the sequences required by independent claim 1.
The scFv of SEQ ID NO: 159 also comprises the VH and VL of clone 10E3 joined by a G4S linker, as recited in claim 22.
Like Loew, Raum teaches that antibody-based targeting of FLT3 could provide additional therapies for AML. [0001]-[0017].
In view of the teachings of Loew, the ordinary artisan before the effective filing date of the claimed invention would have found it obvious to utilize any of the anti-FLT3 scFv’s taught by Raum in a chimeric antigen receptor construct for targeting CAR-T cells to AML tumor targets. While Raum provides one options for treating AML by linking the anti-FLT3 scFv to another scFv specific for the target antigen CD3 on T cells, the ordinary artisan in view of the teachings of Loew would have also been motivated to prepare CAR-T comprising the anti-FLT3 scFv to provide an alternate therapy for AML that could be used in addition to, or as an alternative to, Raum’s bispecific antibody. Loew teaches that any prior art anti-FLT3 antibody could be formulated as a CAR construct for evaluation as a possible targeting domain. Accordingly, any and all of the anti-FLT3 scFv taught by Raum would have been predictably incorporated into the CAR constructs taught by Loew with a reasonable expectation that testing the constructs would identify an alternate therapy for AML. When the incorporated scFv was SEQ ID NO: 159 of Raum, the resulting CAR would meet the limitations of claims 1-5, 8-10, 22, and 23. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Feldman teaches chimeric antigen receptors for targeting the cancer antigen mesothelin. See entire document, e.g., Abstract. Feldman compares several CAR constructs that incorporate an anti-mesothelin specific scFv but varies how the scFv is linked to the intracellular signaling domain. The constructs differ in the leader portion (first highlight, residues 1-21) and the scFv portion (residues 22-270). However, the constructs are identical over residues 271-493, which includes the CD28 portion and the CD3z portion, as well as the linker “AAA” found between the scFv and CD28 portion. SEQ ID NO: 18 of Feldman includes the portions of CD28 found in instant SEQ ID NO: 2 (extracellular, transmembrane, and intercellular), instant SEQ ID NO: 4 (extracellular), instant SEQ ID NO: 6 (transmembrane), and instant SEQ ID NO: 8 (intracellular).
Mukherjee teaches compositions comprising chimeric antigen receptors comprising an antigen binding domain, a transmembrane domain, a costimulatory signaling domain of CD28, and a CD3 zeta signaling domain. Mukherjee teaches SEQ ID NO: 20 which is a 98 amino acid sequence of a human CD28 domain. It corresponds to amino acids 123-220 of GENBANK® Accession No. NP_006130.1 and has 100% consisting identity to instant SEQ ID NO: 2. Mukherjee shows successfully augmentation of T-cell activity and tumor inhibition and therefore one of ordinary skill in the art would be motivated to interchangeable use the truncated CD28 domain taught by Mukherjee in the CAR construct taught by Loew.
The teachings of Feldman and Mukherjee illustrate (as also shown by Loew) that it was routine in the art to prepare multiple CAR constructs comprising alternative domains (including different scFv’s) as part of developing CAR therapies. Mukherjee teachings also illustrate that the CD28 sequences recited in claims 1 and 22, and utilized in SEQ ID NO: 64 recited in claim 79, were art-recognized alternatives to the components exemplified in Loew’s constructs, as taught generally by Loew. And as noted, Loew teaches the alternate CD8 leader peptide required by SEQ ID NO: 64. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive. Applicants argue “Loew provides no working examples of any FLT3 CARs nor does it provide any specific guidance on the properties of a FLT3 binder that would work.” Applicants further point to Raum disclosing several FLT3 binders, however does not provide any clinical data using the select FL-1 binder which has 100% identity to the instantly claimed CDR/VH/VL sequences. Applicant’s additionally point out neither Loew, Raum or Feldman teach a truncated CD28 domain consisting of SEQ ID NO: 2 and all contain the N-terminal portion of CD28 which is not found in Applicant’s SEQ ID NO: 2 nor in Applicant’s SEQ ID NO: 64.
The amended 103(a) rejection set forth above to include the new reference Mukherjee addresses the use of the truncated CD28 sequence consisting of instantly SEQ ID NO: 2. In regards to Loew and Raum not providing motivation to target FLT3 or select the particular FL-1 binder, the references do not need to teach a working example of the instantly claimed product. However the prior art shows the backbone structure of the CAR instantly claimed in well known in the art, and targeting different tumor antigens is well known, in particular targeting FLT3 for AML treatment. Therefore, one of ordinary skill in the art would be motivated when treating AML patients to make CARs targeting FLT3, using any antigen binding molecule that has shown successful binding to FLT3, within the same backbone structure taught by the prior art and instantly claimed. The individual domains are all known in the art as well as the CAR structure linking each domain, therefore as a whole, it would be obvious to arrive at the instantly claimed FLT3 targeting CAR comprising the FL-1 binder CDRs having SEQ ID NOs: 17-19 and 22-24 or a VH having SEQ ID NO: 16 and VL having SEQ ID NO: 21 taught by Raum, a CD3 zeta having SEQ ID NO: 10 taught by Loew and Feldman, and truncated CD28 consisting of SEQ ID NO: 2 taught by Mukherjee, to arrive at the combined sequence of SEQ ID NO: 64.
New Rejection
(necessitated by amendment)
Claim Rejections – Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 22, 23, 79 and 81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,603,380 in view of Raum et al. (US20170037149) or Rattel et al. (WO2016016859) and Mukherjee (US Patent 9,845,362).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims recite chimeric antigen receptors comprising an antigen binding domain that can be specific for any of a variety of tumor antigens, a costimulatory domain consisting of SEQ ID NO: 241, and an intracellular activation domain from CD3 zeta, wherein the antigen binding domain is linked to the costimulatory domain by 1 to 6 heterologous amino acids. SEQ ID NO: 241 of the patented claims is a “CD28T” sequence that consists of the CD28 extracellular, transmembrane, and intracellular regions as set forth in instant SEQ ID NO: 2, comprising instant SEQ ID NOS: 4, 6, and 8. The CD3 zeta domain defined in the patented claims as SEQ ID NO: 9 is also identical to instant SEQ ID NO: 10. The CD8 leader peptide of the patented claims (SEQ ID NO: 11) is the same as the CD8 leader of instant SEQ ID NO: 87. The linker AAA found between the scFv and CD28 region was an art-recognized linker. Accordingly, in view of the anti-FLT3 scFv of SEQ ID NO: 159 (Raum) or SEQ ID NO: 934 (Rattel), the ordinary artisan would have been motivated to substitute the truncated CD28 taught by Mukherjee and the anti-FLT3 scFv into the constructs of the patented claims to provide an alternate CAR that could be used to target another type of cancer, such as AML. When the scFv of Raum or Rattel and the truncated CD28 of Mukherjee are substituted into the CAR defined by the claims of the ‘380, the components together result in a CAR with amino acid sequence set forth in SEQ ID NO: 64, recited in claims 79. The CAR set forth in SEQ ID NO: 64 would have been an obvious alternative to the patented claims at least because that sequence comprises, rather than consists of, SEQ ID NO: 241 recited in the patented claims. For these reasons, the claims are not patentably distinct.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive. Applicants argue “Loew provides no working examples of any FLT3 CARs nor does it provide any specific guidance on the properties of a FLT3 binder that would work.” Applicants further point to Raum disclosing several FLT3 binders, however does not provide any clinical data using the select FL-1 binder which has 100% identity to the instantly claimed CDR/VH/VL sequences. Applicant’s additionally point out neither Loew, Raum or Feldman teach a truncated CD28 domain consisting of SEQ ID NO: 2 and all contain the N-terminal portion of CD28 which is not found in Applicant’s SEQ ID NO: 2 nor in Applicant’s SEQ ID NO: 64.
The amended 103(a) rejection set forth above to include the new reference Mukherjee addresses the use of the truncated CD28 sequence consisting of instantly SEQ ID NO: 2. In regards to Loew and Raum not providing motivation to target FLT3 or select the particular FL-1 binder, the references do not need to teach a working example of the instantly claimed product. However the prior art shows the backbone structure of the CAR instantly claimed in well known in the art, and targeting different tumor antigens is well known, in particular targeting FLT3 for AML treatment. Therefore, one of ordinary skill in the art would be motivated when treating AML patients to make CARs targeting FLT3, using any antigen binding molecule that has shown successful binding to FLT3, within the same backbone structure taught by the prior art and instantly claimed. The individual domains are all known in the art as well as the CAR structure linking each domain, therefore as a whole, it would be obvious to arrive at the instantly claimed FLT3 targeting CAR comprising the FL-1 binder CDRs having SEQ ID NOs: 17-19 and 22-24 or a VH having SEQ ID NO: 16 and VL having SEQ ID NO: 21 taught by Raum, a CD3 zeta having SEQ ID NO: 10 taught by Loew and Feldman, and truncated CD28 consisting of SEQ ID NO: 2 taught by Mukherjee, to arrive at the combined sequence of SEQ ID NO: 64.
All other previous objections and rejections are hereby withdrawn in view of applicant’
amendments to the claims in the response filed 09/10/2025.
Conclusion
Claims 1, 10, 22, 23, 79 and 81 are rejected.
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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/Meera Natarajan/Primary Examiner, Art Unit 1643