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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 20, 2025, has been entered.
The amendment filed August 20, 2025, is acknowledged and has been entered. Claims 1, 40 and 138 have been amended. Claims 2 and 136-137 have been canceled. Claim 139 has been newly added.
Claims 1, 12-13, 15-16, 25-26, 40-41, 80-81, 104, 116, 135, and 138-139 are pending.
Claims 40-41 and 80-81, 104, 116 and 135 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim.
Claims 1, 12-13, 15-16, 25-26 and 138-139 are under examination.
Information Disclosure Statement
The information disclosure statement has been considered.
Grounds of Rejection Maintained
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 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(a) 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, 16 and 25 are rejected under 35 U.S.C. 103(a) as being unpatentable over Raison et al (WO 2003/004056 A1, IDS) and Vera et al (Blood, 108(12):3890-3897, 2006, IDS).
Raison et al disclose the K121 antibody binding to kappa-type myeloma cells (claim 1, "A method for the treatment of kappa-type multiple myeloma in a subject, the method comprising administering to the subject an effective amount of a K121-like antibody") comprising heavy chain variable region comprising CDR1 VH of SEQ ID NO:3 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 31-35, 100% identity), CDR2 VH of SEQ ID NO:4 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 50-66, 100% identity), CDR3 VH of SEQ ID N0:5 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 99-108, 100% identity), and light chain variable region comprising CDR1 SEQ ID NO:6 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 24-34, 100% identity), CDR2 SEQ ID N0:7 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 50-56, 100% identity), CDR3 SEQ ID NO:8 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 89-97, 100% identity).
Vera discloses a CAR (Abstract, the anti-[kappa] light chain CAR) comprising one or more intracellular signaling domains (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain [constant domain spacer] and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described") and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv). The genes coding the variable regions of the heavy chain (VH) and light chain (VL) of the monoclonal antibody were cloned by reverse transcription polymerase chain reaction".
Vera discloses that one or more intracellular signaling and co-stimulatory endodomains is one or more of a CD28 domain, a CD3 zeta domain or combinations thereof (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described").
Vera discloses that the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv) ... The specificity of selected clones was confirmed by flow cytometry'').
Vera discloses that the scFv is attached to the one or more intracellular signaling domains via an immunoglobulin constant region spacer comprising one or more of an lgG hinge domain, an lgG CH2 domain and an lgG CH3 domain (pg 3891, col 1, "The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the chain of the TCR/CD3 complex in the SFG retroviral backbone ... ").
Vera discloses that CARs can be expressed in genetically modified T cells (see abstract).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to combine, with a reasonable expectation of success, Vera and Raison et al by incorporating the VH and VL of the K121 anti-KMA antibody in CAR retroviral constructs and then in CAR T cells as disclosed by Vera (Vera, pg 3891, col 2) by adding the intracellular signaling and co-stimulatory endodomains of a CD28 domain and a CD3zeta domain to the K121 anti-KMA antibody of Raison, to improve antitumor response of the resulting CAR compared to the antibody (see also advantage of CARs in Vera of providing an enhanced antitumor effect, pg 3890, col 1) for multiple myeloma, because the K121 anti-KMA antibody is highly cytotoxic towards cells expressing KMA (Raison et al, pg 6, In 10-16, "Figure 12. Cytotoxic activity of chimaeric K121 (cK121) on HMy2 and K562 lymphoblastoid cells as measured by the leakage of cytoplasmic LOH ... ").
Finally, at the time of invention, creating CARs was well-established in the art so there was a reasonable expectation of success in making a CAR comprising the K121 anti-KMA antibody in CAR retroviral constructs disclosed by Vera.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent unexpected results.
Claims 1, 13, 15-16 and 25 are rejected under 35 U.S.C. 103(a) as being unpatentable over Raison et al (WO 2003/004056 A1, IDS), Vera et al (Blood, 108(12):3890-3897, 2006, IDS), Chessler et al (US 2009/0068199 A1, IDS) and Schonfeld et al (US 2013/0280285 A1, IDS).
Raison et al disclose the K121 antibody binding to kappa-type myeloma cells (claim 1, "A method for the treatment of kappa-type multiple myeloma in a subject, the method comprising administering to the subject an effective amount of a K121-like antibody") comprising heavy chain variable region comprising CDR1 VH of SEQ ID NO:3 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 31-35, 100% identity), CDR2 VH of SEQ ID NO:4 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 50-66, 100% identity), CDR3 VH of SEQ ID N0:5 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 99-108, 100% identity), and light chain variable region comprising CDR1 SEQ ID NO:6 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 24-34, 100% identity), CDR2 SEQ ID N0:7 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 50-56, 100% identity), CDR3 SEQ ID NO:8 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 89-97, 100% identity).
Vera discloses a CAR (Abstract, the anti-[kappa] light chain CAR) comprising one or more intracellular signaling domains (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described") and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv). The genes coding the variable regions of the heavy chain (VH) and light chain (VL) of the monoclonal antibody were cloned by reverse transcription polymerase chain reaction"; NOTE: [kappa] light chain is synonymous with kappa myeloma antigen (KMA), please see instant application, para [0004], "Multiple myeloma is characterized by malignant plasma cells which secrete either a kappa or lambda light chain restricted monoclonal paraprotein"; and a paper titled "lmmunotherapy with chimeric antigen receptors for multiple myeloma" by Garfall (Discov Med. 2014, 17(91):37-46; pg 3 [according to the posted document], "Kappa Light Chain ... CAR-modified T cells to treat multiple myeloma: one study using a CAR targeting the kappa immunoglobulin light chain ... ").
Vera discloses that one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3zeta domain or combinations thereof (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1- CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described").
Vera discloses that the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv) ... The specificity of selected clones was confirmed by flow cytometry'').
Vera discloses that the scFv is attached to the one or more intracellular signaling domains via an immunoglobulin constant region comprising one or more of an lgG hinge domain, an lgG CH2 domain and an lgG CH3 domain (pg 3891, col 1, "The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the chain of the TCR/CD3 complex in the SFG retroviral backbone ... ").
Vera discloses that CARs can be expressed in genetically modified T cells (see abstract).
Chessler et al disclose using flexible linkers in antibody molecules and that the (Gly4Ser)3 15 amino acid peptide is an exemplary linker and linking a VH and VL with a 15 amino acid peptide linker (paragraph 60 “A building block that can be used to create various antibody formats is the single-chain variable (V)-domain antibody fragment (sclv), which comprises V domains from the heavy and light chain (VH and VL domain) joined by a peptide linker of up to about 15 amino-acid residues” and paragraph 64 “Engineered fusion molecules contain a flexible linker between the two modules. The linker can be, for example, derived from the hinge region of an IgG isotope, a small stretch of hydrophobic amino acids such as the (Gly4Ser)3 motif”.
Schonfeld et al disclose chimeric antigen receptors with an antigen binding domain, a flexible linker, a hinge region of CD8 alpha and an effector domain (abstract and paragraph 33).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to combine, with a reasonable expectation of success, the references by incorporating the VH and VL of the K121 anti-KMA antibody with the VH and VL linked by (Gly4Ser)3 in CAR retroviral constructs and CAR T cells disclosed by Vera (Vera, pg 3891, col 2) or by adding the co-stimulatory endodomains of a CD28 domain and a CD3zeta domain to the K121 anti-KMA antibody of Raison, with a (Gly4Ser)3 linker linking the scFv to the CD8 hinge spacer to improve the antitumor response of the resulting CAR compared to the antibody (see also advantage of CARs in Vera of providing an enhanced antitumor effect, page 3890, col 1) for multiple myeloma, because the K121 anti-KMA antibody is highly cytotoxic towards cells expressing KMA (Raison et al, pg 6, In 10-16, "Figure 12. Cytotoxic activity of chimaeric K121 (cK121) on HMy2 and K562 lymphoblastoid cells as measured by the leakage of cytoplasmic LOH ... ") and using (Gly4Ser)3 fleixible linkers are known in the are to be effective at linking antibody domains and domains in antibody constructs.
Finally, at the time of invention, creating CARs was well-established in the art so there was a reasonable expectation of success in making a CAR comprising the K121 anti-KMA antibody in CAR retroviral constructs with the claimed linkers.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent unexpected results.
Claims 1, 16 and 25-26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Raison et al (WO 2003/004056 A1, IDS), Vera et al (Blood, 108(12):3890-3897, 2006, IDS), Pegram et al (Blood, 119(18):4133-4141, 2012, IDS) and Comer et al (US 2010/0330046 A1, IDS).
Raison et al disclose the K121 antibody binding to kappa-type myeloma cells (claim 1, "A method for the treatment of kappa-type multiple myeloma in a subject, the method comprising administering to the subject an effective amount of a K121-like antibody") comprising heavy chain variable region comprising CDR1 VH of SEQ ID NO:3 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 31-35, 100% identity), CDR2 VH of SEQ ID NO:4 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 50-66, 100% identity), CDR3 VH of SEQ ID N0:5 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 99-108, 100% identity), and light chain variable region comprising CDR1 SEQ ID NO:6 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 24-34, 100% identity), CDR2 SEQ ID N0:7 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 50-56, 100% identity), CDR3 SEQ ID NO:8 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 89-97, 100% identity).
Vera discloses a CAR (Abstract, the anti-[kappa] light chain CAR) comprising one or more intracellular signaling domains (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described") and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv). The genes coding the variable regions of the heavy chain (VH) and light chain (VL) of the monoclonal antibody were cloned by reverse transcription.polymerase chain reaction"; NOTE: [kappa] light chain is synonymous with kappa myeloma antigen (KMA), please see instant application, para [0004], "Multiple myeloma is characterized by malignant plasma cells which secrete either a kappa or lambda light chain restricted monoclonal paraprotein"; and a paper titled "lmmunotherapy with chimeric antigen receptors for multiple myeloma" by Garfall (Discov Med. 2014, 17(91):37-46; pg 3 [according to the posted document], "Kappa Light Chain ... CAR-modified T cells to treat multiple myeloma: one study using a CAR targeting the kappa immunoglobulin light chain ... ").
Vera discloses that one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3zeta domain or combinations thereof (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1- CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described").
Vera discloses that the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv) ... The specificity of selected clones was confirmed by flow cytometry'').
Vera discloses that the scFv is attached to the one or more intracellular signaling domains via an immunoglobulin constant region comprising one or more of an lgG hinge domain, an lgG CH2 domain and an lgG CH3 domain (pg 3891, col 1, "The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the chain of the TCR/CD3 complex in the SFG retroviral backbone ... ").
Vera discloses that CARs can be expressed in genetically modified T cells (see abstract).
Pegram et al disclose that tumor targeted CAR T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning (abstract).
Comer et al disclose that IL-12 is composed of p35 and p40 subunits and expressing active IL-12 as a fusion of p35 and p40 separated by a flexible linker (paragraph 87).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to combine, with a reasonable expectation of success, Vera and Raison et al by incorporating the VH and VL of the K121 anti-KMA antibody in CAR retroviral constructs and CAR T cells disclosed by Vera (Vera, pg 3891, col 2) or by adding the co-stimulatory endodomains of a CD28 domain and a CD3zeta domain to the K121 anti-KMA antibody of Raison, as well as expressing a single chain IL-12 as taught by Comer to improve the antitumor response toward the resulting T cell CAR (see also advantage of CARs in Vera of providing an enhanced antitumor effect, pg 3890, col 1) for multiple myeloma, because the K121 anti-KMA antibody is highly cytotoxic towards cells expressing KMA (Raison et al, pg 6, In 10-16, "Figure 12. Cytotoxic activity of chimaeric K121 (cK121) on HMy2 and K562 lymphoblastoid cells as measured by the leakage of cytoplasmic LOH ... ") and the IL-12 construct would eliminate the need for prior conditioning of the CAR T cell.
Finally, at the time of invention, creating CARs was well-established in the art so there was a reasonable expectation of success in making a CAR comprising the K121 anti-KMA antibody in CAR retroviral constructs as expressing IL-12.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent unexpected results.
Claims 1, 16, 25 and 138 are rejected under 35 U.S.C. 103(a) as being unpatentable over Raison et al (WO 2003/004056 A1, IDS), Vera et al (Blood, 108(12):3890-3897, 2006, IDS) and Kaplan, David (US 2014/0170114 A1).
Raison et al disclose the K121 antibody binding to kappa-type myeloma cells (claim 1, "A method for the treatment of kappa-type multiple myeloma in a subject, the method comprising administering to the subject an effective amount of a K121-like antibody") comprising heavy chain variable region comprising CDR1 VH of SEQ ID NO:3 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 31-35, 100% identity), CDR2 VH of SEQ ID N0:4 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 50-66, 100% identity), CDR3 VH of SEQ ID N0:5 (Example 8; Fig 9a, VH, SEQ ID NO:1, amino acids 99-108, 100% identity), and light chain variable region comprising CDR1 SEQ ID NO:6 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 24-34, 100% identity), CDR2 SEQ ID N0:7 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 50-56, 100% identity), CDR3 SEQ ID NO:8 (Example 8; Fig 9a, LH, SEQ ID NO:3, amino acids 89-97, 100% identity).
Vera discloses a CAR (Abstract, the anti-[kappa] light chain CAR) comprising one or more intracellular signaling domains (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain [constant domain spacer] and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described") and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv). The genes coding the variable regions of the heavy chain (VH) and light chain (VL) of the monoclonal antibody were cloned by reverse transcription polymerase chain reaction".
Vera discloses that one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3 zeta domain or combinations thereof (pg 3891, col 2, "Generation of retroviral constructs. The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the [zeta] chain of the TCR/CD3 complex in the SFG retroviral backbone, previously established in our laboratory ... The CD28 domain within the construct was included as previously described").
Vera discloses that the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA (pg 3891, col 2, "We cloned the antibody targeting the light chain of human immunoglobulins produced by the CRL-1758 hybridoma (ATCC) as a single chain (scFv) ... The specificity of selected clones was confirmed by flow cytometry'').
Vera discloses that the scFv is attached to the one or more intracellular signaling domains via an immunoglobulin constant region spacer comprising one or more of an lgG hinge domain, an lgG CH2 domain and an lgG CH3 domain (pg 3891, col 1, "The scFv sequence was cloned in frame with the human lgG1-CH2CH3 domain and with the chain of the TCR/CD3 complex in the SFG retroviral backbone ... ").
Vera discloses that CARs can be expressed in genetically modified T cells (see abstract).
Kaplan et al discloses that CARs can comprise CD28, CD3 zeta and further comprising 4-1BB domains (see paragraphs 37 and 39).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to combine, with a reasonable expectation of success, Vera and Raison et al by incorporating the VH and VL of the K121 anti-KMA antibody in CAR retroviral constructs and then in CAR T cells as disclosed by Vera (Vera, pg 3891, col 2) or by adding the co-stimulatory endodomains of a CD28 domain, CD3 zeta domain and the 4-1BB domain to the K121 anti-KMA antibody of Raison, to improve antitumor response of the resulting CAR compared to the antibody (see also advantage of CARs in Vera of providing an enhanced antitumor effect, pg 3890, col 1) for multiple myeloma, because the K121 anti-KMA antibody is highly cytotoxic towards cells expressing KMA (Raison et al, pg 6, In 10-16, "Figure 12. Cytotoxic activity of chimaeric K121 (cK121) on HMy2 and K562 lymphoblastoid cells as measured by the leakage of cytoplasmic LOH ... ").
Finally, at the time of invention, creating CARs was well-established in the art so there was a reasonable expectation of success in making a CAR comprising the K121 anti-KMA antibody in CAR retroviral constructs suggested by the art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent unexpected results.
Response to Arguments
In the response, Applicant traverses the obviousness rejections together starting at page 7 and argues that, a) the presently claimed CARs show greater than expected property when expressed in T- cells, which confers non-obviousness, b) there is no motivation to alter teachings of prior art to arrive at instantly claimed anti- KMA CAR, c) there is no reasonable expectation of success at arriving at the claimed invention and d) Chessler, Schonfeld, Pegram, Comer and Kaplan do not cure the defects of
Raison and/or Vera.
With respect to argument A, Applicant submits that the K121 antibody which was used for the antigen-binding domain of the claimed Car and which was taught by Raison was known to also bind to free kappa light chain (fKLC) in addition to kappa myeloma antigen (KMA) which is present on myeloma cells. Applicant submits that:
“This point was corroborated by the study conducted by Asvadi using the anti-KMA K-121 like antibody taught in Raison (i.e., MDX-1097), which is submitted herewith as Appendix
A. In fact, Asvadi showed that the presence of kFLC in antibody-dependent cellular cytotoxicity
(ADCC) assay mixtures produced a dose-dependent reduction in target cell toxicity.
Additionally, a person of ordinary skill in the art (POSA) would be aware that CAR T cell
activation typically requires robust and sustained engagement with target antigens, and
interference by soluble antigen, such as fKLC, may reduce cytotoxicity, and contribute to T cell
exhaustion. These effects are well-documented and would have led a skilled artisan to expect
that the presence of fKLC would compromise CAR T-cell function in any T-cell expressing a
CAR that comprises the CDRs of the anti-KMA K-121 like antibody of Raison, just as it
compromises antibody function.
However, Applicant submits T-cells engineered to express the CARs of claim 1 as
amended unexpectedly did NOT show a reduction in efficacy in lysing KMA expressing cells in
the presence of fKLC. In fact, as presented in the Applicant's response filed on January 28, 2025
to the Non-Final Action mailed August 28, 2024 and reiterated here, T-cells engineered to
express the instantly claimed anti-KMA CAR, are able to recognize and activate in response to
KMA positive (KMA+) target cells irrespective of the presence of fKLC (see Figure 1 of
Appendix A of the Dunn Declaration in the response filed on January 28, 2025). In addition,
FIG. 12A-12B of the instant specification demonstrates that T-cells expressing the instantly
claimed CAR are surprisingly not affected by the presence of fKLC. Indeed, FIG. 12A-12B
demonstrates that T cells expressing the instantly claimed CARs specifically recognize KMA
and can induce unexpectedly high levels of cell lysis in multiple KMA positive cell lines.”
While the arguments and declaration of unexpected results have been carefully and fully considered, they were not found to overcome the instant rejection for the following reasons:
In Asvadi et al it is noted that the figure referred to shows that IgG also inhibits MDX-1097 to the same or greater amount than kFLC (see Figure S5 reproduced below). It does not show that kFLC inhibits treatment in vivo. Also Asvadi et al give molar ratios of kFLC:MDX-1097, but the data of the inventors gives concentration of kFLC and it is unclear how much MDX-1097 chimeric antigen receptor is expressed on these CAR T cells. Therefore, it cannot be known if the data presented by the inventors is comparable to the Asvadi et al data. Notably, one of skill in the art would have recognized that the antibody of Asvadi et al acts by a different mechanism of action, i.e., the antibodies bind to the cell and induce ADCC, while CAR T cells express thousands of MDX-1097 chimeric antigen receptors that are cytotoxic to the cells they bind, such that while antibodies bound to kFLC cannot bind the cell, T cells expressing thousands of MDX-1097 chimeric antigen receptors can still bind the cell because only a small percentage of chimeric antigen receptors are bound to kFLC. Therefore, the significance of the data supplied cannot be determined. Notably, as detailed below the affinity of MDX-1097 for KMA is five time higher than for soluble fKLC. It is noted that may of these points were raised in the last office action and were not specifically addressed in the most recent response.
Furthermore, Asvadi et al state that MDX-1097 preferentially binds to KMA over soluble fKLC and that the affinity for KMA is five time higher than for soluble fKLC (see page 335 and Figure S2). Asvadi et also state “our studies indicate that binding of MDX-1097 to KMA is not abrogated to any significant degree by soluble KFLC and provide a rationale, i.e., the higher affinity of MDX-1097 for KMA, for this occurrence. Considering that in the great majority of MM patients the serum KFLC concentrations are below 200 mg/l (Mead et al, 2004), it could be proposed that, in the clinical setting, the presence of soluble kFLC binding will not diminish the clinical potential of MDX- 1097 when targeting KMA bearing MM cells. This proposal is also supported by the results from ADCC experiments in which KFLC were present in the assay mixture.” (see page 339).
Accordingly, while it was known that MDX-1097 preferentially binds to KMA over soluble fKLC, the fact that MDX-1097 binds to a lesser degree to soluble fKLC would not deter its clinical development as an antibody targeting multiple myeloma, and Applicant has not presented sufficient evidence that the antigen binding domain of MDX-1097 would not be expected to function in CAR constructs or that because of the antibody MDX-1097 data a CAR comprising the antigen-binding domain of MDX-1097 displays unexpected results.
This position is further supported by Wong et al (Blood, 114(22):1846, abstract only), which discloses that “the ability of serum kFLC to inhibit MDX-1097 binding to the myeloma cell line, JJN3, was assessed by flow cytometry using serum derived from 32 MMk patients. The results indicated that MDX-1097 at a concentration of 100μg/mL (equivalent to an estimated serum concentration of 5mg/kg dose) is capable of binding to myeloma cells in the presence of 0– 250μg/mL of serum Kflc.” Here the antigen-binding domain of the MDX-1097 antibody is shown to be capable of binding to myeloma cells in the presence of 0–250 μg/mL of serum Kflc, such that one would have reasonably expected the antigen-binding domain of the MDX-1097 antibody in a CAR construct to be capable of binding to myeloma cells in the presence of 0– 250 μg/mL of serum Kflc, so T-cells engineered to express the instantly claimed anti-KMA CAR, would be expected to be able to recognize and activate in response to KMA positive (KMA+) target cells irrespective of the presence of fKLC.
It is further noted that the antibody of Vera binds to free immunoglobulins which significantly expanded CAR46/28ζ+ T lymphocytes, which allowed Vera to conclude that “[f]ree Igκ+ did not compromise the ability of redirected T lymphocytes to eliminate Igκ+ tumors because these free immunoglobulins served to sustain proliferation of CAR-CD28 transgenic T cells” (see figure 5 and abstract). The KMA CAR construct suggested by the prior art would also bind to free kappa light chain which would give another advantage of sustaining proliferation of CAR-CD28 transgenic T cells.
It is also noted that the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." (see MPEP 716.02(d)). With respect to CAR-expressing T cells, as set forth by Lipowska-Bhalla et al (Can. Immunol. Imm., 61:953-962, 2012), “[i]n the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR” (see abstract) and that the function of CARs can be altered by each of its domains such that and “there is a general lack of understanding of the specific structural and biochemical nature of the majority of CARs” (see page 954, right column, second paragraph). Accordingly, while the rejection is being maintained, the evidence provided looks at one specific construct and there is no evidence of record that this evidence is commensurate in scope with the claims which the evidence is offered to support, even if it were persuasive with respect to the tested construct. Notably, it appears this construct comprises instant SEQ ID Nos: 21 and 22, and the prior art does not appear to teach an antigen-binding domain comprising instant SEQ ID Nos: 21 and 22 such that based on the record a CAR comprising the subject matter of claim 139 is allowable.
With respect to argument B, Applicant submits that because the K121 (MDX-1097) antibody of Raison also binds to fKLC there is no motivation to use the antigen-binding domain in a CAR.
In response, the purpose of the CAR construct suggested by the prior art is to be cytotoxic to kappa-type myeloma cells and Raison et al disclose the K121 antibody binding to kappa-type myeloma cells. Raison, Asvadi and Wong all evidence that the K121 antibody binds to kappa-type myeloma cells so fusing the antigen binding domain to appropriate CAR domains which would allow the T cells expressing thousands of CARs to target the kappa-type myeloma cells and lyse them. Therefore, even though the antigen-binding domain displays some binding to fKLC there is motivation to use the K121 antibody antigen-binding domain in a CAR as claimed.
With respect to argument C, that there is not a reasonable expectation of success, this argument is not found persuasive for multiple reasons. First it is noted that the antibody of Vera binds to free immunoglobulins which significantly expanded CAR46/28ζ+ T lymphocytes, which allowed Vera to conclude that “[f]ree Igκ+ did not compromise the ability of redirected T lymphocytes to eliminate Igκ+ tumors because these free immunoglobulins served to sustain proliferation of CAR-CD28 transgenic T cells (see figure 5 and abstract). Thus, the free kappa chains would also be expected to sustain proliferation of KMA CAR-CD28 transgenic T cells in a similar manner. It is also noted that the claims are drawn to products that need not have a particular function in vivo. Here there is evidence that CARs which bind antigen can be made and there was a reasonable expectation that a CAR made with the antibody of Raison could also be made that would bind KMA and lyse cells expressing KMA. Notably, as set forth in MPEP 2143.02 “The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention”.
Additionally, arguendo, even if there was a requirement for in vivo effectiveness, it is also noted that a 103 rejection only requires a reasonable, not absolute, expectation of success in view of the references cited. In the instant case, there is no evidence that the expectation of success for making a CAR comprising the antibody of Raison and the domains of Vera was unreasonable. At the time of invention, creating CARs was well-established in the art and the evidence provided by Applicant has not demonstrated that expectation of success was unreasonable.
Finally, applicant submits that Chessler, Schonfeld, Pegram, Comer and Kaplan do not cure the defects of Raison and/or Vera for the other 103 rejections without any specific arguments, so these rejections are maintained for the reasons set forth above and previously presented in the prior office action.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, these rejections are being maintained.
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Fig S5. Effects of kFLC on MDX-1097 mediated ADCC
To assess the effect of FLC on MDX-1097 mediated ADCC, CFSE-labelled JJN3 cells were spiked with MDX-1097 (200 g/ml final concentration) alone or together with FLC at antibody:FLC molar ratios of 4:1, 8:1, 16:1 and 32:1. JJN3 cells incubated with IgG was used as an untreated control. After 30 minute incubation at 37º C, cells were added to freshly isolated normal PBMCs at a constant E:T ratio of 50:1 and the mixture was incubated for 12 hours. 7-AAD was then added and the cells were analysed on a FACSCalibur flow cytometer. CFSE+/7-AAD+ represented dead JJN3 cells. This experiment was repeated 3 times using PBMCs from independent donors and the data was compiled as shown.
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 obviousness-type double patenting rejection is appropriate where the conflicting claims 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 conflicting 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.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 13, 15-16, 25-26 and 138 are rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over claims 1-18 of US Patent 11,305,011, IDS. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
The claims of the patent recite:
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In the patented claims, SEQ ID NO:1 and 2 comprise the instant claimed CDR sequences of claim 1 but not the sequences of instant claim 12. Therefore, the subject matter claimed in the instant claims 1-2, 13, 15-16, 25-26 and 136-138 would be seen as anticipated by the patented claims.
Response to Arguments
In the response, Applicant requests that the aforementioned non-statutory double patenting rejection be held in abeyance until such time as allowable subject matter can be ascertained.
In response, the rejection is maintained for reasons of record.
Conclusion
Claims 139 is allowed. Claim 12 is objected to for depending from a rejected base claim.
The claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and the claims rejected above could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP §). 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 extension fee 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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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
July 3, 2026
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