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
The Amendments and Remarks filed 11/18/25 in response to the Office Action of 5/21/25 are acknowledged and have been entered.
Claims 1-5, 8, 9, 12, 14, 16, 18, 28-31, 34-37, 44, and 48 are pending.
Claims 4-5 remain withdrawn.
Claims 1, 8, 9, 28, 37, and 44 have been amended by Applicant.
Claims 1-3, 8, 9, 12, 14, 16, 18, 28-31, 34-37, 44, and 48 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Withdrawn
The rejection of claims under 35 U.S.C. 103(a) as being unpatentable over Png et al (US 2018/0148506 A1; 5/31/2018; 5/5/21 IDS) in view of Brogdon et al (US 2014/0322275 A1; 10/30/14) and Sharp et al (WO 2016/049024 A2; 3/31/16) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1-3, 8, 9, 44, and 48 are rejected under 35 U.S.C. 103(a) as being unpatentable over Png et al (US 2018/0148506 A1; 5/31/2018; 5/5/21 IDS) in view of Kamiya et al (Blood Advances, 2018, 2(5): 517-528; 5/5/21 IDS) and Szymczak-Workman et al (Cold Spring Harbor Protoc, 2012, 199-204).
Png et al teaches methods of treating cancer comprising administering anti-CD7-CAR immune cells comprising nucleic acid expressing an anti-CD7 chimeric antigen receptor (anti-CD7-CAR) to patients with cancer ([0024], in particular). Png et al further teaches such immune cells include T cells ([0035], in particular). Png et al further teaches such anti-CD7-CAR immune cells further comprising nucleic acid expressing an anti-CD7 protein expression blocker (anti-CD7 PEBL) that downregulates CD7 and controls fratricide (see Abstract, [0082], [0090], and [0148], in particular). Png et al further teaches vectors include viral expression vectors and teaches polynucleotide vectors carrying both nucleic acids encoding the anti-CD7 PEBL and nucleic acids encoding the anti-CD7-CAR can be generated ([0131], in particular). Png et al further teaches such vectors comprising promoter sequences ([0060], in particular).
Png et al further teaches anti-CD7 PEBL having the structure: CD8a signal peptide- VL-linker-VH-ER-retention domain, wherein the VL-linker-VH is an anti-CD7 scFv (Figure 3E, in particular). At Table 3, Png et al further teaches amino acid sequences for such an anti-CD7-PEBL wherein the CD8a signal peptide comprises SEQ ID NO:7, the VL comprises SEQ ID NO:2, the linker comprises SEQ ID NO:12, the VH comprises SEQ ID NO:1, and the retention/localization domain comprise SEQ ID NO:8. The anti-CD7 PEBL disclosed by the instant specification as SEQ ID NO: 24 is identical to such an anti-CD7 PEBL of Png et al consisting of SEQ ID NOs: 7, 12, 1, and 8.
Png et al further teaches anti-CD7-CAR having the structure anti-CD7 scFv (comprising a VL-linker-VH)-hinge-transmembrane-signaling domains (Figure 17, in particular). At Table 5, Png et al teaches amino acid sequences for such an anti-CD7-CAR wherein the VL of the scFv comprises SEQ ID NO:2, the VH of the scFv comprises SEQ ID NO:1, the hinge-transmembrane comprises SEQ ID NO:10, a 4-1BB intracellular signaling domain comprising SEQ ID NO:3, and a CD3 intracellular signaling domain comprising SEQ ID NO:4. Png et al further teaches (GGGGS)4 as a linker for the scFv of the anti-CD7-CAR ([0109], in particular). Png et al further teaches the anti-CD7-CAR with a CD8a signal peptide comprising SEQ ID NO:7 ([0079], in particular). The anti-CD7 CAR disclosed by the instant specification as SEQ ID NO: 28 is identical to such an anti-CD7 CAR of Png et al consisting of SEQ ID NO:7-SEQ ID NO:2-(GGGGS)4-SEQ ID NO:10-SEQ ID NO:3-SEQ ID NO:4.
Png et al does not specifically teach a bicistronic retroviral vector comprising polynucleotides encoding anti-CD7 PEBL of Png et al and anti-CD7-CAR of Png et al. However, these deficiencies are made up in the teachings of Kamiya et al and Szymczak-Workman et al.
Kamiya et al teaches a PEBL gene can be combined with a CAR gene on a bicistronic construct (left column on page 525, in particular) and teaches generating T cells expressing CAR and corresponding PEBL constructs wherein the constructs are expressed on retroviral vector comprising a sequence encoding a self-cleaving 2A peptide flanking the CAR and PEBL (right column on page 518, in particular). Kamiya et al cites Szymczak-Workman et al as teaching how said CAR and corresponding PEBL constructs were generated (right column on page 518, in particular).
Szymczak-Workman et al teaches self-cleaving 2A peptides include F2A, E2A, P2A, and T2A (Figure 1, in particular). Szymczak-Workman et al further teaches use of such self-cleaving 2A peptides with multicistronic vectors wherein the self-cleaving 2A peptides cloned between genes of a single open reading frame (“operatively linked”) allows for efficient production of discrete protein constructs within a single vector through a novel cleavage event within the 2A peptide sequence (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and treat subjects with cancer by performing a combined method comprising administering anti-CD7-CAR T cells that also express anti-CD7 PEBL of Png et al wherein the T cells express both anti-CD7-CAR of Png and anti-CD7 PEBL of Png using a bicistronic retroviral vector comprising a polynucleotide comprising an open reading frame encoding just any self-cleaving 2A peptide of Szymczak-Workman et al flanked by polynucleotides encoding CD7-CAR of Png and anti-CD7 PEBL of Png because Png et al teaches methods of treating cancer comprising administering anti-CD7-CAR immune cells, such as T cells, comprising nucleic acid expressing an anti-CD7 chimeric antigen receptor, Png et al teaches fratricide of such anti-CD7-CAR immune cells can be controlled by also expressing nucleic acids encoding an anti-CD7 protein expression blocker (anti-CD7 PEBL) to downregulate in CD7 said cells, Kamiya et al teaches such a PEBL gene can be combined with a CAR gene on a bicistronic construct and teaches generating T cells expressing CAR and corresponding PEBL constructs wherein the constructs are expressed on retroviral vector comprising a sequence encoding a self-cleaving 2A peptide flanking the CAR and PEBL that (as taught by Szymczak-Workman et al) allows for efficient production of discrete protein constructs within a single vector through a novel cleavage event within the 2A peptide sequence. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art references or to combine prior art reference teachings to arrive at the claimed invention.
In particular regards to claim 9, one of skill in the art (in view of Figure 27 of the instant specification) would recognize polynucleotides of the bicistronic retroviral vectors of the combined method (ones where the self-cleaving 2A peptide is P2A of Szymczak-Workman et al) include sequences having at least 90% sequence identity to instant SEQ ID NO:13.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 11/18/25, Applicant argues cited references do not teach or suggest a 2A self-cleaving peptide and there is no motivation to select a polynucleotide encoding a 2A self-cleaving peptide instead of a polynucleotide encoding an IRES. Applicant further indicates there would be no expectation of success in generating a functioning bicistronic retroviral vector “wherein the first polynucleotide is operably linked to the second polynucleotide which is operably linked to a third polynucleotide” as recited in claim 1 because Szymczak-Workman teaches limitations and issues with self-cleaving 2A peptide. Applicant cites Szymczak-Workman teaching “potential problems with slipstreaming as well as issues associated with the presence of residual 2A tag on all but the last protein.” See p. 201 last sentence of “ The 2A Peptide Sequence and Gene Order” of Szymczak-Workman. Applicant further argues cited references do not suggest manufacturing problems associated with using separate expression vectors and would not have motivated one to use a bicistronic vector. Applicant further indicates the claims are non-obvious because cells transduced with bicistronic CAR-P2A-PEBL resulted in 79.3% CAR+/CD7-, while cells transduced sequentially with PEBL and CAR resulted in only 51% CAR+/CD7-. Applicant further indicates the claims are non-obvious because cells transduced with bicistronic CAR-P2A-PEBL resulted in 79.3% CAR+/CD7-, while cells transduced sequentially with CAR-IRES-PEBL resulted in only 35.8% CAR+/CD7-. Applicant further indicates the claims are non-obvious because the percentage of cells expressing anti-CD7 CAR and having reduced endogenous CD7 expression increased over time after transduction with bicistronic CAR-P2A-PEBL vectors.
The amendments to the claims and the arguments found in the Reply of 11/18/25 have been carefully considered, but are not deemed persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In regards to the arguments that cited references do not teach or suggest a 2A self-cleaving peptide and there is no motivation to select a polynucleotide encoding a 2A self-cleaving peptide instead of a polynucleotide encoding an IRES, Szymczak-Workman teaches self-cleaving 2A peptides cloned between genes of a single open reading frame (“operatively linked”) allows for efficient production of discrete protein constructs within a single vector through a novel cleavage event within the 2A peptide sequence (Abstract, in particular).
In regards to the indication there would be no expectation of success in generating a functioning bicistronic retroviral vector “wherein the first polynucleotide is operably linked to the second polynucleotide which is operably linked to a third polynucleotide” as recited in claim 1 because Szymczak-Workman teaches limitations and issues with self-cleaving 2A peptide, Szymczak-Workman teaching “potential problems with slipstreaming as well as issues associated with the presence of residual 2A tag on all but the last protein.” See p. 201 last sentence of “ The 2A Peptide Sequence and Gene Order” of Szymczak-Workman: Regarding “potential problems with slipstreaming as well as issue associated with the presence of a residual tag on all but the last protein:” (i) Szymczak-Workman teaches “Thus far, no adverse effects have been reported from the presence of this residual sequence” (page 200, in particular); and (ii) Szymczak-Workman teaches “slipstreaming” can occur for proteins that follow luminally targeted proteins – and provides guidance that if “a mixture of differentially targeted proteins is required an includes one that is targeted to the lumen, one should consider the order in which the proteins are included in 2A-linked vectors” (page 200, in particular). Further, there would be an expectation of success in generating a functioning bicistronic retroviral vector wherein a polynucleotide encoding a CAR is operably linked to a polynucleotide encoding a 2A self-cleaving peptide which is operatively linked to a polynucleotide encoding a PEBL because Kamiya et al teaches generating a functioning bicistronic retroviral vector wherein a polynucleotide encoding a CAR is operably linked to a polynucleotide encoding a 2A self-cleaving peptide which is operatively linked to a polynucleotide encoding a PEBL (see third paragraph of left column on page 518 of Kamiya et al).
In regards to the argument cited references do not suggest manufacturing problems associated with using separate expression vectors and would not have motivated one to use a bicistronic vector, benefits of bicistronic vectors are self-evident. One of skill in the art would recognize that bicistronic vectors, as compared to separate expression vectors, have benefits that include the ability of a single vector to express two constructs in a transduced cell. Further, Kamiya et al teaches: because a PEBL gene can be combined with a CAR gene in a single bicistronic construct, “an allogeneic CAR-T cell product can be obtained after a single transduction procedure” (left column on page 525, in particular).
In regards to the indication the claims are non-obvious because cells transduced with bicistronic CAR-P2A-PEBL resulted in 79.3% CAR+/CD7- and cells transduced sequentially with PEBL and CAR resulted in only 51% CAR+/CD7-, the examiner disagrees. Cells transduced with a bicistronic CAR-P2A-PEBL would be expected to have a greater proportion of CAR+/CD7- cells than those transduced sequentially with PEBL and CAR because those transduced sequentially require two expression vectors to both be successfully transduced to result in a CAR+/CD7- cell, while those transduced with bicistronic CAR-P2A-PEBL require only a single vector to be successfully transduced to result in a CAR+/CD7- cell. When sequentially transducing PEBL and CAR, one would expect populations of cells to include those that only transduce PEBL or CAR – resulting in populations of CAR-/CD7- and CAR+/CD7+ cells.
In regards to the indication the claims are non-obvious because cells transduced with bicistronic CAR-P2A-PEBL resulted in 79.3% CAR+/CD7- and cells transduced sequentially with CAR-IRES-PEBL resulted in only 35.8% CAR+/CD7-, the examiner disagrees. A known problem of IRES is that translation efficiency of a gene placed after an IRES sequence is much lower than that of a gene located before IRES and that this problem is overcome by using a P2A self-cleaving peptide (page 1 of Kim et al (PLOS one, 2011, 6(4): e18556), in particular). Therefore, transduction with CAR-IRES-PEBL constructs would predictably result in a significant number of CAR+/CD7+ cells due to reduced translation of PEBL after the IRES.
In regards to the indication the claims are non-obvious because the percentage of cells expressing anti-CD7 CAR and having reduced endogenous CD7 expression increased over time after transduction with bicistronic CAR-P2A-PEBL vectors, the examiner disagrees. The percentage of cells expressing anti-CD7 CAR and having reduced endogenous CD7 expression would be expected to increase over time after transduction with bicistronic CAR-P2A-PEBL vectors because cells transduced with bicistronic CAR-P2A-PEBL vectors result in CAR+/CD7- cells and those cells would predictably engage in fratricide of CD7+ cells that are not successfully transduced (see [0035] and [0177]-[0179] of Png et al) – resulting in an increased percentage of CAR+/CD7- successfully transduced cells and ongoing reduction in number of CD7+ cells that were not successfully transduced due to fratricide.
Claim Rejections - 35 USC § 103
Claim(s) 1-3, 8, 9, 12, 18, 44, and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Png et al (US 2018/0148506 A1; 5/31/2018; 5/5/21 IDS) in view of Kamiya et al (Blood Advances, 2018, 2(5): 517-528; 5/5/21 IDS) and Szymczak-Workman et al (Cold Spring Harbor Protoc, 2012, 199-204) as applied to claims 1-3, 8, 9, 44, and 48 above, and further in view of Yang et al (Gene Therapy, 2008, 15: 1411-1423).
Teachings of Png et al, Kamiya et al, and Szymczak-Workman et al are discussed above.
Png et al, Kamiya et al, and Szymczak-Workman et al do not specifically teach the bicistronic retroviral vector comprising a polynucleotide comprising an open reading frame encoding a self-cleaving 2A peptide flanked by the sequences encoding the protein constructs of Png et al is a lentiviral vector or that expression of the open reading frame is driven by a MSCV promoter. However, these deficiencies are made up in the teachings of Yang et al.
Yang et al teaches using bicistronic retroviral lentiviral vectors comprising a MSCV promoter driving expression of a polynucleotide comprising an open reading frame encoding a self-cleaving 2A peptide flanked by two different protein sequences (Figure 1, in particular). Yang et al further teaches advantages of lentiviral vectors include the ability to transduce nondividing cells, resistance to gene silencing, and potentially safer integration site profile (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Png et al, Kamiya et al, and Szymczak-Workman et al wherein the bicistronic retroviral vector comprising a polynucleotide comprising an open reading frame encoding a self-cleaving 2A peptide flanked by the sequences encoding the protein constructs of Png et al is a lentiviral vector and expression of the open reading frame is driven by a MSCV promoter of the vector because Yang et al teaches using bicistronic retroviral lentiviral vectors comprising a MSCV promoter driving expression of a polynucleotide comprising an open reading frame encoding a self-cleaving 2A peptide flanked by two different protein sequences and Yang et al teaches advantages of lentiviral vectors include the ability to transduce nondividing cells, resistance to gene silencing, and potentially safer integration site profile. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art references or to combine prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 11/18/25, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1-3, 8, 9, 12, 14, 16, 18, 44, and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Png et al (US 2018/0148506 A1; 5/31/2018; 5/5/21 IDS) in view of Kamiya et al (Blood Advances, 2018, 2(5): 517-528; 5/5/21 IDS), Szymczak-Workman et al (Cold Spring Harbor Protoc, 2012, 199-204), and Yang et al (Gene Therapy, 2008, 15: 1411-1423), as applied to claims 1-3, 8, 9, 12, 18, 44, and 48 and further in view of Brogdon et al (US 2014/0322275 A1; 10/30/14).
Teachings of Png et al, Kamiya et al, Szymczak-Workman et al, and Yang et al are discussed above.
Png et al, Kamiya et al, Szymczak-Workman et al, and Yang et al do not specifically teach an EF-1 promoter comprising SEQ ID NO: 7. However, these deficiencies are made up in the teachings of Brogdon et al.
Brogdon et al teaches using an EF-1 promoter comprising SEQ ID NO:97, which is identical to instant SEQ ID NO:7, as a promoter in a lentiviral vector ([0029], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Png et al, Kamiya et al, Szymczak-Workman et al, and Yang et al comprising administering a lentiviral vector that drives expression with a promoter wherein the EF-1 promoter of Brogdon et al is substituted for the MSCV promoter because Brogdon et al teaches using an EF-1 promoter comprising SEQ ID NO:97, which is identical to instant SEQ ID NO:7, as a promoter in a lentiviral vector. This is an example of a simple substitution of one known element for another to obtain predictable results.
In particular regards to claim 16, one of skill in the art (in view of Figure 4 of the instant specification) would recognize polynucleotides of the bicistronic retroviral vectors of the combined method (ones where the self-cleaving 2A peptide is a P2A of Szymczak-Workman et al and the promoter is EF-1 promoter of Brogdon et al) include sequences having at least 90% sequence identity to instant SEQ ID NO:15.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 11/18/25, Applicant repeats arguments addressed above.
Allowable Subject Matter
Claims 28-31 and 34-37 are allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SEAN E AEDER/Primary Examiner, Art Unit 1642