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 amended claims filed on June 29, 2026, have been acknowledged. Claims 2-5, 7, 16-18, and 28-30 were cancelled. Claims 1, 6, and 25 were amended. Claims 31-38 are new. Claims 1, 6, 8-15, 19-27, and 31-38 are pending and examined on the merits.
Applicant’s response has been considered. Rejections and/or objections not reiterated from the previous office action mailed March 27, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/116,611, filed on November 20, 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 6, 8-15, 19-27, and 31-38 receive domestic benefit from U.S. provisional application No. 63/116,611, filed on November 20, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed on June 29, 2026, has been considered.
Specification
The amendments to the specification filed on June 29, 2026, have been considered and should be entered.
Nucleotide and/or Amino Acid Sequence Disclosures
The amendments to the sequence listing filed on June 29, 2026, have been considered and overcome the prior objection of record.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claim 25 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments to claim 25 to recite the MND promoter comprises a nucleic acid sequence.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 6, 8-15, 19-27, and 31-38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This is a new rejection made in response to Applicant’s amendments to the claims. Applicant’s arguments have been considered but are moot in response to the new rejection of record.
Regarding claims 1, 6, 8, 21-22, and 32, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector encodes the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system).
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Regarding claims 9-10 and 33-36, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140). Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
Regarding claim 11-13, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter (paragraphs 0066-0072).
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1).
Regarding claim 23, as shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
Regarding claim 24, Scharenberg teaches that the promoter can be an MND promoter (paragraphs 0066-0072).
Regarding claim 25, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
Regarding claims 26-27 and 37-38, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6, 8-15, 19-27 and 31-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-11, 13-15, 18-21, and 66-68 of copending Application No. 18262859 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This a new rejection made in response to Applicant’s amendments to the claims. Applicant’s traversal has been considered but the rejection cannot be held in abeyance.
Regarding claims 1, 6, 8, ‘859 claims a lentiviral particle comprising a vector genome comprising a polynucleotide sequence encoding an anti-CD19 chimeric antigen receptor, wherein the vector genome comprises a polynucleotide sequence encoding a multipartite cell-surface receptor comprising a FKBP- rapamycin complex binding domain (FRB domain) or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP) or a functional variant thereof (claims 1-7).
‘859 does not teach that the dimerization of the dimerization domains is able to transduce an IL-2 like signal in a T cell.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
‘859 claims the CAR is encoded in the genome of the lentiviral vector. Therefore, modifying the lentiviral vector genome to incorporate the FRB and FKBR domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Similarly, Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘859 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘859 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘859 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11-13, ‘859 teaches wherein the polynucleotide encoding the anti-CD19 chimeric antigen receptor and/or the polynucleotide encoding the multipartite cell-surface receptor is operatively linked to one or more promoters, and wherein at least one of the one or more promoters is an inducible promoter (claim 13). Similarly, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter (paragraphs 0066-0072).
Regarding claims 14-15 and 31, ‘859 claims wherein the vector genome comprises a polynucleotide sequence that confers resistance to an immunosuppressive agent (claim 8). Furthermore, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘859 claims wherein the viral particle comprises a viral envelope comprising one or more immune cell-activating proteins exposed on the surface and/or conjugated to the surface of the viral envelope, including an anti-CD3 single-chain variable fragment (claims 14-15).
‘859 does not teach how the immune cell activating proteins are exposed on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce the viral particle of ‘859. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 21-22 and 32, ‘859 does not teach that their vectors encode IL-2 subunits.
However, as stated supra, Scharenberg teaches that their CAR constructs can include IL2b and IL2g subunits fused to the dimerization domains and, as shown in Example 2 of Scharenberg, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
Therefore, it would have been obvious to include IL2Rb and IL2Rg subunits fused to the dimerization domains as this was known to lead to increased proliferation of the T cells and would improve the therapeutic efficacy of these CAR cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 23, as shown in Example 2 of Scharenberg, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
Regarding claim 24, ‘859 claims wherein the promoter is an MND promoter (claim 20) and Scharenberg teaches that the promoter can be an MND promoter (paragraphs 0066-0072).
Regarding claim 25, ‘859 is silent regarding the sequence of the MND promoter.
However, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘859 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6, 8-15, 19-27 and 31-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11, 19, 23-26, 33-34, 38-39, 47, 49, 60-61, 63-64, and 84 of copending Application No. 18931597 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This a new rejection made in response to Applicant’s amendments to the claims. Applicant’s traversal has been considered but the rejection cannot be held in abeyance.
Regarding claims 1, 6, and 8, ‘597 claims a lentiviral particle comprising a vector genome comprising a polynucleotide sequence encoding a chimeric antigen receptor, wherein the vector genome comprises a polynucleotide sequence encoding a multipartite cell-surface receptor comprising a FKBP- rapamycin complex binding domain (FRB domain) or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP) or a functional variant thereof (claims 1, 19, 33-34, 60).
‘597 does not teach that the dimerization of the dimerization domains is able to transduce an IL-2 like signal in a T cell.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
‘597 claims the CAR is encoded in the genome of the lentiviral vector (claim 19). Therefore, modifying the lentiviral vector genome to incorporate the FRB and FKBR domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Similarly, Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘597 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘597 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘597 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11-13 and 24, ‘597 is silent regarding the promoter used.
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter or an MND promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘597 claims wherein the viral particle comprises a viral envelope comprising one or more immune cell-activating proteins exposed on the surface and/or conjugated to the surface of the viral envelope, including an anti-CD3 single-chain variable fragment (claims 1-8).
‘597 does not teach how the immune cell activating proteins are exposed on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce the viral particle of ‘597. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 21-22 and 32, ‘597 does not teach that their vectors encode IL-2 subunits.
However, as stated supra, Scharenberg teaches that their CAR constructs can include IL2b and IL2g subunits fused to the dimerization domains and, as shown in Example 2 of Scharenberg, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
Therefore, it would have been obvious to include IL2Rb and IL2Rg subunits fused to the dimerization domains as this was known to lead to increased proliferation of the T cells and would improve the therapeutic efficacy of these CAR cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 23, as shown in Example 2 of Scharenberg, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
Regarding claim 25, ‘597 is silent regarding the sequence of the MND promoter.
However, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘597 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6, 8-15, 19-27 and 31-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18991101 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This a new rejection made in response to Applicant’s amendments to the claims. Applicant’s traversal has been considered but the rejection cannot be held in abeyance.
Regarding claims 1, 6, 8, 21-23, and 32, ‘101 claims a lentiviral particle comprising a vector genome comprising a polynucleotide sequence encoding a FKBP- rapamycin complex binding domain (FRB domain) polypeptide chain or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP) polypeptide chain or a functional variant thereof, and wherein the two polypeptide chains each comprise a transmembrane domain and an intracellular cytokine receptor signaling domain, including a common cytokine receptor gamma chain and a common cytokine receptor beta chain. ‘101 claims wherein binding of the extracellular domains to the small molecule is sufficient for the intracellular cytokine receptor signaling domains of the two polypeptide chains to activate cytokine signal transduction (claims 1, 4-7, 17). IL-2 is a known common cytokine and Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (Example 2) and cause T cell expansion.
‘101 does not teach that the vector also includes a CAR.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘101 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘101 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘101 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 12 and 24-25, ‘101 claims a lentiviral particle comprising a nucleic acid sequence encoding a small molecule controllable T-cell/NK-cell activation receptor, the nucleic acid sequence operatively linked to a promoter and that the promoter can be SEQ ID NO: 5 (an MND promoter) which 98.3% similar to SEQ ID NO: 3 of the instant application.
Regarding claims 11 and 13, ‘101 does not teach using inducible promoters,
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘101 claims wherein the lentiviral particle is a surface-engineered lentiviral particle further comprising a T-cell activation or co-stimulation molecule. (claim 2).
‘101 does not teach how the immune cell activating proteins are exposed on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce the viral particle of ‘101. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘101 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6, 8, 12, 14-15, 21-23 and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74-93 of copending Application No. 18991176, as evidenced by World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS). This a new rejection made in response to Applicant’s amendments to the claims. Applicant’s traversal has been considered but the rejection cannot be held in abeyance.
Although claims 74-93 are methods, the method of 18991176 comprises the product as claimed in the instant application.
Regarding claims 1, 6, 8, 21-22, and 32, ‘176 claims a lentiviral particle comprising a vector comprising a polynucleotide sequence encoding a chimeric antigen receptor, wherein the vector comprises a polynucleotide sequence encoding a first polypeptide comprising a first extracellular dimerization domain linked to an intracellular IL-2Rb signaling domain (a FKBP- rapamycin complex binding domain (FRB domain) or a functional variant thereof); a second polypeptide comprising a second extracellular dimerization domain linked to an intracellular IL-2Ry signaling domain (a FK506 binding protein domain (FKBP) or a functional variant thereof); and wherein the first and second extracellular dimerization domains are configured to dimerize together
Scharenberg evidences that the intracellular domains of the small-molecule controllable receptor comprising FKBP and FRB domains fused separately to IL-2R beta and IL-2R gamma subunits was able to transduce an IL-2-like signal upon rapamycin treatment (i.e. dimerization).
‘176 claims the CAR is encoded with the FRB and FKBR domains in the genome of the lentiviral vector. As such, this would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A of Scharenberg, the RACCR chimeric IL2 receptors encoded by a vector will generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Although ‘176 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that large titers of vectors are used for transduction of T cells and can result in more than one vector infecting the same cell.
Regarding claim 12, ‘116 claims wherein the vector comprises a promoter operably linked to nucleic acid sequences encoding the first, second, and third polypeptides (claim 81).
Regarding claims 14-15 and 31, Scharenberg evidences that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claim 23, as shown in Example 2 of Scharenberg, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 8-13, 19-22, 24-27, and 33-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74-93 of copending Application No. 18991176, as applied to claims 1, 8, 12, and 21-22 above, in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This a new rejection made in response to Applicant’s amendments to the claims. Applicant’s traversal has been considered but the rejection cannot be held in abeyance.
Regarding claims 9-10 and 33-36, ‘176 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11, 13, and 24, the teachings of ‘116 are as discussed above.
‘116 is silent regarding the type of promoter used.
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter or an MND promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 19-20, ‘116 claims wherein the viral particle comprises a viral surface comprising an anti-CD3 antibody or scFv (claim 76).
‘116 does not teach how the anti-CD3 antibody or scFv are exposed on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce the viral particle of ‘116. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 25, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘116 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6, 8-15, 19-27 and 31-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12215337 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This is a new rejection made in response to Applicant’s amendments to the claims. Applicant’s arguments have been considered but are moot in response to the new rejection of record.
Regarding claims 1, 6, 8, 21-23 and 32, ‘337 claims a lentiviral particle comprising a vector genome comprising a polynucleotide sequence encoding a FKBP- rapamycin complex binding domain (FRB domain) polypeptide chain or a functional variant thereof; and the polynucleotide comprises a polynucleotide sequence encoding a FK506 binding protein domain (FKBP) polypeptide chain or a functional variant thereof, and wherein the two polypeptide chains each comprise a transmembrane domain and an intracellular cytokine receptor signaling domain, including a common cytokine receptor gamma chain and a common cytokine receptor beta chain. ‘101 claims wherein binding of the extracellular domains to the small molecule is sufficient for the intracellular cytokine receptor signaling domains of the two polypeptide chains to activate cytokine signal transduction (claims 1, 4-7, 17). IL-2 is a known common cytokine and Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (Example 2) and cause T cell expansion.
‘337 does not teach that the vector also includes a CAR.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘337 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘337 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘337 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11-13, and 24, ‘337 claims a nucleic acid sequence encoding a small molecule controllable T-cell/NK-cell activation receptor, the nucleic acid sequence operatively linked to a promoter but does not teach an inducible promoter nor an MND promoter.
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter or an MND promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘337 claims wherein the lentiviral particle is a surface-engineered lentiviral particle further comprising a viral surface comprising an anti-CD3 antibody or scFv. (claim 1).
‘337 does not teach how the immune cell activating anti-CD3 antibody or scFv are exposed on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L). Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce the viral particle of ‘337. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 25, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘337 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 3-6, 8-15, 19-27 and 31-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12358970 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This is a new rejection made in response to Applicant’s amendments to the claims. Applicant’s arguments have been considered but are moot in response to the new rejection of record.
Although ‘970 is drawn to a method, the combined teachings of ‘970 and Scharenberg teach the product of the instant application.
Regarding claims 1, 6, 8, 21-23, and 32, ‘970 claims one or more lentiviral vectors comprising a first nucleic acid encoding a first chemically inducible signaling complex (CISC) component, wherein the first CISC component comprises in an N-to-C terminal order:
(a) an extracellular domain comprising an FK506-binding protein (FKBP) domain;
(b) an IL-2 receptor γ (IL-2Rγ) transmembrane domain; and
(c) an IL-2Ry cytoplasmic signaling domain; and
(ii) a second nucleic acid encoding a second CISC component, wherein the second CISC component comprises in an N-to-C-terminal order:
(a) an extracellular domain comprising an FKBP-rapamycin-binding (FRB) domain;
(b) an IL-2 receptor β (IL-2RB) transmembrane domain; and
(c) an IL-2Rβ cytoplasmic signaling domain (claims 1, 12, and 14-15).
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (Example 2) and cause T cell expansion (paragraphs 0060-0065 and Example 2).
‘970 does not teach that the vector also includes a CAR.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Even using a different interpretation wherein the FKBP and FRB domains are encoded on separate vectors and not in the same vector, ‘970 claims wherein the first nucleic acid and the second nucleic acid are comprised in separate viral vectors (claims 12 and 14-15).
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘337 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘970 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘970 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11-13, and 24, ‘970 is silent regarding the use of promoters.
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter or an MND promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘337 does not teach exposing immune cell activating anti-CD3 antibody or scFv on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L).
Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce lentiviral particles incorporating T-cell activation or co-stimulation molecules to render the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 25, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘970 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 3-6, 8-15, 19-27 and 31-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11753460 in view of World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg; referenced in IDS), as evidenced by NCBI (NP_000792.1). This is a new rejection made in response to Applicant’s amendments to the claims. Applicant’s arguments have been considered but are moot in response to the new rejection of record.
Regarding claims 1, 6, 8, and 21-23, ‘460 claims one or more lentiviral vectors comprising a first nucleic acid encoding a first chemically inducible signaling complex (CISC) component, wherein the first CISC component comprises in an N-to-C terminal order:
(a) an extracellular domain comprising an FK506-binding protein (FKBP) domain;
(b) an IL-2 receptor γ (IL-2Rγ) transmembrane domain; and
(c) an IL-2Ry cytoplasmic signaling domain; and
(ii) a second nucleic acid encoding a second CISC component, wherein the second CISC component comprises in an N-to-C-terminal order:
(a) an extracellular domain comprising an FKBP-rapamycin-binding (FRB) domain;
(b) an IL-2 receptor β (IL-2RB) transmembrane domain; and
(c) an IL-2Rβ cytoplasmic signaling domain (claims 1 and 6-7).
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (Example 2) and cause T cell expansion (paragraphs 0060-0065 and Example 2).
‘460 does not teach that the vector also includes a CAR.
However, Scharenberg teaches lentiviral vectors that encode:
a controllable targeting receptor encoding a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule.
Scharenberg teaches that the protein subunits that inducibly dimerize can be the FKBP12-rapamycin binding (FRB) domain (a first polypeptide component encoding a first dimerization domain) and FK506-binding protein (FKBP) (a second polypeptide component encoding a second dimerization domain) which dimerizes in the presence of rapamycin.
Scharenberg teaches that the intracellular domains of the small-molecule controllable receptor may comprise one or more domains, such as IL-2R beta and IL-2R gamma. As identified in Example 2, rapamycin (i.e. a ligand) treatment (i.e. dimerization) were able to transduce an IL-2-like signal (paragraphs 0060-0065 and Example 2).
Scharenberg does not specifically identify whether the CAR fusion protein is encoded by a single or multiple lentiviral vectors. However, Scharenberg teaches that the genes are encoded by “the lentiviral vector”, the small-molecule controllable targeting receptor may be encoded by a single transgene or by two transgenes, and each of the identified lentiviral vectors in Figures 6-11 and Example 2 using the RACCR construct encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065 and Example 2). Therefore, one would reasonably conclude that a single lentiviral vector can encode the CAR, the FRB domain, and the FKBP domain.
Regarding the first and the second CAR, as the CAR is a fusion protein fused to subunits that inducibly dimerize in the presence of a small molecule, the fusion protein would be encoded by a polynucleotide sequence encoding the CAR and the first and second polynucleotide sequence.
Additionally, the claims are broadly interpreted to encompass two of the same vectors that encode the same CAR and both of the first and second polypeptide component as there is no specific recitation that the second CAR is different than the first CAR (thus, it is considered that the CARs can be the same CAR) and that the first vector/second vector cannot also encode the first and second polypeptide component, respectively. As shown in Figure 12A, the RACCR chimeric IL2 receptors encoded by a vector will be generate separate monomers (IL2Rb and IL2Rg, respectively) that will dimerize upon rapamycin interaction. It is well understood that these dimerizations could occur between an IL2Rb encoded by one vector and an IL2Rg encoded by a different vector.
Scharenberg teaches generating titers of the lentiviral vectors (paragraph 0048). Therefore, two or more vectors are made and stored together (i.e. a vector system). Although ‘337 does not specifically identify that their viral vector is part of a titer of viral vectors, it is well understood that it can stored with many other vectors as a large titer for later transduction.
As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080, Example 2, and Figure 12).
Scharenberg teaches that administering the small molecule permits activation of the targeting receptor to target transduced cells to target cells, whereas ceasing administration of the small molecule prevents the receptor from targeting transduced cells to target cells. In this way, in vivo TILs generated by administering the lentiviral particles to a subject will activate only while the small molecule is present in the subject. Activity of TILs can be monitored through blood samples, biopsy, or medical imaging, and the small molecule withdrawn if excessive activity is observed. In some cases, pulsed or intermittent administration of the small molecule may used to optimize the treatment protocol. In some cases, the small molecule will be titrated to tune TIL activity. In some cases, the small molecule may be withdrawn or administered in response to remission or relapse of the tumor or for other therapeutic reasons (paragraphs 0060-0065 and Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector genome of ‘460 to encode a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scharenberg teaches that CARs can be fused to protein subunits (FRB and FKBP) that inducibly dimerize in the presence of a small molecule (rapamycin) and that this allows controlling expression of the CAR to respond to therapeutic needs (e.g. increasing/reducing expression as needed, such as after relapse or remission). As such, it would have been obvious to generate a lentiviral particle that encodes a chimeric antigen receptor configured to be controllable by a small molecule by fusion to protein subunits that inducibly dimerize in the presence of a small molecule to allow greater control of the expression of the CAR to respond to therapeutic needs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 9-10 and 33-36, ‘460 is silent regarding the sequence encoding the FRB and FKBP domains.
However, Scharenberg teaches SEQ ID NO: 13 (a FRB domain) which has 99% sequence identity to SEQ ID NO: 2 of the instant application. Scharenberg teaches SEQ ID NO: 16 (a FKRB domain) which has 100% sequence identity to SEQ ID NO: 6 of the instant application (paragraphs 00135-00140) . Although Scharenberg identifies SEQ ID NO: 13 as a FKBP domain and SEQ ID NO: 16 as a FRB domain, NCBI (NP_000792.1) evidences that the FKBP sequence has 100% sequence identity to SEQ ID NO: 16 of Scharenberg. Therefore, Scharenberg incorrectly identified the domains associated with their sequences.
It would have been obvious that these sequences could have been used as the sequences for the FRB domain and FKBP domain as these were known sequences for these domains and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 11-13, and 24, ‘460 is silent regarding the use of promoters.
However, Scharenberg teaches that the lentiviral vector can include promoters that can be operatively linked to the T-cell/NK-cell activation receptor by inserting the promoter sequence 5' to the gene encoded by the lentiviral vector. Scharenberg teaches that the promoter can be an inducible promoter or an MND promoter (paragraphs 0066-0072).
Therefore, it would have been obvious that an inducible promoter or an MND promoter could have been used to drive expression of the transgenes as Scharenberg teaches a similar lentiviral vector and identifies the use of promoters in general, and inducible promoters specifically, to drive expression of their transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 14-15 and 31, Scharenberg teaches that rapamycin is an immunosuppressive drug. The immunosuppressive drug may be the same as the small molecule or different, that is the lentiviral vector may be designed so that the small molecule controllable T-cell/NK-cell activation receptors is induced by an immunosuppressive drug such that whenever the immunosuppressive drug is administered to the subject, expansion of transduced cells is triggered. As shown in Example 2, T cell expansion occurs in T cells transduced with a vector encoding a first fusion protein fusing the cytoplasmic domain of the IL-2 receptor beta chain (IL2Rb) to FK506 binding protein (FKBP) and the second fusion protein is the result of fusing the cytoplasmic domain of IL-2 receptor gamma chain (IL2Rg) to the FKBP-rapamycin-binding (FRB) domain of mammalian target of rapamycin (mTOR) upon administration of rapamycin (paragraphs 0078-0080 and Example 2). Therefore, this combination would confer resistance to an immunosuppressive agent (rapamycin).
Regarding claims 19-20, ‘460 does not teach exposing immune cell activating anti-CD3 antibody or scFv on the surface of the viral particle.
However, Scharenberg teaches that lentiviral particles made using the packaging cell lines of the present disclosure incorporate one or more copies of the T-cell activation or co-stimulation molecule that is expressed by the packaging cell line into the lentiviral particle; and the incorporation of T-cell activation or co-stimulation molecule(s) in the lentiviral particle renders the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. As shown in Example 1, a lentiviral vector was constructed comprising the MND promoter and a 2A peptide-linked multicistronic open reading frame encoding an anti-CD3 single chain Fv fragment (scFv) of the monoclonal antibody OKT3; CD86; and CD137L (anti-CD3scFV-2A-CD86-2ACD137L).
Therefore, Scharenberg teaches another lentiviral vector that can be used as part of the vector system to transduce T cells with the CAR encoding nucleic acid (paragraphs 0086-0087 and Example 1). As such, it would have been obvious that the method of Scharenberg could be used to produce lentiviral particles incorporating T-cell activation or co-stimulation molecules to render the lentiviral particle capable of activating and efficiently transducing T cells in the absence of an exogenous activating agent, i.e. without a stimbead or equivalent agent. This permits the lentiviral particles made from these packaging cell lines to be used in vivo in cases in which exogenous delivery of an activating agent may be impractical. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 25, Scharenberg teaches SEQ ID NO: 6 corresponds to the vector map of Figure 6 which includes an MND promoter. SEQ ID NO: 6 comprises a sequence with 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the MND promoter as this was a known sequence for the promoter and was used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 26-27 and 37-38, ‘460 is silent regarding the sequences for IL2Rg and IL2Rb.
However, Scharenberg teaches that the IL2Rg fusion protein comprises SEQ ID NO: 15 which comprises a sequence with 100% sequence identity to SEQ ID NO: 25 of the instant application and that the IL2Rb fusion protein comprises SEQ ID NO: 12 which comprises a sequence with 100% sequence identity to SEQ ID NO: 33.
It would have been obvious that these sequences could have been used as the sequences for the IL2Rg and IL2Rb subunits as these were known sequences for these subunits and were used in a similar manner by Scharenberg. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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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/KEENAN A BATES/Examiner, Art Unit 1631
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