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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-29; drawn to a vector system) in the reply filed on January 16, 2026, is acknowledged.
Applicant further elected the following species:
a. A vector system with more than one vector
In light of the Applicant’s elected species, claims 3-4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Rejoinder
The species election requirement for the species of number of vectors has been reconsidered in view of the prior art. A vector system with a single vector is rejoined.
DETAILED ACTION
The amended claims filed on January 16, 2026, have been acknowledged. Claims 2, 7, 16-18, and 28-30 were cancelled. Claims 1, 3, 5-6, 8-11, 14-15, 19, 21-22, and 24-27 were amended. Claims 31-38 are new. Claims 1, 3-6, 8-15, 19-27, and 31-38 are pending and examined on the merits.
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, 3-6, 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 statements (IDS) filed on December 15, 2023, and January 16, 2026, have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The “Sequence Listing XML” submitted in the present application contains an incorrect identification of SEQ ID NO: 3 as a protein sequence. However, SEQ ID NO: 3 corresponds to the MND promoter (which is not known to produce an amino acid sequence) and the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence.
Required response - Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
o A statement that identifies the location of all additions, deletions, or replacements of sequence information in the replacement “Sequence Listing XML” as required by 1.835(b)(3);
o A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4),
o A statement that the replacement "Sequence Listing XML" includes no new matter in accordance with 1.835(b)(5), and
o A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 refers to SEQ ID NO: 3 as an amino acid sequence. However, SEQ ID NO: 3 corresponds to the MND promoter (which is not known to produce an amino acid sequence) and the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino 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, 3-4, 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).
Regarding claims 1 and 8, Scharenberg teaches a lentiviral vector that encodes:
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 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).
Regarding the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, 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 encode the FRB, FKBP, and additional transgenes within the same lentiviral vector (paragraphs 0060-0065). Therefore, one would reasonably conclude that “the lentiviral vector” refers to a single lentiviral vector that encodes the CAR, the FRB domain, and the FKBP domain.
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 claims 21-22, 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 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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence. 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.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2019200056 (Scharenberg) as applied to claim 1 above.
The teachings of Scharenberg are as discussed above.
Scharenberg does not teach wherein the vector system comprises two vectors.
However, 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 system of Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
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, 3-6, 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).
Regarding claims 1 and 8, ‘859 claims a lentiviral particle comprising a vector genome comprising a polynucleotide sequence encoding an anti-CD 19 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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, ‘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.
Regarding claims 5-6, the combined teachings of ‘859 and Scharenberg do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘859 and Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. 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 21-23, ‘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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
‘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, 3-6, 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).
Regarding claims 1 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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, ‘597 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.
Regarding claims 5-6, the combined teachings of ‘597 and Scharenberg do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘859 and Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. 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 21-23, ‘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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
‘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, 3-6, 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).
Regarding claims 1, 8, and 21-23, ‘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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, the FRB and FKBR domains and the IL2Rg and IL2Rb subunits are encoded in the genome of the lentiviral vector particle. Therefore, modifying the lentiviral vector genome to incorporate the CAR fused to the FRB and/or FKBP domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Regarding claims 5-6, the combined teachings of ‘101 and Scharenberg do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘101 and Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. 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, regarding claim 25, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence. ‘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, 3-4, 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).
Although claims 74-93 are methods, the method of 18991176 comprises the product as claimed in the instant application.
Regarding claims 1, 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).
Regarding the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (CAR)”, as the size of the first or second polynucleotide sequences are undefined, any size can be considered within the limitations of the claims. As the CAR is in the same viral particle and will be on the same genome as the first and second polynucleotide, it is broadly considered to fall within the first and the second polynucleotide by virtue of it being on the same genome and the lack of limits to defining the first and second polynucleotide (claims 74-75, 82-86, and 92).
Regarding claims 3-4, ‘116 claims the CAR is encoded in a viral particle. Therefore, the lentiviral vector genome within the particle would incorporate the FRB and FKBR domains, the IL2Rb and IL2Rb subunits, and the CAR.
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 and 5-6 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 claim 1 above.
Regarding claims 5-6, the claims of ‘116 do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘116 to use two vectors instead of one 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 it was well understood within the art that different transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of the transgenes by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. Therefore, it would have been obvious that the CAR could be delivered as part of one vector and the FFKBP and FRB and IL2Rg and IL2Rb could be delivered in a separate vector. 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, 8-13, 19-22, 24-27, and 33-28 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).
Regarding claims 9-10 and 33-36, ‘116 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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
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, ‘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, 3-6, 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).
Regarding claims 1, 8, and 21-23, ‘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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, the FRB and FKBR domains and the IL2Rg and IL2Rb subunits are encoded in the genome of the lentiviral vector particle. Therefore, modifying the lentiviral vector genome to incorporate the CAR fused to the FRB and/or FKBP domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Regarding claims 5-6, the combined teachings of ‘337 and Scharenberg do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘337 and Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. 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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
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, ‘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).
Although ‘970 is drawn to a method, the combined teachings of ‘970 and Scharenberg teach the product of the instant application.
Regarding claims 1, 8, and 21-23, ‘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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, ‘970 claims the FRB and FKBR domains and the IL2Rg and IL2Rb subunits can be encoded in the genome of one lentiviral vector. Therefore, modifying the lentiviral vector genome to incorporate the CAR fused to the FRB and/or FKBP domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Regarding claims 5-6, ‘970 claims wherein the first nucleic acid and the second nucleic acid are comprised in separate viral vectors (claims 12 and 14-15).
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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
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, ‘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).
Regarding claims 1, 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 a lentiviral vector that encodes:
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 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.
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 the limitation “the first and/or second polynucleotide sequence comprises a sequence encoding a chimeric antigen receptor (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/or second polynucleotide sequence.
Regarding claims 3-4, ‘460 claims the FRB and FKBR domains and the IL2Rg and IL2Rb subunits can be encoded in the genome of one lentiviral vector (claim 6). Therefore, modifying the lentiviral vector genome to incorporate the CAR fused to the FRB and/or FKBP domains would result in a single lentiviral vector encoding the CAR and the dimerization domains.
Regarding claims 5-6, the combined teachings of ‘460 and Scharenberg do not teach wherein the vector system comprises two vectors.
However, 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 system of ‘460 and Scharenberg to use two vectors instead of one 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 the small-molecule controllable targeting receptor may be encoded by two transgenes. It was well understood within the art that two transgenes can be administered in separate lentiviral vectors as this would allow for modulation of the expression of each transgene by altering the amount of administered vector to achieve the optimal expression of each of the transgenes. 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, as per the 112b rejection above, the Specification in paragraphs 0101-0102 appear to identify the sequence as a polynucleotide sequence and not an amino acid sequence. Therefore, SEQ ID NO: 3 is considered a nucleotide sequence and not an amino acid sequence.
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, ‘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
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/KEENAN A BATES/Examiner, Art Unit 1631