Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
1. Claims 1-20 are the original claims filed 5/3/2022. In the Reply of 7/20/2022, claims 1-20 are pending without amendment made thereto. In the Reply of 10/14/2025, claims 1-20 are pending without amendment made thereto.
Claims 1-20 are all the claims.
Election/Restrictions
2. Applicant’s election without traverse of Group I (Claims 1-10) in the reply filed on 10/14/2025 is acknowledged.
3. Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention of Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/14/2025.
4. Claims 1-10 are the claims under examination.
Priority
5. USAN 17/735,197, filed 05/03/2022, is a Continuation of 16/159,517, filed 10/12/2018, now abandoned, 17/735,197 is a Continuation in Part of 15/893,629, filed 02/10/2018 ,now U.S. Patent # 11173179,15/893,629 is a Continuation in Part of 15/739,596, filed 12/22/2017, now U.S. Patent # 11655452 and having 2 RCE-type filing therein, 15/739,596 is a National Stage entry of PCT/US2016/039306, International Filing Date: 06/24/2016; PCT/US2016/039306 Claims Priority from Provisional Application 62/184,321, filed 06/25/2015, PCT/US2016/039306 Claims Priority from Provisional Application 62/235,840, filed 10/01/2015, PCT/US2016/ 039306 Claims Priority from Provisional Application 62/244,435, filed 10/21/2015,
17/735,197 is a Continuation in Part of 15/538,620, filed 06/21/2017, now U.S. Patent # 11820819 and having 3 RCE-type filing therein, 15/538,620 is a Continuation of PCT/US2016/068349, filed 12/22/2016, PCT/US2016/068349 is a Continuation of PCT/US2016/039306, filed 06/24/2016, PCT/US2016/068349 Claims Priority from Provisional Application 62/369,004, filed 07/29/2016.
Thus, the earliest possible priority for the instant application is June 25, 2015. That is the filing date of provisional application 62/184,321.
Information Disclosure Statement
6. As of 12/3/2025, no IDS filing is of record.
Objections
Specification
7. The disclosure is objected to because of the following informalities:
a) The use of the term NCBI, Redi-Ject, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) Amend the specification to correct
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c) The figure legends to Figure 30E, 30I-30K are absent;
The figure legend for Figure 41G is absent the details of the summary results; and
The description in the figure legends for figures 50B-50C is absent.
d) The terms “CD123” and “CD123b” are used interchangeably throughout the specification. No clear distinction or meaning is given for the separate terms. Clarification is requested.
Appropriate correction is required.
Claim Objections
8. Claims 1-10 are objected to because of the following informalities:
a) Claims 1-10 are unclear for the order in which the domains for each of the CAR structures are depicted.
AS regards claim 1, the order is as follows for a first polypeptide: a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a co-stimulatory domain, and a first signaling domain; and for a second polypeptide: a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain and a second signaling domain.
As regards claim 6, the order is as follows: an antigen recognition domain, a signal peptide, a hinge region, a transmembrane domain, a co-stimulatory domain, and a signaling domain.
The claimed depiction of the CAR polypeptide in the claims differs from what is taught in the specification, for example, “a CAR comprises a leader sequence and scFv, a hinge (H) region, a transmembrane domain (TM).” (paragraph [0205]).”
The ordinary artisan would appreciate from the specification that the signal peptide domain on each of the first CAR polypeptide and the second polypeptide of claim 1 should be positioned or located before the antigen recognition domain, which for all intent purposes, is required for the polypeptides to be expressed via membrane transport to the extracellular surface.
The ordinary artisan would appreciate from the specification that the signal peptide domain on the CAR polypeptide of claim 6 should be positioned or located before the antigen recognition domain, which for all intent purposes, is required for the polypeptides to be expressed via membrane transport to the extracellular surface.
As such the structures for each of the CAR polypeptides is unclear.
b) Claims 1-10 are unclear as to whether the enhancer of claims 1 and 6 is co-expressed separately (e.g., under a different promoter) with the 1st and 2nd polypeptides of claim 1 or the polypeptide of claim 6 or is part one contiguous polypeptide.
c) Claims 1-10 recite “CD123” and “CD123b” interchangeably. CD123 and CD123b are not two different proteins or markers; rather, CD123 (the alpha chain of the interleukin-3 receptor) is a single entity, and the "b" is generally used to refer to its dim or negative expression level in immunophenotyping. The specification provides no distinction between the terms. Clarification is requested.
d) Claim 2 recites SEQ ID NO: 42 in duplicate and SEQ ID NO: 32 in duplicate. This appears to be a typographical error.
e) Amend claim 6 to remove “(i.)” since no other elements are seemingly required of the claimed invention.
f) Claim 7 recites SEQ ID NO: 56 in duplicate and SEQ ID NO: 32 in duplicate. This appears to be a typographical error.
g) Claims 2 and 7 recite “the cell includes”. It is not clear whether the species in those claims is the specific CAR, is a part of the CAR or is in addition to the bispecific CAR of claim 1 and the monospecific CAR of claim 6, respectively. To "include" means to have or contain as part of a whole, or to add something into a group or category.
h) Claims 8 and 10 depend from claim 7 which is drawn to species of engineered cells and some of which comprise the IL-15/IL-15sushi enhancer, e.g., SEQ ID NO:18, 20, 22, 49, 58, etc., and 4-1BBL/ IL-15/IL-15sushi enhancer, e.g., SEQ ID NO:58, 49, 20, 18, etc.
Claims 8 and 10 are drawn to any enhancer that is broadening in scope compared to the example of the IL-15/IL-15sushi or 4-1BBL/ IL-15/IL-15sushi enhancers in claim 7. As regards claim 8 that requires a secreted enhancer, claim 7 recites enhancers seemingly being contiguous within a single polypeptide.
i) It is not clear how the super2 polypeptide is integrated into the structure of the bispecific CAR of claim 1 and the monospecific CAR of claim 6.
j) It is not clear how an IL-21 anchor polypeptide (claim 2) is integrated into the structure of the bispecific CAR of claim 1.
k) Claims 6-10 are confusing as to the meaning of having one CAR polypeptide in element (i) in claim 6, whilst claim 7 is drawn to “polypeptides” for SEQ ID NO: 40. See “SEQ ID NO. 40 (a BCMA-CD38a chimeric antigen receptor polypeptides and 4-1BBL ligand, and IL-15/IL-15sushi).”
Appropriate correction is required.
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.
9. Claims 1-10 are 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.
a) Claims 1-5 are indefinite and confusing as to the meaning of having two CAR polypeptides in elements (i) and (ii) for claim 1, whilst claim 2 is drawn to apparent single polypeptides comprising a variety of different constructs that do not appear to represent two separate polypeptides. For example, bispecific cCAR polypeptide and the enhancer IL-15/IL-15sushi. See, e.g., SEQ ID NO. 42 (a BCMA-CS1 cCAR polypeptide and IL-15/IL-15sushi): SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO. 60 (a CLLI-CD33 eCAR polypeptide and IL-15/IL-15sushi), or the enhancer 4-1BBL: SEQ ID NO:40. Other species comprise a chimeric CAR polypeptide minus an enhancer. See SEQ ID NO: 18.
It is not clear what the meaning of “cCAR” is in claim 2 with respect to elements (i) and (ii) of claim 1. For example, Figure 1A shows a cCAR prototype:
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The figure does not depict a 1st nor a 2nd signal peptide but leader sequences N-terminal to each of the 1st and 2nd polypeptides. The figure depicts a self-cleaving peptide domain (PA2) that is not a claimed in claim 1. Thus, sequences comprising a cCAR in claim 2 contain more structural elements than what is described in claim 1.
b) Claims 2 and 7 are indefinite for reciting parenthetical text. The POSA cannot determine whether the text is optional or descriptive of the claimed invention. The parenthetical text is indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
c) Claim 7-10 recite the limitation "SEQ ID NO. 54 (a CD45 chimeric antigen receptor polypeptide and IL-15/IL- 315sushi; SEQ ID NO. 44 (a CLL-1 CAR polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 40 (a BCMA-CD38a chimeric antigen receptor polypeptides and 4-1BBL ligand, and IL-15/IL-15sushi)" in Claim 7. There is insufficient antecedent basis for this limitation in the claim. Claim 6 is limited to the target antigens “CD3, CD4, CD5, CD19, CD20, CD33, CD123, BCMA, GD2, and GD3”. Target antigens CD45, CCL-1 and CD38a of claim 7 are not identified in the closed Markush group of Claim 6.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
10. Claim(s) 1 and 4 are rejected under 35 U.S.C. 103(a) as being unpatentable over Milone et al., (US 2014/0322183; USPN 9745368) in view of Rowle et al., (Eur. J. Immunol. 2009. 39: 491-506).
Regarding claim 1, Milone in general teaches the advantage of dual-targeting CAR-T cells in order to improve the specificity of the lytic activity of the CAR-T and reducing the potential for depleting normal health tissue (“compositions and methods related to genetically modifying T cells to express a plurality of types of KIR-CARs, where KIR-CAR T cell activation is dependent on the binding of a plurality of types of KIR-CARs to their target receptor. Dependence on the binding of a plurality of types of KIR-CARs improves the specificity of the lytic activity of the KIR-CAR T cell, thereby reducing the potential for depleting normal healthy tissue” paragraph [0272] of the published application).
Milone teaches T cells or NK cells comprising a first chimeric antigen receptor polypeptide (a) and a second chimeric engineered polypeptide (b), wherein (a) is different from (b); e.g., a second KIR-CAR that is different from said first KIR-CAR. (paragraphs [0022]-[0023]); comprising:
(a.) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain (paragraph [0005]) where the NKR-CAR comprises a transmembrane domain and an extra-cellular antigen binding domain, and further comprises a hinge domain disposed between said transmembrane domain and said extra-cellular antigen binding domain, Para. [0006]; and wherein “the term "TCAR" comprises an antigen domain, an intracellular signaling domain, and optionally one or more costimulatory domains” (paragraph [0169]) and
(b) a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain (paragraph [0005]) where the NKR-CAR comprises a transmembrane domain and an extra-cellular antigen binding domain, and further comprises a hinge domain disposed between said transmembrane domain and said extra-cellular antigen binding domain, Para. [0006]; and wherein “the term "TCAR" comprises an antigen domain, an intracellular signaling domain, and optionally one or more costimulatory domains” (paragraph [0169]).
A "KIR-CAR" which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells (abstract)
Milone teaches antigens or targets for the first and second CARs will depend on the type of cancer being targeted and teaches the elected species along with others:
(240) Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses. The selection of the antigen binding domain of the invention will depend on the particular type of cancer to be treated. Tumor antigens are well known in the art and include, for example, a glioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII, IL-11Ra, IL-13Ra, EGFR, B7H3, Kit, CA-IX, CS-1, MUC1, BCMA, bcr-ab1, HER2, β-human chorionic gonadotropin, alphafetoprotein (AFP), ALK, CD19, CD123, cyclin B1, lectin-reactive AFP, Fos-related antigen 1, ADRB3, thyroglobulin, EphA2, RAGE-1, RU1, RU2, SSX2, AKAP-4, LCK, OY-TES1, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM, EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid, PLAC1, RU1, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K, mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYP1B1, BORIS, prostase, prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1, LAGE-1a, LMP2, NCAM, p53, p53 mutant, Ras mutant, gp100, prostein, OR51E2, PANX3, PSMA, PSCA, Her2/neu, hTERT, HMWMAA, HAVCR1, VEGFR2, PDGFR-beta, legumain, HPV E6, E7, survivin and telomerase, sperm protein 17, SSEA-4, tyrosinase, TARP, WT1, prostate-carcinoma tumor antigen-1 (PCTA-1), ML-IAP, MAGE, MAGE-A1, MAD-CT-1, MAD-CT-2, MelanA/MART1, XAGE1, ELF2M, ERG (TMPRSS2 ETS fusion gene), NA17, neutrophil elastase, sarcoma translocation breakpoints, NY-BR-1, ephrinB2, CD20, CD22, CD24, CD30, CD33, CD38, CD44v6, CD97, CD171, CD179a, androgen receptor, insulin growth factor (IGF)-I, IGF-II, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3, GPRC5D, GPR20, CXORF61, folate receptor (FRa), folate receptor beta, ROR1, Flt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2, and mesothelin. In a preferred embodiment, the tumor antigen is selected from the group consisting of folate receptor (FRa), mesothelin, EGFRvIII, IL-13Ra, CD123, CD19, CD33, BCMA, GD2, CLL-1, CA-IX, MUC1, HER2, and any combination thereof.
Moreover, Milone teaches conditions appropriate for T cell culture that may contain factors necessary for proliferation and viability, including IL-15 (paragraph [0399]). However, Milone does not teach that the engineered cell comprises an enhancer selected from the group consisting IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-lBBL, and IL-15.
Rowle et al. discloses methods to enhance the viability and proliferation of primary CD8+ T cells and cytotoxic potential of antigen-specific CD8+ T cells comprising transfecting CD8+ T cells with a recombinant a chimeric construct comprising IL-15/IL-15RA sushi domain recombinant fusion. Rowle states:
“This dramatic increase in bioactivity of the IL-15/IL-15RA fusion construct compared to mixed and transfected IL-15 + IL-15RA is consistent with a previous report describing an IL-15/IL-15RA sushi domain recombinant fusion protein that exhibited a 10 fold increase in bioactivity in vitro compared to recombinant IL-15 mixed with recombinant IL15RA [31].”
Regarding claim 4, Milone teaches a cytotoxic cell, e.g., a naturally or non-naturally occurring T cell, NK cell or cytotoxic T cell or NK cell line comprising a NKR-CAR (paragraph [0008]).
The ordinary artisan would have found more than sufficient motivation to have produced the claimed engineered cell in view of Milone where the reference teaches dual targeting CAR-T having the ability for regulating: a cytotoxic cell, e.g., T cell, and specificity to control off-target activity of the engineered T cell. Accordingly, where Milone solved and overcome the several caveats that would otherwise compromise a single CAR-T, the dual targeting aspect under regulatory control would have been the motivation for the ordinary artisan to create an improved engineered cell of this nature and kind. Because Milone’s teachings are vast and the techniques to create such engineered cells was available to ordinary artisan, there would have been a reasonable assurance of success in having generated an engineered cell based on the platform technology taught in Milone.
Therefore, in view of the benefits of transfecting CD8+ T cells with IL-l5RA and/or IL-15, it would have been prima facie obvious to modify the T cells expressing a first chimeric antigen receptor polypeptide and a second chimeric antigen receptor polypeptide with a chimeric construct comprising IL-15 receptor alpha or IL-l5RA. One would have been motivated to modify CD8+ T cells as taught by Rowle to improve the efficacy of the therapeutic T-cells composition.
11. Claims 3 and 5 are rejected over Milone et al., (US 2014/0322183; USPN 9745368) in view of Rowle et al., (Eur. J. Immunol. 2009. 39: 491-506) as applied to claim 1 above, and further in view of Mortier et al., (J Biol Chem (2006 Jan 20;281(3):1612-9.).
With regard to instant claims 3 and 5, the combined teachings of Milone et al., and Rowle et al., Mortier renders obvious the claimed product, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety. The combined teachings fail explicitly disclose a soluble sushi domain of IL-15Rα linked to IL-15.
Mortier et al teaches a recombinant, soluble sushi domain of IL-15Rα, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R β/γ heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R α/β/γ membrane receptor. Furthermore, Mortier et al., discloses that a fusion protein in which IL-15 and IL-15Rα are attached by a linker are even more potent than the combination of separate IL-15 plus sIL-15Rα-sushi. After binding to the IL-15R β/γ, this fusion protein is internalized and induces a biological response very similar to the IL-15 high affinity response “Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.” (abstract).
It would have been prima facie obvious for one of ordinary skill in the art to modify the engineered cell of Milone et al., and Rowle et al., to have a second enhancer such as IL-15 and a soluble sushi domain of IL-15Rα that are attached by a linker , e.g., IL-15/IL-15Rα-sushi, to further potentiate the therapeutic effect of the engineered cell, particularly because Mortier teaches the IL-15/IL-15Rα-sushi constitutes a potent adjuvants for the expansion of lymphocyte subsets. Given the enhancement of IL-15 activity by IL-15Rα-sushi one of skill in the art would have been motivated to engineer a cell with IL-15/IL-15Rα-sushi to stimulate the proliferation of the CAR T-cells of Milone et al., and Rowle et al., having a first chimeric antigen receptor polypeptide and a second chimeric antigen receptor polypeptide. The manipulation of previously identified DNA fragments, secretory signal and cell transformation systems is within the ordinary level of skill in the art of molecular biology. The practitioner in the art would readily understand that a soluble fusion protein in which IL-15 and IL-15Rα are attached by a linker can be designed to be secreted from the engineered cell to and presented in trans to neighboring NK or CD8 T cells expressing only the IL-15R β/γ.
12. Claim(s) 6 and 9 are rejected under 35 U.S.C. 103(a) as being unpatentable over Milone et al., (US 2014/0322183; USPN 9745368) in view of Rowle et al., (Eur. J. Immunol. 2009. 39: 491-506).
Regarding claim 6, Milone teaches T cells or NK cells comprising a chimeric antigen receptor polypeptide comprising: chimeric antigen receptor polypeptide comprising an antigen recognition domain, a signal peptide, a hinge region, a transmembrane domain, a co-stimulatory domain, and a signaling domain (paragraph [0005]) where the NKR-CAR comprises a transmembrane domain and an extra-cellular antigen binding domain, and further comprises a hinge domain disposed between said transmembrane domain and said extra-cellular antigen binding domain, Para. [0006]; and wherein “the term "TCAR" comprises an antigen domain, an intracellular signaling domain, and optionally one or more costimulatory domains” (paragraph [0169])
A "KIR-CAR" which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells (abstract)
Milone teaches antigens or targets for the CAR will depend on the type of cancer being targeted and teaches the elected species along with others:
(240) Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses. The selection of the antigen binding domain of the invention will depend on the particular type of cancer to be treated. Tumor antigens are well known in the art and include, for example, a glioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII, IL-11Ra, IL-13Ra, EGFR, B7H3, Kit, CA-IX, CS-1, MUC1, BCMA, bcr-ab1, HER2, β-human chorionic gonadotropin, alphafetoprotein (AFP), ALK, CD19, CD123, cyclin B1, lectin-reactive AFP, Fos-related antigen 1, ADRB3, thyroglobulin, EphA2, RAGE-1, RU1, RU2, SSX2, AKAP-4, LCK, OY-TES1, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM, EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid, PLAC1, RU1, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K, mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYP1B1, BORIS, prostase, prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1, LAGE-1a, LMP2, NCAM, p53, p53 mutant, Ras mutant, gp100, prostein, OR51E2, PANX3, PSMA, PSCA, Her2/neu, hTERT, HMWMAA, HAVCR1, VEGFR2, PDGFR-beta, legumain, HPV E6, E7, survivin and telomerase, sperm protein 17, SSEA-4, tyrosinase, TARP, WT1, prostate-carcinoma tumor antigen-1 (PCTA-1), ML-IAP, MAGE, MAGE-A1, MAD-CT-1, MAD-CT-2, MelanA/MART1, XAGE1, ELF2M, ERG (TMPRSS2 ETS fusion gene), NA17, neutrophil elastase, sarcoma translocation breakpoints, NY-BR-1, ephrinB2, CD20, CD22, CD24, CD30, CD33, CD38, CD44v6, CD97, CD171, CD179a, androgen receptor, insulin growth factor (IGF)-I, IGF-II, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3, GPRC5D, GPR20, CXORF61, folate receptor (FRa), folate receptor beta, ROR1, Flt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2, and mesothelin. In a preferred embodiment, the tumor antigen is selected from the group consisting of folate receptor (FRa), mesothelin, EGFRvIII, IL-13Ra, CD123, CD19, CD33, BCMA, GD2, CLL-1, CA-IX, MUC1, HER2, and any combination thereof.
Milone teaches CD3 targets for a CAR construct at (370) and (441).
Moreover, Milone teaches conditions appropriate for T cell culture that may contain factors necessary for proliferation and viability, including IL-15 (paragraph [0399]). However, Milone does not teach that the engineered cell comprises an enhancer selected from the group consisting IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-lBBL, and IL-15.
Rowle et al. discloses methods to enhance the viability and proliferation of primary CD8+ T cells and cytotoxic potential of antigen-specific CD8+ T cells comprising transfecting CD8+ T cells with a recombinant a chimeric construct comprising IL-15/IL-15RA sushi domain recombinant fusion. Rowle states:
“This dramatic increase in bioactivity of the IL-15/IL-15RA fusion construct compared to mixed and transfected IL-15 + IL-15RA is consistent with a previous report describing an IL-15/IL-15RA sushi domain recombinant fusion protein that exhibited a 10 fold increase in bioactivity in vitro compared to recombinant IL-15 mixed with recombinant IL15RA [31].”
Regarding claim 9, Milone teaches a cytotoxic cell, e.g., a naturally or non-naturally occurring T cell, NK cell or cytotoxic T cell or NK cell line comprising a NKR-CAR (paragraph [0008]).
The ordinary artisan would have found more than sufficient motivation to have produced the claimed engineered cell in view of Milone where the reference teaches monospecific targeting CAR-T having the ability for regulating: a cytotoxic cell, e.g., T cell, and specificity to control off-target activity of the engineered T cell. Because Milone’s teachings are vast and the techniques to create such engineered cells was available to ordinary artisan, there would have been a reasonable assurance of success in having generated an engineered cell based on the platform technology taught in Milone.
Therefore, in view of the benefits of transfecting CD8+ T cells with IL-l5RA and/or IL-15, it would have been prima facie obvious to modify the T cells expressing a chimeric antigen receptor polypeptide with a chimeric construct comprising IL-15 receptor alpha or IL-l5RA. One would have been motivated to modify CD8+ T cells as taught by Rowle to improve the efficacy of the therapeutic T-cells composition.
13. Claims 8 and 10 are rejected over Milone et al., (US 2014/0322183; USPN 9745368) in view of Rowle et al., (Eur. J. Immunol. 2009. 39: 491-506) as applied to claim 1 above, and further in view of Mortier et al., (J Biol Chem (2006 Jan 20;281(3):1612-9.).
With regard to instant claims 3 and 5, the combined teachings of Milone et al., and Rowle et al., Mortier renders obvious the claimed product, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety. The combined teachings fail explicitly disclose a soluble sushi domain of IL-15Rα linked to IL-15.
Mortier et al teaches a recombinant, soluble sushi domain of IL-15Rα, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R β/γ heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R α/β/γ membrane receptor. Furthermore, Mortier et al., discloses that a fusion protein in which IL-15 and IL-15Rα are attached by a linker are even more potent than the combination of separate IL-15 plus sIL-15Rα-sushi. After binding to the IL-15R β/γ, this fusion protein is internalized and induces a biological response very similar to the IL-15 high affinity response “Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.” (abstract).
It would have been prima facie obvious for one of ordinary skill in the art to modify the engineered cell of Milone et al., and Rowle et al., to have a second enhancer such as IL-15 and a soluble sushi domain of IL-15Rα that are attached by a linker , e.g., IL-15/IL-15Rα-sushi, to further potentiate the therapeutic effect of the engineered cell, particularly because Mortier teaches the IL-15/IL-15Rα-sushi constitutes a potent adjuvants for the expansion of lymphocyte subsets. Given the enhancement of IL-15 activity by IL-15Rα-sushi one of skill in the art would have been motivated to engineer a cell with IL-15/IL-15Rα-sushi to stimulate the proliferation of the CAR T-cells of Milone et al., and Rowle et al., having a first chimeric antigen receptor polypeptide and a second chimeric antigen receptor polypeptide. The manipulation of previously identified DNA fragments, secretory signal and cell transformation systems is within the ordinary level of skill in the art of molecular biology. The practitioner in the art would readily understand that a soluble fusion protein in which IL-15 and IL-15Rα are attached by a linker can be designed to be secreted from the engineered cell to and presented in trans to neighboring NK or CD8 T cells expressing only the IL-15R β/γ.
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.
14. Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11905528.
AS regards claims 1-5
Ref ‘582 claims:
1. An ex vivo engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5′ to 3′ a first polynucleotide encoding a first chimeric antigen receptor polypeptide (first CAR), a second polynucleotide encoding a second chimeric antigen receptor polypeptide (second CAR), a nucleotide encoding porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), FMDV 2A (F2A) or equine rhinitis A virus (ERAV) 2A (E2A1 disposed between the first CAR and second CAR, under the transcriptional control of a single promoter, wherein: (i.) the first CAR polypeptide comprises a first antigen recognition domain; a first signal peptide; a first hinge region; a first transmembrane domain; a first co-stimulatory domain; and a first signaling domain; and (ii.) the second CAR comprises a second antigen recognition domain; a second signal peptide; a second hinge region; a second transmembrane domain; a second co-stimulatory domain; and a second signaling domain; wherein the first antigen recognition domain and the second antigen recognition domain are different; wherein the engineered T cell or NK cell comprises an enhancer selected from the group consisting of IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15: and wherein the engineered T cell or NK cell comprises SEQ ID NO: 1, SEQ ID NO: 28, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 50, SEQ ID NO: 52, or SEQ ID NO: 60.
2. The engineered cell according to claim 1, wherein the engineered T cell or NK cell comprises SEQ ID NO: 60.
3. The engineered cell according to claim 1, wherein the enhancer is secreted by the engineered cell.
4. The engineered cell according to claim 1, wherein the engineered T cell is an NK T cell.
5. A method of treating a cell proliferative disease comprising administering an engineered T cell or NK cell according to claim 1 to a patient in need thereof.
6. The method according to claim 5, wherein the cell proliferative disease comprises a t-cell malignancy, leukemia, or a lymphoma.
7. The method according to claim 5, wherein the engineered T cell is an NK T cell.
Although the ‘582 claims recite that the cells are “ex vivo”, product claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). Thus, the T cells or NK cells of the ‘582 claims are the same as the claimed T cells or NK cells.
The ‘582 claims teach as set forth above, a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter whilst instant claims 1-5 make no mention. Notably the species of cCAR (compound CAR) taught in claim 2 comprise the missing elements of claim 1 and share 100% identify with the clones of ‘582:
SEQ ID NO: 28:
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SEQ ID NO: 40:
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SEQ ID NO: 50:
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SEQ ID NO: 52:
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SEQ ID NO: 60:
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It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘582 claims express the first and second CAR of the ‘582 claims with a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter because a single open reading frame for expression of two CARs with an in-frame viral self-cleaving protein sequence resulting in two proteins that are separately expressed at the cell surface is effective for expression of two CARs in a single cell. The single open reading frame for expression of two CARs would only require a single promoter to express the single protein.
AS regards claims 6-10 (and claims 14-16 and 18-20), ‘582 claims the SEQ ID NO: 40 that shares 100% identify with the species of the clone for SEQ ID NO: 40 in claim 7 of the instant claims:
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Accordingly, claims 6-10 are drawn under this rejection where the structure taught in ‘582 is identical to the structures falling within claims 6-10.
15. Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims -3 and 8 of copending Application No. 18/411,101 (reference application 20250002550).
As regards claims 1-10
Ref claims
1. (Original) An ex vivo engineered T cell or NK cell expressing a chimeric antigen receptor (CAR) at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5' to 3' a polynucleotide encoding of chimeric antigen receptor polypeptide, and a nucleotide encoding porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), FMDV 2A (F2A), or equine rhinitis A virus (ERAV) 2A (E2A), and a nucleotide encoding an enhancer, wherein said enhancer is IL-15/IL-I5sushi, IL-18, IL-21, or 4- 1BBL/IL-15/IL-15sushi (superl); wherein the engineered T cell or NK comprises SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 38, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, and SEQ ID NO: 58.
2. (Original) The engineered cell according to claim 1, wherein the enhancer is secreted by the engineered cell or anchored on the engineered cell surface.
3. (Original) The engineered cell according to claim 1, wherein the engineered T cell is an NK T cell.
4. (Withdrawn) A method of treating a cell proliferative disease comprising administering an engineered T cell or NK cell according to claim 1 to a patient in need thereof.
5. (Withdrawn) The method according to claim 4, wherein the cell proliferative disease is leukemia, lymphoma or myeloma.
6. (Withdrawn) A method of treating an autoimmune disease comprising administering an engineered T cell or NK cell according to claim 1 to a patient in need thereof.
7. (Withdrawn) A method of depleting B cells associated with autoimmune disease comprising administering an engineered T cell or NK cell according to claim 1 to a patient in need thereof.
8. (New) The ex vivo engineered T cell or NK cell expressing a chimeric antigen receptor (CAR) at the cell surface according to claim 1, wherein the cell comprises a nucleotide encoding porcine teschovirus-1 2A (P2A), said enhancer is IL-15/IL-15sushi, and the engineered T cell or NK comprises SEQ ID NO: 22.
Although the ‘101 claims recite that the cells are “ex vivo”, product claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). Thus, the T cells or NK cells of the ‘101 claims are the same as the claimed T cells or NK cells.
The ‘101 claims teach as set forth above, a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter whilst instant claims 1-5 make no mention. Notably the species of cCAR (compound CAR) taught in claim 2 comprise the missing elements of claim 1 and share 100% identify with the clones of ‘101 for SEQ ID NO: 22 (SEQ ID NO: 22 comprises the CD4 CAR and IL15/IL15sushi linked by the P2A peptide sequence, ATNFSLLKQAGDVEEMPGBP. See Appendix, pp. 53-54 of US 20220348633. The IL15/IL15sushi is secreted. See paragraph 0164 and Fig. 43 of US 20220348633), SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 38, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, and SEQ ID NO: 58.
Given the T cells or NK cells of the ‘101 claims express identical CAR structures to those instantly claimed, it would have been prima facie obvious given the level of skill in the art was high to express the CARs of the of the ‘101 claims with a nucleic acid vector, such as a retroviruses or lentiviruses, because Jena teaches such vectors are routinely used in the art to express CARs in T cells to produce clinically significant numbers of T cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11655452. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are wholly encompassed by, and significantly overlap in scope with the ref claims
Ref claim
1. An ex vivo engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5′ to 3′ a single promoter selected from human elongation factor-1 alpha (EF-1α) or spleen focus forming virus (SFFV), a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a viral self-cleavage peptide, a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR), and an enhancer selected from the group consisting of secreted IL-15/IL-15sushi, Il-15/Il-15 sushi anchor, PD-1, PD-L1, CSF1R, CTLA-4, TIM-3, TGFR-beta, IL-2, Il-7, IL-12, IL-15, IL-15RA, IL-21 or a functional fragment thereof, or a combination thereof, wherein said enhancer is separated from the first CAR and second CAR by a second cleavage site that flanks either end of the two distinct CAR units, wherein: the first CAR comprises a first signal peptide, a first antibody binding domain, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain; and the second CAR comprises a second signal peptide, a second antibody binding domain, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain; and wherein the first antibody binding domain and the second antibody binding domain are different and each bind to a different target, wherein the targets of the first and second antibody binding domains irrespective of order are CD19 and CD20, or CD123 and CD33, or B cell maturation antigen (BCMA) (CD269) and CD19, or BCMA (CD269) and CD38, or and BCMA (CD269) and CS1, wherein the first and second co-stimulatory domains are intracellular, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
2. The engineered T cell or NK cell according to claim 1, wherein the target of the first antibody binding domain comprises CD123, the target of the second antibody binding domain comprises CD33, the first co-stimulatory domain comprises CD28, the second co-stimulatory domain comprises 4-1BB, the cleavage site comprises P2A, and the engineered cell is a T cell.
3. The engineered T cell or NK cell according to claim 1, wherein the first co-stimulatory domain and the second co-stimulatory domain are different.
4. The engineered T cell or NK cell according to claim 1, wherein the first co-stimulatory domain comprises CD28, and the second co-stimulatory domain comprises 4-1BB.
AS regards claims 1-10
1. (Original) An engineered cell comprising: (i.) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain selected from the group consisting of CS-1, CD5, CD19, CD20, CD123, BCMA, CD38, CLL-L, and CD33: a first signal peptide: a first hinge region; a first transmembrane domain; a first co-stimulatory domain: and a first signaling domain; and (ii.) a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain selected from the group consisting of CS-1, CD5, CD 19, CD20, CD123, BCMA, CD38, CLL-1, and CD33; a second signal peptide; a second hinge region: a second transmembrane domain; a second co-stimulatory domain; and a second signaling domain; wherein the first antigen recognition domain and the second antigen recognition domain are different: wherein the first antigen recognition domain and the second antigen recognition domain each have a single antigen recognition domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
2. (Original) The engineered cell according to claim 1, wherein the engineered cell includes SEQ ID NO. 42 (a BCMA-CS1 cCAR polypeptide and IL-15/IL-15sushi): SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO. 60 (a CLLI-CD33 eCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO.40 (a BCMA-CD38 cCAR polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 18 (a CD5-CD38 chimeric antigen receptor polypeptide); SEQ ID NO. 42 (a BCMA-CSIcCAR polypeptide and IL- 15/IL-15sushi; SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide, and IL-15/IL-15sushi); SEQ ID NO. 36 (CD123-CLLIcCARpolypeptide, and IL-15/IL-15sushi); SEQ ID NO. 28 (a CD20-CD19cCAR polypeptide, and IL-15/IL-15sushi: SEQ ID NO. 52 (a CD20-CD19cCAR polypeptide); SEQ ID NO. 1 (IL-21 anchor polypeptide); or SEQ ID NO. 50 (super2 polypeptide).
3. (Original) The engineered cell according to claim 1, wherein the enhancer is secreted by the engineered cell.
4. (Original) The engineered cell according to claim 1, wherein the engineered cell is an NK T cell, T cell, or NK cell.
5. (Original) The engineered cell according to claim 1, wherein the engineered cell comprises at least two enhancers.
6. (Original) An engineered cell comprising: (i.) a chimeric antigen receptor polypeptide comprising an antigen recognition domain selected from the group consisting of CD3, CD4, CD5, CD19, CD20, CD33, CD123, BCMA, GD2, and GD3: a signal peptide: a hinge region; a transmembrane domain; a co- stimulatory domain; and a signaling domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/iL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
7. (Original) The engineered cell according to claim 6,wherein the engineered cell includes SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide); SEQ ID NO. 58 (aGD2 chimeric antigen receptor polypeptide, 4-1BBL ligand and IL-15/IL-15sushi); SEQ ID NO. 49 (a CD5 chimeric antigen receptor polypeptide and IL-15/IL-15sushi; SEQ ID NO. 22 (a CD4 chimeric antigen receptor polypeptide and IL-15/IL-15sushi); SEQ ID NO. 20 (a CD4 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 18 (a CD3 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 24 (a CD19chimeric antigen receptor polypeptide and IL-15/IL-15sushi): SEQ ID NO. 26 (a CD19 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi): SEQ ID NO. 30 (a CD33 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 32 (a CD123 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi):SEQ ID NO. 38 (a BCMA chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL- 15sushi); SEQ ID NO.46 (a GD2 chimeric antigen receptor polypeptide, 4-1BBL and IL- 15/IL-15sushi); SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide; SEQ ID NO. 32 (a CD123b chimeric antigen receptor polypeptide and 4-1BBL ligand, and IL-15/IL- 1Ssushi); SEQ ID NO. 54 (a CD45 chimeric antigen receptor polypeptide and IL-15/IL- 315sushi; SEQ ID NO. 44 (a CLL-1 CAR polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 40 (a BCMA-CD38a chimeric antigen receptor polypeptides and 4-1BBL ligand, and IL-15/IL-15sushi); SEQ ID NO. 21 (a CD33 CAR polypeptide, 4-1BBL and IL-15/IL- ISsushi; or SEQ ID NO. 50 (super2 polypeptide).
8. (Original) The engineered cell according to claim 7, wherein the enhancer is secreted by the engineered cell.
9. (Original) The engineered cell according to claim 7, wherein the engineered cell is an NK T cell, T-cell, or NK cell.
10. (Original) The engineered cell according to claim 7, wherein the engineered cell comprises at least two enhancers.
Although the ‘452 claims recite that the cells are “ex vivo”, product claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). Thus, the T cells or NK cells of the ‘452 claims are the same as the claimed T cells or NK cells.
The ‘452 claims teach as set forth above, a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter whilst instant claims 1-5 make no mention. Notably the species of cCAR (compound CAR) taught in claim 2 comprise the missing elements of claim 1:
SEQ ID NO: 28:
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It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘452 claims express the first and second CAR of the ‘452 claims with a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter because a single open reading frame for expression of two CARs with an in-frame viral self-cleaving protein sequence resulting in two proteins that are separately expressed at the cell surface is effective for expression of two CARs in a single cell. The single open reading frame for expression of two CARs would only require a single promoter to express the single protein.
Because claim 1 and 6 of the instant application are drawn broadly to an engineered cell comprising a first CAR polypeptide (and a second CAR polypeptide) the claims 1-5 and 11-13 of the instant invention embrace the invention as set forth in ‘452.
17. Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11820819.
Ref claims
1. A method for treating leukemia or lymphoma in a patient in need thereof, said method comprising: administering to said patient in need thereof a composition comprising an engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5′ to 3′ a promoter selected from human elongation factor-1 alpha (EF-1α) or spleen focus forming virus (SFFV), a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a first, self-cleavage peptide, a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR) a nucleotide encoding a second self-cleavage peptide, and a third polynucleotide encoding a fusion protein consisting of IL-15 linked to a soluble domain of IL-15Rα (sushi) and secreted as a soluble IL-15/IL-15 sushi complex wherein: (i) the first CAR comprises a first signal peptide, a first antibody binding domain, a first hinge region, a first transmembrane domain, a first CD28 or 4-1BB co-stimulatory domain, and a first signaling domain; and (ii) the second CAR comprises a second signal peptide, a second antibody binding domain, a second hinge region, a second transmembrane domain, a second CD28 or 4-1BBz co-stimulatory domain, and a second signaling domain; and wherein the first antibody binding domain and the second antibody binding domain are different from each other, and each bind to a different target, wherein the targets of the first and second antibody binding domains irrespective of order are CD33 and CLL-1, CD123 and CD33, BCMA and CD19 or BCMA and CS-1, wherein the first and second co-stimulatory domains are intracellular, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
2. The method according to claim 1, wherein the leukemia is acute myeloid leukemia (AML).
3. A method for treating multiple myeloma in a patient in need thereof, said method comprising: administering to said patient in need thereof a composition comprising an engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5′ to 3′ a promoter selected from human elongation factor-1 alpha (EF-1α) or spleen focus forming virus (SFFV), a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a first, self-cleavage peptide, a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR) a nucleotide encoding a second self-cleavage peptide, and a third polynucleotide encoding a fusion protein consisting of IL-15 linked to a soluble domain of IL-15Rα (sushi) and secreted as a soluble IL-15/IL-15 sushi complex wherein: (i) the first CAR comprises a first signal peptide, a first antibody binding domain, a first hinge region, a first transmembrane domain, a first CD28 or 4-1BB co-stimulatory domain, and a first signaling domain; and (ii) the second CAR comprises a second signal peptide, a second antibody binding domain, a second hinge region, a second transmembrane domain, a second CD28 or 4-1BBz co-stimulatory domain, and a second signaling domain; and wherein the first antibody binding domain and the second antibody binding domain are different from each other, and each bind to a different target, wherein the targets of the first and second antibody binding domains irrespective of order are BCMA and CD19 or BCMA and CS-1, wherein the first and second co-stimulatory domains are intracellular, wherein the promoter is strong spleen focus forming virus promoter (SFFV) or elongation factor-1 alpha (EF-1α), and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
4. A method for depleting antibody producing B cells and/or plasma cells in a patient with an autoimmune condition, said method comprising: administering to said patient in need thereof a composition comprising an engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5′ to 3′ a promoter selected from human elongation factor-1 alpha (EF-1α) or spleen focus forming virus (SFFV), a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a first, self-cleavage peptide, a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR) a nucleotide encoding a second self-cleavage peptide, and a third polynucleotide encoding a fusion protein consisting of IL-15 linked to a soluble domain of IL-15Rα (sushi) and secreted as a soluble IL-15/IL-15 sushi complex wherein: (i) the first CAR comprises a first signal peptide, a first antibody binding domain, a first hinge region, a first transmembrane domain, a first CD28 or 4-1BB co-stimulatory domain, and a first signaling domain; and (ii) the second CAR comprises a second signal peptide, a second antibody binding domain, a second hinge region, a second transmembrane domain, a second CD28 or 4-1BBz co-stimulatory domain, and a second signaling domain; and wherein the first antibody binding domain and the second antibody binding domain are different from each other, and each bind to a different target, wherein the wherein the targets of the first and second antibody binding domains irrespective of order are BCMA and CD19 or BCMA and CS-1, wherein the first and second co-stimulatory domains are intracellular, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A), and wherein said patient's autoimmune condition improves as a result of said depletion of antibody producing B cells and/or plasma cells.
5. The method according to claim 4, wherein the autoimmune condition is selected from systemic scleroderma, multiple sclerosis, psoriasis, dermatitis, inflammatory bowel disease, systemic lupus erythematosus, pemphigus vulgaris, vasculitis, rheumatoid arthritis, Sjorgen's syndrome, polymyositis, pulmonary alveolar proteinosis, granulomatosis, vasculitis, Addison's disease, antigen-antibody complex mediated disease, and anti-glomerular basement membrane disease.
Claims 1-10
1. (Original) An engineered cell comprising: (i.) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain selected from the group consisting of CS-1, CD5, CD19, CD20, CD123, BCMA, CD38, CLL-L, and CD33: a first signal peptide: a first hinge region; a first transmembrane domain; a first co-stimulatory domain: and a first signaling domain; and (ii.) a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain selected from the group consisting of CS-1, CD5, CD 19, CD20, CD123, BCMA, CD38, CLL-1, and CD33; a second signal peptide; a second hinge region: a second transmembrane domain; a second co-stimulatory domain; and a second signaling domain; wherein the first antigen recognition domain and the second antigen recognition domain are different: wherein the first antigen recognition domain and the second antigen recognition domain each have a single antigen recognition domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
2. (Original) The engineered cell according to claim 1, wherein the engineered cell includes SEQ ID NO. 42 (a BCMA-CS1 cCAR polypeptide and IL-15/IL-15sushi): SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO. 60 (a CLLI-CD33 eCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO.40 (a BCMA-CD38 cCAR polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 18 (a CD5-CD38 chimeric antigen receptor polypeptide); SEQ ID NO. 42 (a BCMA-CSIcCAR polypeptide and IL- 15/IL-15sushi; SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide, and IL-15/IL-15sushi); SEQ ID NO. 36 (CD123-CLLIcCARpolypeptide, and IL-15/IL-15sushi); SEQ ID NO. 28 (a CD20-CD19cCAR polypeptide, and IL-15/IL-15sushi: SEQ ID NO. 52 (a CD20-CD19cCAR polypeptide); SEQ ID NO. 1 (IL-21 anchor polypeptide); or SEQ ID NO. 50 (super2 polypeptide).
3. (Original) The engineered cell according to claim 1, wherein the enhancer is secreted by the engineered cell.
4. (Original) The engineered cell according to claim 1, wherein the engineered cell is an NK T cell, T cell, or NK cell.
5. (Original) The engineered cell according to claim 1, wherein the engineered cell comprises at least two enhancers.
6. (Original) An engineered cell comprising: (i.) a chimeric antigen receptor polypeptide comprising an antigen recognition domain selected from the group consisting of CD3, CD4, CD5, CD19, CD20, CD33, CD123, BCMA, GD2, and GD3: a signal peptide: a hinge region; a transmembrane domain; a co- stimulatory domain; and a signaling domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/iL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
7. (Original) The engineered cell according to claim 6,wherein the engineered cell includes SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide); SEQ ID NO. 58 (aGD2 chimeric antigen receptor polypeptide, 4-1BBL ligand and IL-15/IL-15sushi); SEQ ID NO. 49 (a CD5 chimeric antigen receptor polypeptide and IL-15/IL-15sushi; SEQ ID NO. 22 (a CD4 chimeric antigen receptor polypeptide and IL-15/IL-15sushi); SEQ ID NO. 20 (a CD4 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 18 (a CD3 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 24 (a CD19chimeric antigen receptor polypeptide and IL-15/IL-15sushi): SEQ ID NO. 26 (a CD19 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi): SEQ ID NO. 30 (a CD33 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 32 (a CD123 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi):SEQ ID NO. 38 (a BCMA chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL- 15sushi); SEQ ID NO.46 (a GD2 chimeric antigen receptor polypeptide, 4-1BBL and IL- 15/IL-15sushi); SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide; SEQ ID NO. 32 (a CD123b chimeric antigen receptor polypeptide and 4-1BBL ligand, and IL-15/IL- 1Ssushi); SEQ ID NO. 54 (a CD45 chimeric antigen receptor polypeptide and IL-15/IL- 315sushi; SEQ ID NO. 44 (a CLL-1 CAR polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 40 (a BCMA-CD38a chimeric antigen receptor polypeptides and 4-1BBL ligand, and IL-15/IL-15sushi); SEQ ID NO. 21 (a CD33 CAR polypeptide, 4-1BBL and IL-15/IL- ISsushi; or SEQ ID NO. 50 (super2 polypeptide).
8. (Original) The engineered cell according to claim 7, wherein the enhancer is secreted by the engineered cell.
9. (Original) The engineered cell according to claim 7, wherein the engineered cell is an NK T cell, T-cell, or NK cell.
10. (Original) The engineered cell according to claim 7, wherein the engineered cell comprises at least two enhancers.
Although the ‘819 claims recite that the cells are “ex vivo”, product claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). Thus, the T cells or NK cells of the ‘819 claims are the same as the claimed T cells or NK cells.
The ‘819 claims teach as set forth above, a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter whilst instant claims 1-5 make no mention. Notably the species of cCAR (compound CAR) taught in claim 2 comprise the missing elements of claim 1:
SEQ ID NO: 28:
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536
680
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Greyscale
SEQ ID NO: 34:
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530
648
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SEQ ID NO: 36:
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532
664
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SEQ ID NO: 40:
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528
666
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SEQ ID NO: 42:
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530
670
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SEQ ID NO: 50:
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534
674
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SEQ ID NO: 52:
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536
658
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SEQ ID NO: 60:
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536
658
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It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘819 claims express the first and second CAR of the ‘819 claims with a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter because a single open reading frame for expression of two CARs with an in-frame viral self-cleaving protein sequence resulting in two proteins that are separately expressed at the cell surface is effective for expression of two CARs in a single cell. The single open reading frame for expression of two CARs would only require a single promoter to express the single protein.
18. Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-29 of copending Application No. 17/502238 (reference application 20220241327) in view of Rowle et al., (Eur. J. Immunol. 2009. 39: 491-506).
Ref claims
20. (Withdrawn - Currently amended) An ex vivo engineered T cell or NK cell co- expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5’ to 3’ a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter, wherein: (i) the first CAR comprises a first signal peptide, a first antigen recognition domain, a first hinge region, a first transmembrane domain, a first 4- IBB or CD28 co-stimulatory domain, and a first CD3 signaling domain that form a first fusion protein; and (ii) the second CAR comprises a second signal peptide, a second antigen recognition domain, a second hinge region, a second transmembrane domain, a second 4- IBB or CD28 co- stimulatory domain, and a second CD3 signaling domain that form a second fusion protein; and wherein the first antigen recognition domain and the second antigen recognition domain are different and each bind to a different target, wherein the targets of the first antigen recognition domain and the second antigen recognition domain are a combination of an antibody binding portion scFv of BCMA and an antibody binding portion seFv of CD19, or a combination of an antibody binding portion seFyv of BCMA and an antibody binding portion seFv of CD20 or a combination of an antibody binding portion seFv of BCMA and an antibody binding portion seFv of CS-1 (CD319) or a combination of an antibody binding portion scFv of BCMA and an antibody binding portion scFv of CD38 or a combination of an antibody binding portion seFy of CD20 and an antibody binding portion scFv of CD19, wherein the first and second costimulatory, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
21. (Withdrawn - Currently amended) The ex vivo engineered T or NK cell according to claim 20, wherein the first antigen recognition domain comprises an antibody binding portion scFv of BCMA and the second antigen recognition domain comprises an antibody binding portion scFv of CD19.
22. (Withdrawn - Currently amended) The ex vivo engineered T or NK cell according to claim claim 20, wherein the first Antigen recognition domain comprises an antibody binding portion scFv of BCMA and the second antigen recognition domain comprises an antibody binding portion scFv of CD20.
23. (Withdrawn - Currently amended) The ex vivo engineered T or NK cell according to claim 20, wherein the first antigen recognition domain comprises an antibody binding portion scFv of BCMA and the second antigen recognition domain comprises an antibody binding portion scFv of CS-1.
24, (Withdrawn - Currently amended) An ex vivo engineered T or NK cell according to claim 20, wherein the first antigen recognition domain comprises an antibody binding portion scFv of BCMA and the second antigen recognition domain comprises an antibody binding portion scFy of CD38.
25. (Withdrawn - Currently amended) An ex vivo engineering T or NK cell according to claim 20, wherein the first antigen recognition domain comprises an antibody binding portion scFv of CD20 and the second antigen recognition domain comprises an antibody binding portion seFv of CD19.
26. (Withdrawn - Currently amended) An ex vivo engineered T cell or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5‘ to 3' a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter, wherein the targets of the first antigen recognition domain and the second antigen recognition domain are a combination of an antibody binding domain seFy of BCMA and an antibody binding portion seFv of CD19, or a combination of an antibody binding portion seFv of BCMA and an antibody binding portion scFv of CD20 or a combination of an antibody binding portion scFv of BCMA and an antibody binding portion seFv of CS-1 or a combination of an antibody binding portion scFv of BCMA and an antibody binding portion scFv of CD38 or a combination of an antibody binding portion scFv of CD20 and an antibody binding portion seFv of CD19.
27. (Currently amended) A method for treating a cell proliferation disease, said method comprises administering to a patient in need thereof an ex vivo engineered T cell according to claim 20 or NK cell co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5' to 3’ a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter, wherein:
(1) the first CAR comprises a first signal peptide, a first antigen recognition domain, a first hinge region, a first transmembrane domain, a first 4- IBB or CD28 co-stimulatory domain, and a first CD3 signaling domain that form a first fusion protein: and
(11) the second CAR comprises a second signal peptide, a second antigen recognition domain, a second hinge region, a second transmembrane domain, a second 4- IBB or CD28 co- stimulatory domain, and a second CD3 signaling domain that form a second fusion protein: and wherein the first antigen recognition domain and the second antigen recognition domain are different and each bind to a different target, wherein the targets of the first antigen recognition domain and the second antigen recognition domain are a combination of an antibody binding domain of BCMA and an antibody binding domain of CD19, or a combination of an antibody binding domain of BCMA and an antibody binding domain of CD20 or a combination of an antibody binding domain of BCMA and an antibody binding domain of CS-1 (CD319) or a combination of an antibody binding domain of BCMA and an antibody binding domain scFv of CD38 or a combination of an antibody binding domain of CD20 and an antibody binding domain of CD19, wherein the first and second costimulatory, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
28. (Previosuly presented) The method according to claim 27, wherein said cell proliferation disease comprises B-cell lymphoma, T-cell lymphoma, multiple myeloma, chronic myeloid leukemia, acute myeloma leukemia, myelodysplastic syndromes, chronic myeloproliferative neoplasms, or B-cell acute lymphoblastic leukemia (B-ALL).
29, (Currently amended) A method for reducing antibody producing cells selected from B cells and plasma cells, said method comprises administering to a patient in need thereof an ex vivo engineering T cell or NK cell according to claim 20 co-expressing two distinct chimeric antigen receptor (CAR) units at the cell surface, wherein the engineered T cell or NK cell comprises a nucleotide sequence comprising from 5' to 3' a first polynucleotide encoding a first chimeric antigen receptor polypeptide (CAR), a second polynucleotide encoding a second chimeric antigen receptor polypeptide (CAR), a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter, wherein:
(1) the first CAR comprises a first signal peptide, a first antigen recognition domain, a first hinge region, a first transmembrane domain, a first 4- IBB or CD28 co-stimulatory domain, and a first CD3 signaling domain that form a first fusion protein; and (11) the second CAR comprises a second signal peptide, a second antigen recognition domain, a second hinge region, a second transmembrane domain, a second 4- IBB or CD28 co- stimulatory domain, and a second CD3 signaling domain that form a second fusion protein; and wherein the first antigen recognition domain and the second antigen recognition domain are different and each bind to a different target, wherein the targets of the first antigen recognition domain and the second antigen recognition domain are a combination of an antibody binding portion of BCMA and an antibody binding portion of CD19, or a combination of an antibody binding portion of BCMA and an antibody binding portion of CD20 or a combination of an antibody binding portion of BCMA and an antibody binding portion of CS-1 (CD319) ora combination of an antibody binding portion of BCMA and an antibody binding portion of CD38 or a combination of an antibody binding portion of CD20 and an antibody binding portion of CD19, wherein the first and second costimulatory, and wherein the cleavage site is selected from the group consisting of porcine teschovirus-1 2A (P2A), thoseaasigna virus 2A (T2A), equine rhinitis A virus (ERAV) 2A (E2A), and FMDV 2A (F2A).
Claims 1-10
1. (Original) An engineered cell comprising: (i.) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain selected from the group consisting of CS-1, CD5, CD19, CD20, CD123, BCMA, CD38, CLL-L, and CD33: a first signal peptide: a first hinge region; a first transmembrane domain; a first co-stimulatory domain: and a first signaling domain; and (ii.) a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain selected from the group consisting of CS-1, CD5, CD 19, CD20, CD123, BCMA, CD38, CLL-1, and CD33; a second signal peptide; a second hinge region: a second transmembrane domain; a second co-stimulatory domain; and a second signaling domain; wherein the first antigen recognition domain and the second antigen recognition domain are different: wherein the first antigen recognition domain and the second antigen recognition domain each have a single antigen recognition domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/IL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
2. (Original) The engineered cell according to claim 1, wherein the engineered cell includes SEQ ID NO. 42 (a BCMA-CS1 cCAR polypeptide and IL-15/IL-15sushi): SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO. 60 (a CLLI-CD33 eCAR polypeptide and IL-15/IL-15sushi); SEQ ID NO.40 (a BCMA-CD38 cCAR polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 18 (a CD5-CD38 chimeric antigen receptor polypeptide); SEQ ID NO. 42 (a BCMA-CSIcCAR polypeptide and IL- 15/IL-15sushi; SEQ ID NO. 34 (a CD123-CD33 cCAR polypeptide, and IL-15/IL-15sushi); SEQ ID NO. 36 (CD123-CLLIcCARpolypeptide, and IL-15/IL-15sushi); SEQ ID NO. 28 (a CD20-CD19cCAR polypeptide, and IL-15/IL-15sushi: SEQ ID NO. 52 (a CD20-CD19cCAR polypeptide); SEQ ID NO. 1 (IL-21 anchor polypeptide); or SEQ ID NO. 50 (super2 polypeptide).
3. (Original) The engineered cell according to claim 1, wherein the enhancer is secreted by the engineered cell.
4. (Original) The engineered cell according to claim 1, wherein the engineered cell is an NK T cell, T cell, or NK cell.
5. (Original) The engineered cell according to claim 1, wherein the engineered cell comprises at least two enhancers.
6. (Original) An engineered cell comprising: (i.) a chimeric antigen receptor polypeptide comprising an antigen recognition domain selected from the group consisting of CD3, CD4, CD5, CD19, CD20, CD33, CD123, BCMA, GD2, and GD3: a signal peptide: a hinge region; a transmembrane domain; a co- stimulatory domain; and a signaling domain; and wherein the engineered cell comprises an enhancer selected from the group consisting of IL-15/iL-15sushi, IL-15/IL-15 sushi anchor, 4-1BBL, and IL-15.
7. (Original) The engineered cell according to claim 6,wherein the engineered cell includes SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide); SEQ ID NO. 58 (aGD2 chimeric antigen receptor polypeptide, 4-1BBL ligand and IL-15/IL-15sushi); SEQ ID NO. 49 (a CD5 chimeric antigen receptor polypeptide and IL-15/IL-15sushi; SEQ ID NO. 22 (a CD4 chimeric antigen receptor polypeptide and IL-15/IL-15sushi); SEQ ID NO. 20 (a CD4 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 18 (a CD3 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi; SEQ ID NO. 24 (a CD19chimeric antigen receptor polypeptide and IL-15/IL-15sushi): SEQ ID NO. 26 (a CD19 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi): SEQ ID NO. 30 (a CD33 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 32 (a CD123 chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL-15sushi):SEQ ID NO. 38 (a BCMA chimeric antigen receptor polypeptide, 4-1BBL and IL-15/IL- 15sushi); SEQ ID NO.46 (a GD2 chimeric antigen receptor polypeptide, 4-1BBL and IL- 15/IL-15sushi); SEQ ID NO. 56 (a GD2 chimeric antigen receptor polypeptide; SEQ ID NO. 32 (a CD123b chimeric antigen receptor polypeptide and 4-1BBL ligand, and IL-15/IL- 1Ssushi); SEQ ID NO. 54 (a CD45 chimeric antigen receptor polypeptide and IL-15/IL- 315sushi; SEQ ID NO. 44 (a CLL-1 CAR polypeptide, 4-1BBL and IL-15/IL-15sushi); SEQ ID NO. 40 (a BCMA-CD38a chimeric antigen receptor polypeptides and 4-1BBL ligand, and IL-15/IL-15sushi); SEQ ID NO. 21 (a CD33 CAR polypeptide, 4-1BBL and IL-15/IL- ISsushi; or SEQ ID NO. 50 (super2 polypeptide).
8. (Original) The engineered cell according to claim 7, wherein the enhancer is secreted by the engineered cell.
9. (Original) The engineered cell according to claim 7, wherein the engineered cell is an NK T cell, T-cell, or NK cell.
10. (Original) The engineered cell according to claim 7, wherein the engineered cell comprises at least two enhancers.
Rowle et al. discloses methods to enhance the viability and proliferation of primary CD8+ T cells and cytotoxic potential of antigen-specific CD8+ T cells comprising transfecting CD8+ T cells with a recombinant a chimeric construct comprising IL-15/IL-15RA sushi domain recombinant fusion. Rowle states:
“This dramatic increase in bioactivity of the IL-15/IL-15RA fusion construct compared to mixed and transfected IL-15 + IL-15RA is consistent with a previous report describing an IL-15/IL-15RA sushi domain recombinant fusion protein that exhibited a 10 fold increase in bioactivity in vitro compared to recombinant IL-15 mixed with recombinant IL15RA [31].”
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘238 claims express the first and second CAR of the ‘238 claims with a nucleotide encoding a viral self-cleavage peptide disposed between the first CAR and second CAR, under the transcriptional control of a single promoter because a single open reading frame for expression of two CARs with an in-frame viral self-cleaving protein sequence resulting in two proteins that are separately expressed at the cell surface is effective for expression of two CARs in a single cell. The single open reading frame for expression of two CARs would only require a single promoter to express the single protein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-14 of copending Application No. 17/283,450 (reference application 20210338729).
The copending claims recite engineered T cells expressing CARs that target CD19 and expresses cytokine enhancers including IL-15 and the IL-15/IL-15 sushi and IL-15/IL-15 sushi anchor fusion protein .
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
20. No claims are allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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