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 .
Application Status
Claims 1, 3-10, 15-18, and 20 are pending and examined on the merits herein.
Specification
The use of the term NK MACS®, MACSquant®, and G-Rex® (pages 16-17) 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.
Claim Rejections - 35 USC § 102
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.
Claims 1, 3-8, 10, 15-16, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rezvani (WO 2021/108671 A1; published 06/03/2021; PTO-892).
Regarding claims 1 and 15, Rezvani teaches an in vitro method of producing engineered NK cells, comprising the steps of: a2) expanding the cells; b2) delivering to the expanded NK cells of (a) an effective amount of Cas9 and one or more guide RNAs to disrupt expression of one or more genes in the NK cells, thereby producing gene edited NK cells; c2) after a second time period, transducing or transfecting the gene edited NK cells with one or more vectors each encoding one or more heterologous antigen receptors to produce gene edited modified NK cells; and d2) further expansion (claims 1 and 3), wherein the gene that has disruption of expression in the NK cells is an inhibitory gene (claim 27), wherein the inhibitory gene is selected from CISH and CD38 (claim 28). Rezvani further teaches in specific cases; the genes are one or more of CISH and CD38 (para 00151). Rezvani further teaches a population of NK cells produced by the method of any one of claims 1-35 (claim 36).
Regarding claims 3-7, Rezvani teaches in specific cases this is performed as a knockout using CRISPR/Cas9 RNP and the CAR- NK KO cells are assessed for KO efficiency (para 00215). A complete knockout meets all of the percentage minimums of the instant claims.
Regarding claim 8, Rezvani teaches the NK cells may be transfected or transduced with a vector that allows for the NK cells to express multiple heterologous proteins, such as a heterologous antigen receptor(s), a suicide gene, and one or more cytokines, such as IL-15 (para 0062).
Regarding claim 10, Rezvani teaches wherein the heterologous antigen receptor is a chimeric antigen receptor or a T cell receptor (claim 24), wherein the heterologous antigen receptor targets CD19, CD38, or CLL-1 (claim 26).
Regarding claim 16, Rezvani teaches a method of treating an individual for a medical condition, comprising the step of administering to the individual a therapeutically effective amount of NK cells produced by the method of any one of claims 1-35 (claim 39), wherein the medical condition is cancer (claim 40).
Regarding claim 18, Rezvani teaches wherein the cancer comprises a hematological malignancy or a solid tumor (claim 41), including acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); and multiple myeloma (para 00169).
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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Rezvani (WO 2021/108671 A1; published 06/03/2021; PTO-892) as applied to claims 1, 3-8, 10, 15-16, and 18 above, and further in view of O’Dwyer (WO 2017/017184 A1; PTO-892).
The teachings of Rezvani regarding claims 1, 3-8, 10, 15-16, and 18 are detailed above.
Rezvani does not teach further modification of the cell or cell line to express WT TRAIL or a TRAIL variant with increased affinity for TRAIL.
O’Dwyer teaches a natural killer (NK) cell or NK cell line that has been genetically modified to have reduced expression of one or more checkpoint inhibitory receptors (claim 1), further modified to express a mutant TRAIL ligand (claim 4), wherein the mutant TRAIL ligand has an increased affinity for TRAIL receptors, e.g. DR4 and/or DR5 (claim 5), wherein the mutant TRAIL ligand has reduced affinity for decoy TRAIL receptors (claim 6). O’Dwyer further teaches that genetic modification to remove inhibitory receptor function on NK cells has been suggested as a method for increasing the cytotoxicity of NK cells against cancer cells that lack MHC class I expression but are able to dampen NK cytotoxicity (page 1, lines 33-35). O’Dwyer further teaches that NK cells are known to kill cancer cells by expressing TRAIL on their surface as TRAIL ligand is able to bind TRAIL receptors on cancer cells and induce apoptosis of said cancer cells (page 2, lines 29-31). O’Dwyer further teaches that cancer cells have developed evasive and protective mechanisms for dealing with NK cells expressing TRAIL through decoy TRAIL receptors that are often expressed on cancer cell membranes, and binding of TRAIL to these decoy receptors is unable to induce apoptosis (page 3, lines 1-4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add a variant TRAIL as taught by O’Dwyer to the NK cells expressing a CD38-CAR, with CD38 and CISH knockdown and IL-15 expression as taught by Rezvani. The ordinary artisan would have been motivated to do so because O’Dwyer and Rezvani are analogous arts generating improved NK-CARs for treatment of cancer. O’Dwyer teaches that NK cells are known to kill cancer cells by expressing TRAIL on their surface as TRAIL ligand is able to bind TRAIL receptors on cancer cells and induce apoptosis of said cancer cells. O’Dwyer further teaches that cancer cells have developed evasive and protective mechanisms for dealing with NK cells expressing TRAIL through decoy TRAIL receptors that are often expressed on cancer cell membranes, and binding of TRAIL to these decoy receptors is unable to induce apoptosis. The ordinary artisan has a reasonable expectation of success to add a variant TRAIL to the NK cells expressing a CD38-CAR, with CISH and CS38 knockdown and IL-15 to improve treatment of cancer.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Rezvani (WO 2021/108671 A1; published 06/03/2021; PTO-892) as applied to claims 1, 3-8, 10, 15-16, and 18 above, and further in view of Gurney (Haematologica. 2022 Feb 1;107(2):437-445; published online Dec 2020; PTO-892)
The teachings of Rezvani regarding claims 1, 3-8, 10, 15-16, and 18 are detailed above.
Rezvani does not teach wherein the cancer is a CD38 expressing cancer.
Gurney teaches that acute myeloid leukemia (AML) is the most common acute leukemia in adults, accounting for approximately 2% of all cancer deaths and that the multifunctional cell surface glycoprotein CD38, a breakthrough immunotherapeutic target in multiple myeloma, is also considered a potential target antigen in AML. Gurney further teaches the CD38 monoclonal antibody daratumumab has been investigated in AML and has shown promising pre-clinical activity and CD38 CAR-T cells have confirmed cytotoxicity against primary AML (introduction). Gurney further teaches that to reduce the anticipated NK cell fratricide that would occur using ex vivo expanded NK cells, we applied CRISPR/Cas9 to disrupt the CD38 gene during NK cell expansion, creating fratricide-resistant NK cells prior to CD38 CAR expression (introduction).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the NK expressing a CD38-CAR, with CD38 and CISH knockdown and IL-15 expression as taught by Rezvani to treat CD38 expressing cancers as taught by Gurney. The ordinary artisan would have been motivated to do so because Gurney and Rezvani are analogous arts generating NK-CARs for treatment of cancer. Gurney teaches that CD38, is a breakthrough immunotherapeutic target in multiple myeloma and is also considered a potential target antigen in AML. Gurney further teaches that the CD38 monoclonal antibody daratumumab has been investigated in AML and has shown promising pre-clinical activity and CD38 CAR-T cells have confirmed cytotoxicity against primary AML. The ordinary artisan has a reasonable expectation of success to add treat CD38 expressing MM or AML with the NK cell expressing a CD38-CAR, with CISH and CS38 knockdown and IL-15 expression.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Rezvani (WO 2021/108671 A1; published 06/03/2021; PTO-892) as applied to claims 1, 3-8, 10, 15-16, and 18 above, and further in view of Alfolabi (Immunology, 2019, 158: 63-69; PTO-892).
The teachings of Rezvani regarding claims 1, 3-8, 10, 15-16, and 18 are detailed above.
Rezvani does not teach wherein the method comprises knocking in expression of the IL-15 gene.
Alfolabi teaches that NK cells are potent cytotoxic lymphocytes specialized in recognizing and eliminating transformed cells, and in orchestrating adaptive anti-tumour immunity but are usually functionally exhausted in the tumour microenvironment (summary). Alfolabi further teaches that the discovery and development of the CRISPR/Cas9 technology offer a flexible and efficient gene-editing capability in modulating various pathways that mediate NK cell exhaustion (summary). Alfolabi further teaches that NK cells, particularly primary NK cells, are well known to resist ordinary transfection, making the delivery of the Cas9 system difficult, and thus representing an important concern in gene-editing of NK cell immunotherapy, so to achieve the delivery, integrating (lentivirus and retrovirus) transduction is an applicable approach (page 64, col 1, para 4). Alfolabi further teaches that NK cells could be triggered and/or sustained by activating cytokines such as IL-15 and that IL-15 is well established for its survival-promoting effects on NK cells (page 65 last para- page 66 1st para). Alfolabi further teaches that genetic editing of NK cells from various sources via the CRISPR/Cas9 multiplexing by knocking out inhibitory signals, bolstering its tumour infiltration by integrating tissue homing receptors, improving its anti-tumour activity by providing extra activating signalling, as well as enhancing its tumour specificity by arming with chimeric antigen receptors (CARs); the forced expression of stimulatory cytokines is included in the figure (Figure 1). Alfolabi further teaches that in order to fully exploit the anti-tumour potential of NK cell immunotherapy, it would be beneficial to simultaneously enhance some, while suppressing other, pathways and the multiplex capability of the CRISPR/Cas9 system perfectly fits this requirement (page 65, col 1, para 2). Alfolabi further teaches that CRISPR/Cas9 offers the ease of site-specific integration of gene of interest (with donor gene through homology-directed repair pathway), while concurrently deleting multiple genes of interest (page 65, col 1, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application knock-in the IL-15 expression as taught by Alfolabi in the CD38-CAR, with CD38 and CISH knockdown and IL-15 expression as taught by Rezvani. The ordinary artisan would have been motivated to do so because Alfolabi further teaches that NK cells could be triggered and/or sustained by activating cytokines such as IL-15 and that IL-15 is well established for its survival-promoting effects on NK cells. Alfolabi further teaches that NK cells, particularly primary NK cells, are well known to resist ordinary transfection and that CRISPR/Cas9 offers the ease of site-specific integration of gene of interest (with donor gene through homology-directed repair pathway), while concurrently deleting multiple genes of interest via lentiviral transduction. The ordinary artisan has a reasonable expectation of success to use CRISPR/Cas in a lentiviral vector to knock-in expression of IL-15 in the NK cell expressing a CD38-CAR, with CISH and CS38 knockdown and IL-15 expression.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1, 3-8, 10, 15-16, 18, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-39 of copending Application No. 19/525,470 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1, 3-8, 10, 15, and 20, the copending claims teach a human NK cell or NK cell line wherein the cell is modified to have: CISH and CD38 expression knocked out; and genes IL-15 and a CD38 CAR knocked in to the CISH locus (claims 21-33).
Regarding claims 16, the copending claims teach a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the human immune effector cell of claim 21 (claim 34 and 36), wherein the human immune effector cell is an NK cell (claim 37), wherein the human immune effector cell further expresses a chimeric antigen receptor (CAR) (claim 38), wherein CISH expression is knocked out in the human immune effector cell (claim 39).
Regarding claim 18, the copending claims teach wherein the cancer is a blood cancer (claim 35).
Conclusion
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/AMBER K FAUST/ Examiner, Art Unit 1643
/GARY B NICKOL/ Primary Examiner, Art Unit 1643
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