DETAILED ACTION
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 .
Claim Status
Claims 1-95 have been cancelled.
Claims 96-115 are currently pending.
Claims 96-115 are being examined in this application.
Election/Restrictions
Upon further consideration and in light of applicant’s argument, the previous set forth Restriction Requirement has been withdrawn, and all groups of inventions (claims 96-115) are rejoined.
Priority
This application is filed under 35 U.S.C 371 of PCT/US2022/028839 (filed on 05/11/2022), which claims priority to US provisional applications 63/269,316 (filed on 03/14/2022) and 63/201,792 (filed on 05/13/2021).
Information Disclosure Statement
The IDS filed on 7/7/26, 12/23/25 and 5/31/24 have been considered. See the attached PTO 1449 forms.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification. MPEP 608.01.
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.
Hariri and Others
Claims 96-115 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), in view of Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The instant claims recite “A method for the treatment of a cancer, comprising administering to a subject having a cancer a dosing cycle comprising a first dose of natural killer (NK) cells, a second dose of NK cells, and a third dose of NK cells, wherein:
the second dose of NK cells is administered to the subject between 5-10 days after the first dose of NK cells, and the third dose of NK cells is administered to the subject between 5-10 days after the second dose of NK cells;
each of the first, second and third doses of NK cells comprises between about 1.0 x109 NK cells and about 3.0 x109 NK cells;
the first dose of NK cells is administered to the subject after the subject has undergone a lymphodepletion process comprising administration of fludarabine (Flu) and cytosine arabinoside (Ara-C) to the subject; and
the NK cells are allogeneic to the subject.”
Hariri et al., throughout the patent, teach methods of making NK cells, and method of using the NK cells to treat cancer (e.g. Abstract; claims).
For claims 96, 107, A method for the treatment of a cancer, comprising administering to a subject having a cancer a dosing cycle comprising a first dose of natural killer (NK) cells, a second dose of NK cells, and a third dose of NK cells, wherein:
the second dose of NK cells is administered to the subject between 5-10 days after the first dose of NK cells, and the third dose of NK cells is administered to the subject between 5-10 days after the second dose of NK cells;
The reference teaches “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days.
…each of the first, second and third doses of NK cells comprises between about 1.0 x109 NK cells and about 3.0 x109 NK cells;
The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
…the first dose of NK cells is administered to the subject after the subject has undergone a lymphodepletion process comprising administration of fludarabine (Flu) and cytosine arabinoside (Ara-C) to the subject; and
The reference teaches administering “fludarabine” combining with NK cells to the subject having leukemia (e.g. col.8, ll, 30+).
…the NK cells are allogeneic to the subject
The reference teaches the NK cells are “allogeneic to a recipient” (e.g. col.32, ll, 60+).
For claims 101-102, 105, 110, 113-114, the reference teaches “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. And this teaching also reads on or renders obvious the dosing schedule of instant claim 102, and the dosing cycle days of claims 105, 113 and 110. It would also be obvious to add another dosing cycle as recited in claim 114 if the therapy duration is one months based on the once per week dose regime.
For claims 103-104, 111-112, the reference teaches treating AML (acute myelogenous leukemia) or MDS (myelodysplastic syndrome) (e.g. col.42, lls 20+; lls 50+).
Hariri et al., does not explicitly teach lymphodepletion using combination of fludarabine and Ara-C as recited in Claim 96, as well as the doses of Flu and Ara-C of claims 97-100, 107-109. The reference also does not teach the NK cells are genetically engineered to express CAR as recited in claims 106-107.
However, Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
A person of ordinary skill in the art would have reasonable expectation of success of achieving such modifications since all cited references have demonstrated treating cancer (such as AML) with NK cells (engineered) with various dosing cycles.
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.
‘548 Patent
Claims 96-115 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,560,548 in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference patent claims the followings, for example,
1. A method of treating a cancer, the method comprising:
administering to a subject having the cancer a population of cells that express all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein and results in the IL-15 being expressed as a cell membrane-bound polypeptide (mbIL15) on the surface of the cells,
wherein the transmembrane protein is a CD8 transmembrane domain, and
wherein the mbIL15 has the sequence of SEQ ID NO: 2.
2. The method of claim 1, wherein the population of cells comprises one or more of natural killer (NK) cells, T-cells, dendritic cells and monocytes.
3. The method of claim 2, wherein the population of cells comprises isolated CD56+CD3−natural killer cells.
The reference patent does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
‘575 Patent
Claims 96-115 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,154,575 in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference patent claims the followings, for example,
1. A method of treating a cancer using immunotherapy, the method comprising:
administering to a subject having the cancer a population of immune cells that express a CD19-directed chimeric antigen receptor (CAR), the chimeric antigen receptor comprising:
an extracellular anti-CD19 binding moiety comprising a single chain Fragment variable (scFv), wherein the scFv comprises:
a variable heavy (VH) domain, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 120, and
a variable light (VL) domain;
a hinge, wherein the hinge is a CD8 alpha hinge…
2. The method of claim 1, wherein the population of immune cells comprises Natural Killer (NK) cells, wherein the OX40 subdomain is encoded by SEQ ID NO. 5, and wherein the CD3 zeta subdomain is encoded by SEQ ID NO. 7.
9. The method of claim 1, wherein the population of immune cells comprises a mixture of NK cell and T cells.
24. A method of treating a cancer using immunotherapy, the method comprising:
administering to a subject having the cancer a population of immune cells that express a CD19-directed chimeric antigen receptor (“CAR”), the CAR comprising:
an extracellular anti-CD19 binding moiety comprising a variable heavy (VH) domain and a variable light (VL) domain; and
an intracellular signaling domain, wherein the intracellular signaling domain comprises:
an OX40 subdomain and a CD3 zeta subdomain;
wherein the immune cells also express membrane-bound interleukin-15 (mbIL15), and
wherein the CD19-directed CAR and mbIL15 comprises the amino acid sequence set forth in SEQ ID NO: 187.
25. The method of claim 24, wherein the immune cells comprise Natural Killer cells and wherein the immune cells are allogeneic with respect to the subject.
The reference patent does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
‘311 Patent and others
Claims 96-115 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,774,311 (or US 10,428,305 or US 11,560,548) in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference patent claims the followings, for example,
1. A method of treating a cancer, the method comprising:
administering to a subject having the cancer a population of Natural Killer (NK) cells that expresses all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and wherein the all or a functional portion of IL-15 promotes one or more of:
(i) NK cell survival,
(ii) regulation of NK cell and T cell activation and proliferation, and
(iii) support of NK cell development from hematopoietic stem cells.
The reference patent does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
‘116 Application
Claims 96-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 16, 18, 27-28, 45-46, 50, 71-74, 87, 94-95, 107-108 of copending Application No. 18/877,116 in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference application claims the followings, for example,
A method of treatment comprising administering genetically engineered natural killer (NK) cells to a subject having a disease or condition associated with CD19 expression, wherein the method comprises: administering at least a first dosing cycle to the subject, wherein the first dosing cycle comprises a first dose of genetically engineered natural killer (NK) cells administered to the subject at a first time point, a second dose of genetically engineered NK cells administered to the subject between 5-10 days after the first time point, and a third dose of genetically engineered NK cells administered to the subject between 5- 10 days after the second dose, wherein: each of the first, second and third doses comprise at least about 1[[1.5]] x109 NK cells, at least a portion of the genetically engineered NK cells is engineered to express a chimeric antigen receptor (CAR) that binds to CD19, and first dosing cycle is initiated after the subject has undergone a lymphodepletion process that reduces native immune cell numbers.
The method of Claim 1, wherein the first dosing cycle is followed by one or more additional dosing cycle.
The method of Claim 1, wherein, if the subject exhibits a clinical response following the first dosing cycle, the dosing regimen comprises an additional dosing cycle.
The reference application does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
This is a provisional nonstatutory double patenting rejection.
‘376 Application
Claims 96-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61-80 of copending Application No. 19/325,376 in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference application claims the followings, for example,
61. A method for treating colorectal cancer (CRC), the method comprising administering to a subject having CRC a composition comprising natural killer (NK) cells engineered to express a chimeric receptor and a membrane-bound interleukin-15 (mbIL15), wherein the chimeric receptor comprises the amino acid sequence encoded by SEQ ID NO:7.
67. The method of claim 61, wherein the engineered NK cells are allogeneic to the subject.
The reference application does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
This is a provisional nonstatutory double patenting rejection.
‘550 Application
Claims 96-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 18/657,550 in view of Hariri et al (US 8,926,964; 1/6/2015; filed on 7/13/20211 or earlier; cited in IDS), Zhang et al (US 2018/0273903; 9/27/2018; filed on 12/28/2017 or earlier; cited in IDS) and Chaudhary (WO 2019/232503; 12/5/2019; filed on 6/1/2019 or earlier).
The reference application claims the followings, for example,
A method of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered immune natural killer (NK) cells expressing an anti-CD70 chimeric antigen receptor (CAR) comprising an anti- CD70 binding domain comprising a heavy chain variable (VH) region and a light chain variable (VL) region; a transmembrane domain; and a cytotoxic signaling complex, wherein:
The reference application does not explicitly claim lymphodepletion using combination of fludarabine and Ara-C with the specific dosage and dosing regimen as well as the dosing cycle for administering the NK cells.
However, Hariri et al., teach “administering the NK cells… to an individual having the cancer…” (e.g. Abstract; cols.6-7 bridging para; cols. 46-47, 50-52). The reference also teaches administering the NK cells to subjects having cancer “once every 1, 2, 3, 4, 5, 6 or 7 days” or “once every 1… weeks during therapy”, which would encompass and/or render obvious the instant dosage cycle since if the therapy duration is one month, the once every 1 week would have at least three dosages every 7 days. The reference teaches various amounts of NK cells can be used, for example, 1.0 x109 NK cells per milliliter (e.g. col.51, ll. 40+).
Zhang et al., throughout the reference, teaches generating genetically modified (GM) NK cells, and using the NK cells to treat cancer (e.g. Abstract). The reference teaches the cancer can be acute myeloid leukemia (AML) (e.g. [0012]). The reference also teaches administering the GM NK cells every few days or every week or any amount of time during the time of the therapy (e.g. [0226]). The reference also teaches administering fludarabine and cytarabine (which is Ara-C) to “condition” the patient “prior to administering said natural killer cells” (e.g. [0012]), which reads on the pre-treatment of lymphodepletion by administering Flu and Ara-C of claim 96, 107 and 115.
In addition, Chaudhary, throughout the reference, teaches using engineered immune cells including T-cells and NK cells to treat cancer (e.g. Abstract; [0008]; [00406]; [00486]-[00487]). The reference also teaches lymphodepletion using Flu and Ara-C (e.g. [00581]). The reference teaches FluCyE regimen for lymphodeletion with 30mg/m2/day of Flu and 1.5 g/m2/day from -6 to -1 days (e.g. [00581]), which reads the 5 daily doses of claims 97, 107, amounts of claim 99-100, 108-109, and about 7 days prior administration of claims 98, 107. The reference also teaches treating refractory/relapsed cancer such as relapsed myeloma (e.g. [00113]; [00733]) as well as acute myeloid leukemia (e.g. [0022]; [00504]; [00545]; claim 41).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR for treating cancer as taught by Zhang and Chaudhary, because generating genetic engineered NK cells with CAR and administering the cells to cancer patients are known in the art and have been demonstrated in clinical trials. In addition, because the Hariri, Zhang and Chaudhary references all teach methods of administering NK cells (enriched or genetically engineered with CAR) for treating various cancers including leukemia, it would have been obvious to one skilled in the art to substitute isolated NK cells with CAR expressing NK cells to improve cancer treatment based on the type of cancer.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to precondition or lymphodeplete especially blood cancer patients prior to administering genetically engineered CAR expressing NK cells since lymphodepletion of patients own immune cells are needed so that the external NK cells can be better received by the patients as taught by Zhang and Chaudhary. In addition, Chaudhary teaches various lymphodepletion regimes are known and routine in the art as discussed above, and thus it would have been obvious for one of skilled in the art to select a known lymphodepleting chemotherapy such as combination of Flu and Ara-C with the appropriate dosages and dosing schedule to achieve the predictable result of pre-condition and lymphodepleting the blood cancer patient prior to NK cell administration.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering genetically engineered NK cells that express CAR with prior lymphodepletion treatment to treat r/r AML as taught by Chaudhary, because the Hariri, Zhang and Chaudhary references all teach treating AML using NK cells are known and have been demonstrated. Further, it would have been obvious to treat r/r AML patients with the same treatment as AML since Chaudhary teaches the need to treat r/r cancers.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administering NK cells with known and set dosing cycle based on the disease that is being treated as taught by all the cited references. it would have been obvious to administer specific engineered NK cells in multiple infusion such as 3 doses with 6-8 days apart and various days between each treatment cycle to optimize the treatment effectiveness and efficacy.
This is a provisional nonstatutory double patenting rejection.
Conclusion and Correspondence
No claims are allowed.
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/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616
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