Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed August 11, 2025 in response to the Office Action of March 10, 2025 is acknowledged and has been entered.
Claims 24, 28, 36 have been amended.
Claims 32 and 37 has been cancelled.
Claim 60 and 61 has been added.
Claims 1, 6, 7, 15, 16, 19, 24, 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 50, 60 and 61 are pending.
Claims 1, 6, 7, 15, 16, 19, 50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 24, 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 60 and 61 are currently under consideration as drawn to the elected invention.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 24, 28, 30, 31, 40, 41, 47 and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record).
It is noted that the amended claim 24 deletes “and” between step (b) and step (c). Thus, it is unclear whether the method of claim 24 requires all steps (a), (b) and (c), or either one step. Given Broadest Reasonable Interpretation (BRI), any step from (a), (b), or (c) would read the claim.
Oyer teaches that NK cells are a small subpopulation of lymphocytes that have long been recognized to hold high potential for cancer treatment. NK cell treatment leads to 30% of patients with relapsed/refractory acute myelogenous leukemia (AML) (page 1, col. 2, para. 2).
Oyer teaches using feeder cells in a co-culture system to enable NK cell expansion. NK cells expanded by the K562-membrane bound IL21 feeder cell method are currently used in multiple clinical trials and showing encouraging clinical efficacy for leukemia relapse (the bridging paragraph of pages 1-2 and p. 8 Cell Culture). This reads on the step (a) of the claim 24.
Oyer teaches K562-mb21 feeder cell-expanded NK cell (FC21-NK cells, or PM21-NK cells) for treatment of blood cancers which resulted in decreased relapse rate (the bridging paragraph of pages 3-4).
Oyer teaches that FC21-NK cell or PM21-NK cell treatment significantly decrease tumor growth and longer animal survival (page 4, col. 1, para. 1; and Fig. S3).
Oyer teaches administration of FC21-NK or PM21-NK cell to mice bearing SKOV-3 tumor (Fig. 5 and description of Fig. S3).
Regarding claim 28, the mice bearing a SKOV-3 tumor meet said limitation because the mice has not been treated before NK cell treatment.
Regarding claim 30, Oyer teaches that T-cell was depleted from PBMCs with ExaySep CD3 positive selection kit from StemCell Technologies) (§ Cell Culture, on page 8), which uses a magnetic bead separation, See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025). Regarding claim 31, Oyer teaches healthy donors were used as sources of NK cells (§ Cell Culture, on page 8).
Regarding claims 40 and 41, Oyer teaches that blocking PD-L1 to mitigate induction of Treg expansion and the associated immunosuppression should lead to improved NK cell function and persistence (page 5, col. 1, para. 1).
Oyer teaches PD-L1 blockade improves anti-SKOV-3 efficacy of PM21-NK cell treatment (Fig. 5B). Combination of PM21-NK cell with anti-PD-L1 antibody resulted in further improvement of survival over the PM21-NK cells alone group (see description for Fig. 5).
Regarding claims 47 and 48, Oyer teaches further comprising administering an anticancer therapy that comprises an NK cell-activating agent, e.g IL-2 (see Fig. 5A and description for Fig. 5).
Response to Arguments
For the rejection under 35 U.S.C. 102, Applicant argues:
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Applicant’s arguments have been fully considered but they are only partially persuasive. The rejection for claims 32, 36 and 37 are withdrawn in view of claim amendments and applicant’s argument. However, as set forth above and set forth in 112(b) rejection, given BRI, step (b) of claim 24 is only optional for the recited method. Thus, Oyer still reads on the method of the amended claim 24 (e.g. comprising step (a)), as set forth above. The rejection is properly maintained for the reasons of record.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 25 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record), as applied to claims 24, 28, 30, 31, 40, 41, 47 and 48.
As set forth above, Oyer teaches the method of treating cancer as recited by claim 24. However, Oyer does not explicitly teach treating lung cancer (the elected species).
Oyer teaches NK cells show similar cytotoxicity to leukemia, lung and colon cancer cells (page 2, col. 2). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to apply the treatment to patients with lung cancer given that the activated NK cells show cytotoxicity to lung cancer cells. One of ordinary skill in the art would have had a reasonable expectation that the treatment would be effective for lung cancer in vivo. The motivation would have been to develop a new and effective treatment for lung cancer.
Claim 28 is alternatively rejected under 35 U.S.C. 103 as being unpatentable over Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record), as applied to claims 24, 25, 28, 30, 31, 40, 41, 47 and 48 above, further in view of Ciurea (Ciurea et al., Blood 2017; 130 (16): 1857-1868; Publication Date: 08/23/2017, of record).
As set forth above, Oyer teaches the method of treating cancer as recited by claim 24. However, Oyer does not explicitly teach the patient is a cancer patient relapsed from a treatment.
Oyer also teaches that haploid NK cell treatment leads to complete remission in 30% of patients with relapsed/refractory AML (page 1, col. 2, para. 2). NK cells expanded by K562-mb21 feeder cell show good efficacy for leukemia relapse prevention (page 2, col. 1, para. 1).
Ciurea teaches that using K562 feeder cells expressing membrane-bound IL-21 (mbIL21) can expand NK cells up to 35000-fold in 3 weeks and produces highly functional NK cells (page 1857, col. 2, para. 2).
Ciurea teaches that infusions of high doses of ex vivo-expanded donor-derived haploidentical NK cells in haploidentical bone marrow transplantation are safe and may be potentially effective in controlling leukemia relapse with no major toxicity (page 1866, the bottom paragraph of col. 2)
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancer patient with K562-co-cultured NK cells as taught by Oyer, and to apply the treatment to a cancer patient relapsed from a treatment, because 1) haploid NK cell treatment leads to complete remission in 30% of patients with relapsed/refractory AML; 2) NK cells expanded by K562-mb21 feeder cell show good efficacy for leukemia relapse prevention; 3) ex vivo-expanded donor-derived haploidentical NK cells in haploidentical bone marrow transplantation are safe and may be potentially effective in controlling leukemia relapse with no major toxicity, as taught by Oyer and Ciurea. One of ordinary skill in the art would have had a reasonable expectation that the treatment would effective for a relapsed cancer patient. The motivation would have been to develop a new effective therapy for the patient population and to expand applications of ex vivo-expanded NK cells.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record), as applied to claims 24, 25, 28, 30, 31, 40, 41, 47 and 48 above, and further in view of TECENTRIQ (Reference ID: 4085236, Revised Date: April 2017, of record).
As set forth above, Oyer teaches method of claim 41 e.g. treating cancers with K562-co-cultured NK cells in combination with an anti-PD-L1 antibody. However, Oyer does not explicitly teach that the PD-L1 antibody is atezolizumab, avelumab or durvalumab.
TECENTRIQ teaches that TECENTRIO (atezolizumab) is a PD-L1 blocking antibody approved by FDA for treating various cancers (§ INDICATIONS AND USAGE).
TECENTRIQ teaches administer 1200 mg as an intravenous infusion every 3 weeks (§ DOSAGE AND ADMINISTRATION).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancers with K562-co-cultured NK cells in combination with an anti-PD-L1 antibody, as taught by Oyer, and to substitute the anti-PD-L1 antibody with atezolizumab, as taught by TECENTRIQ, because atezolizumab is an FDA approved antibody for cancer therapy, and the dosage and administration regimens have been well tested in human. One of ordinary would have had a reasonable expectation that atezolizumab would be effective in the combination therapy taught by Oyer. The motivation would have been to use an FDA approved antibody for human application and to expand the application of atezolizumab.
Response to Arguments
For the rejection under 35 U.S.C. 103, Applicant argues:
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Applicant’s arguments have been fully considered but they are not persuasive. The references do not teach the PD-L1 (+) NK cells produced by the recited step (b) of claim 24, as set forth above and set forth in 112(b) rejection and given BRI, step (b) of claim 24 is only optional for the recited method. Thus, Oyer still reads on the method of the amended claim 24 (e.g. comprising step (a)). Oyer in combination with above references would make the rejected claims obvious as set forth above.
The rejection is properly maintained for the reasons of record.
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.
Application No. 18/023,536
Claims 24, 28, 36, 47 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13, 14, 16-18, 20-27 of copending Application No. 18/023,536 (hereinafter Appl. 536, US 2024/0141295 A1, of record).
It is noted that the amended claim 24 deletes “and” between step (b) and step (c). Thus, it is unclear whether the method of claim 24 requires all steps (a), (b) and (c), or either one step. Given Broadest Reasonable Interpretation (BRI), any step from (a), (b), or (c) would read the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 536 teach:
1. Modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL-21) and 4-1 BB ligand (4-1BBL).
2. The Tyro3+ K562 cells of claim 1, wherein the Tyro3+ K562 cells enhance the expansion of human natural killer (NK) cells that contact the K562 cells by at least about 10% compared to K562 cells that do not express exogenous human Tyro3 (Tyro3− K562 cells).
3. The Tyro3+ K562 cells of claim 1, wherein the human Tyro3 expression is under the control of a strong promoter.
4. The Tyro3+ K562 cells of claim 3, wherein the strong promoter is a retroviral promoter.
5. A method of expanding a population of human NK cells, comprising co-culturing the population of NK cells with K562 myeloid leukemia cells, wherein the K562 cells (Tyro3+ K562 cells) are modified to exogenously express human Tyro3 polypeptide, which polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, wherein the human Tyro3 gene expression is under the control of a constitutive promoter, and wherein the K562 cell expresses membrane bound interleukin 21 (IL-21) and 4-1 BB ligand (4-1BBL). This reads on step (a) of the instant claim 24.
13. The method of claim 5, wherein the expanded NK cells are activated NK cells.
17. The method of claim 5, wherein the expanded NK cells are Programmed death-ligand 1 (PD-L1)+ cells. This reads on the instant claim 36.
20. A composition comprising the population of expanded NK cells produced by the method claim 5.
21. A composition comprising expanded NK cells, wherein at least 20% of the NK cells in the population are Tyro3+ NK cells.
22. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 20, thereby treating cancer in the subject. Thus, the claims of Appl. 536 teach a method of treating cancer in a subjected by administering activated PD-L1(+) NK cells, which is derived from a human NK cell population co-cultured with K562 cells.
23. The method of claim 22, wherein the cancer is selected from a group consisting of lung cancer, breast cancer, ewing sarcoma, central nervous system neoplasm, skin cancer, head and neck cancer, ovarian cancer, colon cancer, anal cancer, stomach cancer, gastrointestinal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, testicular cancer, brain stem glioma, pituitary cancer, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, lymphoma, liver cancer, kidney cancer, bone cancer, bladder cancer, colorectal cancer, endometrial cancer, renal cell cancer, pancreatic cancer, prostate cancer, thyroid cancer, mesothelioma, neuroblastoma, retinoblastoma, melanoma, rhabdomyosarcoma, leukemia and lymphoma. This claim reads on the instant claim 25.
26. A method of suppressing the proliferation of tumor cells comprising contacting the tumor cells with a therapeutically effective amount of a composition of claim 20.
27. The method of claim 26, wherein said tumor cells are primary ductal carcinoma cells, glioblastoma cells, leukemia cells, acute T cell leukemia cells, chronic myeloid lymphoma (CML) cells, acute myelogenous leukemia cells, chronic myelogenous leukemia (CML) cells, lung carcinoma cells, colon adenocarcinoma cells, histiocytic lymphoma cells, multiple myeloma cells, colorectal carcinoma cells, colorectal adenocarcinoma cells, prostate cancer cells, or retinoblastoma cells.
Regarding claims 37, 47 and 48, the claims of Appl. 536 teach, wherein the human NK cells are expanded in the presence of interleukin 2 (IL-2), wherein the IL-2 is present at a concentration of about 0 IU/ml to about 5000 IU/ml, about 50 IU/ml to about 2000 IU/ml, or about 150 IU/ml to about 900 IU/ml (claim 7).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 40, 41 and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13, 14, 16-18, 20-27 of copending Application No. 18/023,536 (hereinafter Appl. 536, US 2024/0141295 A1, of record), as applied to claims 24, 28, 36, 47 and 48 above; and further in view of Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record) and TECENTRIQ (Reference ID: 4085236, Revised Date: April 2017, of record).
As set forth above, the claims of Appl. 536 teach the method of treating cancer as recited by claim 24. However, the claims of Appl. 536 do not explicitly teach further comprising administering an anticancer therapy, e.g. a checkpoint or atezolizumab.
Oyer and TECNTRIQ teach as set forth above. In particular:
Oyer teaches PD-L1 blockade improves anti-SKOV-3 efficacy of PM21-NK cell treatment (Fig. 5B). Combination of PM21-NK cell with anti-PD-L1 antibody resulted in further improvement of survival over the PM21-NK cells alone group (see description for Fig. 5).
TECENTRIQ teaches that TECENTRIO (atezolizumab) is a PD-L1 blocking antibody approved by FDA for treating various cancers (§ INDICATIONS AND USAGE).
TECENTRIQ teaches administer 1200 mg as an intravenous infusion every 3 weeks (§ DOSAGE AND ADMINISTRATION).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancers with K562-co-cultured NK cells as taught b the claims of Appl. 536 and to combine the NK cells with an anti-PD-L1 antibody, as taught by Oyer, and to substitute the anti-PD-L1 antibody with atezolizumab, as taught by TECENTRIQ, because the combination of the NK cells and anti-PD-L1 antibody enhances the therapeutic activity; and atezolizumab is an FDA approved anti-PD-L1 antibody for cancer therapy, and the dosage and administration regimens have been well tested in human. One of ordinary would have had a reasonable expectation that atezolizumab would be effective in the combination therapy taught by Oyer. The motivation would have been to use an FDA approved antibody for human application and to expand the application of atezolizumab.
This is a provisional nonstatutory double patenting rejection.
Application No. 18/685,854
Claims 24, 25, 40, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 78-95 of copending Application No. 18/685,854 (hereinafter Appl. 854, of record).
It is noted that the amended claim 24 deletes “and” between step (b) and step (c). Thus, it is unclear whether the method of claim 24 requires all steps (a), (b) and (c), or either one step. Given Broadest Reasonable Interpretation (BRI), any step from (a), (b), or (c) would read the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 854 teach:
1. A PD-L1 (+) natural killer cell, wherein the PD-L1 (+) natural killer cell expresses soluble IL-15.
2. The PD-L1(+) natural killer cell of claim 1, wherein the PD-L1(+) natural killer cell expresses soluble IL-15 and truncated EGFR.
78. The PD-L1(+) natural killer cell of claim 1, wherein: (a) the PD-L1(+) natural killer cell is an activated cord blood natural killer cell; (b) the PD-L1(+) natural killer cell was derived from an umbilical cord blood natural killer cell; or (c) the PD-L1(+) natural killer cell does not express a CD19 chimeric antigen receptor.
79. A population of PD-L1(+) natural killer cells of claim 1.
80. A pharmaceutical composition comprising the PD-L1(+) natural killer cell of claim 1. Thus, the claims of Appl. 854 teach the step (a) of the instant claim 24.
81. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount the PD-L1 (+) natural killer cell of claim 1.
Thus, the claims of Appl. 854 teach the method of instant claim 24, a derived PD-L1(+) NK cell population from isolated NK cells, and administering the population for treating cancers.
Regarding instant claims 40 and 41, the claims of Appl. 854 teach the method of claim 81, further comprising administering to the patient an effective amount of a checkpoint inhibitor (claim 88); the method of claim 88, wherein the checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor (claim 89).
Regarding instant claims 25 and 28, the claims of Appl. 854 teach the method of claim 81, wherein the cancer is non-small cell lung cancer (claim 90).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 45, 47 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 78-95 of copending Application No. 18/685,854 (hereinafter Appl. 854, of record), as applied to claims 24, 25, 28, 40, and 41 above; and further in view of Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record) and TECENTRIQ (Reference ID: 4085236, Revised Date: April 2017, of record).
As set forth above, the claims of Appl. 854 teach the method of treating cancer as recited by claim 24 and in combination with a PD-L1 inhibitor. However, the claims of Appl. 854 do not explicitly teach the PD-L1 inhibitor is atezolizumab, or further comprising administering an NK-cell activating agent, e.g. a cytokine.
Oyer and TECNTRIQ teach as set forth above. In particular:
Oyer teaches PD-L1 blockade improves anti-SKOV-3 efficacy of PM21-NK cell treatment (Fig. 5B). Combination of PM21-NK cell with anti-PD-L1 antibody resulted in further improvement of survival over the PM21-NK cells alone group (see description for Fig. 5).
TECENTRIQ teaches that TECENTRIO (atezolizumab) is a PD-L1 blocking antibody approved by FDA for treating various cancers (§ INDICATIONS AND USAGE).
TECENTRIQ teaches administer 1200 mg as an intravenous infusion every 3 weeks (§ DOSAGE AND ADMINISTRATION).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancers with K562-co-cultured NK cells as taught b the claims of Appl. 536 and to combine the NK cells with an anti-PD-L1 antibody, as taught by Oyer, and to substitute the anti-PD-L1 antibody with atezolizumab, as taught by TECENTRIQ, because the combination of the NK cells and anti-PD-L1 antibody enhances the therapeutic activity; and atezolizumab is an FDA approved anti-PD-L1 antibody for cancer therapy, and the dosage and administration regimens have been well tested in human. One of ordinary would have had a reasonable expectation that atezolizumab would be effective in the combination therapy taught by Oyer. The motivation would have been to use an FDA approved antibody for human application and to expand the application of atezolizumab.
Regarding claims 47 and 48, Oyer teaches further comprising administering an anticancer therapy that comprises an NK cell-activating agent, e.g IL-2 (see Fig. 5A and description for Fig. 5). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the NK cells with a cytokine e.g. IL-2 as taught by Oyer to further enhance the therapeutic activity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
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Applicant’s arguments have been fully considered but they are only partially persuasive. The rejection based on Appl. 145 are withdrawn in view of claim amendments and applicant’s argument. However, as set forth above and set forth in 112(b) rejection, given BRI, step (b) of claim 24 is only optional for the recited method. The rejections based on Appl. 536 and Appl. 854 are maintained because the recited step (b) of the instant claim 24 is only optional. As set forth above, the claims of Appl. 536 or Appl. 854 alone or in combination with cited references would teach/suggest the rejected claims as set forth above.
NEW GROUNDS OF REJECTION
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.
Claims 24, 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 60 and 61are 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.
The amended claim 24 deletes “and” between step (b) and step (c). Thus, it is unclear whether the method of claim 24 requires all steps (a), (b) and (c), or either one step. For examination purpose, given Broadest Reasonable Interpretation (BRI), any step from (a), (b), or (c) would read the claim.
Claim 36, which depends on claim 24, recites “wherein the population of PD-L1 (+)NK cells is expanded prior to administrating into the patient”. Step (b) of the method of claim 24 is a step of expanding step for PD-L1 (+)NK cells, as evidenced by the cancelled claim 32. It is unclear whether the step of amended claim 36 is an additional step different from step (b) of claim 24, or step (b) of claim 24 can be considered as the expanding step recited by the amended claim 36.
Claims 25, 28, 30, 31, 40, 41, 45, 47, 48, 60 and 61 are also rejected because these claims depend on claim 24 directly or indirectly.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 24, 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 60 and 61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 24 was amended after the filing date. The limitation of “a population of irradiated K562 cells expressing membrane-bound IL-2l in the presence of IL-2” in claim 24 has no clear support in the specification as originally filed. Applicant’ Remarks filed August 11, 2025 argue that support for the limitation can be found in previous claim 32 and paragraph [0011] of the specification.
Previous claim 32 discloses: “The method of claim 24, wherein deriving comprises expanding PD-L1(+)NK cells by exposing the isolated NK cells to a feeder cell optionally selected from a K562 cell and a K562 cell expressing IL-15 or IL-21 or both thereby producing a population of PD-L1(+) NK cell, or wherein deriving comprises fluorescence-activated cell sorting, magnetic bead separation, or column purification thereby producing a population of PD-L1(+) NK cell, or wherein deriving comprises exposing the isolated NK cells to an NK activating agent to induce PD-L1 expression thereby producing a population of PD-L1(+) NK cell, or wherein deriving comprises genetically engineering PD-L1 expression in the population of isolated NK cells thereby producing a population of PD-L1(+) NK cell.” Thus, the claim only discloses K562 cells expressing membrane-bound IL-2l.
Paragraph [0011] of specification discloses: “… FIG. 2E shows PD-L1− and PD-L1+ NK cells were sorted from three (3) healthy donors and cultured with feeder cells (feeder cells were K562 cells with membrane-bound IL-21, treated with 100 Gy radiation) for 20 days in the presence of IL-2. Cells were counted by trypan blue exclusion…”. Thus, the paragraph only disclose a population of K562 cells treated with 100 Gy radiation expressing membrane-bound IL-2l in the presence of IL-2.
Thus, the previous claim 32 and paragraph [0011] do not provide support for the amended claim 24 which encompasses a cell population treated with a broad range of radiation dosages. The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See MPEP 2163.05 (II). See also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (“Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads.”) Thus the limitation of amended claim 24 and its dependent claims is new matter because it is not supported by the as-filed disclosure. Thus, the subject matters claimed in the rejected claims broaden the scope of the invention as originally disclosed in the specification and claims from what was originally disclosed in the specification and claims as filed.
Claims 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 60 and 61 are also rejected because these claims encompass new matter encompassed by the rejected claim above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 24, 25, 28, 30, 31, 36, 40, 41, 47 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Denman (Denman et al., PLoS One, Vol. 7, Issue 1, e30264, Publication Date: 01/18/2012), in view of Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record).
.
It is noted that the amended claim 24 deletes “and” between step (b) and step (c). Thus, it is unclear whether the method of claim 24 requires all steps (a), (b) and (c), or either one step. Given Broadest Reasonable Interpretation (BRI), any step from (a), (b), or (c) would read the claim.
Denman teaches that NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy (Abstract).
Denman teaches K562 cells expressing membrane bound IL-2l (Table 1 – Clone 9.mbIL2l; and § Cells and cell lines).
Denman teaches that NK cells were enriched from human donor buffy coats with RosetteSep Human NK cell Enrichment Cocktail. The NK cells can be further purified by depleting unwanted cells (§ Cells and cell lines; and § NK cell purification by negative selection). This would read on step (a) of the instant claim 24.
Denman teaches that NK cells were cultured in NK cell media (comprising IL-2). In brief, peripheral blood mononuclear cells (PBMC) were first isolated from buffy coats. PBMC were co-cultured with irradiated (100 cGy) K562 aAPCs (including K562 cells expressing membrane bound IL-2l) in NK cell media (Table 1; and § Ex vivo expansion of human NK cells).
Denman teaches that mbIL21 resulted in significantly greater fold expansion at 3 weeks (47,967+/−42,230, mean +/− SD) (Fig. 3A). Thus, Denman teaches the same method for NK cell expansion as the step (b) of claim 24. In addition, since the method of producing these NK cells is the same as in the present application, the properties of the cells will be the same, i.e. PD-L1 (+).
Denman teaches that the cytolytic ability of the mbIL21-expanded NK cells were much greater than that of freshly isolated NK cells (Fig. 7A); mbIL21-expanded NK cells expressed significantly higher amounts of IFN-γ (mean 2629 pg/ml vs 26 pg/ml) and TNF-α (mean 90 pg/ml vs. 2 pg/ml) than mbIL15-expanded NK cells (Fig. 7B).
Denman teaches that NK cells expanded with mbIL21 retain cytotoxicity against a wide variety of tumor cell lines and participate in ADCC (Fig. 8).
Denman teaches as set forth above. However, Denman does not teach treating cancers with the NK cells.
Oyer teaches as set forth above. In particular, Oyer teaches that K562-mb21 feeder cell-expanded NK cell (FC21-NK cells, or PM21-NK cells) for treatment of mice bearing SKOV-3 tumor (Fig. 5 and description of Fig. S3). Oyer teaches K562-mb21 feeder cell-expanded NK cell (FC21-NK cells, or PM21-NK cells) for treatment of blood cancers which resulted in decreased relapse rate (the bridging paragraph of pages 3-4). Oyer teaches using feeder cells in a co-culture system to enable NK cell expansion. NK cells expanded by the K562-membrane bound IL21 feeder cell method are currently used in multiple clinical trials and showing encouraging clinical efficacy for leukemia relapse (the bridging paragraph of pages 1-2 and p. 8 Cell Culture).
Thus, It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to produce a population of K562-mbIL2 cell-expanded NK cells taught by Denman and to administer the NK cell population to treat cancers, because Denman teaches: 1) the expansion method produces large amount NK cells with high cytotoxicity; 2) the expanded NK cells have good cytotoxicity; 3) the NK cell population show anti-tumor activity to multiple tumor cell lines. Oyer teaches that NK cells, which are produced by a similar expansion method, can be used to treat various cancers. Based on the teachings of Denman and Oyer, one of ordinary skill in the art would have had a reasonable expectation of success that the NK cells population produced by the method of Denman would be effective to treat cancers. The motivation would have been to expand the application of the NK cells to clinical settings, as recognized by Denman (see the last paragraph of the article).
Regarding claim 25, Denman teaches that the NK cells have anti-tumor activity to AML cell lines (Fig. 8 A, B). Oyer teaches that NK cells are a small subpopulation of lymphocytes that have long been recognized to hold high potential for cancer treatment. NK cell treatment leads to 30% of patients with relapsed/refractory acute myelogenous leukemia (AML) (page 1, col. 2, para. 2).
Regarding claim 28, Oyer teaches NK-cells is effective for the mice bearing a SKOV-3 tumor meet said limitation because the mice has not been treated before NK cell treatment.
Regarding claim 30, Denman teachea that the NK cells can be further purified by depleting unwanted cells (§ Cells and cell lines; and § NK cell purification by negative selection), such as CD3 depletion (Fig. 2 and description of Fig. 8). Oyer teaches that T-cell was depleted from PBMCs with ExaySep CD3 positive selection kit from StemCell Technologies) (§ Cell Culture, on page 8), which uses a magnetic bead separation, See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record).
Regarding claim 31, Denman teaches healthy donors were used as sources of NK cells (§ Cells and cell lines).
Regarding claim 36, Denman teaches that mbIL21 resulted in significantly greater fold expansion at 3 weeks (47,967+/−42,230, mean +/− SD) (Fig. 3A).
Regarding claims 40 and 41, Oyer teaches that blocking PD-L1 to mitigate induction of Treg expansion and the associated immunosuppression should lead to improved NK cell function and persistence (page 5, col. 1, para. 1). Oyer teaches PD-L1 blockade improves anti-SKOV-3 efficacy of PM21-NK cell treatment (Fig. 5B). Combination of PM21-NK cell with anti-PD-L1 antibody resulted in further improvement of survival over the PM21-NK cells alone group (see description for Fig. 5). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method based on the teachings of Oyer and to add a PD-L1 inhibitor in the method to further enhance the efficacy of the treatment.
Regarding claims 47 and 48, Oyer teaches further comprising administering an anticancer therapy that comprises an NK cell-activating agent, e.g IL-2 (see Fig. 5A and description for Fig. 5). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the treatment method based on the teachings of Oyer because Oyer teaches detailed step by step protocol for NK-cell based treatment and the treatment is effective in vivo. One of ordinary in the art would have had a reasonable expectation that the method of Oyer would be effective because it has been tested in real tumor model in vivo.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Denman (Denman et al., PLoS One, Vol. 7, Issue 1, e30264, Publication Date: 01/18/2012), in view of Oyer (Oyer et al., Oncoimmunology, 2018, Vol. 7, NO. 11, e1509819, Publication Date: 08/27/2018, cited by IDS of 01/16/2025, of record), as evidenced by See EasySep (downloaded from: https://www.stemcell.com/products/brands/easysep-cell-separation.html, on 2/26/2025, of record), as applied to claims 24, 25, 28, 30, 31, 36, 40, 41, 47 and 48 above, and further in view of TECENTRIQ (Reference ID: 4085236, Revised Date: April 2017, of record).
As set forth above, Denman and Oyer teach method of claim 41 e.g. treating cancers with K562-co-cultured NK cells in combination with an anti-PD-L1 antibody. However, Denman and Oyer do not explicitly teach that the PD-L1 antibody is atezolizumab, avelumab or durvalumab.
TECENTRIQ teaches that TECENTRIO (atezolizumab) is a PD-L1 blocking antibody approved by FDA for treating various cancers (§ INDICATIONS AND USAGE).
TECENTRIQ teaches administer 1200 mg as an intravenous infusion every 3 weeks (§ DOSAGE AND ADMINISTRATION).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancers with the claimed NK cells in combination with an anti-PD-L1 antibody, as taught by Denman and Oyer, and to substitute the anti-PD-L1 antibody with atezolizumab, as taught by TECENTRIQ, because atezolizumab is an FDA approved antibody for cancer therapy, and the dosage and administration regimens have been well tested in human. One of ordinary would have had a reasonable expectation that atezolizumab would be effective in the combination therapy taught by Oyer. The motivation would have been to use an FDA approved antibody for human application and to expand the application of atezolizumab.
Conclusion
No claims are allowed.
All other objections and rejections set forth in the previous Office Action of March 10, 2025 are hereby withdrawn in view of the claim amendments and applicant’s arguments.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner