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 .
Status of The Application
On the 26th of May 2026, Applicant filed an After-Final response, which has been acknowledged, considered, and entered.
In view of further search and consideration, the finality of the previous Office Action is withdrawn, and prosecution has been reopened. The following rejections are applicable and necessitated by Applicants amendments to the claims. Thus, the instant action is a Non-final Office Action.
Priority
This application was filed Oct. 19, 2022, and is a 371 application of PCT/KR2021/007091 filed on June 7, 2021, which claims benefit to the foreign application KR10-2021-0046107 filed on April 8, 2021, and foreign application KR10-2020-0069854 filed on June 9, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in foreign Application KR10-2021-0046107 and KR10-2020-0069854, filed on Oct. 19, 2022.
Claim Status
In the response filed 26th of May 2026, Applicant has amended claim 1, and cancelled claims 13-14.
Applicant elected, with traverse, Group I, drawn to a feeder cell for culturing natural killer (NK) cells on the 2nd of September 2025. Claims 5-12 are directed to Group II drawn to a method of proliferating NK cells are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Currently, claims 1-12 are pending and claims 5-12 are withdrawn.
Claims 1-4 are under examination in this office action.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Kamiya, Takahiro and Campana, Darlo, (WO2018/182511, published 2018, hereinafter as “Kamiya”, cited IDS 2/01/2024, prior art of record) in view of Min et al., (US2020/0108096 A1, published April 9, 2020, hereinafter as “Min”), Kweon, SoonHo, et al. (Frontiers in immunology 10: 879, published 2019, hereinafter as “Kweon”, cited IDS 10/14/22), and Erokhina, Sofya A., et al. (Journal of Leukocyte Biology 109.2 (2020): 327-337, published May 2020, hereinafter as “Erokhina”)
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the Final Official action mailed on 24th of March 2026, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 1, and 3-4, Kamiya discloses a feeder cell (i.e. stimulatory cells)(e.g. K562 derived cells, NK cells or T-lymphocytes) for culturing natural killer (NK) cells (see e.g. abstract, para. 3, 8, 21, 28-33, 42, 61-62, and 72, claims 1-36, fig. 1, 3-4, page 14-25), wherein the feeder cell is genetically engineered to express membrane bound interleukin-18 (mbIL-18)(see e.g. claims 1, 14-17, and 33-36). (see e.g. para. 8, 21, 30-42, and 61; page 14, claim 6). Further, Kamiya discloses K562 variants that are generated by transducing the K562-mb15-41BBL cells with a retroviral vector containing the cDNA sequence encoding membrane bound interleukin (IL), and a nucleic acid encoding mbIL-18 (SEQ ID NO: 8) (see e.g. para. 6, 26-30, 35, 50, 55, claims 33-34). Further, Kamiya discloses genetically engineering a cell to express membrane bound IL-21 (mbIL21)(i.e. SEQ ID NO. 10 or SEQ ID NO: 36)(see e.g. para. 11, 18, 27, 50, 60-62, claims 35-36, 79, 91).
Kamiya does not explicitly teach wherein the feeder cell is genetically engineered to express OX40 ligand (OX40L), thereby having a feeder cells expressing membrane bound interleukin-18 (mbIL-18), membrane bound interleukin-21 (mbIL-21), and OX40 ligand (OX40L).
However, the prior art of Min discloses a feeder cell (e.g. genetically modified T-lymphocyte) expressing mbIL-21 and OX40L (see e.g. para. 9, 119-122, 127, 137, 182, and fig. 1). Additionally, the prior art of Kweon discloses that feeder cells with IL-21 had a synergistic effect with OX40 signaling for NK cell expansion (see e.g. abstract).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified a feeder cell expressing membrane bound interleukin-18 (mbIL-18), membrane bound interleukin-21 (mbIL-21), as taught by Kamiya, and incorporate OX40L, as taught by Min and Kweon, to produce and OX40 ligand (OX40L) with a reasonable expectation of success because one of ordinary skill in the art would have wanted a method for culturing natural killer cells that enables effective proliferation and production of natural killer cells from a smaller amount of source cells (as taught by Min, see e.g. abstract). Further, Kweon discloses that feeder cells with IL-21 had a synergistic effect with OX40 signaling for NK cell expansion (see e.g. abstract). Additionally, both Kamiya and Min discloses genetically manipulated feeder cells that provides robust expansion of NK cells (see e.g. abstracts, respectively). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Although Kamiya and Min do not explicitly disclose a feeder cell expressing membrane bound interleukin-18 (mbIL-18), membrane bound interleukin-21 (mbIL-21), and OX40 ligand (OX40L). However, the prior art of Erokhina discloses that feeder cells with various stimulation conditions with mbIL-18 and mbIL-21 combinations were known to aid in obtaining therapeutically significant amounts of natural killer cells in vitro (see e.g. page 333). Further, Erokhina discloses that the presence of activated natural killer cells and OX40-OX40L interactions are important for adequate co-stimulation of T-cells (see e.g. page 330).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined a feeder cell expressing membrane bound interleukin-18 (mbIL-18), membrane bound interleukin-21 (mbIL-21), as taught by Kamiya and Erokhina, with OX40 ligand (OX40L), as taught by Min, Kweon, and Erokhina, with a reasonable expectation of success because one of ordinary skill in the art would have known that OX40L is necessary for NK cell expansion and that IL-21 has synergistic effect with OX40 signaling for NK cell expansion (as taught by Kweon, see e.g. page 1) would have provided adequate expansion and stimulation of the cell population. As discussed above, the prior art of Erokhina discloses that feeder cells with various stimulation conditions with mbIL-18 and mbIL-21 combinations were known to aid in obtaining therapeutically significant amounts of natural killer cells in vitro (see e.g. page 333). Further, Erokhina discloses that natural killer cells with additional co-stimulatory molecules and/or targeting molecules (i.e. OX40L) suggest adequate targeting of adoptively transferred NK cells to T-cell compartments of the lymph nodes or the intratumor tertiary lymphoid structures (see e.g. page 334). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 2, Kamiya discloses wherein the feeder cell is selected from the group consisting of K562, EBV transformed B cell line (i.e. EBV-LCL), 721.221, HFWT (see e.g. para. 8, 21, 42, and 61; page 14, claim 6).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that neither the prior art of Kamiya nor Wald suggest a feeder cell engineered to express OX40L (Remarks, page 4-5).
Applicant’s arguments with respect to the previous rejection as being obvious over Kamiya and Wald have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn.
However, upon further consideration, a new grounds of rejection is made in view of Kamiya, et al., (WO2018/182511, published 2018, hereinafter as “Kamiya”, cited IDS 2/01/2024, prior art of record) in view of Min et al., (US2020/0108096 A1, published April 9, 2020, hereinafter as “Min”), due to the amendment to the claims.
Applicant asserts that independent claim 1 is now amended to recite "a feeder cell for culturing NK cells, genetically engineered to express membrane bound interleukin-18 (mbIL-18), membrane bound interleukin-21 (mbIL-21), and OX40 ligand (OX40L), and the prior art of Kweon does not disclose the use of mbIL-21 expressed on a feeder cell (Remarks, page 5).
Applicant’s arguments with respect to the previous rejection as being obvious over Kamiya and Wald, and previously cited art Kweon, have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn.
However, upon further consideration, a new grounds of rejection is made in view of Kamiya, Takahiro and Campana, Darlo, (WO2018/182511, published 2018, hereinafter as “Kamiya”, cited IDS 2/01/2024, prior art of record), Min et al., (US2020/0108096 A1, published April 9, 2020, hereinafter as “Min”), Kweon, SoonHo, et al. (Frontiers in immunology 10: 879, published 2019, hereinafter as “Kweon”), and Erokhina, Sofya A., et al. (Journal of Leukocyte Biology 109.2 (2020): 327-337, published May 2020, hereinafter as “Erokhina”)due to the amendment to the claims.
Applicant argues unexpected synergistic effect of mbIL-18 and mbIL-21 and OX40L (see Example 1)(Remarks page 5-6).
Applicant’s arguments have been acknowledged, considered and deemed unpersuasive. It is noted that the results demonstrate that combination enables production of NK cells with high purity and increase NK fold expansion (remarks, page 6).
However, it is noted that MPEP 716.02(a) discloses “A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism”). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). In the instant case, it is noted that the combination of IL-18, IL-21, and OX40L enables production of NK cells in remarkably large quantities with remarkably high purity (page 6, fig. 3). However, Applicants have not shown how the NK expansion fold results are synergistic rather than just being additive (i.e. the K562-OX40L cells with IL-18 and the K562-OX40L cells with IL-21 reach above 1,000 expansion fold, and the combined K562-OX40L cells with IL-18 and IL-21 reaches above 2,000 expansion fold). Furthermore, the synergistic results have not been compared to the closest prior art of Kamiya (i.e. K562 cells with IL-18 and IL-21) and Min (i.e. K562 cells with IL-21 and OX40L). Therefore, applicants’ arguments are considered but deemed unpersuasive.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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