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 .
Priority
The instant application, filed 09/14/2021 is a 371 filing of PCT/KR2020/003523, filed 03/13/2020. This application claims priority to Republic of Korea Application No. KR10-2019-0030022, filed 03/15/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of Application, Amendments, and/or Claims
The amendment, filed on 09/17/2025, in which claims 1 and 16 are amended and claims 2-9 and 13-15 are cancelled, is acknowledged. Claims 1, 10-12, and 16-17 are currently pending and examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 07/21/2025,
Claim 16 was rejected under 35 U.S.C 112(a) for reciting “preventing” a cancer without enablement. Applicant’s amendment to the claim to remove this limitation has rendered the rejection moot and the rejection is withdrawn.
Claims 1, 10-12, and 16 were rejected under 35 U.S.C. 103 as being unpatentable over Campana, Schomer, Liu, Zha, and Shah. Applicant’s amendment to the claim to remove linker comprising SEQ ID NO:10 has overcome the rejection and the rejections (as previously stated) are withdrawn. However, upon further consideration, new grounds of rejection are made in view of newly found prior art, necessitated by applicant’s amendment.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 10-12, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,428,305 B2 (herein Campana), Schomer (Blood. 2018; 132 (Supplement 1): 4547), US 11,421,010 B2 (herein Li), and Zha (PNAS. 2017;114(33):E6867-E6874).
Campana teaches immune NK cells (practical examples using NK-92 cells; Figure 11) genetically engineered to express a membrane bound IL-15 (mbIL-15), wherein IL-15 is fused to a transmembrane domain (TMD) protein, examples of which include receptors, ligands, immunoglobins, glycophorins or a combination thereof (column 7, lines 40-42), to promote NK cell survival, regulate NK and T cell activation and proliferation, and/or support NK cell development (claim 1, FIG1A). Campana further teaches that NK cell survival and proliferation in vivo requires stimulation by cytokines such as IL-2 and IL-15, and clinical protocols using NK cell infusions typically rely on exogenous IL-2 to prolong NK survival in patients (column 1, lines 23-29). However, IL-2 administration can have considerable side effects at high doses and at lower dose can result in stimulation of immunosuppressive regulatory T cells (column 1, lines 31-36). Campana teaches that membrane-bound IL-15 (mbIL-15) promotes the survival and expansion of primary NK cells and NK-92 cells in the absences of exogenous cytokine (IL-2) supplementation (Figure 2C; Figure 11C; claims 1 and 2). Therefore, NK cells expressing membrane bound interleukins offers a means for effective NK cell therapy without the potential adverse effects of exogenous cytokine administration (abstract).
Campana does not teach additional expression of homing receptors nor the specific membrane bound cytokine embodiment as recited in the instant claim: wherein the TMD is derived from RTK receptors EGFR, IR, or VEGFR; the cytokine is IL-2; and the peptide linker is any one of the listed sequences (SEQ ID NOs: 1-9 or 11).
Schomer teaches an inability to reach tumor cells, either by lack of homing or by the accumulation of ECM surrounding a tumor, can be responsible for failure of CAR based immunotherapies (Background). Schomer teaches that engineering CAR-NK-92 cells that additionally express CCR7 receptor improves homing towards lymph node chemokines both in vitro and in vivo (Figure 1), suggesting expressing additional homing receptors (e.g. CCR7) in CAR engineered NK cells can increased efficiency for targeted migration to lymphoid tissue including lymphoma tumor types (Abstract).
Li teaches membrane anchored IL-12 wherein a linker separates the cytokine from the transmembrane domain (claim 16). Li teaches a transmembrane domain comprising SEQ ID NO:3 (claim 19) which shares 100% identity to EGFR TMD (as evidenced by Uniprot_P00533; see alignment below). Li further teaches the TMD may comprise other transmembrane domain sequences known in the art (i.e. other receptor tyrosine kinases such as PDGFR), and a variety of linkers can be used including random strings of one or more amino acids or specific known linkers including G4S linkers (i.e. instant SEQ ID NO:1)
Li SEQ ID NO:3 (Query) aligned with human EGFR Uniprot-P00533 (Sbjct):
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Zha teaches a lentivirus library of cytokines, including IL-2, fused to TMD of platelet-derived growth factor receptor (RTK) via an undisclosed flexible linker (mbIL-2) is sufficient for autocrine signaling in dental pulp stem cells (DPSCs) (Figure 1A; Figure 1C).
One of ordinary skill would recognize that engineering immune cells with membrane bound cytokines can be utilized to enable survival through autocrine signaling and avoid off-target effects from exogenous cytokine administration as taught by Campana. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that an mbIL-15 expressed by an NK-92 cell as taught by Campana could substituted for a mbIL-2 with a reasonable expectation of success to predictably induce NK cell self-stimulation as Zha teaches that mbIL-2 is capable of persistent stimulation and Campana teaches both IL-2 and IL-15 positively regulate NK cell function. As IL-2 administration was still widely used in the clinic at the time of filing to prolong NK survival as taught by Campana, a skilled artisan would be motivated to perform this substitution to test whether this mitigates off-target effects of the standard treatment (i.e. known product ready for improvement). Moreover, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that membrane tethering can be accomplished by combining known fusion methods - i.e. fusing IL-2 to known transmembrane domains (i.e. derived from RTKs as taught by Campana - e.g. EGFR TMD as taught by Li) via any known flexible linker sufficient for self-signaling (e.g. G4S as taught by Li - identical to SEQ ID NO:1). Furthermore, a skilled artisan would also be motivated to include homing receptors (e.g. CCR7) into said engineered immune cells as Schomer teaches co-expression with homing receptors could improve migration to target tumor microenvironments (i.e. cancer treatment).
Response to Arguments - 35 U.S.C § 103
Applicant's arguments filed 09/17/2025 have been fully considered but they are not persuasive.
Applicant states:
“Applicants have amended claim 1 to remove SEQ ID NO: 10 from the list of peptide linkers. None of the remaining claimed linkers (SEQ ID NOs: 1-9, 11) are taught or suggested in Liu, Zha, or Campana… An obviousness rejection cannot rest on broad generalizations about "flexible linkers" when the claims recite expressly defined sequences absent from the art.” (Remarks, pg. 6, ¶ 3)
Applicant’s argument regarding specific species of linkers is not persuasive because the scope of claim 1 has been amended to exclude previous embodiments referenced in the prior art of record. As Applicant has altered the scope of the claims, new grounds of rejection are made in view of newly found prior art references that teaches specific GS-linker as recited in the instant claim are known in the art.
Applicant states:
“IL-2 and IL-15 differ significantly in receptor usage, glycosylation, and biological behavior. Campana discloses constructs involving mbIL-15, not IL-2. The assumption that mbIL-2 tethered via RTK transmembrane domains in NK-92 cells would function in the same way as mbIL-15 is speculative and unsupported by the cited references. Obviousness requires a reasonable expectation of success, not speculation. None of the references provides data or teaching suggesting that mbIL-2 constructs in NK-92 cells would yield the persistence and therapeutic benefit described in the present application.” (Remarks, pg. 6-7, pg. spanning ¶)
In response to applicant’s argument regarding difference between IL-2 and IL-15 signaling, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference (i.e. that IL-2 and IL-15 need to be functionally identical); nor is it that the claimed invention must be expressly suggested in any one or all of the references (i.e. Campana need not teach a mbIL-2). Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Moreover, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Campana teaches that both IL-2 and IL-15 are important for positive regulation of NK cells and Zha teaches that mbIL-2 is capable of autocrine signaling. Therefore a skilled artisan would recognize that substituting and mbIL-15 within NK cells for a mbIL-2 as taught by Campana would feasibly also facilitate positive autocrine stimulation in NK cells.
Applicant states:
“The Examiner also contends that substitution among RTK transmembrane domains
would have been routine. However, Liu specifically discloses PDGFR, while the present claims require EGFR, insulin receptor, or VEGFR transmembrane domains. These domains are not structurally interchangeable; each has distinct sequences, membrane integration properties, and roles in signaling. Shah may disclose truncated HER1 (EGFR) fragments in unrelated fusion contexts, but there is no teaching or suggestion that EGFR, insulin receptor, or VEGFR domains could be predictably substituted for PDGFR in cytokine-tethering constructs. Such a conclusion can only be reached through hindsight reconstruction of Applicants' disclosure, which is impermissible under established case law.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding applicants argument that the recited EGFR, insulin receptor, or VEGFR transmembrane domains are not structurally interchangeable because of different integration properties and roles in signaling, as noted in the previous office action filed 7/21/2025, these features are not recited in the rejected claims. By broadest reasonable interpretation of the claims, the transmembrane domain as recited in the instant claim is only necessary for its ability to span the cell membrane to facilitate cell surface expression, and not necessarily for based on potential signaling properties. Therefore, so long as the domain is capable of inserting the cytokine-fusion protein within the cell membrane, (e.g. fusions created with relevant TMD domains are present at the cell surface) then a skilled artisan would have a reasonable expectation of success substituting similar transmembrane domains (i.e. RTK transmembrane domains as recited in the instant claim). However, not conceding to this point, the new grounds of rejection, necessitated by applicant’s amendment, teaches an embodiment showing specific cytokine-tethering using an EGFR TMD.
Applicant states:
“While Schomer teaches CCR7 in the context of CAR-NK-92 cells, the cited art does not suggest combining homing receptor expression with RTK-tethered IL-2 in NK-92 cells. The Examiner's rejection therefore depends on piecing together disparate elements from multiple unrelated references, without an articulated reasoning that would have motivated such a combination.” (Remarks, pg. 7, last ¶)
In response to applicant's argument regarding piecing together disparate elements from unrelated references. As discussed above, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As discussed in the rejection above, Schomer teaches that co-transfection of homing receptors in already engineered CAR NK cells improves migration to tumor sites therefore a skilled artisan would be motivated to include homing receptors in addition to any other transfected fusion proteins (i.e. CARs as taught by Schomer; or a tethered cytokine as suggested by the combined teachings of Campana, Li, and Zha).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable Campana, Schomer, Li, and Zha as applied to claim 1 above, and further in view of Zanoni (Cell Rep. 2013;4(6):1235-1249).
The combined teachings of Campana, Schomer, Zha, and Li teach claim 1 (engineered immune cell comprising recited mbIL-2) as discussed above.
None of these references mentions the administration of the recited engineered immune cells as a method for treating an infectious disease.
Zanoni teaches NK cells have anti-tumor, antiviral, and antibacterial functions (abstract). NK cell release of IFNγ is critical in the immune response to a variety of infections by activating macrophages and favoring Th1 lineage commitment in CD4+ T cells (pg. 1235, right column, ¶ 1; pg. 1236, left column, ¶ 2). Zanoni teaches dendritic cell (DC)-derived IL-2, in combination with IL-18 and IFN-β, are necessary for NK-IFNγ production (i.e. NK cell activation) in vivo upon LPS stimulation (Figure 4). Furthermore, Zanoni teaches cis presentation of IL-15 (i.e. membrane bound interleukin) in NK cells is equally optimal to trans-presented DC-derived IL-15 NK cell activation (abstract), suggesting that autocrine based interleukin signaling could replicate signals necessary for the potentiation of NK dependent immune response.
One of ordinary skill in the art would appreciate that genetically engineering NK cells to express membrane bound cytokines would facilitate self-activation or at a minimum prime the cells via lowering the threshold of activation (i.e. providing the cells already with one positive regulator). Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that an NK cell expressing mbIL-2 and a homing receptor CCR7 which improves migration to lymphoid tissues as taught by the combined teaching of Campana, Schomer, Zha, and Li can be administered for treatment of infectious with a reasonable expectation of success because Zanoni teaches NK cells activated by IL-2 (in addition to other cytokines) are important for potentiating adaptive immunity through release of IFNγ to drive Th1 polarization in secondary lymphoid organs.
Response to Arguments - 35 USC § 103 (continued)
Applicant's arguments filed 09/17/2025 did not specifically address the rejection of claim 17 in view of the combined teachings of previously cited reference. However, applicant’s amendment to the base claim has necessitated new grounds of rejection which is reflected in the rejection discussed above and a new interpretation of the previously applied reference is provided. Should applicant wish to contest current rejection, applicant should submit an argument under the heading “Remarks” pointing out disagreements with the examiner’s contentions. Applicant must also discuss the references applied against the claims, explaining how the claims avoid the references or distinguish from them.
Conclusion
No claims are allowed.
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 HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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