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.
Claim Status
The Amendment, filed on 02/23/2026, is acknowledged in which:
Claims 2-9 and 13-15 are canceled.
Claim 1 is currently amended.
Claims 11 and 16-17 were previously presented.
Claims 10 and 12 are original.
Claims 1, 10-12, and 16-17 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 07/21/2025,
Claims 1, 10-12, and 16 were rejected under 35 U.S.C. 103 as being unpatentable over Campana, Schomer, Liu, Li and Zha; and claim 17 as being unpatentable over Campana, Schomer, Liu, Li and Zha in view of Zanoni. Applicant’s amendment to the claims to exclude previous embodiments has overcome the rejections, and the rejections (as previously stated) are withdrawn.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. Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
New Claim Rejections - 35 USC § 112(b)
Claim 1 and 10 are 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.
Regarding claim 1, as currently written, “a homing receptor” is classified as an immune cell. For examination purposes based on the instant specification, examiner has instead interpreted this limitation to mean the immune cells are NK-92 cells modified to express said homing receptor. Moreover, the claim recites insulin receptor or a vascular endothelial growth factor receptor (VEGFR) as the transmembrane domain (TMD). This renders the limitation of a transmembrane domain as ambiguous because the recited receptors also comprise extracellular and intracellular domains. For examination purposes, examiner has instead interpreted this limitation to mean the RTK from which the TMD is derived is either an insulin receptor or a VEGFR. To overcome this rejection, examiner recommends amending the claim to recite:
“(unchanged text)…wherein the immune cells are NK-92 cells comprising a homing receptor selected from CXCR4 or VEGFR2,
…(unchanged text)…
wherein the transmembrane domain is a transmembrane domain of a receptor tyrosine kinase[[s]] (RTK[[s]]) selected from an insulin receptor or a vascular endothelial growth factor receptor (VEGFR),
… (unchanged text)…
Regarding claim 10, the instant claim recites “the immune cells of claim 1” wherein these cells are transformed with a vector comprising a polynucleotide encoding a fusion protein with features identical to the base claim. As written, its unclear if the fusion protein is in reference to the fusion of the base claim or if it is an independent fusion protein (i.e. cells already comprising a fusion protein as disclosed in claim 1 are additionally transformed with a second fusion protein). As the metes and bounds of the claim are ambiguous, the claim is rendered indefinite. To overcome this rejection, examiner recommends amending the claim to clarify the relationship of all overlapping subject matter to its base claim 1.
Modified Claim Rejections - 35 USC § 103
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), WO 2016/109668 A1 (herein Kang), US 11,421,010 B2 (herein Li; priority to provisional application No. 62/405,796 filed 10/07/2016), US 8,568,713 B2 (herein Frost), 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 IR, or VEGFR; the cytokine is IL-2; and the peptide linker is an amino acid sequence as disclosed in SEQ ID NOs: 6 or 7.
Kang teaches NK cells with genetic modifications comprising homing receptors for target specificity in the treatment of diseases including hematological disorder, solid tumor, or an infectious disease (¶ [0007]). Kang further teaches circulatory chemotactic homing receptors (¶ [00334]): CXCR4, specific for bone marrow (¶ [00335]), and VEGFR2, specific for the vascular endothelium (¶ [00337]).
Li teaches membrane anchored IL-12 wherein a linker separates the cytokine from the transmembrane domain (claim 16). Li teaches a transmembrane domain an EGFR TMD (claim 19) and GS linker (claim 20). Li further teaches the TMD may comprise other transmembrane domain sequences known in the art including other receptor tyrosine kinases such as (i.e. not limited to) insulin like growth factor 1 receptor (IGFR) and platelet-derived growth factor receptor (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 (column 18, ¶ 3-4).
Frost teaches linkers identical to instant SEQ ID NOs: 6 and 7 (SEQ ID NOs: 166 and 167, respectively) in a list of suitable species of flexible peptide linkers, including G4S linkers, for fusion proteins (column 62, ¶ 3).
Zha teaches a lentivirus library of cytokines, including IL-2, fused to TMD of platelet-derived growth factor receptor (PDGFR) 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, Li, and Zha) via any known flexible linker sufficient for protein fusion (e.g. linkers as taught by Frost - identical to instant SEQ ID NOs:6 and 7) (See MPEP 2144.07 – art recognized suitability for an intended purpose). Furthermore, a skilled artisan would also be motivated to include homing receptors (e.g. CXCR4 or VEGFR2) into said engineered immune cells as Kang teaches co-expression with homing receptors improves migration to target tumor microenvironments (e.g. hematological diseases sites such as bone marrow and vasculature (blood and lymphatic)).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable Campana, Kang, Li, Frost, 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, Kang, Li, Frost, and Zha teach claim 1 (engineered immune cell comprising a homing receptor and an 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 which improves migration to lymphoid tissues as taught by the combined teaching of Campana, Kang, Li, Frost, and Zha 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 U.S.C § 103
Applicant's arguments filed 02/23/2026 have been fully considered but they are not persuasive.
Applicant states:
“Claim 1 has been amended to narrowly recite genetically engineered NK-92 cells expressing membrane-bound IL-2, wherein the cytokine is tethered via a praline-rich linker selected from SEQ ID NOs: 6 or 7 and anchored by a transmembrane domain derived from an insulin receptor or a vascular endothelial growth factor receptor (VEGFR), and further comprising a homing receptor selected from CXCR4 or VEGFR2. These limitations define a specific structural configuration that is not disclosed or suggested by the cited references, either individually or in combination.” (Remarks, pg 5, last ¶)
“The Examiner's prior rationale was premised on the availability of known fusion methods, GS-based linkers, EGFR-derived transmembrane domains, and CCR7 homing receptors. Each of these features has been expressly excluded by amendment. The Office Action
does not articulate, and the prior art does not provide, a motivation or reasonable expectation of success for arriving at the amended claims' particular arrangement of elements. Accordingly, the prior combination rationale no longer applies.” (Remarks, pg. 6, last ¶)
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 as discussed above. Briefly, Kang teaches instant homing receptors (CXCR4 or VEGFR2) and Frost teaches proline rich linkers as recited in the instant claims (SEQ ID NOs: 166 and 167, identical to instant SEQ ID NOs: 6 and 7, respectively) are known in the art. Moreover, regarding the TMD, while Li explicitly teaches an embodiment using EGFR TMD, Li also teaches the TMD may comprise other transmembrane domain sequences known in the art including other receptor tyrosine kinases. The office maintains that the selection of a known material based on its suitability for its intended use supports a prima facie obvious determination (See MPEP 2144.07).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). However, it is just one of a number of valid rationales for doing so (see MPEP 2141(III)). In this case, it would be obvious to one of ordinary skill simply substituting elements as taught by Campana, Li, and Zha and newly added references Zang and Frost cited above to arrive at the instantly claimed genetically engineered immune cells would have a reasonable expectation of success, as prior art teaches these elements as known elements suitable alternatives for the intended purposes claimed (i.e. flexible linkers for fusion proteins and homing receptors) (See MPEP 2144.07); and this knowledge would be within the level of ordinary skill at the time the claimed invention was made (See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971)).
Conclusion
No claims are allowed.
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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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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