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
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 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.
Response to Amendments
Applicant’s amendments, corrected specification, and response filed Mar. 3, 2026 have been received and entered into the case.
Status of the Claims
Claims 1, 9, 13-16, 18-20 and 22-29 are currently pending.
Claims 1, 9, 13-16, 18-20 and 22-25 are amended.
Claims 26-29 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2-8, 10-12, 17, 21 and 30 are cancelled.
Claims 1, 9, 13-16, 18-20 and 22-25 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Objections
The claim objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(a)
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn a statement by an attorney of record over their signature and registration number stating that the NK-92® cell line has been deposited under the Budapest Treaty and that the cell line will be irrevocably and without restriction or condition released to the public upon the issuance of a patent has been submitted.
Claim Rejections - 35 USC § 112(b)
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are maintained, since claim 15 still contains a trademarked product.
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.
Claim 15 is 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.
Claim 15 contains the trademark/trade name NK-92®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a cell line and, accordingly, the identification/description is indefinite. In the present case, the trademark/trade name is used to identify/describe types of NK cells that lack the major inhibitory receptors that are displayed by normal NK cells, while retaining the majority of the activating receptors and, accordingly, the identification/description is indefinite (see published Specification 0051-0052).
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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, 13-16, 18-20, 24 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Engels (US 2017/0260268 A1) (ref. of record) in view of Lee (WO 2016/201304 A1) (ref. of record).
With respect to claim 1, Engels teaches a genetically modified natural killer (NK) cell. Specifically, Engels teaches a NK cell containing the NKR-CAR or a vector encoding it (0043-0045). With respect to claims 1 and 13 (i), Engels teaches an NK cell comprising a chimeric antigen receptor (CAR), wherein the CAR contains: an extracellular antigen binding domain, a hinge domain, a transmembrane domain, and a signaling domain (0004, 0007-0008, 0017 and 0175). Further with respect to claims 1 and 13 (i), Engels also teaches nucleic acids encoding the above CAR (0036). Engels teaches that the above construct may be encoded by a single nucleic molecule in the same frame and as a single polypeptide chain (0579). Engels further teaches that the CAR may include a functional signaling domain of FcɛRIγ (0037). Additionally, with respect to claims 1 and 13 (i), Engels further teaches the cells engineered to express a BCMACAR, an antiBCMA binding domain (0436 and 0767). With respect to claims 1 and 13 (ii), Engels teaches the cell expressing a recombinant CD16 (0005 and 0022). With respect to claims 1 and 13 (iv) and claims 24 and 25, Engels teaches a NK cell modified to express a CAR and a chemokine receptor molecule where the chemokine receptor is a CXC chemokine receptor such as CXCRl, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, or CXCR7; a CC chemokine receptor such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRl0, or CCRl 1; a CX3C chemokine receptor such as CX3CR1; or a XC chemokine receptor (e.g., XCRl) (0557).
Engels does not teach the NK cells expressing an autocrine growth stimulating cytokine as recited in claims 1 and 13 (iii). Similarly, Engels does not teach the NK cells expressing an autocrine growth stimulating cytokine which is IL-2 or IL-15 as recited in claim 19, or where the autocrine IL-2 or IL-15 contain an endoplasmic retention sequence as recited in claim 20.
However, Lee teaches genetically modified NK-92® cells expressing a CAR which are further modified to express IL-2 (0012, 0033 and 0085-0086). Lee teaches the cytotoxicity of NK cells is dependent on the presences of cytokines such as IL-2 (0084). Lee teaches by genetically modifying the NK-92® cells (would be understood to be by a recombinant nucleic acid) to express IL-2, costs of culturing the cells are reduced since there is no need of adding exogenously IL-2 to the culture medium of the NK-92® cells and when the NK-92® cells are administered to human subjects, IL-2 administration, which can cause adverse side effects, to activate the cells is not necessary (0084). Lee teaches the cytokine is targeted to the endoplasmic reticulum by a signal sequence (0012 and 0085-0086). Lee further teaches that the cytotoxicity of NK-92® cells is dependent on the presence of cytokines and the expression of IL-2 at the endoplasmic reticulum permits expression of IL-2 at levels sufficient for autocrine activation, but without releasing IL-2 extracellularly (0085-0086).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the genetically modified NK cell of Engels to include a recombinant nucleic acid encoding IL-2 and which contains an endoplasmic retention sequence for the benefit of maintaining activation of the NK cells in culture and when administered without the use of exogenous IL-2 or the administration of IL-2 to a subject and without releasing IL-2 extracellularly as taught by Lee. It would have been obvious to one of ordinary skill in the art to modify the genetically modified NK cell of Engels to include a recombinant nucleic acid encoding IL-2 with an endoplasmic retention sequence, since similar genetically modified NK cells which target tumors were known to include a recombinant nucleic acid encoding IL-2 with an endoplasmic retention sequence for maintaining the cytotoxicity of the cells and to prevent release of IL-2 from the cells as taught by Lee. One of ordinary skill in the art would have a reasonable expectation of success in making such a modification to the genetically modified NK cell of Engels, since both Engels and Lee are directed to genetically modified NK cell expressing CARs for targeting cancer.
With respect to claim 14, Engels further teaches that nucleic acids encoding the above CAR may be RNA (0036) and that the RNA-CAR may be transfected into the cell (0591). Engels also teaches that the nucleic acids and vectors encoding the above CAR may by bicistronic (0544). Under the broadest reasonable interpretation of the claim term “polycistronic”, a bicistronic nucleic acid, which results in the production of two proteins by cleavage of a single translation product or by the translation of two separate protein products, satisfied this limitation of claim 14.
With respect to claim 15, Engels teaches the NK cells are NK-92® (0065).
With respect to claim 16, Engels teaches antigen binding domain may be an scFv and expressed on the cell surface (0054 and 0067).
Engels does not teach the cell expressing recombinant CD16 that is a CD16158V mutant as recited in claim 18.
However, Lee teaches genetically modified natural killer (NK) cells, NK-92®, containing a recombinant expression vector containing a chimeric antigen receptor (CAR) for treating a disease such as cancer (abstract and 0006). Lee teaches the CAR encoding polypeptide target s tumor-associated antigen (0011). Lee teaches NK-92® cells modified to express a CAR and a high-affinity CD16 on the cell surface (0011 and 0065). Lee teaches the recombinant CD16 is a CD16158V mutant which is a higher affinity mutant (0011 and 0065). Lee teaches CD16, a Fc receptor, stimulates the phagocytic or cytotoxic activity of the cell by antibody mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity (0038). Lee further teaches that NK cells expressing a CAR and an Fe receptor such as CD16 may be more selective for cancer cells than non-cancerous cells (e.g. para 0114).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the genetically modified NK cell of Engels to include a recombinant CD16 which is CD16158V for the benefit of stimulating the phagocytic or cytotoxic activity of the NK cell and for having NK cells more selective for cancer cells as taught by Lee. It would have been obvious to one of ordinary skill in the art to modify the genetically modified NK cell of Engels to include a recombinant CD16 which is CD16158V, since similar genetically modified NK cells which target tumors were known to include recombinant CD16 and, in particular, CD16158V as taught by Lee. One of ordinary skill in the art would have a reasonable expectation of success in making such a modification to the genetically modified NK cell of Engels, since both Engels and Lee are directed to genetically modified NK cell expressing CARs for targeting cancer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1, 9, 13, 22 and 23 are rejected under 35 U.S.C. 103(a) as being unpatentable over Engels in view of Lee (as applied to claims 1, 13-16, 18-20, 24 and 25 above), and further in view of Sabzevari et al. (WO 2020/014285 A1, published Jan. 16, 2020, priority to Jul. 9, 2019) (ref. of record).
The teachings of Engels and Lee can be found in the previous rejection above.
Neither Engels or Lee teach the genetically modified NK cells where cells further include a TGF-beta trap or a recombinant nucleic acid encoding TGF-beta trap as recited in claims 1 and 13 (iv), respectively. Likewise, neither Engels or Lee teach the TGF-beta trap contains a single chain dimer of the TGF-beta Receptor II ectodomain as recited claims 9 and 22. Additionally, neither Engels or Lee teach the TGF-beta Receptor II ectodomain is a secreted form as recited in claim 23.
However, Sabzevari teaches engineered CAR-T cells and a TGF-beta trap for treating cancer (0002, 0004, 0025-0026, and 0150). Sabzevari further teaches the TGF-beta trap is a single chain dimer of the TGF-beta receptor II extracellular domain (ectodomain) (0006, 0150-0152 and Fig. 4). Sabzevari teaches TGFβRII is a dimeric receptor (0143 and 0148). Sabzevari teaches that the TGFβRII can bind to TGF-β1, -β2 or -β3 and elicit a synergistic anti-tumor effect due to the neutralization of the TGF-β in the tumor microenvironment and teaches by inhibiting TGFβ signaling pathway can be a key therapeutic strategy in treating cancer (0142-0155). Sabzevari teaches the TGFβRII being fused to a PD-antibody which would be understood to be secreted (0156).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the genetically modified NK cell of Engels and Lee so that the cells further include a TGF-beta trap or a recombinant nucleic acid encoding a TGF-beta trap and TGF-beta trap contains a single chain dimer of the TGF-beta Receptor II ectodomain and is secreted for benefit of further treating cancer cells and its anti-tumor effect as taught by Sabzevari. It would have been obvious to one of ordinary skill in the art to modify the genetically modified NK cell of Engels and Lee so that the cells further include a TGF-beta trap or a recombinant nucleic acid encoding a TGF-beta trap and TGF-beta trap contains a single chain dimer of the TGF-beta Receptor II ectodomain and is secreted, since Sabzevari teaches such TGF-beta traps for treating cancer. Additionally, one of ordinary skill in the art would have a reasonable expectation of success in making such a modification to the genetically modified NK cell of Engels and Lee, since both Engels and Lee teach including additional components in the genetically modified NK cell expressing CARs for targeting cancer and Sabzevari teaches the effectiveness of TGF-beta traps for treating cancer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is withdrawn due amendment.
Response to Arguments
Applicant's arguments filed Mar. 3, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that neither Batchu nor Lee teach a CAR containing a FcϵRIγ signaling domain, but instead teach a CD3ζ signaling domain (Remarks pg. 6 para. 4). The Applicant’s amendments limiting claims 1 and 3 so that the signaling domain is a FcϵRIγ signaling domain necessitated the withdrawal of the previous rejections. Applicant’s arguments are drawn to Batchu and Lee failing to teach this new limitation. However, this new limitation is addressed in the new rejection and is taught by Engels.
Applicant argues that at the time of filing it was the view in the art that CD3ζ based CARs were superior to FcϵRIγ based CARs as explained in the specification in 009 and 031 (Remarks pg. 6 para. 5). However, this argument was not found to be persuasive, since Engels teaches a CAR containing a FcϵRIγ signaling domain (0037). Furthermore, a preferred embodiment does not constitute a teaching way from a nonpreferred embodiment (MPEP 2123).
Applicant argues that they unexpectedly found that NK-92 cells expressing a first generation CAR containing a FcϵRIγ signaling domain with a single ITAM (immunoreceptor tyrosine-based activation domains) had equal or greater cytotoxic activity compared to that NK-92 cells expressing a CD3ζ based CARs with three ITAMS and when the CD3ζ is combined with additional signaling domains. In addition, Applicant argues that there is enhanced surface expression of FcϵRIγ containing CARs in NK-92 cells (Remarks pg. 6-7 bridging para.). However, these arguments were not found to be persuasive, since the Applicant did not provide any data to support these assertions. MPEP 716.01 (c) I states: Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results. Since the Applicant provided no experimental data to support these results, the Applicant's assertions of unexpected results are considered argument. M.P.E.P 2145 is clear that "A showing of unexpected results must be based on evidence, not argument or speculation". Furthermore, Engels teaches NK-cells expressing a CAR containing a FcϵRIγ signaling domain.
Applicant argues that there is nothing in Batchu or Lee to motivate the skilled artisan to select FcϵRIγ over CD3ζ (Remarks pg. 7 para. 2). However, this argument was not found to be persuasive, since Engels is now being relied upon for the teaching of a CAR containing a FcϵRIγ signaling domain (0037) and not Batchu or Lee.
Applicant argues that none of Lieschke, Sabzevari or Engels teach a NK cell expressing CAR containing a FcϵRIγ signaling domain. However, this argument was not found to be persuasive, since Engels teaches a NK cell containing CAR containing a FcϵRIγ signaling domain (0037) as explained in the current rejection.
Additionally, Applicant argues that Sabzevari is directed to CAR-T cells and TGF-beta traps in T cells, and teachings directed to T cells cannot be extrapolated to NK cells with a reasonable expectation of success since they are two different cells types. However, this argument was not found to be persuasive, since Engels teaches engineering both T cells and NK cells or immune effector cells with the same constructs (0043-0045). Accordingly, one of ordinary skill in the art would have a reasonable expectation of success for T cells and NK cells when expressing TGF-beta traps in the cells.
Applicant further argues that although Engels teaches NK cells modified to express a CAR and a chemokine the engineered cells that are actually described are T cells in 0557 (Remarks pg. 7 para. 3-5). However, this argument was not found to be persuasive since the engineered cells referred to in 0557 appear to be an immune effector cell including T cells or NK cells (0043-0045). Additionally in 0057, there is a statement describing a study by Craddock et al. where they found enhanced trafficking to CCL2 or CXCR2-secreting tumors of transgenic expression of chemokine receptors CCR2b or CXCR2 in T cells which the Applicant might be referring to.
Applicant argues that the claimed genetically modified NK cells provide three distinct cytotoxic mechanisms, a natural NK mediated cytotoxicity, ADCC via CD16 and CAR mediated cytotoxicity (Remarks pg. 7-8 bridging para.). Applicant argues that the therapeutic efficacy of the cells is further enhanced by the expression of a TGF-beta trap or homing receptor and explained and illustrated in para. 066 and 088 of the specification (Remarks pg. 8 para. 2). In response to applicant's arguments that claimed genetically modified NK cells provide three distinct cytotoxic mechanisms and that the therapeutic efficacy of the cells is further enhanced by the expression of a TGF-beta trap or homing receptor, the fact that the inventor has recognized additional advantages which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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