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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/29/2025 has been entered.
Applicant' s amendment and response filed on 10/29/2025 has been received and entered into the case.
Amendments
In the reply filed 10/29/2025, Applicant has amended claims 1, 10, 12 and 15.
Claim Status
Claims 1-2, 5-7, 9-10 and 12-21 are pending.
Claims 16-21 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/15/2024.
Claims 1-2, 5-7, 9-10 and 12-15 are considered on the merits.
Withdrawn Claim Objections
The prior objection to claims 1, 10, 12 and 15 because of typographic errors is withdrawn in light of Applicant’s amendment to the claims.
New Claim Objections
Claims 1, 12 and 15 are objected to because of the following informalities:
Claim 1, c), line 1, recites “IL-18the GSK3β inhibitor” that contains a typographic error. It should be replaced with “IL-18, the GSK3β inhibitor”.
Claim 12, i), line 2, recites the term “Fc-y”. It should be changed to “Fc-γ”.
Claim 15, line 2, recites “CD3-cells”. It should be changed to “CD3- cells”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of claims 1-2, 5-7, 9-10 and 12-15 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 because the limitation of “without passing through an induced pluripotent stem cells (iPSC) stage or a hematopoietic stem cells (HSC) stage” represents new matter, is withdrawn in light of Applicant’s amendment to remove the limitation “or a hematopoietic stem cells (HSC) stage”, and Applicant’s argument that the present specification expressly supports the feature of directly producing NK cells from human somatic cells without passing through induced pluripotent stem cells (see Remarks, p. 8-9).
The prior rejection of claims 1-2, 5-7, 9-10 and 12-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for a method for producing CAR-iNK cells by reprogramming PBMCs into NK cells without passing through an iPSC stage or a HSC stage by introducing reprogramming factors Oct4, Sox2, Klf4 and Myc and by culturing sequentially in defined media, is withdrawn in light of Applicant’s amendment to remove the limitation “or a hematopoietic stem cells (HSC) stage”, and Applicant’s arguments that the specification enables this subject matter, providing step-by-step procedures, concrete media compositions, timings and multiple working examples, and that “Practicing the protocol as written inherently avoids an iPSC stage”, and further “following the provided recipe yields NK cells directly, within the stated timeline, and with confirmed NK phenotype and function, commensurate with the claim scope” (Remarks, p. 9-11).
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-2, 5-7, 9-10 and 12-15 under 35 U.S.C. 103 as being unpatentable over Burton et al. in view of Roeven et al., Freud et al., Son et al., and Kaufman et al., is withdrawn in light of Applicant’s arguments that the negative limitation, of the PBMCs being directly reprogrammed into NK cells without passing through an iPSC stage, defines the route and outcome of the process that must be given patentable weight. The cited references do not teach, suggest, or motivate the iPSC-free, direct PBMC[Wingdings font/0xE0]NK conversion that is required (Remarks, p. 12-14).
New Claim Rejections - 35 USC § 112(a)
(Scope of Enablement)
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 1-2, 5-7, 9-10 and 12-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for producing CAR-iNK cells comprising: i) introducing a reprogramming factor that is a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated peripheral blood mononuclear cells (PBMCs); and, ii) from the following day after the introduction, culturing the cells of step i) sequentially in a) a first medium containing SCF, FLT3, IL-3, IL-6, and a GSK3β inhibitor; b) a second medium containing SCF, FLT3, IL-15, IL-7, IL-2 and an AHR antagonist; and c) a third medium containing IL-2, IL-15, IL-21, IL-12, IL-18, the GSK3β inhibitor, and the AHR antagonist, and thereby directly reprogramming into NK cells without passing through an induced pluripotent stem cells (iPSC) stage, does not reasonably provide enablement for a method for producing CAR-iNK cells comprising: i) introducing a reprogramming factor that is a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated peripheral blood mononuclear cells (PBMCs); and, ii) from any period of time after the introduction, culturing the cells of step i) sequentially in a) a first medium containing SCF, FLT3, IL-3, IL-6, and a GSK3β inhibitor; b) a second medium containing SCF, FLT3, IL-15, IL-7, IL-2 and an AHR antagonist; and c) a third medium containing IL-2, IL-15, IL-21, IL-12, IL-18, the GSK3β inhibitor, and the AHR antagonist, and thereby directly reprogramming into NK cells without passing through an induced pluripotent stem cells (iPSC) stage. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
Independent claim 1 encompasses a genus of method for producing CAR-iNK cells comprising: i) introducing a reprogramming factor that is a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated peripheral blood mononuclear cells (PBMCs); and, ii) from any period of time after the introduction, culturing the cells of step i) sequentially in a) a first medium containing SCF, FLT3, IL-3, IL-6, and a GSK3β inhibitor; b) a second medium containing SCF, FLT3, IL-15, IL-7, IL-2 and an AHR antagonist; and c) a third medium containing IL-2, IL-15, IL-21, IL-12, IL-18, the GSK3β inhibitor, and the AHR antagonist, and thereby directly reprogramming into NK cells without passing through an induced pluripotent stem cells (iPSC) stage.
However, the specification only discloses one single species of the method (see Example 2: “Direct Reprogramming of NK Cells from PBMC” in p. 32):
“in order to transform PBMC with the reprogramming factors (i.e., a combination of Oct4, Sox2, Klf4, and Myc recited prior), the cells were cultured in a standard culture medium (SCM medium) containing the Sendai virus (5 MOI), PBMC and polybrene (4 µg/mL) for 1 day, and then sequentially cultured in the first medium, second medium, and third medium shown below” (specification, Example 2, p. 32, last para. Emphasis added by Examiner). Thus, it is clear that the one and only example disclosed in the specification comprises a very short culture period after introduction of reprogramming factors (i.e., only 1 day) to ensure the transduced cells are not reprogrammed all the way back to iPSC stage. In other words, this short culture period (about 1 day) is crucial to the instant invention directed to “directly reprogramming into NK cells without passing through an induced pluripotent stem cells (iPSC) stage”.
Dependent claims 2, 5-7, 9-10 and 12-15 encompass the timing of CAR gene introduction, the compositions of the first medium, the second medium and the third medium, the culture duration in each of the three media, the additional reprogramming factor, the CAR, the defined source cells and the phenotype of the CAR-iNK cells. However, the specification only discloses a single species of the combinations in example 2.
Therefore, the specification fails to describe the genus of method encompassed by the claimed invention.
ACTUAL REDUCTION TO PRACTICE
The specification merely provides one single species of method for producing CAR-iNK cells by direct reprogramming without passing through an iPSC stage, but does not provide guidance for or other working examples for a method for producing CAR-iNK cells comprising i) introducing a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated PBMCs; and, ii) from any period of time after the introduction, culturing the cells of step i) sequentially in three media to directly reprogramming the cells into NK cells without passing through an iPSC stage. The absence of guidance or working examples necessitates further experimentation.
In regard to the claimed genus of method, Applicant only discloses one method comprising i) introducing a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated PBMCs; and, ii) from the following day after the introduction, culturing the cells of step i) sequentially in three media to directly reprogramming the cells into NK cells without passing through an iPSC stage.
Therefore, the specification does not provide sufficient guidance on how to make and use the claimed genus of method for directly reprogramming PBMCs into NK cells without passing through an iPSC stage.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. Although reprogramming techniques are known, one of skill in the art would neither expect nor predict the direct reprogramming into NK cells without passing through an iPSC stage according to the claimed genus of method as broadly as is claimed.
Regarding a method of reprogramming PBMCs by a set of four reprogramming factors Oct4, Sox2, Klf4, and Myc, these four reprogramming factors are well known as Yamanaka factors that can convert somatic cells into induced pluripotent stem cells as evidenced by Brown et al., (US 2016/0257939 A1) and Kim et al., (Stem Cells International. 2016, Article ID 1329459, p. 1-9). Brown evidences that PBMCs (such as T cells) are transduced with viruses expressing Oct4, Sox2, Klf4, and Myc (Example 4), transduced cells are plated onto irradiated MEFs at day 3 post initial transduction (Example 5), and are maintained from day 5 to day 30 (Example 6), during that period well-defined iPS cell colonies begin to appear on day 23 (Example 7). Thus, Brown evidences that iPS cell colonies appear on day 23 after the introduction of reprogramming factors. Nevertheless, Kim evidences that PBMCs are transduced with virus expressing Oct4, Sox2, Klf4, and Myc (see diagram in Fig 1), and “transduced PBMCs formed iPSC-like colonies 6 days after transduction. iPSC colonies with clean boundaries were obtained 18 days after infection” (p. 3, end of left col – right col, line 1). Accordingly, it is not well established in the field regarding the culture period required for the PBMCs to be reprogrammed into iPSCs after introduction of reprogramming factors, thus it is not well known how to avoid an iPSC stage. In other words, it is highly unpredictable to directly reprogram PBMCs, without passing through an iPSC stage.
Furthermore, the instant specification supports this unpredictability by disclosing that “there has been no report on a technology for directly producing CAR-NK cells without passing through iPSCs by somatic cell reprogramming” (p. 4, para 1, emphasis added).
Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in introducing a combination of Oct4, Sox2, Klf4, and Myc into isolated PBMCs, and, from any period of time after the introduction, culturing the introduced cells sequentially in three media to directly reprogramming the cells into NK cells without passing through an iPSC stage.
Since prior art did not provide guidance for directly reprogramming PBMCs into NK cells without passing through an iPSC stage encompassed by the instant invention, it is incumbent upon the instant specification to do so. As stated supra, Applicant has only discloses a single method for introducing a combination of Oct4, Sox2, Klf4, and Myc into isolated PBMCs, and, from the following day after the introduction, culturing the introduced cells sequentially in three media to directly reprogram the cells into NK cells without passing through an iPSC stage, but is silent on characterizing any other culture periods after the introduction, thus does not provide guidance on what rational approach to take to adjust this culture period and still predictably achieve direct reprogramming the cells without passing through an iPSC stage.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; … in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art and the specification teach that the method for directly reprogramming PBMCs into NK cells without passing through an iPSC stage is highly unpredictable, and the specification does not provide ample guidance with respect to how to characterize the culture period after introduction of reprogramming factors in order to ensure the introduced cells are not reprogrammed into iPSCs, one would be burdened with undue experimentation to use the claimed invention for directly reprogramming PBMCs into NK cells without passing through an iPSC stage.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method for producing CAR-iNK cells comprising: i) introducing a reprogramming factor that is a combination of Oct4, Sox2, Klf4, and Myc, and a CAR gene into isolated peripheral blood mononuclear cells (PBMCs); and, ii) from the following day after the introduction, culturing the cells of step i) sequentially in a) a first medium containing SCF, FLT3, IL-3, IL-6, and a GSK3β inhibitor; b) a second medium containing SCF, FLT3, IL-15, IL-7, IL-2 and an AHR antagonist; and c) a third medium containing IL-2, IL-15, IL-21, IL-12, IL-18, the GSK3β inhibitor, and the AHR antagonist, and thereby directly reprogramming into NK cells without passing through an induced pluripotent stem cells (iPSC) stage.
Response to Traversal:
Applicant’s arguments filed on 10/29/2025 are acknowledged.
As stated supra, Applicant argues that the specification enables this subject matter, providing step-by-step procedures, concrete media compositions, timings and multiple working examples, and that “Practicing the protocol as written inherently avoids an iPSC stage”, and further “following the provided recipe yields NK cells directly, within the stated timeline, and with confirmed NK phenotype and function, commensurate with the claim scope” (Remarks, p. 9-11).
Applicant’s arguments have been fully considered but they are not persuasive.
As Applicant has correctly pointed out that enablement of the subject matter, i.e., directly reprogramming PBMCs without passing through an iPSC stage, requires “step-by-step procedures, concrete media compositions, timings”, and “practicing the protocol as written inherently avoids an iPSC stage”, and further “following the provided recipe yields NK cells directly, within the stated timeline, and with confirmed NK phenotype and function, commensurate with the claim scope” (Remarks, p. 9-11, emphases added by Examiner). Thus, as agreed by Applicant, in the absence of teaching from prior art, practicing the protocol as written, that comprises detailed step-by-step procedures, concrete media compositions and timings, would be crucial to inherently avoid an iPSC stage. Accordingly, the instant specification does not reasonably provide enablement for a genus of method beyond the scope of the protocol as written disclosed in Example 2.
Maintained Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 5-7, 9-10 and 12-15 stand rejected on the ground of nonstatutory double patenting as being unpatentable over patent claims of US Patent No. 12,421,496 (being allowed from Application No. 16/649,417) in view of Burton et al. (WO 2018/195175, cited in IDS 09/28/2021), Roeven et al. (Stem Cells and Dev. 2015; 24(24): 2886-2898, prior art of record), Son et al., (Cancer Res. 2001; 61: 884-888. Prior art of record) and Kaufman et al., (WO 2016/123333. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent claims recite a method for producing NK cells comprising directly reprogramming consisting of (a) introducing a reprogramming factor into isolated cells such as PBMCs, wherein the reprogramming factors is Oct4, Sox2, Klf and Myc (related to instant claims 1 and 10), (b) from the following day after the introduction, culturing the cells in i) a first medium comprising cytokines (selected from IL-2, IL-3, IL-6, related to instant claims 1 and 5), growth factors (selected from SCF and FLT3 ligand, related to instant claims 1 and 5) and GSK3β inhibitor (CT99021, also known as CHIR99021, related to instant claims 1 and 5) and a second medium comprising cytokines (IL-2, IL-7, IL-15, related to instant claims 1, 4 and 6), growth factors (SCF and FLT3, related to instant claims 1, 3 and 6) and AHR inhibitor (StemRenenin, related to instant claims 1 and 6), wherein the isolated cells being PBMCs (related to instant claim 14), the NK cells expressing CD56 and CD16 (related to instant claim 15). Thus, the patent claims recite a method of producing induced NK cells by directly reprogramming.
However, patent claims are silent on a third medium in the instant claims 1 and 7 comprising IL-2, IL-15, IL-21, IL-12, IL-18, a GSK3β inhibitor CHIR99021and an AHR antagonist StemRenenin I.
In regard to a third medium containing IL-2, IL-15, IL-21, IL-12, IL-18, a GSK-3β inhibitor and an AHR antagonist, Burton teaches a step of differentiating CD34+ HPCs to NK cells and further expanding NK cells (see e.g., Burton claim 1 step (c, d) and [0005]), comprising culturing the HPCs in a medium (equivalent to the claimed third medium) comprising cytokines such as IL-7, IL-2, and IL-12 (Burton claims 27-29), a GSK-3β inhibitor CHIR99021 (Burton claims 28-29 and Fig 1B), and further comprising additional cytokines IL-15 and IL-21 (e.g. [00211] and Fig 1B). Thus, Burton teaches a third medium containing IL-2, IL-15, IL-21, IL-12, and a GSK-3β inhibitor for NK cell differentiation and expansion.
Roeven teaches a method for in vitro producing NK cells from CD34+ HSPCs (abstract). Roeven teaches a differentiation medium contains cytokines and an AHR antagonist StemRegenin I (p. 2887, last para). Roeven teaches addition of an aryl hydrocarbon receptor (AHR) antagonist StemRegenin1 (SR1) potently induces expression of NK-cell-associated transcription factors promoting NK-cell differentiation (abstract, see e.g., p. 2887, last para and Fig 1A for culture protocol, e.g., p. 2889, last para and Fig 1B-C for HPSC expansion and CD56+ NK cell differentiation).
Regarding IL-18 in NK cell expansion, Son teaches a method for in vitro expansion of NK cells (abstract). Son teaches that combining IL-18 and IL-2 have synergistical effect on preferential expansion of CD56+CD3- NK cells (abstract, p. 885, left col, Results section “Combined Use of IL-2 and IL-18 Promotes Synergistic Proliferation of PBMCs” and section “Preferential Expansion of NK Cells”, see Fig 1C-D and Fig 2, and p. 887, right col, para 2).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for producing iNK cells recited in the patent claims, by combining a third medium for NK cell differentiation and expansion containing IL-2, IL-15, IL-21, IL-12, and a GSK-3β inhibitor taught by Burton, StemRegenin I suggested by Roeven, and IL-18 suggested by Son with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to combine a third medium containing the above compositions such as taught by Burton and an AHR antagonist and IL-18 as suggested by Roeven and Son in order to enhance NK cell differentiation and to take advantage of the synergistic effect of IL-18 and IL-2 to preferentially expand NK cells.
However, copending claims are silent on a CAR in the NK cells.
Burton teaches the method is for producing antigen-specific effector NK cells from pluripotent stem cells which express a chimeric antigen receptor (CAR) for treating cancer (see abstract and Burton claims 1a and 61). Burton teaches an exemplary second generation anti-CD19 CAR comprising a CD19 scFv domain, CD28 co-stimulatory domain and CD3ζ signaling domain (e.g. [00233]), and further comprising a CD8 hinge ([00149]) and a CD8 transmembrane domain ([00157]).
Kaufman teaches a CAR expressed in NK cells (abstract). Kaufman teaches the ectodomain of the CAR includes a signal peptide (i.e. a leader) to direct the polypeptide into the endoplasmic reticulum for proper processing and anchoring into the plasma membrane and teaches the CD8a leader sequence can be used (p. 5, last para – p. 6, para 1). Kaufman teaches chimeric antigen receptors are cloned into a pkt2 vector containing the chimeric antigen receptor (CAR) sequence, Internal ribosomal entry site (IRES), and GFP:Zeo selection marker (p. 2, Fig 2 legend).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in the patent claims, by combining introducing a CAR gene comprising domains taught by Burton and a CD8 leader, an IRES and a GFP taught by Kaufman with a reasonable expectation of success. Since Burton teaches the CAR-NK cells are useful in treating cancers, and since Kaufman teaches a signaling peptide is necessary for proper processing and anchoring to plasma membrane and reduces to practice an IRES and a GFP for selecting the CAR-NK cells, one of ordinary skill in the art would have had a reason to combine a CAR gene comprising the taught domains as taught by Burton and Kaufman in the NK cells produced by the method in the patent in order to produce CAR-NK cells for cancer treatment.
Since the instant application claims are obvious over cited patent claims, in view of Burton, Roeven, Son and Kaufman, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 10/29/2025 are acknowledged.
Applicant argues that the cited reference claims do not recite the route-defining and sequence-defining limitations, nor the distinct use of OSKM for direct conversion rather than for inducing pluripotency (Remarks, p.14-15).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, patent claims recite a method for directly reprogramming PBMCs into NK cells by OSKM reprogramming factors and sequential culturing in defined media. Burton makes obvious a third culturing to expand NK cells, and Roeven and Son make obvious the defined compositions in the third medium, and Kaufman makes obvious a CAR-modified NK cell. Thus, the instant claims are made obvious over the patent claims in view of Burton, Roeven, Son and Kaufman to one of ordinary skill in the art.
In regard to the argument of direct conversion rather than for inducing pluripotency, since the patent claims clearly and specifically recite “directly reprogramming” consisting of (a) introducing a reprogramming factor into isolated cells such as PBMCs, and (b) from the following day after the introduction, culturing the cells in a hematopoietic-promoting medium, one of ordinary skill in the art would have immediately expected that the introduced cells would not have been induced pluripotency (i.e., by mere one day of culture after introduction), but would rather have been directly converted to hematopoietic fate and then NK cells.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631