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 .
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 07, 2026 has been entered.
2. Claims 1, 5, and 19 have been amended. Claim 4 and 6-11 have been cancelled.
3. Claims 1-3, 5, 12-16 and 19-21 are pending. Claims 20-21 were previously withdrawn as being drawn to a non-elected invention. Claims 1-3, 5, 12-16 and 19 are currently under consideration.
Priority
4. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed Application No. 62/945,512, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Examiner has established a priority date of December 08, 2020 for claims 1-3, 5, 12-16 and 19 because the claims as currently constituted recite SEQ ID NO: 1, SEQ ID NO: 2, and the at least two transgenes encode a tumor associated antigen and a review of Application No. 62/945,512 does not reveal the claimed limitations. Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
Claim Objections
5. Claim 1 is objected to because of the following informalities: the registered trademark NK-92 (See NK-92, US Reg. No. 5512531, July 10, 2018) on line 14 should be labeled with the proper symbol, i.e. ®. Appropriate correction is required.
Claim 5 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n).
Claim Rejections - 35 USC § 112
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.
6. Claims 1-3, 5, 12-16 and 19 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.
Claim 1 recites the limitations "the plurality of transfected NK-92® cells" at line 15. There is insufficient antecedent basis for these limitations in the claim. Thus claim 1 and its dependent claims are indefinite.
Response to Arguments
7. Applicant argues that the amendments have overcome the instant rejection. This argument has been considered, but has not been found persuasive because the antecedent portion of the claims does not explicitly refer to a plurality of transfected NK-92® cells. Amendment of claim 1, e.g., so that both lines 14 and 15 refer to “transfected NK-92® cells” would help to obviate the rejection.
Claim Rejections - 35 USC § 103
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.
Maintained Rejection
8. Claims 1-3, 5, 12-16 and 19 are rejected under 35 U.S.C. 103 as being obvious over US 2020/0038441 A1 (Klingemann et al. Feb. 6, 2020, filed Aug. 1, 2019), “Klingemann-441” in view of US 2018/0258397 (Klingemann et al. Sep. 13, 2018, IDS), “Klingemann-397” and in view of Tosh et al. (Wellcome Open Res. 2018 Oct 10; 2: 84; pp. 1-13, of record), “Tosh” for the reasons of record below.
Klingemann-441 teaches modified NK-92® cells comprising one or more nucleic acids encoding i) a homing receptor, ii) Antigen Binding Protein (ABP) or Chimeric Antigen Receptor (CAR) that specifically binds to a target antigen, iii) an Fc Receptor such as CD16 or CD16-158V, and/or iv) a cytokine, wherein the nucleic acid sequence is operably linked to a promoter. Further provided herein are modified NK-92® cells comprising one or more nucleic acids encoding i) IL-12 and/or TGF-beta trap, ii) an Antigen Binding Protein (ABP) or Chimeric Antigen Receptor (CAR) that specifically binds to a target antigen, iii) an Fc Receptor such as CD16 or CD16-158V, and/or iv) a cytokine, wherein the nucleic acid sequence is operably linked to a promoter. Also provided are compositions and kits comprising the modified NK-92® cells, as well as methods of treating cancer using the modified cells. See abstract.
Klingemann-441 teaches the nucleic acid construct with a promoter is a multi-cistronic vector comprising one or more Internal Ribosome Entry Site (IRES) to allow for initiation of translation from an internal region of an mRNA transcribed from the nucleic acid sequences. In some embodiments, the nucleic acid construct comprises a sequence that encodes a 2A peptide, such as a T2A, P2A, E2A, or F2A peptide or the IRES of SEQ ID NO: 27. See ¶¶ 0031, 0117, an 0141,
Klingemann-441 teaches the first element encoded by the nucleic acid construct is a cytokine that provides selection for NK-92® cells that express the cytokine, such as IL-2 or IL-15. Thus, in some embodiments, the nucleic acid encodes a cytokine such as IL-2 or IL-15. In one embodiment, the IL-2 is expressed with a signal sequence that directs the IL-2 to the endoplasmic reticulum IL-2 (“erIL-2”). In another embodiment, the IL-15 is expressed with a signal sequence that directs the IL-15 to the endoplasmic reticulum IL-15 (“erIL-15”). See ¶¶ 0010 and 0012.
Klingemann-441 teaches a TGFβ trap composed of a single chain dimer of the extracellular domain of TGFβRII was cloned into a quadricistronic plasmid vector that also contains PD-L1 CAR, CD16 and erIL-2 transgenes (FIG. 21). The quadricistronic plasmids were electroporated into the aNK cells to create modified NK-92 cells. The modified NK-92® cells were selected by IL-2-depleted media because untransformed aNK cells, being IL-2 dependent, could not survive in IL-2 depleted media. See ¶ 0285.
Klingemann-441 teaches using limiting clonal dilution in medium without IL-2 to select the aTGFβ/PD-L1 t-haNK™ cells which were checked for cell growth. See ¶ 0286.
Klingemann-441 aTGFβ/PD-L1 t-haNK™ cells were characterized by flow cytometry, ADCC activity, TGFb trap secretion ELISA, and cytotoxicity. See ¶¶ 0292-0295.
SEQ ID NO: 14 of Klingemann-441 comprises the claimed ER-IL2, SEQ ID NO: 1. See Appendix of the Office Action May 22, 2025.
Klingemann-441 teaches the multi-cistronic constructs can also express chemokines like CCR7 and CXCR2 or secreted cytokines like IL-12. See ¶¶ 0013-0016, 0025, 0054, Examples 4 and 5 and Figs.10 and 11..
Klingemann-441 teaches NK cells expressing CCR7 and CCL21 under the control of a NFAT responsive promoter construct. See Examples 2 and 3 and ¶¶ 0124-0129 and 0176.
Klingemann-441 teaches target engagement of susceptible cell lines is shown to be recognized in NK-92® cells by activation of the NFAT transcription factor and its nuclear translocation. Target binding involving the FceRIg or CD3zeta pathway (including ADCC or CAR mediated target recognition) is sufficient to induce NFAT activation in NK-92® cells. See¶¶ 0124.
Klingemann-441 teaches that the vectors of the invention may be integrated into chromosomal DNA. See ¶¶ 0102.
Klingemann-441 does not teach that the transgenes are integrated into the genome at a single, non-exonic site or sequencing the genome.
Klingmann-397 teaches a natural killer cell, NK-92, modified to express an Fc receptor on the surface of the cell, such as CD16 (Fc g RIII-A), or other Fcg or Fc receptors and IL-2. See abstract.
Klingmann-397 teaches NK-92 [CD16.176V, ER IL-2] (haNK003) was generated through the modification of NK-92 cells. See ¶¶ [0084-0085].
Klingmann-397 teaches that the IL-2 sequence is tagged with the endoplasmic reticulum retention signal, KDEL, to prevent IL-2 protein secretion from the endoplasmic reticulum (ER). Inclusion of the IL-2 sequence allows haNK™ to be IL-2 independent. See ¶ 0084.
Klingmann-397 teaches that the NK-92 cells were transfected with the plasmid pNEUKv1_FcRIL2 plasmid (SEQ ID NO:1). See ¶¶ [0086-0087].
Klingmann-397 teaches that the plasmid used the EF-1 alpha promoter for the transgene. ¶ [0086].
Klingmann-397 teaches the mRNA molecules comprise from 5′ to 3′ a sequence encoding CD16, an IRES sequence, and a sequence encoding IL-2. See ¶¶ 0037 and claim 3.
Klingmann-397 teaches at paragraph [0088]:
To generate the haNK003 cell line, a vial of the NK-92 (aNK) Master Cell Bank (MCB) (aNK COA) and 250 mg of pNEUKv1_FcRIL2 plasmid were sent to EUFETS GmbH. EUFETS thawed the MCB vial and cultured the NK-92 cells to an adequate number for transfection with the plasmid. The transfected cells were grown in media with IL-2, X-Vivo 10, and 5% heat inactivated Human AB Serum for the first two days post transfection. After two days, IL-2 was no longer added to the growth media and any cells that were transfected and producing adequate amount of IL-2 continued to grow. Multiple clones were isolated by limiting dilution and preliminarily screened for phenotype and Fc Receptor expression. Six (6) clones that exhibited good viability (>70%), acceptable doubling time, expected phenotype and positive Fc Receptor expression were sent to the German Red Cross GMP Testing Laboratory (GRC) for more extensive screening and final selection of a single clone. At GRC, all clones were tested for phenotype (including Fc Receptor expression), ADCC, cytokine profile, growth characteristics, and radiation sensitivity.
SEQ ID NO: 1 of Klingmann-397 comprises ER-IL2, SEQ ID NO: 1. See Appendix of the Office Action of May 22, 2025.
Klingmann-397 teaches that DNA from the haNK003 cells was analyzed by whole genome sequencing. See ¶¶ 0034 and 0090.
Klingmann-397 teaches that the integration site of the bicistronic plasmid on chromosome 17 was at least 10 kbp away from any gene, i.e. at a single, non-exonic site See ¶¶ 0034. 0091, and 0092
Klingmann-397 teaches haNK003 cells express CD16. See ¶¶ 0095-0097, Table 1 and Fig. 2.
Klingmann-397 teaches measuring IL-2 release from the haNK003 cells with ELISA. See Example 3.
Tosh teaches the random insertion of exogenous genes (exogenes) into the genome of a cell can potentially disrupt the endogenous gene expression and/or alter the phenotype of the cell, necessitating an assessment of the effects of disrupting the gene, particularly when the insertion is in an exon of the gene; see entire document (e.g., the abstract; and page 7). Moreover, Tosh teaches integration of a transgene into the coding sequences (exons) of a gene can induce new mutations, which might cause, for example, haploinsufficiency, such that it is important to know where in the genome the insertion of the transgene has occurred (see, e.g., page 3). Tosh describes determining the site of insertion of the transgene into the genome of transfected cells using deep sequencing following targeted locus amplification (see, e.g., the abstract; and page 4).
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Klingemann-441, Klingemann-397 and Tosh to have generated a clonal population of transfected NK-92 cells comprising a multicistronic vector encoding at least two transgenes separated by an IRES or 2A sequence under control of a single promoter and comprising a nucleotide sequence encoding a positive selection marker or more particularly erIL-2 and/or erIL-15, as suggested by the teachings of Klingemann-441 and Klingemann-397, and to have screened independent clones isolated following serial dilution using whole genome sequencing or genome walking as taught by Klingemann-397 and Tosh to determine that the site at which the insertion has occurred in the genome of the cells is not within an exon of a gene. This is because if the insertion were to be in an exon of a gene, it might disrupt expression of the gene and/or cause the expression of a non-functional or misfunctioning gene product, which could have or cause undesirable effects upon the phenotype of the cells. Thus, it would be preferable for the site of the insertion to be non-exonic, so as to reduce the risk or potential of disrupting gene expression and/or causing undesirable changes in the phenotype of the cells.
Response to Arguments
9. Applicant argues that Klingemann-441 is a prior art reference under §102(a)(2). In this regard, Applicant hereby invokes the prior art exception under 35 U.S.C. §102(b)(2)(C). Applicant's representative, Dr. Priti Phukan (USPTO Reg No.: 70109) makes the following statement about Common Ownership under MPEP §717.02(a):
The present application (17/115,360) and the W02020028656 Al publication were, not later than the effective filing date of the claimed invention in the present application (17/115,360), owned by Company ImmunityBio, Inc., which was previously known as NantKwest, Inc.
Thus, based on the law recited in 35 U.S.C. §102(b)(2)(C), Klingemann-441 is not a prior art to this presently claimed invention. Withdrawal of the §103 rejection is therefore requested.
Applicant’s argument has been considered, but has not been found persuasive. Although Applicant’s representative statement about Common Ownership invokes the prior art exception under 35 U.S.C. §102(b)(2)(C) and removes Klingemann-441 as a prior art reference under §102(a)(2), Klingemann-441 is still available as prior art under §102(a)(1). In particular, the claims have a priority date of December 08, 2020 as set forth above and Klingemann-441 was published Feb. 6, 2020, which is prior to December 08, 2020. Given that Klingemann-441 was published less than 1 year prior to the effective filing date, the prior art exceptions under 35 U.S.C. §102(b)(1)(A) or (b)(1)(B) could be applied as appropriate to overcome the Klingemann-441 rejection.
Maintained Rejection
10. Claim(s) 1-3, 5, 12, 14-16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0258397 (Klingemann et al. Sep. 13, 2018, IDS), “Klingemann-397” in view of US Pat. No. 7,618,817 B2 (Campbell, KS Nov. 17, 2009, IDS), “Campbell” in view of US 2018/0193383 A1 (Lee et al. July 12, 2018, of record), “Lee” in view of Alici et al. (Methods in Mol. Biol, Methods and Protocols, Baum, C. (ed.), 2009, vol. 506, Ch. 10: 127-137, of record), “Alici” and in view of Tosh et al. (Wellcome Open Res. 2018 Oct 10; 2: 84; pp. 1-13, of record), “Tosh” for the reasons of record.
Klingmann-397 teaches a natural killer cell, NK-92, modified to express an Fc receptor on the surface of the cell, such as CD16 (Fc g RIII-A), or other Fcg or Fc receptors and IL-2. See abstract.
Klingmann-397 teaches NK-92 [CD16.176V, ER IL-2] (haNK003) was generated through the modification of NK-92 cells. See ¶¶ [0084-0085].
Klingmann-397 teaches that the IL-2 sequence is tagged with the endoplasmic reticulum retention signal, KDEL, to prevent IL-2 protein secretion from the endoplasmic reticulum (ER). Inclusion of the IL-2 sequence allows haNK™ to be IL-2 independent. See ¶ 0084.
Klingmann-397 teaches that the NK-92 cells were transfected with the plasmid pNEUKv1_FcRIL2 plasmid (SEQ ID NO:1). See ¶¶ [0086-0087].
Klingmann-397 teaches that the plasmid used the EF-1 alpha promoter for the transgene. ¶ [0086].
Klingmann-397 teaches the mRNA molecules comprise from 5′ to 3′ a sequence encoding CD16, an IRES sequence, and a sequence encoding IL-2. See ¶¶ 0037 and claim 3.
Klingmann-397 teaches at paragraph [0088]:
To generate the haNK003 cell line, a vial of the NK-92 (aNK) Master Cell Bank (MCB) (aNK COA) and 250 mg of pNEUKv1_FcRIL2 plasmid were sent to EUFETS GmbH. EUFETS thawed the MCB vial and cultured the NK-92 cells to an adequate number for transfection with the plasmid. The transfected cells were grown in media with IL-2, X-Vivo 10, and 5% heat inactivated Human AB Serum for the first two days post transfection. After two days, IL-2 was no longer added to the growth media and any cells that were transfected and producing adequate amount of IL-2 continued to grow. Multiple clones were isolated by limiting dilution and preliminarily screened for phenotype and Fc Receptor expression. Six (6) clones that exhibited good viability (>70%), acceptable doubling time, expected phenotype and positive Fc Receptor expression were sent to the German Red Cross GMP Testing Laboratory (GRC) for more extensive screening and final selection of a single clone. At GRC, all clones were tested for phenotype (including Fc Receptor expression), ADCC, cytokine profile, growth characteristics, and radiation sensitivity.
SEQ ID NO: 1 of Klingmann-397 comprises ER-IL2, SEQ ID NO: 1. See Appendix of the Office Action of May 22, 2025.
Klingmann-397 teaches that DNA from the haNK003 cells was analyzed by whole genome sequencing. See ¶¶ 0034 and 0090.
Klingmann-397 teaches that the integration site of the bicistronic plasmid on chromosome 17 was at least 10 kbp away from any gene, i.e. at a single, non-exonic site See ¶¶ 0034. 0091, and 0092
Klingmann-397 teaches haNK003 cells express CD16. See ¶¶ 0095-0097, Table 1 and Fig. 2.
Klingmann-397 teaches measuring IL-2 release from the haNK003 cells with ELISA. See Example 3.
Unmodified NK-92 cells are the NK-92 cells that have American Type Culture Collection (ATCC) Deposit No. CRL-2407™. See Klingmann-397, ¶ 0036 and Campbell column 16-lines 15-22.
Klingemann-397 teach as set forth above, but does not teach expressing at least two transgenes, wherein one is a secreted cytokine like IL-12, and identifying single, non-exonic integration of the two transgenes.
Lee teaches genetically modified NK-92 cells (with Deposit No. CRL-2407) expressing the CD16, Fc receptor and one more cytokines for the treatment of cancer. See abstract and ¶¶ 0006-0008, 0054 and claims 1-5.
Lee teaches the cytokines can be IL-2 targeted to the endoplasmic reticulum, IL-12, IL-15, or IL-21. See ¶¶ 0046, 0076, and 0077 and claims 6, 7 and 10.
SEQ ID NO: 7 of Lee is encoded by the claimed SEQ ID NO: 1. See Appendix of the Office Action of May 22, 2025.
Lee teaches that the expressed transgene is the human CD16 158V sequence followed by an IRES sequence itself followed by the ERIL-2 sequence (IL-2 KDEL) such that the IL-2 is targeted to the endoplasmic reticulum. The resulting mRNA is a bicistronic transcript under the control of the EF1α promoter, with the ERIL-2 translated independently from CD16, under the control of the IRES sequence. See ¶ 0125.
Alici teaches that NK cells play an important role in the early response against many types of microorganisms and tumors. See p. 127-Introduction.
Alici teaches gene therapy into NK cells may open new possibilities in immunotherapy of tumors. See p. 128- 1st paragraph.
Alici teaches that IL-2, IL-15 and IL-21 play important roles in NK cell differentiation, maturation. Alici teaches that IL-12 is important for the induction of NK lytic capacity. Alici teaches that by transfer of such cytokines to the NK cells the NK cells can be made independent of such cytokines for growth and cytotoxicity. See paragraph bridging pp. 128-129.
Tosh teaches the random insertion of exogenous genes (exogenes) into the genome of a cell can potentially disrupt the endogenous gene expression and/or alter the phenotype of the cell, necessitating an assessment of the effects of disrupting the gene, particularly when the insertion is in an exon of the gene; see entire document (e.g., the abstract; and page 7). Moreover, Tosh teaches integration of a transgene into the coding sequences (exons) of a gene can induce new mutations, which might cause, for example, haploinsufficiency, such that it is important to know where in the genome the insertion of the transgene has occurred (see, e.g., page 3). Tosh describes determining the site of insertion of the transgene into the genome of transfected cells using deep sequencing following targeted locus amplification (see, e.g., the abstract; and page 4).
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Klingemann-397, Campbell, Lee Alici and Tosh and express additional cytokines like IL-12, IL-15 and/or IL-21 in the NK-92 cells of Klingemann-397 from a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter because Klingemann-397 and Lee teach multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter, Lee teaches genetically modified NK-92 cells (with Deposit No. CRL-2407) expressing the CD16, Fc receptor and one more cytokines, including IL-2, IL-12, IL-15, or IL-21 for the treatment of cancer and Alici teaches that by transfer of such cytokines to NK cells the NK cells can be made independent of such cytokines for growth and cytotoxicity. Thus, one would have been motivated to express additional cytokines like IL-12, IL-15 and/or IL-21 in the NK-92 cells of Klingemann-397 to make the NK cells independent of such cytokines for growth and cytotoxicity.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Klingemann-397, Campbell, Lee Alici and Tosh to have generated a clonal population of transfected NK-92 cells comprising a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter and comprising a nucleotide sequence encoding a positive selection marker or more particularly erIL-2, as suggested by the teachings of Klingemann-397 and Lee, and to have screened independent clones isolated following serial dilution using whole genome sequencing or genome walking as taught by Klingemann-397 and Tosh to determine that the site at which the insertion has occurred in the genome of the cells is not within an exon of a gene. This is because if the insertion of the two transgenes were to be in an exon of a gene, it might disrupt expression of the gene and/or cause the expression of a non-functional or misfunctioning gene product, which could have or cause undesirable effects upon the phenotype of the cells. Thus, it would be preferable for the site of the insertion of the two transgene to be non-exonic, so as to reduce the risk or potential of disrupting gene expression and/or causing undesirable changes in the phenotype of the cells.
Response to Arguments
11. Applicant argues that they have amended claim 1 to incorporate the limitations previously recited in claims 4, 6, and 7. Notably claim 6 was determined to be non-obvious over the above cited references. Accordingly, it is respectfully submitted that the present amendment renders claim 1, as well as its dependent claims, non-obvious over the cited art. Withdrawal of the § 103 rejection is therefore respectfully requested.
Applicant’s arguments have been considered, but have not been found persuasive. The limitations previously recited in claims 4, 6, and 7 were incorporated into amended claim 1 in the alternative. So the cited art does not need to teach or suggest all of the limitations previously recited in claims 4, 6, and 7, just at least two of the recited transgenes. As previously set forth, it would have been obvious to combine the teachings of Klingemann-397, Campbell, Lee Alici and Tosh and express additional cytokines like IL-12 in the NK-92 cells of Klingemann-397 that express the Fc receptor CD16 and ER-IL2 to make the NK cells independent of such cytokines for growth and cytotoxicity. Thus, the rejection is maintained for the reasons of record.
Maintained Rejection
12. Claim(s) 1-3, 5, 12, 14-16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0258397 (Klingemann et al. Sep. 13, 2018, IDS), “Klingemann-397” in view of US Pat. No. 7,618,817 B2 (Campbell, KS Nov. 17, 2009, IDS), “Campbell”, in view of CN 110106202 A (Huang et al. Aug. 9, 2019, of record), “Huang” and in view of and in view of Tosh et al. (Wellcome Open Res. 2018 Oct 10; 2: 84; pp. 1-13, of record), “Tosh” for the reasons of record.
Klingemann-397 and Campbell teach as set forth above, but do not teach that least one of the two transgenes is a chemokine receptor like CCR7 and identifying single, non-exonic integration of the two transgenes.
Tosh teaches as set forth above.
Huang teach making NK-92 cell that express the chemokine receptor genes CCR7 and CXCR4 that inhibit tumor growth. See Abstract, Examples 3, 7, and 8.
Huang teaches a multicistronic vector with an IRES and a 2A sequence. See p. 8-5th to last line and p. 10-last full paragraph.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Klingemann-397, Campbell, Huang and Tosh and express additional the chemokine receptor genes CCR7 and CXCR4 in the NK-92 cells of Klingemann from a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter because Klingemann-397 and Huang teach multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter and because Huang teaches making NK-92 cell that express the chemokine receptor genes CCR7 and CXCR4 to inhibit tumor growth. Thus, one would have been motivated to express the chemokine receptor genes CCR7 and CXCR4 in the NK-92 cells of Klingemann-397 to enhance the anti-tumor activity of the NK-92 cells.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Klingemann-397, Campbell, Huang and Tosh to have generated a clonal population of transfected NK-92 cells comprising a multicistronic vector encoding at least two transgenes separated by an IRES or 2A sequence under control of a single promoter and comprising a nucleotide sequence encoding a positive selection marker or more particularly erIL-2, as suggested by the teachings of Klingemann-397 and Huang, and to have screened independent clones isolated following serial dilution using whole genome sequencing or genome walking as taught by Klingemann-397 and Tosh to determine that the site at which the insertion has occurred in the genome of the cells is not within an exon of a gene. This is because if the insertion of the two transgenes were to be in an exon of a gene, it might disrupt expression of the gene and/or cause the expression of a non-functional or misfunctioning gene product, which could have or cause undesirable effects upon the phenotype of the cells. Thus, it would be preferable for the site of the insertion of the two transgenes to be non-exonic, so as to reduce the risk or potential of disrupting gene expression and/or causing undesirable changes in the phenotype of the cells.
Response to Arguments
13. Applicant argues that they have amended claim 1 to incorporate the limitations previously recited in claims 4, 6, and 7. Notably claim 7 was determined to be non-obvious over the above cited references. Accordingly, it is respectfully submitted that the present amendment renders claim 1, as well as its dependent claims, non-obvious over the cited art. Withdrawal of the § 103 rejection is therefore respectfully requested.
Applicant’s arguments have been considered, but have not been found persuasive. The limitations previously recited in claims 4, 6, and 7 were incorporated into amended claim 1 in the alternative. So the cited art does not need to teach or suggest all of the limitations previously recited in claims 4, 6, and 7, just at least two of the recited transgenes. As previously set forth, it would have been obvious to combine the teachings of Klingemann-397, Campbell, Huang and Tosh and express additional the chemokine receptor genes CCR7 and CXCR4 in the NK-92 cells of Klingemann that express the Fc receptor CD16 and ER-IL2 to enhance the anti-tumor activity of the NK-92 cells. Thus, the rejection is maintained for the reasons of record.
Maintained Rejection
14. Claim(s) 1-3, 5, 12-16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0258397 (Klingemann et al. Sep. 13, 2018, IDS), “Klingemann-397” in view of US Pat. No. 7,618,817 B2 (Campbell, KS Nov. 17, 2009, IDS), “Campbell”, in view of US 2023/0142916 A1 (Schambach et al May 11, 2023, effectively file June 21, 2019), “Schambach” and in view of Tosh et al. (Wellcome Open Res. 2018 Oct 10; 2: 84; pp. 1-13, of record), “Tosh” for the reasons of record.
Klingemann-397 and Campbell teach as set forth above but do not teach that least one of the transgenes is a secreted cytokine like IL-12 or the nucleic vector comprises a promoter with a NFAT binding domain and identifying single, non-exonic integration of the two transgenes.
Tosh teaches as set forth above.
Schambach teaches immune cells for the treatment of cancer or autoimmune diseases which contain nucleic acid construct comprises a second expression cassette for constitutive expression of a CAR or a TCR, the binding of which to its target antigen results in signaling and induces the expression of an effector molecule from a first expression cassette, which is contained on the same nucleic acid construct, and which first expression cassette encodes the effector molecule under the control of a promoter inducible by signaling of the CAR or TCR. See abstract.
Schambach teaches that the promoter controlling the inducible expression of the effector molecule can contain NFAT binding elements. See ¶¶ 0018, 0019 and 0021 and Figs. 1 and 2.
Schambach teaches that effector molecule includes cytokines like IL-12 and IL-15. See ¶¶ 0001, 0008, 0013, and 0015, Example 1 and Fig. 3.
Schambach teaches that the immune cells include NK-92 cells. See ¶¶ 0016 and 0035 and Example 4.
Schambach teaches that vector can integrate into the DNA of a recipient cell. See ¶¶ 0001-0002 and 0006-0007.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Klingemann-397, Campbell, Schambach and Tosh and include the expression cassettes encoding a CAR or a TCR and effector molecule cytokines like IL-12 and IL-15 in the vector of Klingemann-397 for expression in the NK-92 cells from a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter because Klingemann-397 teaches a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter and because Schambach teaches that these expression cassettes can be used for the treatment of cancer. Thus, one would have been motivated to express a CAR or a TCR and effector molecule and include cytokines like IL-12 and IL-15 in the NK-92 cells of Klingemann-397 to enhance the anti-tumor activity of the NK-92 cells.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Klingemann-397, Campbell, Schambach and Tosh to have generated a clonal population of transfected NK-92 cells comprising a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter and comprising a nucleotide sequence encoding a positive selection marker or more particularly erIL-2, as suggested by the teachings of Klingemann-397, and to have screened independent clones isolated following serial dilution using whole genome sequencing or genome walking as taught by Klingemann-397 and Tosh to determine that the site at which the insertion has occurred in the genome of the cells is not within an exon of a gene. This is because if the insertion of the two transgenes were to be in an exon of a gene, it might disrupt expression of the gene and/or cause the expression of a non-functional or misfunctioning gene product, which could have or cause undesirable effects upon the phenotype of the cells. Thus, it would be preferable for the site of the insertion of the two transgenes to be non-exonic, so as to reduce the risk or potential of disrupting gene expression and/or causing undesirable changes in the phenotype of the cells.
Response to Arguments
15. Applicant argues that they have amended claim 1 to incorporate the limitations previously recited in claims 4, 6, and 7. Notably claim 7 was determined to be non-obvious over the above cited references. Accordingly, it is respectfully submitted that the present amendment renders claim 1, as well as its dependent claims, non-obvious over the cited art. Withdrawal of the § 103 rejection is therefore respectfully requested.
Applicant’s arguments have been considered, but have not been found persuasive. The limitations previously recited in claims 4, 6, and 7 were incorporated into amended claim 1 in the alternative. So the cited art does not need to teach or suggest all of the limitations previously recited in claims 4, 6, and 7, just at least two of the recited transgenes. As previously set forth, it would have been obvious to combine the teachings of Klingemann-397, Campbell, Schambach and Tosh and include the expression cassettes encoding a CAR or a TCR and effector molecule cytokines like IL-12 in the NK-92 cells of Klingemann that express the Fc receptor CD16 and ER-IL2 to enhance the anti-tumor activity of the NK-92 cells. Thus, the rejection is maintained for the reasons of record.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Maintained/Modified Rejections
16. Claim 1-3, 5, 12-16 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following patents and co-pending applications in view of in view US 2018/0258397 (Klingemann et al. Sep. 13, 2018, IDS), “Klingemann-397” , in view of US Pat. No. 7,618,817 B2 (Campbell, KS Nov. 17, 2009, IDS), “Campbell”, in view of Tosh et al. (Wellcome Open Res. 2018 Oct 10; 2: 84; pp. 1-13, of record), “Tosh”, in view of US 2018/0193383 A1 (Lee et al. July 12, 2018, of record), “Lee”, in view of Alici et al. (Methods in Mol. Biol, Methods and Protocols, Baum, C. (ed.), 2009, vol. 506, Ch. 10: 127-137, of record), “Alici”, and in view of US 2023/0142916 A1 (Schambach et al May 11, 2023, effectively file June 21, 2019), “Schambach”.
17/115,360 claims
Patent or Application
Conflicting claims
1
1-3, 5, 12-16 and 19
US 11,058,723
1-7
2
1-3, 5, 12-16 and 19
US 11,129,850
1-4
3
1-3, 5, 12-16 and 19
17/446,024 (US 2021/0386785-Allowed)
1-3, 5, 6, 11-14 and 17-20
4
1-3, 5, 12-16 and 19
17/732,190 (US 12,516,093)
1-15
5
1-3, 5, 12-16 and 19
US 10801013
1-14
6
1-3, 5, 12-16 and 19
US 10774310
1-11
7
1-3, 5, 12-16 and 19
US 11753625
1-18
8
1-3, 5, 12-16 and 19
18/223,338 (US 12,492,377)
1-19
9
1-3, 5, 12-16 and 19
US 11,813,292
1-3
10
1-3, 5, 12-16 and 19
18/463,907 (US 12,403,178)
1-22
11
1-3, 5, 12-16 and 19
18/945002 (US 20250073305)
1-20
12
1-3, 5, 12-16 and 19
US 11,643,452
1-8
13
1-3, 5, 12-16 and 19
17/056,385 (US 12,435,122)
135-139, 144, 145, and 186
14
1-3, 5, 12-16 and 19
US 11,077,143
1-9
15
1-3, 5, 12-16 and 19
17/356,423 (US 12,473,348)
1-18
16
1-3, 5, 12-16 and 19
17/356,411 (US 12,473,347)
1-20
17
1-3, 5, 12-16 and 19
US 10,765,701
1-24
18
1-3, 5, 12-16 and 19
16/934,606 (US 12,378,300)
1-24 and 26
19
1-3, 5, 12-16 and 19
19/207,222
1-18
20
1-3, 5, 12-16 and 19
US 11,547,727
1-13
21
1-3, 5, 12-16 and 19
US 12,109,238
1-16
22
1-3, 5, 12-16 and 19
US 12,180,283
1-21
23
1-3, 5, 12-16 and 19
18/949,473 (US 2025/0066484)
1-20
24
1-3, 5, 12-16 and 19
US 11,992,504
1-11
25
1-3, 5, 12-16 and 19
18/610961 (US 2024/0252540)
1-20
26
1-3, 5, 12-16 and 19
10,456,420
1-11
27
1-3, 5, 12-16 and 19
10,736,921
1-12
28
1-3, 5, 12-16 and 19
11,000,550
1-9
29
1-3, 5, 12-16 and 19
11,207,350
1-11
30
1-3, 5, 12-16 and 19
17/530211 (US 12,384,852 )
1-20
31
1-3, 5, 12-16 and 19
11230699
1-27
32
1-3, 5, 12-16 and 19
17/489607 (US 12,365,874)
1 -18
33
1-3, 5, 12-16 and 19
19/034,027 (US 2025/0154465)
1-20
34
1-3, 5, 12-16 and 19
17/264990 (US 12540170 )
1-7
35
1-3, 5, 12-16 and 19
16/964,962 (US 2021/0040451)
1-8, 10-14, 16,17, and 19-22
36
1-3, 5, 12-16 and 19
18/179,995 (US 2023/0272042)
1-14
37
1-3, 5, 12-16 and 19
18/765084 (US 2024/0366972)
1-20
38
1-3, 5, 12-16 and 19
17/795,735 (US 2023/0172982)
1, 8-9, and 13-29
39
1-3, 5, 12-16 and 19
10,738,279
1-20
40
1-3, 5, 12-16 and 19
11,788,059
1-20
41
1-3, 5, 12-16 and 19
18/463,213 ( US 2024/0002802)
1-20
42
1-3, 5, 12-16 and 19
19/272,876 (US2025/0340664)
1-15
43
1-3, 5, 12-16 and 19
19/085,903 (US 20250298030)
1, 3-5, 8-13, and 18-20
The conflicting claims are drawn compositions comprising or methods using NK-92 cells expressing a cytokine, IL-2, ER-IL2, IL-15, or ER-IL5 with a transgene. The conflicting claims do not teach that the transgene(s) is integrated into the genome at a single, non-exonic site or sequencing the genome and not all of the conflicting teach at least two transgenes expressed with an NFAT containing promoter.
Klingemann-397, Campbell, Tosh, Lee, Alici, and Schambach teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the claims of the cited patents or co-pending applications to have generated a clonal population of transfected NK-92 cells comprising a multi-cistronic vector encoding at least two transgenes from a multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter comprising inducible NFAT domains because Klingemann-397 and Lee teach multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promote and comprising a nucleotide sequence encoding positive selection marker erIL-2, as suggested by the teachings of Klingemann-397 and Lee because Klingemann-397 teaches the er-IL-2 makes the NK-92 of the need for exogenous IL-2 for growth and because Schambach teaches that the NFAT expression cassettes can be used for the treatment of cancer. One would been motivated to have screened independent clones isolated following serial dilution using whole genome sequencing or genome walking as taught by Klingemann-397 and Tosh to determine that the site at which the insertion has occurred in the genome of the cells is not within an exon of a gene as taught by Tosh. This is because if the insertion were to be in an exon of a gene, it might disrupt expression of the gene and/or cause the expression of a non-functional or misfunctioning gene product, which could have or cause undesirable effects upon the phenotype of the cells. Thus, it would be preferable for the site of the insertion to be non-exonic, so as to reduce the risk or potential of disrupting gene expression and/or causing undesirable changes in the phenotype of the cells.
Additionally, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the teachings of the claims of the cited patents or co-pending applications Klingemann-397, Campbell, Tosh, Lee and Alici and express additional cytokines like IL-12, IL-15 and/or IL-21 in the NK-92 cells from a multi-cistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter because Klingemann-397 and Lee teach multicistronic vector encoding at least two transgenes separated by an IRES sequence under control of a single promoter, Lee teaches genetically modified NK-92 cells (with Deposit No. CRL-2407) expressing the CD16, Fc receptor and one more cytokines, including IL-2, IL-12, IL-15, or IL-21 for the treatment of cancer and Alici teaches that by transfer of such cytokines to NK cells the NK cells can be made independent of such cytokines for growth and cytotoxicity. Thus, one would have been motivated to express additional cytokines like IL-12, IL-15 and/or IL-21 with the CD16, Fc receptor in the NK-92 cells of the claims of the cited patents or co-pending applications to make the NK cells independent of such cytokines for growth and cytotoxicity.
Response to Arguments
17. Applicant argues that the Office has rejected the pending claims on ground of non-statutory double patenting as being unpatentable over a list of 41 different patents or patent applications. It is respectfully submitted that double patenting rejections #1-24, #26-30, #34-37, #39-41 should be overcome in view of the amendments to claim 1. Applicant respectfully requests the Examiner to hold the rest of the double patenting rejections in abeyance until other issues have been resolved. At that time, if there are any remaining double patenting issues, Applicant will file terminal disclaimer(s) to overcome them
Applicant’s arguments have been considered, but have not been found persuasive. The conflicting claims of the cited patents or co-pending applications make the currently amended claims for the reasons previously set forth and above and no terminal disclaimer has been filed. The amendments to claim 1 recite at least two of the transgenes are expressed and expressing at least IL-12 with the CD16, Fc receptor in the NK-92 cells of the claims of the cited patents or co-pending applications to make the NK cells independent of such cytokines for growth and cytotoxicity is obvious for the reasons previously set forth and above. Thus, the rejections are maintained for the reasons previously set forth and above.
Conclusion
18. No claims allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646