DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 23, 2025 has been entered.
Claims 1-20 are pending.
Claims 12-20 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 17, 2023.
Claims 1-11 are currently under consideration as the read on the elected invention of NK-92MI cell.
3. In view of applicant’s amendment, following rejections are set forth.
4. 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 (i.e., changing from AIA to pre-AIA ) 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.
5. 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.
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.
6. Claims 1-10 stand rejected under 35 U.S.C. 103 as being unpatentable over Cheng (WO 2020/150475, reference on IDS) in view of Braun (WO2008/070647) and Lopez-Verges (Blood, 2010, 116;19:3865-3874, reference on IDS), and as evidenced by Jochems et al. (Oncotarget, 2016, 7;52:86359-86373, reference on IDS) as further evidenced by [0031] of the instant specification as filed that CD16+CD57+ NK-92 MI cells also express NKG2D for the reasons of record.
Cheng teaches a CD16+ NK-92 cells sorted from the NK-92 cell deposited as ATCC CRL-2407 (e.g. see Fig. 1 or copy below):
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Such sorted NK-92 cells would have high expression of CD16 compared to NK-92 before the sorting. The sorted NK-92 cells are CD56+/CD16+/CD3-, can be cultured for 7-202 days with a cell survival of rate of 89.5% during culture, and confirmed to have ADCC function (e.g. see pages 47-48). The ATCC CRL-2407 is IL-2 dependent parent NK-92 cell line of IL-2 independent NK-92MI.
Cheng teaches that CD16 receptor is necessary for antibody-dependent cell mediated cytotoxicity (ADCC) carried out by human NK cells (e.g. see lines 17-20 in page 1). Cheng teaches that NK-92 cell (ATCC 2407) is a human NK cell line continuously grows in culture without aging and death problem; it is also non-tumorigenic and NK-92 cell expressing CD16 has been injected into cancer patients and shown to be able to induce ADCC effect against cancer cells (e.g. see page 3). Cheng teaches NK cell composition that contains 1x107 cells (e.g. see [0022]). Cheng teaches that the sorted NK-92 cells also express NKG2D (e.g. see [0053]). Cheng teaches that the NK-92 cells can further contain exogenously transfected polynucleotides encoding a chimeric antigen receptor (e.g. see page 29). Cheng teaches sorted NK-92 cells cultured in human serum (e.g. see [0386]).
Cheng teaches that NK-92 cell line deposited as ATCC CRL-2407 was known to be CD16- and thus unable to destroy cancer cell through ADCC (e.g. see pages 2-3), but shows that 2.5-2.6% the NK-92 cells do express CD16 (e.g. see [0229]) and were sorted to obtain high-purity CD16+ cells (e.g. see [0230]) and CD3-CD56+ (e.g. see [0232]). Cheng teaches that the sorted cells are cultured in the container for multiple days to let the cells proliferation (e.g. see [0238]). Cheng also teach that the methods can be used for other human CD16+ NK cells including transgenic NK-92 cell line (e.g. see [0238]).
Cheng teaches multiple days of the sorted cell culture reaching 5x107 cells (e.g. see [0248]). Cheng teaches that the sorted NK-92 having endogenous CD16+ on cell surface is cytotoxic against human tumor cells (e.g. see 56).
The reference teachings differ from the instant invention by not teaching NK-92 MI cells enriched in CD16+CD57+ cells wherein the enriched NK-92 MI cells contain more CD16+CD57+NK-92MI cells and express higher quantities of NKG2D compared to the unenriched NK-92 MI cells.
Braun teaches NK-92MI having ATCC Accession No. CRL-2408 was IL-2 independent progeny derived from NK-92 cell line in which the gene for IL-2 has been inserted into the genome of the cells, and thus the cells can be culture without the need of using IL-2 (e.g. see lines 5-10 in page 9). Braun also teach NK-92 ATCC CRL-2407 cell line, an IL-2 dependent cell line (e.g. see lines 26-32 in page 8).
Lopez-Verges teaches that CD57 is expressed on CD16+ NK cells (e.g. see last paragraph in right col. in page 3866). Lopez-Verges teaches sorting NK cells with anti-CD57 antibody (e.g. see Cytotoxicity assays in left col. in page 3866). Lopez-Verges teaches that CD57 is expressed on 30%-60% of CD16+ NK cells (e.g. see Results in right col. in page 3866).
It would thus be obvious to one of ordinary skill in the art at the time to combine the teachings of the prior art to select CD16+ NK-92MI cells from the well-known IL-2 independent NK-92MI cells ATCC CRL-2408 following the methods disclosed in Cheng in the same way as the IL-2 dependent NK-92 ATCC CRL-2407. Such enriched CD16+ NK-92MI cells would also be expected to express CD57 and the enriched population of NK-92MI cells would be expected to contain more CD16+CD57+ NK-92MI cells as compared to not enriched NK-92MI cells. Also note that the CD16and CD57 are natively expressed in the NK-92MI enriched cells.
As evidenced by [0031] of the instant specification as filed that CD16+CD57+ NK-92 MI cells also express NKG2D. Thus, the enriched CD16+ NK-92 MI would be CD57+ and have higher NKG2D than unenriched NK-92 MI cells.
Given that the prior art NK-92MI cells contains the same NK-92MI cells (natively express CD16 and CD57) and can grow without IL-2, the prior art NK-92MI cells will inherently have the same recited functions, e.g. enhanced direct cytotoxicity against Ramos cells, post-thaw maintaining high expression of CD57, CD16, and NKG2D, a faster replenishment post degranulation as the instantly claimed NK-92MI.
One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since NK-92MI cell line ATCC CRL-2408 is well established and readily available and is an obvious variant of the NK-92 cells ATCC CRL-2407 used by Cheng. Further, given that CD16 on NK cells is known to be necessary for ADCC effect and CD57 is known for a marker for highly cytotoxic, it would be obvious the selected CD16+NK-91MI cells would also express CD57. An ordinary skill in the art would have a reasonable expectation of success in view of detail methods disclosed in Cheng by using well known NK-92MI cell line as taught by Tam.
As evidenced by Jochems et al., CD16 can be engineered to express on the surface of NK-92 cells that were also engineered to express IL-2 cytokine; NK-92 cells engineered to express CD16 and IL-2 are capable of proliferate in the absence of exogenous IL-2 and kill tumor cells via ADCC (e.g. see last paragraph on the right col. in page 86369).
As further evidenced by [0031] of the instant specification as filed that CD16+CD57+ NK-92 MI cells also express NKG2D.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues Cheng teaches genetically engineered NK-92 with artificially expressed CD16, and teaches that NK-92 cells do not naturally express CD16 and therefore require genetic modification to enable CD16 expression and ADCC activity. Applicant further asserts that the secondary references Braun, Lopez-Verges or Jochems do no teach NK-92 or NK-92MI cess that natively express CD16. Therefore, applicant argues that Cheng teaches away from the instant invention by not teaching natively expressed CD16 but only teaches genetically expressed CD16 which is identical structurally to the natively expressed CD16. Applicant asserts that Lopez-Verges does not teach CD57 expression in NK-92 or NK-92-MI cells but rather, teaches only primary NK cells and that CD57 is a marker for terminally differentiated NK cells and associated with cellular senescence and reduced proliferative potential. Applicant further asserts that the references do not provide motivation to combine with a reasonable expectation of success because:
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Applicant argues that the prior art does not recognize the existence of CD16+CD57+ NK-92MI cells, and thus would not recognize the functions associated with them.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In response to applicant’s arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combination of references. See MPEP 2145.
Further, contrary to applicant’s arguments that Cheng teaches away from using NK-92 MI for selecting CD16+ cells, note that a prior art reference must be considered in its entirety. See MPEP 2141.02. Further, "the prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." See MPEP 2123. Furthermore, a prior art reference may be considered to teach away when "a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1131 (Fed. Cir. 1994).
Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. In re McLaughlin , 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). See MPEP 2145.
Here, contrary to applicant’s mischaracterization of Cheng, note that Cheng does not teach NK-92 genetically engineered to express CD16. Rather, Cheng was able to enrich NK-92 (ATCC CRL-2407) CD16+ cells using anti-CD16 antibody from very low native CD16 expressing cells (only 2.5%-2.6% of unenriched NK-92 cells express CD16). Note that the NK-92 cell line (ATCC CRL-2407) used by Cheng is the parent of NK-92MI (genetically engineered to express IL-2) taught by Braun. Given that Cheng teaches that NK-92 cell (ATCC CRL-2407) were known to have very low native CD16 expression (2.5-2.6%) and that sorting methods of using anti-CD16 antibody are able to select and enrich CD16+ NK-92 cell (ATCC CRL-2407) and gain the function of tumor cell killing via ADCC, an ordinary skill in the art would have been motivated to using this method to sort NK-92 MI cell line (ATCC CRL-2408), a cell line improved from NK-92 (ATCC CRL-2407) by having engineered IL-2 gene with a reasonable expectation of success.
It would thus be obvious to one of ordinary skill in the art at the time to combine the teachings of the prior art to select CD16+ NK-92MI cells from the well-known NK-92MI cells ATCC CRL-2408 (IL-2 independent) following the methods disclosed in Cheng in the same way as the NK-92 ATCC CRL-2407 (parent of NK-92 MI).
Note that the mere recognition of latent properties (CD16 enriched NK-92 MI cell also have enriched CD57) in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979).
This is because the NK-92 MI can grow without addition of IL-2 and the NK-92 MI sorted with anti-CD16 antibody following Cheng’s method would be expected to be cytotoxic against human tumor cells without the need to have added IL-2 since NK-92 MI is engineered to express IL-2 recombinantly. Given that it was known that CD57 is also expressed on 30-60% of CD16+ NK cells as taught by Lopez-Verges (e.g. see Results in right col. in page 3866), the enriched natively expressed CD16+ NK-92 MI cells would also be expected to natively express CD57. The enriched cells would contain more CD16+CD57+ NK-92 MI cells (both markers CD16 and CD57 are natively expressed) than NK-92 MI (ATCC CRL-2408) unsorted by anti-CD16 antibody.
As such, applicant’s arguments have not been found persuasive.
7. Claim 11 stands rejected under 35 U.S.C. 103 as being unpatentable over Cheng (WO 2020/150475, reference on IDS) in view of Cheng (WO 2020/150475, reference on IDS) in view of Braun (WO2008/070647) and Lopez-Verges (Blood, 2010, 116;19:3865-3874, reference on IDS) as evidenced by Jochems et al. (Oncotarget, 2016, 7;52:86359-86373, reference on IDS) as further evidenced by [0031] of the instant specification as filed that CD16+CD57+ NK-92 MI cells also express NKG2D, as applied to claim 8 above, and further in view of Smith (Drug Discovery & Development. September 16, 2021, pages 1-7) for the reasons of record.
The teachings of Cheng, Braun, and Lopez-Verges have been discussed above.
The reference teachings differ from the instant invention by not describing AB serum.
Smith teaches that commercially available human AB serum is from human donors having both A and B antigens on their red blood cells and therefore lacks blood group antibodies. The AB serum is a staple in the biological research field, providing nutrients, vitamins and necessary growth factors in cellular culture and reliable controls in in vitro diagnostics (e.g. see pages 1-2).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to add human AB serum to the NK-92MI cells selected to have CD16 and CD57 on the cell surface. One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success since Smith teaches the well-known benefits of AB serum in cell culture – the lack of blood group antibodies and capable of providing necessary nutrients, vitamins, and growth factors. As such, adding commercially available AB serum to the NK-92MI cells that are CD16+CD57+ would be expected to be beneficial for in vitro diagnostic uses.
Applicant’s arguments and the Examiner’s rebuttals regarding the teachings of Cheng, Braun, and Lopez-Verges are essentially the same as discussed above.
As such, the rejection has been maintained for the reasons of record.
8. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641