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
The amendment filed July 7, 2026, is acknowledged and has been entered. Claim 1 has been amended. Claim 25 has been newly added.
Claims 1-25 are pending in the application.
Claims 9-24 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-8 and 25 are under examination.
Grounds of Rejection Withdrawn
Unless specifically reiterated below, Applicant’s amendments have obviated or rendered moot the grounds of objection and rejection set forth in the previous Office action mailed.
Grounds of Rejection Maintained
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.
Claims 1-6, 8 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/187207 A1 (Saxena et al) and Ndhlovu et al (Blood, 119(16):3734-3743, 2012).
Saxena et al disclose methods of generating memory-like cytokine enhanced natural killer (M-CENK) cells from a apheresis product, the method comprising: a) purifying NK cells from an apheresis product, incubating the NK cells with IL-15 or N-803 (IL-15 analog) to expand the NK cells and then activating the cells with a cytokine composition comprising IL-15, IL-18 and IL-12 to produce CD56+ M-CENK cells (see pages 3, 5, 13 and 16 and Figures 1 and 6). Saxena et al disclose that the cytokine composition comprises IL-15 at 50 ng/mL, IL-18 at 50 ng/mL, and IL-12 at 10 ng/mL (see pages 4 and 6). Saxena et al disclose that the NK cells can be autologous NK cells from cancer patients (see Figure 39 and pages 1 and 6). Saxena et al disclose that the M-CENK cells are a potent killer of ovarian, breast and leukemia cells (see Figures and page 3).
Saxena et al disclose that the step of incubating is performed over until the NK cells are enriched to at least 65% of all live cells (see page 2).
Saxena et al do not disclose using separation techniques to remove CD3+ cells and CD14+ cells from a sample to obtain NK cells.
Ndhlovu et al disclose methods of isolating NK cells by methods using FACS sorting that remove CD3+ cells and CD14+ cells (see page 3735).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to combine these references and incorporate the methods of isolating NK cells as disclosed by Ndhlovu et al from whole blood of ovarian, breast and leukemia cancer patients to remove CD3+ cells and CD14+ cells to enrich for NK cells that are CD3- and CD14- cells and then incubating those cells with IL-15 or N-803 (IL-15 analog) to expand the NK cells until they are at least 65% of the cells and then activating the cells with a cytokine composition comprising IL-15 at 50 ng/mL, IL-18 at 50 ng/mL, and IL-12 at 10 ng/mL to produce CD56+ M-CENK cells because this method has the advantage of enriching NK cells as desired by Saxena et al which can be used to produce autologous CD56+ M-CENK cells that can be used to treat the patient. Furthermore, the method of Saxena et al which discloses isolating NK cells from an apheresis product using beads is taught as having the disadvantages that this approach limits the ability to expand the
cells and such isolated and induced NK cells tend to have relatively lower cytotoxic potential, so using FACS sorting to remove CD3+ cells and CD14+ cells would have the advantage of not using beads as in the process of Saxena et al which has known disadvantages. In this case, one of ordinary skill in the art would see these methods as combining prior art elements according to known methods to yield predictable results. Furthermore, one of skill in the art would have expected success in practicing such methods as the prior art discloses how to enrich NK cells from whole blood and how to obtain M-CENK cells from those NK cells
Then with respect to the first incubating period of 7-12 days or 8-10 days as set forth in claims 8 and 25, Saxena et al demonstrates that the NK cells should be enriched to at least 65% of cells and this enrichment time would vary based on the percent of starting NK cells and how fast the NK cells expand, so a first incubating period of 7-12 days or 8-10 days would be considered obvious because the incubation period was considered a result-effective variable. As set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977).
It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, the optimization of the first incubating period of Saxena would be seen as routine optimization, absent a showing otherwise.
Accordingly, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
In the response filed July 7, 2026, Applicant traverses the rejection arguing that:
The cited references don teach every limitation of the claims because Saxena is directed to generating M-CENK cells from mononuclear cells. Saxena's method begins by "obtaining a plurality of mononuclear cells," contacting those cells with a corticosteroid and optionally a cytokine, to enrich for NK cells, and only then inducing the enriched NK cells with the TxM fusion protein. Paragraphs [0013]-[0018]. In cases where Saxena uses an apheresis product as the starting material, enrichment for NK cells must first be achieved.
This argument is not found persuasive because while Saxena discloses generating M-CENK cells from mononuclear cells, Saxena also discloses using an apheresis product as the starting material (see pages 3, 5, 13 and 16 and Figures 1 and 6) and enriching for NK cells which is what removing CD3+ cells (comprises T cells) and CD14+ cells (comprises monocytes/macrophages) accomplishes.
There is no motivation to combine Saxena and Ndhlovu because Saxena teaches away from such a modification. Saxena expressly states that prior approaches in which NK cells are first isolated from an apheresis product, although reducing CD3-positive cells, "limit[s] the ability to expand the cells" and yield cells with "relatively lower cytotoxic potential." See, Saxena, paragraph [0011].
This argument is not found persuasive because Saxena is referencing other protocols specifically using beads (Saxena, paragraph [0011]) and these other protocols disclosed in Saxena are not part of the FACs technique of Ndhlovu. Therefore, this disclosure instead provides further motivation to incorporate the FACs method of Ndhlovu to enrich for NK cells from apheresis product.
The claimed invention produced surprising results because the methods produced M-CENK cells product with surprisingly high CD16 expression-the M-CENK cells had 73% CD16 expression and greater cytotoxicity against target cancer cell lines, the claimed methods also reduced the time required to manufacture M-CENK cells from apheresis product from 14 days to 8 days, and the claimed methods directly result in a final cell product that possesses completely undetectable levels of residual CD3+T cells.
This argument is not found persuasive because as set forth in MPEP 716.02(d) “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
In this case, as set forth in Example 2, starting at page 38, a specific protocol using specific components (involving magnetic cell sorting, for example) resulted in the results pointed to by Applicant, but the claims are drawn to generic methods that need not produce such results, such that it is clear the claimed methods are not commensurate in scope to the evidence offered in support.
Furthermore, these arguments of counsel that the results are unexpected do not establish that the evidence presented is unexpected. The argument merely presents data obtained using a specific protocol and submits that the results are surprising. For example, removing CD3+ cells as taught by Ndhlovu et al removes CD3+T cells such that it would appear to be expected that the final product would
possesses completely undetectable levels of residual CD3+T cells, such that the methods suggested by the prior art references would appear to result in the outcome presented here. Objective evidence of unexpected results which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Therefore, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons of record as explained in the preceding Office action, this rejection is maintained.
Claims 1-8 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/187207 A1 (Saxena et al) and Ndhlovu et al (Blood, 119(16):3734-3743, 2012), as applied to claims 1-6, 8 and 25 above and in further view of US 2020/0281977 A1 (Mantovani et al).
The above 103 rejection suggests and teaches that which is set forth above.
Mantovani et al disclose that magnetic cell sorting can be used to enrich NK cells (see page 12).
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to substitute magnetic cell sorting for FACS of Ndhlovu et al to enrich NK cells in the methods suggested above because either step could be used to enrich NK cells so one of skill in the art would see that this would be considered as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results and would have reasonably expected success in substituting magnetic cell sorting for FACS. Notably, Mantovani et al do not disclose issues with their magnetic cell sorting technique such that their method would be seen as simple substitution of one known element for another to obtain predictable results.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
In the response filed July 7, 2026, Applicant traverses the rejection arguing that:
“As discussed above, Saxena is directed to generating M-CENK cells from mononuclear cells instead of beginning directly from an apheresis product. Ndhlovu does not remedy Saxena's deficiency as discussed above because Ndhlovu is silent on apheresis products. Mantovani, like Ndhlovu, is also silent on apheresis products, and thus cannot cure Ndhlovu's deficiency. Mantovani also does not disclose or suggest removing both CD3+ cells and CD 14+ cells from apheresis product.”
This argument is not found persuasive because while Saxena discloses generating M-CENK cells from mononuclear cells, Saxena also discloses using an apheresis product as the starting material (see pages 3, 5, 13 and 16 and Figures 1 and 6) and enriching for NK cells which is what removing CD3+ cells (comprises T cells) and CD14+ cells (comprises monocytes/macrophages) accomplishes.
Therefore, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons of record as explained in the preceding Office action, this rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached on Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
August 12, 2026
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