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 .
Claims 1, 14, 16, 29-30, 43, and 57-64 are pending.
Claim 64 is new.
Applicant's election with traverse of Group 1, claims 1-3, 5, 7-9, and 13, in the reply filed on 04/09/2025 is re-acknowledged. The traversal was on the ground(s) that the inventions possess unity of invention. This is not found persuasive because the traversal argument fails to point to any deficiency in the Examiner’s argument that the inventions, lacking unity of invention for lack of a special, shared technical feature, upon which the restriction requirement was based.
The requirement is still deemed proper and is therefore remains FINAL.
Claims 14, 16, 29-30, 43, and 63 remain withdrawn and newly added claim 64 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected groups/inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/09/2025.
Claims 2-13, 15, 17-28, 31-42, and 44-56 are cancelled.
Claims 1, 29, and 61 are amended.
Claims 1 and 57-62 are under examination on the merits.
Priority
This application is a 371 of PCT/US2020/050112, filed 09/10/2020, which claims benefit of priority to US Provisional Applications 62/898,170, filed 09/10/2019, and 62/904,843, filed 09/24/2019.
Information Disclosure Statement
The IDS submission filed on 02/17/2026 has been considered by the Examiner.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/17/2026 has been entered.
Maintained-Claim Interpretation
Where ‘recovery’ is recited in the claims, recovery is being interpreted to mean restoration of immune cell function (such as cytotoxic activity), as supported by exemplary page 11 of the specification (see for example, point 48).
The term ‘increased’, in the interest of advancing prosecution, being interpreted to mean any increase relative to a specified control (as is consistent with the entirety of the disclosure, see for example point 13 at exemplary page 3 of the specification).
The recitation that the NK cell comprises a CAR NK cell is being interpreted to mean that the NK cell to be frozen, thawed, and assayed in the method of claim 1 comprises a chimeric antigen receptor (CAR) prior to freezing, thawing, and assaying for CD16 expression (see for example, claim 58).
The recitation that the NK cell is an expanded NK cell is being interpreted to mean that the NK cell to be frozen, thawed, and assayed in the method of claim 1 has been expanded prior to freezing, thawing, and assaying for CD16 expression (see claim 59).
The recitation that the expression level of CD16 on the NK cell within 3 hours after thawing (test cell) is 80% or more of an expression level of CD16 on a control is being interpreted to mean that the measured level of CD16 expression of the test cell is a value which is 80% or more of the measured level of CD16 expression on the control cell (for example, if the control cell had a CD16 expression level of 100, then the test cell level of CD16 expression selected for having an increased CD16 expression correlated with an increased likelihood of recovery would have a CD16 expression level of 80 or higher).
New-Claim Interpretation
Recitations of “suitable for immunotherapy” are being interpreted to mean that the cell(s) have a likelihood of recovery of cytotoxic function related to measured CD16 as is consistent with what is described and disclosed in the entirety of the instant specification, noting that the term “suitable for immunotherapy” is never used or specifically defined. The only remote disclosure is the constructive definition set forth in this claim interpretation.
Recitations of “lots of cells” is interpreted to refer to lots as disclosed at the second sentence of the background section at page 1 of the specification. This being the only mention/disclosure of “lots”, “lots” are interpreted to refer to a number or plurality of cells that are selected (art teaching selection of cells, a plurality of cells, or a batch(es) of cells would be deemed to anticipate or make obvious this limitation). This is further consistent with the drafting of newly added step a of claim 1.
Withdrawn Objections and Rejections
The objection to claim 1 presented in the office action dated 12/17/2025 is withdrawn in light of the corrective claim amendment dated 02/17/2026. The rejection of claim 61 under 35 USC §103 over Romee et al and Mata et al is withdrawn and replaced with the rejection under 35 USC §103 presented, below, in this Office Action to better account for the 02/17/2026 amendments to the claim.
Claim Objections
Claim 1 is objected to because of the following informalities: “lots of” in line 1 is plural, but the modified “a Natural Killer cell” is singular. For consistency, it is recommended that “a natural killer cell” should be amended to “natural killer cells”.
Claims 1, 57-59, and 61-62 are objected to because of the following informalities: ‘natural killer’ cell(s) is not a proper noun and should not be capitalized unless appearing at the beginning of a sentence.
Appropriate correction is required.
Maintained-35 U.S.C. 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 57-62 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is directed to a judicial exception (natural correlation), specifically, the presence/increase of a measurement of CD16 as an indicator of ADAM-17 activity and a likelihood of recovery of a natural killer (NK) cell after a freeze thaw cycle/event. Furthermore the claim does not integrate said judicial exception in to practical application, and the claim does not recite additional elements that amount to significantly more than said judicial exception.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extrasolution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to a natural phenomenon.
Regarding claim 1, the claim language reciting the judicial exception is, “[a] method of selecting lots of a natural killer cell suitable for use in immunotherapy, the method comprising obtaining one or more of thawed NK cells previously subjected to a freeze thaw cycle, assaying the natural killer cell within 3 hours after thawing to determine an expression level of CD16 expressed on the natural killer cell, and selecting lots of thawed natural killer cells from step b) that express an increased level of CD16 compared to expression of CD16 on a cell-surface-damaged negative control natural killer cell for use as a natural killer cell suitable for an immunotherapy, wherein the increased level of CD16 expression indicates low A disintegrin and metalloprotease domain 17 (ADAM-17) activity and positively correlates with the likelihood of natural killer cell recovery.”
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 1 recites, “[the method of…” selecting lots of a natural killer cell. Therefore, the instant claim 1 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 1 recites a method comprising steps, including, obtaining a cell(s), assaying for the amount of CD16 expression as an indicator of ADAM-17 activity predictive of the likelihood of recovery after a freeze-thaw cycle and interpreting an increase as a measurement of likelihood of recovery of an immune cell, and selecting lots of thawed NK cells from step b that express an increased level of CD16. The correlation of a cleaved receptor (CD16) and likelihood of recovery represents a natural phenomenon, which is a judicial exception. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 1 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition. Therefore the answer to prong two of the Step 2A analysis is “No” and the analysis progresses to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101. Here, the instant claim 1 pertains to a method of selecting lots of cells, as discussed above. Claim 1 fails to recite additional limitations that would add significantly more than the judicial exception to the metes and bounds of the claim. Here, the generic steps of obtaining, measuring/assaying the expression of the recited cleaved-receptor and identifying likelihood of recovery based upon said measurement, and selecting cells amount to no more than mere data gathering steps and do not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). Therefore, the answer to prong 2B is “No” and the instant claim 1 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Claim 57, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step.
Claim 58, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step.
Claim 59, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step.
Claim 60, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step. Claim 60, does not integrate by addition of, for example, a treatment or prophylaxis step and does not add further active steps over the method of claim 1.
Claim 61, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step.
Claim 62, incorporates the judicial exception of claim 1 by dependence and fails to add significantly more or to integrate the exception through recitation of a specific treatment step.
An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016).
Therefore, claim 1 and its dependents, claims 57-62, are deemed patent ineligible under 35 USC §101.
Maintained-Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 57, 60, and 62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romee et al (NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 2013 May 2;121(18):3599-608. doi: 10.1182/blood-2012-04-425397. Epub 2013 Mar 13) in view of Mata et al (Effects of cryopreservation on effector cells for antibody dependent cell-mediated cytotoxicity (ADCC) and natural killer (NK) cell activity in (51)Cr-release and CD107a assays. J Immunol Methods. 2014 Apr;406:1-9. doi: 10.1016/j.jim.2014.01.017. Epub 2014 Feb 20).
Regarding claim 1, it is noted that the only explicit, active step is measuring/assaying the amount of CD16 expression with a further implied mental step of comparing the measured amount of CD16 to a control/reference value. The preamble recitation that the selected cell is suitable for use in an immunotherapy is not an active step breathing life and meaning into the claim so as to lend patentable weight.
Romee et al teach that CD16 is present on the surface of NK cells and plays an important role in antibody-NK cell mediated cytotoxic activity of the NK cell. Romee et al further teach that the metalloprotease ADAM-17 cleaves CD16 (see for example the abstract at pg. 3599). Note that Romee et al teach measurement of CD16 (see for example Figure 1 and its caption at pg. 3602 and pg. 3604, right hand column). Romee et al further teach measurement of the surface-expressed receptor CD16 using commercially-available antibodies against CD16 and a commercially-available flow cytometer and software (see for example, column 1 at page 3600 under the Antibodies heading and Figure 4 and its caption at page 3604).
Romee et al do not explicitly teach a connection between CD16 and freezing and thawing cells or between a freeze-thaw and diminished recovery of cell function.
However, Mata et al teach that CD-16 is decreased in frozen and thawed NK cells which have a decreased level of cytotoxic (ADCC) activity (see for example pg. 8). Mata et al further teach that the freeze-thawed NK cells were used either immediately or after overnight incubation, which would read upon and make obvious any use within the time frame of 0-12 hrs (see for example, Figures 2-3 at pages 3-4 and paragraph 1 of column 1 of page 5). While Mata et al may initially appear to show that NK cells used after thawing (not rested) have lower NK cell activity, this is not taken to be a teaching against assaying for CD16 expression within 3 hrs of thawing (in thawed/non-rested cells) because thawed NK cells thawed/non-rested (held to read on being assayed within 3 hrs of thawing) and thawed/rested (held to mean the cells were assayed after 8-12 hours of thawing) were reported to have the same mean CD16 expression (see for example, page 6, paying particular attention to Table 1 and its caption).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Romee et al and Mata et al. The artisan would have been motivated to make and use the invention as claimed because Romee et al teach that CD16 is important for NK cell cytotoxic function (as well as how to measure the level of CD16) and Mata et al teach that CD16 is decreased after freeze-thawing cells. The combined disclosures lead the artisan to measure and select (where the generic recitation encompasses any known means in the art, up to and including mental selection) cells with a greater amount (aka an increased amount) of CD16 (so as to lead to a cell (or lot(s) thereof) more likely to function at any point in time including after a potentially membrane-damaging event, such as a freeze-thaw cycle) purely in the interest of optimizing known NK cell function (such as desirable cytotoxic (ADCC) function). The MPEP provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)). Therefore, the cited references and teachings are held to make obvious before the effective filing date of the claimed invention the active step of measuring/assaying for the level of a surface-expressed receptor (CD16), comparison of said measurement to some reference/control value, and selection of cells bearing more CD16 as a means of selecting cells most likely to have the greatest degree of (cytotoxic) function (understood to be a cell with a greater likelihood of recovery, see the claim interpretation section of this Office Action). Where the active steps are the same (obtaining the cell, measuring/assaying, and selecting cells) and the starting population is the same (NK cells after a freeze/thaw cycle), the results are presumed to be the same. It is noted that cells selected based upon a higher CD16 expression level are suitable for immunotherapy as claimed, such that prior art teaching or making obvious such selection makes obvious the instant claim (see for example, the claim interpretation section above). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 57, Mata et al teach that the frozen PBMCs (including NK cells) were thawed using a water bath (see for example, paragraph 1 of column 1 of page 5).
Regarding claim 60, Mata et al teach analysis of CD16 expression using flow cytometry (see for example, section 2.5 at columns 1-2 of page 5 and Figure 2 and its caption at page 3; see also, for example, Romee et al at column 1 at page 3600 under the Antibodies heading and Figure 4 and its caption at page 3604).
Regarding claim 62, as discussed above, Romee et al and Mata et al teach and make obvious the method of claim 1. Mata et al appears to further teach that cells frozen and thawed are capable of having as much and even more CD16 expression as measured by flow cytometry (see for example, Table 1 and its caption at page 6). Mata et al does not point to an increase of 80% or more being particularly significant.
However, Romee et al and Mata et al both point to the significance of CD16 expression for NK cell activity and show that sufficient CD16 expression is important for NK cell function and cytotoxicity. The artisan, in light of Mata using a fresh NK cell (not frozen and thawed) as a positive control/baseline, would have understood the desirability of selecting (not a required active step of the claim) an NK cell with a higher (close to the positive control-fresh cell expression level) expression of CD16 would be more likely to have or recover immune function(s) associated with NK cells (such as cytotoxic functionality).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Romee et al and Mata et al. The artisan would have been motivated to make and use the invention as claimed because Romee et al teach that CD16 is important for NK cell cytotoxic function and Mata et al teach that CD16 is decreased after freeze-thawing cells. The combined disclosures lead the artisan to measure and select for cells with a greater amount (aka an increased amount which would have been understood to be an amount up to the expression observed in positive control (non-frozen-thawed/fresh cells)) of CD16 in order to select for a cell with a greater likelihood of having/recovering cytotoxic (immune) function. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romee et al and Mata et al, as applied to claims 1, 57, and 60-62 above, in further view of Hermanson et al (Front Immunol. 2015 Apr 28;6:195. doi: 10.3389/fimmu.2015.00195).
Regarding claim 58, as discussed above, Romee et al and Mata et al teach and make obvious the method of instant claim 1.
Romee et al and Mata et al do not explicitly teach that the NK cell is a CAR NK cell.
However, Hermanson et al teach that chimeric antigen receptors (CARs) have also been evaluated in peripheral blood NK cells (PB-NK cells). In contrast to NK-92 cells, activated PB-NK cells express a wider range of activating receptors, such as CD16. A greater variety of CAR constructs have been used and directly compared in PB-NK cells (see for example, column 2 of page 3). Hermanson et al further teach that NK cells recognize infected or transformed cells through multiple cell surface receptors including, CD16 [the receptor that mediates antibody-dependent cellular cytotoxicity (ADCC)] (see for example, the abstract at page 1). Note that Hermanson et al teach that a disadvantage of a common NK cell line (NK-92 cells) is that they do not express CD16, implicitly teaching that expression of CD16 would be beneficial for a CAR NK cell (see for example, the last paragraph of column 1 of page 2).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Romee et al, Mata et al, and Hermanson et al. The artisan would have been motivated to make and use the invention as claimed because Romee et al teach that CD16 is important for NK cell cytotoxic function (as well as how to measure the level of CD16) and Mata teach that CD16 is decreased after freeze-thawing cells. The combined disclosures lead the artisan to measure and select cells with a greater amount (aka an increased amount) of CD16 (whether that increase is relative to a membrane-damaged cell as the negative control or non-membrane-damage-exposed cell would appear to be irrelevant where the combination of the cited references teach that an increase in the amount of CD16 expression enhances function (so as to lead to a cell more likely to function at any point in time including after a potentially membrane-damaging event such as a freeze-thaw cycle) purely in the interest of optimizing known NK cell function (such as desirable cytotoxic (ADCC) function). Hermanson et al teach that CAR NK cells are helpful in treating cancers (see for example, the abstract at page 1 and column 2 of page 3) and that NK cells expressing CD16 are advantageous for use/incorporation into a CAR NK cell (see for example, the last paragraph of column 1 of page 2). Therefore, the artisan, motivated to make a CAR NK cell for treating cancer, would have been further motivated to select an NK cell expressing CD16 in developing the CAR NK cell. Additionally, the cells of Romee et al would have been understood, in light of the teachings of Mata et al, to have a greater likelihood of recovery (which is interpreted to encompass a restoration of/capacity for immune function) and Romee et al, Mata et al, and Hermanson et al teach that CD16 is positively correlated with NK cell immune function (ADCC/cytotoxicity; see the cited teachings as discussed in the rejections above). Likewise, selection of frozen CAR NK cell based upon an increased CD16 expression would have been understood as obvious in light of the cited prior art teachings in order to select an NK cell most able to function in the therapeutic/cytotoxic process associated with CAR NK therapy, where the inclusion of the CAR would not have been expected to alter predictability of said correlation between CD16 and actual/recovered cytotoxic activity/capacity (immune function). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romee et al and Mata et al , as applied to claims 1, 57, and 60-62 above, in further view of Lee et al (Sci Rep 7, 11075 (2017). https://doi.org/10.1038/s41598-017-09259-1).
Regarding claim 59, it is unclear what significance the nature of the NK cell (expanded versus non-expanded would have for the practice of the method of instant claim 1.
Regardless, as discussed above, Romee et al and Mata et al teach and make obvious the method of claim 1.
Romee et al and Mata et al do not teach that the NK cell is expanded prior to use in the method of claim 1.
However, Lee et al teach that an NK cell activating signal is mediated by various NK cell receptors, including CD16, which is responsible for ADCC (see page 1). In particular, CD16 has a unique ability to induce NK cell activation without additional receptor signals (see page 2). Thus, combinations of NK cell-activating receptors, including CD16 can be a promising strategy to induce NK cell activation and expansion. While the level of CD16 did not significantly differ between expanded and non-expanded NK cells, the expanded NK cells had higher levels of other receptors known to act synergistically with CD16 for NK cell activation and immune function (see pages 1-3).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Romee et al, Mata et al, and Lee et al. The artisan would have been motivated to make and use the invention as claimed because Romee et al teach that CD16 is important for NK cell cytotoxic function (as well as how to measure the level of CD16) and Mata teach that CD16 is decreased after freeze-thawing cells. The combined disclosures lead the artisan to measure and select cells with a greater amount (aka an increased amount) of CD16 (whether that increase is relative to a membrane-damaged cell as the negative control or non-membrane-damage-exposed cell would appear to be irrelevant where the combination of the cited references teach that an increase in the amount of CD16 expression enhances function (so as to lead to a cell more likely to function at any point in time including after a potentially membrane-damaging event such as a freeze-thaw cycle) purely in the interest of optimizing known NK cell function (such as desirable cytotoxic (ADCC) function). Lee et al teach that CD16 aids in expansion of NK cells and that expansion increases expression of other receptors which are synergistic with CD16 for NK cell activity/activation. Therefore, the artisan would have expected an expanded NK cell to function in the method of Romee et al and Mata et al and would have understood that using an expanded T cell in the method may further enhance the likelihood of recovery of immune function of the NK cell having increased CD16 (through combining the teachings of Romee et al and Mata et al regarding CD16 and the teachings of synergy from Lee et al). Additionally, the cells of Romee et al would have been understood, in light of the teachings of Mata et al, to have a greater likelihood of recovery (which is interpreted to encompass a restoration of/capacity for immune function) because Romee et al, Mata et al, and Lee et al teach that CD16 is positively correlated with NK cell immune function (ADCC/cytotoxicity; see the cited teachings as discussed in the rejections above). Likewise, there is no reason to believe that the method of Romee et al and Mata et al would not function to predictably identify frozen-thawed, expanded (before or after the freeze-thaw) NK cells which are more likely to have recovered functionality based upon a relatively increased expression of CD16. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
New-Claim Rejections - 35 USC § 103
Claim(s) 61 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romee et al in view of Mata et al , as applied to claims 1, 57, 60, and 62 above, in further view of Min et al (Immune Netw. 2018 Aug 21;18(4):e31. doi: 10.4110/in.2018.18.e31).
Regarding claim 61, as discussed above in the rejection of claim 1, an increased level of CD16 is correlated (using an assay) with the likelihood of NK cell recovery (interpreted to be a restoration/preservation of NK cell immune function) within 0-12 hrs, where use of the array to mentally correlate the likelihood of function with an increased CD16 expression is made obvious as soon as immediately after thawing the cells where restoration of function after overnight thawing is supported after thawing and overnight resting (held to make obvious restoration within 24 hrs) (see for example, Figure 3 and its caption at pages 4-5 and page 6 of Mata et al).
Romee et al and Mata et al do not teach that the increased level of CD16 expression on NK cells positively correlates with the likelihood of NK cell recovery 24 hours after thawing.
However, Min et al assessed the effect of cryopreservation on the expanded NK cells in regards to viability, phenotype, and anti-tumor activity (see for example, page 1/25). Min et al analyzed cryopreserved NK cells not only immediately after thawing but also after incubation for 24 or 48 h with or without IL-2 (500 IU/ml) following thawing. As results, the cell number, viability, and cytotoxic activity of thawed NK cells were not significantly influenced by the incubation time and/or the presence of IL-2 (see pages 8/25-9/25 and Supplemental Fig. 3).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because as discussed above, the combination of Romee et al and Mata et al motivate the artisan to measure/assay for CD16 expression in thawed NK cells and to select NK cells with an increased relative CD16 expression as an indicator of an increased likelihood of recovery, understood per the claim interpretation section, to mean that the cells are likely to have or recover pre-freeze-thaw level cytotoxic/ADCC activity which makes the cell(s) suitable for immunotherapy (see the claim interpretation section above) and teach/make obvious that increased CD16-expression positively correlates with the likelihood of recovery up to 12 hrs post-thaw. The artisan would have expected this positive correlation (an effect of practicing the method of claim 1, notably not an active step) to extend to 24 hrs post-thaw, predictably, because Min et al, examining cryopreserved NK cells (post freeze-thaw), looked at NK cells immediately post-thaw, 24 hrs post-thaw, and 48 hrs post-thaw and found that cytotoxic activity was not different at any of the three time points (indicating that cytotoxic activity is relatively stable such that cells with indicators of higher actual or likely recovered cytotoxic activity would predictably exhibit that property across a 48 hr post-thaw period. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues that the limitations added in the 02/17/2026 claim amendments recite significantly more sufficient to warrant withdrawal of the rejections under 35 USC §101 (see for example, page 1 of the remarks dated 02/17/2026).
Response: The amendments do not substantively alter the scope of the claims. Applicant does not point to what they view as adding significantly more, but merely alleges that the amendments add significantly more. 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); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Therefore, the rejections under 35 USC § 101 as they appear in this office action are maintained at this time.
B. Applicant argues that the rejections under 35 USC §103 should be withdrawn by attacking the Mata et al reference individually and casting doubt on the predictability of damage caused by a freeze-thaw event (see for example, pages 1-4, focusing on pages 1-2, of the remarks dated 02/17/2026).
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Looking to the substance of Applicant’s arguments, Applicant focuses factors which are not recited in the instant claims. For example, Applicant points out that Mata et al do not show a significant difference in viability, cytotoxicity, or CD16 expression in NK cells that were frozen and thawed. The claims do not require that the NK cells exhibit these effects after being thawed. Moreover, where the art teaches the use of NK cells after a freeze-thaw and makes obvious the desirability to measure and select cells with a relatively increased CD16 expression level, it is obvious to the artisan to practice the method. If anything, Applicant’s points go towards the unpredictable or mild effect of a freeze-thaw event, not towards unpredictability or a surprising result of practicing the method made obvious by the prior art of record. It is noted that Romee et al teach that CD16 is predictive of cytotoxicity which would motivate the artisan to select for NK cells with a relatively higher CD16 expression (as iterated in the rejections under35 USC §103 above in greater detail). The rejections of claims 1, 57, 60, and 62 are maintained because the arguments presented at pages 1-3 of the 02/17/2026 remarks are unpersuasive. Applicant relied on the points rebutted above to support withdrawal of the rejections of claim 58 under 35 USC §103, therefore said rejection of claim 58 is maintained(see page 3 bridging page 4 of the 02/17/2026 remarks). Applicant relied on the points rebutted above to support withdrawal of the rejections of claim 59 under 35 USC §103, therefore said rejection of claim 59 is maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. CN105838677 A (citation 2 under Foreign Patent Documents on the 02/17/2026 IDS) is deemed relevant.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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