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
1. Applicant’s amendment and response filed 9/19/25 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I, drawn to a method of selecting universal donor NK cells for therapeutic administration comprising the recited method steps and to a method of preparing a population of universal donor NK cells for therapeutic administration comprising selecting the cells and exposing the cells to IL-21 (the protein) in vitro for a time sufficient to expand the NK cells, in Applicant’s said amendment and response filed 9/5/2024.
Claims 1-3, 5, 19-21 and 25-45 are presently being examined. Instant claims 1, 19, 28 and newly added claim 37 are independent.
3. 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.
4. 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.
5. Claims 1-3, 5, 28-31 and 37-40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
This is a new ground of rejection necessitated by Applicant’s amendment filed 9/19/25.
Note that the broadest reasonable interpretation for the limitation “preparing” in the absence of a limiting definition in the instant specification therefore can be for example, placing the NK cells in a different container or drawing a sample of blood containing NK cells from the donor (i.e., “preparing a collection of NK cells from an ex vivo batch of NK cells” as is recited in instant base claim 1 or 28 or “preparing a collection of NK cells from an ex vivo batch of NK cells” recited in instant base claim 37).
a). Claims 1-3 and 5 recite a method of selecting universal donor NK cells, the method comprising:
selecting candidate NK cells having (i) an HLA genotype carrying C1, C2, and B24 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1 as universal donor NK cells (as is recited in instant base claim 1).
With regard to the 35 USC 101 Subject Matter Eligibility Guidelines, it is clear that independent claim 1 is drawn to a method and thus meets step 1 of the analysis.
Moving to step 2A prong 1, the claim is directed to an abstract idea, as the “selecting” step may be a purely a mental step. This is also the case for dependent claims 3 and 5 that also have “selecting” steps that can constitute purely mental steps. In the case of instant dependent claim 2, the “obtaining a KIR genotype of the candidate NK cells”, “obtaining an HLA genotype of the candidate NK cells”, “and/or evaluating expression of 2DL1, 2DL2 or 3DL3, and 3DL1 in the candidate NK cells” may also be purely mental steps. In dependent claim 2, the obtaining KIR genotype, obtaining an HLA genotype, and evaluating expression of the recited markers may also be purely mental steps.
Moving to step 2A prong 2, the claims do not recite additional elements that integrate the judicial exception into a practical application, as “preparing a collection of NK cells from the universal donor NK cells selected from cell donor” recited in base claim 1 may be an isolation step.
Moving to step 2B, there is no integration into a practical application as the outcome of the claim does not require any application of the selected NK cells. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements recited.
b). Claims 28-31 recite a method of preparing a collection of NK cells from a donor, the method comprising:
a) selecting from one or more donors a universal door having (i) an HLA genotype carrying C1, C2 and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1; and
b) preparing a collection of NK cells from an ex vivo batch of NK cells of said universal donor (as is recited in instant base claim 28.
With regard to the 35 USC 101 Subject Matter Eligibility Guidelines, it is clear that independent claim 28 is drawn to a method and thus meets step 1 of the analysis.
Moving to step 2A prong 1, the claim is directed to an abstract idea, as the “selecting” step in base claim 28 may be a purely a mental step. This is also the case for dependent claims 29 and 31that also have “selecting” steps that can constitute purely mental steps, as well as for dependent claim 30 that has “evaluating” and “obtaining steps”.
Moving to step 2A prong 2, the claims do not recite additional elements that integrate the judicial exception into a practical application, as “preparing a collection of NK cells from an ex vivo batch of NK cells of said universal donor” recited in base claim 28 may be an isolation step.
Moving to step 2B, there is no integration into a practical application as the outcome of the claim does not require any application of the selected NK cells. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements recited.
c) Claims 37-40 recite:
A method of cell preparation, the method comprising preparing a collection of NK cells from an ex vivo batch of NK cells of a universal donor, wherein the universal donor is selected from one or more donors having (i) an HLA genotype carrying C1, C2 and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRS comprising 2DL1, 2DL2 or 3, and 3DL1 (as is recited in instant base claim 37).
With regard to the 35 USC 101 Subject Matter Eligibility Guidelines, it is clear that independent claim 37 is drawn to a method and thus meets step 1 of the analysis.
Moving to step 2A prong 1, the claim is directed to an abstract idea, as the “wherein the universal donor is selected from” clause in base claim 37 is not an active method step, and even if it were, may be a purely a mental step. This is also the case for dependent claim 38 in the recitation of “wherein the universal donor is further selected for having a KIR genotype possessing at least 3 activating KIRs comprising 2DS1 and 3DS1” and also is the case for dependent claim 40 that recites “wherein the universal donor is further selected for having a CMV seropositive profile indicative of [the] presence of NKG2C+ NK cells”. This is also the case for dependent claim 39 that recites “wherein: a) expression of 2DL1, 2DL2 or 2DL3, and 3DL1 is evaluated in the one or more donors; b) an HLA genotype of the one or more donors is obtained; and/or c) a KIR genotype of the one or more donors is obtained. The said “wherein” clause is not an active method step, and even if it were, the said evaluation and obtaining may be purely mental steps.
Moving to step 2A prong 2, the claims do not recite additional elements that integrate the judicial exception into a practical application, as “preparing a collection of NK cells from an ex vivo batch of NK cells of said universal donor” recited in base claim 37 may be an isolation step.
Moving to step 2B, there is no integration into a practical application as the outcome of the claim does not require any application of the selected NK cells. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements recited.
6. Applicant’s amendment filed 9/19/25 has overcome the prior rejection of record of claims 1-3, 5, 26, 27, 35 and 36 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.
7. 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.
8. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
9. The following is a new ground of rejection necessitated by Applicant’s IDS with fee filed 6/3//25 and by Applicant’s amendment filed 9/19/25.
Instant independent claim 1 recites: (Currently Amended) A method of selecting universal donor preparing a collection
of NK cells, the method comprising:
selecting candidate NK cells from a donor, the candidate NK cells having (i) an
HLA genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1,
as universal donor NK cells; and preparing a collection of NK cells from the universal donor NK cells
selected from said donor.
Independent claim 28 recites:
28. Previously Presented) A method of preparing a collection of NK cells from a
donor, the method comprising:
a) selecting from one or more donors a universal donor having (i) an HLA
genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1; and
b) preparing a collection of NK cells from an ex vivo batch of NK cells of said
universal donor.
Independent claim 37 recites:
37. (New) A method of cell preparation, the method comprising preparing a collection
of NK cells from an ex vivo batch of NK cells of a universal donor, wherein the
universal donor is selected from one or more donors having (i) an HLA genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory
KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1.
Claims 1, 2, 28, 30, 37 and 39 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Pittari et. al. (J. Immunol. 2013, 190: 4650-4660, IDS reference) or WO2015154012 A1 (IDS reference).
Pittari et. al. teach genotyping HLA class I and KIR on donor NK cells (Materials and Methods section at “NK cell donors”) and preparing an NK cell composition (Materials and Methods section at “NK Cloning”). Donor NK cells from subject UDN007 were positive for HLA C1:C2 and Bw4 and positive for KIR 2DL1, 2DL3, and 3DL1 as well as 2DS1 and 3DS1 (Table I). Pittari et. al. teach that NK cells from this donor were detected in the PMBC of the transplanted patient and that the said NK cells were proliferated (see entire reference).
WO2015154012 A1 also provide the same teachings (see entire reference, especially Table I for donor “UDN 007”, [0047]).
10. 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.
11. The following is a new ground of rejection necessitated by Applicant’s IDS with fee filed 6/27/25 and by Applicant’s amendment filed 91/19/25.
Instant independent claim 1 recites:
1. (Currently Amended) A method of selecting universal donor preparing a collection
of NK cells, the method comprising:
selecting candidate NK cells from a donor, the candidate NK cells having (i) an
HLA genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1,
as universal donor NK cells; and preparing a collection of NK cells from the universal donor NK cells
selected from said donor.
Instant independent claim 19 recites:
(Currently Amended) A method for preparing a population of universal donor NK
cells, the method comprising:
(a) selecting universal donor candidate NK cells by the method of claim 1 from
a donor, the candidate NK cells having (i) an HLA genotype carrying C1, C2,
and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1, to obtain an initial population of
universal donor NK cells; and
(b) exposing the initial population of universal donor NK cells to IL-21 in vitro
for a time and under conditions sufficient to expand the initial population of
universal donor NK cells to obtain a population of universal donor NK cells.
Independent claim 28 recites:
28. Previously Presented) A method of preparing a collection of NK cells from a
donor, the method comprising:
a) selecting from one or more donors a universal donor having (i) an HLA
genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1; and
b) preparing a collection of NK cells from an ex vivo batch of NK cells of said
universal donor.
Independent claim 37 recites:
37. (New) A method of cell preparation, the method comprising preparing a collection
of NK cells from an ex vivo batch of NK cells of a universal donor, wherein the
universal donor is selected from one or more donors having (i) an HLA genotype carrying C1, C2, and Bw4 alleles and (ii) a KIR genotype or phenotype possessing inhibitory
KIRs comprising 2DL1, 2DL2 or 2DL3, and 3DL1.
Note that the optimal donor is one who possesses an HLA genotype carrying C1, C2 and Bw4 alleles, has a KIR genotype possessing the inhibitory KIR (2DL1, 2DL2 or 3, and 3DL1) that bind to C1, C2, and B24 (leading to maximum licensing) and with a high proportion of activating KIR (greater than or equal to 3 of the variably inherited activating genes including 2DS1 and 3DS1), and has been exposed to CMV resulting in high NKG2C expression.
Claims 1-3, 5, 28-31 and 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Cooley et. al. (Blood, 2009, 113(3): 726-732, of record) in view of WO2018169793 A1 (of record), McQueen et al. (IDS reference), and Handgretinger et. al. (Blood, 2016, 127(26): 3341-3349, IDS reference).
Cooley et. al. teach that NK cell alloreactivity determined by donor KIR and recipient HLA correlates with successful therapy for AML (abstract). Cooley et. al. further teach that in the setting of allogeneic transplantation, donor NK cells attack the allogeneic cells if the recipient HLA class I ligands do not sufficiently engage their inhibitory receptors. Cooley et. al. teach combining KIR and HLA genotyping to select transplant donors and improve the outcome of transplantation (see introduction and abstract). Cooley et. al. teach that the HLA-Bw4 is a ligand for its cognate inhibitory receptor KIR3DL1. Cooley et. al. teach detection of at least one of the KIR B haplotype-defining loci (i.e., KIR2DL5, 2DS1, 2DS2, 2DS3, 2DS5 or 3DS1 [plus the inhibitory receptors that are also present in group A KIR haplotype]) in a sample dictated that the genotype contains at least one B haplotype. Cooley et. al. teach that the NK cell is selected as a universal donor NK cell for therapeutic administration with the KIR genotype that indicates the presence of at least three of the activating KIRs 2DS1/2, 2DS3/5, 3DS1 and/or 2DS4 (page 730, left column at the last paragraph). Cooley et. al. teach that their results indicate that “all donors with 1 or 2 KIRB haplotypes have the potential to provide an improved clinical benefit in HCT for AML and should be selected over an otherwise equivalent donor who lacks a KIRB haplotype” (page 790 at the last sentence at column 1). Note that Cooley et. al. teach that their results suggesting that donor 2DL1 and 2DS2 may independently be advantageous were not definitive because of the limited comparative power of the study. All donors with one or two KIR B genotype (denoted “B/x”) have the potential to provide an improved clinical benefit in HCT for AML (see entire reference, especially abstract, introduction, KIR genotyping section). Thus, the B/x haplotype NK cells comprise the said activating receptors as well as the inhibitory KIRs (KIR2DL-1, -2, -3 and KIR3DL1). Cooley et. al. teach that CMV serostatus is also important in donor selection, and they evaluate it, as well as HLA genotype (abstract). Note that in Table 1, a significant proportion of the B/x genotype is CMV seropositive. (See entire reference).
Cooley et. al. do not teach selecting donor NK cells having an HLA genotype carrying C1, C2 and Bw4 alleles in addition to the genotype present in B/x, although they do teach combining KIR and HLA genotyping to select transplant donors and improve the outcome of transplantation.
WO 2018169793 A1 teaches a method for selecting donor hematopoietic cells, including NK cells, for therapeutic administration to a subject in need thereof, such as for treatment of AML, wherein candidate donor cells are genotyped for HLA-Bw4 and also for HLA-KIR3DL1, and in some instances also genotyping for the entire HLA. WO 2018169793 A1 teaches that these NK cells are low inhibitory and may also express HLA-C1 or HLA-C2 and KIR2DS1 (the latter being an activating receptor). WO 2018169793 A1 teaches evaluating donor CMV serostatus (see entire reference, particularly claims, [0006], [0011], [0013], [0070], [0071]).
McQueen et. al. teach a correlation between the presence of KIR3DL1 and the HLA-Bw4 ligand alleles with reduced relapse-free mortality rates. McQueen et. al. teach that KIR3DL1 is a protective factor against chronic GVHD. McQueen et. al. teach the screening criteria for KIR genes (including 2DL1, 2DL2 or 2DL3, and 3DL1; and 2DS1 and 3DS1) associated with NK cell alloreactivity and the KIR-binding HLA-C and HLA-B (Bw4/X and Bw6/Bw6/Bw6). McQueen et. al. teach that the group A haplotypes have seven KIR genes and two pseudogenes and are diversified through allelic polymorphism. The genes include those specifying inhibitory receptors for each of the four KIR ligands (KIR2DL-1, -2, -3 and KIR3DL1) as well as KIR2DL4 and KIR3DL3 (inhibitory receptor of unknown specificity and function). The group B haplotypes are diversified by both gene content and allelic polymorphism: “Although all genes of the group A haplotype are represented in the group B haplotypes, what distinguishes group B haplotypes is the presence of a variable number of KIR genes that are not components of the group A haplotypes: KIR2DS -1-3, -5, KIR3DS1 and KIR2DL5.
Most of the activating KIR are associated only with the group B haplotypes whereas both group A and group B haplotypes have comparable complements of inhibitory receptors that the group A haplotypes have seven KIR genes and two pseudogenes and are diversified through allelic polymorphism. The genes include those specifying inhibitory receptors for each of the four KIR ligands (KIR2DL-1, -2, -3 and KIR3DL1) as well as KIR2DL4 and KIR3DL3 (inhibitory receptor of unknown specificity and function). The group B haplotypes are diversified by both gene content and allelic polymorphism, “Although all genes of the group A haplotype are represented in the group B haplotypes, what distinguishes group B haplotypes is the presence of a variable number of KIR genes that are not components of the group A haplotypes: KIR2DS -1-3, 5, KIR3DS1 and KIR2DL5. Most of the activating KIR as associated only with the group B haplotypes whereas both group A and group B haplotypes have comparable complements of inhibitory receptors (see entire reference, especially paragraph spanning pages 309-310, abstract, page 310 at the right column at paragraph 1, page 311 at the left column at paragraph 3, and discussion section).
Handgretinger et. al. teach that KIR-2DL1 binds to an HLA-C group 2 allele, KIR-2DL2 and KIR-2DL3 bind to HLA-Group 1 alleles, and KIR3-DL1 binds to an HLA-Bw4 allele. Handgretinger et. al. teach that KIR2DL1 NK cells will be inhibited by cells having HLA-C2 receptors, KIR2DL2/3 NK cells will recognize HLA-C1. Handgretinger et. al. teach that when the donor is an HLA-C1 homozygote, the activation signal for KIR2DS1 will overcome the inhibition of KIR2DL2/3, whereas in HLA-C2 donors, KIR2DS1 will inhibit NK cell function to prevent autoreactivity. Handgretinger et. al. further teach that CMV infection promotes the clonal expansion of an NKG2C+ (ligand HLA-E) aKIR+ (“aKIR” or activating KIR, short-tailed “S” such as 2DS1 and 3DS1) NK cell, that NK cell activity is triggered via NKG2D (ligand MICA/B, ULBPs), and that NK cell alloreactivity towards leukemic cells is promoted thereby. Handgretinger et. al. teach that NK cell therapy can be improved by optimal donor selection based on phenotypic and genotypic properties and by adoptive transfer of NK cells with ex vivo cytokine stimulation (see entire reference, especially introduction, page 3342, page 3343 at the right column at paragraph 1, and page 3345 at Table 1 and at the right column). Thus, Handgretinger et. al. teach prediction of NK cell alloreactivity by analysis of the HLA type of the donor and recipient.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the KIR genotype of 2DL1, 2DL2 or 2DL3, 3DL1, 2DS1 and 3DS1 (i.e., the B/x haplotype taught by the primary art reference) and CMV serostatus (taught by the primary art reference) as well as the HLA-genotype of C1, C2, and Bw4 alleles (taught by the secondary art references) as the screening criterion.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so in order to screen for and prepare a collection of donor NK cells associated with lower risk of GVHD, as the primary art reference teaches that all donors with one or two KIR B genotype (denoted “B/x” that comprise the said activating receptors as well as the inhibitory KIRs (KIR2DL-1, -2, -3 and KIR3DL1) have the potential to provide an improved clinical benefit in HCT for AML and also teaches that CMV serostatus is also important in donor selection and the evaluation of it as well as HLA genotype, while the secondary art references teach selecting donor NK cells for treatment of AML wherein candidate donor NK cells are genotyped for HLA-Bw4 and for KIR3DL1 and in some instances for the entire HLA (WO 2018169793 A1), a correlation between the presence of KIR3DL1 and the HLA-Bw4 ligand alleles with reduced relapse-free mortality rates and screening for KIR genes (including 2DL1, 2DL2 or 2DL3, and 3DL1; and 2DS1 and 3DS1) associated with NK cell alloreactivity and the KIR-binding HLA-C and HLA-B (Bw4/X and Bw6/Bw6/Bw6) (McQueen et. al.), and the correlation of HLA-C1 and HLA-C2 and their inhibitory KIR ligands and effects on alloreactivity, that NK cell therapy can be improved by optimal donor selection based on phenotypic and genotypic properties, and the importance of CMV exposure for NK cell vs leukemia effect (Handgretinger et. al.).
12. Claims 19-21, 25-27, 32-36 and 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over Cooley et. al. (Blood, 2009, 113(3): 726-732, of record) in view of WO2018169793 A1 (of record), McQueen et al. (IDS reference), and Handgretinger et. al. (Blood, 2016, 127(26): 3341-3349, IDS reference), as applied to claims 1-3, 5, 28-31 and 37-40 above, and further in view of WO2014037422 A1 (of record) and WO2016197108 A1 (IDS reference).
The teachings and combination of Cooley et. al. in view of WO2018169793 A1, McQueen et. al. (IDS reference), and Handgretinger et. al. have been discussed above, hereafter referred to as the “combined references”.
The combined references do not teach wherein the NK cells are exposed to soluble IL-21, nor to 41BBL.
WO2014037422 A1 teaches an in vitro method for expanding NK cells of a given KIR specificity comprising selecting donor cells of a given KIR specificity that are CMV seropositive, and contacting them with IL-21, either soluble or as an engineered membrane bound form expressed on feeder cells and/or another cytokine such as IL-12, IL-15, IL-7, including wherein the donor cells are homozygous for HLA-C1/C2. WO2014037422 A1 teaches administering these cells to a patient having AML. WO2014037422 A1 further teaches that anti-CD92 and/or anti-NKG2A antibodies may also be used to expand the NK cells (see entire reference, especially claims, paragraph spanning pages 17-18).
WO2016197108 A1 teaches a method of treating a disease such as leukemia in a subject by administering NK cells (e.g., abstract, claims). WO2016197108 A1 teaches that artificial antigen presenting cells or aAPCs are useful in preparing therapeutic compositions and cell therapy products ([0066]), including wherein the aAPCs may comprise at least one exogenous assisting molecule such as costimulatory molecules such as for example 41BBL and IL-21 and adhesion molecules ([0067]). WO2016197108 A1 teaches
It would have been prima facie obvious to one of ordinary skill in the art to have contacted the donor CMV seropositive/KIR/HLA NK cells taught by the combined references with IL-21 in vitro, either in soluble form or in the form of an engineered cell-surface expressed form as taught by WO2014037422 A1, or with the aAPCs comprising 41BBL and/or IL-21 taught by WO2016197108 A1.
One of ordinary skill in the art would have been motivated to do this in order to expand the donor NK cells to sufficient numbers for administration.
13. The following is a new ground of rejection necessitated by Applicant’s IDS with fee filed 6/3//25 and by Applicant’s amendment filed 9/19/25.
Claims 1, 2, 19, 21, 25-28, 30, 32-37, 39 and 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over Pittari et. al. (J. Immunol. 2013, 190: 4650-4660, IDS reference) or WO2015154012 A1 (IDS reference), either in view of WO2014037422 A1 (of record) and WO2016197108 A1 (IDS reference).
Pittari et. al. teach genotyping HLA class I and KIR on donor NK cells (Materials and Methods section at “NK cell donors”) and preparing an NK cell composition (Materials and Methods section at “NK Cloning”). Donor NK cells from subject UDN007 were positive for HLA C1:C2 and Bw4 and positive for KIR 2DL1, 2DL3, and 3DL1 as well as 2DS1 and 3DS1 (Table I). Pittari et. al. teach that NK cells from this donor were detected in the PMBC of the transplanted patient and that the said NK cells were proliferated (see entire reference).
WO2015154012 A1 also provide the same teachings (see entire reference, especially Table I for donor “UDN 007”, [0047]).
Pittari et. al. or WO2015154012 A1 do not teach wherein the NK cells are exposed to soluble IL-21, nor to 41BBL.
WO2014037422 A1 teaches an in vitro method for expanding NK cells of a given KIR specificity comprising selecting donor cells of a given KIR specificity that are CMV seropositive, and contacting them with IL-21, either soluble or as an engineered membrane bound form expressed on feeder cells and/or another cytokine such as IL-12, IL-15, IL-7, including wherein the donor cells are homozygous for HLA-C1/C2. WO2014037422 A1 teaches administering these cells to a patient having AML. WO2014037422 A1 further teaches that anti-CD92 and/or anti-NKG2A antibodies may also be used to expand the NK cells (see entire reference, especially claims, paragraph spanning pages 17-18).
WO2016197108 A1 teaches a method of treating a disease such as leukemia in a subject by administering NK cells (e.g., abstract, claims). WO2016197108 A1 teaches that artificial antigen presenting cells or aAPCs are useful in preparing therapeutic compositions and cell therapy products ([0066]), including wherein the aAPCs may comprise at least one exogenous assisting molecule such as costimulatory molecules such as for example 41BBL and IL-21 and adhesion molecules ([0067]). WO2016197108 A1 teaches
It would have been prima facie obvious to one of ordinary skill in the art to have contacted the NK cells taught by the primary art reference with IL-21 in vitro, either in soluble form or in the form of an engineered cell-surface expressed form as taught by WO2014037422 A1, or with the aAPCs comprising 41BBL and/or IL-21 taught by WO2016197108 A1, in place of or in addition to the IL-15/IL-15R expression on the feeder cells taught by the primary reference.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so in order to expand the donor NK cells to sufficient numbers for administration, particularly in light of the teaching of WO2014037422 A1 that the donor cells can be contacted with IL-21 alone or in combination with IL-15.
14. Claim 40 is objected to because of the following informality: Applicant should amend the claim to recite ‘the’ after “indicative of” and before “presence” at line 2.
Appropriate correction is required.
15. Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 8/26/25 as well as Applicant’s amendment filed 9/19/25 prompted the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(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.
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641