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 .
This action is NON-FINAL.
Claim Status
As of the Non-Final Office Action mailed 8/12/2025, claims 83-162 and 164-165 were pending.
In Applicant's Response filed on 11/12/2025, claims 146, 164, and 165 were amended.
As such, claims 83-162 and 164-165 are pending and claims 146-150 and 164-165 have been examined herein.
Withdrawn Objections/Rejections
The rejection of record of claim 146-150 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment(s).
The rejection of record of claim 146-150 under 35 USC § 112(a) have been withdrawn in view of Applicant’s amendment(s).
Maintained Rejections
Claim Rejections - 35 USC § 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.
Claim 164 and 165 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception (product of nature) without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the claim falls within any statutory category. Here, the claim recites (1) composition comprising human CD 16+ natural killer cells deposited at NPMD under a deposit number NITE BP-03017, wherein a number of the human CD16+ natural killer cells in the composition is at least 5 x105 and the human CD 16+ natural killer cells are in an amount equal to or more than 50% by number, based on the total number of the cells in the composition as 100% and wherein the human CD16+ natural killer cells are capable of producing a cell population comprising at least 80% CD16+ natural killer cells, based on the total number of cells in the cell population as 100%, after at least 1544- fold cell expansion, and (2) A composition comprising human CD16+ natural killer cells deposited at NPMD under a deposit number NITE BP-03017, wherein the CD16 expression of human CD 16+ natural killer cells in the composition sustains at least 65 days. This is a composition of matter/product; therefore, the claim falls within a statutory category of invention. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or described in the claim (see MPEP 2106.04(II)). The claim recites at least one judicial exception. The claims recite a nature-based product limitation (a human natural killer cell), as such the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception (see MPEP 2106.04(c)(I) and MPEP 2106(c)(I)(A)). The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claims to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart (see MPEP 2106.04(c)(II)).
The closest natural counterpart to the human natural killer cell of claim 164 and 165 is a naturally occurring human natural killer cell. The human natural killer cell as claimed broadly encompasses any human natural killer cell (CD16+ or CD16-). Keskin et al (Proc Natl Acad Sci U S A. 20 Feb 2007; 104(9):3378-83) teaches that human peripheral blood natural killer (pNK) cells are divided into two main populations (p. 3378, col 1, para 2). Specifically, the reference evidences that approximately 95% of pNK cells are CD56dimCD16+ (i.e., CD16+) and the minor population (~5%) of pNK cells are CD56brightCD16- (i.e., CD16-) (same para). Thus, the claim recites at least one judicial exception, a nature-based product. [Step 2A, Prong 1: YES] Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application. The claims fail to recite any other steps that would integrate it into practical application. [Step 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). This is based on an additional consideration of whether the elements in addition to the judicial exception add beyond what was well-understood, routine, and conventional to the claims. The specification indicates that there are two main NK cell subsets in human peripheral blood, wherein the majority (> 90 %) of peripheral blood NK cells are CD3-CD56ImCD16 NK cells and the minority (10 %) of peripheral blood NK cells are CD3-CD56bnghtCD16- NK cells. The specification also states that human NK cells expressing CD16 receptor can kill various types of target cells such as cancer cells, tumor cells, and HIV-infected cells through ADCC processes, making Applicant’s instantly claimed cell functionally the same as naturally occurring CD16+ NK cells (para 0003).
The culture steps as recited is well-known, routine, and conventional in the art.
Berg (Cytotherapy. 2009;11(3):341-55; Ref. 4 in Non-Patent Literature of IDS filed 1/22/2024; previously cited) teaches small- and large-scale expansion of NK cells (abstract). The reference teaches that small scale expansions were performed on human NK cells isolated from peripheral blood mononuclear cells in flasks (i.e., container) in 15 ml of X-VIVO 20, supplemented with 10% heat inactivated human AB serum, or 10% heat inactivated AB single donor or pooled plasma or serum, 500 IU/mL rhIL-2, and 2mM GlutaMAX-1 at 37°C and 6.5% CO2 (“Cell isolation, culture and cryopreservation”, para 1 and step 1). Following 14 days of culture, 1.0 × 106 expanded NK cells were co-cultured with 20 × 106 of irradiated feeder cells and the culture was expanded for an additional 14 days (same para). NK cells obtained from 9 different donors and expanded over 10-22 days had a mean expression of CD56+/CD16+ and CD56+/CD16- of 84.3±7.8% (range of 66.5-97.5%) and 14.7±7.7% (range of 2.1-31.9%) respectively (“Phenotype of resting vs. expanded NK cells” para 3).
Canestrari (Cytotherapy, May 2018; 20(5):S61; previously cited) teaches human platelet lysate as media supplement for expansion of immune cells (title). The reference teaches that adoptive cellular therapy involves the ex vivo expansion of lymphocytes under cGMP regulations and that Human AB serum, a cell culture option for T cells and NK cells, has supply limitations and therefore may not be sufficient to meet the expected demand for immunotherapies (para 1). Platelet lysate (HPL) obtained from is widely recognized as a valuable, alternative to both FBS and human AB serum for cell culture (same para). NK cells were expanded in vitro using basal media supplemented with either FBS, AB serum or HPL with the addition of CD3/CD28 activator plus interleukin-2 for T cells and interleukin-2 plus interleukin-15 for NK cells (same para). Higher expansion rate and better viability was observed for NK cells expanded with HPL compared to FBS and AB serum, showing human platelet lysate as a successful alternative to FBS and human AB serum (same para).
Finally, Tsukerman et al (Eur J Immunol. 20 Feb 2014;44(5):1517-25; previously cited), which details the expansion of CD16-positive and -negative human NK cells (title). The reference teaches that human NK cells expansion capacity is in response to stimulation within culture conditions such as, e.g., stimulation with tumor cells (abstract). The reference also teaches that CD16 expression is maintained on the cell surface of expanded NK cells due to antibody-dependent mechanisms (same para). It was also hypothesized that immunoglobulins found in human sera may play a role in CD16 expression levels (“Antibodies are essential for maintaining CD16 expression” para 1). No NK cell expansion was observed in absence of IgGs and in the absence of IgGs, after 72 h following the coculturing, the NK-cell numbers were reduced and a CD16 negative population started to emerge (“Antibodies are essential for maintaining CD16 expression” para 2). The teachings of Tsukerman suggest that the proliferative capacity of CD16+ NK cells does not depend on the cell itself but rather the culture conditions in which the cell is in.
These references, in combination, show that culturing NK cells in IL-2 and human platelet lysate is well-known, routine, and conventional in the art. [Step 2B: NO]
In view of the above, the claims are considered to be directed to a judicial exception without integration into a practical application, or adding significantly more to the claims over the judicial exception. Therefore, the claims do not qualify as subject matter under 35 USC § 101.
Response to Arguments
Applicant’s arguments regarding the 101 rejection of record has been fully considered but are not persuasive.
On p. of Remarks, Applicant argues that the claimed inventions are not “products of nature” because the NK cells of the instant application have “superior viability with 96% cell survival rate after cryopreservation and thawing, comparable to 95% pre-cryopreservation,” that since there was no 103 rejections on the record that the cells are non-obvious over the prior art and are sufficiently distinguishable therefrom. Applicant argues that since the Examiner has made 112(a) rejections over the method claims, that it evidences that the CD16 expression and “high-fold expansion” as claimed is not an inherent property of naturally occurring cells. Applicant argues that maintaining CD16 expression in CD16+ cells is a major technical challenge in the art and none teach or suggest how to effectively and continuously maintain in expanded CD16+ cells.
In response, the examiner disagrees. First, the examiner reminds Applicant that 112(a) and 101 rejections are completely separate analyses and that the previously posited 112(a) rejection was applied to the instant method claims and NOT the instant product claims. The addition of the method steps within the product claims 164-165 are product-by-process limitations that do not impart patentable weight to these claims. Second, as shown in the 101 rejection above, maintenance of NK cells is a by-product of culture steps and manipulations as shown in Applicant’s instant specification and Declaration. There is no structural or functional difference between naturally occurring CD16+ NK cells and the instantly claimed cell population.
As previously asserted, as per MPEP § 2106.04(c), “[i]f [a] claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim recites a "product of nature" exception.” Thus, the issue presented is whether one of ordinary skill would consider the property of “retain[ing] its capability to proliferate after subculture for at least 3 months” as argued to be a markedly different characteristic imbued upon the instantly claimed cell as a result of it being CD16+. Put more simply, would subjecting a naturally occurring CD16+ cell to the same culture conditions as Applicant’s claimed deposited CD16+ NK cell result in a markedly different proliferative capacity between the two?
In Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. The patentee in Myriad had discovered the location of the BRCA1 and BRCA2 genes in the human genome, and isolated them, i.e., separated those specific genes from the rest of the chromosome on which they exist in nature. As a result of their isolation, the isolated genes had a different structural characteristic than the natural genes, i.e., the natural genes had covalent bonds on their ends that connected them to the rest of the chromosome, but the isolated genes lacked these bonds. However, the claimed genes were otherwise structurally identical to the natural genes, e.g., they had the same genetic structure and nucleotide sequence as the BRCA genes in nature. The Supreme Court concluded that these isolated but otherwise unchanged genes were not eligible, because they were not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring BRCA genes. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977.
Here, like the isolated genes of Myriad, Applicant’s CD16+ NK cell derived from a CD16- NK cell is structurally identical to a naturally occurring CD16+ NK cell. Even if accepting, arguendo, the premise that the instantly claimed cell has a better proliferative capacity, the argument that that Applicant’s instantly claimed cell is markedly different is not persuasive. Solely to rebut Applicant’s argument, the examiner again provides Tsukerman et al (Eur J Immunol. 20 Feb 2014;44(5):1517-25), which details the expansion of CD16-positive and -negative human NK cells (title). The reference teaches that human NK cells expansion capacity is in response to stimulation within culture conditions such as, e.g., stimulation with tumor cells (abstract). The reference also teaches that CD16 expression is maintained on the cell surface of expanded NK cells due to antibody-dependent mechanisms (same para). It was also hypothesized that immunoglobulins found in human sera may play a role in CD16 expression levels (“Antibodies are essential for maintaining CD16 expression” para 1). No NK cell expansion was observed in absence of IgGs and in the absence of IgGs, after 72 h following the coculturing, the NK-cell numbers were reduced and a CD16 negative population started to emerge (“Antibodies are essential for maintaining CD16 expression” para 2). The teachings of Tsukerman seems to suggest that the proliferative capacity of CD16+ NK cells does not depend on the cell itself but rather the culture conditions in which the cell is in. Thus, Applicant’s deposited CD16+ NK cell is not markedly different from naturally occurring NK cells. Thus, the rejection is proper.
New Grounds of Rejections
Claim Interpretation
Claim 146 recites “CD16+ natural killer cells obtained or derived from a population of human CD16- natural killer cells”. Claim 164 and 165 were amended to recite “wherein the human CD16+ natural killer cells are obtained or derived from a population of human CD16- natural killer cells with a culture medium comprising 2.5-10 vol% human platelet lysate and 500-1000 IU/mL IL-2”. These are product-by-process limitations and does not impart any patentable weight to the instant claims. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113.
Claim 149 recites “are capable of retaining their capability to proliferate after subculture for at least 3 months”. The examiner is interpreting this limitation as an intended result of the positive method steps recited in claim 146.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 146-150 and 164-165 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Seong et al (KR20160066837A, 12/3/2014; published 6/13/2016).
Seong teaches a method of preparing stable natural killer cells by setting a culture condition ensuring stable maintenance of cytotoxicity and proliferation rate of natural killer cell (abstract). The method includes culturing the supernatant by suspending the supernatant and supporting cells in a ratio of 1: 2 to 1:10 in a medium containing platelet lysate; re-stimulating and culturing the raw material cells obtained in the step (a) and the supporting cells in a ratio of 1: 2 to 1:10 in a medium containing platelet lysate; and recovering the cultured cells (see claim 1 of Seong). The reference teaches that the medium also comprises an anti-CD3 antibody and a cytokine, where the cytokine is selected from a group consisting of IL-2 (see claims 4 and 6 of Seong). The platelet lysate is contained in an amount of 0.1 to 5%, and the IL-2 is present at 500 U/mL (see examples). The culturing in step (a) is performed for 2 to 10 days, and the culturing in step (b) is performed for 2 to 15 days (see claims of Seong) (“wherein the step (y) comprises substeps: (yl) culturing the cells for at least one day; and (y2) sub-culturing the cells for at least two weeks” as in instant claim 148). These teachings anticipate “a method of culturing and expanding human CD16+ natural killer cells and maintaining CD16 expression during the culture; the method comprising (x) in a container, contacting the human CD16+ natural killer cells obtained or derived from a population of human CD16- natural killer cells with a culture medium comprising 2.5-10 vol% human platelet lysate and 500-1000 IU/mL IL-2; and (y) culturing the cells for at least 7 days, thereby producing the human CD16+ natural killer cells having sustained CD16 expression after at least a 1544-fold cell expansion” as in instant claim 146 (see claim interpretation above). In the culturing of natural killer cells by the method of Example 1 and 2, bags were used from the beginning of culturing in bags, and cultured in flasks were cultured in flask containers from 0 to 12 days (“wherein the container comprises a bottom for seeding cells, and the bottom is air-permeable and water-impermeable” as in instant claim 147).
The cells produced by the method as taught by Seong anticipates “a human CD16+natural killer cell which has the following characteristics: i) expressing a CD 16 receptor, and ii) x) not including synthetic, genetically modified and/or deliberately delivered polynucleotide encoding the CD16 receptor” as in instant claim 150; “A composition comprising human CD16+ natural killer cells deposited at NPMD under a deposit number NITE BP-03017, wherein a number of the human CD16+ natural killer cells in the composition is at least 5 x105 and the human CD16+ natural killer cells are in an amount equal to or more than 50% by number, based on the total number of the cells in the composition as 100%; and wherein the human CD16+ natural killer cells are obtained or derived from a population of human CD16- natural killer cells with a culture medium comprising 2.5-10 vol% human platelet lysate and 500-1000 IU/mL IL-2, and the human CD16+ natural killer cells are capable of producing a cell population comprising at least 80% CD 16+ natural killer cells, based on the total number of cells in the cell population as 100%, after at least 1544-fold cell expansion” as in instant claim 164, and “A composition comprising human CD16+ natural killer cells deposited at NPMD under a deposit number NITE BP-03017, wherein human CD16+ natural killer cells are obtained or derived from a population of human CD16- natural killer cells with a culture medium comprising 2.5-10 vol% human platelet lysate and 500-1000 IU/mL IL-2, and the CD16 expression of the human CD16+ natural killer cells in the composition sustains at least 65 days.” as in instant claim 165. Please note that, absent evidence to the contrary, and in view of the references cited above, there are no patentably distinguishable differences between the cells of the prior art and the instantly claimed cells (both are expanded CD16+ NK cells with enhanced proliferative capabilities).
Thus, Seong anticipates the instantly claimed invention of claims 146-150 and 164-165.
Conclusion
No claim is allowed.
This action is NON-FINAL.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632