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 .
Applicant’s submission filed on May 29, 2026 has been entered and considered. Rejections and/or objections not reiterated from the previous action mailed December 1, 2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 73 have been amended to recite a population of “ex vivo expanded natural killer cells”. Claims 16, 21 and 22 have been amended to adjust claim dependency. Claims 16, 22, 34, 72 have been amended for clarity.
Claims 1-3, 13-19, 21-22, 30, 33-34, 51, and 70-73 are pending and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2021/063745, filed on December 16, 2021. The instant application claims priority under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to U.S. provisional applications 63/127098, filed on December 17, 2020 and 63/172417, filed on April 8, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 29, 206 is in compliance with the provisions of 37 CFR 1.97 based on filing of the fee as set forth in 37 C.F.R 1.17(p) and is being considered by the examiner.
The information disclosure statements (IDS) submitted on October 11, 2024 and January 6, 2025 are in compliance with the provisions of 37 CFR 1.97 were previously considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Maintained Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16 is rejected 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.
With regard to claim 16, which depends from claim 1, claim 16 recites the limitation "from the same umbilical cord blood donor" in line 3. There is insufficient antecedent basis for this limitation in the claim as there no prior recitation of an umbilical cord blood donor. Appropriate correction is required.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 which depends from claims 16, 2, and 1, recites that the population of expanded natural killer (NK) cells is from an umbilical cord blood donor having the KIR-B haplotype and homozygous from the CD 158V polymorphism. Claim 1 recites that the expanded NK cells comprise a KIR-B haplotype and are homozygous for CD16 158V polymorphism, claim 2 recites that the NK cells are derived from umbilical cord blood, and claim 16 recites that the umbilical cord blood NK cells are derived from a donor. As the NK cells of claim 1 already comprise a KIR-B haplotype and homozygous from the CD 158V polymorphism, the donor as recited in claim 16 would be understood to also have a KIR-B haplotype and homozygous from the CD 158V polymorphism.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
New Claim Rejections - 35 USC § 101
This is a new rejection necessitated by Applicant’s amendment. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated December 1, 2025. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
Claims 1-3, 13-17, 21-22, 30, and 33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more. The claims recite a population of ex vivo expanded NK (NK) cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well-understood, routine, and conventional in the development of therapeutics.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then does the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, claims 1-3, 13-17, 21-22, 30, and 33 are drawn to a composition of matter-a population of NK cells.
In regard to Step 2A prong one, claims 1-3, 13-17, 21-22, 30, and 33 are drawn to a nature-based product which is not markedly different from its naturally occurring counterpart. Specifically, independent claim 1 is directed to an ex vivo expanded population of human NK cells comprising KIR-B haplotype and homozygous for a CD16 158V polymorphism. Dependent claims 2, 13-16, and 21 recite that the NK cells are derived from the umbilical cord blood of donor, do not comprise a transgene, do not express endogenous proteins, and are not genetically engineered. Further, the instant specification indicates in Para. [0008] that these NK cells are derived from an umbilical cord blood bank and can be selected by existing presence of naturally occurring preferred characteristics.
Thus, the instant invention of the claims is a naturally occurring product. Applicant has not provided any special definition as to what is to be considered an “expanded” NK cell and has defined “ex vivo” as only occurring outside the body (Para. [0614]). Therefore, broadly interpreted, NK cells which have been obtained from a subject and expanded in vitro by a single cell division are considered to be an ex vivo population of expanded NK cells. Because instant claims are directed to a nature-based product, i.e., NK cells, the nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterparts in their natural state. Applicant is directed to the publication of Manser et al. (2019, KIR polymorphism modulates the size of the adaptive NK cell pool in human cytomegalovirus–infected individuals. J. of Immun., 203(8), 2301-2309) which indicated that prior to the date of the instant invention, it was known that CD16 158V polymorphism and KIR-B haplotype were known polymorphisms which could influence NK cell expansion (Table 1). Although Manser does not explicitly state that the homozygous CD16 158V population also comprise a KIR-B haplotype, since there are only A/A, A/B, and B/B karyotypes, about 2/3 of individuals would inherently possess at least one KIR-B allele. Thus, instant claims encompass NK cells that are identical (no difference in structural or functional characteristics) to naturally occurring NK cells comprising KIR-B haplotype and CD16 158V polymorphisms. In regard to the NK cells being expanded in vitro, as a first matter, this limitation, interpreted broadly, encompasses a single doubling of cells by any stimulus. Furthermore, Manser explicitly states that “the expansion of NKG2C NK cells could be recapitulated in vitro by cocultures using HCMV-infected cells” (Pg. 2302, left col., 2nd to last para.). Thus, NK cells expanded in vitro in response to HCMV would produce a population identical to in vivo expanded natural killer cells in response to HCMV. In regard to the marker profile of Claim 3, as stated supra, CD16 was known to be naturally expressed in the vast majority of NK cells. Regarding expanded NK cells derived from cord blood, Manser cites the prior art of Pereira et al. (2005, Insights into viral transmission at the uterine–placental interface. Trends in Microbio., 13(4), 164-174) which discloses that CMV infections cross the placenta and are transmitted from mother to fetus (Table 1). Vaaben et al. (2022, In utero activation of natural killer cells in congenital cytomegalovirus infection. J. of Infectious Dis., 226(4), 566-575) evidences that congenital CMV infection also results in the expansion of NK cells in cord blood (Pg. 571, left col., 1st para.). Therefore, because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. Accordingly, instant claims are directed to a judicial exception.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application. In particular, claims 30 and 33 recite no additional elements to integrate the claimed cell into a practical application. Claim 30 recites a single additional element of a vial or cryobag. Claim 33 recites a single additional element of a bioreactor. The terms vial or bioreactor are extremely broad and encompass many embodiments including a glass or plastic container and a vessel in which cells can be viably maintained. Thus, merely placing the naturally occurring product in a container in order to package it or into vessel in order to maintain viability does not add a meaningful limitation as it is nominal extra-solution component of the claim which is a necessary precursor for the therapeutic use of the cells and is nothing more than an attempt to generally link the NK cell product to therapeutic use.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, claims 30 and 33 recite no additional elements to the cell. In regard to claim 30, which recites a single additional element as a vial or cryobag and claim 33 which recites a single additional element as a bioreactor, as discussed above with respect to the integration of the natural product into a practical application, the additional elements of adding a vial or cryobag in which to package cells and a bioreactor in which to maintain cell viability amounts to no more than a place in which to store cells and thus do not provide inventive concepts.
Therefore, 1-3, 13-17, 21-22, 30, and 33 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrated into a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Response to Arguments
Applicant’s arguments, see Pg. 11-12, filed May 29, 2026, with respect to the rejection under 35 U.S.C. 101 of claims 18 and 19 have been fully considered and are persuasive. The rejection under of claims 18 and 19 has been withdrawn.
Applicant's arguments filed May 29, 2026 with respect to claims 1-3, 13-17, 21-22, and 30 have been fully considered but they are not persuasive.
First, Applicant traverses on Pg. 8-9 (bridging para.) that the Office has not established a prima facie case that the claimed NK cell population exists in nature and is relying on unsupported inherency. Applicant asserts on Pg. 9 (1st full para.) that an ex vivo expanded population of NK cells derived from a donor having the KIR-B haplotype and homozygous for CD16 158V polymorphism would not necessarily be the same as a naturally occurring population of expanded NK cells. Applicant asserts that the prior art of Manser teaches that CD16 158 dimorphism and KIR haplotype do not influence in vivo expansion of NKG2C+ NK cells and that the Office’s assertion that about 2/3rd of individuals would comprise a KIR-B haplotype is incorrect as Pyo et al. as teaches that the homozygous KIR-B karyotype exists in 6% of the population. Applicant traverses on Pgs. 10-11 that Manser’s teaching that individuals having a KIR-B haplotype and CD16 158 V/V polymorphism does not establish that a population of ex vivo expanded NK cells from individuals having a KIR-B haplotype and CD16 158 V/V polymorphism as recited in claim 1 would be identical to NK cells from individuals having a KIR-B haplotype and CD16 158 V/V polymorphism found in nature and that nothing in Manser suggests that in vitro population of NK cells expanded in response to HCMV infection would produce a population of NK cells identical to ex vivo expanded NK cells comprising a KIR-B haplotype and CD16 158 V/V polymorphism.
Applicant’s arguments have been fully considered but are but are not persuasive.
As an initial matter, it is noted that Applicant has not provided any special definition as to what is to be considered an “expanded” NK cell and has defined “ex vivo” as only occurring outside the body (Para. [0614]). Broadly interpreted, NK cells which have been obtained from a subject and expanded in vitro by a single cell division is considered to be an ex vivo population of expanded NK cells. Although Applicant describes functional properties associated with the claimed “expanded and stimulated NK cells” (See Section E on Pg. 38), these properties appear to be a result of the specific method by which the NK cells are expanded (See Example 1) and neither the properties nor the method of expansion is recited in claims 1-3, 13-17, 21-22, 30, and 33.
With regard to Applicant’s arguments regarding populations of naturally occurring NK cells, Applicant has cited Pyo et al. as teaching that the homozygous KIR-B karyotype exists in 6% of the population. However, the instant claims do not require a homozygous KIR-B karyotype and include KIR-A/B karyotypes which, based on Pyo et al., would be present in approximately 40% of the population. It is also noted that Pyo et al. only examined the representative frequency of the KIR haplotypes sequenced from 12 individuals (Pg. 2, Results, 1st & 2nd para.) which may not be representative of all existing KIR-B haplotypes. Additionally, Miller (2013, Therapeutic applications: natural killer cells in the clinic. Hematology 2013, the American Society of Hematology Education Program Book, 2013(1), 247-253, found in IDS dated 10/11/2024) teaches that the frequency distribution of KIR-B haplotypes varies between populations and that the KIR-B haplotype are found in 2/3rds of the white population (Pg. 247, right col., last para.). Manser teaches investigation of genetic polymorphisms “which have the potential to influence expansion” of NKG2C+ NK cells (Pg. 2303, left col., 2nd para.) , including KIR haplotype and CD16 158 polymorphisms, in the same population of cells which indicates that at least some of those cells would naturally have a KIR-B haplotype and CD16 158V/V polymorphism and, although Manser concludes that KIR-B haplotype and CD16 158 V/V are not associated with significantly increased NKG2C+ NK expansion, both are indicated as being present in NKG2C NK populations expanded by HCMV infection (See Table 1, Fig. 3A). Thus, Manser appears to indicate that an expanded population of NK cells having KIR-B haplotype and CD16 158 V/V exist in nature. Although Applicant asserts that nothing in Manser indicates the NK cells expanded in vitro in response to HCMV would produce a population identical to ex vivo expanded natural killer cells, Manser teaches that expansion NKG2C NK cells can be recapitulated in vitro using coculture of HCMV-infected cells (Pg. 2302, left col., 2nd to last para.).
Based on the broad interpretation of ex vivo expansion as encompassing a single cellular division, a skilled artisan would not expect isolated NKG2C+ NK cells having KIR-B haplotype and CD16 158 V/V expanded via a single division to be structurally distinct from those as taught in Manser. In fact, Applicant’s instant specification indicates that the instantly claimed NK cell population could be from a single individual and therefore share a genotype, but that it is the process of expansion which results in phenotypic differences (Para. [0270], [0271]). The Min PCT teaches that the cells with which NK cells are co-cultured play a significant role in NK cell proliferation rate with Hut78 feeder cells leading to higher proliferation (See Example 3.2 and Table 4) and specific combinations of genes transduced into Hut78 cells also affecting proliferation rate (Example 3.2, Table 5). The Min PCT also teaches that proliferation rate could be increased by repeated stimulations of co-cultured engineered Hut78 cells (Para. [0192]). Further, the Min PCT teaches that the specific cells with which NK cells are co-cultured affects expression of activation markers including NKG2D, NKp30, NKp44, NKp46, DNAM-1, and CXC23 (Para. [0214], Figs 8a-11l) and costimulatory proteins (Para. [0240],Figs. 18a-18f) as well as the cytotoxic ability against K562 cells (Para. [0221], Figs. 13a-14d). Similarly, the Min PCT teaches that repeated stimulations of co-cultured engineered Hut78 cells affect the level of costimulatory proteins (Para. [0241], Figs. 19a-19f). Thus, since NK cell phenotype depends on the parameters by which the NK cells are expanded, without limitations regarding the method of expansion, it is not possible for a skilled artisan to determine the scope of the ex vivo expanded NK cell population which comprises naturally occurring genetic variants as instantly claimed.
Second, Applicant asserts on Pg. 11 that ex vivo expansion results in NK cell populations which are markedly different from naturally occurring NK cell populations and points to the instant specification which demonstrate differences in surface marker and gene expression between freshly isolated NK cells and those which have been subjected to expansion by co-culture with genetically modified feeder cells (Example 1, Examples 16 and 17). Applicant further asserts that NK cells expanded in vitro in response to HCMV infection as in Manser exhibit increased in CD57+ cells whereas the ex vivo expanded NK cells produced by Applicant’s method comprising co-culture with genetically modified feeder cells exhibit reduced CD57+ expression. Applicant concludes that the population of NK cells as instantly claimed is structurally distinct from those which are naturally occurring.
Applicant’s arguments have been fully considered but are not persuasive.
As stated supra, it appears that it is the process by which NK cells are expanded which results in any phenotypic differences. Applicant asserts points to Example 16 as indicating differences in expression markers, Example 17 as indicating differences in gene expression, and Para. [0670] as indicating increased CD57+ cells. However, these examples depict differences between the starting naturally occurring NK cell populations and NK cell populations “expanded and stimulated with eHut-78 cells” as described in Example 1. The specific method steps for NK cell expansion are recited in claims 18 and 19 and therefore, the rejection of claims 18 and 19 have been withdrawn. However, the expanded NK cell population as recited in claims 1-3, 13-17, 21-22, 30 and 30 does not require limitations regarding the method of expansion. Thus, Applicant’s assertion regarding the structural differences between the claimed NK cell population and naturally occurring NK cells are not commensurate in scope with the instant claims.
New Claim Rejections - 35 USC § 102
Claims 1, 3, 13-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Manser et al. (2019, KIR polymorphism modulates the size of the adaptive NK cell pool in human cytomegalovirus–infected individuals. J. of Immun., 203(8), 2301-2309, hereafter “Manser”).
This is a new rejection necessitated by Applicant’s amendment. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated December 1, 2025 and provides additional interpretation. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
Claim 1, as amended, is drawn to a population of ex vivo expanded NK cells comprising a KIR-B haplotype and homozygous for a CD16 158 V/V polymorphism.
The limitations regarding ex vivo method of expansion are interpreted as product-by-process.
MPEP 2113(I) states:
“Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps… “Even 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” and “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made…”
In the instant case, there are no specific recited method steps by which the instantly claimed NK cell population is expanded ex vivo. Applicant has also not provided a definition of what is to be considered “expanded” NK cells. Broadly interpreted, NK cells which have been obtained from a subject and expanded in vitro by a single cell division is considered to be an ex vivo population of expanded NK cells. Absent evidence to the contrary, it does not appear that ex vivo expansion imparts and structural difference in the instantly claimed NK cells over those as disclosed in Maser as naturally occurring.
With regard to claims 1 and 3, Manser discloses an NK cell population comprising CD16 158V polymorphism and KIR-B haplotype (Table 1). Although Manser does not explicitly state that the homozygous CD16 158V population also comprise a KIR-B haplotype, since there are only A/A, A/B, and B/B karyotypes, about 2/3 of individuals would inherently possess at least one KIR-B allele. Further, CD16 is known to be a naturally expressed in the vast majority of NK cells.
With regard to claims 13-15, Manser discloses NK cells isolated from PMBCs derived from buffy coat and whole blood doners (Pg. 2302, right col., Blood samples) which is considered to reasonably read on NK cells which do not comprise a CD16 transgene, do not express an exogenous CD16 protein, and are not genetically engineered.
With regard to claim 17, Manser discloses an expanded population of NKG2C+ NK cells comprising 40-80% of the total number of NK cells which is considered to reasonably read on a population of expanded NK cells comprising at least 100 million expanded NK cells.
Maintained Claim Rejections - 35 USC § 103
Applicant has requested that the US filing of Min et al., US 2020/0108096 (found in IDS dated 10/11/2024), be used instead of a translation of the Min et al. PCT filing WO 2018/217064 A2 as currently applied. In view of this request, the citations to “US ‘096” have been added to the rejection in addition to the existing citations of Min utilizing the WO ‘064 art as already applied.
Claims 1, 3, 13-15, 17, 30, 33-34, 51, and 70-72 are rejected under 35 U.S.C. 103 as being unpatentable over Min et al. (WO 2018217064 A2, found in IDS and Espacenet translation attached, hereafter “Min”) and Manser et al. (2019, KIR polymorphism modulates the size of the adaptive NK cell pool in human cytomegalovirus–infected individuals. J. of Immun., 203(8), 2301-2309, hereafter “Manser”) in view of Bachanova et al. (2016, Donor KIR B genotype improves progression-free survival of non-Hodgkin lymphoma patients receiving unrelated donor transplantation. Bio Blood Marrow Trans, 22(9), 1602-1607, hereafter “Bachanova”) and Hatjiharissi et al. (2007, Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphism. Blood, 110(7), 2561-2564, hereafter “Hatjiharissi”).
With regard to claim 1, Min teaches a method of culturing NK cells comprising co-culturing NK source cells with transformed CD4+ T cells (Para. [0010]; US ‘096 Para. [0010]) which can be used to proliferate NK cells from a small amount of starter cells (Para. [0013]; US ‘096 Para. [0013]) and a population of NK cells produced by their culturing method (Para. [0012]; US ‘096 Para. [0012]). Min teaches that the “seed cells” can be from various sources including PMBCs and isolated NK cells (Para. [0139] US ‘096 Para. [0139]). Min further teaches the NK cells produced by their method are effective for the treatment of cancer (Para. [0152]; US ‘096 Para. [0153]).
Min does not teach wherein the NK cells comprise KIR-B haplotype and are homozygous for CD16 158V polymorphism.
Manser teaches an expanded subset of NKG2C+ NK cells (Abstract) isolated from PMBCs derived from buffy coat and whole blood doners (Pg. 2302, right col., Blood samples) which were assessed for various genetic polymorphisms which are known to influence NK cell expansion (Pg. 2303, left col., 2nd full para.), including KIR-B haplotype and CD16 158V polymorphism (Table 1). Although Manser does not explicitly state that the homozygous CD16 158V population also comprise a KIR-B haplotype, since there are only A/A, A/B, and B/B karyotypes, about 2/3 of individuals would inherently possess at least one KIR-B allele.
Bachanova teaches that HLA-matched KIR-B/x donor grafts reduce relapse and improve progression free survival in patients receiving cell therapy for non-Hodgkin lymphoma (Abstract and Impact of KIR genetics of transplant outcomes, lines 1-6) and that KIR-B/x donors improve leukemia free survival after cell therapy for acute myelogenous leukemia (Introduction, lines 23-24).
Hatjiharissi teaches that the presence of a valine (V) at position 158 of FcγRllla (CD16) improves the clinical response to rituximab in non-Hodgkin lymphoma (Abstract), that individuals having one valine at FcγRllla position 158 had increased number of CD16 receptors on NK cells (Pg. 2562, right col., 1st para.), and that individuals having at least one valine at position 158 of FcγRllla might have better clinical outcomes due to increased CD16 expression (Pg. 2563, left col., last para.).
Therefore it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to apply the method of proliferating NK cells to produce a larger population of NK cells as taught by Min to the NK cells having KIR-B haplotype and CD16 158V polymorphism which have improved function for cancer treatment as taught by Manser, Bachanova, and Hatjiharissi with a reasonable expectation of success. Min teaches that NK cells produced by their method have enhanced killing ability and can be used to produce commercialized cell therapy agents (Para. [0013]; US ‘096 [0013]) which can be used for treating cancer (Para. [0152]; US ‘096 Para. [0153]) and the combined teachings of Manser, Bachanova, and Hatjiharissi teach that the KIR-B haplotype and CD16 158V polymorphism lead to better clinical outcomes and improved progression free survival in at least some types of cancer. Thus, it would have been obvious to select NK cells with the combination of the KIR-B haplotype and homozygous CD15 158V polymorphism to treat cancer. MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
With regard to claim 3, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches wherein the “seed cells” used in the culture method are preferably CD3- after removal of CD3+ (Para. [0139]; US ‘096 [0139]). This is considered to reasonably read on a population of expanded NK cells comprising less than 20% CD3+ cells. Figures 7a and 7g are diagrams showing the purity of NK cells (CD3-CD56 +) prepared by co-culture with Hut78 T cell line.
With regard to claims 13-15, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Manser teaches wherein NK cells (Abstract) were isolated from PMBCs derived from buffy coat and whole blood doners (Pg. 2302, right col., Blood samples). This is considered to reasonably read on NK cells which do not comprise a CD16 transgene, do not express an exogenous CD16 protein, and are not genetically engineered.
With regard to claim 17, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches a dosage of NK cells produced by their method which comprises 1.0x108 cells/kg (Para. [0155]; US ‘096 Para. [0156]), which is considered to reasonably read on a population of NK cells comprising at least 100 million expanded NK cells.
With regard to claim 30, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches wherein NK cells produced by their method can be used as a pharmaceutical composition and divided into doses (Para. [0154] and [0155]; US ‘096 Para. [0155] and [00156]). Although Min is silent to the specific use of a vial or cryobag for the pharmaceutical composition, vials and cryobags are commonly used storage methods for pharmaceutical compositions with are widely known in the art. Thus it would have been obvious to one of ordinary skill in the art to use a vial or cryobag in order to store the pharmaceutical composition generated by the combined teachings of Min, Manser, Bachanova, and Hatjiharissi.
With regard to claim 33, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches wherein the cultivation of cells can be performed continuously in a cultivated batch process, a fed batch process, or a repeated batch process (Para. [0147]; US ‘096 Para. [0147]). One having ordinary skill in the art would recognize that Min’s teachings support the use of a bioreactor comprising the NK cells for use in cell culture.
With regard to claim 34, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches wherein starting “seed cells” which can be isolated NK cells (Para. [0139]; US ‘096 Para. [0139]) can be suspended in freezing medium, which is considered to reasonably read on a cryopreservation solution, and frozen in liquid nitrogen (Para. [0186]; US ‘096 Para. [0176]). Min further teaches that NK cells cultured by their method can be frozen (Para. [0152]; US ‘096 Para. [0153]). Although Min is silent to use of a cryopreservation solution with cultured NK cells, one having ordinary skill in the art could have easily applied the cryopreservation solution used for seed cells as taught by Min to the cultured NK cells produced by Min’s method, especially given Min’s teaching that the cultured NK cells can be frozen.
With regard to claim 51, as detailed above, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Min teaches wherein the NK cells are co-cultured with feeder cells (Para. [0137]; US ‘096 Para. [0137]) which would result in a composition comprising genetic material, protein, or cell from a feeder cell line.
With regard to claims 70-72, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism and Min provides support for use of a cryopreservation solution. Min teaches wherein NK cells produced by their method can be used as a pharmaceutical composition and divided into doses (Para. [0154] and [0155]; US ‘096 Para. [0155] and [0156]) and wherein the dosage can be 1.0x109 cells/kg (Para. [0155]; US ‘096 Para. [0156]) which is considered to reasonably read on a dosage unit comprising between 100 million and 1.5 billion cells.
Claims 2, 16, 18-19, 21-22, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Min and Manser in view of Bachanova and Hatjiharissi as applied to claims 1 above, and further in view of Goldenson et al. (2020, Umbilical cord blood and iPSC-derived NK cells demonstrate key differences in cytotoxic activity and KIR profiles. Frontiers in immunology, 11, 561553, hereafter “Goldenson”).
With regard to claims 2, 16, and 21, the combined teachings of Min, Manser, Bachanova, and Hatjiharissi as detailed above in incorporated herein teach a method of expanding NK cells and population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism. Manser teaches wherein expanded NK cells comprising KIR-B haplotype and CD16 158V polymorphism are isolated from PMBCs derived from buffy coat and whole blood doners (Pg. 2302, right col., Blood samples).
Manser does not teach wherein NK cells were isolated from umbilical cord blood.
Goldenson teaches wherein NK cells are derived or isolated from various sources including umbilical cord blood, peripheral blood, and iPSCs (Abstract). Goldenson teaches wherein umbilical cord blood units were purchased from a blood bank and NK cells were expanded under culture conditions (Pg. 2, right col., Derivation and Expansion of NK Cells From Umbilical Cord Blood and Peripheral Blood). Additionally, Goldenson teaches that umbilical cord blood derived NK cells exhibit more potent cytotoxicity compared to NK cells derived from other sources such as hematopoietic stem cells, even when derived from the same donor (Pg. 11, left col., Discussion, 1st para.).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism derived from buffy coat or whole blood donors as taught by Manser, Bachanova, and Hatjiharissi with the NK cells derived from umbilical cord blood as taught by Goldenson with a reasonable expectation of success. A skilled artisan would have been motivated to do this as Goldenson teaches that NK cells derived from umbilical cord blood exhibit more potent cytotoxicity which is important in selecting NK cells which can be used in therapeutic treatments. As Goldenson teaches enhanced cytotoxicity in umbilical cord derived NK cells compared to other NK cells from the same donor and the combined teachings of Manser, Bachanova, and Hatjiharissi teach that the KIR-B haplotype and CD16 158V polymorphism lead to better clinical outcomes and improved progression free survival in at least some types of cancer, one having ordinary skill in the art would recognize that using umbilical cord blood from a single donor would allow for selection of a donor having KIR-B haplotype and homozygous for the CD16 158V polymorphism leading to generation of NK cell line that has demonstrated better clinical outcomes and improved progression free survival and enhanced cytotoxicity which can be used in cell therapy treatments for cancer.
With regard to claim 22, as detailed above, the combined teachings of Min, Manser, Bachanova, Hatjiharissi, and Goldenson teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism which can be derived from umbilical cord blood. Min teaches that NK cells can be proliferated 436,032-fold (Para. [0205]; US ‘096 Para. [0192]), which is considered to reasonably read on expanding NK cells at least 10,000 fold.
With regard to claims 18 and 19 and 73, as detailed above, the combined teachings of Min, Manser, Bachanova, Hatjiharissi and Goldenson teach a population of expanded NK cells comprising KIR-B haplotype and homozygous for CD16 158V polymorphism wherein the NK cells are derived from umbilical cord blood. Min teaches a method of culturing NK cells comprising obtaining “seed cells” (Para. [0139]; US ‘096 [0139]), removing CD3+ cells (Para. [0139]; US ‘096 [0139]), and co-culturing the seed cells with Hut78 cells expressing mTNF-α, mbIL-21, and 4-IBBL (i.e., “triple gene”) in order to proliferate NK cells (Para. [0196]; US ‘096 [0184]). Min further teaches wherein repeated “re-stimulation” of the NK cell culture (Para. [0199]; US ‘096 [0186]) was performed by adding additional pluralities of Hut78 cells with mTNF-α, mbIL-21, and 4-IBBL to the NK cell culture (Para. [203]; US ‘096 [0190]) which was repeated at 7 or 11 day intervals (Para. [0204]; US ‘096 [0191]). Min further teaches that re-stimulation of NK cell culture results in increased proliferation of NK cells (Para. [0205]; US ‘096 [0192]). This is considered to reasonably read on expanding an already expanded NK cell population using a second plurality of Hut78 cells engineered to express mTNF-α, mbIL-21, and 4-IBBL.
Therefore, it would have been obvious before the effective filing date of the claimed invention, to apply the method of NK cell proliferation as taught by Min to the NK cells which comprise KIR-B haplotype and homozygous for CD16 158V polymorphism wherein the NK cells are derived from umbilical cord blood as taught by the combined teachings of Manser, Bachanova, Hatjiharissi and Goldenson with a reasonable expectation of success. Since Min teaches that NK cells produced by their method have enhanced killing ability and can be used to produce commercialized cell therapy agents (Para. [0013]; US ‘096 [0013]) for the treatment of cancer (Para. [0152]; US ‘096 [0153]), the combined teachings of Manser, Bachanova, and Hatjiharissi teach that the KIR-B haplotype and CD16 158V polymorphism lead to better clinical outcomes and improved progression free survival in at least some types of cancer, and Goldenson teaches that NK cells from umbilical cord blood exhibit more potent cytotoxicity which is important in selecting NK cells which can be used in therapeutic treatments, a skilled artisan would have been motivated to make this combination in order to generate a large number of NK cells comprising polymorphisms which lead to better clinical outcomes and improved progression free survival and enhanced cytotoxicity for use in a commercialized cell therapy product which can be used to treat cancer.
Response to Arguments
Applicant's arguments filed May 29, 2026 have been fully considered but they are not persuasive.
Claims 1, 3, 13-15, 17, 22, 30, 33-34, 51, and 70-72 were rejected under 35 U.S.C. 103 as being unpatentable over Min, Manser, Bachanova, and Hatjiharissi.
Applicant has requested that the US filing of Min et al. US 2020/0108096 (found in IDS dated 10/11/2024), be used instead of a translation of the Min et al. PCT filing WO 2018/217064 A2 as currently applied. In order to comply with Applicant’s request, citations reflective of the US filing US 2020/0108096 have been added to the 103 rejections above.
First, Applicant traverses on Pg. 13 (last para.) that the Office’s assertion that the KIR-B haplotype would be being present in 2/3 of the population is incorrect based on Pyo et al. which indicates that the B/B haplotype occurs in 6% of the population. Applicant further traverses on Pg. 14 that the Office’s assertion only establishes that individuals having KIR-B haplotype and homozygous CD16 158 V polymorphism exist in nature and that a skilled artisan would not have looked to Min, Manser, Bachanova, and Hatjiharissi to select the instantly claimed donor source having a KIR-B haplotype and CD16 158V/V polymorphism in order to produce an ex vivo expanded population of NK cells (1st para.). Applicant asserts that Bachanova and Hatjiharissi teach the KIR-B and CD16 158V/V polymorphism respectively in isolated clinical indicators of disparate treatment regimens and would not provide blueprint for making a manufactured cell product (2nd para.). Applicant asserts on Pg. 15 that Bachanova and Hatjiharissi teach each genotypes in isolation and in different contexts with Bachanova teaching KIR-B as being important for HLA matching in cancer treatment and Hatjiharissi teaching the CD16 158V/V genotype being beneficial for cancer treatment and that neither discuss ex vivo NK cell expansion (1st para.).
Second, Applicant asserts that the instant application demonstrates alleged unexpected results of choosing donor cells having a KIR-B haplotype and CD16 158V/V polymorphism which would not have been obvious based on Min, Manser, Bachanova, and Hatjiharissi including high CD16 expression and low CD38 expression (Pg. 15, 2nd para.).
In response to Applicant’s assertion of the frequency of KIR-B in the population. Although Applicant has cited Pyo et al. as teaching that the homozygous KIR-B karyotype exists in 6% of the population, the instant claims do not require a homozygous KIR-B karyotype and include KIR-A/B karyotypes which, based on Pyo et al., would be present in approximately 40% of the population. It is also noted that Pyo et al. only examined the representative frequency of the KIR haplotypes sequenced from 12 individuals (Pg. 2, Results, 1st & 2nd para.) which may not be representative of all existing KIR-B haplotypes. Additionally, Miller (2013, Therapeutic applications: natural killer cells in the clinic. Hematology 2013, the American Society of Hematology Education Program Book, 2013(1), 247-253, found in IDS dated 10/11/2024) teaches that the frequency distribution of KIR-B haplotypes varies between populations and that the KIR-B haplotype are found in 2/3rds of the white population (Pg. 247, right col., last para.).
In response to Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Min teaches that NK cells can be expanded ex vivo by co-culture with genetically modified feeder cells in order to generate large numbers of NK cells which have improved therapeutic potential for diseases such as cancer. Bachanova and Hatjiharissi teach that the KIR-B haplotype and CD16 158V polymorphism lead to better clinical outcomes and improved progression free survival in at least some types of cancer. Manser teaches a subset of NK cells having KIR-B haplotype and CD16 158V polymorphism. Therefore, the combination of Min, Manser, Bachanova, and Hatjiharissi render obvious the NK cell type having KIR-B haplotype and CD16 158V/V polymorphism, both of which are associated with improved outcomes in cancer treatment, for use in Min’s method of ex vivo expansion of NK cells which results in improved anti-cancer therapeutic effect (US ’096 Para. [0153]).
In response to Applicant’s assertion of alleged unexpected results, Min teaches that CD16 expression is “highly maintained” in NK cells which have been cultured with feeder cells (US ‘096 Para. [0213]), Figs 7b; 7d; 7f; 7h; 8a; 9a; 10a; 11a; 12a) and that NK cells cultured with feeder cells as taught by Min express CD16 at a high level (US ‘096 Para. [0214]). Therefore, based on the teachings of Min, high CD16 expression in NK cells cultured by Min’s method would be expected by one of ordinary skill in the art and does not appear to be related to the instantly claimed phenotype. Min does not examine CD38 expression in NK cells. However, low CD38 expression after NK cell expansion appears to be a naturally occurring result of selection of KIR-B and CD16 158 V/V donors based on Example 15 and Figs. 33 and 34 which show that low CD38 expression in KIR-B and CD16 158 V/V donors compared to control donors who are assumed to not have KIR-B haplotype and CD 16 158 V/V polymorphism. Therefore, as the combination of Manser, Bachanova, and Hatjiharissi render NK cells having KIR-B haplotype and CD 16 158 V/V polymorphism obvious to choose in the method of expansion as taught by Min, a skilled artisan would expect to generate an expanded NK cell population having low CD38 expression. Furthermore, MPEP 2145, Section II, states that the mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). The court held that granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.).
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-3, 13-17, and 21 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 16-23, 25-32 of copending Application No. 18/977,119, in view of the combined teachings of Manser, Bachanova, Hatjiharissi, and Goldenson. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the NK cell of cited application makes obvious the composition of instant application. It is clear that elements of the cited application claims are to be found in the instant claims. The difference between the cited application claims and the instant claims lies in the fact that the instant application claims are more specific to the genotype and source of the NK cells.
With regard to claims 1, 3, 13-15, and 17, as detailed above in incorporated herein, the combined teachings of Manser, Bachanova, and Hatjiharissi teach NK cells comprising KIR-B haplotype and CD16 158V polymorphism wherein KIR-B/x haplotype is associated with reduced relapse and improved progression free survival in cell therapy for non-Hodgkin lymphoma and wherein the presence of least one valine at position 158 of FcγRllla (CD16) improves the clinical response to rituximab in non-Hodgkin lymphoma and increases CD16 expression which may improve clinical outcomes. Additionally, CD16 is known to be a naturally expressed in the vast majority of NK cells and Manser teaches that the NK cells comprising KIR-B haplotype and CD16 158V polymorphism were isolated from PMBCs from blood donors, therefore the NK cells would not comprise a CD16 transgene, express a endogenous CD16 protein, or be genetically altered. Further, Manser teaches wherein the expanded NKG2C NK cells comprise 40-80% of the whole NK cell repertoire. Even accounting for the subset of cells which would comprise KIR-B haplotype and CD16 158V polymorphism, the population would comprise greater than 100 million expanded NK cells. Thus, based on the teachings of Manser, Bachanova, and Hatjiharissi KIR-B and CD16 158V NK cells would have been an obvious NK cell type to claim Since the instant application claims are obvious over cited application claims in view of Manser, Bachanova, and Hatjiharissi, said claims are not patentably distinct.
With regard to claims 2, 16, and 21, as detailed above and incorporated herein, the combined teachings of Manser, Bachanova, Hatjiharissi, and Goldenson teach wherein NK cell comprising KIR-B haplotype and CD16 158V polymorphism are derived from an umbilical cord blood donor. The combined teachings of Manser, Bachanova, and Hatjiharissi teach NK cells comprising KIR-B haplotype and CD16 158V polymorphism derived from whole blood PMBCs. Goldenson teaches that umbilical cord blood derived NK cells exhibit more potent cytotoxicity compared to NK cells derived from other sources such as hematopoietic stem cells, even when derived from the same donor. Thus, based on the teachings of Manser, Bachanova, Hatjiharissi, and Goldenson, KIR-B and CD16 158V NK cells derived from an umbilical cord blood donor would have been an obvious source of NK cells to claim. Since the instant application claims are obvious over cited application claims in view of Manser, Bachanova, Hatjiharissi, and Goldenson, said claims are not patentably distinct.
Response to Arguments
Applicant's arguments filed May 29, 2026 have been fully considered but they are not persuasive.
Applicant asserts on Pg. 17 that the copending application U.S. Application No. 18/977,119 is a divisional of U.S. Application number 16/613,601 which was published as US 2020/0108096. US 2020/0108096 is the U.S. filing of the Min PCT WO 2018217064 A2 which has been applied as prior art. Applicant traverses that US 2020/0108096 is the specification of the reference disclosure and is therefore not considered prior art and that the double patenting rejection which uses the prior art of Min PCT, Manser, Bachanova, Hatjiharissi, and Goldenson should be withdrawn for the same reasons as stated in the traversal of the rejections under 35 U.S.C. 103.
Although Applicant has requested use of U.S. filing US 2020/0108096 as the translation for the Min PCT, the Min PCT, WO 2018/217064A2, is considered prior art based on the publication date of November 11, 2018. The response to Applicant’s rejections under 35 U.S.C. 103 have been addressed above.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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