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 .
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 statements (IDS) submitted on October 11, 2024 and January 6, 2025 are in compliance with the provisions of 37 CFR 1.97 and are being 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.
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 16-17, 21-22, and 72 are 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 lines 2-3. 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.
With regard to claim 17, the phrase "for example", as recited in the instant claim as “e.g.” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Appropriate correction is required.
With regard to claim 21, which depends from claim 1, claim 21 recites the limitation "wherein the umbilical cord blood" in line 2. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of umbilical cord blood. Appropriate correction is required.
With regard to claim 22, which depends from claim 1, claim 22 recites the limitation "the method" in line 2. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of a method. Appropriate correction is required.
With regard to claim 22, which depends from claim 1, claim 22 recites the limitation "the NK cells from umbilical cord blood" in lines 2 and 3. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of NK cells from umbilical cord blood. Claim 1 recites a population of expanded NK cells. Appropriate correction is required.
With regard to claim 22, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 22 recites the broad recitation “NK cells”, and the claim also recites “NK cells from umbilical cord blood” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
With regard to claim 22, the phrase "for example", as recited in the instant claim as “e.g.” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Appropriate correction is required.
With regard to claim 34, which depends from claim 1, claim 34 recites the limitation “a population of expanded and stimulated NK cells”. There is insufficient antecedent basis for this limitation as there is no prior recitation of a population of expanded and stimulated NK cells. Claim 1 recites a population of expanded NK cells. Appropriate correction is required.
Claims 51 and 70-72, which depend from claim 34, are also rejected as incorporating the limitations from a rejected claim while failing to correct the deficiencies.
With regard to claim 72, the phrase "for example", as recited in the instant claim as “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Appropriate correction is required.
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.
Claims 1-3, 13-19, 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 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, 13-19, 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, 13-19, 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 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. 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 CD 16 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 marker profile of Claim 3, as stated supra, CD16 was known to be naturally expressed in the vast majority of NK cells. In regard to the expansion method features of instant claims 18 and 19, claims 18 and 19 are interpreted as product-by-process (See MPEP 2113) and thus, there is no indication that the expansion method results in NK cells having markedly different characteristics (structural, functional, or otherwise) from the naturally occurring cells that have been activated by cytokines and antigen presenting cells in vivo, absent evidence to the contrary. 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, 13-19, 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.
Claim Rejections - 35 USC § 102
Claims 1, 3, 13-15, 17, and 22 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”).
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 13-15, 17, 22, 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]) which can be used to proliferate NK cells from a small amount of starter cells (Para. [0013]) and a population of NK cells produced by their culturing method (Para. [0012]). Min teaches that the “seed cells” can be from various sources including PMBCs and isolated NK cells (Para. [0139]. Min further teaches the NK cells produced by their method are effective for the treatment of cancer (Para. [0152]).
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]) which can be used for treating cancer (Para. [0152]) 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]). 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]), which is considered to reasonably read on a population of NK cells comprising at least 100 million expanded NK cells.
With regard to claim 22, 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 method wherein the culture conditions can be modified in order to increase NK cell proliferation 436,032-fold (Para. [0205]), which is considered to reasonably read on expanding NK cells at least 10,000 fold.
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]). 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]). 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]) can be suspended in freezing medium, which is considered to reasonably read on a cryopreservation solution, and frozen in liquid nitrogen (Para. [0186]). Min further teaches that NK cells cultured by their method can be frozen (Para. [0152]). 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]) 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]) and wherein the dosage can be 1.0x109 cells/kg (Para. [0155]) which is considered to reasonably read on a dosage unit comprising between 100 million and 1.5 billion cells.
Claims 2, 16, 18-19, and 21 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, 3, 13-15, 17, 22, 30, 33-34, 51, and 70-72 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 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 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]), removing CD3+ cells (Para. [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]). Min further teaches wherein repeated “re-stimulation” of the NK cell culture (Para. [0199]) was performed by adding additional pluralities of Hut78 cells with mTNF-α, mbIL-21, and 4-IBBL to the NK cell culture (Para. [203]) which was repeated at 7 or 11 day intervals (Para. [0204]). Min further teaches that re-stimulation of NK cell culture results in increased proliferation of NK cells (Para. [0205]). 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]) for the treatment of cancer (Para. [0152]), 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 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.
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.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631