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
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional applications 62/342396 (filed 5/16/2022) and 63/382598 (filed 11/7/2022).
Claims Status
A preliminary amendment was received on 9/20/23. Claims 1-4, 9, 12, 15-18, 22, 25, 27-28, 31, 36, 38, 40, 42, 45 are pending, all of which have been considered on the merits.
Claim Interpretation
For clarity of record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
None of the ‘optionally’ limitations are required.
Given the absence of a firm definition in the specification, the phrase “substantially comprising [specified cell type]” is interpreted as meaning a non-negligible number of [specified cell type] are present in the population. “Substantially” does not require any minimum value or percentage.
Claims 16 and 36 are interpreted as reciting intended use limitations. Specifically, claim 16 states the expanded NK cells population is used for administering to a subject. Claim 36 states the expanded NK cell populations is used for administration to patients diagnosed with cancer or an infectious disease. Actual administration is not required by the claim.
Claim 18 recites product-by-process limitations. Specifically, limitations regarding how the population of immune cells were obtained. The method does not require active steps of obtaining the immune cells. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. In the instant case, the source of the immune cells does not affect their actual structure. NK cells obtained via any of the techniques claimed will have the same phenotype.
Drawings
The drawings filed 5/15/2023 are objected to because they contain color images, with no granted petition.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 1 and 9 are objected to because of the following informalities:
In claim 1, line 1, the term ‘and’ is written twice.
In
Appropriate correction is required.
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.
Claim 1,3,9,12,15-18, 25, 27-28, 31, 36, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al (US 6849452B1), in view of Van Wetering et al (WO 2014/006058), evidenced by Hu et al (Frontiers in Immunology, 2019).
Zitvogel et al teaches a method of activating Natural Killer (NK) cells by contacting NK cells and dendritic cells (DC) through co-culture (See col 2, lines 25-26). Zitvogel et al further teach using the activated NK cells as a therapeutic, wherein the activated NK cells are used to stimulate cytotoxic activity against target cells sensitive to NK cells (See col. 2, ln 56-62).
Specifically, Zitvogel et al teach isolating populations of NK cells (See col 13 lines 11-41) and DCs (See col 13 line 42-col. 14, ln 53) via standard methods. The technique for isolating NK cells can yield a cell population comprising greater than 70% NK cells (See col. 13, ln 29-37). The NK cells can come from sources such as PBMCs (See col 13 lines14-16). The NK and / or dendritic cells can be from autologous, allogenic or commercially available cell lines (See col 14 lines 44-50).
Zitvogel et al teaches co-culturing the NK cells with the dendritic cells (See col. 6, ln 40- col. 8, ln 2). Zitvogel et al teach that activation efficiency can be enhanced by optimizing the ratio of NK to DCs as well as by optimizing the duration of the co-culture (See col. 6, ln 64-col. 7, ln 18). A time period of 18-48 hours is disclosed, as well as a time period of less than 20 hours (See col 7 lines 1-4).
During the co-culturing of the NK and dendritic cells, there are significant levels of growth factor IFN γ found in the supernatant (See col 23 lines 48-50). The results exemplified by figure 2 in Zitvogel et al. shows mature dendritic cells that had high expression of CD11c, I-Ab, B7.2 and CD40 molecules were co-cultured with NK cells for 40 to 48 hours (See col 23 lines 22-30, Fig 2).
Following the co-culture, Zitvogel et al teach the activated NK cells and/or the DC can be isolated and stored for future use (See col. 8, ln 3-29). The isolated, activated NK cells can be administered into subjects (See col 16 lines 34-37)
Regarding claim 1, Zitvogel et al. teaches a method of activating NK cells. The method comprises co-culturing NK cells and dendritic cells. The NK cells clearly read on immune cells substantially comprising NK cells. The dendritic cells are comparable to the population of modified cells of leukemic origin, wherein the modified cells exhibit a mature dendritic cell phenotype. Co-culture necessarily requires placing the two cell types in contact, which reads on step (a) contacting... The act of co-culturing clearly reads on step (b) co-culturing…which results in an expanded population of activated NK cells.
Zitvogel differs from the method of claim 1 in that Zitvogel does not teach the DC are modified cells of leukemic origin.
Van Wetering et al. teaches DCOne cells which are DC cell line derived from peripheral blood of a patient with acute myeloid leukemia or cells of leukemic origin (See col 11 lines 26-27), that were co-cultured for 4 hours with T-cells, another immune cell (See col 20 line 3). DCOne are commercially available cells that can be differentiated into mature dendritic cells (DCs) and used to activate T-cells in Van Wetering et al.
Given that both Zitvogel and Van Wetering teach dendritic cells for activating and co-culturing with leukocytes, it would have been prima facie obvious to have substituted one for the other. Specifically, it would have been prima facie obvious to have modified the method of Zitvogel. to substitute the dendritic cells with DCOne cells of Van Wetering. One would have had a reasonable expectation that the DCOne cells of Van Wetering et al would serve to activate the NK cells because the DCOne cells of Van Wetering et al are DCs, and are shown as being capable of activating other lymphocytes. Substitution of one element for another known in the field, wherein the results of the substation would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Therefore, the method of claim 1 is obvious over Zitvogel in view of Van Wetering.
Regarding claim 3, following the discussion of claim 1 above, Zitvogel teaches isolating the activated NK cells following the co-culture. This clearly reads on the additional isolating step as claimed.
Therefore, the method of claims 3 is obvious over Zitvogel in view of Van Wetering.
Regarding claim 9, following the discussion of claim 1 above, Zitvogel et al specifically states there are various technique to isolate a population of NK cells that are known to skilled persons within the field (See col 13 lines 12-13). Among those techniques disclosed, a technique that produces a population of immune cells with more than 70% of NK cells, that can be used for the claimed invention of co-culturing (See col 13 lines 29-31). This reads on the claim option 1) [at] least 70% of the immune cell population is composed of NK cells.
Therefore, the methods of claims 9 is obvious over Zitvogel in view of Van Wetering
Regarding claim 12, following the discussion of claim 1 above, Zitvogel et al specifically teaches the supernatant of co-cultured NK and dendritic cells contains significant levels of interferon γ (IFNγ). Therefore, the co-culture of claim 1 and claim 12 is in the presence of a growth factor and this reads on option (1) of claim 12.
Therefore, the method of claim 12 is obvious over Zitvogel in view of Van Wetering.
Regarding claim 15: Claim 15 is interpreted as stating that if IL-12 is present, it is present at the disclosed concentrations. Claim 15 is included in the rejection in so far as claim 15 does not further limit the embodiment wherein the supernatant includes growth factor IFNγ.
Regarding claims 16 and 17, following the discussion of claim 1 above, Zitvogel discloses the cell compositions of activated NK cells can be administered loco-regionally (See col 16 lines 34-37) which reads on method of administrating the expanded population of activated NK cells to a subject of claim 17. Therefore, claim 16 intended use of administrating the activated NK Cells is obvious and the step of administrating in claim 17 of the activated NK cells is obvious in view of Van Wetering et al.
Therefore, the methods of claims 16 and 17 are obvious over Zitvogel et al. in view of Van Wetering et al.
Regarding claim 18, following the discussion of claim 1 above, Zitvogel et al. specifically teaches that the NK cells can be obtained by different techniques and the isolation can be from PMBCs (See col 13 lines 14-16) and that the NK and dendritic cells can be of allogenic origin for the invention (See col 13 lines 44-45 and col 14 line 50), which reads on the elements (1) of claim 18.
Therefore, the methods of claim 18 is obvious in view of Zitvogel et al. in view of Van Wetering et al.
Regarding claim 25, following the discussion of claim 1 above, Van Wetering et al. specifically teaches that DCOne cells express WT-1 protein (See col 11 lines 29-31).
Therefore, the method of claim 25 is obvious in view of Zitvogel et al in view of Van Wetering et al.
Regarding claim 27-28 and 31, following the discussion of claim 1 above, Van Wetering et al. teaches DCOne cells have varying expressions of receptors including CD40 and CD80 (See col 11 lines 29-31), this reads on the limitation of claim 27, the modified cell of leukemic origin comprises a co-stimulatory molecule. This all reads on the option 2) of claim 28 further limiting the co-stimulatory molecule of …CD80 or CD40, and on option 1 of claim 31. Furthermore, since DC cells inherently express MHC I class molecules, the DCOne cells also satisfy the limitation of option 1) of claim 28 and option 3) of claim 31.
Therefore, the method of claim 27-28 and 31 is obvious in view of Zitvogel et al in view of Van Wetering et al.
Regarding claim 36, following the discussion of claim 1 above, the NK cells could be administered to subjects with cancer, therefore the teachings set above read on the claim limitation. It is emphasized claim 36 is considered to recite an intended use of the activated NK cells, it does not require actual administration.
Therefore, the methods of claims 36 is obvious over Zitvogel in view of Van Wetering
Regarding claim 38, following the discussion of claim 1 above, activated NK cells inherently increase ADCC, evidence by Hu et al (Frontiers in Immunology, 2019). Hu et al. teaches that NK cell activation can either maintain their in vivo survival or proliferation or mediate NK cell cytotoxicity by ADCC (See Hu et al, p 11).
Claims 1-3,9,12,15-18, 25, 27-28, 31, 36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al (US 6849452B1), in view of Van Wetering et al (WO 2014/006058) and furthering in view of Min et al (Immune Network, 2018).
The teachings of Zitvogel et al. and Van Wetering et al. are set forth above.
Regarding claim 2, following the teachings of claim 1 above, Zitvogel et al teaches that NK cells co-cultured are activated in less than 20 hours and up to 48 hours (See col 7 lines 3-4).
This differs from claim 2, which requires the co-culturing step occurs for period of about 7 to 21 days, about 7 to 14 days or 14 days.
Min et al teaches a method for large expansion of NK cells that can last for 2 weeks (14 days) and up to 21 days (Figure 1A).
It would have been prima facie obvious to have modified the method of Zitvogel et al to co-culture the NK cells and DCOne cells for a period of up to 14 or 21 days because the duration of culture is based on variables such as culture conditions (temperature, cell density, growth medium, etc.). Furthermore, Min et al teach that the duration of culture directly effects the level of NK cell expansion. Thus, the duration of culture is a result effective variable. Optimization of result effective variables is considered prima facie obvious, absent evidence of criticality (See MPEP 2144.05).
This reads on the elements of claim 2, where the co-culturing is performed for a period of about 7 to 14 days or about 7 to 21 days.
Therefore, the method of claim 2 is obvious in view of Zitvogel et al, in view of Van Wetering et al., and further in view of Min et al.
Claims 1, 3, 4, 9,12,15-18, 25, 27-28, 31, 36, 38 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al (US 6849452 B1), in view of Van Wetering et al (WO 2014/006058) and furthering in view of Kobyzeva et al (Journal of leukocyte, 2020).
The teachings of Zitvogel et al. and Van Wetering et al. are set forth above.
Regarding claim 4 and 42, following the discussion of claim 1 above, Zitvogel et al and Van Wetering et al differ from claims 4 and 42 in that they do not teach the phenotypic characteristics of the NK cells as claimed.
Kobyzeva et al. teaches that NK cells that are CD57−NKG2C+ have an increased proliferation activity when comparing CD57+NKG2C+ and CD57+NKG2C− NK cells and maintain their cytotoxicity. These teachings also include that the generation of adaptive (memory) NK cells are characterized by the expression of receptor of NKG2C.
It would have been obvious to have modified the method of Zitvogel et al. to have substituted NK cells that are CD57+NKG2C+ for the NK cells taught in the method of Zitvogel et al for expansion of activated NK cells because Kobyzeva et al demonstrates the increased proliferative ability of these cells, which would increase the activated NK cells for the invention during co-culture. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have had a reasonable expectation of success using CD57+NKG2C+ of Kobyzeva et al. in the method of Zitvogel because Kobyzeva teaches how to obtain these cells and Zitvogel teaches the co-culturing method.
These teachings read on the elements (1) and (2) of claim 4 and the activation and proliferation of NK cells with cells not expressing NKG2C (NKG2C−) of claim 42.
Therefore, the method of claim 4 and 42 is obvious in view of Zitvogel et al, in view of Van Wetering et al, and further in view of Kobyzeva et al.
Claims 1, 3, 9,12,15-18, 22, 25, 27, 28, 31, 36, 38, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al (US 6849452B1), in view of Van Wetering et al (WO 2014006058A1) and further in view of Liu et al (The New England Journal of Medicine, 2020).
The teachings of Zitvogel et al. and Van Wetering et al. are set forth above.
Regarding claim 22, following the teachings of claim 1 above, Zitvogel et al teaches that NK cells co-cultured are within the method.
This differs from claims 22 and 40 which requires engineered NK cells.
Liu et al. teaches that engineered or CAR-NK cells can be co-cultured, activated and expanded ex-vivo (See pg547). It would have been obvious to have modified the method of Zitvogel et al. with the substitution of NK cells with the engineered CAR-NK cells taught in Liu et al. because Liu et al. demonstrates that CAR-NK cells are effective candidates for cancer treatments (See pg. 546), which would overcome the limitations of NK cell treatments in Zitvogel et al. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have had a reasonable expectation of success using engineered NK cells of Liu et al. in the method of Zitvogel because Liu teaches how to obtain these cells and Zitvogel teaches the co-culturing method.
These teachings read on the claim 22 and a step of introducing a chimeric antigen receptor (CAR)…into the NK cells...of claim 40.
Therefore, the method of claim 22 and 40 is obvious in view of Zitvogel et al. in view of Van Wetering et al., and further in view of Liu et al.
Claims 1, 3 ,9,12,15-18, 25, 27, 28, 31, 36, 38, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Zitvogel et al (US 6849452B1), in view of Van Wetering et al (WO 2014006058A1) and further in view of Björkström et al. (Blood, 2010) and Godal et al. (Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation, 2010).
The teachings of Zitvogel et al. and Van Wetering et al. are set forth above.
Regarding claim 45, following the teachings of claim 1 above, Zitvogel et al teaches that NK cells are co-cultured within the method.
This differs from claim 45 which requires the activated NK cells predominantly comprise of NKG2A- and KIR+ NK cells.
Björkström et al. teaches that expression of CD57, NKG2A, and KIRs is correlated to the proliferative capacity of NK cells and that loss of NKG2A expression and obtaining KIRs is part of the differentiation or activation of NK cells.
Godal et al. teaches NK cell killing capacity is attributed to the inhibitory effects of KIRs, indicates that having NK cells with NKG2A- and KIRs positive, increase the efficacy of the NK cells.
It would have been obvious to have modified the method of Zitvogel et al with the substitution of NK cells with NKG2A- and KIR+ NK cells taught in the method of Zitvogel et al for expansion of activated NK cells because Björkström et al. and Godal et al demonstrates the increased the proliferation capacity and efficacy of the NK cells, which would increase the activated NK cells for the invention during co-culture. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have had a reasonable expectation of success using NKG2A- and KIR+ NK cells of Björkström et al. and Godal et al in the method of Zitvogel because Björkström et al. and Godal et al teaches about these cells and Zitvogel teaches the co-culturing method.
These teachings read on the element (1) of claim 45. Therefore, the method of 45 is obvious in view of Zitvogel et al, in view of Van Wetering et al, and further in view of Björkström et al. and Godal et al.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633