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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 22Jul2025 has been entered.
Claims Status
Applicant’s election without traverse of (1) NK cell for immune cell; (2) cord blood as the source of the immune cells; (3) cancer as the disease to be treated; and (4) anti-cancer agent as the second therapeutic agent in the reply filed on 28Jun2023 is acknowledged.
In response to the election of species filed 28Jun2023, claims 24, 26, 51, 52 and 57 were withdrawn from further consideration pursuant to 37 CFR l.142(b) as being drawn to a nonelected invention.
The Amendment filed on 25No2025 is acknowledged in which claims 2, 4-5, 22-24, and 49-50 are canceled, and claims 30-31 are amended by Applicant.
Claim(s) 1, 3, 6-21, 25, 27-48, 53-56, and 58-67 are pending and presented for examination on the merits.
Oath/Declaration
The declaration under 37 CFR 1.132 filed on 25Nov2025 has been fully considered (see below).
Response to Amendment, Arguments, and Oath/Declaration
The objection(s) to claim(s) 10, have been withdrawn in view of the Amendment to the claims filed on 25Nov2025.
The rejection(s) of claim(s) 30-31 under 35 U.S.C. § 112(b), of claim(s) 1, 3, 6-9, 11-21, 25, 27-48, 53-56, and 58-67 under 35 U.S.C. § 103 have been withdrawn in view of the Oath/Declaration and Applicant Remarks filed on 25Nov2025.
As all previously presented rejection(s) and/or objection(s) have been withdrawn, only Applicant arguments that pertain to the new rejection(s) provided below are addressed herein (see “Response to Arguments and/or Oath/Declaration” below).
New Rejections/Objections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
Claim(s) 1, 3, 6-21, 25, 27-48, 53-56, and 58-67 is/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.
Regarding instant claim 1 (and dependent claims 3, 6-21, 25, 27-48, 53-56, and 58-67), the phrase “universal antigen presenting cell (UAPC)” renders the claim(s) indefinite because it is unclear which cells qualify as “universal” APCs. The instant specification discloses “…"UAPC(s)" refer herein to antigen presenting cells designed for the optimized expansion of immune cells, such as NK cells…” [e.g., ¶ 0033]. However, this definition does not make clear the metes and bounds of what is required to make an APC qualify as a UAPC, or further what qualifies as “designed for the optimized expansion of immune cells…”. Specifically, it is unclear if UAPCs means (a) endogenous APCs which are necessarily designed (by evolution) to expand immune cells; (b) engineered APCs of any variety; (c) APCs that are either naturally or are engineered to be MHC class I negative; or (d) something else. For the purposes of compact prosecution, the phrase “universal antigen presenting cell (UAPC)” is considered to mean any MHC I negative APCs. This rejection may be overcome by amending claim 1 (a) as recited above, or (2) to clearly define UAPCs. Dependent claims 3, 6-21, 25, 27-48, 53-56, and 58-67 can overcome this rejection by amending claim 1 as described above.
Regarding instant claim 1 (and dependent claims 3, 6-21, 25, 27-48, 53-56, and 58-67), the phrase “essentially no expression of endogenous HLA class I, II, or CD1d molecules” in line 3 renders the claim indefinite because the metes and bounds of the phrases are unclear. Specifically, it is unclear if:
“essentially” means the molecules must (a) be expressed below some specific measurable threshold, (b) not be expressed, or (c) something else;
“endogenous” means that (a) naturally MHC I-/MHC II-/CD1d- cells engineered to express one of more of MHC I, MHC II, or CD1d would meet the limitations, (b) cells are naturally MHC I-/MHCII-/CD1d-, (c) cells are engineered to be MHC I-/MHC II-/CD1d-, or (d) something else; and
the “or” joining “HLA class I, II, or CD1D” means one, two, or all three of the recited molecules (e.g., MHC 1-; or MHC I-/MHC II-; or MHC I-/CD1d-; or MHC I-/MHC II-/CD1d-; etc.), or something else.
For the purposes of compact prosecution, the phrase “essentially no expression of endogenous HLA class I, II, or CD1d molecules” is considered to mean “no expression of HLA class I, HLA class II, and CD1d”, and is considered part of the instant invention. Applicant may overcome this rejection by amending claim 1 (a) as described above, or (2) to clearly state the limitations of the claimed invention. Dependent claims 3, 6-21, 25, 27-48, 53-56, and 58-67 can overcome this rejection by amending claim 1 as described above.
Claim Rejections - 35 USC § 112(a)
Claim(s) 1, 3, 6-7, 9-21, 25, 27-48, 53-56, and 58-67 is/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inducing NK cell expansion by coculturing with MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ engineered K562 APCs, does not reasonably provide enablement for NK cell expansion via coculture with any MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ UAPC cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation."' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The nature of the invention; (B) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claims 1, 3, 6-7, 9-21, 25, 27-48, 53-56, and 58-67 are drawn to a MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ UAPC that induces NK cell expansion when cocultured.
The breadth of the claims
The claim is broad in that it encompasses the any and all MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ UAPCs.
The instant specification discloses “…"UAPC(s)" refer herein to antigen presenting cells
designed for the optimized expansion of immune cells, such as NK cells…” [e.g., ¶ 0033].
As recited above, the instant disclosure definition of UAPCs and therefore is non-limiting. Further,
The claim is inclusive of all types of APCs (e.g., macrophages, dendrocytes, B cells, K562, etc.). The breadth of the claim exacerbates the complex nature of the subject matter to which the instant claims are directed. UAPCs are not necessarily a single cell type, or a cluster of closely related cell subtypes. There are numerous UAPCs, which have some commonality (e.g., MHC I deficiency, see 112b rejection above). Despite the broad related grouping of ‘UAPCs’, these cell types are heterogeneous at both the molecular (e.g., specific antigen engineering/expression, cell type, signaling) and clinical level (e.g., CAR NK expansion can vary by specific engineered cells used in coculture).
The amount of direction provided by the inventor/the existence of working examples
The examples of the instant disclosure studied the NK expanding effect(s) of UAPCS: growth kinetics of NK cells stimulated with Clone 9 or UAPC [e.g., fig. 2E]; Example 1- Combination of mbIL21, 4-lBBL, and SLAM (CD48/CS1) [e.g., ¶ 00117-00122].
The examples provided do not demonstrate that all UAPCs engineered to be MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ induce NK cell expansion in coculture. Additionally, the disclosure does not discuss, or demonstrate through working examples, that any UAPCs other thank K562s have the instant claimed properties.
The state of the art/the level of predictability in the art
NK cell expansion upon coculturing was known to depend on a variety of factors, considered highly complex, and context-dependent at the time of filing. Specifically, some receptors may be activating or inhibitory, depending on the co-expression profile of other surface proteins, and further that can differ by APC cell type. For instance, McNerney et al. (BLOOD, 15 August 2005, Vol. 106, No. 4; hereinafter “McNerney”) taught that 2B4-CD48 signaling in the absence of MHC class I signaling leads to NK cell inhibition [e.g., title, abstract]. McNerney’s study focused on RMA-S cells, which are a murine-derived H-2b (e.g., an MHC class II gene) low, thymoma cell line. In contrast, Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”) teaches that 2B4-CD48 signaling results in NK cell activation and expansion [e.g., title, abstract]. Nakajima’s study utilized CD48+ engineered K562 cells, which are a human-derived, naturally MHC I negative cell line [e.g., pg. 1677, col. 1, ¶ 1; pg. 1680, “2.4…”; pg. 1681, “4 Materials and Methods”; fig. 5].
Given the above, one of ordinary skill in the art would understand that UAPCs from different sources and/or cell types can exhibit distinct effects on NK cells (e.g., inhibitory vs. activating), even when those UAPCs have similar marker expression (e.g., MHC I-/CD48+). Therefore, one of ordinary skill in the art would understand there is no way to predictably determine which UAPCs would result in NK cell expansion without testing.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict which UAPCs would have predictably induced NK cell expansion. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to (1) develop a method which accurately predicts (1) UAPC-mediated NK cell expansion or (2) genetically engineer and test every single UAPC possible. Applicant is enabled for MHC I-/MHC II-/CD1d-/mbIL21+/41BBL+/CD48+ engineered K562 UAPCs inducing NK cell expansion.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claims 1, 3, 6-21, 25, 27-48, 53-56, and 58-67 were determined to not meet the scope of enablement requirement of 35 USC § 112(a).
Enablement can be met by amending claim 1 to state “A K562 universal antigen presenting cell (UAPC)…” in line 1. Dependent claims 3, 6-21, 25, 27-48, 53-56, and 58-67 can overcome this rejection by amending claim 1 as described above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1, 6-8, 12-19, 21, 25, 27, 30-31, 40, 62-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Clinical and Experimental Immunology, 172: 104–112, hereinafter “Wang”) as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1); hereinafter “Butler”), in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”).
Regarding claim 1, 6-8, 12, 40, 62-67, Wang teaches a mbIL21+/CD137L+ (C137L is the same as 4-1BBL) K562 UPACs induce functional NK cell expansion in coculture [e.g., title, abstract; pg. 105, Methods and Materials; fig. 1]. K562 cells are naturally MHC I-/MHC II-/CD1d-/CD54+/CD58+ (CD54 is the same as LCAM-1, and CD58 is the same as LFA-3), as evidenced by Butler [e.g., pg. 5, ¶ 1]. Wang further teaches these functional NK cells provide valuable clinical applications in NK cell immunotherapy against viral infectious diseases and cancers [e.g., abstract].
Regarding claims 13-14, Wang further teaches coculturing at a ratio of 2:1 PBMCs (e.g. comprising NK cells) to engineered K562s [e.g., pg. 172, “”NK cell expansion”; fig. 1].
Regarding claims 15-19, 21, Wang further teaches the expansion is in the presence of 200 U/mL recombinant human IL2, and that repeated stimulation was performed weekly (e.g., K562s more than once) [e.g., pg. 173, “Reagents” and “NK cell expansion”].
Regarding claim 25, 27, 30, Wang further teaches functional NK cells expanded from cord blood (e.g., NK cells from cord blood are a type of cord blood mononuclear cell) [e.g., pg. 172, col. 2, ¶ 2].
Regarding claim 31, Wang further teaches the NK cells are CD56+ [e.g., abstract; pg. 107, col. 1, ¶ 2].
Wang does not expressly teach CD48+/mbIL21+/CD137L+ K562 mediated expansion of NK cells wherein (a) the coculture ratio is 2:1 immune cells comprising NK cells to engineered K562s, (b) expansion is in the presence of 200 U/mL recombinant human IL2, (c) the NK cells are derived from CBMCs, or (d) the NK cells are CD56+.
Regarding claim 1, Nakajima teaches CD48+ K562s augment non-MHC restricted NK cell cytotoxicity, and further that CD48+ K562s are more efficient than CD48- K562s [e.g., pg. 1680, “2.4…”].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to combine the mbIL21+/CD137L+ K562s in the method of K562 mediated NK cell expansion as taught by Wang, with the C48+ K562s as taught by Nakajima, in the context of designing and developing CD48+/mbIL21+/CD137L+ K562s K562 UAPCs for NK cell expansion. A PHOSITA would have been motivated to combine the mbIL21+/CD137L+ K562s in the method of K562 mediated NK cell expansion as taught by Wang, with the C48+ K562s as taught by Nakajima, because Wang teaches mbIL21+/CD137L+ K562s induce functional human NK cells and provide valuable clinical applications in NK cell immunotherapy, and Nakajima teaches that engineering K562s to express CD48 augments non-MHC restricted NK cell cytotoxicity, and is more efficient than CD48 negative K562s (see above). There would have been a reasonable expectation of success for a PHOSITA to combine the mbIL21+/CD137L+ K562s in the method of K562 mediated NK cell expansion as taught by Wang, with the C48+ K562s as taught by Nakajima, because Wang teaches mbIL21+/CD137L+ K562s induce functional human NK cells and provide valuable clinical applications in NK cell immunotherapy, Nakajima CD48+ K562s augment non-MHC restricted NK cell cytotoxicity more efficiently than CD48 negative K562s, and methods of K562 engineering are well-known in the art. This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143).
Further, it would have been obvious to a PHOSITA to modify the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion of Wang and Nakajima (see above) to include that (a) the coculture ratio is 2:1 immune cells comprising NK cells to engineered K562s, (b) expansion is in the presence of 200 U/mL recombinant human IL2, (c) the NK cells are derived from CBMCs, and (d) the NK cells are CD56+.as taught by Wang, because Wang and Nakajima teach the modified method of CD48+/mnIL21+/CD137L+ K562 mediated NK cell expansion, and Wang further teaches modifications to the base method of K562 mediated NK cell expansion. There is an expectation of success for a PHOPSITA to substitute the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion of Wang and Nakajima (see above) to include the further method modifications as taught by Wang above, because Wang and Nakajima teach the modified method of CD48+/mnIL21+/CD137L+ K562 mediated NK cell expansion, and Wang further teaches modifications to the base method of K562 mediated NK cell expansion. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Clinical and Experimental Immunology, 172: 104–112, hereinafter “Wang”) as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1); hereinafter “Butler”), in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”) as applied to claim 1 above, and further in view of Malaer et al. (Am J Cancer Res 2017; 7(8):1637-1641; hereinafter “Malaer”).
The teachings of Wang and Nakajima as recite above apply for claim 1.
Wang and Nakajima do not expressly teach that the K562s further express CS1.
Regarding claim 3, Malaer teaches CS1 is a homophilic activation receptor expressed on K cells, and that such stimulation results in NK cell activation and enhanced cytotoxic function [e.g., fig. 1, pg. 1637-1638, “CS1”].
Further, it would have been obvious to a PHOSITA to modify the CD48+/mbIL21+/CD137L+ K562 cells of the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima (see above) to include that the K562s are further engineered to express CS1 as taught by Malaer, because Wang and Nakajima teach NK cell activation is desirable as it results in increased cytotoxic activity and Malaer teaches that activation of the CS1 receptor on NK cells results in activation and induces enhanced NK cytotoxic functions (e.g., desirable for an NK therapeutic). There is an expectation of success for a PHOPSITA to add the CS1 expression as taught by Malaer to the CD48+/mbIL21+/CD137L+ K562 cells of the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima to arrive at CS1+/CD48+/mbIL21+/ CD137L+ K562 mediated NK cell expansion, because Wang and Nakajima teach NK cell activation teach CD48+/mbIL21+/CD137L+ K562s increase cytotoxic activity , and Malaer teaches CS1 is a homophilic NK cell activator that induces enhanced cytotoxic function thereof. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 9, 11, 20, 28-29, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Clinical and Experimental Immunology, 172: 104–112, hereinafter “Wang”) as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1); hereinafter “Butler”), in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”) as applied to claim(s) 1 and 12 above, and further in view of Ayello et al. (Exp. Hematology 2017; 46:38-47; hereinafter “Ayello”), as evidenced by Chu et al. (Cancer Immunol Res. 3(4) April 2015; hereinafter “Chu”).
The teachings of Wang and Nakajima as recited above apply for claim(s) 1 and 12.
Wang and Nakajima do not expressly teach that (1) the K562 is engineered by retroviral transduction, (2) the K562s are irradiated, (3) the expansion media with IL2 is replaced every 2 days, (4) the cord blood is pooled from 6 donors, or (5) the NK cells are engineered to express CAR.
Ayello teaches genetically engineered mbIL21+/CD157L+ K562 cells significantly expand and functionally activate cord blood nature killer cells, and are promising for adoptive cellular immunotherapy [e.g., title, abstract; pg. 45, col. 1, ¶ 1]. Regarding claim 9, Ayello further teaches K562 cells were genetically engineered by transduction with constructs “…as we and others have described previously…” [e.g., pg. 39, “Mononuclear cell isolation…”]. According to Ayello’s self-citation, the K562s were transduced with a recombinant retroviral vector (e.g., MSCV), as evidenced by Chu [e.g., pg. 334, “Production of…”]. Regarding claim 11, Ayello teaches the K562s are irradiated [e.g., pg. 39, “mononuclear cell isolation…”]. Regarding claim 20, Ayello further teaches NK cells expansion media containing IL-2 is replaced every 48 hrs. (e.g., replenished every 2 days) [e.g., pg. 39, col 1, ¶ 3; pgs. 39-40, “mononuclear cell isolation…”]. Ayello further teaches restimulation at Day 7 with engineered K562 cells [e.g., pg. 45, col 1, ¶ 1]. Regarding claims 28-29, Ayello further teaches the 6 units of CB (e.g., 6 donors) were combined [e.g., pg. 39, methods, “CB collection” and “Mononuclear cell isolation…”]. Regarding claim 33, Ayello further teaches NK cells are engineered to express an anti-CD20 CAR [e.g., pg. 46, col. 1, ¶ 2].
Further, it would have been obvious to a PHOSITA to modify the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima (see above) to include that (1) the K562 is engineered by retroviral transduction, (2) the K562s are irradiated, (3) the expansion media with IL2 is replaced every 2 days, (4) the cord blood is pooled from 6 donors, and (5) the NK cells are engineered to express CAR as taught by Ayello, because Wang and Nakajima teach the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion, Nakajima teaches the benefits of CD48+ K562s for NK cell expansion, Wang teaches mbIL21+/CD137L+ K562 mediated NK cell expansion related methods, and Ayello also teaches mbIL21+/CD137L+ K562 mediated NK cell expansion and associated modified methods (rel. to Wang) that benefit cord blood NK cell expansion (see above). There is an expectation of success for a PHOPSITA to substitute the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and with the further modified method of K562 mediated NK cell expansion as taught by Ayello, because Wang and Nakajima teaches the base K562s mediated expansion of NK cell method and that the NK cells may be derived from cord blood (see above), and Ayello teaches modifications to K562 mediated cord blood NK cell expansion that results in functional NK cells for therapeutics. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 32-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Clinical and Experimental Immunology, 172: 104–112, hereinafter “Wang”) as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1); hereinafter “Butler”), in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”) as applied to claim(s) 1 and 12 above, and further in view of Springer Protocols (Methods in Mol Bio 1441, Natural Kill Cells Methods and Protocols, 2016; hereinafter “Springer”), as evidenced by Chabannon et al. (Frontiers in Immunology, Nov2016, Vol7, Article 504; hereinafter “Chabannon”).
The teachings of Wang and Nakajima as recited above apply for claim(s) 1 and 12.
Wang and Nakajima do not expressly teach that (1) the method is performed in serum-free media, or (2) the NK cells is an anti-CD19 CAR NK cell.
Springer teaches Natural Killer Cells Methods and Protocols, including K562 mediated NK cell expansion [e.g., title; pgs. V, 14, 58, 62, 105, 108, 167, etc.]. Regarding claim 32, Springer teaches NK cells and K562s are cocultured in serum free media [e.g., pg. 254, materials], which one of ordinary skill in the art would understand to be a well-recognized Good Manufacturing Practice (GMP), as evidenced by Chabannon [e.g., pg. 4, col 1, ¶ 2]. Regarding claims 33-36, Springer teaches a CD19 directed CAR NK cell [e.g., pg. 196, ¶ 1].
Further, it would have been obvious to a PHOSITA to modify the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima (see above) to include that (1) the method is performed in serum-free media, or (2) the NK cells is an anti-CD19 CAR NK cell as taught by Springer, because Wang and Nakajima teach the base K562 mediated NK cell expansion method, and Spring teaches modified methods of K562 mediated cell expansion known in the art, including GMP methods. There is an expectation of success for a PHOPSITA to substitute the CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima with the modified methods of K562 mediated NK cell expansion as taught by Springer because Wang and Nakajima teach the base K562 mediated NK cell expansion method, and Spring teaches modified methods of K562 mediated cell expansion known in the art, including GMP methods (e.g., best practices in the art). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 33-39, 41-48, 53-56, and 58-61 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Clinical and Experimental Immunology, 172: 104–112, hereinafter “Wang”) as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1); hereinafter “Butler”), in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”) as applied to claim(s) 1 and 12 above, and further in view of WO 2016/197108 A1 (hereinafter “WO108”).
The teachings of Wang and Nakajima as recited above apply for claim(s) 1 and 12.
Wang and Nakajima do not expressly teach that (1) the NK cells are CD19 directed CAR NK cells wherein the CAR NK Cells (a) co-express IL15, (b) co-express the IC9 suicide gene, (c) are autologous or allogeneic, or (d) are humanized; or (2) a method of treating disease comprising administration of a pharmaceutical composition comprising CD19 CAR NK cells wherein (a) the pharmaceutical composition further comprises a carrier, (b) the disease treated by the CAR NK cells is ALL, CLL, AML, or CML, (c) the subject is a human, (d) the CAR NK is administered intravenously, subcutaneously, intracavitary, intraperitoneally, by direct tumor injection, or intramuscularly, or (e) rituximab is co-administered.
WO108 teaches method of treatment with NK cells [e.g., title, abstract], and K562 mediated CAR NK cell expansion [e.g., ¶ 0022, 0029, 0053, 0072, 00122, etc.]. Regarding instant claims 33-37, 41-43, WO108 teaches the treatment of a disease or disorder by the administration of a therapeutically effective amount of NK cells engineered to express anti-CD19 CAR receptor and IL-15 [e.g., ¶ 0006]. A method of treating comprising administration of a composition (e.g., anti-CD19 CAR NK cells that also expresses IL-15), necessarily disclose the CAR NK of the composition administered. WO108 teaches the CAR (e.g., comprising a binding domain) is humanized to reduce immunogenicity [e.g., ¶ 0054-0057].WO108 further teaches a pharmaceutical composition comprising the CAR NK and a pharmaceutically acceptable carrier [e.g., ¶ 0088, 0090]. Regarding instant claims 38-39, WO108 further teaches the CAR NK co-express an inducible caspase 9 (IC9) suicide gene [e.g., ¶ 0013]. WO108 teaches that because of concerns over autonomous, uncontrolled NK cell growth due to production of IL-15, an IC9 suicide gene was incorporated into the construct. Regarding instant claims 44-46, WO108 further teaches the disease or disorder treated is ALL CLL, AML, or CML [e.g., ¶ 0015, 0080, 0084]. Regarding instant claims 47-48, W108 further teaches the source of NK cells that are modified “..may be of any kind…” obtained from a bank of umbilical cord (e.g., allogeneic), peripheral blood (e.g., autologous from subject) [e.g., ¶ 0087, 0051]. Regarding instant claim 53, WO108 further teaches the subject is human [e.g., ¶ 0015, 0039]. Regarding instant claims 54-56, 59-61, WO108 further teaches the CAR NK can be administer alone or in combination with the anti-cancer, immunomodulatory, monoclonal antibody rituximab (e.g., an immunotherapy) [e.g., ¶ 0088]. Regarding instant claim 58, WO108 further teaches the CAR NK may be administered intravenously, subcutaneously, intracavitary, intraperitoneally, by direct tumor injection, or intramuscularly [e.g., ¶ 0087-0088].
Further, it would have been obvious to a PHOSITA to the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima (see above) to include that (1) the NK cells are CD19 directed CAR NK cells wherein the CAR NK Cells (a) co-express IL15, (b) co-express the IC9 suicide gene, (c) are autologous or allogeneic, or (d) are humanized; and (2) a method of treating disease comprising administration of a pharmaceutical composition comprising CD19 CAR NK cells wherein (a) the pharmaceutical composition further comprises a carrier, (b) the disease treated by the CAR NK cells is ALL, CLL, AML, or CML, (c) the subject is a human, (d) the CAR NK is administered intravenously, subcutaneously, intracavitary, intraperitoneally, by direct tumor injection, or intramuscularly, or (e) rituximab is co-administered as taught by WO108, because Wang and Nakajima teach the base method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion and clinical NK cell therapy utility (see rejection above), and WO108 teaches K562 mediated CD19 directed CAR NK cell expansion, as well as modified methods for CD19 directed CAR NK cell therapy. There is an expectation of success for a PHOPSITA to substitute the modified method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion as taught by Wang and Nakajima to include the CD19 directed CAR NK cell modified methods as taught by WO108, because Wang and Nakajima teach the base method of CD48+/mbIL21+/CD137L+ K562 mediated NK cell expansion and clinical NK cell therapy utility (see rejection above), and WO108 teaches K562 mediated CD19 directed CAR NK cell expansion, as well as modified methods for CD19 directed CAR NK cell therapy. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments and Oath/Declaration
Applicant arguments:
The production of clinically sufficient quantities of clinically functional NK cells was a problem in the art.
In response, the instant claims do not expressly require “clinically sufficient quantities of clinically functional NK cells”, and the instant specification does not (1) use the term “clinically functional”, or (2) define the term “clinically sufficient” (only used in ¶ 0004, lines 18-19). The closest limitations thereto of the instant invention are considered to be instant claim 43, which requires a “therapeutically effective amount” of expanded immune cells, and instant claim 53, which requires the subject is a human. Briefly, these limitations were met by WO108, which taught a therapeutically effective amount of CAR NK cells administered to human subjects. Therefore, Applicant arguments have been fully considered but are not found persuasive.
CD48-2B4 signaling was known to be highly context dependent based at least on the presence of adaptors that can induce different downstream signaling mechanisms. Indeed, McNerney et al. showed that 2B4-CD48 signaling in the absence of MHC class I signaling leads to NK cell inhibition. Thus, it would have been expected that CD48 signaling in the absence of MHC class I signaling, as is the case in our claimed UAPCs, would lead to NK cell inhibition. Unexpectedly, the claimed UAPCs were capable of stimulating NK cells at much higher rates than other APCs known in the art. Lack reasonable expectation of success: restates arguments that CD48 is not only context dependent, but also dose dependent and in most cases leads to NK inhibition (see Chlewicki et. al.). Briefly, Chlewicki showed (1) high levels of CD48 signaling or high levels of 2B4 (CD244) stimulation induced inhibitory NK cell phenotype, (2) NK cells express CD244 and CD48 at levels that skew CD48 signaling towards an inhibitory phenotype, (3) lists several examples that indicate CD48-CD244 stimulation favors an inhibitory phenotype on NK cells, (4) CD48 may inhibit NK cell function in EBV or HIV infection, (5) killing of NK cells by other NK cells is inhibited by CD244-CD48 interactions; and (6) engagement of CD244-CD48 on adjacent NK cells likely polarizes NK cells towards an inhibitory phenotype. Unexpectedly, Applicant’s engineered cells were capable of activating NK cell at higher levels than other APCs known in the art, thus a PHOSITA would lack an expectation of success that engineering cells to exogenously express CD48 would activate NK cells and could instead expect NK cell inhibition.
In response, McNearny’s teachings utilize RMA-S cells for NK cell stimulation [e.g., pg. 1338, “Mice, cell lines, and NK-cell Preparation”]. As indicated by Applicant’s own arguments (see Remarks and Declaration for details), CD48 signaling in NK cells is highly context dependent. In the current rejection, Nakajima was relied upon to teach CD48+ K562 mediated NK cell expansion (see rejection above for details). As McNearny teaches a different stimulatory cell line, and the teachings of Nakajima apply to K562s, one of ordinary skill in the art at the time of filing would have expected the signaling of CD48+ K562s to be stimulatory to NK cells based on the teachings of Nakajima, and would not have considered the results of McNearny as pertinent because the CD48 signaling is known to be complex with regards to NK cell outcome. Additionally, based on the teachings of Nakajima, there would have been a reasonable expectation of success that CD48 expression in K562s would increase NK cell expansion (see rejection above for details). Therefore, Applicant arguments have been considered and are not considered persuasive.
The art indicated immature NK cells, such as those form cord blood, express weak or inhibitory 2B4-mediated responses, due at least to lower levels of SAP and EAT-2. Sivori et al. noted (1) 2B4 is inhibitory during early differentiation of NK cells, reflecting lower SAP expression, and (2) blocking 2B4/CD48 interactions could restore cytolytic activity of immature NK cells. Thus, it could have been expected that CD48 signaling in immature NK cells would result in NK cell inhibition. Unexpectedly, the claimed UAPCs were capable of stimulating cord blood NK cells at much higher rates than other APCs known in the art
In response, Nakajima was relied upon to teach CD48+ K562 mediated NK cell expansion (see rejection) and additionally teach that the NK cells may be cord blood derived as all tested cord blood were 2B4+ [e.g., pg. 1678, “2.2…”]. Based on the teachings of Nakajima, one of ordinary skill would expect that the 2B4+ cord blood NK cells would expand in the presence of CD48+ K562s. Additionally, Sivori is focused on the study of CBMC NK cell differentiation, and does not test if 2B4 is inhibitory when the CBMN NK cells are expanded or differentiated in the presence of CD48+ K562s. Given the complexity of NK cell responses (see response to arguments above), Sivori is not considered to teach away and rather Nakajima is considered to teach towards CD48+ expression in K562s for NK cell expansion. Therefore, Applicant arguments have been considered and are not considered persuasive.
Liu et al is a post-filing publication which showed that the claimed UAPCs dramatically expand cord blood immature NK cells and endow them with superior antitumor activity. Fig. 3A shoed the UAPCs achieved a 903-fold expansion of NK cells at day 14. The NK cells expanded with the claimed UAPCs (approximately 35% alive at day 55 post infusion) were therapeutically superior to NK cells expanded with C9 cells (100% fatality by day 35 post infusion) in treating aggressive mouse xenograft cancer(s).
In response, Wang and Nakajima collectively teach the instant CD48+/mbIL21+/CD137L+ K562 UAPCs of the instant invention responsible for the claimed fold-expansion (see above). The C9 K562s cells are different from the claimed K562s which have CD48, mbIL21, and CD137L expression which is taught to be NK cell stimulatory in the art, and would therefore coculture with C9s vs the instant claimed K562s would be expected to have different fold-expansion outcomes. Therefore, Applicant arguments have been considered and are not considered persuasive.
Mechanistically distinct approach to what was taught in the art. Instant invention expressed CD48 on K562 lacking MHC class I, and showed robust NK cell expansion and improved in vivo antitumor activity compared to APCs that did not express CD48. This outcome runs counter to established observations and highlights unexpected results of CD48 to expand NK cells when expressed in cells also expressing mbIL-21 and 4-1BBL.
In response, Nakajima was relied upon to teach that CD48+ K562 stimulation of NK cells is superior to CD48- K562 mediated NK cell expansion (see above). Based on the teachings of Nakajima, the results are expected. Therefore, Applicant arguments have been considered and are not considered persuasive.
Claimed UAPCs differ from Ayello in that claimed UAPCs are dramatically superior and produced unexpected results compared to the teachings of Ayello: (1) Ayello achieved 35-fold expansion of NK cell whereas instant claimed UAPCs achieved up to 1671-fold expansion, (2) Ayello failed to see change in tumor bearing mouse survival with a dose of 5x10^6 expanded NK cells, whereas the instant application saw extended survival with 3x10^6 UAPC expanded NK cells, and (3) Ayello does not provide guidance for how its cells could be modified to achieve Applicant’s vastly superior results.
In response, Ayello (and Wang) teach mbIL21+/CD137+ K562 mediated NK cell expansion, and Nakajima was relied upon to teach that CD48+ K562 stimulation of NK cells is superior to CD48- K562 mediated NK cell expansion (see above). Therefore, as the instant invention UAPCs are CD48+/ mbIL21+/CD137+ K562s, based on the teachings of Nakajima, the results claimed are expected. Further, comparison of Ayello or Wang alone (no CD48 expression in K562s) directly to the instant invention is not appropriate because they are not identical and therefore one of ordinary skill would not expect identical results. To claim superior (unexpected) results, Applicant would need to show that the observed effects are above the expected additive effects of the instant claimed markers. Therefore, Applicant arguments have been considered and are not considered persuasive.
Additional post-filing data was provided for instant claimed expanded NK cells in a single SLE patient (pt). Briefly, (1) pt SLE history was provided, (2) pt was administered a flat dose of 120x10^6 transduced cryopreserved PluReceptor NK ex vivo expanded with UAPCs, (3) pt response at 4 wks was partial, SRI4 responder, BICLA responder, and (4) asserts the results indicate UAPC-expanded NK cells can treat severe SLE. Disclosure ¶ 00106 demonstrates that immune cells, such as NK cells expanded with UAPCs are useful in the treatment of autoimmune diseases in which suppressing undesirable or inappropriate immune response is desirable. This is in part due to NK cells eliminating pathogenic immune cells and producing cytokines that can dampen inflammation. The partial clinical response in severe SLE demonstrated that the instant claimed UAPCs can produce expanded NK cells suitable for human and clinical purposes.
In response, arguments are drawn to a non-elected species and/or invention. Specifically, Applicant elected the disease “cancer” in the response filed on 28Jun2023, therefore the findings in SLE (e.g., an autoimmune disease) are not drawn to the elected invention. However, in the interest of compact prosecution, it is noted that the results in SLE lack the proper controls to demonstrate that the outcome(s) are due to the CD48+/mbIL21+/CD137L+ K562 mediated expansion and that similar results wouldn’t be expected for identical PluReceptor NK cells expanded with different co-culture UAPCs. Therefore, Applicant arguments have been considered and are not considered persuasive.
Prior art teaches away: restates argument in declaration that the claimed combination could have been inhibitory to NK cells due to lack of MHC class I (see McNerney et al).
In response, as discussed above, Nakajima is relied upon in the new rejections to teach the benefits of CD48+ K562s for NK cell expansion, whereas McNearny teaches a different cell line (see above for details). Therefore, one of ordinary skill would have expected the teachings in the claimed cell line (e.g., K562s) to be pertinent, and therefore the teachings of McNearny in a different cell line (not K562s) would not be pertinent, and therefore is not considered to teach away. Therefore, Applicant arguments have been considered and are not considered persuasive.
Claim 27 is independently Patentable: Claim 27 recite inter alia the method of claim 12 for expanding NK cells by co-culturing with the UAPCs of claim 1, wherein the NK cells are obtained from cord blood. As described in the Declaration and discussed above, Sivori teaches that CD48 is inhibitory to immature NK cells from cord blood. In effect, the art at the time of filing teaches away from present claim 27. Sivori showed that 2B4 cross-linking induced an inhibitory effect on cord-blood derived NK cells and that the effect could be rescued by blocking 2B4-CD8 interactions with an antibody. A PHOSITA would therefore be led in a path divergent from the path that was taken by the Applicants” in which the Applicants use a UAPC expressing, inter alia, CD48 to induce expansion of cord-blood derived NK cells.
In response, as discussed above, Nakajima was relied upon to teach CD48+ K562 mediated NK cell expansion (see rejection) and additionally teach that the NK cells may be cord blood derived as all tested cord blood were 2B4+ [e.g., pg. 1678, “2.2…”]. Based on the teachings of Nakajima, one of ordinary skill would expect that the 2B4+ cord blood NK cells would expand in the presence of CD48+ K562s. Additionally, Sivori is focused on the study of CBMC NK cell differentiation, and does not test if 2B4 is inhibitory when the CBMN NK cells are expanded or differentiated in the presence of CD48+ K562s. Given the complexity of NK cell responses (see response to arguments above), Sivori is not considered to teach away and rather Nakajima is considered to teach towards CD48+ expression in K562s for NK cell expansion. Therefore, Applicant arguments have been considered and are not considered persuasive.
In summary, Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 1, 3, 6-9, 11-21, 25, 27-48, 53-56, and 58-67 are 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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6-8, 11-13, 15, 25, 27-28, 31, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 8-10, 12-18, 33, 35, and 43 of copending Application No. 16/970,937 (hereinafter “A937”) in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass the expansion of NK cells using artificial/universal antigen presenting cells and CAR NK cells.
A937 has been allowed and upon publication this provisional rejection will become nonprovisional.
Regarding instant claims 1, 6-8, 12, 25, 27, 31, A937 teaches expanding cord blood (CB) NK cells (CD56+) in the presence of mbIL21+/4-1BBL+(CD137L+)/HLAI-/HLAII-/CD1d-/CD54+/CD58+ K562 artificial antigen presenting cells (aAPCs) [e.g., claims 1, 8-10, 12-16]. One of ordinary skill in the art would understand the terms aAPC and UAPC may be used interchangeably, as evidenced by the instant application referring to engineered K562s as UAPCs, and A937 referring to similarly engineered K562s as aAPCs.
Regarding instant claim 9, A937 claim 17 teaches the aAPCs are engineered by retroviral transduction.
Regarding instant claim 11, A937 claim 18 teaches the aAPCs are irradiated.
Regarding instant claim 13, A937 claim 33 teaches the NK cells and aAPCs are present in the expansion culture at a ratio of 3:1 to 1:3.
Regarding instant claim 15, A937 claim 35 teaches expanding in the presence of IL-2.
Regarding instant claim 28, A937 claim 5 teaches the CB is pooled from 2 or more individual CB units.
Regarding instant claim 33, A937 claim 43 teaches the NK cells are engineered to express a CAR.
A937 does not expressly teach that the aAPCs additionally express CD48.
Nakajima teaches CD48+ K562s augment non-MHC restricted NK cell cytotoxicity, and further that CD48+ K562s are more efficient than CD48- K562s [e.g., pg. 1680, “2.4…”].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to modify the mbIL21+/4-1BBL+ K562 aAPC mediated expansion of NK cells as taught by A937 to include CD48 expression by K562 aAPCs as taught by Nakajima, in the context of designing and developing a method of aAPC mediated NK cell expansion. A PHOSITA would have been motivated to add CD48 expression taught by Nakajima, to the mbIL21+/4-1BBL+ K562 aAPCs taught by A937 because both A937 and Nakajima teach K562 mediated NK cell expansion, and Nakajima further teaches CD48 expression improved K562 mediated NK cell expansion. There would have been a reasonable expectation of success for a PHOSITA to engineer the mbIL21+/4-1BBL+ K562 aAPCs for NK cell expansion taught by A937 to also express CD48 as taught by Nakajima, because both A937 and Nakajima teach engineered K562 mediated NK cell expansion, Nakajima teaches the benefits of engineering K562s to express CD48, and methods for engineering of K562 aAPCs are well known in the art, as evidenced by the disclosures of A937 and Nakajima. This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6-8, 11-12, 15, 31, 33, 43, 47-48, 54-56, and 58-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 76-88 of copending Application No. 17/304,585 (A585) (2 common inventors and common applicant as instant application) in view of Nakajima et al. (Eur. J. Immunol. 1999. 29: 1676–1683; hereinafter “Nakajima”), as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1):. doi:10.1111/imr.12129; hereinafter “Butler”). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass the expansion of NK cells using artificial/universal antigen presenting cells and use of the expanded NK cells in treating a subject with cancer.
Regarding instant claims 1, 6-8, 11-12, 15, 31, A585 teaches CAR NK (CD56+) cells are expanded in the presence of mbIL21+/4-1BBL+(CD137+) aAPCs in the presence of IL-2 [e.g., claims 76-78, 81, 84-88].
Regarding instant claim 33, A585 claim 79 teaches the NK cells are engineered to express a CAR.
Regarding instant claims 43, 54-56, 59-60, A585 teaches a method of treating hematological cancer comprising administration of the expanded NK cells and an NK re-directing monoclonal antibody [e.g., claims 76, 80].
Regarding instant claims 47-48, A585 claim 83 teaches the CAR NK cells are autologous or allogeneic.
Regarding instant claim 58, A585 claim 82 teaches the NK cells and/or the antibodies are administered intravenously, intraperitoneally, intratracheally, intratumorally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, or by direct injection or perfusion.
A585 does not expressly teach that (1) the aAPCs additionally express CD48, or (2) that the aAPCs are K562 cells.
Nakajima teaches CD48+ K562s augment non-MHC restricted NK cell cytotoxicity, CD48+ K562s expand functional NK cells, and further that CD48+ K562s are more efficient than CD48- K562s [e.g., pg. 1680, “2.4…”]. It was well-known in the art before the time of filing that K562 cells do not express endogenous HAL class I, II, or CD1d molecules but doe express ICAM-1 (CD54) and LFA-3 (CD58), as evidenced by Butler [e.g., pg. 5, ¶ 1].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to modify the mbIL21+/4-1BBL+ aAPC mediated expansion of NK cells as taught by A937 with include CD48 expression by the K562 aAPCs as taught by Nakajima, in the context of designing and developing a method of aAPC mediated NK cell expansion. A PHOSITA would have been motivated to add CD48 expression taught by Nakajima, to the mbIL21+/4-1BBL+ aAPCs taught by A585 because both A585 and Nakajima teach engineered aAPC mediated NK cell expansion, and Nakajima further teaches the benefits of CD48+ K562s for NK cell expansion. There would have been a reasonable expectation of success for a PHOSITA to engineer the mbIL21+/4-1BBL aAPCs for NK cell expansion taught by A585 to also express CD48 as taught by Nakajima, because both A585 and Nakajima teach engineered aAPC mediated NK cell expansion, Nakajima teaches the benefits of CD48+ K562s for NK cell expansion, and methods for engineering of aAPCs are well known in the art, as evidenced by A585 and Nakajima disclosures. This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143).
Further, it would have been obvious to a PHOSITA to modify the modified composition of CD48+/mbIL21+/4-1BBL+ aAPCs as taught by A585 and Nakajima (see above) to include that the aAPCs are K562 (inherently HLAI-/HLAII-/CD1d-/ICAM1+/LFA3+) cells as taught by Nakajima and Butler, because while both A585 and Nakajima teach aAPCs, Nakajima specifically teaches CD48+ K562s are known in the art to be beneficial for NK cell expansion. There is an expectation of success for a PHOPSITA to substitute the general “aAPCs” of the CD48+/mbIL21+/4-1BBL+ aAPC cell composition for NK cell expansion taught by A585 and Nakajima for the specific “K562 aAPCs” taught by Nakajima and Butler to arrive at the CD48+/mbIL21+/4-1BBL+ K562 aAPC cells for NK cell expansion of the instant invention, because engineering K562 cells for NK cell expansion is common in the art, as evidenced by the disclosures of Nakajima and Butler. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6-7, 12, 15, 20, 25, 27-28, 30, 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16, 25, 44, 48-49, 53 of copending Application No. 17/309,426 (hereinafter “A426”). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass the expansion of NK cells using artificial/universal antigen presenting cells and use of the expanded NK cells in treating a subject with cancer.
Regarding instant claims 1, 3, 6-7, 12, 25, 27, 30, 40, A426 teaches a method of NK cell expansion comprising coculturing UAPCs engineered to express CD48 and/or CS1(CD319), mbIL21, and 4-1BBL, with cord blood MNCs and re-stimulating the cells with UAPCs to produce expanded NK cells [e.g., claims 1, 16, 48-49]. A426 claim 53 further teaches the UAPCs have essentially no expression of endogenous HLA I/II or CD1d molecules, and express ICAM1 (CD54) and LFA3 (CD58), or are defined as leukemia cell-derived aAPCs.
Regarding instant claims 15, 20, A426 claim 25 further teaches the cells are fed twice with IL-2.
Regarding instant claim 28, A426 claim 44 further teaches the cord blood is pooled. One of ordinary skill in the art would understand that “pooling” requires more than one of something (e.g., 2 or more).
Regarding instant claim 41, A426 claim 58 further teaches a pharmaceutical composition comprising the NK cells (of the base claim) and a pharmaceutically acceptable carrier.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6-8, 11-15, 25, 27, 33, 35-37, 40, and 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 8, 17-19, 21-22, 35, 37, 39 of copending Application No. 17/593,085 (hereinafter “A085”), as evidenced by Butler and Hirano (Immunol Rev. 2014 January; 257(1):. doi:10.1111/imr.12129; hereinafter “Butler”). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass the expansion of NK cells using artificial/universal antigen presenting cells and use of the expanded NK cells in treating a subject with cancer.
Regarding instant claims 1, 3, 6-8, 12, 40, A085 method for expanding NK cells in the presence of universal antigen presenting cell (UAPCs) engineered to express (1) CD48 and/or CS1 (CD319), (2) membrane-bound interleukin-21 (mbll-21), and (3) 418B ligand (41BBL) [e.g., claims 1, 18-19]. It was well-known in the art at the time before the effective filing date of the claimed invention that UAPCs (e.g., aAPCs) are designed/engineered such that they do not express endogenous HLA class I, II, or CD1d molecules as that would the APCs non-universal, as evidenced by Butler [e.g., pg. 5, ¶ 1].
Regarding claim 11, A085 claim 17 teaches that the APCs are irradiated.
Regarding claims 13-14, A085 claim 21 teaches that the NK cells and APCs are present at a 1:2 ratio.
Regarding claim 15, A085 claim 22 teaches coculturing in the presence of IL-2.
Regarding claims 25, 27, A085 claim 8 teaches that the immune cells are derived from cord blood.
Regarding claim 33, 35-36, A085 further teaches that the immune cells are engineered to express an anti-CD19 chimeric antigen receptor (CAR) [e.g., claims 1, 5, 37].
Regarding claims 37, A085 claim 39 teaches that the CAR comprises IL-15.
Regarding claims 47-48, A085 claim 35 teaches that the immune cells are allogeneic or autologous.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments and Oath/Declaration
Applicant arguments:
Indicates to refer to the arguments as recited above regarding the 103 rejections.
In response, please see the responses to arguments and Oath/Declaration above.
Free From the Prior Art
During the course of examination, the viral constructs of SEQ ID NO: 1, 2 that encode the engineered genes of the UAPC from instant claim 1 were found to be non-obvious in view of the prior art. Briefly, a sequence search of the prior art returned no 100% matches to the instant claimed nucleotide sequences.
Closest prior art
The alignment of instant SEQ ID NO: 1 with WO2016070119-A1 (Mouse TCR containing DNA, SEQ:4) resulted in a 67.8% query match, with an 84.8% best local similarity match.
The alignment of instant SEQ ID NO: 2 with WO2019090355-A1 (Hyperproliferative disorder treatment related vector DNA, SEQ: 26) resulted in a 69.1% query match with an 86.3% best local similarity match.
Conclusion
A review of the closest prior art (see above) resulted in no 100% sequence identity matches to the instant claimed sequence(s), and additionally did not result in any matches that encode the engineered genes of the UAPCs. Based on the state of the art, it is not obvious to modify the sequence of WO2016070119-A1 or the sequence of WO2019090355-A1 to arrive at the instant claimed SEQ ID NOs: 1 or 2, respectively. For these reasons, instant SEQ ID NOs: 1 and 2 are considered free from the prior art.
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643