DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed February 3, 2026 is pending.
Claims 7-30 are canceled.
Claims 31-40 are new.
Claims 1-6 and 31-40 are pending.
Claims 1 and 5 are independent claims.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-4 and 31-40, drawn to modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide) in the reply filed on February 3, 2023 is acknowledged.
Claim 5 and 6 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1-4 and 31-40 are currently under consideration.
Claim Objections
Claims 1-4 and 31-40 are objected to because of the following informalities:
Claim 1 recites “Modified K562 myeloid leukemia cells (Tyro3* K562 cells) expressing human Tyro3 polypeptide” where it should recite “Modified K562 myeloid leukemia cells (Tyro3* K562 cells) expressing a human Tyro3 polypeptide” in lines 1 and 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite language
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 2, 3, and 31-35 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.
Claim 2 recites “the K562 cells” in line 2. However, claim 2 is dependent on claim 1 which only recites “Modified K562 myeloid leukemia cells (Tyro3+ K562 cells)” not “K562 cells.” Therefore, the limitation in claim 2 lacks antecedent basis. Amending claim 2 to recite “the Tyro3+ K562 cells” in line 2 would obviate this part of the rejection.
Claim 3 recites “the human Tryo3” in lines 1 and 2. However, claim 3 is dependent on claim 1 which only recites “human Tyro3 polypeptide” not “human Tyro3.” Therefore, the limitation in claim 3 lacks antecedent basis. Amending claim 3 to recite “the human Tyro3 polypeptide” would obviate this part of the rejection.
Claims 31-35 “the Tyro3 polypeptide” in lines 1. However, claims 31-35 are dependent on claim 1 which only recites “human Tyro3 polypeptide” not only “Tyro3 polypeptide.” Therefore, the limitation in claims 31-35 lacks antecedent basis. Amending claims 31-35 to recite “the human Tyro3 polypeptide” would obviate this part of the rejection.
Written Description
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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 1-4, 31-34, and 36-40 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL-21) and 4-1BB ligand (4-1BBL).
The Applicant has disclosed several Tyro3+ K562 cell species including those that express full-length wild-type Tyro3 (SEQ ID NO: 2), only the extracellular domain of Tyro3 (SEQ ID NO: 6), and a kinase dead full-length Tyro3 K550A mutant (e.g. see [0122]). NK cells that were cultured with K562 cells expressing full-length wildtype Tyro3 showed increased levels of STAT5, p-AKT and p-ERK when compared to K562 cells not expressing Tyro3. This increase in STAT5, p-AKT and p-ERK indicates a Tyro3+ K562 cell-dependent enhanced expansion of NK cells. It is noted that while the K562 cells expressing only the extracellular domain of Tyro3 and the K562 cells expressing the kinase dead full-length Tyro3 K550A mutant were able to transfer their respective Tyro3 proteins to NK cells, both cells failed to show the same benefits to NK cell expansion as observed with the K562 cells expressing full-length wild-type Tyro3 (e.g. see [0122]).
Independent claim 1 is drawn to modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL- 21) and 4-1 BB ligand (4-1BBL).
Dependent claim 2 recites that the Tyro3+ K562 cells enhance the expansion of human natural killer (NK) cells that contact the Tyro3+ K562 cells compared to Tyro3- K562 cells.
Dependent claim 31 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 96% identical to SEQ ID NO:2.
Dependent claim 32 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 97% identical to SEQ ID NO:2.
Dependent claim 33 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 98% identical to SEQ ID NO:2.
Dependent claim 34 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 99% identical to SEQ ID NO:2.
When given the broadest reasonable interpretation in light of specification, the Tyro3+ K562 cells of the instant invention is defined broadly to be any Tyro3+ K562 cell that expressed any Tyro3+ polypeptide that comprises an amino acid sequence that is at least 95% (or 96-99%) identical to SEQ ID NO:2 and can enhance the expansion of human NK cells.
It is noted that while claim 1 does not explicitly recite that the Tyro3+ K562 cells enhance the expansion of human NK cells, given noted that claim 2 is dependent on claim 1 and recites an inherent function of Tyro3+ K562 cells of the instant invention, the Tyro3+ K562 cells of claim 1 would inherently have the function recited in claim 2.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Lu et al. 2021 (Cancer Immunol Res. 9 (10): 1229–1241, an IDS reference filed 03/19/2024) teach that all of APC K562Tyro3, APC K562ED-Tyro3, and APC K562Tyro3_K550A cells are able to transfer their respectively expressed Tyro3 polypeptide to NK cells (e.g. see page 1237, left column, second and third paragraphs). However, only K562 cells expressing full-length wildtype were able to increase the expansion of the Tyro3+ NK cells. The K562 cells expressing only the extracellular domain (ED) of Tyro3 or the kinase dead full-length Tyro3 K550A mutant did not confer the same benefits on NK-cell expansion observed with APC K562Tyro3 cells even though expression of TYRO3 was detected on the surface of NK cells when NK cells were co-cultured with the APC K562ED-Tyro3 or APC K562Tyro3_K550A cells (e.g. see page 1237, left column, second and third paragraphs).
Ultimately, the art teaches that only full-length wild-type Tyro3, and not the kinase dead full-length Tyro3 K550A mutant or the truncated Tyro3 only comprising its ED, can enhance the expansion of human NK cells. Thus, the art teaches that modifications within or complete loss of the intracellular kinase domain of Tyro3 abolishes its ability to enhance NK expansion.
As noted above, the Applicant has disclosed Tyro3+ K562 cell species including APC K562Tyro3, APC K562ED-Tyro3, and APC K562Tyro3_K550A. However, the Applicant has also disclosed and the art also teaches that, while all of the cell types are able to transfer a Tyro3 polypeptide to NK cells, only the K562 cells expressing full-length wildtype Tyro3 are able to enhance the expansion of human NK cells after the transfer of the Tyro3 polypeptide is made. Such a disclosure does not serve to provide sufficient written description of the claimed genus of Tyro3+ K562 cells that express a Tyro3 polypeptide that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:2. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of enhancing the expansion of human NK cells. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited genus of Tyro3+ K562 cells that express a Tyro3 polypeptide that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2 which gives rise to their functional activity. Ultimately, identifying Tyro3+ K562 cells that express a Tyro3 polypeptide that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:2 simply on the basis of enhancing the expansion of human NK cells rather than by identifying the sequence/structure, namely the entire amino acid sequence, of the Tyro3+ K562 cells in question is generally insufficient to provide written description.
Furthermore, it is noted that claims 1-4 and 31-34 recite that the Tyro3 polypeptide comprises an amino acid sequence that is at least 95% (claims 1-4), 96% (claim 31), 97% (claim 32), 98% (claim 33) and 99% (claim 34) identical to SEQ ID NO: 2. These claims do not satisfy the written description requirement because the claim language allows for up to 5, 4, 3, 2, and 1% variability in the amino acid sequence structure of Tyro3, respectively. This is inclusive of the intracellular kinase domain. The art clearly teaches that modifications within, such as the K550A point mutation, or complete loss of the intracellular kinase domain of Tyro3 abolishes its ability to enhance NK expansion (see Lu et al. above). Claims 1-4 are drawn to a broad genus of Tyro3+ K562 cells and claims 31-34 are drawn to broad subgenera thereof all of which are functionally defined by their ability to enhance NK expansion but fail to recite a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Ultimately, there is insufficient written description for the breadth of Tyro3+ K562 cells that express a Tyro3 polypeptide that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:2 as currently claimed. Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of Tyro3+ K562 cells that express a Tyro3 polypeptide that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2 encompassed by the claims at the time the instant application was filed.
Amending the claims to recite that the Tyro3 polypeptide comprises the amino acid sequence of SEQ ID NO: 2, such as is done in claim 35, would obviate this part of the rejection.
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.
Claims 1-4 and 31-40 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. 2014 (PLOS ONE. 9(10); e109352, 1-8, a reference of record) in view of Caraux et al. 2006 (Nat. Immunol. 7(7); 747-754, an IDS reference filed 03/19/2024).
Independent claim 1 is drawn to modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL- 21) and 4-1 BB ligand (4-1BBL).
Dependent claim 2 recites that the Tyro3+ K562 cells enhance the expansion of human natural killer (NK) cells that contact the Tyro3+ K562 cells compared to Tyro3- K562 cells.
Dependent claim 3 recites that the human Tyro3 expression is under the control of a strong promoter.
Dependent claim 4 recites that the strong promoter is a retroviral promoter.
Dependent claim 31 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 96% identical to SEQ ID NO:2.
Dependent claim 32 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 97% identical to SEQ ID NO:2.
Dependent claim 33 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 98% identical to SEQ ID NO:2.
Dependent claim 34 limits the Tyro3 polypeptide to that comprising an amino acid sequence that is at least 99% identical to SEQ ID NO:2.
Dependent claim 35 limits the Tyro3 polypeptide to that comprising the amino acid sequence of SEQ ID NO:2.
Dependent claim 36 limits the IL-21 to that which comprises the amino acid sequence of amino acids 25-162 of SEQ ID NO:23.
Dependent claim 37 limits the 4-1BBL to that which comprises the amino acid sequence of amino acids 50-254 of SEQ ID NO:25.
Dependent claim 38 limits the 4-1BBL to that which comprises the amino acid sequence of amino acids 29-254 of SEQ ID NO:25.
Dependent claim 39 limits the 4-1BBL to that which comprises the amino acid sequence of amino acids 1-254 of SEQ ID NO:25.
Dependent claim 40 limits the IL-21 to that which comprises the amino acid sequence of amino acids 25-162 of SEQ ID NO:23 and limits the 4-1BBL to that which comprises the amino acid sequence of amino acids 50-254 of SEQ ID NO:25.
Regarding claims 1 and 2, Cho et al. teach that K562 cells have been genetically modified to express 41BBL and membrane-bound IL21, which allowed the establishment of co-culture methods for the in vitro expansion of NK cells (e.g. see page 7, left column, second paragraph).
Regarding claims 36-40, instant SEQ ID NO: 25 is the wildtype amino acid sequence for 4-1BBL and instant SEQ ID NO: 23 is the wildtype amino acid sequence for IL-21 (e.g. see [0098] of the instant specification). Therefore, the 4-1BBL and IL-21 proteins expressed by the K562 cells taught by Cho et al. would necessarily have the same amino acid sequence as instant SEQ ID NOs: 25 and 23, respectively, especially in the absence of evidence to the contrary. Therefore, 4-1BBL would necessarily comprise amino acids 50-254 (claims 37 and 40), 29-254 (claim 38), and 1-254 (claim 39) of SEQ ID NO: 25 and IL-21 necessarily comprise amino acids 25-162 of SEQ ID NO: 23 (claims 36 and 40).
Further regarding claim 1, Cho et al. also teach that NK cells have the capacity to target tumors and are ideal candidates for immunotherapy (e.g. see abstract). Viral vectors have been used to genetically modify in vitro expanded NK cells, but the application of viral transduction is very limited because of the complexity of the procedures and high costs (e.g. see abstract and page 7, left column, first paragraph). Therefore, Cho et al. teach the usefulness of trogocytosis as a relatively simple non-viral method that can be readily scaled up to modify large numbers of NK cells with a single K562-based donor cell line (e.g. see page 7, left column, first paragraph). Trogocytosis is a process in which membrane patches are exchanged between target and immune cells (e.g. see page 1, right column). When an NK cell interacts with a target cell, an immune synapse, which is strong enough to allow the transfer of small membrane patches from one cell to its partner cell, is formed. Therefore, target cell surface molecules can be found on the surface of NK cells (e.g. see page 1, right column).
Cho et al. also teach that the K562 cell line is a typical NK cell target because it lacks major histocompatibility complex class I expression, which triggers inhibitory signals to abolish NK cell activation (e.g. see page 7, left column, second paragraph). Cho et al. also teach that K562 cells are able to donate anti-CD19 CARs to expanded NK cells in co-cultures via trogocytosis (e.g. see page 7, left column, second paragraph). Cho et al. teach that further studies are warranted to examine the utility of their method for treating diverse tumor types in vivo (e.g. see page 7, right column, fourth paragraph).
Cho et al. do not teach that the 41BBL- and IL21-expressing K562 cells also express a human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2. Cho et al. also do not teach that the human Tyro3 expression is under the control of a strong promoter or that the strong promotor is a retroviral promotor.
Caraux et al. teach that the three receptors of the Tyro3 family are essential in the terminal differentiation and functional maturation of NK cells (e.g. see 753, left column, second paragraph). In the absence of those receptors, the repertoire of inhibitory and activating NK cell receptors is considerably altered and the NK cells show substantially diminished cytolytic activity against target cells (e.g. see 753, left column, second paragraph). In fact, compared to wildtype NK cells, the Axl–/–Tyro3–/– NK cells, Tyro3–/–Mertk–/– NK cells, and Axl–/–Tyro3–/–Mertk–/– NK cells showed at least a 90% reduction in killing activity (e.g. see page 749, paragraph spanning the left and right columns and figure 3a).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Cho et al. to incorporate the teachings of Caraux et al. to include that the 41BBL- and IL21-expressing K562 cell line also express a human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2. This is because the expression of Tyro3 is essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.).
The challenges of using viral vectors to genetically modify NK cells is well known and so is the usefulness of trogocytosis as a relatively simple non-viral method that can be readily scaled up to modify large numbers of NK cells with a single K562-based donor cell line (Cho et al.).
Given that that K562 cells expressing 41BBL and membrane-bound IL21 direct the in vitro expansion of NK cells when in co-culture (Cho et al.), the ability of K562 cells to donate cell surface proteins, such as CARs, to NK cells via trogocytosis (Cho et al.), and that the expression of Tyro3 is essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.); it would have been obvious to a skilled artisan to modify the K562 cells expressing 41BBL and membrane-bound IL21 taught by Cho et al. to also express Tyro3 with a reasonable expectation of success. A skilled artisan would reasonably expect that, given the ability of K562 cells to donate cell surface proteins (CARs) to NK cells in co-cultures via trogocytosis, Tyro3-, 41BBL- and IL21-expressing K562 cells could be co-cultured with NK cells allowing for the transfer of Tyro3 from the K562 cells to the NK cells by trogocytosis. This co-culture and transfer of Tyro3 would be expected to increase the terminal differentiation and functional maturation (or expansion) of the NK cells.
Regarding the limitation in claim 1 which recites that the human Tyro3 polypeptide comprises “an amino acid sequence that is at least 95% identical to SEQ ID NO:2” in lines 2 and 3, it is noted that SEQ ID NO: 2 is the wildtype full-length amino acid sequence of human TYRO3 isoform 1 (e.g. see NCBI Reference Sequence: NP_006284.2). Thus, the Tryo3 expressed by the modified 41BBL- and IL21-expressing K562 cells as taught by Cho et al. in view of Caraux et al. would necessarily have the same amino acid sequence as instant SEQ ID NO: 2, especially in the absence of evidence to the contrary. Furthermore, it would be obvious to a skilled artisan to select human Tyro3 to be expressed by the human K562 cell line to activate human NK cells with a reasonable expectation of success.
This also applies to claims 31-34 which recite that Tyro3 polypeptide comprises an amino acids sequence that is at least 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, respectively.
Regarding the property of enhancing “the expansion of human natural killer (NK) cells that contact the K562 cells by at least about 10% compared to K562 cells that do not express exogenous human Tyro3 (Tyro3- K562 cells)” as recited in lines 1-4 of claim 2, Cho et al. and Caraux et al. are both silent on this property. However, silence about a particular result/property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the methods/materials, i.e., that the claims are directed to new methods/materials, and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious.
In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed methods/materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Cho et al. and Caraux et al. are silent with regard to enhancing the expansion of human NK cells that contact the K562 cells by at least about 10% compared to Tyro3- K562 cells, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the Tyro3-, 41BBL- and IL21-expressing K562 cells taught by Cho et al. in view of Caraux et al. would have the claimed property as recited in claim 2. The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Regarding the limitations of claims 3 and 4, which recite that “the human Tyro3 expression is under the control of a strong promoter” and “the strong promoter is a retroviral promoter,” respectively, it is noted that it would be obvious to a skilled artisan to have the expression of the human Tyro3 polypeptide under the control of a strong retroviral promotor to allow for high, stable, and long-term expression of Tyro3 in the K562 cells. Retroviral vectors are routinely applied for the expression of exogenous proteins in cell lines, such as the K562 cell line. A skilled artisan, with the goal of overexpressing a stable Tryo3 protein, would select a strong retroviral promotor for control the expression of Tryo3 with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1-4 and 31-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 27, and 29-32 of co-pending U.S. Application No. 17/908,585 (the ‘585 Application) in view of Cho et al. 2014 (PLOS ONE. 9(10); e109352, 1-8, a reference of record) and Caraux et al. 2006 (Nat. Immunol. 7(7); 747-754, an IDS reference filed 03/19/2024).
The instant claims are drawn to modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL- 21) and 4-1 BB ligand (4-1BBL).
The claims in the ‘585 Application are drawn to a method of expanding natural killer cells, comprising: providing a population of internally gelated cells, each of which includes a gelated interior and a fluid cell membrane that contains one or more membrane-bound proteins each or collectively are capable of stimulating expansion of natural killer (NK) cells; and culturing a population of cells containing NK cells, which are capable of responding to the one or more membrane-bound proteins, with the population of internally gelated cells under conditions that allow expansion of NK cells; a method of generating a population of internally gelated cells; a population of internally gelated cells; a composition; and a method of inducing an immune response in a subject.
The claims in the ‘585 Application differ from the instant invention by failing to recite that the internally gelated cells are only K562 cells that express IL-21, 4-1BBL, and Tyro3.
The teachings of Cho et al. and Caraux et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to have modify the claims in the ‘585 Application to incorporate the teachings of Cho et al. and Caraux et al. to specifically select that the internally gelated cells are only K562 cells that express IL-21, 4-1BBL, and Tyro3. This is because K562 cells expressing 41BBL and membrane-bound IL21 direct the in vitro expansion of NK cells when in co-culture (Cho et al.) and the expression of Tyro3 is essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.).
The challenges of using viral vectors to genetically modify NK cells is well known and so is the usefulness of trogocytosis as a relatively simple non-viral method that can be readily scaled up to modify large numbers of NK cells with a single K562-based donor cell line (Cho et al.).
Given that that K562 cells expressing 41BBL and membrane-bound IL21 direct the in vitro expansion of NK cells when in co-culture (Cho et al.), the ability of K562 cells to donate cell surface proteins, such as CARs, to NK cells via trogocytosis (Cho et al.), and that the expression of Tyro3 essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.); it would be obvious to a skilled artisan, with the goal of increasing the terminal differentiation and functional maturation of NK cells, to specifically select that the internally gelated cells are only K562 cells that express IL-21, 4-1BBL, and Tyro3 with a reasonable expectation of success. A skilled artisan would reasonably expect that, given the ability of K562 cells to donate cell surface proteins (CARs) to NK cells in co-cultures via trogocytosis, Tyro3-, 41BBL- and IL21-expressing K562 cells could be co-cultured with NK cells allowing for the transfer of Tyro3 from the K562 cells to the NK cells by trogocytosis. This co-culture and transfer of Tyro3 would be expected to increase the terminal differentiation and functional maturation (or expansion) of the NK cells.
Regarding the claims in the ‘585 Application that are drawn to a method of generating the internally gelated cells; it is noted that "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113.I.
This applies to the instant case, where the claims in the ‘585 Application are drawn to a method of making the internally gelated cells which would be obvious to a skilled artisan to modify into Tyro3-, 41BBL- and IL21-expressing K562 cells for the reasons stated above. Therefore, the in instant Tyro3-, 41BBL- and IL21-expressing K562 cells would also be obvious of the method of making the internally gelated Tyro3-, 41BBL- and IL21-expressing K562 cells.
Regarding the claims in the in the ‘585 Application which are drawn to methods that use the internally gelated cells to expand NK cells or to induce an immune response in a subject; it is noted that the instant product is obvious over the claims in the ‘585 Application in view of Cho et al. and Caraux et al. for the reasons stated above and therefore, the product’s use in the methods of the ‘585 Application would also render the instant claims obvious when viewed in light of Cho et al. and Caraux et al.
Regarding the limitation in claim 1 which recites that the human Tyro3 polypeptide comprises “an amino acid sequence that is at least 95% identical to SEQ ID NO:2” in lines 2 and 3, it is noted that SEQ ID NO: 2 is the wildtype full-length amino acid sequence of human TYRO3 isoform 1 (e.g. see NCBI Reference Sequence: NP_006284.2). Thus, the Tryo3 expressed by the modified 41BBL- and IL21-expressing K562 cells as taught by the ‘585 Application in view of Cho et al. and Caraux et al. would necessarily have the same amino acid sequence as instant SEQ ID NO: 2, especially in the absence of evidence to the contrary. Furthermore, it would be obvious to a skilled artisan to select human Tyro3 to be expressed by the human K562 cell line to activate human NK cells with a reasonable expectation of success.
This also applies to claims 31-34 which recite that Tyro3 polypeptide comprises an amino acids sequence that is at least 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, respectively.
Regarding the property of enhancing “the expansion of human natural killer (NK) cells that contact the K562 cells by at least about 10% compared to K562 cells that do not express exogenous human Tyro3 (Tyro3- K562 cells)” as recited in lines 1-4 of claim 2, the ‘585 Application, Cho et al., and Caraux et al. are all silent on this property. However, silence about a particular result/property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the methods/materials, i.e., that the claims are directed to new methods/materials, and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious.
In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed methods/materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although the ‘585 Application, Cho et al., and Caraux et al. are silent with regard to enhancing the expansion of human NK cells that contact the K562 cells by at least about 10% compared to Tyro3- K562 cells, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the Tyro3-, 41BBL- and IL21-expressing K562 cells taught by the ‘585 Application in view of Cho et al. and Caraux et al. would have the claimed property as recited in claim 2. The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Regarding the limitations of claims 3 and 4, which recite that “the human Tyro3 expression is under the control of a strong promoter” and “the strong promoter is a retroviral promoter,” respectively, it is noted that it would be obvious to a skilled artisan to have the expression of the human Tyro3 polypeptide under the control of a strong retroviral promotor to allow for high, stable, and long-term expression of Tyro3 in the K562 cells. Retroviral vectors are routinely applied for the expression of exogenous proteins in cell lines, such as the K562 cell line. A skilled artisan, with the goal of overexpressing a stable Tryo3 protein, would select a strong retroviral promotor for control the expression of Tryo3 with a reasonable expectation of success.
Therefore, the claims in the ‘585 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4 and 31-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24, 25, 28, 30, 31, 36, 40, 41, 45, 47, 48, 50, 60, and 61 of co-pending U.S. Application No. 17/621,909 (the ‘909 Application) in view of Cho et al. 2014 (PLOS ONE. 9(10); e109352, 1-8, a reference of record) and Caraux et al. 2006 (Nat. Immunol. 7(7); 747-754, an IDS reference filed 03/19/2024).
The instant claims are drawn to modified K562 myeloid leukemia cells (Tyro3+ K562 cells) expressing human Tyro3 polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and wherein the Tyro3+ K562 cells express membrane bound interleukin 21 (IL- 21) and 4-1 BB ligand (4-1BBL).
The claims in the ‘909 Application are drawn to a method of treating cancer in a patient comprising: a. isolating natural killer (NK) cells from a subject thereby producing a population of isolated NK cells; b. deriving a population of PD-L1(+)NK cells from said population of isolated NK cells by exposing the isolated NK cells to a population of irradiated K562 cells expressing membrane-bound IL-21 in the presence of IL-2 for 20 days; and c. administering the population of PD-L1(+) NK cells into said patient; and a method of treating cancer in a subject comprising administering an NK cell activating agent and an immunotherapeutic to said subject.
The claims in the ‘909 Application differ from the instant invention by failing to recite that the K562 cells also express 4-1BBL and Tyro3 or that the activating agent is a Tyro3-, 41BBL- and IL21-expressing K562 cell.
The teachings of Cho et al. and Caraux et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to have modify the claims in the ‘909 Application to incorporate the teachings of Cho et al. and Caraux et al. to include that the K562 cells also express 4-1BBL and Tyro3 and that the activating agent is a Tyro3-, 41BBL- and IL21-expressing K562 cell. This is because K562 cells expressing 41BBL and membrane-bound IL21 direct the in vitro expansion of NK cells when in co-culture (Cho et al.) and the expression of Tyro3 is essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.).
The challenges of using viral vectors to genetically modify NK cells is well known and so is the usefulness of trogocytosis as a relatively simple non-viral method that can be readily scaled up to modify large numbers of NK cells with a single K562-based donor cell line (Cho et al.).
Given that that K562 cells expressing 41BBL and membrane-bound IL21 direct the in vitro expansion of NK cells when in co-culture (Cho et al.), the ability of K562 cells to donate cell surface proteins, such as CARs, to NK cells via trogocytosis (Cho et al.), and that the expression of Tyro3 essential for the terminal differentiation and functional maturation of NK cells (Caraux et al.); it would be obvious to a skilled artisan, with the goal of increasing the terminal differentiation and functional maturation of NK cells, to modify the K562 cells taught by the ‘909 Application to also express 4-1BBL and Tyro3 and specifically select a Tyro3-, 41BBL- and IL21-expressing K562 cell as the NK cell activating agent with a reasonable expectation of success. A skilled artisan would reasonably expect that, given the ability of K562 cells to donate cell surface proteins (CARs) to NK cells in co-cultures via trogocytosis, Tyro3-, 41BBL- and IL21-expressing K562 cells could be co-cultured with NK cells allowing for the transfer of Tyro3 from the K562 cells to the NK cells by trogocytosis. This co-culture and transfer of Tyro3 would be expected to increase the terminal differentiation and functional maturation (or expansion) of the NK cells.
Regarding the claims in the in the ‘909 Application which are drawn to methods that use the K562 cells to derive NK cells from a population of NK cells or as an agent to activate NK cells; it is noted that the instant product is obvious over the claims in the ‘909 Application in view of Cho et al. and Caraux et al. for the reasons stated above and therefore, the product’s use in the methods of the ‘909 Application would also render the instant claims obvious when viewed in light of Cho et al. and Caraux et al.
Regarding the limitation in claim 1 which recites that the human Tyro3 polypeptide comprises “an amino acid sequence that is at least 95% identical to SEQ ID NO:2” in lines 2 and 3, it is noted that SEQ ID NO: 2 is the wildtype full-length amino acid sequence of human TYRO3 isoform 1 (e.g. see NCBI Reference Sequence: NP_006284.2). Thus, the Tryo3 expressed by the modified 41BBL- and IL21-expressing K562 cells as taught by the ‘909 Application in view of Cho et al. and Caraux et al. would necessarily have the same amino acid sequence as instant SEQ ID NO: 2, especially in the absence of evidence to the contrary. Furthermore, it would be obvious to a skilled artisan to select human Tyro3 to be expressed by the human K562 cell line to activate human NK cells with a reasonable expectation of success.
This also applies to claims 31-34 which recite that Tyro3 polypeptide comprises an amino acids sequence that is at least 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, respectively.
Regarding the property of enhancing “the expansion of human natural killer (NK) cells that contact the K562 cells by at least about 10% compared to K562 cells that do not express exogenous human Tyro3 (Tyro3- K562 cells)” as recited in lines 1-4 of claim 2, the ‘909 Application, Cho et al., and Caraux et al. are all silent on this property. However, silence about a particular result/property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the methods/materials, i.e., that the claims are directed to new methods/materials, and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious.
In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed methods/materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although the ‘909Application, Cho et al., and Caraux et al. are silent with regard to enhancing the expansion of human NK cells that contact the K562 cells by at least about 10% compared to Tyro3- K562 cells, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the Tyro3-, 41BBL- and IL21-expressing K562 cells taught by the ‘909 Application in view of Cho et al. and Caraux et al. would have the claimed property as recited in claim 2. The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Regarding the limitations of claims 3 and 4, which recite that “the human Tyro3 expression is under the control of a strong promoter” and “the strong promoter is a retroviral promoter,” respectively, it is noted that it would be obvious to a skilled artisan to have the expression of the human Tyro3 polypeptide under the control of a strong retroviral promotor to allow for high, stable, and long-term expression of Tyro3 in the K562 cells. Retroviral vectors are routinely applied for the expression of exogenous proteins in cell lines, such as the K562 cell line. A skilled artisan, with the goal of overexpressing a stable Tryo3 protein, would select a strong retroviral promotor for control the expression of Tryo3 with a reasonable expectation of success.
Therefore, the claims in the ‘909 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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