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 .
DETAILED ACTION
1. Applicant’s amendment filed 11/3/23 and Applicant’s response filed 6/8/26 are acknowledged and have been entered.
2. Applicant's election without traverse of Group I in Applicant’s response filed 6/8/26 is acknowledged. Upon further consideration, the species election requirement made in the action mailed 3/9/26 is hereby withdrawn by the Examiner.
Accordingly, claims 41-43 (non-elected Groups II and III) are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to non-elected inventions.
Claims 24-40 are presently being examined. Claim 24 is an independent claim.
3. The Examiner is making of record in this application the Declaration of Inventor Bo Kyung Min under 37 C.F.R. 1.132 filed 8/29/22 in parent application serial no. 17/220,865. The said Declaration evidences that the CD4+ T cell lines Hut78, H9, Molt-3, and PEER can be used as feeder cells for expansion of NK cells, that PBMCs whether CD3+ depleted or not can be used as seed cells for expansion of NK cells using CD4+ T feeder cells, as can cord blood cells. The Examiner would also like to point out that Applicant has stated on the record in grandparent application serial no. 15/527,752 (in the amendment and response filed 3/2/20 on page 12) that “HuT78” refers only to HuT78 cells and not to HuT78 derivative cell lines.
4. In addition to the evidence presented above at item #3 of this office action, the Examiner points out that IDS reference Min et al. (Cell. Molec. Immunol., 2022, 19: 296-298, of record) teaches that CD4+ T cells, including some not recited in the instant dependent claims, contributed to the highest NK cell proliferation amongst the feeder cells tested (see entire reference, especially 2nd and 3rd paragraph and suppl. Figure 4). The Examiner further points out that even though there are different levels of cell surface CD3 expressed on T cells*, it would not constitute undue experimentation to determine which embodiments of the claimed invention with respect to use of inactivated CD4+ T cells are operable. *(Evidentiary reference Valle et al. (Immunol. 2015, 194: 2117-2127, of record) teaches that different CD4+ T cells express different levels of CD3)).
5. 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.
6. Claims 34, 37 and 38 are 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(s) 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. This is a written description rejection.
Applicant has broadly claimed a method for producing a population of NK cells comprising: (a) providing seed cells comprising NK cells; and (b) expanding the NK cells by culturing the seed cells with a plurality of cells from an inactivated CD4+ T cell line to produce expanded NK cells, thereby producing the population of NK cells (as is recited in instant base claim 24), wherein the culturing is carried out in a medium comprising a T cell stimulating antibody and an interleukin protein (as is recited in instant dependent claim 34), and including wherein in dependent claims 37 and 38 the T cell stimulating antibody is the generic T cell stimulating antibody recited in claim 34 upon which they depend.
The specification does not disclose a representative number of species of such T cell stimulating antibodies used in the claimed method, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
As such, the claims encompass a method wherein the culturing step is carried out in a medium comprising an antibody that has the functional properties of binding to and stimulating a T cell (i.e., it is a “T-cell stimulating antibody”). As such, the claims also encompass a method in which an interleukin protein must possess the functional property of expanding NK cells from seed cells comprising NK cells in concert with the recited inactivated CD4+ T cell line, either alone or in further combination with a T cell stimulating antibody.
The specification discloses that the step of culturing NK cells is in a medium containing an interleukin protein and a T cell stimulating antibody having a low affinity for T cells in the presence of inactivated T cells (e.g., paragraph spanning pages 12-13), including wherein the T cell stimulating antibody having a low affinity for T cells is a protein that reacts specifically with CD3 antigen, including antibodies OKT3, UCHT1 and HT3a (e.g., first full paragraphs on page 16 and page 17). Therefore, the antibody used in the claimed method is a functional subgenus of a T cell stimulating antibody, including of a CD3 stimulating antibody, as it must possess the functional property of low affinity binding to a T cell receptor or other protein, including CD3:
The specification discloses that “As used herein, the term “stimulating” means inducing the proliferation of natural killer cells by adding feed cells or the like. In the stimulation step, a T cell-stimulating antibody having a low affinity for T cells may also be used. As used herein, the term “re-stimulating” means re-inducing the proliferation of natural killer cells by adding feeder cells and/or a t cell-stimulating antibody which has a low affinity for T cells to the medium after a certain time of culture” (paragraph spanning pages 19-20).
The specification does not disclose a limiting definition for “T cell stimulating antibody”, nor does it disclose which antibodies are T cell stimulating antibodies having low affinity for T cells, with the exception of three anti-CD3 antibodies (OKT3, UCHT1, and HT3a). Thus, the specification does not provide a representative number of antibodies for the genus of T cell stimulating antibodies that are used in the claimed method.
As pertains to a lack of structure/function relationship, the skilled artisan was aware that the genus of antibodies that bind to an antigen (such as CD3 or any other T cell expressed cell surface antigen), an epitope of an antigen, or to overlapping epitopes of an antigen is extremely broad and extremely structurally diverse, encompassing the full repertoire of species that can produce such antibodies or of artificial repertoires (e.g., artificial antibody/antibody fragment libraries). The cognate sets of CDRs (the amino acid sequences of) that can bind to the same antigen or epitope or overlapping epitopes of an antigen can be extensively diverse. One of skill in the art was aware that there is no structure/function relationship between the CDRs in the antibody and the epitope or epitope residues bound by the antibody. (See for example, IDS references Edwards et al. (JMB, 2003, 334: 103-118), Lloyd et al. (Protein Engineering, Eng.Design & Selection, 2009, 22(3): 159-168), Goel et al. (J. Immunol., 2004, 173: 7358-7367), Poosarla et al. (Biotechn. Bioeng. , 2017, 114(6): 1331-1342)).
Although one of skill in the art could employ methods of discovery to make T cell stimulating antibodies and test them for low affinity binding to T cells:
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the T cell stimulating antibody recited in the method of instant claims 34, 27 and 38. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such T cell stimulating antibodies at the time the instant application was filed and hence was not in possession of the claimed method that uses them.
7. Claims 24-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S, 108F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999F2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)). In In re Wands 8 USPQ2d 1400 (CAFC 1988), a number of factors are set forth which a court may consider in determining whether a disclosure would require undue experimentation. These factors were set forth as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. All the factors need not be reviewed when determining whether a disclosure is enabling. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927F2.d 1200, 1213, 18 USPQ2d 1016, 1027 (Fed. Cir. 1991) (noting that the Wands factors “are illustrative, not mandatory. What is relevant depends upon the facts.”).
The specification does not disclose how to use the instant invention, a method for producing a population of NK cells comprising: (a) providing seed cells comprising NK cells; and (b) expanding the NK cells by culturing the seed cells with a plurality of cells from an inactivated CD4+ T cell line to produce expanded NK cells, thereby producing the population of NK cells (as is recited in instant base claim 24), and
wherein the cells are not expanded in step “(b)” in a medium comprising IL-2, IL-15, or a combination of IL-2 and/or IL-15, including with one or more of IL-12, IL-18 and or IL-21 (claims 24-37, 39 and 40), or
wherein the cells are not expanded in step “(b)” in the presence of a T cell stimulating antibody that is an anti-CD3 antibody having low affinity of binding to CD3 such as one of UCHT1, OKT3, HT3a, or a combination thereof (claims 24-34, 37-40), or
wherein the seed cells comprising NK cells provided in step (a) are selected from enriched natural killer cells (do not further comprise mononuclear cells) and isolated natural killer cells” (that also do not comprise mononuclear cells) (claims 24-26, 29-40, with claim 29 reciting “wherein the seed cells provided in step (a) are selected from enriched natural killer cells and isolated natural killer cells”), or
“wherein the cells from an inactivated CD4(+) T cell line are selected from the group consisting of “ … Loucy….and combinations thereof” (as is recited in instant dependent claim 30).
The specification has not enabled the breadth of the claimed invention because:
(1) with regard to the expansion medium, it is unpredictable that the claimed method can be used to expand NK cells without inclusion of IL-2 and/or IL-15 in the context of the claimed method; or
(2) with regard to the absence of an anti-CD3 antibody having a low affinity of binding such as UCHT1, OKT3, HT3a, or a combination thereof, it is unpredictable that the claimed method can be used to expand NK cells, and including without inclusion of IL-2 and/or IL-15 in the context of the claimed method; or
(3) with further regard to claim 29, the seed cells only comprise isolated NK cells or comprise enriched NK cells that do not further comprise the mononuclear cell subsets that are present in CD3+ depleted PBMCs, non-CD3+ depleted PBMCs, or other sources of enriched NK cells or,
with regard to claims 24-26 and 30-40, the seed cells that comprise NK cells do not further comprise the mononuclear cell subsets that are present in CD3+ depleted PBMCs, PBMCs, or other sources of enriched NK cells; or
(4) with further regard to claim 30, the inactivated CD4+ T cell line is Loucy (due to the Markush recitation in that claim), wherein use of the said cell line may result in a non-operative embodiment of the claimed invention.
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed method can be used for its recited purpose in producing expanded NK cells.
The specification discloses that the term “seed cells” means cells capable of proliferating to NK cells by suitable culture…the seed cells that are used in the invention may be one or more types selected from the group consisting of peripheral blood cells, peripheral blood leukocytes, PBMCs, enrich NK cells and isolated NK cells, but are not limited thereto (paragraph spanning pages 15-16).
The working examples in the instant specification are limited to use of seed cells that are PBMCs or CD3+-depleted PBMCs. The specification does not disclose a definition for “enriched natural killer cells”, but the CD3+-depleted PBMCs may be considered to be a species of the genus of enriched NK cells (by negative selection, wherein the CD3+ depleted PBMC population comprises not only NK cells but also other CD3- cells). Please note that as per item #3 above in this office action, Applicant has provided evidence that PBMCs that are not CD3+ -depleted can also be used, but also note that the complement of mononuclear cells in PBMCs are also present in CD3+ -depleted PBMCs.
Evidentiary reference Kim et al. (Cytotherapy, 2013, 15: 231-241, IDS reference) teaches that cytokines are necessary but are not sufficient for expansion of NK cells. Kim et al. further teach that it is generally agreed that sustained proliferation of NK cells requires additional stimulatory signals such as the presence of monocytes of B-lymphoblastoid cells, although autologous lymphocytes and umbilical cord mesenchymal cells or genetically modified K562 cells were also used. Kim et al. also teach that NK cells from different sources have different phenotypes. Kim et al. indicate that when irradiated PBMCs depleted of CD3+ cells were used as feeder cells, IL-2 and anti-CD3 mAb OKT3 were utilized to obtain NK cells. See entire reference.
As to seed cells comprising NK cells, there is no evidence of record that isolated NK cells or enriched NK cells (except for CD3+ depleted PBMCs as the NK enriched NK cells) can be sustainably proliferated using irradiated (inactivated) CD4+ T cells. There is no evidence of record and it is unpredictable that seed cells comprising NK cells but not comprising other mononuclear cells present in (CD3+ depleted or not depleted) PBMCs can be used to expand NK cells in the context of the claimed method.
The HuT78 feeder cells in the working examples are irradiated feeder cells. Although Applicant has presented evidence that several CD4+ T cell lines can be used in the claimed method (see item #3 above in this Office Action for evidence that the other cell lines recited in claim 30 exclusive of the Loucy cell line are operative embodiments) and it would not constitute undue experimentation to determine cell lines that could be used in the claimed method, none-the-less, instant claim 30 recites a Markush group of CD4+ T cell lines, meaning that the method may exclusively use the Loucy cell line as feeder cells, while there is no evidence of record that this cell line produces an operative embodiment of the claimed method.
As regards the absence of cytokines or the presence of some in the expansion medium in step “(b)” in claims 24-37, 39 and 40, evidentiary reference Pahl et al. (Front. Immunol. 2018, volume 9, pages 1-9) teaches that IL-2 and IL-15 drive NK cell differentiation, proliferation (i.e., expansion), and activation, while IL-15 trans-presented by activated dendritic cells (i.e., a dendritic cell is a type of non-T cell mononuclear cell in PBMCs) is critical for NK cell survival (second paragraph of introduction). Pahl et al. teach that IL-12 and IL-18 induce potent NK cell IFN-g production and cytotoxicity, in particular in combination, and synergistically augment IL-2 and IL-15-induced NK cell activation (second paragraph of introduction). Pahl et al. teach that the combination of IL-12/18 plus IL-15 upregulate the IL-2 receptor alpha chain on murine and human NK cells and undergo rapid proliferation and expansion in response to IL-2 or IL-15 (Figure 1 legend). Pahl et al. discuss IL-12/IL-18 plus IL-15 as supporting factors after pre-treatment/expansion/proliferation and activation with IL-2 and/or IL-15 in culture; that is IL-18 appears to work as a supportive or priming stimulus rather than a standalone proliferative factor. See entire reference. (Please note additionally that instant dependent claim 26 recites “wherein the seed cells provided in step (1) have not been expanded ex vivo or in vitro.” Evidentiary reference Shrestha et al. (Cancer Immunol. Immunother., 2024, volume 73, pages 1-19) teaches that a combination of IL-12, IL-15 and IL-18 domains in a fusion protein could replace individual cytokines for priming human memory like NK cell programming, but this approach does not include ex vivo expansion (abstract). There is no evidence of record that IL-18 or IL-12 or IL-21 alone can expand NK cells, including those that have not been pre-expanded ex vivo or in vitro.
It is therefore unpredictable that the claimed method can be used to expand NK cells without the inclusion of IL-2 and/or IL-15 in the expansion step “(b)”.
As regards the lack of a T cell stimulating antibody that is an anti-CD3 antibody having low affinity of binding to CD3 such as one of UCHT1, OKT3, HT3a, or a combination thereof, the instant specification discloses that “As used herein, the term “stimulating” means inducing the proliferation of natural killer cells by adding feed cells or the like. In the stimulation step, a T cell-stimulating antibody having a low affinity for T cells may also be used. As used herein, the term “re-stimulating” means re-inducing the proliferation of natural killer cells by adding feeder cells and/or a T cell-stimulating antibody which has a low affinity for T cells to the medium after a certain time of culture” (paragraph spanning pages 19-20).
Although it would not constitute undue experimentation to test other anti-CD3 antibodies for low affinity binding to CD3 and to test such antibodies in the method recited in the instant claims, it would constitute undue experimentation to determine which antibodies with specificities and particular low affinity of binding to other T cell surface receptors that can cause T cell stimulation can be used in the instant method.
There is insufficient guidance in the specification as to how use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. 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.
9. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/2856,647 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-31, 33 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 11, 12, 21, 28, 34 and 45-52 of copending Application No.18/285,647 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference) , as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ‘647 are drawn to a method for treating a patient suffering from a HER2+ cancer comprising administering a population of NK cells and an anti-human HER2 antibody, wherein the population of NK cells is produced by a method comprising obtaining seed cells comprising NK cells from cord blood, deleting the seed cells of CD3+ cells, expanding the NK cells by culturing the depleted seed cells with a first plurality of Hut78 cells engineered to express mIL-21, mutated TNFa and a 4-1BBL gene to produce a cell bank population, and the method may further comprise expanding the cell bank population by culturing with a second plurality of said Hut78 cells.
The claims of ‘647 do not recite that the Hut78 (CD4+ T cell line, feeder cell lines) is inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
10. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/285,637 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-31, 33 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-10, 14-17, 26, 33, 56, 57 and 59 of copending Application No.18/285,637 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ‘637 are drawn to a method for treating a patient suffering from a CD20+ cancer comprising administering a population of NK cells and an anti-human CD20 antibody, wherein the population of NK cells is produced by a method comprising obtaining seed cells comprising NK cells from cord blood, deleting the seed cells of CD3+ cells, expanding the NK cells by culturing the depleted seed cells with a first plurality of Hut78 cells engineered to express mIL-21, mutated TNFa and a 4-1BBL gene to produce a cell bank population, and the method may further comprise expanding the cell bank population by culturing with a second plurality of said Hut78 cells
The claims of ‘637 do not recite that the Hut78 (CD4+ T cell line, feeder cell lines) is inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
11. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/285,648 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-31, 33 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 9-11, 19, 26, 32 and 43-50 of copending Application No.18/285,648 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ‘648 are drawn to a method for treating a patient suffering from an EGFR+ cancer comprising administering a population of NK cells and an anti-human EGFR antibody, wherein the population of NK cells is produced by a method comprising obtaining seed cells comprising NK cells from cord blood, deleting the seed cells of CD3+ cells, expanding the NK cells by culturing the depleted seed cells with a first plurality of Hut78 cells engineered to express mIL-21, mutated TNFa and a 4-1BBL gene to produce a cell bank population, and the method may further comprise expanding the cell bank population by culturing with a second plurality of said Hut78 cells.
The claims of ‘648 do not recite that the Hut78 (CD4+ T cell line, feeder cell lines) is inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
12. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/977,119 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-23 and 25-32 of copending Application No.18/977,119.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16-23 and 26-32 of 18/977,119 recite a method of culturing NK cells comprising coculturing seed cells with genetically modified CD4+ T cells that express one or more of a 4-1BBL gene, a mIL-21 gene, and a mutated TNF-a gene. The seed cells may be any one of peripheral blood, PBMCs, peripheral blood leukocytes, enriched NK cells, or isolated NK cells. The seed cells may be CD3+ depleted. The seed cells may be cultured once or two or more times with the feeder cells and the first culture is performed for 5-60 days. The culture medium may comprise an anti-CD3 antibody and an interleukin protein. The anti-CD3 antibody may be one of OKT3, UCHT1, and HT3a, or the IL protein may comprise any one of IL-2, IL-12, IL-15, IL-18 or IL-21. CD4+ T cells may be one of Hut78, H9 or Jurkat, and/or the CD4+ T cell may be inactivated.
Claim 25 of 18/977,119 is drawn to an NK cell prepared by the said method.
13. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/707,276 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29 and 34-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 115-117 of copending Application No. 18/707,276, as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 115-117 of ‘276 are drawn to a pharmaceutical composition comprising cord blood derived NK cell produced by the method comprising providing a sample of cord blood cells comprising NK cells, depleting the cells of CD3+ cells, expanding the NK cells by culturing the seed cells with a first plurality of cells from an inactivated CD4+ T cell line in a medium comprising IL-2 and a T cell stimulating antibody that is selected from the group consisting of OKT3, UCHT1, HT3a or a combination thereof.
Instant claim 39 is included in this rejection because the culturing period is a result effective variable within the purview of one of ordinary skill in the art to have determined.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
14. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/268,135 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-31, 33 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 12-16, 22, 45, 49-52, 57 and 72 of copending Application No.18/268,135 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-6, 12-16, 22, 45, 49-52, 57 and 72 of 18/263,135 are drawn to a method for treating a patient suffering from a CD20+ cancer, comprising administering allogenic expanded NK cells and an anti-human CD20 antibody, wherein the expanded NK cells are produced by a method comprising: a) obtaining seed cells comprising NK cells from umbilical cord blood, b) depleting the seed cells of CD3+ cells, and c) expanding the NK cells by culturing the depleted seed cells with a first plurality of Hut78 cells engineered to express a mIL-21, a mutated TNFa, and a 4-1BBL gene.
The claims of 18/263,135 do not recite wherein the Hut78 cells are inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
Instant claim 39 is included in this rejection because the culturing period is a result effective variable within the purview of one of ordinary skill in the art to have determined.
15. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/268,167 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-31, 33, 39 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13-19, 21, 22, 30, 33, 34, 51 and 70-73 of copending Application No.18/268,167 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of 18/268,167 are drawn to a population of expanded NK cells/vial or cryobag or composition/pharmaceutical composition thereof, produced by a method comprising: obtaining seed cells comprising NK cells from umbilical cord blood, depleting the seed cells of CD3+ cells, expanding the NK cells by culturing the depleted seed cells with a first plurality of Hut78 cells engineered to express mIL-21, a mutated TNFa and a 4-1BBL to produce a cell bank of NK cells, and expanding the cell band by culturing with a second plurality of the said engineered Hut78 cells.
The claims of 18/268,167 do not recite wherein the Hut78 cells are inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
Instant claim 39 is included in this rejection because the culturing period is a result effective variable within the purview of one of ordinary skill in the art to have determined.
16. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/293,372 case that issued as US 12,398,372 as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-26, 29, 30-34, 37, 38, 39 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,398,372 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
The claims of ‘372 are drawn to a method for expanding NK cells comprising coculturing seed cells comprising cord blood-derived NK cells with a first population of feeder cells that are genetically engineered CD4+ T cells expressing 4-1BBL, mIL-21 and TNF-a comprising a mutated TACE recognition site, and the cells are cocultured in a medium comprising an anti-CD3 antibody and IL-2 (base claim 1 of ‘372). The T cells may be from a cell line selected from the group consisting of Jurkat, Peer, H9, and Hut78 (claims 2, 3 of ‘378). The method comprises coculturing the cells for 5-60 days, and the method further comprises coculturing the seed cells with a second population of feeder cells.
The claims of ‘372 do not recite that the T cell line is inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Instant dependent claims 34 and 37 are included in this rejection in addition to the claims of ‘372 reciting coculturing in a medium comprising an anti-CD3 antibody and IL-2 because the medium also comprises membrane-expressed IL-21 on the T cell.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
Instant claim 39 is included in this rejection because the culturing period is a result effective variable within the purview of one of ordinary skill in the art to have determined.
17. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 19/219,648 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 24-27, 29-34, 37, 39 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-45 of copending Application No. 19/219,648 in view of Childs and Berg (Hematol. Am. Soc. Hematol. Educ. Program, 2013, 1: 234-246, IDS reference), as evidenced by Kikuta et al. (Frontiers Immunol. 2025, pages 1-12, DOI: 10.3389/fimmu.2025.1614230).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 27-45 of ‘648 are drawn to a method for expanding NK cells comprising coculturing seed cells comprising cord blood derived NK cells with a first population of feeder cells, wherein the feeder cells comprise genetically engineered CD4+ T cells expressing a 4-1BBL polypeptide, a mIL-21 polypeptide, and a mutated TNF-a polypeptide. The CD4+ T cell may be Hut78, H9, Peer, or Jurkat (cell lines). The seed cells may be depleted of CD3+ cells. The medium may comprise an anti-CD3 antibody.
The culturing can be performed for 5 to 60 days, and/or the method may further comprise coculturing the seed cells with a second population of feeder cells.
The claims of ‘648 do not recite that the T cells are inactivated.
Childs and Berg teach when coculturing seed cells comprising NK cells such as from PBMCs after depleting them of CD3+ cells, irradiating the feeder cells before the coculturing. (See entire reference, especially Ex vivo NK cell expansion using feeder cells section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have inactivated the feeder cells prior to the coculturing step as is taught by Childs and Berg.
One of ordinary skill in the art would have been motivated to do this in order to ensure that the T cells provide the signals for proliferation and activation without proliferating themselves as the goal is to expand NK cells.
Instant dependent claims 34 and 37 are included in this rejection because the medium comprises membrane-expressed IL-21 on the T cell.
Evidentiary reference Kikuta et al. teach that umbilical cord blood cells comprise not only NK cells, but other mononuclear cells such as T lymphocytes, B lymphocytes and monocytes (see entire reference, for example, Figure 1.) This pertains to the inclusion of instant dependent claims 27 and 29 in the instant rejection.
18. Claims 31 and 37 are objected to because of the following informalities: Appropriate correction is required.
a) Claim 31 recites “wherein the cells from an inactivated CD4(+) T cell line are selected from the group consisting of H9, HuT78, and combinations thereof”. However, there is only one combination of H9 and HuT78 (as Applicant has stated on the record in the grandparent application serial no. 15/527,752 (in the amendment and response filed 3/2/20 on page 12) that “HuT78” refers only to HuT78 cells and not to HuT78 derivative cell lines.
b) Claim 37 recites “IL18, IL21” whereas it should recite ‘IL-18, IL-21’.
19. Applicant’s IDS filed 4/22/24 cites US 2012/0015423 A1. It also cites document 188 which is an English Translation of CN office action in Chinese application No. 20150063858.5. The latter document discusses the prior said document US 2012/0015423 A1. As was stated in the prosecution history in parent application serial no. 17/220,865, US 2012/0015423 A1 is not being cited as prior art against the presently claimed invention for the following reasons. The instant claims require expanding NK cells by culturing seed cells with a plurality of cells from an inactivated CD4+ T cell line, including in a medium comprising a T cell stimulating antibody that is one of OKT3, UCT1, HT3a or a combination thereof and IL-2 (the latter two limitations being recited in instant dependent claims 35, 36, 37 and 38).
The instant specification does not disclose a definition for a T cell line or a cell line. IDS reference Biology Online Dictionary 2021 teaches that a cell line is a permanently established cell culture that will proliferate indefinitely given appropriate fresh medium and space. It also teaches that establishment of cell lines from human tissue is difficult and that a cell line is by definition already abnormal and is on the way towards becoming the culture equivalent of a neoplastic cell. IDS reference Cell-line meaning 2021 teaches that a cell culture is derived from one cell or a set of cells of the same type and in which certain conditions the cells proliferate indefinitely in the laboratory or is a group of individual cells that are genetically identical as a result of dividing mitotically from a single progenitor cell.
US 2012/0015423 A1 discloses a population of T cells that possess a combination of Th1 and also NK cell characteristics, whereby these cells are generated by ex vivo culture of purified resting CD25-CD4+ T cells having mixed memory and naïve phenotype (CD45RA and CD45RO) that are activated multiple times with immobilized anti-CD3/anti-CD28 mAbs in the absence of exogenous cytokines. These cells are disclosed as producing cytokines that can stimulate other cells such as NK cells (see entire reference, especially [0019]. [0030], [0031]).
Evidentiary reference PromoCell (2019, 7 pages) teaches that primary human T cells are isolated directly from tissues and retain the morphological and functional characteristics of their tissue of origin. PromoCell further teaches that cell lines may have an altered genomic content and lack key morphological or functional features as compared to the original primary cells, as serial passages can cause variations in genotype and phenotype (see entire reference, especially human primary cells and cell lines sections).
There is no evidence of record that the T cells disclosed by US 2012/0015423 A1 are capable of proliferating indefinitely in culture (i.e., there is no evidence of record that these cells constitute a T cell line). Furthermore, there is no evidence of record that T cell lines can be generated from the cultured CD4+ T cells disclosed by US 2012/0015423 A1, including wherein they retain the functional features necessary to stimulate NK cells in culture. Also, there is no evidence of record that even if a T cell line could be generated from the cells disclosed in US 2012/0015423 A1 that cell surface receptors/proteins present on the cell line would not negatively influence expansion of the seed cells to NK cells. The same can be said for Applicant’ IDS reference 32 which has an English language abstract for reference 188.
20. No claim is allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights