DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application was filed March 4, 2020, and claims benefit to the foreign application JP2019-007868 filed on Jan. 21, 2019.
Traversal: Applicant request that the Examiner acknowledges that the certified copy of the priority application was recorded on 4th of November 2020 as shown in the patent center (Remarks, page 3).
In response, the Office Action summary has been updated to acknowledge that the certified copy of the priority application has been received.
Status of Application
In view of further search and consideration, the previous non-final office action is withdrawn. The following rejection are applicable, although not necessitated by Applicants arguments. It should be noted that the instant action is a non-final office action.
In the response filed on May 1, 2026, Applicant has asserted that claims 12-13, 18-24 are under examination and has cancelled claims 1-11, and 14-17.
Status of the Claims
Currently, claims 12-13, and 18-24 are under examination in this Office Action.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
It is noted that the disclosure statements filed (e.g. 4/29/2025, 2/25/2025, 9/25/2024, 2/23/2024, 11/9/2023) lists Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 103
The following is a quotation of AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained through the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 12-13, and 18-24 are rejected under AIA 35 U.S.C. 103(a) as obvious over Yonemitsu et al., (U.S. Patent No. 9,404,083B2, Application No. 14/129,143, published Aug. 2, 2016), in view of Koehl, Ulrike, et al. (Frontiers in oncology 3: 118, published 2013), Rose, Mingus JJ, et al. (The Journal of Immunology 183.7: 4502-4508, published 2009), Ruggeri L, et al., (Blood. Jul 1;94(1):333-9. PMID: 10381530, published 1999), Henno et al., (WO 2015132415A1; published September 11, 2015, cited in IDS 10/6/2020, hereinafter as “Henno”), and Fujisaki, Hiroyuki, et al. (Cancer research 69.9: 4010-4017, published 2009, prior art of record).
This rejection is a new rejection of record. However, any aspect of applicant's response considered relevant to the rejection as set forth is responded to following the statement of rejection.
Regarding claims 12, 18, and 23-24, Yonemitsu discloses a method for producing mixed cell populations including natural killer (NK) cells (see e.g. col. 8, Example 1), the method comprising: (1) removing CD3-positive cells from a cell population of mononuclear cells originating in each donor, the cell population including NK cells (see e.g. col. 8, ln. 51-59, Example 1, claims 1-2); (2) mixing the plurality of the cell populations of mononuclear cells from patients or volunteers (see e.g. col. 5, Example 1); and (3) culturing the plurality of the cell populations under conditions effective for proliferation of NK cells to obtain the mixed cell populations including NK cells (see e.g. col. 8-9, Example 1). Yonemitsu discloses wherein the cell populations are prepared from peripheral blood or prepared from apheresis blood (see e.g. col. 15, Example 1 or 4, claims 7-8). Yonemitsu discloses wherein the plurality of donors includes a first donor and a second donor, the cell populations from the first donor having a genotype of at least one of HLA or KIR which is different from a genotype of the cell populations from the second donor (i.e. HLA genotype is different)(see e.g. col. 3-4, Fig. 11). Further, Yonemitsu discloses wherein the mixed cell population have a cytotoxicity activity of 50% or higher in co-culture of the NK cells as effector cells (E) and K562 cells as target cells (T) at a mixing ratio of 1:1 (E:T)(see e.g. cols. 12, 15, and Example 3, Fig. 13). Further, Yonemitsu discloses pooling mononuclear cells from peripheral blood of volunteers and patients (see e.g. col. 8). Further, Yonemitsu discloses cell amplification of individual donors (fig. 3) and the component faction percentage of NK cells, which represents a percentage ratio of NK cells individually and relative to the entirety of cultured cell (see e.g. col. 8-12, Example 1, fig. 3-5).
Yonemitsu does not explicitly disclose (2) mixing the plurality of the cell populations of mononuclear cells from the plurality of cell populations originating in the plurality of donors, and a proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor which is the first or second donor.
However, the prior art of Koehl discloses clinical-scale NK purification and expansion comprising mixing (i.e. pooling) the plurality of the cell population of mononuclear cells from the plurality of cell populations originating in the plurality of donors (see e.g. page 1-3, 10, and fig. 1). Further, the prior art of Rose cites Ruggeri for culture systems for expanding peripheral blook NK clones using feeder cells obtained from a random pool of donors and discloses using the same strategies for donor and feeder cell selections with bulk cultures (see e.g. page 4505). Further, Rose teaches pooling peripheral blood NK cells form different donors (see e.g. fig. 1-4), which directs ex vivo NK cell proliferation (see e.g. page 4504-4505). Additionally, the prior art of Henno discloses a method of mixing (i.e. pooling) cell populations including natural killer cells from cord blood of different donors that can then produce a collection or therapeutic cell bank of pooled activated/expanded NK cells (see e.g. abstract, page 3-4, 13, 22, 30, table 1-2, fig. 1-3, Examples 1-3).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Yonemitsu, and incorporate a mixing step of a plurality of cell populations from a plurality of donors, as taught by Koehl, Rose, and Henno, with a reasonable expectation of success because one of ordinary skill in the art would know that mixing NK cells from a plurality of donors would allow for amplification of NK cells for clinical amounts (as taught by Koehl and Henno, see e.g. page 2 and 6, respectively), which would lead to more efficient therapeutic cells (as taught by Henno, see e.g. para. 5 and pg 6). Although Henno discloses cord blood, a person of ordinary skill in the art would have a reasonable expectation of success because both Yonemitsu and Koehl discloses obtaining NK cells from peripheral blood or apheresis blood (see e.g. para. 93 and page 2, respectively). Additionally, Henno discloses obtaining NK cells that can then produce a collection or therapeutic cell bank of pooled activated/expanded NK cells (see e.g. para. 81). Further, it would have been prima facie obvious for one of ordinary skill in the art to employ the methods of amplifying NK cells from the limited supply of cord blood in the readily available peripheral blood in order to maximize the amount of NK cells one of ordinary skill in the art would be able to obtain. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
As stated supra, Yonemitsu is silent regarding a proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor which is the first or second donor.
However, the prior art of Henno teaches that when “NK didn't amplify properly in CD3-non depleted, pooling of umbilical cord blood (UCB) after 9 days amplification (increasing NK% and NK activation status) seemed to overcome the problem. They showed an in vitro similar good cytotoxicity against B lymphoma tumoral cells (overnight, ratio E:T 1: 1)”(page 27, lns. 21-26; Fig. 8-9).
Nevertheless, although Yonemitsu is silent regarding a proliferation ratio, the effect of a mixture (i.e. pooled) of cell populations and at a 1:1 ratio would naturally have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor, which is the first donor or the second donor. Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims."
Accordingly, it would have been obvious for one of ordinary skill in the art to have the methods of Yonemitsu with a proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor as taught by Henno because Yonemitsu discloses that the NK cells from mononuclear cells may be separated by umbilical cord blood and peripheral blood (see e.g. col. 4). Therefore, a person of ordinary skill in the art would have naturally had a higher proliferation ratio with the mixed cell population compared to a single donor with a reasonable expectation of success because Yonemitsu discloses that the amplification methods of NK cells may be employed to both umbilical cord blood and peripheral blood. Additionally, the prior art of Campana discloses that contact of NK cells with K562 cells is known to augment NK cell proliferation (see e.g. page 7, col. 2). Furthermore, Yonemitsu teaches that as many as six times the number of NK cells are obtained (Yonemitsu, col. 6). Therefore, a person of skill in the art would have been motivated to modify the methods of Henno in order to ensure that the maximum number of NK cells would be obtained. Moreover, a person of ordinary skill in the art would have combined similar NK cell amplification methods, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. NK cell amplification methods) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 13, Yonemitsu discloses the method further (4) removing CD34-positive cells from the cell population of mononuclear cells including NK cells (see e.g. Fig. 16, Example 5, claim 4).
Regarding claim 19-20, as stated supra, Yonemitsu discloses a pharmaceutical composition for adoptive immunotherapy cell therapy, which comprises the mixture of cell populations, and a pharmaceutical composition for treating infectious disease and/or cancer (see e.g. abstract, col. 3-6).
Regarding claim 21, as stated supra, Yonemitsu discloses that “while carrying out further experiments of amplifying NK cells, it was found that the component fraction of CD3-positive cells relative to the entirety of culture cells may exceed 30%” (see e.g. col. 13).
Yonemitsu does not explicitly disclose the steps of (1) removing CD3-positive cells, (2) mixing the cell populations, and (3) culturing the plurality of cell populations are performed in this order.
However, Fujisaki discloses the methods of NK Cell Activation and Expansion System (NKAES) (see e.g. page 4010, Fig. 1), wherein steps (1) removing CD3-positive cells from a cell population of mononuclear cells originating in each donors, (2) mixing the plurality of cell populations of mononuclear cells from the plurality of cell populations originating in the plurality of donors, and (3) culturing the plurality of cell population conditions effective for proliferation of NK cells to obtain the mixed cell populations including NK cells are performed in this order (see e.g. pages 4010-411).
Accordingly, it would have been obvious for one of ordinary skill in the art would have to remove CD3-positive cells at the beginning as taught by Fujisaki and modify the expanding and amplifying NK cell methods as taught by Yonemitsu because Yonemitsu suggests that CD3-positive cells relative to the entirety of culture cells may increase with further culturing (see e.g. col. 13). A person would have had a reasonable expectation of success because Yonemitsu discloses carrying out the step of removing CD3-positive cells more than once (see e.g. col. 13, fig. 15). Furthermore, an artisan of ordinary skill in the art of (i.e. amplification of NK cells) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding 22, Yonemitsu does not explicitly disclose the steps of (2) mixing, (1) removing CD3-positive cells, and (3) culturing the plurality of cell populations under conditions effective for proliferation of NK cells to obtain the mixed cell populations including NK cells are performed in this order.
However, the prior art of Koehl discloses the steps of (2), (1), and (3) are performed in this order, and discloses that T-cell depletion is performed in a single or additional T-cell depletion step (see e.g. page 2).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Yonemitsu, with the steps of (2) mixing, (1) removing CD3-positive cells, and (3) culturing the plurality of cell populations, as taught by Koehl, with a reasonable expectation of success because one of ordinary skill in the art would know that removing CD3-positive populations before culturing would allow for a better quality of purified NK cell population (as taught by Koehl, see e.g. pages 2-6). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that Yonemitsu does not disclose the limitation of “mixing the plurality of cell populations of mononuclear cells from the plurality of cell populations originating in the plurality of donors” (Remarks, page 3-4). Applicant asserts that “the pooled step in Yonemitsu is merely an internal sample-processing step and does not disclosure combining mononuclear-cell populations originating from different donors”(Remarks, page 4). Applicant argues that Example 1 of Yonemitsu shows separate donor-based experiments and not mixed plurality-donor culture (fig.2-3)(Remarks, page 4). Applicant asserts that the averaged results do not disclose mixing cells from different donors into the claimed mixed cell population (Remarks, page 5).
Applicant’s arguments with respect to the claims have been acknowledged, fully considered, and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yonemitsu et al., (U.S. Patent No. 9,404,083B2, Application No. 14/129,143, published Aug. 2, 2016), in view of Koehl, Ulrike, et al. (Frontiers in oncology 3: 118, published 2013), Rose, Mingus JJ, et al. (The Journal of Immunology 183.7: 4502-4508, published 2009), Henno et al., (WO 2015132415A1; published September 11, 2015, cited in IDS 10/6/2020, hereinafter as “Henno”), and Fujisaki, Hiroyuki, et al. (Cancer research 69.9: 4010-4017, published 2009, prior art of record).
Applicant argues that Example 1 of Yonemitsu shows separate donor-based experiments and not mixed plurality-donor culture (fig.2-3)(Remarks, page 4). Applicant asserts that the averaged results do not disclose mixing cells from different donors into the claimed mixed cell population (Remarks, page 5).
In response to Applicants argument that Yonemitsu does not disclose mixing cells from different donors. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, it is noted that Yonemitsu does not teach mixing cells from different donors, but Yonemitsu does discloses that peripheral blood was collected from healthy volunteers and patients, which reads on a plurality of cell population and a plurality of donors (col. 8). As discussed above, the prior art of Koehl, Rose, and Henno are now cited for discloses mixing (i.e. pooling) the plurality of the cell population of mononuclear cells from the plurality of cell populations originating in the plurality of donors. Therefore, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness
Applicant argues that Henno does not cure the defect of Yonemitsu, and the cited combination does not teach the subject matter of claim 18, and that the dependent claims 19, 20, 21, and 24 are patentable over the cited references for at least the same reasons as claim 18. Applicants asserts request withdrawal of the obviousness rejection of claims 18-20, 21 and 24. (Remarks, page 5).
Applicant’s arguments with respect to the claims have been acknowledged, fully considered, and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yonemitsu et al., (U.S. Patent No. 9,404,083B2, Application No. 14/129,143, published Aug. 2, 2016), in view of Koehl, Ulrike, et al. (Frontiers in oncology 3: 118, published 2013), Rose, Mingus JJ, et al. (The Journal of Immunology 183.7: 4502-4508, published 2009), Henno et al., (WO 2015132415A1; published September 11, 2015, cited in IDS 10/6/2020, hereinafter as “Henno”), and Fujisaki, Hiroyuki, et al. (Cancer research 69.9: 4010-4017, published 2009, prior art of record).
As discussed above, Henno discloses a method of mixing (i.e. pooling) cell populations including natural killer cells from cord blood of different donors (see e.g. abstract, page 3, 13, 22, 30, table 1-2, fig. 1-3, Examples 1-3). Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Yonemitsu, and incorporate a mixing step of a plurality of cell populations from a plurality of donors, as taught by Koehl, Rose, and Henno, with a reasonable expectation of success because one of ordinary skill in the art would know that mixing NK cells from a plurality of donors would allow for amplification of NK cells for clinical amounts (as taught by Koehl and Henno, see e.g. page 2 and 6, respectively), which would lead to more efficient therapeutic cells (as taught by Henno, see e.g. para. 5 and pg 6). Although Henno discloses cord blood, a person of ordinary skill in the art would have a reasonable expectation of success because both Yonemitsu and Koehl discloses obtaining NK cells from peripheral blood or apheresis blood (see e.g. para. 93 and page 2, respectively). Additionally, Henno discloses obtaining NK cells that can then produce a collection or therapeutic cell bank of pooled activated/expanded NK cells (see e.g. para. 81). Further, it would have been prima facie obvious for one of ordinary skill in the art to employ the methods of amplifying NK cells from the limited supply of cord blood in the readily available peripheral blood in order to maximize the amount of NK cells one of ordinary skill in the art would be able to obtain. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Claims 12-13, and 18-24 are rejected under AIA 35 U.S.C. 103(a) as obvious over Lowdell et al., (US2011/0014162 A1, published 2011, cited IDS 11/17/2022), in view of Koehl, Ulrike, et al. (Frontiers in oncology 3: 118, published 2013), Henno et al., (WO 2015132415A1; published September 11, 2015, cited in IDS 10/6/2020, hereinafter as “Henno”), and Campana and Imai (US2006/0093605 A1, published 2006, hereinafter as “Campana”, prior art of record), and Clausen J, et al., (Biol Blood Marrow Transplant. Oct;10(10):691-7, published 2004).
This rejection is a new rejection of record.
Regarding claims 12, 18, 21, and 23-24, Lowdell discloses a method for producing mixed cell populations including natural killer (NK) cells from multiple donors (see e.g. para. 92, Example 1.1.4) corresponding to the claim limitation of a plurality of cell populations originating in a plurality of donors. Further, Lowdell discloses the method comprising: (1) removing CD3-positive cells from a cell population of mononuclear cells originating in each donor, the cell population including NK cells (see e.g. para. 92, Example 1.1.4). Further, Lowdell discloses mixing the purified NK cells with stimulator cells to obtain cell mixtures (see e.g. para. 92, Example 1.1.4), and (3) culturing the plurality of the cell populations under conditions effective for proliferation of NK cells to obtain the mixed cell populations including NK cells (see e.g. para. 92, Example 1.1.4). Further, Lowdell discloses wherein the cell populations are prepared from peripheral blood or prepared from apheresis blood, wherein the plurality of donors include a first donor and a second donor (i.e. multiple donors)(see e.g. para. 92-93 and page 8, Example 1.1.4-2). Further, Lowdell discloses that the donor NK cells may be HLA-KIR mismatched (see e.g. para. 43, 92, and 124), which reads on the claim limitation of the cell populations from the first donor having a genotype of at least one of HLA or KIR which is different from a genotype of the cell populations from the second donor. Further, Lowdell discloses a cytotoxicity of 50% or higher (i.e. specific lysis)in co-culture of NK cells as effector cells (E) and K562 cells as target cells (T) at a mixing ratio of 1:1 (E:T)(see e.g. Example 1.1.1-1.1.7, fig. 3).
Lowdell does not explicitly disclose (2) mixing the plurality of the cell populations of mononuclear cells from the plurality of cell populations originating in the plurality of donors, a proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor which is the first or second donor.
However, the prior art of Koehl discloses mixing (i.e. pooling) the plurality of the cell population of mononuclear cells from the plurality of cell populations originating in the plurality of donors (see e.g. page 1-3, fig. 1). Additionally, the prior art of Henno discloses that the method of mixing (i.e. pooling) cell populations including natural killer cells from cord blood of different donors (see e.g. abstract, page 3, 13, 22, 30, table 1-2, fig. 1-3, Examples 1-3) was well known in the art.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Lowdell, and incorporate a mixing step of a plurality of cell populations from a plurality of donors, as taught by Koehl and Henno, with a reasonable expectation of success because one of ordinary skill in the art would know that mixing NK cells from a plurality of donors would allow for amplification of NK cells for clinical amounts (as taught by Koehl and Henno, see e.g. page 2 and 6, respectively), which would lead to more efficient therapeutic cells (as taught by Henno, see e.g. para. 5 and pg 6). Although Henno discloses cord blood, a person of ordinary skill in the art would have a reasonable expectation of success because both Lowdell and Koehl discloses obtaining NK cells from peripheral blood or apheresis blood (see e.g. para. 93 and page 2, respectively). Additionally, Henno discloses obtaining NK cells that can then produce a collection or therapeutic cell bank of pooled activated/expanded NK cells (see e.g. para. 81). Further, it would have been prima facie obvious for one of ordinary skill in the art to employ the methods of amplifying NK cells from the limited supply of cord blood in the readily available peripheral blood in order to maximize the amount of NK cells one of ordinary skill in the art would be able to obtain. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
As stated supra, Lowdell does not explicitly discloses proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor which is the first or second donor.
However, the prior art of Henno teaches that when “NK didn't amplify properly in CD3-non depleted, so pooling of umbilical cord blood (UCB) after 9 days amplification (increasing NK% and NK activation status) seemed to overcome the problem. They showed an in vitro similar good cytotoxicity against B lymphoma tumoral cells (overnight, ratio E:T 1: 1)”(page 27, lns. 21-26; Fig. 8-9). Thus, a person of ordinary skill in the art would know that a population of a plurality of donors would have a higher proliferation ratio than a single donor.
Therefore, although Lowdell is silent regarding a proliferation ratio, the effect of a mixture (i.e. pooled) of cell populations and at a 1:1 ratio would naturally have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor, which is the first donor or the second donor. Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims."
Accordingly, it would have been obvious for one of ordinary skill in the art to have the methods of Lowdell with a proliferation ratio wherein the mixed cell population have a higher proliferation ratio than a proliferation ratio of any cell population from a single donor as taught by Henno because a person of ordinary skill in the art would understand that Lowdell discloses NK cells from mononuclear cells may be separated by peripheral blood (see e.g. para. 92-93 and page 8, Example 1.1.4-2). Therefore, a person of ordinary skill in the art would have naturally had a higher proliferation ratio with the mixed cell population compared to a single donor with a reasonable expectation of success because Lowdell discloses that the amplification methods of NK cells may be employed to peripheral blood. Additionally, the prior art of Campana discloses that contact of NK cells with K562 cells is known to augment NK cell proliferation (see e.g. page 7, col. 2). Furthermore, a person of skill in the art would have been motivated to modify the methods of Lowdell in order to ensure that the maximum number of NK cells would be obtained. Moreover, a person of ordinary skill in the art would have combined similar NK cell amplification methods, which would have led to predictable results with a reasonable expectation of success.
Regarding claim 13, Lowdell is silent regarding (4) removing CD34-positive cells from the cell population of mononuclear cells including NK cells.
However, the prior art of Clausen discloses that it was well known in the prior art to remove CD34-positive cells from the population of mononuclear cells including NK cells because CD34-positive cells are known to have an inhibitory effect on the proliferation of purified NK cells (see e.g. abstract).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Lowdell, and incorporate the step of removing CD34-positive cells, as taught by Clausen, with a reasonable expectation of success because one of ordinary skill in the art would know CD34-positive cells are known to have an inhibitory effect on the proliferation of purified NK cells (as taught by Clausen, see e.g. abstract).
Regarding 19-20, Lowdell discloses a pharmaceutical composition for cell therapy (see e.g. claim 1, para. 10-12) for treating an infectious disease and/or cancer (see e.g. para. 105-121).
Regarding 22, Lowdell does not explicitly disclose the steps of (2) mixing, (1) removing CD3-positive cells, and (3) culturing the plurality of cell populations under conditions effective for proliferation of NK cells to obtain the mixed cell populations including NK cells are performed in this order.
However, the prior art of Koehl discloses the steps of (2), (1), and (3) are performed in this order, and discloses that T-cell depletion is performed in a single or additional T-cell depletion step (see e.g. page 2).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods, as taught by Lowdell, with the steps of (2) mixing, (1) removing CD3-positive cells, and (3) culturing the plurality of cell populations, as taught by Koehl, with a reasonable expectation of success because one of ordinary skill in the art would know that removing CD3-positive populations before culturing would allow for a better quality of purified NK cell population (as taught by Koehl, see e.g. pages 2-6). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious 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.
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Claims 12-13, and 18-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-6, and 9 of U.S. Patent No. 11,723,924 in view of in view of Yonemitsu, et al. (US 20140120072A1, published August 2, 2014; hereinafter as “Yonemitsu”, prior art of record) and Henno et al., (WO 2015132415A1; published September 11, 2015, cited in IDS 10/6/2020, prior art of record).
This rejection is new rejection of record. However, any aspect of applicant's response considered relevant to the rejection as set forth is responded to following the statement of rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims. More specifically, the patented claims are not identical because no single patented claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are disclosed by separate patented claims, or rendered obvious by the accompanying prior art. The fact that each of the elements were claimed in the patent application, just not in a single claim, still renders obvious the instant invention because each of the features, though separately claimed, can be physically combined into a single embodiment.
Regarding claims 12-13 and 18-24, the patented ‘924 claims recites: Claim 1 recites “a population of NK cells having the following characteristics (1), (2), and (3): (1) the NK cell is CD16-positive, highly expresses CD56, and is CD57-negative; (2) the NK cell is NKG2C-positive, is NKG2A-negative or lowly expresses NKG2A, and is CD94-positive; and (3) when the NK cell is used as effector cells (E), and co-cultured with K562 cells as target cells (T) at a mixing ratio (E:T) of 1:1, the NK cells show a cytotoxicity of 50% or higher”. Claim 5 and 9 recites “a method for preparing the population according to claim 1, which comprises the following steps: collecting peripheral blood monocytes from a healthy volunteer using Ficoll; adding CD3 beads to the obtained peripheral blood monocytes, and incubating the monocytes and the beads at 4° C. for 15 minutes; adding a separation buffer to the monocytes and the beads to obtain a suspension, and centrifuging the suspension at 300×g for 10 minutes; removing a supernatant from the centrifuged suspension to obtain a residue, suspending the residue in a separation buffer, and adding the resulting suspension to LD Column wetted beforehand with the separation buffer; collecting an eluate from the LD Column, and centrifuging the eluate at 500×g for 5 minutes; removing a supernatant from the centrifuged eluate to obtain resultant cells, and suspending the resultant cells in NK medium I at a density of 5×105 cells/mL which are collected as primary NK cells; culturing the primary NK cells in a medium in a CO2 incubator at 37° C. under 5% CO2 atmosphere; collecting the cells on day 14 of the culturing step as the population; and wherein the medium is COSMEDIUM 008 containing 5% of human AB type serum which is obtained by inactivation at 56° C. for 30 minutes.” Claim 6 recites “The method according to claim 5, wherein the population of primary NK cells has undergone the step of removing CD3-positive cells”.
The co-pending ‘924 application does not explicitly teach a mixed cell populations. However, as stated above, the prior art of Henno et al. teaches a method for producing a mixed (i.e. pooling) cell populations including natural killer (NK) cells from different donors (i.e. plurality of donors)(abstract; Example 1-3; Tables 1-2; Fig. 1-3). Further, Henno et al teaches that NK expressing inhibitory receptors when the recipient doesn't express the corresponding HLA (absence of inhibitory signal = iKIR-HLA mismatch) lead to better tumor killing without leading to graft versus host disease (GvHD).” (page 2, para. 1).
Accordingly, it would have been obvious for a person of ordinary skill in the arts to choose a mixed NK cell as the immune cells because it could have been done with predictable results and a reasonable expectation of success. Further, Henno et al teaches that a Natural Killer (NK) cells are a fundamental component of the innate immune system (page 1, para. 2).
The co-pending ‘439 application does not explicitly teach removal of CD34-positive cells. However, as discussed above, the prior art of Yonemitsu et al teaches removing CD34-positive cells from the cell population of mononuclear cells including NK cells (para. 10, 22, 57-59, 109-113; Fig. 16-17; Example 5; claim 4 and 15). Therefore, a person of ordinary skill in the art would have been motivated to practice the method of Henno et al and remove the CD34-positive cells as taught by Yonemitsu with a reasonable expectation of success. A person of ordinary skill in the art would have been motivated to do so because CD34 positive cells are not natural killer (NK) cells. Methodologically, Henno et al and Yonemitsu et al both teaches that NK cells may be isolated and identified using flow cytometry (FACS) to obtain a specific cellular composition in the culture (Henno et al see pg 24 and 30, and Yonemitsu et al para. 22, 31, 33).Therefore, a person of ordinary skill in the art would also have been motivated to remove CD34 positive cells to create a pure population of NK cells and avoid contamination of other cell types.
As discussed above, as taught by Henno et al., which teaches a pharmaceutical composition according to claim 19, which is for treating an infectious disease and/or cancer (abstract, page 1, lns.5-8, page 17, ln. 29 to page 18, ln. 1, claim 20). A person of ordinary skill in the art would have been motivated to use the NK cells as the immune cells because Henno et al teaches that a Natural Killer (NK) cells are a fundamental component of the innate immune system (page 1, para. 2). Furthermore, because as taught by Henno et al., that a pharmaceutical composition comprising a population of pooled and activated and/or expanded cells, particularly NK cells, obtained or obtainable by the method (pg. 16, lns 17-20), it could have been done with predictable results and a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Response to Traversal:
Applicants respectfully submit that the rejection should likewise be withdrawn because the asserted factual premise is incorrect. Yonemitsu does not disclose a mixed plurality-donor mononuclear-cell population, and the reference instead reports separate donor experiments and averaged results. For at least the same reasons as above, the presently pending claims are patentably distinct from any claim construction that depends on the unsupported plurality-donor "pooling" theory (Remarks, page 6-7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Contrary to Applicants assertion, the prior art of Yonemitsu is not cited for the mixed plurality-donor population. Applicants are reminded that the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). In the instant case, the prior art of Henno is cited for teaching a method for producing a mixed (i.e. pooling) cell populations including natural killer (NK) cells from different donors (i.e. plurality of donors)(abstract; Example 1-3; Tables 1-2; Fig. 1-3).
Conclusion
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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