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
The claims filed on September 28, 2025, have been acknowledged. Claims 3-5 were cancelled. Claims 1-2 were amended. Claims 1-2 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from KR10-2019-0071257, filed on June 17, 2019, and PCT/KR2020/007660, filed on June 12, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received December 12, 2021, and translations, filed on March 27, 2025. Claims 1-2 find support in foreign application KR10-2019-0071257, filed on June 17, 2019.
Withdrawn Claim Objections
The prior objection to claim 1 is withdrawn because of the Applicant has amended the claims to recite a single nomenclature for a normal-person.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 1-2 and 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments to claim 1 to remove the broad-narrow language and the cancellation of claim 5.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Baxevanis et al. (British Journal of Cancer 76: 1072-1080. 1997), Fasbender et al. (Scientific Reports 8: 1-9. 2018), and United States Patent Application No. 2013/0295671 (Deng). This is a new rejection that is substantially similar to a previous rejection made in response to Applicant’s amendments to claim 1. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claim 1, the method of increasing natural killer cells positively recites culturing cancer patient PBMCs in a culture medium comprising a mixture of a first and second culture media. However, the method does not positively recite active method steps regarding the generation of the mixture of culture media as recited in claim 1, subclaims (i) and (ii). Therefore, the mixture of the first culture medium and the second culture medium are considered a product-by-process limitation and only the positively recited structures of the culture mixture are considered germane to the patentability of the method. The recited structures of the culture mixture are considered:
A culture media
CD3 antibody
CD16 antibody
CD56 antibody
As one of the initial culture solutions comprises CD16, the final mixed solution will comprise CD16. Therefore, although solution (ii) recites that the second culture solution does not comprise CD16 antibody, this is not considered to be a structural component of the mixed culture solution.
The recitation of a process limitation in claim 1 is not viewed as positively limiting the claimed culture mixture absent a showing that the process of making the culture mixture recited in claim 1 imparts a novel or unexpected property to the claimed culture mixture, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced culture mixtures. The method in which the culture mixture was produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product (i.e. the culture mixture) itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Baxevanis teaches that they collected supernatant from healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) and cultured cancer patients' PBMCs with the ACD3S supernatant. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer (abstract).
Baxevanis teaches that they generated the ACD3S media by culturing healthy donor PBMCs (2 x 106 cells ml) in 25-cm2 flasks (Costar, Cambridge, MA, USA), precoated with anti-CD3 MAb, in 5 ml of complete medium. After a 3- to 4-day incubation at 37°C with 5% carbon dioxide and 95% air, cultures were harvested and centrifuged. Supernatants from these cultures (ACD3S) were filter sterilized, aliquoted and stored at -80°C until use (page 1075, column 1, paragraph 3).
Baxevanis teaches that they cultured cancer patient derived PBMCs in 5 ml of complete medium supplemented with 25% ACD3S in 25-ml flasks (Costar) for 3 h (page 1075, column 2, paragraph 1 and Table 1). Baxevanis teaches that ACD3S contains no detectable levels of anti-CD3 (page 1076, column 1, paragraph 1).
Baxevanis teaches ACD3S enhanced NK cell mediated cytotoxicity (Abstract), ACD3S restores the deficient NK cytotoxicity in cancer patients (Fig. 2, Table 1).
Although Baxevanis teaches culturing cancer patient derived PBMCs in ACD3S media, Baxevanis does not teach wherein the culture media includes CD3, CD16, and CD56 antibodies.
However, Fasbender teaches that they examined the stimulation of NK cells using different antibodies, including CD16 and CD56 (abstract). Fasbender teaches that engagement of CD16 antibodies caused stimulation in freshly isolated and activated NK cells while engagement of CD56 antibodies only caused stimulation in activated NK cells (Figure 3 and page 3, paragraph 3-page 4, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of increasing NK cell mediated cytotoxicity by culturing cancer patient PBMCs with ACD3S PBMC supernatant from healthy donors of Baxevanis by including CD16 and CD56 during the culturing of the healthy donor PBMCs to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Fasbender teaches that engagement of CD16 antibodies caused stimulation in freshly isolated and activated NK cells while engagement of CD56 antibodies only caused stimulation in activated NK cells. As CD3, CD16, and CD56 were all known to activate PBMCs, it would have been obvious that one could include CD16 and CD56 in the media with CD3 to improve the stimulation of the PBMCs. Furthermore, MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Secondarily, Fasbender teaches that CD56 only had a stimulatory effect on activated NK cells and not freshly isolated cells. As such, in order for CD56 to have a stimulatory effect, it would have to be cultured with NK cells that had been activated (i.e. underwent at least one round of culturing). As such, CD56 stimulation would only occur in at least P1 PBMCs. Therefore, it would have been obvious to use at least P1 cells to generate PBMCs stimulated by CD3, CD16, and CD56. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding Baxevanis’s use of immobilized anti-CD3 for stimulating the healthy donor PBMCs and, thus, not including anti-CD3 in the ACD3S media, Deng teaches methods of applying stimulation to PBMCs that involve stimulation with anti-CD16 and anti-CD3 antibodies using soluble forms of the antibodies (paragraphs 0099-0120). Therefore, it would have been obvious to one of ordinary skill in the art that soluble anti-CD3 antibodies can also be used for stimulation of PBMCs. Furthermore, soluble anti-CD3 would have been a known alternative to the immobilized CD3 of Baxevanis that would have been readily envisioned by one of ordinary skill in the art for use in stimulating PBMCs. As a result of using soluble anti-CD3 antibodies, these antibodies would remain in the supernatant upon removal of the normal person PBMCs and during culture with the cancer patient PBMCs.
Furthermore, since Fasbender makes obvious that the cells must undergo a first passage to activate the cells (passage 1) and a second passage with CD3, CD16, and CD56 of the activated cells, the final culture solution would naturally include media from the second passage.
Therefore, the culture media of the combined teachings of Baxevanis, Fasbender, and Deng would have all of the positively recited structures of the culture mixture of claim 1.
Baxevanis teaches that ACD3S comprises high levels of IL-2 and IL-12 cytokines (Table 3).
Although Baxevanis teaches ACD3S enhanced NK cell mediated cytotoxicity, the combined teachings of Baxevanis and Fasbender do not teach wherein the culture media comprising CD3, CD16, and CD56 increased natural killer cell content of the PBMCs derived from a cancer patient.
However, Deng teaches methods of increasing NK cell content by culturing PMBC cells in a media comprising NK growth stimulating factors. Deng teaches that NK cell growth-stimulating factor refers to a factor directly or indirectly inducing the growth of NK cells. Examples of the factor indirectly inducing the growth include factors inducing the production and release of liquid factors such as cytokines through the binding to the Surface receptors (e.g. antibody bound receptors) of cells other than NK cells, such as monocytes. In this case, the growth of NK cells is indirectly induced by the released liquid factor (paragraph 0086). Deng directly identifies CD3 and CD16 antibodies and cytokines IL-2 and IL-12 as known NK cell growth stimulating factors (paragraph 0087), and that the PBMCs are cultured with the NK cell growth stimulations for 14 days (paragraphs 153-162).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of increasing NK cell mediated cytotoxicity by culturing cancer patient PBMCs with PBMC supernatant from healthy donors of Baxevanis, Fasbender, and Deng by extending the time period for culturing the cancer patient PBMCs with the supernatant to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Deng teaches that 14 days of stimulation led to a 500-fold increase in NK cell numbers. Furthermore, Deng teaches that NK cell growth-stimulating factors indirectly inducing the growth include factors inducing the production and release of liquid factors such as cytokines through the binding to the Surface receptors (e.g. antibody bound receptors) of cells other than NK cells, such as monocytes. In this case, the growth of NK cells is indirectly induced by the released liquid factor. Furthermore, Deng directly identifies cytokines IL-2 and IL-12 as known NK cell growth stimulating factors and Baxevanis teaches that ACD3S comprises high levels of IL-2 and IL-12 cytokines. As such, it would have been obvious that the supernatant media of the combined teachings of Baxevanis and Fasbender would include NK cell growth stimulating factors. Therefore the supernatant could be used to increase NK cell content during culture with cancer PBMCs. Furthermore, it would have been obvious to expand the NK cells as part of a culturing method to increase the number of cytotoxic NK cells that could be administered to a patient for treating their cancer.
Regarding the concentration of CD3 antibody, Deng teaches that as part of their PBMC stimulating method, 0.01 ng/mL to 1000 ng/mL (which equates to 0.000001%-0.1% w/v) anti-CD3 antibody can be included in the media for stimulating the PBMCs.
As this was a known quantity that could be used for stimulating PBMCs, it would have been obvious that
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of increasing natural killer cell content of the combined teachings of Baxevanis, Fasbender, and Deng by including a concentration of 0.025-0.05% (w/v) anti-CD3 antibody, as identified by Deng to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Deng teaches that 0.01 ng/mL to 1000 ng/mL (which equates to 0.000001%-0.1% w/v) anti-CD3 antibody can be used for stimulating PBMCs. As such, it would have been obvious that a concentration of 0.025-0.05% (w/v) anti-CD3 antibody could be used as it falls within the range identified by Deng. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 2, Baxevanis teaches that cancer patient PBMCs were collected from 120 men and 90 women ranging from 39 to 79 years of age with age with healthy donor PBMCs collected from age and sex-matched donors (page 1074, column 1, paragraph 1-column 2, paragraph 1). As such, at least one of the age matched donors was 39 years old, which is within the 16-40 year old normal person limitations of claim 2.
Response to Arguments
Applicant's arguments filed October 28, 2025, are acknowledged.
Applicant argues that Baxevarnis does not treat ACD3S with anti-CD16 or anti-CD56. Further, there is no mention or suggestion in Baxevarnis that the method described by Baxevarnis increases NK cell counts in cancer patients.
Fasbender contains no mention or suggestion of stimulation of NK cells with PBMC culture solution. Fasbender mentions that NK cell activation occurs when NK cells are stimulated with anti-CD16 and anti-CD56, but does not actually add anti-CD16 or anti-CD56. Furthermore, there is no disclosure in Fasbender of increased NK cell content in cancer patients, nor is there any indication of an effect on cancer-derived NK cells.
Deng contains no disclosure or suggestion of stimulation of NK cells with PBMC culture solution, but identifies CD3 and CD16 antibodies and IL-2 and IL-12 as NK cell growth stimulators and describes culturing of PBMCs for 14 days with NK cell growth stimulation. Deng teaches culturing PBMCs in a medium containing 1 ng/mL (0.0001%) of CD3 antibody, which is different and distinct from the applicant’s claimed method. Deng expands NK cells by culturing them in a medium that essentially contains CD16 antibody, OK432, and IL-2 in addition to CD3 antibody.
The applicant’s claimed invention correspondingly differs from the teachings and compositions of Baxevarnis, Fasbender, and Deng (page 5, paragraph 2-page 7, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection recited above is based on the combined teachings of Baxevanis, Fasbender, and Deng and does not require that each of these references anticipate the claimed invention. As stated supra, Baxevanis teaches the concept of culturing cancer patient PBMCs in conditioned media from healthy donor PBMCs that were incubated with stimulatory anti-CD3 antibodies. Fasbender teaches that CD16 and CD56 antibodies are also stimulatory towards PBMCs and could be combined with CD3 to improve the stimulatory effect. Deng provides teaches for using soluble CD3 instead of the immobilized CD3 of Baxevanis as soluble CD3 antibodies were also known to be stimulatory. Furthermore, Baxevanis teaches expanding NK cells by culturing them in a medium that contains CD16 antibody and CD3, as well as other known growth factors, such as IL-2 and IL-12. As stated supra, it would have been obvious to expand the NK cells as Baxevanis shows that their cancer patient PBMCs had improved NK cell cytotoxicity against cancer and expansion would increase the number of NK cells that could be transplanted to a patient for treatment.
As such, it would have been obvious to combine the methods of Baxevanis, Fasbender, and Deng to arrive at the instantly claimed invention.
Regarding Applicants’ arguments regarding increasing NK cell content in cancer patients, it is noted that these features are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997) (The court held that the PTO is not required, in the course of prosecution, to interpret claims in applications in the same manner as a court would interpret claims in an infringement suit. Rather, the “PTO applies to verbiage of the proposed claims the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in applicant’s specification.”). See MPEP 2111]
Claim 1 only requires an increase in NK cell content of the cancer patient PBMCs. Claim 1 does not require that this occur in cancer patients, as argued. Furthermore, it is unclear how the method of claim 1 could be used to increase NK cell content in a cancer patient as the method occurs in a culture dish and does not include administration to a patient.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KEENAN A BATES/Examiner, Art Unit 1631 /JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631