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 .
Status of the Claims
Claims 1-8, 10-14, 16-17, and 19-22 are currently pending.
Claims 1-3, 7-8, 10-11, 19, and 22 are amended.
Claims 9, 15, and 18 remain cancelled.
Claims 1-8, 10-14, 16-17, and 19-22 have been considered on the merits.
Withdrawn Rejections
The 112(a) new matter rejection onto claims 1-8, 10-14, 16-17, and 19-22 is withdrawn in light of the amendments submitted on 09/08/2025.
The 112(b) rejection made onto claims 1-8, 10-14, 16-17, and 19-22 is withdrawn in light of the amendments submitted on 09/08/2025.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
Claims 1-4, 8, 10-14, 16, and 19-21 remain rejected under 35 U.S.C. 103 as being unpatentable over Min et al. (US9834753), referred to as Min, as evidenced by Carelide (Hartmann’s solution Package Leaflet), in view of Klingemann et al. (Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells, Mar 2016), referred to as Klingemann, all of which are references of record.
Regarding claim 1, Min teaches a method for harvesting NK cells from cell culture (column 12, line 58) and washing and resuspending in 1-5% albumin in Hartmann’s buffer (column 8, line 11-12). Min also teaches that the cytotoxicity and viability of the NK cells are maintained at substantially the same levels as cells which have not been harvested, using the Hartmann’s solution with 0.5%, 1%, and 2% albumin (Figure 5A and 5B). Min teaches the albumin used in the buffer is human albumin, or human serum derived albumin (column 12, line 61), or human plasma derived albumin as required by claim 1. Further, Min teaches that the NK cells may be administered to a patient in need of treatment (column 8, lines 3-5), which meets the limitations of the NK-92 cells being “ready to be infused to the human patient”. Although, Min does not explicitly state that the patient can be human, one of ordinary skill in the art would readily understand from the disclosure of Min that the cells intended for clinical use are intended for the use in a human patient (Background art section and Col. 3 lines 48-62). Min meets the limitations of the 1-10 mg/ml sodium buffer because the claims recite characteristics of Hartmann’s solution which was used as the buffer as evidenced by Carelide. Carelide teaches that the Hartmann’s solution contains 6g of sodium chloride per liter of solution. By converting 6 g/L NaCl to mg/ml (6 g/L * 1000mg/g * 0.001 ml/L) the concentration of the solution is 6 mg/ml. Further, Carelide teaches that the components of the Hartmann’s solution are sodium, chloride, potassium chloride, calcium chloride dihydrate and sodium lactate 60% in water (pg. 1, column 1, lines 9-10). Therefore, Min also meets the limitation of the buffer lacking sugar (as required by claim 1). Regarding claim 2, Min teaches the method for harvesting the cells is through centrifugation (column 12, line 58). Min teaches the method for harvesting by placing cells in an infusion bag as required by claim 3 (column 12, line 66-67). Min teaches the method of washing the cells is performed through centrifugation and resuspension in wash buffer as required by claim 4 (column 12, lines 58-59). With regards to claim 8, Min teaches that the viability of the harvested cells is at least 90% (column 13, lines 7-8). Min teaches that the cytotoxicity and viability of the NK cells are maintained at substantially the same levels as cells which have not been harvested, using the Hartmann’s solution with 0.5%, 1%, and 2% albumin as required by claim 10 (Figure 5A and 5B). Min teaches that the harvested cells have a cytotoxicity of 80-100% on K562 cells as required by claim 11 (column 11, lines 27-28). Min teaches that the buffer contains 2-5% albumin as required by claim 12-14 (column 8, line 11-12). Min teaches that the buffer lacks dextran as required by claim 16 (column 14, line 27-35). Although Min cites use of human serum albumin, one skilled in the art would understand that human albumin, whether derived from serum or plasma is functionally the same. Min teaches that the cells washed with the disclosed method are capable of expressing a cytokine as required by claim 19 (column 19-20, lines 67-2).
Min teaches this method using primary NK cells and does not teach the method using NK-92 cells as required by claim 1.
However, Klingemann teaches that primary NK cells differ from NK-92 cells due to the technical challenges that accompany obtaining the cells from a patient’s blood (abstract, lines 2-4). Klingemann explains that of 6 NK cell lines, only NK-92 cells have been able to reproducibly show cytotoxicity, as primary NK cells do. Further, Klingemann teaches that CAR-modified NK-92 cells have been shown to eliminate lymphoma using a CD19-CAR (as required by claims 19-21; pg. 3, column 1, lines 11-12). Therefore, it would be obvious to someone of ordinary skill in the art at the time of the effective filing date of the claimed invention to apply the method of washing and harvesting primary NK cells found in Min to the NK-92 cell line for ease of technical burden. The motivation to combine Min with Klingemann would be the technical ease of using NK-92 cells rather than obtaining primary NK cells from a patient’s blood (abstract, lines 2-4). One of ordinary skill in the art would have a reasonable expectation of success when combining Min with Klingemann because Klingemann teaches that only NK-92 cells have been able to show reproducible cytotoxicity seen in primary NK cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Min (US9834753), as evidenced by Carelide (Hartmann’s solution Package Leaflet) in view of Klingemann et al. (Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells, Mar 2016), referred to as Klingemann, as applied to claims 1-4, 8, 10-14, 16, and 19-21 above, in further view of Bedner et al. (Laser scanning cytometry distinguishes lymphocytes, monocytes, and granulocytes by differences in their chromatin structure, Dec 1998), referred to as Bedner, all of which are references of record unless otherwise stated.
Regarding claims 5 and 6, Min in view of Klingemann teaches the limitations of the independent claim above.
Min and Klingemann does not teach that the wash step is performed at least 3 times as required by claims 5 and 6.
Bedner teaches repeated centrifugation steps up to 7 times (as required by claim 5 and 6; pg. 195, table 1 description lines 1-2) using PBS or PBS supplemented with FBS. Further, Bedner teaches that suspending cells in the salt solution containing either serum or serum albumin lowers the degree of cell loss (pg. 196, column 1, lines 12-14). Bedner compares the effect of repeated centrifugation using lymphocytes, monocytes, and granulocytes.
It would be obvious for one of ordinary skill in the art at the time of the effective filling date of the claimed invention to apply multiple washing steps seen in Bedner to the harvesting method taught by Min and Klingemann. The motivation to combine would be because Bedner teaches that suspending cells in the salt solution containing either serum or serum albumin lowers the degree of cell loss (pg. 196, column 1, lines 12-14). One of ordinary skill in the art would have a reasonable expectation of success when combining because the lymphocyte population, which includes NK cells, saw the least amount of cell loss after multiple centrifugations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Koepsell et al (Transfusion, 2013, “Successful “in-flight” activation of natural killer cells during long-distance shipping”, new reference), Min (US9834753), as evidenced by Carelide (Hartmann’s solution Package Leaflet) in view of Klingemann et al. (Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells, Mar 2016), referred to as Klingemann, as applied to claims 1-4, 8, 10-14, 16, and 19-21 above, in further view of Jong et aI. (Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells, Feb 2017), referred to as Jong, all of which are references of record unless otherwise stated.
Regarding claim 17, Min in view of Klingemann teaches the limitations of the independent claim above.
Min in view of Klingemann does not teach that the wash steps performed in claim 4 are done by continuous centrifugation, which is defined in the specification to be centrifugation times between 45-60 min ([0 0 40]).
However, Jong et al. teaches centrifugation times of 3 hours on NK cells.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filling date of the claimed invention that centrifugation of 45-60 min can be performed on NK cells since Jong et al. are capable of centrifuging for 3 hours with the same cell type. Such modifications of the teaching of Min in view of Klingemann and further in view of Jong is within the ordinary artisan's capabilities and would not negatively alter or modify results of harvesting the cultured cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Min (US9834753), as evidenced by Carelide (Hartmann’s solution Package Leaflet) in view of Klingemann et al. (Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells, Mar 2016), referred to as Klingemann, and Bedner et al. (Laser scanning cytometry distinguishes lymphocytes, monocytes, and granulocytes by differences in their chromatin structure, Dec 1998), referred to as Bedner, all of which are references of record.
Regarding claim 22, Min teaches a method for harvesting NK cells from cell culture (column 12, line 58) and washing and resuspending in 1-5% albumin in Hartmann’s buffer as required by claim 22 (column 8, line 11-12). Min also teaches that the cytotoxicity and viability of the NK cells are maintained at substantially the same levels as cells which have not been harvested, using the Hartmann’s solution with 0.5%, 1%, and 2% albumin as required by claim 22 (Figure 5A and 5B). Min teaches the albumin used in the buffer is human albumin, or human serum derived albumin (column 12, line 61), or human plasma derived albumin as required by claim 22. Further, Min teaches that the NK cells may be administered to a patient in need of treatment (column 8, lines 3-5), which meets the limitations of the NK-92 cells being “ready to be infused to the human patient”. Although, Min does not explicitly state that the patient can be human, one of ordinary skill in the art would readily understand from the disclosure of Min that the cells intended for clinical use are intended for the use in a human patient as required by claim 22 (Background art section and Col. 3 lines 48-62).
Min meets the limitations of the 1-10 mg/ml sodium buffer because the claims recite characteristics of Hartmann’s solution which was used as the buffer as evidenced by Carelide. Carelide teaches that the Hartmann’s solution contains 6g of sodium chloride per liter of solution. By converting 6 g/L NaCl to mg/ml (6 g/L * 1000mg/g * 0.001 ml/L) the concentration of the solution is 6 mg/ml as required by claim 22. Further, Carelide teaches that the components of the Hartmann’s solution are sodium, chloride, potassium chloride, calcium chloride dihydrate and sodium lactate 60% in water (pg. 1, column 1, lines 9-10). Therefore, Min also teaches that the buffer lacking sugar.
Min in view of Klingemann does not teach that the wash step is performed at least 3 times as required by claim 22.
Bedner teaches repeated centrifugation steps up to 7 times as required by claim 22 (pg. 195, table 1 description lines 1-2) using PBS or PBS supplemented with FBS. Further, Bedner teaches that suspending cells in the salt solution containing either serum or serum albumin lowers the degree of cell loss (pg. 196, column 1, lines 12-14). Bedner compares the effect of repeated centrifugation using lymphocytes, monocytes, and granulocytes.
It would be obvious for one of ordinary skill in the art at the time of the effective filling date of the claimed invention to apply multiple washing steps seen in Bedner to the harvesting method taught by Min and Klingemann. The motivation to combine would be because Bedner teaches that suspending cells in the salt solution containing either serum or serum albumin lowers the degree of cell loss (pg. 196, column 1, lines 12-14). One of ordinary skill in the art would have a reasonable expectation of success when combining because the lymphocyte population, which includes NK cells, saw the least amount of cell loss after multiple centrifugations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 09/08/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 6, para 3-4) that claim 1 requires “that a single step of cell resuspension in a wash buffer is applied to the immortalized (NK-92) cells” and that the cells produced are “ready to be infused into human patients”.
This argument is not found persuasive. Claim 1 uses the language “A method of harvesting cells from an immortalized non-Hodgkin’s lymphoma derived cytolytic cancer cell line (CRL-2407) for infusion into a human patient comprising…”. This claim language is open-ended and does not require the only step performed to be “a single step of cell resuspension in a wash buffer” as implied. Therefore, the argument is not found to be persuasive.
Applicant argues (Remarks, pg. 6-7, last para of pg. 6 spanning para 3 of pg. 7) that “Klingemann discloses that NK-92 cells can be infused into patients, but does not disclose the specific method steps and wash buffer recited in amended claim 1 for producing those cells for that specific purpose”. That “Nowhere in Koepsell is there any disclosure on successfully administering those cells to patients after the cells were prepared as disclosed”. Additionally, that “Min specifically teaches that primary NK cells may be administered to patients, by Min, like Koepsell, provides no evidence that this was successfully performed”. Therefore, Applicant concludes that based on the data of Min, which Applicant admits demonstrates successful outcomes in animal models, “one of ordinary skill would not assume that Min’s methods would produce cells that are safe and ready for infusion to human patients”.
This argument is not found persuasive. As an initial matter, Koepsell is no longer required nor relied upon in the rejections presented above, based on the amendments made onto claim 1.
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 claim limitation of “ready to be infused into the human patient” does not required that the cells are actively administered into a human patient, only that at the end of the method steps the cells are theoretically capable of being infused into a human patient. Additionally, the limitation does not require that the cells are tested and proven safe to administer to a human patient, only that the cells must be capable of being infused into a human patient. Therefore, the limitation of “ready to be infused into a human patient” only requires that the cells be capable of administration into a human patient. As previously presented in the main 103 rejection above, “Further, Min teaches that the NK cells may be administered to a patient in need of treatment (column 8, lines 3-5), which meets the limitations of the NK-92 cells being “ready to be infused to the human patient”. Although, Min does not explicitly state that the patient can be human, one of ordinary skill in the art would readily understand from the disclosure of Min that the cells intended for clinical use are intended for the use in a human patient (Background art section and Col. 3 lines 48-62).” Additionally, Applicant states in the Remarks that both Min and Klingemann disclose that the cells are able to infused into human patients.
Therefore, the arguments are not found persuasive.
Applicant argues (Remarks, pg. 7, para 3 spanning para 1 of pg. 8) that Bedner nor Jong teach or suggest the method of amended claim 1 nor remedy the alleged deficiencies of Min and Klingemann.
This is not found persuasive for the reasons detailed at point 15 above.
Applicant argues (Remarks, pg. 8, para 2 spanning pg. 10) that the invention is nonobvious over the cited art based on public disclosures including clinical trials. Applicant states that cells made according to the claimed methods have been used in clinical trials and that the clinical trial approval is a rigorous process. Additionally, Applicant states “the lack of evidence in Koepsell, Min, Klingemann, Bedner, and Jong for using a specific method to produce cells that were directly infused to humans illustrates the failure of others in the field to produce a cell-based therapy for safe and direct administration to humans using a simple harvesting method”.
In response to applicant's argument that the cells of the instant invention are safe to be infused into a patient, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Therefore, the argument is not found persuasive.
Response to Declaration Under 37 C.F.R. § 1.132 of Syed Raza Ali, PH.D.
The declaration under 37 C.F.R. § 1.132 filled 09/08/2025 is insufficient to overcome the rejection of the claims based upon 35 U.S.C. 103 as set forth in the last office action because:
Dr. Ali explains in the declaration at paragraph 5 that the cited art does not disclose any clinical trials or human safety data as evidence that NK cells (whether the cells are from the NK-92 cell line or primary cells) prepared according to any specific method were directly infused to human patients. Firstly, as previously stated in the response to arguments above, the claim limitation of “ready to be infused into the human patient” does not required that the cells are actively administered into a human patient, only that at the end of the method steps the cells are theoretically capable of being infused into a human patient. Additionally, Applicant states in the Remarks that both Min and Klingemann disclose that the cells are able to infused into human patients. In fact, Klingemann explicitly teaches about active clinical trials employing NK-92 cells. Klingemann teaches “Four phase I trials in three different countries (US, Canada, and Germany) for different malignancies have been conducted with NK-92. All patients had treatment-resistant advanced cancer… Except for some mild fever reactions in the occasional patient, the infusions were well tolerated” (pg. 3 , col. 2, para 1).
In reference to Klingemann, Dr Ali explains at paragraph 6 that “Klingemann does not disclose how to prepare NK-92 cells for direct human infusion”. However, given that Min teaches the preparation method that maintains the cells cytotoxicity and their ability to be infused into a patient, and Klingemann teaches that NK-92 cells have been proven generally safe for use in humans through various clinical trials; the use of these cells for safe infusion to a patient is rendered obvious and expected by the art.
Dr. Ali explains the various clinical trials that the cells harvested by the method of claim 1 have been employed in throughout paragraphs 7-10, Dr, Ali concludes that these clinical trials demonstrate that without testing in human patients, one of ordinary skill in the art cannot predict whether any cell therapy can be administered to humans without causing undesirable adverse effects. However, given that Min teaches the preparation method that maintains the cells cytotoxicity and their ability to be infused into a patient, and Klingemann teaches that NK-92 cells have been proven generally safe for use in humans through various clinical trials; the use of these cells for safe infusion to a patient is rendered obvious and expected by the art.
Conclusion
No claims are allowed.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632