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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 24, 2026 has been entered.
Applicants previously canceled claims 4-10, 12-13, 15, 17-21, 23, 26-31, 33-41, 43, 45-47, 50-52, 54-56, and 59-78, and now cancel claims 48-49. Applicants amend claims 1, 16, and 53. Claims 1-3, 11, 14, 16, 22, 24-25, 32, 42, 44, 53, and 57-58 are pending in this application, and are under examination.
Any objection or rejection of record in the previous Office and Advisory Actions, mailed April 9, 2026 and June 24, 2026, respectively, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Information Disclosure Statement
The Information Disclosure Statement filed September 24, 2026 has been considered.
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.
Claim Objections
Claim 1 is objected to because of the following informalities:
At claim 1, line 1, “ex vivo” should be italicized.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 11, 14, 16, 22, 24-25, 32, 42, 44, 53, and 57-58 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ang et al. (U.S. Patent Application Publication No. 2020/0390815, published December 17, 2020, filed August 18, 2020, and claiming priority to PCT Patent Application No. PCT/US2019/018989 and U.S. Provisional Patent Application No. 62/633,587, filed February 21, 2019 and February 21, 2018, respectively, and cited in the Information Disclosure Statement filed December 30, 2024 as U.S. Patent Application No. 16/970,930) in view of Shah et al. (8(10) PLOS One e76781, 1-9 (2013), and cited in the Information Disclosure Statement filed May 26, 2021) and Kaur et al. (19 Cytotherapy 433-439 (2017)). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claim 1, Ang discloses a method of expanding natural killer (NK) cells by stimulating mononuclear cells from cord blood in the presence of antigen presenting cells (APCs) and IL-2 (paragraphs [0010]-[0011]). Ang discloses re-stimulation of the cells with APCs (paragraph [0012]). Ang discloses universal antigen presenting cells (uAPCs) (paragraph [0006]). Ang discloses that the uAPCs express CS1, CD48, membrane bound IL-21, and 41BB ligand (paragraph [0006]).
Regarding claim 2, Ang discloses depletion of CD3 positive cells (paragraph [0081]).
Regarding claim 3, Ang discloses that the depletion takes place between the first stimulation and the re-stimulation (paragraphs [0081] and [0109]).
Regarding claim 5, Ang discloses that the cord blood is thawed out in the presence of Ficoll® (paragraph [0109]).
Regarding claim 11, while Ang discloses that in some embodiments IL-2 is replenished, Ang also discloses that nothing is added or removed during the initial stimulation (paragraphs [0010]-[0011).
Regarding claim 16, Ang discloses that the APCs express membrane-bound IL-21 (mbIL-21), IL-21, IL-15, IL-7, IL-18, and or IL-2 (paragraph [0006]).
Regarding claim 22, Ang discloses that the stimulation takes place over 6 – 8 days. (paragraphs [0082]-[0083]).
Regarding claim 24, Ang discloses that the cells are not split during the stimulation (paragraphs [0010]-[0011]).
Regarding claim 25, Ang discloses that the cells are fed twice with IL-2 (paragraph [0011]).
Regarding claim 32, Ang discloses that the method takes less than 15 days to perform (paragraphs [0082]-[0083]).
Regarding claim 42, Ang discloses that the cord blood is frozen cord blood (paragraph [0109]).
Regarding claim 44, Ang discloses that the cord blood is pooled cord blood (paragraph [0013]).
Regarding claim 53, Ang discloses that the uAPCs do not express HLA class I, II or CD1d (paragraph [0007]). Ang discloses that that the uAPCs express ICAM-1 (CD54) and LFA-3 (CD58) and are leukemia cell-derived uAPCs (paragraph [0007]).
Regarding claim 57, Ang discloses cryopreservation of the expanded NK cells (paragraph [0083]).
Regarding claim 58, Ang discloses a pharmaceutical composition comprising the expanded immune cells and a pharmaceutically acceptable carrier (paragraph [0018]).
Ang fails to disclose or suggest that the method of expanding NK cells is performed in a bioreactor using good manufacturing practice (GMP). Ang fails to disclose or suggest amount of media used in the first stimulation. Ang fails to disclose or suggest that the starting population is thawed in the presence of dextran, human serum albumin, DNAse and magnesium chloride.
Shah discloses ex vivo expansion of NK cells (abstract and Figure 1). Shah discloses that cryopreserved cord blood is used to expand NK cells in the presences of antigen presenting cells and IL-2 (abstract). Shah discloses a first stimulation, depletion of CD3 cells, and a second stimulation (abstract and page 2, column 2, first full paragraph). Shah discloses that the expansion of the NK cells is performed under GMP compliant method (page 2, column 1, second full paragraph). Shah discloses that the expansion is performed in a bioreactor (page 2, column 2, first full paragraph). Shah discloses that the expanded NK cells show significant in vivo activity against multiple myeloma and provide a clinically acceptable strategy for treating and eradicating multiple myeloma (abstract).
Kaur discloses that umbilical cord blood is a source of hematopoietic stem cells, which can be expanded, along with natural killer (NK) cells (abstract). Kaur discloses that the cord blood can by cryopreserved cord blood (abstract and paragraph bridging pages 433 and 434). Kaur discloses thawing the cord blood and contacting the thawed cord blood with dextran, human serum albumin, DNAse, and magnesium chloride (page 434, paragraph bridging columns 1 and 2). Kaur discloses that the magnesium chloride prevents the cells from clumping (page 434, paragraph bridging columns 1 and 2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Shah’s GMP-compliant protocol to expand NK cells in a bioreactor in the presence of Kaur’s dextran, HSA, DNAse, and magnesium chloride using the protocol of Ang and Shah because this provides a method of obtaining clinically useful NK cells that can be used to treat multiple myeloma, without the cells clumping, which provides for better expansion of the NK cells. One of ordinary skill in the art would be motivated to perform Ang’s NK expansion method in Shahs’ bioreactor using GMP-compliant protocols and in the presence of Kaur’s dextran, HSA, DNAse, and magnesium chloride, to obtain an in vivo treatment of multiple myeloma.
Further, it would have been obvious to one with ordinary skill in the art to increase the amount of media in the protocol of Ang, Shah, and Kaur to a desired level, such as 3-5 L, because using Shah’s bioreactor allows for a greater amount of NK cells to be expanded, which is desirable in light of the intended use of treating a disease, such as multiple myeloma. It would have been well within the purview of one ordinarily skilled in the art to increase the amount of media used in Shah’s bioreactor in order to obtain the amount of expanded NK cells necessary for treatment of cancers, such as multiple myeloma.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 25, 42, 44, and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 15, 20,22-23, 25, 27-30, and 41 of copending Application No. 19/734,174 in view of Shah et al. (8(10) PLOS One e76781, 1-9 (2013), and cited in the Information Disclosure Statement filed May 26, 2021) and Kaur et al. (19 Cytotherapy 433-439 (2017)).
Regarding claim 1, the ‘174 application claims a method of expanding immune cells comprising culturing the cells in an effective amount of universal antigen presenting cells (UAPCs) (claim 12). The ‘174 application claims that the UAPCs are engineered to express CD48 and/or CS1 (CD319), membrane-bound interleuking-21, and 41BB ligand (claim 1). The ‘174 application claims that the immune cells are NK cells (claims 22-23). The ‘174 application claims that the expanding is in the presence of IL-1 (claim 15). The ‘174 application claims that the immune cells are derived from cord blood (claims 25 and 27). The ’174 application claims that the NK cells are cord blood mononuclear cells (claim 30). Regarding claim 25, the ‘174 application claims that the IL-2 is replenished every 2-3 days, which is interpreted as being fed twice (claim 20).
Regarding claim 44, the ‘174 application claims that the cord blood is pooled cord blood (claims 28-29).
Regarding claim 58, the ‘174 application claims a pharmaceutical composition comprising a population of NK cells (claim 41).
The ’174 application does not claim that the method is performed in a bioreactor or that the cord blood is frozen and thawed in the presence of dextran, human serum albumin (HSA), DNAse, and magnesium chloride. The ‘174 application does not claim that cells positive for CD3 are depleted.
Shah discloses ex vivo expansion of NK cells (abstract and Figure 1). Shah discloses that cryopreserved cord blood is used to expand NK cells in the presences of antigen presenting cells and IL-2 (abstract). Shah discloses a first stimulation, depletion of CD3 cells, and a second stimulation (abstract and page 2, column 2, first full paragraph). Shah discloses that the expansion of the NK cells is performed under GMP compliant method (page 2, column 1, second full paragraph). Shah discloses that the expansion is performed in a bioreactor (page 2, column 2, first full paragraph). Shah discloses that the expanded NK cells show significant in vivo activity against multiple myeloma and provide a clinically acceptable strategy for treating and eradicating multiple myeloma (abstract).
Kaur discloses that umbilical cord blood is a source of hematopoietic stem cells, which can be expanded, along with natural killer (NK) cells (abstract). Kaur discloses that the cord blood can by cryopreserved cord blood (abstract and paragraph bridging pages 433 and 434). Kaur discloses thawing the cord blood and contacting the thawed cord blood with dextran, human serum albumin, DNAse, and magnesium chloride (page 434, paragraph bridging columns 1 and 2). Kaur discloses that the magnesium chloride prevents the cells from clumping (page 434, paragraph bridging columns 1 and 2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Shah’s GMP-compliant protocol to expand NK cells in a bioreactor in the presence of Kaur’s dextran, HSA, DNAse, and magnesium chloride using the protocol of the ‘174 application and Shah because this provides a method of obtaining clinically useful NK cells that can be used to treat multiple myeloma, without the cells clumping, which provides for better expansion of the NK cells. One of ordinary skill in the art would be motivated to perform the ‘174 application’s NK expansion method in Shahs’ bioreactor using GMP-compliant protocols and in the presence of Kaur’s dextran, HSA, DNAse, and magnesium chloride, to obtain an in vivo treatment of multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
Response to Amendments and Arguments
Regarding the rejection under 35 U.S.C. § 103, Applicants’ arguments have been fully considered, but are not deemed to be persuasive.
Applicants assert that the cited references to do not render the instant invention obvious because the references in combination do not teach or suggest the claimed invention. Specifically, applicants assert that Ang and Shah are directed to NK cell manufacture and immunotherapy and Kaur discloses both manual and automated methods of enriching MNCs from frozen cord blood. Applicants assert that this specific combination of media components is not obvious over the cited prior art.
To begin, while Applicants state that they are not attacking each reference individually in order to provide context for why the combination of references do not render the invention obvious, Applicants go on to discuss each specific reference and what is taught, or not taught by each one. However, as discussed previously one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, the combination of references would lead one of ordinary skill in the art directly to the claimed invention. As noted by Applicants, both Ang and Shah are directed to expansion of NK cells for immunotherapy. Applicants assertion that Shah's use of a bioreactor can introduce variables due to introduction of thaw reagents, which would not be predictable. Applicants assertions that Kaur would prefer the Sepax method of obtaining cells including NK cells rather than a manual method that thaws cord blood in the presence of dextran, HSA, DNAse, and magnesium chloride. However, as discussed above and previously, Ang and Shah disclose and suggest methods of NK expansion from cord blood mononuclear cells using stimulation of the MNCs in the presence of antigen presenting cells and IL-2. Shah further disclose use of a bioreactor for the production of NK cells.
Regarding Kaur, while Applicants are correct in noting that Kaur proposes that the Sepex method of MNC enrichment, Kaur also compares the Sepex method to the manual method of thawing MNCs from cord blood using a protocol that requires the use of Dextran, HSA, DNAse, and magnesium chloride. Regarding Applicants' assertion that the thaw components of Kaur would potentially interfere with bioreactor production of NK cells, it is noted that the dextran, DNAse, and magnesium chloride of Kaur is removed prior to final production of the enriched cell product, with the cell pellet finally resuspended in DPSB-HSA (see page 434, paragraph bridging columns 1 and 2). In addition, Kaur notes that, while recovery of NK cells was greater using Sepax, there was no difference in viability between the two methods. Kaur also notes that the manual method was superior in reducing the hematocrit. And Kaur notes that one of the most improvements with the Sepax method was reduction in processing time (see pages 435-437). Kaur's Sepex method, while having a higher recovery and reduced production time, also notes that the manual method has advantages as well. Therefore, one of ordinary skill in the art would naturally refer to Kaur for thawing protocols, and note that the manual method using dextran, HSA, DNAse, and magnesium chloride is a well-known and viable method for use in a method of NK expansion, as disclosed by Ang and Shah.
Applicants further assert that there is no motivation to combine the references because they address different technical problems, that combining the reference requires hindsight, and that there is allegedly no expectation of success. However, while the references might address different technical issues, each reference does relate to production of NK cells, which can be prepared from frozen cord blood. Each reference provides disclosure to different parts of the method of expanding NK cells, and thus, one of ordinary skill in the art would naturally look to each of these references. Each of the references, taken together and as a whole provide the motivation to combine in order to provide a method of expanding NK cells for use in a variety of methods, including therapeutic uses.
Regarding the use of hindsight, it is noted that "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Regarding Applicants’ assertion that there is no expectation of success, it is noted that Applicants have not yet provided any objective factually-supported evidence that the cited combination of prior art references would not lead one of ordinary skill in the art directly to the claimed invention. Applicants have provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
For all these reasons, and those noted previously, the combination of Ang, Shah, and Kaur is deemed to render the instant invention obvious.
Regarding the non-statutory double patenting rejection over U.S. Patent Application No. 16/970,930, this application issued as U.S. Patent No. 12,734,239 on September 15, 2026. Applicants have filed a Terminal Disclaimer over the ‘239 patent, which has been approved. Therefore, this rejection is withdrawn.
However, a new non-statutory double patenting rejection over U.S. Patent Application No. 17/734,174 in view of Shah and Kaur is set forth above.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Each of U.S. Patent Application Publication Nos. 2020/0390816 (U.S. Patent Application No. 16/970,937); 2021/0230548 (U.S. Patent Application No: 17/050,775); 2022/0118013 (U.S. Patent Application No. 17/304,585); and 2022/0265718 (U.S. Patent Application No. 17/661,057) are assigned to the Board of Regents, The University of Texas System, have overlapping inventive entities, and are deemed to have cumulative disclosures, as compared with U.S. Patent Application Publication No. 2020/0390815, which is cited above. Each of the ‘816, ‘548, ‘013, and ‘718 publications are cited in the Information Disclosure Statements filed July 19, 2023 and/or December 30, 2024 (by application number).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
