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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/26/2026 has been entered.
Claims 69-75, 77-82, and 103-111, of record 6/26/2026, are pending and subject to prosecution. Claims 69 and 82 are amended. Claims 105-111 are newly added.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claim 82 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Bitter et al. (US 20160362472 A1):
The amendment to claim 82 to require the cells to have altered expression of TGFβRII is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 69-73, 77-80, and 103-104 under 35 U.S.C. 103 over Bitter et al. (US 20160362472 A1) in view of Viel et al. (Science Signaling, 2016) and Busch et al. (Cancer Research, 2015):
RE: Rejection of claims 69-75, 77-80, and 103-104 under 35 U.S.C. 103 over Bitter et al. (US 20160362472 A1) in view of Viel et al. (Science Signaling, 2016) and Busch et al. (Cancer Research, 2015), further in view of Imamura et al. (Blood, 2014):
RE: Rejection of claims 69-74, 77-81, and 103-104 under 35 U.S.C. 103 over Bitter et al. (US 20160362472 A1) in view of Viel et al. (Science Signaling, 2016), further in view of Chen et al. (US 20180362975 A1) and Eddy et al. (Cellular Immunology, 2014):
The applicant asserts that:
The prior art combination does not teach or suggest all of the claimed limitations (Applicant Remarks, page 5-6).
One of ordinary skill would not be motivated to apply the teachings of Viel et al. on mice for engineering human NK cells for therapy in combination with azacitidine, and Viel et al. do not teach how to engineer human NK cells with altered TGFβRII expression or use them specifically in conjunction with azacitidine (Applicant Remarks, page 6-7).
Busch et al. teach away from the reduction of TGFβRII signaling in the context of chemotherapy by demonstrating that the reduction is associated with tamoxifen resistance and impaired drug-induced apoptosis and suggesting that TGFβRII knockdown my broadly impair cancer drug efficacy via upregulation of the ABCG2 multidrug resistance transporter (Applicant Remarks, page 7).
The combination of references requires impermissible hindsight reconstruction, as the references are from different fields (Applicant Remarks, page 7-8).
The applicant’s arguments have been considered but are not found wholly persuasive. As an initial matter, 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). Viel et al. need not teach human NK cells or administration with azacitidine for their findings (that inhibiting TGFβRII expression in NK cells promotes anti-tumor activity) to be relevant to the anti-cancer CAR cells (which can be NK cells and can be used with azacitidine) taught by Bitter et al. As the teachings of Bitter et al. and Viel et al. pertain to the use of engineered NK cells for the treatment of cancer, they constitute analogous, thus combinable, art. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). It is also noted that neither the instant claims nor the prior art require that the engineered NK cells be human.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Modification of the cells in the composition of Bitter et al. for a perceived benefit taught by Viel et al. would not have required improper hindsight reasoning in order to yield the claimed invention.
The applicant’s argument regarding the teachings of Busch et al., however, is found persuasive. The rejections of record are withdrawn.
New Objections/Rejections
Claim Objections
Claims 69, 74, 82, 109, and 111 are objected to because of the following informalities:
In line 2 of claim 69, line 1 of claim 82, line 1 of claim 109, and line 1 of claim 111, “engineered NK” should be inserted in front of “cells”.
in line 1 of claim 74, “engineered” should be inserted in front of “NK”.
Appropriate correction is required.
Claim Interpretation
Claim 82 recites the limitation “wherein the cells have altered expression of TGF-RII”. Because this limitation is not defined by the instant specification, the broadest reasonable interpretation of “altered expression” is considered to encompass any increase or decrease in TGFβ-RII expression, not necessarily resulting from engineering.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 108 and 110 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bitter et al. (US 20160362472 A1), of record.
Bitter et al. teach compositions and methods for treating diseases using CD19 CAR-expressing cells as a monotherapy or in combination therapy (See Abstract).
Regarding claims 108 and 110: Bitter et al. teach combination therapies with CAR-expressing cells for treating cancer and autoimmune or inflammatory diseases (See Abstract and ¶0071, 0364, and 0938). The CAR can target CD19 and can be expressed in a mammalian or human NK cell (which reads on “engineered NK cell”) (See ¶0006-0007, 0068, 0077, 0079, 0239, and 0920). Cell compositions can be administered in a therapeutically effective amount, either alone or in combination with other anti-cancer agents, such as azacitidine (See ¶0998-0999, 1114, and 1072).
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.
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 69-73, 77-80, 82, and 103-111 are rejected under 35 U.S.C. 103 as being unpatentable over Bitter et al. (US 20160362472 A1), of record, in view of Viel et al. (Science Signaling, 2016), of record, and Ray et al. (Cell Transplantation, 2000).
The teachings of Bitter et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 69-73, 77-80, 82, 103-107, 109, and 111: Following the discussion of claims 108 and 110, Bitter et al. teach combination therapies with anti-CD19 CAR-expressing cells for treating cancer and autoimmune or inflammatory diseases (which read on “an immune-related disorder”) (See Abstract and ¶0006-0007, 0071, 0364, and 0938). The cells can be NK cells (See ¶0068, 0077, and 0079). Cell compositions can be administered in a therapeutically effective amount, either alone or in combination with other anti-cancer agents, such as azacitidine (See ¶0998-0999, 1114, and 1072). Compositions can be formulated together as a combination therapeutic or administered separately (which reads on “in the same formulation” and “not in the same formulation”) and can be provided as a kit (See ¶1115-1116 and 1118). The cells can be edited to modulate expression of molecules that inhibit cell function, such as TGFRβ (See ¶0780-0781). Bitter et al. do not expressly teach alteration of TGFβRII expression.
Viel et al. teach that inhibition of TGFβ signaling enhances NK cell cytotoxic activity against tumors (See Abstract and fig. 2-3). TGFβRII was specifically deleted in NK cells in mice using Cre-loxP recombination (which reads on “engineered altered expression of TGFβ-RII”) without affecting NK cell distribution or maturation (See page 2, col. 2, ¶1 and page 11, col. 1, full ¶3).
Ray et al. review Cre-loxP recombination (See Abstract). The Cre-loxP system is simple and efficient for enabling cell- or tissue-specific editing, and loxP recognition sites for Cre recombinase can be easily introduced into target gene sequences in vitro (See Abstract and page 806, col. 2, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cells of Bitter et al. to comprise deletion of TGFβRII by Cre-loxP recombination. One would have been motivated to make this modification because Viel et al. teach that NK cell activity against tumor cells is enhanced by preventing TGFβRII expression (See Abstract and fig. 2-3) and because Bitter et al. teach that the cells can be edited to inhibit molecules such as TGFRβ that negatively regulate immune cell function (See ¶0780-0781). There would be a reasonable expectation of success in making this modification because Viel et al. demonstrate that NK cells in which TGFβRII is deleted with Cre-loxP can be generated in mice (See page 2, col. 2, ¶1 and page 11, col. 1, full ¶3) and because Ray et al. teach that Cre-loxP recombination can be easily applied for cell-specific gene editing in vitro (See Abstract and page 806, col. 2, full ¶1).
Claims 69-75, 77-80, 82, and 103-111 are rejected under 35 U.S.C. 103 as being unpatentable over Bitter et al. (US 20160362472 A1), of record, in view of Viel et al. (Science Signaling, 2016), of record, and Ray et al. (Cell Transplantation, 2000), further in view of Imamura et al. (Blood, 2014), of record.
The teachings of Bitter et al., Viel et al., and Ray et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 74-75: Following the discussion of claims 69-73, 77-80, 82, and 103-111, Bitter et al., modified by Viel et al. and Ray et al., render obvious a composition of TGFβRII-deleted CAR-NK cells that can comprise azacitidine but do not teach the cells as expressing a heterologous cytokine.
Imamura et al. teach increased growth and cytotoxicity in NK cells expressing membrane-bound IL-15 (which reads on “heterologous cytokine”) (See Abstract and fig. 1-3 and 5).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the composition of Bitter et al., modified by Viel et al. and Ray et al., to comprise mbIL-15 expression in the NK cells. One would be motivated to make this modification because Imamura et al. teach mbIL-15 as demonstrating increased survival and expansion as well as increased cytotoxicity against cancer cells (See Abstract and fig. 1-3 and 5). There would be a reasonable expectation of success in doing so because the cells of Bitter et al., modified by Viel et al. and Ray et al., could be readily modified to express mbIL-15.
Claims 69-73, 76-82, and 103-111 are rejected under 35 U.S.C. 103 as being unpatentable over Bitter et al. (US 20160362472 A1), of record, in view of Viel et al. (Science Signaling, 2016), of record, and Ray et al. (Cell Transplantation, 2000), further in view of Chen et al. (US 20180362975 A1), of record, and Eddy et al. (Cellular Immunology, 2014), of record.
The teachings of Bitter et al., Viel et al., and Ray et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 76 and 81: Following the discussion of claims 69-73, 77-80, 82, and 103-111, Bitter et al., modified by Viel et al. and Ray et al., render obvious a composition of TGFβRII-deleted CAR-NK cells that can comprise azacitidine but do not teach altered glucocorticoid receptor expression.
Chen et al. teach CRISPR-mediated knockout of genes such as NR3C1 (which reads on “modified to have altered expression of glucocorticoid receptor” and “essentially no expression of glucocorticoid receptor” (See ¶0005, 0021, 0557, and 0603). The edited cell can be an NK cell (See ¶0094, 0132, and 0382). The edited cell can be further engineered to express a CAR for use in treating a cancer or inflammatory disorder (See ¶1405).
Eddy et al. teach that glucocorticoid-induced signaling through the glucocorticoid receptor is associated with decreased NK cell cytotoxicity and increased production of proinflammatory cytokines (See fig. 1 and 4-5).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the composition of Bitter et al., modified by Viel et al. and Ray et al., to comprise NK cells having a NR3C1 gene deletion for the treatment of cancers or inflammatory disorders. One would be motivated to make this modification because Eddy et al. teach that signaling via glucocorticoid receptors is associated with decreased NK cell cytotoxicity and increased proinflammatory cytokine production (See fig. 1 and 4-5). There would be a reasonable expectation of success in doing so because Chen et al. teach that NR3C1 can be edited in NK cells using CRISPR (See ¶0005, 0021, 0094, 0132, 0382, 0557, and 0603).
Double Patenting: Warning
Applicant is advised that should claims 78-80 be found allowable, claims 105-107 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight change in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP 608.01(m).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE whose telephone number is (571)272-8590. The examiner can normally be reached M-F 8:30-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JENNIFER S SPENCE/Examiner, Art Unit 1633
Prosecution Insights