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 .
Claims 69-75, 77-82, and 103-104, of record 11/20/2025, are pending and subject to prosecution. Claims 69, 73, 75, and 81 are amended. Claim 76 is cancelled. Claims 103-104 are newly added.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 73 and 75:
The amendment to claims 73 and 75 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claim 81 under 35 U.S.C. 112(b):
The amendment to claim 81 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 69-73, 77-80, and 82 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Bitter et al. (US 20160362472 A1):
RE: Rejection of claims 69-75, 77-80, and 82 under 35 U.S.C. 103 over Bitter et al. (US 20160362472 A1) in view of Imamura et al. (Blood, 2014):
RE: Rejection of claims 69-73 and 76-82 under 35 U.S.C. 103 over Bitter et al. (US 20160362472 A1) in view of Chen et al. (US 20180362975 A1) and Eddy et al. (Cellular Immunology, 2014):
The cancellation of claim 76 renders the rejection thereto moot.
The applicant asserts that the prior art do not teach or suggest a composition comprising engineered NK cells having altered expression of TGFβ-RII and azacitidine, as required by the amended claims (Applicant Remarks, page 4-5).
The amendment to independent claim 69 to require altered expression of TGFβ -RII is effective to obviate the rejections over claims 69-75 and 76-81 over the base reference of Bitter et al., with and without secondary references. Therefore, all 102 and 103 rejections over claims 69-75 and 76-81 are withdrawn.
The 102 rejection over claim 82, which does not require the amended limitation, is maintained.
New/Maintained Rejections
Claim Interpretation
Claim 69 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.
Claim 82 is 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 claim 82: 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 an NK cell (which reads on “engineered NK cell”) (See ¶0006-0007, 0068, 0077, 0079, and 0239). 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 and can be provided as a kit (See ¶1115-1116 and 1118).
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, and 103-104 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) and Busch et al. (Cancer Research, 2015).
Regarding claims 69-73, 77-80, and 103-104: 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”) (See ¶1115-1116). Inhibitory nucleic acids, including shRNA and CRISPR, can be used to modulate expression of molecules within the CAR-expressing cells 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 deletion of TGFβRII in mice enhances NK cell cytotoxic activity against tumors (See Abstract and fig. 2-3).
Busch et al. teach the knockdown of TGFβRII expression in cancer cells using shRNAs (See page 1458, col. 2, full ¶3).
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 shRNA depletion of TGFβRII. 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). There would be a reasonable expectation of success in doing so because Bitter et al. teach that the TGFβ expression in the CAR-expressing cells can modulated by inhibitory nucleic acids (See ¶0780-0781β) and because Busch et al. teach that TGFβRII expression can be inhibited by shRNA (See page 1458, col. 2, full ¶3).
Claims 69-75, 77-80, and 103-104 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) and Busch et al. (Cancer Research, 2015), further in view of Imamura et al. (Blood, 2014), of record.
The teachings of Bitter et al., Viel et al., and Busch 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, and 103-104, Bitter et al., modified by Viel et al. and Busch et al., render obvious a composition of CAR-NK cells having reduced TGFβRII expression 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 Busch 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 Busch et al., could be readily modified to express mbIL-15.
Claims 69-74, 77-81, and 103-104 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), 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 Busch 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, and 103-104, Bitter et al., modified by Viel et al. and Busch et al., render obvious a composition of CAR-NK cells having reduced TGFβRII expression that can comprise azacitidine but do not teach altered glucocorticoid receptor expression.
Chen et al. teach CRISPR-mediated knockout of genes encoding 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 Busch 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).
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.
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.
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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.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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