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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 5, 2026 has been entered.
Claim Status
Claims 1 and 12 have been amended.
Claims 13-34 were previously canceled.
Claims 1-12 are pending and under consideration.
Priority - Updated
This application is a continuation-in-part of PCT/US19/59275 filed October 31, 2019, which claims the benefit of US Provisional Application No. 62/753,485 filed October 31, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
In light of Applicant’s claim amendments, the previous objection regarding the priority date of the instant application has been withdrawn.
The amended instant claims are drawn to a method for reducing severity of CAR-T cell related neurotoxicity in a mammal, comprising administering an anti-GM-CSF antibody and CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down, or GM-CSF gene knockout, wherein GM-CSFk/o CAR-T cells comprise an eliminated level of GM-CSF.
Prior application 62/753,485 does not disclose or contemplate reducing severity of CAR-T neurotoxicity by administrating an anti-GM-CSF antibody and GM-CSFk/o CAR-T cells.
Applicant acknowledges in the reply received March 5, 2026 that instant invention as recited was first disclosed in PCT/US19/59275. Accordingly, claims 1-12 are entitled to the benefit of the PCT/US19/59275 filing date of October 31, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 5, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
In view of the Applicant’s amendment, the previous objections to the claims and the specification are withdrawn.
Claim Rejections - 35 USC § 112(a) - Withdrawn
In view of the Applicant’s claim amendments, the previous grounds of rejection are withdrawn.
Claim Rejections - 35 USC § 103 - Updated
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.
The following rejection has been updated to reflect Applicant’s amendment to instant claim 1.
Claims 1-6, 8, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Durrant et al. (US 2019/0194343) (“Durrant”).
The instant claims are drawn to a method for reducing severity of CAR-T cell related neurotoxicity in a mammal, comprising administering an anti-GM-CSF antibody (lenzilumab) and CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSFk/o), wherein said GM-CSFk/o CAR-T cells comprise an eliminated level of GM-CSF, wherein the GM-CSFk/o CAR-T cells target CD19 on lymphoma or leukemia cells.
Durrant discloses methods of inhibiting or reducing the severity of CAR-T related neurotoxicity and/or cytokine release syndrome (CRS), comprising administering a GM-CSF neutralizing antibody [0020] or GM-CSFk/o CART19 cells [0051] to subjects with a cancer in which GM-CSF contributes to tumor or cancer cell growth, including leukemias and lymphomas [0240, 0353] (instant claims 1, 3-4). Durrant discloses the subject is a human [0024] (instant claim 2).
Durrant teaches all patients that respond to CAR-T therapy experience some degree of CRS or neurotoxicity that is initiated by GM-CSF resulting in the trafficking and recruitment of myeloid cells to the tumor site that produce cytokines and perpetuating the inflammatory cascade [0068].
Durrant carried out in vivo studies using either CD19 positive NALM6 engrafted xenografts, or patient derived xenografts with primary acute lymphoblastic leukemia (ALL) (instant claims 6, 8).
Example 17 explicitly teaches the effect of GM-CSF blockade on CAR-T cell effector functions using the human GM-CSF neutralizing antibody lenzilumab (instant claims 10-12). The combination of CART19 and lenzilumab resulted in significant reduction in neurotoxicity and CRS anti-tumor activity and overall survival benefit compared to control T cells in the primary acute lymphoblastic leukemia (ALL) xenograft model. Subsequently, Durrant disrupted GM-CSF through CRISPR/Cas9 gene editing during the process of CAR-T cell manufacture to generate functional GM-CSF knockout CAR-T cells with reduced expression of GM-CSF resulting in enhanced disease control in a high tumor burden relapse xenograft model (instant claim 1). These CAR-T cells produce significantly less GM-CSF upon activation, but continue to exhibit production of other cytokines and exhibit normal effector functions. In addition, the GM-CSF knockout CAR-T cells recruit fewer NK cells, CD8+ cells, myeloid cells, and neutrophils to the tumor site in comparison to CD19CAR-T. Thus, modulating myeloid cell behavior through GM-CSF blockade can help control CAR-T mediated toxicities and reduce their immunosuppressive features to improve leukemic control. Specifically, the methods taught by Durrant can be used to abrogate neurotoxicity and CRS through GM-CSF neutralization and to enhance CAR-T cell function, in patients with various leukemias and lymphomas, including diffuse large B cell lymphoma [0070, 0349-0353] (instant claim 5).
Durrant does not teach lenzilumab and GM-CSFk/o CAR-T cells as a combination therapy, or that the GM-CSFk/o CAR-T cells comprise an eliminated level of GM-CSF.
However, Durrant teaches that administering lenzilumab after CART19 therapy resulted in significant reduction in neurotoxicity and CRS anti-tumor activity and overall survival benefit compared to control T cells. Durrant also teaches administering GM-CSFk/o CAR-T cells significantly reduced GM-CSF expression and resulted in greater tumor control however, low levels of GM-CSF expression were detected. Therefore, a skilled artisan would have a reasonable expectation of success in combining both treatments (i.e., administration of lenzilumab and GM-CSFk/o CAR-T cells) for greater control over developing neurotoxicity because addition lenzilumab would neutralize the low level of GM-CSF produced by the GM-CSFk/o CAR-T cells. One of ordinary skill in the art would be motivated to combine both protocols because CAR-T therapy is limited by life-threatening neurotoxicity and CRS driven by GM-CSF expression, thus neutralizing GM-CSF through administration of both lenzilumab and GM-CSFk/o CAR-T cells would provide better control over CAR-T mediated neurotoxicity than treatment with either lenzilumab or GM-CSFk/o CAR-T as a monotherapy. Additionally, one of ordinary skill in the art would be further motivated to generate GM-CSFk/o CAR-T cells that completely eliminates GM-CSF expression which would further ensure that GM-CSF produced by surrounding cells in the tumor microenvironment can be neutralized by lenzilumab thus reducing incidence and/or severity of neurotoxicity in the presence of other GM-CSF secreting immune cells and tumor cells. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Durrant et al. (US 2019/0194343) (“Durrant”) as applied to claims 1-6, 8, and 10-12 above, and in further view of Garfall et al. (US 2018/0252727; cited in IDS 9/30/2021) (“Garfall”).
The instant claims are drawn to a method for reducing severity of CAR-T cell related neurotoxicity in a mammal, comprising administering after CAR-T cell therapy an anti-GM-CSF antibody (lenzilumab) and CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSFk/o), wherein said GM-CSFk/o CAR-T cells comprise an eliminated level of GM-CSF and wherein the GM-CSFk/o CAR-T cells target BCMA on multiple myeloma cells.
The teachings of Durrant are set forth above.
Durrant does not teach treating multiple myeloma.
Garfall teaches CAR-T cells with anti-CD19 specificity are effective in treating hematologic malignancies, associated with CD19 expression, such as diffuse large B cell lymphoma and multiple myeloma [0156] (instant claim 7). However, cytokine release syndrome (CRS) is a common adverse side effect of CAR-T cell treatment, with potentially life-threatening toxicity [0005]. CRS associated with elevated levels of GM-CSF released from CAR-T cells [0238] including BCMA CAR-expressing cells [0236] (instant claim 9).
The teachings of Durrant differ from the instant invention in that although lenzilumab and GM-CSF deficient CAR-T cells are disclosed to reduce severity of neurotoxicity associated with CD19 CAR-T therapy for treating various cancers, multiple myeloma and anti-BCMA CAR-T cells are not. Given that Durrant teaches administration of both lenzilumab and GM-CSFk/o CAR-T can alleviate CAR-T related neurotoxicity driven by expression of GM-CSF, a skilled artisan would have a reasonable expectation of success in using the same treatment for treating neurotoxicity associated with anti-BCMA CAR-T therapy because the neurotoxicity is triggered by a cytokine storm from the GM-CSF secreted from the CAR-T cells as evidenced by Garfall. Thus, the prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Double Patenting - Withdrawn
The terminal disclaimers filed March 5, 2026 to obviate the nonstatutory double patenting rejections over copending applications 17/290,185 and 18/283,196 are in compliance with 37 CFR 1.321(c) or 1.321(d). Accordingly, the previous nonstatutory double patenting rejections are withdrawn.
Response to Arguments
Applicant argues in the reply received March 5, 2026 (pg. 2-3), that Durrant, either alone or in combination with the Garfall, does not teach or suggest that a person having ordinary skill in the art should carry out such a method for reducing severity of CAR-T cell related neurotoxicity in a mammal by administering an anti- GM-CSF antibody and the recited GM-CSFk/o CAR-T cells having an eliminated level of GM- CSF.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive.
Durrant specifically teaches methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity [Abstract] using an anti-hGM-CSF neutralizing antibody (lenzilumab) and GM-CSFk/o CAR-T cells with reduced GM-CSF secretion when activated in vivo. Reasons of obviousness for combining GM-CSFk/o CAR-T cell therapy with an anti-hGM-CSF antibody to neutralize low levels of GM-CSF expressed by the GM-CSFk/o CAR-T cells which could trigger CRS and neurotoxicity have been set forth above. One would be motivated to fully abrogate GM-CSF expression in the CAR-T cells to reduce overall GM-CSF in the TME. Although T cells are a major source of GM-CSF in the TME, GMC-CSF is produced by other cells in the TME, including the tumor itself, which could be neutralized with the addition of an anti-hGM-CSF antibody. Accordingly, the rejection is maintained.
Conclusion
No claims are allowed.
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 MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642