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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2021/051387, filed on 09/21/2021, which claims domestic benefit to US provision applications 63/223,514 and 63/081,905, filed 07/19/2021 and 09/22/2020, respectively.
Claim Status
The Amendment, filed on 02/20/2024, in which claims 2-3, 7, 10-22, 24-28, 30-31, 33-55, 58, 60-62, 65-69, 72-73, and 78-86 are canceled; and claims 1, 4-6, 8-9, 23, 29, 32, 56-57, 59, 63-64, 70-71, and 74-77 are currently amended, is acknowledged
Claims 1, 4-6, 8-9, 23, 29, 32, 56-57, 59, 63-64, 70-71, and 74-77 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/20/2023 has been considered by the examiner.
Applicant is notified that the listing of references in the specification (pg 127-132) 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code (¶ [00198]; ¶ [00199]; ¶ [00447]; pg 130, reference no 58; pg 131, reference nos. 64, 65, 70, 73, 76, 78, and 79); references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 57 is objected to because of the following informalities:
“homogenous” is referenced in the specification with alternative spelling “homogeneous” (¶ [00189]). While neither spelling is strictly improper, examiner recommends conforming to one spelling to avoid issues with ambiguity.
“cells claim 1” is improper grammar.
Appropriate correction is required.
Claim Interpretation
Applicant is notified that for examination purposes, claim 1 “engineered to” has been interpreted as an example of an “adapted to” clause (See MPEP 2111.04). Accordingly, the claim language does not limit the claim to a particular structure beyond “an engineered immune cell” and the remaining language only limits the structure in so far as the recited engineered immune cell would have an observed increase in expression and/or function of BATF and/or IRF4.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 76 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 9, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. While the use of the term “optionally” is not pro se indefinite, as used in the instant claims the term reads as exemplary claim language and introduces ambiguity to the claims as the intended scope of the claims becomes unclear. See MPEP § 2173.05(d) and MPEP § 2173.05(h)(II).
Regarding claim 76, the instant claim recites the limitations "the pathogen infection" in line 1. There is insufficient antecedent basis for these limitation in the claim. For examination purposes, examiner has interpreted the claim to mean any pathogenic infection.
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 1, 6, 29, 56, and 75-76 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xin (Cell Rep. 2015;13(6):1118-1124).
Xin teaches a method using a retroviral vector to overexpress BATF in CD8 T cells (i.e. immune cell(s) engineered to increase expression of BATF) (pg 1120-1121, pg spanning ¶). Adoptive transfer of these BATF overexpressing cells improved anti-viral response to persistent Clone 13 variant of lymphocytic choriomeningitis virus (LCMV) infection in mice (Figure 3) (i.e. within scope of a pathogen as defined in the instant specification; ¶ [00196]).
Claims 1, 6, 29, 32, 56-57, 59, 70, 74 and 77 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 12,115,190 B2 (herein US’190) as evidenced by Medvec (Mol Ther Methods Clin Dev. 2017;8:65-74).
US’190 teaches a method to treat cancer (i.e. disease(s) that inherently expresses tumor antigens) in a subject comprising administering to the subject a therapeutically effective amount of T-cells having increased IRF4 expression; wherein the increased IRF4 expression comprises introducing a nucleic acid into the T-cells (i.e. method of generating an immune cell overexpressing IRF4) (claim 1; Examples 1 and 2). US’190 further teaches the T-cells can be CD8+ T-cells (claim 6). US’190 teaches that these T-cells can be used in compositions with a pharmaceutically acceptable carrier (column 28, ¶ 4). US’190 teaches culturing the isolated pmel-1 splenocytes with retroviral particles for 6h and then incubating at 37°C for 16h in complete (10% FBS) RPMI 1640 medium (i.e. conditions that favor T-cell expansion as evidenced by Medvec; Figure 1A) prior to flow cytometry analysis and in vivo transfer (column 29, ¶ 5). US’190 further teaches that almost all live CD8+ T cells in the cultures were Vβ13+ pmel-1 T cells, and more than 60% were successfully transduced (column 29, lines 50-54) (i.e. substantially homogenous as defined in the instant specification; ¶ [00189).
Claims 1, 4-6, 29, 32, 56-57, 59, 63-64, 70-71, 74 and 77 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Long (Nat Med. 2015;21(6):581-590).
Regarding claims 1, 4-6, 29, 32, 56-57, 59, 63-64, 70-71, 74 and 77, Long teaches increased mRNA expression of BATF and/or IRF4 in engineered CD19- and GD2-targeted CAR-T cells (i.e. engineered T-cells expressing receptors that bind to known tumor antigens) in comparison to non-transduced T cells (mock) after 9 days in culture (Supplementary Table 1; results summarized in the table below).
CD19-28z
CD19-BBz
GD2 28z
GD2 BBz
Gene ID
fold change
p-value
fold change
p-value
fold change
p-value
fold change
p-value
BATF
1.08
ns
1.20
3.05E-02
1.75
1.68E-05
1.96
3.35E-06
IRF4
1.16
1.90E-02
1.18
1.26E-02
1.57
7.98E-06
1.66
2.97E-06
Long teaches methods of producing said CAR-T cells wherein transduction efficiencies were routinely 80-90% for all CARs (i.e. substantially homogenous population of cells) (online methods, pg 1, “Retroviral vector production and transduction”), which therefore would also inherently be a method of increasing BATF and/or IRF4 expression in an immune cell (See MPEP 2112.02). CD19 and GD2 CAR-T cells (CD19.28z and GD2.28z) had cytolytic activity in vitro against 143B osteosarcoma cell line expressing CD19 (143B-CD19 tumors; Figure 1b) (i.e. cell-mediated immune response), and CD19.28z induced regression of established 143B-CD19+ tumors in vivo (i.e. methods of treating cancer or providing anti-tumor immunity). In mice treated with CD19.28z CAR-T cells, tumor regrowth lacked CD19 expression (Supplementary Figure 3a), suggesting a tumor antigen CD19 specific immune response.
Regarding claim 63, While Long does not teach explicit use of the disclosed vectors within a kit, the court has determined where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art (i.e. the kit itself as claimed does not structurally provide more to the product anticipated by the prior art) - In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (See MPEP 2112.01 (III)).
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.
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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Long as applied to claim 1 above, and further in view of Gargett (Front Pharmacol. 2014;5:235).
Long teaches claim 1 as discussed above.
Long does not teach incorporating a suicide gene in engineered immune cells (CAR-T cells) that have increased expression of BATF and/or IRF4.
Gargett teaches uncontrolled activation of CAR-T cells, including CD19 CAR-T cells, may produce immunopathology when used as cancer therapeutics (abstract; Table 1). Gargett teaches incorporating a suicide genes (e.g. inducible caspase 9 (iCasp9) gene together with the small-molecule, bio-inert, chemical induction of dimerization (CID) drug (AP1903)), as “safety switch” for targeted deletion of inappropriately activated T cells (pg 3, right column, ¶ 3). Gargett references preclinical studies using CD19-CAR T cells co-expressing iCasp9, which were effectively eliminated in vivo within 3 days of CID administration (pg 4, column spanning ¶). Gargett also references clinical trials using GD2-specific and iCasp9-expressing CAR T cells in advanced melanoma, neuroblastoma, sarcoma, and other GD2+ solid tumors (pg 5, left column, ¶ 2).
Therefore, It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to incorporate a suicide gene as taught by Gargett into a CD19- or GD2- targeting CAR T cell (i.e. an engineered immune cell with inherent increase in BATF and/or IRF4) as taught by Long to provide a safety switch to avoid serious adverse events when using said CAR T cells in patients.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Long as applied to claim 9 above, and further in view of Chen (Nature. 2019;567(7749):530-534) and Morello (Cancer Discov. 2016;6(2):133-146).
Long teaches claim 9 as discussed above.
Long further teaches that tonic activation and exhaustion markers were observed higher in GD2 targeting CAR-T cells (solid tumor/sarcoma associated antigen), and that T cell exhaustion is a major limiting factor in antiviral and antitumor responses in the setting of chronic antigen exposure.
Long does not explicitly teach immune cells with antigen binding domains as recited in the instant claim (anti-mesothelin antibody, anti-ROR1 antibody, or anti-EGFRvIII antibody).
Chen teaches that while CAR-T cells have been shown as clinically effective against B-cell malignancies expressing CD19, CAR-T cells have been less effective against solid tumors in part due to exhaustion mechanisms triggered by chronic antigen stimulation (pg 530, left column, ¶ 1). Chen similarly observed exhaustion markers, specifically PDCD1 (PD-1) and HAVCR2 (TIM3) inhibitory receptor expression, positively correlated with BATF and IRF4 expression CD8+ TILs infiltrating human melanoma (i.e. solid tumor) (extended data Fig 4f).
Morello teaches solid tumor specific antigens targeted for CAR T-cell therapies in active clinical trials at the time of publication, including MSLN (mesothelin) and EGFRvIII (Figure 1).
One of ordinary skill in the art would recognize that other CAR-T cells (i.e. engineered immune cells) designed to target solid tumor antigens (e.g. mesothelin or EGFRvIII as taught by Morello) would likely be susceptible to exhaustion mechanism as taught by Chen. Long and Chen teach said exhaustion mechanisms correspond to upregulation of BATF and IRF4 expression. The courts have determined "[t]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) (See MPEP 2112). Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of that CAR-T cells designed to target solid tumors (e.g. MSLN and EGFRvIII as taught by Morello; i.e. species within scope of the instant claim) would have a reasonable expectation of inherently acquiring increased expression of BATF and/or IRF4 within the target solid tumor cell TME as taught by Long and Chen.
Claim 59 is rejected under 35 U.S.C. 103 as being unpatentable over Long as applied to claim 1 above, and further in view of Rodriguez-Garcia (Chimeric Antigen Receptor T Cells: Development and Production. 1st ed. Springer; 2020;251-271 - epub 2019).
Long teaches claim 1 as discussed above.
Long further teaches adoptive transfer of transduced CAR T cells via intravenous injection to mice (Online methods, pg 2, “In vivo studies”).
However, long does not explicitly disclose a composition comprising a carrier in addition to the T cells.
Rodriguez-Garcia teaches general methods for intravenous injection of CAR-T cells for analysis of anti-tumor effects of CAR-T cells in mice with solid tumors. Rodriguez-Garcia teaches resuspending T cell in PBS (i.e. a carrier) at an appropriate concentration for injection.
A skilled artisan would recognize that IV injection for adoptive transfer of CAR-T cells as taught by Long requires cells to be suspended at an appropriate concentration within an aqueous solution. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the cells as taught by long can be combined with a suitable carrier, such as PBS as taught by Rodriguez-Garcia, with a reasonable expectation of success of arriving at a composition within scope of the instant claim.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683