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
The current application claims priority to U.S. provisional applications 63/227115, filed on 29 July 2021, and 63306862, filed on 04 February 2022, and is 371 of PCT/US2022/038640, filed on 28 July 2022. The effective filing date is 29 July 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 26 January 2024, 27 June 2025, 16 January 2026, and 25 June 2026 were considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-67 are the original claims. In the amendment of 27 August 2024, claims 3, 5, 6, 9, 13, 16-22, 24, 26-30, 32-35, 37, 38, 40-45, 48-61, 63, 64, and 65 were cancelled and claims 4, 7, 8, 10, 11, 23, 25, 31, 36, 39, 46, 47, 62, 65, and 67 were amended. Claims 1, 2, 4, 7, 8, 10-12, 14, 15, 23, 25, 31, 36, 39, 46, 47, 62, 65, and 67 are pending and the subject of this office action.
Claim Rejections - 35 USC § 102
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, 2, 11, 12, 15, 31, 36, 39, 46, 47, 62, 65, and 67 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2019160956 A1 (herein Scholler).
Scholler relate to compositions and methods for treating diseases, such as cancer, comprising administering a therapy comprising a chimeric antigen receptor, an IL-15R molecule, and an IL-15 molecule (Abstract). It is taught that the disclosed method and compositions feature immune effector cells (e.g. T cells or NK cells) comprising nucleic acid molecule(s), which encode tumor antigen-specific-CAR molecules, IL-15R, and/or IL-15 (Page 1 line 25 -Page 2 line 6). The authors disclose a nucleic acid molecule comprising a first nucleic acid encoding a chimeric antigen receptor that binds an antigen (e.g. CD19, mesothelin, or BCMA) (Page 2 lines 9-10). It is also disclosed that this nucleic acid molecule also comprises a second nucleic acid sequence encoding an IL-15R molecule as well as third nucleic acid sequence encoding an IL-15 molecule (Page 2 lines 11-12). The authors describe embodiments, in which the first (chimeric antigen receptor), second (IL-5R), and third (IL-15) nucleic acids sequences are disposed on the same nucleic acid molecule (e.g. vector or viral vector) (Relevant to instant claim 1 and 31) (Page 2 lines 13-15). The authors disclose an exemplary embodiment of the nucleic acid molecules, described above, which encodes a chimeric antigen receptor (referred to as “CARmeso+ IL-15R/IL-15”), shown below, comprising an anti-mesothelin scFv, a CD8 hinge, a CD8 transmembrane domain, a 4-1BB co-stimulatory domain, a CD3 zeta intracellular region, IL-15R, and an IL-15 domain (Relevant to instant claims 1 and 2) (Figure 1 and Page 15 lines 12-25).
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In example 1 (Pages 178-180), Scholler et al teach CAR T cells comprising a lentivirus vector comprising the nucleic acid molecule, described above, and demonstrate that these cells show a more persistent anti-tumor effect, compared to CAR T cells, which only expressed an anti-mesothelin CAR molecule and lacked IL-15R and IL-15 expression, when administered to a AsPC1 pancreatic cancer xenograft NSG mouse model (Relevant to instant claims 31, 36, 39, 46, 47, 62, and 65) (Page 180 lines 8-20 and Figure 5).
Scholler teaches amino acid sequences of 4-1BB (SEQ ID NO: 1029), CD8 transmembrane domain (SEQ ID NO: 1026), and CD3 zeta (SEQ ID NO: 1037), all of which share 100% sequence identity with the corresponding amino acid sequences, referenced in instant claims 11 (SEQ ID NO: 24), 15 (SEQ ID NO: 27), 12 (SEQ ID NO: 25) (Relevant to instant claims 11, 12, and 15).
In regard to claim 67, Scholler teaches a nucleic acid molecule, that satisfies the limitations established in instant claim 1, as discussed above. Instructions of use are considered nonfunctional descriptive material, and as such are not given patentable weight, because no functional relationship exists between the printed material and the claimed invention (see MPEP 2111.05 and In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864).
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.
Claims 4, 7, 8, 14, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019160956 A1 (herein Scholler) in view of US20200352997 A1 (herein Tamada) and Adachi K, et al. (2018) IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018 Apr;36(4):346-351 (herein Adachi).
In regard to claim 4, Scholler teaches a nucleic acid molecule comprising nucleic acid sequences encoding anti-mesothelin CAR molecules, which further comprise a 4-1BB co-stimulatory domain, and IL-15 and/or IL-15R molecules, as discussed for the 35 U.S.C 102(a)(1) rejection of claim 1, see above.
Scholler does not teach that the nucleic acid molecule further comprises a polynucleotide encoding CCL19. Tamada and Adachi teach this deficiency.
Adachi relates to a study investigating the effect of IL-7 and CCL19 expression in anti CD20 CAR T cells, in terms of immune cell infiltration, CAR T cell survival, and anti-tumor activity (Abstract). CCL19 is taught to be a chemoattractant for T cells and DCs (Paragraph 5). IL-7 is taught to be a known T cell proliferation and survival enhancer (Paragraph 4). Adachi teaches that IL-7 and CCL19 produced by T-cell zone fibroblastic reticular cells are “essential for the formation and maintenance of the T-cell zone in lymphoid organs, where both T cells and DCs are recruited from the periphery” (Paragraph 2). Based on this teaching, the authors sought to develop persistent CAR-T cells, that produce IL-7 and CCL19, to recruit T cells and DCs to tumor tissues, which could improve the therapeutic effects of CAR-T cells against solid tumors. The CAR cells disclosed in this article, comprise a tandem construct encoding an anti-hCD20-CAR molecule- 2A peptide - IL-7- 2A peptide- CCL19 (Paragraph 3 and Supplementary Figure 1a). These CAR T cells were shown to effectively secrete both cytokines (Paragraph 3 and Supplementary Figure 1c). When co-incubated with responder T cells, in a transwell migration assay, the CAR T cells, expressing Il-7 and CCL19, caused a significant increase in responder T cell migration, compared to that caused by conventional T cells (Paragraph 5 and Figure 1c). The authors credit the increased responder T cell to the expression of CCL19 (Paragraph 5). Additionally, histopathological analysis also showed that treatment with the CAR T cells, expressing CCL19 and Il-7, induced massive T-cell infiltration into the tumor tissue, which was not observed for conventional CAR T cell treatment (Paragraph 14, Figure 3b, and Supplementary Figure 14a). Additionally, Adachi also teaches that anti-mesothelin CAR T cells, expressing CCL19 and Il-7, when administered to a murine model of pancreatic ductal adenocarcinoma, PAN02, suppressed tumor growth and prolonged survival, whereas conventional CAR T cells did not confer any therapeutic benefit (Paragraph 12 and Supplementary Figure 11). Thus, Adachi et al demonstrates that the expression of CCL19 in anti-mesothelin CAR therapy leads to suppressed tumor growth and prolonged survival and that CCL19 expression enhances tumor infiltration, as compared to conventional CAR therapy. Adachi et al are vague regarding technical guidance for the embodiment of the disclosed anti-mesothelin CAR T cells expressing CCL19. Tamada et al provide technical guidance, lacking in the teachings of Adachi.
Tamada relates to a claimed invention providing an enhancer for endogenous T-cells or B-cells having a memory function and a malignant tumor recurrence inhibitor (Abstract). An exemplary embodiment of this invention comprises anti-mesothelin CAR T cells expressing IL-7 and CCL19 ([0109-0115] and Figure 8). The CAR referenced in this embodiment comprises a scFv comprising VH and VL regions corresponding to SEQ ID Nos: 3 and 5, respectively. These variable regions share 100% sequence identity with those referenced in instant claim 8, as shown in the alignments below.
Heavy chain variable region (VH):
Instant SEQ ID NO:22 QVQLQQSGPGLVTPSQTLSLTCAISGDSVSSNSATWNWIRQSPSRGLEWLGRTYYRSKWY 60
Reference SEQ ID NO: 3 QVQLQQSGPGLVTPSQTLSLTCAISGDSVSSNSATWNWIRQSPSRGLEWLGRTYYRSKWY 60
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Instant SEQ ID NO:22 NDYAVSVKSRMSINPDTSKNQFSLQLNSVTPEDTAVYYCARGMMTYYYGMDVWGQGTTVT 120
Reference SEQ ID NO: 3 NDYAVSVKSRMSINPDTSKNQFSLQLNSVTPEDTAVYYCARGMMTYYYGMDVWGQGTTVT 120
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Instant SEQ ID NO:22 VSSGILGS 128
Reference SEQ ID NO: 3 VSSGILGS 128
********
Light chain variable region (VL):
Instant SEQ ID NO:23 QPVLTQSSSLSASPGASASLTCTLRSGINVGPYRIYWYQQKPGSPPQYLLNYKSDSDKQQ 60
Reference SEQ ID NO: 5 QPVLTQSSSLSASPGASASLTCTLRSGINVGPYRIYWYQQKPGSPPQYLLNYKSDSDKQQ 60
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Instant SEQ ID NO:23 GSGVPSRFSGSKDASANAGVLLISGLRSEDEADYYCMIWHSSAAVFGGGTQLTVLS 116
Reference SEQ ID NO: 5 GSGVPSRFSGSKDASANAGVLLISGLRSEDEADYYCMIWHSSAAVFGGGTQLTVLS 116
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Tamada also teaches a glycine-serine linker (SEQ ID NO: 4), which when placed between the VH and VL regions, as is common for scFvs, would result in a sequence identical to SEQ ID NO: 1, referenced in instant claim 10. It is also taught that the anti-mesothelin CAR comprises an amino acid sequence defined by SEQ ID NO: 6, which is comprised of a 4-1BB domain, a CD8 hinge, a CD8 transmembrane domain, and a CD3 zeta domain, all of which share 100% sequence identity with their counterparts in the current application (SEQ ID Nos: 24, 26, 27, and 25, respectively), shown below.
Reference SEQ ID NO: 6:
FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
4-1BB
CD8 Hinge
CD8 Transmembrane domain
CD3 zeta
These CAR T cells are also taught to express CCL19, as defined by SEQ ID NO: 2, which shares 100% sequence identity to SEQ ID NO: 13, referenced in claim 25, as shown in the alignment below.
Instant SEQ ID NO: 13 ---------------------GTNDAEDCCLSVTQKPIPGYIVRNFHYLLIKDGCRVPAV 39
Reference SEQ ID NO: 2 MALLLALSLLVLWTSPAPTLSGTNDAEDCCLSVTQKPIPGYIVRNFHYLLIKDGCRVPAV 60
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Instant SEQ ID NO: 13 VFTTLRGRQLCAPPDQPWVERIIQRLQRTSAKMKRRSS 77
Reference SEQ ID NO: 2 VFTTLRGRQLCAPPDQPWVERIIQRLQRTSAKMKRRSS 98
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Tamada demonstrates that anti-mesothelin CAR T cells expressing CCL19 and IL-7, when administered to immunodeficient mice engrafted with ACC-MESO1 tumors, showed superior inhibition of tumor recurrence than conventional anti-mesothelin CAR T cells (i.e. CAR T cells that do not express CCL19 and IL-7). Tamada also teaches CAR cells that express additional immune function control factors and suggests several candidates, such as IL-15 ([0049]).
It would have been obvious to one skilled in the art to incorporate the teachings of Adachi and Tamada (engineered CAR cells that express CCL19) with the method for treating disease comprising administering a therapy comprising a chimeric antigen receptor, an IL-15R molecule, and an IL-15 molecule, taught by Scholler. As taught by Adachi, the combination of CAR therapy and CCL19 expression leads to enhanced tumor infiltration compared to a similar therapy lacking CCL19 expression/secretion (Paragraph 14, Figure 3b, and Supplementary Figure 14a). This teaching provides ample motivation for the inclusion of CCL19 expression into CAR therapy, as tumor infiltration is a known challenge for CAR therapy for the treatment of solid tumors. Additional motivation is provided by Adachi’s demonstration that anti-mesothelin CAR T cells, expressing CCL19 and IL-7, showed superior inhibition of tumor growth and improved survival, when administered to a PAN02 murine tumor model, as compared to conventional CAR cells (Paragraph 12 and Supplementary Figure 11). When combined with the technical guidance provided by Tamada, the combination of teachings presents a high expectation of success.
Claim 23 is rejected 35 U.S.C. 103 as being unpatentable over WO2019160956 A1 (herein Scholler) in view of Bergamaschi C, et al. (2009) Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo. J Immunol. 2009 Sep 1;183(5):3064-72 (herein Bergamaschi).
Scholler teaches that IL-15 molecule may be full-length, a fragment, or a variant of human IL-15, as defined by SEQ ID NO: 1007, and also teaches the use of IL-15/IL-15Rα fusion proteins/complexes (Page 159 line 24-Page 162 line 3). Scholler does not explicitly teach any of the IL-15 sequence referenced in claim 23. Bergamaschi teaches this deficiency.
The sequence defined by SEQ ID NO: 11 of the instant application, is a full-length wild-type form of IL-15, which only differs from the referenced IL-15 in the signal peptide region, shown in the alignment below (signal peptides colored in red).
Reference SEQ ID NO: 1007 ---------------------------MVLGTIDLCSCFSAGLPKTEANWVNVISDLKKI 33
Instant SEQ ID NO: 11 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI 60
. : : .***********************
Reference SEQ ID NO: 1007 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 93
Instant SEQ ID NO: 11 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 120
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Reference SEQ ID NO: 1007 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 135
Instant SEQ ID NO: 11 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 162
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Bergamaschi teaches that IL-15 naturally exists in the two isoforms, resulting from alternative splicing, and that the two isoforms only differ in the signal peptide amino acid sequence (Abstract and Figure 1), as illustrated in the following figure:
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Bergamaschi et al compared expression, localization, degradation, and function of the two endogenously produced forms of IL-15, long signal peptide (LSP) and short signal peptide (SSP) (Whole document). It is taught that co-expression of IL-15 (SSP and LSP) with IL-15Rα is necessary for IL-15 bioactivity in vivo, and that once secreted there is no qualitative difference between SSP and LSP IL-15 (Results: In vivo comparison of SSP IL-15 and LSP-15 in combination with IL-15Rα). The authors did note that the LSP IL-15 was produced at much higher levels than the SSP isoform, despite similar mRNA levels, and that, prior to signal peptide cleavage, SSP has a considerably lower cellular half-life than the LSP isoform (Results sections 1-3).
Based on these teachings it would have been obvious, to one skilled in the art, to use an IL-15 amino acid sequence corresponding to instant SEQ ID NO: 11. As taught by Bergamaschi, the LSP IL-15 isoform, SEQ ID NO: 11, once processed into its mature form shares 100% sequence identity with the mature form of SSP, taught by Scholler and corresponding to SEQ ID NO: 1007, and as such functionally equivalent. Additionally, Bergamaschi teaches that the LSP IL-15 isoform is produced in a much higher quantity than the SSP isoform. This difference in expression level provides motivation to use the LSP isoform over the SSP isoform in the context of the current invention, which is intended to overexpress exogenous IL-15.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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