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/KR2021/001904, filed on 02/15/2021. This application claims priority to Republic of Korea Application No. KR10-2020-0018169, filed 02/14/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 12/29/2025, is acknowledged in which:
Claims 3, 5-21, 24, 31, 34, 37, 44-67, 69 and 71 are canceled.
Claims 1, 23, and 70 are currently amended.
Claims 22, 29, 38, 41-42, 68, and 72 were previously presented.
Claims 2, 4, 25-28, 30, 32-33, 35-36, 40, and 43 are original.
Claims 1-2, 4, 22-23, 25-30, 32-33, 35-36, 38-43, 68, 70, and 72 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 12/29/2025,
The specification was objected to informalities in the text and tradenames or marks used in commerce without appropriate symbols. Applicant’s submission of an amended specification with appropriate corrections has overcome the objections and the objections are withdrawn.
All previous rejections regarding claims 3, 5, and 20 are rendered moot in view of claim cancellations.
Claim 70 was rejected under 35 USC 112(a) for reciting cancer prevention without sufficient enablement. Applicant’s amendment to the claim to remove “preventing” from the claim language has overcome the rejection and the rejection is withdrawn.
Claims 1-2, 4, 23, 26-27, 29-30, 33, 36, 38, 41-43, 68, 70 and 72 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tamada as evidenced by You. Applicant’s amendment to the base claim to recite the structural formula (i.e. 2-3 domains) and specific species of the signaling pathway modulator(s) has overcome the rejection and the rejection as previously stated is withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Tamada and newly found prior art as discussed below.
Claims 1-3, 5, 23, 26-27, 29-30, 32-33, 35-36, 38-43, 68, 70, and 72 were rejected under 35 USC 102(a)(2) as being anticipated by Jarjour. Applicant’s amendment to the base claim to recite the structural formula (i.e. 2-3 domains) and specific species of the signaling pathway modulator(s) has overcome the rejection and the rejection is withdrawn.
Claims 22, 25, 28, 35, 39 and 40 were rejected under 35 USC 103 as being unpatentable over Tamada and Suri. Applicant’s amendment to the base claim to recite the structural formula (i.e. 2-3 domains) and specific species of the signaling pathway modulator(s) has overcome the rejection and the rejection as previously stated is withdrawn. However, upon further consideration, a new ground(s) of rejection for claims 25, 28, 35, 39, and 40 are made in view of Tamada, Suri, and newly found prior art as discussed below.
Claim 22 was rejected under 35 USC 103 as being unpatentable over Tamada and Wu. Applicant’s amendment to the base claim to recite the structural formula (i.e. 2-3 domains) and specific species of the signaling pathway modulator(s) has overcome the rejection and the rejection is withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Modified 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 1-2, 4, 20, 23, 26-27, 29-30, 33, 36, 38, 41-43, 68, 70 and 72 are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over US 10,316,102 B2 (herein Tamada) and Celis-Gutierrez (Cell Rep. 2019;27(11):3315-3330.e7).
Tamada teaches a CAR expression vector comprising a polynucleotide encoding a CAR (SEQ ID NO: 7) comprising (i) an scFv (positions 1-819), (ii) CD8 hinge and transmembrane domain (TMD) (positions 829-1074), and (iii) CD28-41BB-CD3ζ intracellular motifs (positions 1075-1197, 1198-1332, and 1333-1674, respectively; i.e. co-stimulatory domains derived from CD28 and 41BB and primary signaling domain derived from CD3ζ), and nucleic acids encoding T cell immune function-enhancing (i.e. T cell stimulation pathway) factors IL-7 and CCL19 (SEQ ID NO: 9), wherein the T cell immune function enhancing factors are linked via self-cleaving peptide (e.g. F2A peptides) (i.e. instant structural formula (I) N’-X-L1-Y-C’, wherein X is IL-7, L1 is F2A, and Y is CCL19) (Claims 1-2; Figures 1-2; column 13, ¶ 4). Tamada further teaches sequences for anti-CD20 scFv (SEQ ID NO:10, which comprises a signal peptide inserted before the antigen binding domain as evidenced by MRC; see alignment below) CAR fused via 2A self-cleaving peptides to SHP2 dominant negative mutant (SHP2DN) (Figure 29) comprising an N-terminal SH2 domain (SEQ ID NO: 6; see alignment below) which inhibits the effects of endogenous SHP2 by competing for interactions with cytoplasmic YVKM motifs as disclosed in the instant specification (page 10, ¶ 5). Tamada teaches inhibitory signals in the tumor microenvironment are transduced within immune cells in part by SHP-1 and SHP-2 mediated signaling, and teaches CAR-T cells expressing either CAR-SHP1DN or CAR-SHP2DN have significantly higher cytotoxicity against tumor cells (P815 mastocytoma cells) in comparison to CAR only T cells (Example 11, Figure 30). Tamada teaches preparation of these vectors to involve insertion into retroviral vectors (pMSGV) for transduction in T cells (column 24, ¶ 1-2), and teaches transduced CAR-T cells can be used as an anti-cancer agent with a pharmaceutically acceptable additive (column 11, ¶ 5) to treat cancers that overlap with the instant claims (column 11-12 spanning ¶).
While Tamada teaches the feasibility of incorporating cleavable domains within a CAR vector that function as intracellular signaling regulators and teaches SHP1/SHP2 SH2 domains, Tamada does not teach co-expression of both SHP1 and SHP2 domains within the same vector.
Celis-Gutierrez teaches SHP-1 and SHP-2, have partially overlapping roles for inhibition of TCR and CD28 signaling (graphical abstract; Abstract). Celis-Gutierrez teaches SHP-1 can interact with PD-1 in the absence of SHP-2 (Figure 5), and TCR signaling pathway and CD28 were sensitive to dephosphorylation by PD-1 irrespective of its use of SHP-1 or SHP-2 (Figure 7). Celis-Gutierrez teaches SHP-1 can also exert PD-1 independent negative effects on T cell activation (Figure 5C).
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 modify the CD20-CAR SHP1DN or CD20-CAR SHP1DN as taught by Tamada into a dual targeting CD20-CAR SHP1DN/SHP2DN vector as Tamada teaches the feasibility of including two immune function-enhancing factors (separated by cleavable domains) within the same CAR vector, and a skilled artisan would be motivated to do so because Celis-Gutierrez teaches partially redundant and independent roles for SHP-1 and SHP-2 in T cell immunosuppression suggesting a benefit in inhibiting the activity of both to improve CAR-T resistance to the immunosuppressive tumor microenvironment.
Claims 39 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Tamada and Celis-Gutierrez as applied to claim 38 above, as evidenced by Stothard (Biotechniques. 28:1102-1104) and MRC Centre for Protein Engineering (www2.mrc-lmb.cam.ac.uk/vbase/alignments2.php)
Tamada and Celis-Gutierrez teach claim 38 as discussed above.
Tamada further teaches an antigen binding domain nucleotide sequence (SEQ ID NO:10), which comprises a signal peptide inserted prior to the antigen binding domain sequence (i.e. the start of the VH domain of the scFv) as evidenced by Stothard (translate tool) and MRC (catalogue of all mapped V gene segments) (see alignment results below).
Tamada SEQ ID NO:10 (translated) aligned with leader peptide VH1 1-02 (evidenced by MRC):
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Claims 25, 28, 32, 35, 39 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Tamada and Celis-Gutierrez as applied to claim 1, 29, and 38 above, and further in view of WO 2018/161017 A1 (herein Suri).
The combined teachings of Tamada and Celis-Gutierrez teach claims 1, 29, and 38 as discussed above.
Tamada further teaches CD19 as an alternative CAR target (column 6, line 26).
However, Tamada teaches mouse specific nucleic acid sequences (column 13, lines 18-27) and does not explicitly teach human specific amino acid sequences SEQ ID NO: 3 (CD19 scFv), SEQ ID NO: 5 (CD8α hinge-TMD), SEQ ID NO: 7 (4-1BB co-stimulatory domain), and SEQ ID NO: 9 (CD3ζ intracellular signaling domain) as instantly claimed.
Suri teaches sequence for a CD19 CAR (amino acid sequence SEQ ID NO:635 and corresponding nucleic acid SEQ ID NO:701) with domains identical to instant sequences claimed in all but one residue of the CD3ζ domain and comprising a signal peptide preceding the antigen binding domain (scFv) (e.g. identical to instant SEQ ID NO:1) (alignment shown below). Regarding the single amino acid difference in the CD3ζ domain, Suri also teaches known alternative intracellular domain sequences that can be used within their constructs (Table 6), including CD3ζ variant (SEQ ID NO:323) identical to instant SEQ ID NO: 9.
Fusion of Instant SEQ ID NOs: 1, 3, 5, 7, and 9 aligned with Suri CD19 CAR (SEQ ID NO:635)
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Instant SEQ ID NO:9 (CD3ζ domain) aligned with Suri SEQ ID NO:323
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the various domains of a mouse construct as taught by the combined teachings of Tamada and Celis-Gutierrez (i.e. CAR-SHP1DN/SHP2DN vector) for CAR domains as taught by Suri for use in improving CAR-T cell response in CD19 expressing human cancers. An ordinarily skilled artisan would have had a reasonable expectation of success, because Suri teaches CAR domains can be interchangeable depending on target cancer and signaling goals.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered in so far as they apply to the modified rejections discussed above, but they are not persuasive.
Applicant states:
“Tamada is directed to a CAR expression vector and CAR-expressing T cells, disclosing a
CAR expression vector comprising a nucleic acid encoding an SHP-1 dominant-negative variant (SHP1DN) or an SHP-2 dominant-negative variant (SHP2DN) that transmits inhibitory signals to immune cells…
According to Tamada, each of SHP1DN or SHP2DN consists of a sequence in which at
least one amino acid in the sequence of SHP-1 or SHP-2 is substituted with another amino acid and can inhibit the effect of SHP-1 or SHP-2 while working dominantly over SHP-1 or SHP-2 respectively…
Accordingly, Tamada fails to disclose, teach or suggest the effects of SHP-1 or SHP-2 on
CAR cells and also teaches away from introducing of SHP-1 or SHP-2 to the vector.” (Remarks, pg 14-15)
In response to applicant’s argument regarding SHP1DN and SHP2DN domains, the claim nor specification indicate the nature of “a signaling pathway modulator” nor does the claim limit the sequences within scope of the recited SHP1, SHP2, or fragments thereof.
The instant specification does not provide a strict definition of a signaling pathway modulator nor the scope of “fragment thereof” as recited in the instant claim. The specification only indicates the modulator should operate in the cytoplasm and may be selected from a group consisting of “…a) a protein located in the immunosuppressive signaling pathway, b) an immunophilin or a fragment thereof, c) a protein involved in the antigen loss-mediated relapse, d) a protein located in the T cell stimulatory signaling pathway, e) a protein involved in the inhibition of negative feedback, and f) a combination thereof” (Instant Specification, pg 8); and a SHP-1/SHP-2 “fragment” may include variation in the amino acid sequence (“about 80%...or more homology” - pg 12, ¶ 1 and 2). While the specification recites specific sequences for the SHP1/2 protein domains (pg 53, Example 2.2), these sequences are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, by broadest reasonable interpretation of the claim the “signaling pathway modulator(s)” selected from a group listing “an N-SH2 domain of a SHP-1 protein or a fragment thereof: an N-SH2 domain of a SHP-2 protein, or a fragment thereof” as recited in the amended claim does not limit the claim scope sufficiently to exclude DN mutant domains as taught by Tamada, nor would these nonpreferred/alternative embodiments be considered as teaching away from the broader disclosure because the instant specification implies the overexpression of the N-SH2 domains of the instant invention are meant to block the activity of the endogenous SHP-1 or SHP-2 (instant specification, pg 12, ¶ 1-2) ("the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)
In response to applicant’s argument regarding the individual teachings of Tamada (i.e. Tamada only teaches SHP1DN or SHP2DN, not both), as applicant’s amendment has altered the scope of the claims, new grounds of rejection are made in view of Celis-Gutierrez that teaches the motivation for simultaneous targeting (i.e. formula (II) format) as discussed above. Subsequent arguments regarding the deficiencies of Tamada are therefore considered unpersuasive.
Applicant states:
“Applicant submits that polynucleotides encoding fusion proteins commensurate in scope with the claims, as amended, show unexpected results over the cited references. For example, the present specification demonstrates the anti-cancer efficacy of the claimed fusion protein, specifically, immune cells into which the fusion protein is introduced as an antigen-binding domain (for example, proteins 19bbz#FCS2, Hbbz#FCS2, and Pbbz#FCS2).” (Remarks, pg 19, last ¶)
Applicant’s arguments, with respect to unexpected superior results of FCS2 vectors have been fully considered and are persuasive. As such the rejection regarding claim 22 has been withdrawn, though the claim is objected to as being dependent upon a rejected base claim.
However, the evidence provided is not commensurate in scope with the remaining instant claims, as the results provided are only for Formula (II) embodiments wherein the intracellular domains are FCS2 (FKBP12, CYPA, and N-SH2 of SHP2), and does not provide evidence regarding alternative embodiments within scope of the instant claim (i.e. comprising Formula (I) and/or other signaling pathway modulator species recited in the instant claim: SHP1, TC21, RhoG, NCK1, LAT, NEMO, TLR4, GADD45α, CDC42, HRAS, or SOCS1) (In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983); See MPEP 716.02(d)).
Allowable Subject Matter
Claim 22 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are currently allowed.
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 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 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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