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/US2020/047274, filed on 08/20/2020, which claims domestic benefit to US provisional application 62/889,324, filed 08/20/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
3. The amendment, filed on 07/21/2025, in which claims 1, 4, 6-11, 15, and 18 are amended; and claim 2 is cancelled, is acknowledged. Claims 1 and 3-20 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/10/2025 has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action dated 04/21/2025,
The specification was objected to for an embedded hyperlink. Applicant’s amendment to delete the hyperlink has overcome the objection and the objection is withdrawn.
Claims 4 and 18 were objected to for typographical errors. Applicant’s amendment to the claims have overcome the objections and the objections are withdrawn.
Claims 4, 6, 7, 8, 9, 10, 11, and 15 were rejected under 35 USC 112(b) for reciting “optionally,” which introduced ambiguity to the scope of respective claims. Applicant’s amendment to the claims has clarified the claim scope and have overcome the rejections and the rejections are withdrawn.
Claims 4, 6, 7, 8, 9, 10, 11, and 15 were rejected under 35 USC 112(b) for reciting “optionally,” which introduced ambiguity to the scope of respective claims. Applicant’s amendment to the claims has clarified the claim scope and have overcome the rejections and the rejections are withdrawn.
Claims 1, 3-18, and 20 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-17, 22-26, 28-31, 33 and 35 of copending Application No. 17/820,525. Applicant’s amendment to the add the limitations of claim 2 to instant claim 1 has overcome the rejections and the rejections are withdrawn.
Claims 1, 3-5, 7-20 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-19, 21-30, and 33 of copending Application No. 17/820,804. Applicant’s amendment to the add the limitations of claim 2 to instant claim 1 has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Specification
As stated in the previous office action filed 04/21/2025, trade names or marks used in commerce, have been noted in the instant application. While, terms have been amended for capitalization, proper symbols indicating use in commerce (i.e. ™, SM , or ® following the terms) have not been added. Therefore, the objection is maintained.
Modified Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-9 and 11-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 10,172,885 B2 (herein Pulé).
Regarding claims 1, 3-9, 11, and 14-16, Pulé teaches an inhibitory chimeric antigen receptor (iCAR) expressed in T-cells or NK cells comprising an extracellular antigen binding domain (i.e. ligand binding domain), spacer, transmembrane domain (TMD) (i.e. membrane localization domain), and an inhibitory endodomain comprising a tyrosine phosphatase domain from a Src homolog (SH2) domain-containing protein phosphatase. This iCAR co-localizes (i.e. becomes proximal) to a ligated activation CAR, and in some embodiments inhibits activation of this immune receptor upon simultaneous iCAR ligation (claim 2; column 9, lines 21-27).
Pulé teaches multiple iCAR embodiments expressed in T cells (Figure 13, included for reference below) of which utilize various elements that anticipate the instant claims. Of these include dimerized receptors composed of N-terminal anti-CD33 (expressed by AML and normal stem cells – Table 6) scFv antigen binding domains fused to stalk (i.e. extracellular linker) and TMD of CD8α with a intracellular phosphatase domain of PTPN6 (gene name for SHP-1; SEQ ID NO:20 and 21 identical to instant SEQ ID NO:3 and 4, respectively) (Figure 13B), TM domain and intracellular segments of LAIR1 (Figure 13C), or fused PTPN6 and CD148 phosphatase domain (Figure 13D) (column 4, lines 34-43).
PNG
media_image1.png
530
639
media_image1.png
Greyscale
Regarding claim 12, Pulé teaches a nucleic acid encoding an iCAR (antigen binding domain, transmembrane domain, and inhibitory endodomain) that co-localizes to an activating CAR with simultaneous ligation (i.e. proximal inhibition) (claim 4).
Regarding claim 13, Pulé teaches a vector of the aforementioned nucleic acid (claim 10).
Regarding claim 17, Pulé teaches a pharmaceutical composition comprising a plurality of T or NK cells expressing the iCAR as previously described (claim 14).
Regarding claim 18, Pulé teaches that T cells expressing iCAR when challenged with other cells expressing targets (i.e. antigens) demonstrated reduced activation only when the inhibitory receptor antigen was present in tandem (Figure 21).
Regarding claim 19, Pulé teaches an embodiment of iCAR utilizing and “AND NOT Gate” to inhibit immune response of a tumor targeting chimeric receptor with an inhibitory receptor for normal cell antigens (column 23, lines 33-39; Table 6). Furthermore, Pulé teaches that cells expressing this “AND NOT” iCAR mechanism can be administered to a subject as a method of treating cancer (claims 1, 14-17), meaning that the activating CAR would inherently be designed for tumor-targeting.
Regarding claim 20, Pulé teaches a method of inhibiting a tumor-targeting CAR (anti-CD19) on T cell via proximal iCAR, by presenting the cognate ligand for iCAR (GD2) through co-culture with target cells expressing the varying respective antigens. Pulé demonstrates that cells presenting only activating antigen maintain cell activation, but dual expressing cells inhibited this response (Figure 31; Column 68, lines 38-54).
Response to Arguments - 35 USC § 102
Applicant's arguments filed 07/21/2025 have been fully considered but they are not persuasive.
Applicant states:
“Pule does not teach or disclose a chimeric inhibitory receptor having an enzymatic inhibitory domain comprising an enzyme catalytic domain from an enzyme selected from CSK, SHP-1, SHP-2, PTEN, PTP-MEGl, PTP-PEST, c-CBL, CBL-b, PTPN22, LAR, PTPHl, SHIP-1, ZAP70, and RasGAP" (Remarks, page 16, ¶ 2)
In response to applicant’s argument regarding the amended group of catalytic enzyme domains, Pule as stated in the previous office action teaches iCARs with PTPN6 endodomains as discussed above. A person having ordinary skill in the art would recognize that proteins have various alternative names that can be used interchangeably. Therefore, as Pule anticipates each element as set forth in the amended claim, the rejection is maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pulé as applied to claim 1 above, and further in view of Chen (cited previously).
Pulé teaches claim 1 as discussed above.
While Pulé teaches an extracellular spacer with IgG1 hinge (instant SEQ ID NO:50) and a GS linker (instant SEQ ID NO:39) between fused endodomain elements (between SH2 domain of PTPN6 and phosphatase domain of CD148; Figure 17), which by BRI would be positioned between the TM and an enzymatic inhibitory domain. These linkers are not operably and/or physically linked to the TM and inhibitory endodomain, and thus Pulé does not explicitly teach an intracellular spacer region as claimed.
Chen teaches that GS linkers (e.g. SEQ ID NO: 29-43) are the most commonly used flexible linkers and function to increase stability and folding in fusion proteins (i.e. chimeric receptors) (Table 3).
A person having ordinary skill in the art would recognize that incorporating an additional GS linker as taught by Chen as a spacer between TM and the inhibitory endodomain of an iCAR as taught by Pulé would likely not affect inhibitory activity of the iCAR as these linkers are commonly used in the art in chimeric fusion proteins. 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 adding a common spacer as claimed to operably link the TM to the endodomain would not substantially change the effectiveness of an iCAR as taught by Pulé and could be added with a reasonable expectation of success.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 07/21/2025 have been fully considered but they are not persuasive.
Applicant states:
“Applicant respectfully asserts that neither Pule or Chen, individually or in combination,
disclose or suggest a chimeric inhibitory receptor of claim 1 or claims dependent thereon." (Remarks, page 17, ¶ 3)
In response to applicant’s argument, Pulé as discussed above teaches iCARs with PTPN6 (i.e. SHP-1) enzymatic inhibitory endodomains rendering the argument of nonobviousness unpersuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647