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 .
Status of Claims
Claims 1, 4, 6, 9-11, 14, 16, 18, 20-21, 23, 25-28, 34, and 40 are amended. Claims 2, 4, 8, 13, 15, 17, 19, 24, 29-33, and 35-39 are cancelled. Claims -----1, 3, 5-7, 9-12, 14, 16, 18, 20-23, 25-28, 34, and 40 are currently pending and under examination.
Priority
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. The claims have an earliest effective filing date of 06/05/2020, corresponding to application China 202010507858.2.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Response to Remarks filed 12/08/2025
Applicant’s arguments and amendments regarding the 35 USC 112 rejections have been fully considered and are persuasive. Specifically, the insertion of “CLDN18.2-expressing” in claims 26 and 28 and insertion of “wherein said the synergistic domain comprises 0X40, OX40L, CCR7 or CXCR5, or a fragment thereof” in claim 1 overcome the rejection. Therefore, the 35 USC 112 rejection is withdrawn.
Applicant’s arguments and amendments regarding the 35 USC 102 rejection have been fully considered and are not persuasive.
Applicant states: “Sahin clearly discloses that CARs may generally comprise three domains including a binding domain, a co-stimulation domain and a activation signally domain. (See Sahin et al, pg. 43, paragraphs 2-3). However, claim 1 of the present application requires that, besides the CAR targeting claudin 18.2 (CLDN18.2) including a CLDN18.2-binding domain, a transmembrane domain, a costimulatory domain and an intracellular signaling domain, the fusion protein further includes a synergistic domain that can improve a tumor cells killing capacity of said chimeric antigen receptor targeting CLDN18.2, as shown in FIG. 1 of the present disclosure.”
However, Sahin et al disclose both costimulatory and synergistic domains associated with CLDN18.2 CARs (Sahin et al, Figures 2-3). Therefore, the 35 USC 102 rejection is maintained.
Applicant’s arguments and amendments regarding the 35 USC 103 rejection have been fully considered and are not persuasive.
Applicant states “As mentioned above, Sahin fails to disclose a fusion protein including a CAR targeting claudin 18.2 (CLDN18.2) and a synergistic domain. Neither Soto nor Brulliard remedy this deficiency. Soto is related to an OX40R binding agent with no disclosure about the CAR structure. Brulliard is related to CCR7 with no disclosure about the CAR structure. Therefore, neither Sahin, Brulliard, or Soto , along or putting together, provides a protein as disclosed in claim 1 The technical problem solved by claim 1 is to improve a tumor cells killing capacity of said chimeric antigen receptor targeting CLDN18.2, which is not disclosed by prior arts. Since neither Sahin, Brulliard, or Soto disclose the synergistic domain, there is no teaching or motivation to combine the CAR targeting CLDN18.2 and the synergistic domain improve a tumor cells killing capacity of said chimeric antigen receptor targeting CLDN18.2. Besides, as shown in FIG. 8 of the present application, compared with Ab1OBBZ CAR-T cells (with no synergistic domain), Ab1OBBZ-CCR7 CAR-T cells and Ab1OBBZ-CXCRS CAR-T cells (with synergistic domains) could selectively kill more CLDN18.2-positive tumor cells, with the in vitro killing capacity increased by 13.1% and 44.7%, respectively. Furthermore, as shown in FIG. 9 for the results obtained for each group, Ab1OBBZ- 0X40 CAR-T (with synergistic domains) cells delivered a superior control ability in tumor burden compared with Ab1OBBZ CAR-T cells. The results showed that Ab1OBBZ-0X40 CAR- T cells reduced the mouse tumor size by 82.9% (3.798 mm3 to 0.646 mm3) compared to the control Ab1OBBZ CAR-T cells. Besides, as shown in FIG. 10 , Ab1OBBZ-CXCR5 CAR-T cells had a superior control ability in tumor burden compared with Ab1OBBZ CAR-T cells. The results showed that Ab1OBBZ-CXCR5 CAR-T cells reduced the mouse tumor size by 67.7% (30.98 mm3 to 10.24 mm3) compared to the control Ab1OBBZ CAR-T cells. These data show that protein of claim 1 improves the tumor cells killing capacity of said chimeric antigen receptor targeting CLDN18.2.”
However, as mentioned, Sahin discloses costimulatory and synergistic domains (Sahin et al, Fig 2-3). Additionally, as disclosed in the 103 rejection below, Sahin, Brulliard, and Soto together meet the limitations of all the claims. One would be motivated to include the synergistic domain of Soto et al. in the CAR of Sahin et al because one of ordinary skill in the art would have a reasonable expectation of success of treating diseases, including cancer.
Lastly, Applicant's arguments are not found persuasive with respect to unexpected results, because the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must. be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the unexpected properties are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted. In order to demonstrate that the claimed invention yields unexpected results, Applicant is encouraged to provide evidence of such in the form of an affidavit or declaration, or clearly point out such evidence in the specification as originally filed.
Rejections Maintained- Nonfinal 08/06/2025
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.
Claim(s) 1, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40 are rejected under 35 U.S.C. 102a1 as being anticipated by Sahin et al (WO2016180782, published 11/17/2016).
Regarding claims 1, 2, 9, 11, 12, 14, 16, and 18, Sahin et al teach an artificial T- cell receptor with a CLDN18.2 scFV binding domain with an intracellular T cell signaling domain, a CD28 transmembrane costimulatory domain and a CD3z intracellular domain (Sahin et al, pg. 12 paragraph 4- pg. 13 paragraph 4, and Figure 3). Sahin et al also teach that the costimulatory domains can comprise OX40 (Sahin et al, pg. 43, paragraphs 2-3), which according to [5] and [6] of the specification, meets the limitation of a synergistic domain that improved tumor killing.
Regarding claim 9 and 12, it is noted that an scFV is a single-chain antibody.
Regarding claim 11, it is noted that the antibody comprises a CLDN18.2 binding domain, a transmembrane domain, a costimulatory domain and intracellular signaling domain.
Regarding claim 14 and 16, it is noted that the transmembrane costimulatory domain is CD28.
Regarding claim 18, the intracellular domain is a CD3z signaling domain.
Regarding claim 6, Sahin et al teach the C-terminus of the CAR receptor is linked to the N-terminus of the synergistic domain (Sahin et al, Figure 3).
Regarding claims 7 and 10, Sahin et al teach the fusion protein binding domain and costimulatory domains can be connected via linker (Sahin et al, pg. 13, paragraph 3 and figure 3). Regarding claim 10, it is noted that the spacer is used to link the binding domain to the transmembrane domain in order from N-terminus to C-terminus (Sahin et al, Figure 3).
Regarding claims 21 and 23, Sahin et al teach an isolated nucleic acid encoding the fusion protein and a cell expressing the fusion protein (Sahin et al, pg. 102, claims 33 and 34).
Regarding claim 22, Sahin et al teach a vector comprising the nucleic acid (Sahin et al, pg. 32, paragraph 4- pg. 33, paragraph 1).
Regarding claim 25, Sahin et al teach a pharmaceutical composition comprising a cell expressing the nucleic acid and a pharmaceutically acceptable adjuvant (Sahin et al, pg. 81, paragraph 5).
Regarding claims 26, 28, and 34, Sahin et al teach the method of treating cancer in a subject with a pharmaceutical composition comprising the cell in a subject (Sahin et al, pg. 103, claim 38). Furthermore given that Sahin et al teach the active steps of claims 28 and 34, absent evidence to the contrary, the invention of Sahin et al would represent a method for improved tumor killing as well as a method for improving the proliferation capability of T cells.
Regarding claim 27, Sahin et al teach the cancer can be lymphoma, gastric cancer, and pancreatic cancer (Sahin et al, pg. 72, paragraph 3 and pg. 73, paragraph 4).
Regarding claim 40, Sahin et al teach the T- cells can be derived from PBMCs (Sahin et al, pg. 70, paragraph 5).
Claim Rejections - 35 USC § 103
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.
Claim(s) 3 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin et al (WO2016180782, published 11/17/2016) in view of Soto et al (WO03082919, published 10/09/2003).
The teachings of Sahin et al are discussed above and incorporated herein.
Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Sahin et al further teach that the synergistic domain can be an OX40L domain. Sahin et al do not teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprises instant SEQ ID NO: 24. This deficiency is remedied by Soto et al.
Soto et al teach an OX40L synergistic domain comprising instant SEQ ID NO: 24. Based upon the teachings of Soto et al, one of ordinary skill in the art would have been motivated to include a synergistic binding domain comprising instant SEQ ID NO: 24 (Soto et al, Figure 5).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Sahin et al with those of Soto et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprise instant SEQ ID NO: 24. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Soto et al, one of ordinary skill in the art would have been motivated to include an OX40L synergistic domain comprising instant SEQ ID NO: 24. As such one of ordinary skill in the art would have been motivated to modify the invention of Sahin et al, which teaches the fusion protein comprising a CAR and synergistic domain, to further include an OX40L synergistic domain comprising OX40L, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an OX40L synergistic domain, is effective in treating cancer. The invention of Sahin et al and Soto et al meets the limitations of claims 3 and 20.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Sahin et al (WO2016180782, published 11/17/2016) in view of Brulliard et al (EP2080812, published 07/22/2009).
The teachings of Sahin et al are discussed above and incorporated herein.
Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Sahin et al further teach that the synergistic domain can be an OX40L domain. Sahin et al do not teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprises instant SEQ ID NO: 25. This deficiency is remedied by Brulliard et al.
Brulliard et al teach a CCR7 synergistic domain comprising instant SEQ ID NO: 25. Based upon the teachings of Brulliard et al, one of ordinary skill in the art would have been motivated to include a synergistic binding domain comprising instant SEQ ID NO: 25 Brulliard et al, pg. 48, reference SEQ ID NO: 136).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Sahin et al with those of Brulliard et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprise instant SEQ ID NO: 25. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Brulliard et al, one of ordinary skill in the art would have been motivated to include an CCR7 synergistic domain comprising instant SEQ ID NO: 25. As such one of ordinary skill in the art would have been motivated to modify the invention of Sahin et al, which teaches the fusion protein comprising a CAR and synergistic domain, to further include an CCR7 synergistic domain comprising CCR7, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an CCR7 synergistic domain, is effective in treating cancer. The invention of Sahin et al and Brulliard et al meets the limitations of claims 4-5.
Therefore the claims as a whole were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 1, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of Application No 18047750 in view of Sahin et al (WO2016180782, published 11/17/2016)
The instant claims and the conflicting claims both recite a fusion protein comprising a CAR against CLDN18.2 and costimulatory domains. However, the conflicting claims do not recite a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain. This deficiency is remedied by Sahin et al.
The teachings of Sahin et al are detailed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the conflicting claims with the teachings of Sahin et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. As such one of ordinary skill in the art would have been motivated to modify the conflicting claims to include a synergistic domain comprising OX40L, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an OX40L synergistic domain, is effective in treating cancer. The invention of the conflicting claims and Sahin et al
Regarding claim 9 and 12, it is noted that an scFV is a single-chain antibody.
Regarding claim 11, it is noted that the antibody comprises a CLDN18.2 binding domain, a transmembrane domain, a costimulatory domain and intracellular signaling domain.
Regarding claim 14 and 16, it is noted that the transmembrane costimulatory domain is CD28.
Regarding claim 18, the intracellular domain is a CD3z signaling domain.
Regarding claims 2, 16, 28, and 34 Sahin et al teach the costimulatory domains can comprise OX40 (Sahin et al, pg. 43, paragraphs 2-3). It is noted that improving proliferation and cytotoxic capacity is inherent to the addition of the synergistic domain.
Regarding claim 6, Sahin et al teach the C-terminus of the CAR receptor is linked to the N-terminus of the synergistic domain (Sahin et al, Figure 3).
Regarding claims 7 and 10, Sahin et al teach the fusion protein binding domain and costimulatory domains can be connected via linker (Sahin et al, pg. 13, paragraph 3 and figure 3). Regarding claim 10, it is noted that the spacer used to link the binding domain to the transmembrane domain in order from N-terminus to C-terminus (Sahin et al, Figure 3).
Regarding claims 21 and 23, Sahin et al teach an isolated nucleic acid encoding the fusion protein and a cell expressing the fusion protein (Sahin et al, pg. 102, claims 33 and 34).
Regarding claim 22, Sahin et al teach a vector comprising the nucleic acid (Sahin et al, pg. 32, paragraph 4- pg. 33, paragraph 1).
Regarding claim 25, Sahin et al teach a pharmaceutical composition comprising a cell expressing the nucleic acid and a pharmaceutically acceptable adjuvant (Sahin et al, pg. 81, paragraph 5).
Regarding claim 26, Sahin et al teach the method of treating cancer in a subject with a pharmaceutical composition comprising the cell in a subject (Sahin et al, pg. 103, claim 38).
Regarding claim 27, Sahin et al teach the cancer can be lymphoma, gastric cancer, and pancreatic cancer (Sahin et al, pg. 72, paragraph 3 and pg. 73, paragraph 4).
Regarding claim 40, Sahin et al teach the T- cells can be derived from PBMCs (Sahin et al, pg. 70, paragraph 5).
Therefore the instant claims are prima facie obvious over the conflicting claims in view of Sahin et al.
Claim(s) 3 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of Application No 18047750 in view of Sahin et al (WO2016180782, published 11/17/2016), as applied to claims 1, 2, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40, and further in view of Soto et al (WO03082919, published 10/09/2003).
The invention of the conflicting claims and Sahin et al does not recite a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprises instant SEQ ID NO: 24. This deficiency is remedied by Soto et al.
The teachings of Soto et al are detailed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the invention of the conflicting claims and Sahin et al with the teachings of Soto et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprise instant SEQ ID NO: 24. One of ordinary skill in the art would have been motivated to do so, because as indicated above, Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Soto et al, one of ordinary skill in the art would have been motivated to include an OX40L synergistic domain comprising instant SEQ ID NO: 24. As such one of ordinary skill in the art would have been motivated to modify the invention of the conflicting claims and Sahin et al, which teaches the fusion protein comprising a CAR and an OX40L synergistic domain, to further include an OX40L synergistic domain comprising instant SEQ ID NO: 24, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an OX40L synergistic domain, is effective in treating cancer. The invention of the conflicting claims, Sahin et al, and Soto et al meets the limitations of claims 3 and 20.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of Application No 18047750 in view of Sahin et al (WO2016180782, published 11/17/2016), as applied to claims 1, 2, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40, and further in view of Brulliard et al (EP2080812, published 07/22/2009).
The instant claims and the conflicting claims both recite a fusion protein comprising a CAR against CLDN18.2 and costimulatory domains. However, the conflicting claims do not recite a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprises instant SEQ ID NO: 25. This deficiency is remedied by Brulliard et al.
The teachings of Brulliard et al are discussed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the invention of the conflicting claims and Sahin et al with the teachings of Brulliard et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprise instant SEQ ID NO: 25. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Brulliard et al, one of ordinary skill in the art would have been motivated to include an CCR7 synergistic domain comprising instant SEQ ID NO: 25. As such one of ordinary skill in the art would have been motivated to modify the invention of the conflicting claims and Sahin et al, which teaches the fusion protein comprising a CAR and synergistic domain, to further include an CCR7 synergistic domain comprising CCR7, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an CCR7 synergistic domain, is effective in treating cancer. The invention of the conflicting claims, Sahin et al and Brulliard et al meets the limitations of claims 4-5.
Claim(s) 1, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of Application No 18159887 in view of Sahin et al (WO2016180782, published 11/17/2016).
The instant claims and the conflicting claims both recite a fusion protein comprising a CAR and costimulatory domains. However, the conflicting claims do not recite a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain. This deficiency is remedied by Sahin et al.
The teachings of Sahin et al are detailed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the conflicting claims with the teachings of Sahin et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. As such one of ordinary skill in the art would have been motivated to modify the conflicting claims, to further include an OX40L synergistic domain comprising OX40L, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an OX40L synergistic domain, is effective in treating cancer. The invention of the conflicting claims and Sahin et al meets the limitations of claims 1, 3 and 20.
Regarding claim 9 and 12, it is noted that an scFV is a single-chain antibody.
Regarding claim 11, it is noted that the antibody comprises a CLDN18.2 binding domain, a transmembrane domain, a costimulatory domain and intracellular signaling domain.
Regarding claim 14 and 16, it is noted that the transmembrane costimulatory domain is CD28.
Regarding claim 18, the intracellular domain is a CD3z signaling domain.
Regarding claims 2, 16, 28, and 34 Sahin et al teach the costimulatory domains can comprise OX40 (Sahin et al, pg. 43, paragraphs 2-3). It is noted that improving proliferation and cytotoxic capacity is inherent to the addition of the synergistic domain.
Regarding claim 6, Sahin et al teach the C-terminus of the CAR receptor is linked to the N-terminus of the synergistic domain (Sahin et al, Figure 3).
Regarding claims 7 and 10, Sahin et al teach the fusion protein binding domain and costimulatory domains can be connected via linker (Sahin et al, pg. 13, paragraph 3 and figure 3). Regarding claim 10, it is noted that the spacer used to link the binding domain to the transmembrane domain in order from N-terminus to C-terminus (Sahin et al, Figure 3).
Regarding claims 21 and 23, Sahin et al teach an isolated nucleic acid encoding the fusion protein and a cell expressing the fusion protein (Sahin et al, pg. 102, claims 33 and 34).
Regarding claim 22, Sahin et al teach a vector comprising the nucleic acid (Sahin et al, pg. 32, paragraph 4- pg. 33, paragraph 1).
Regarding claim 25, Sahin et al teach a pharmaceutical composition comprising a cell expressing the nucleic acid and a pharmaceutically acceptable adjuvant (Sahin et al, pg. 81, paragraph 5).
Regarding claim 26, Sahin et al teach the method of treating cancer in a subject with a pharmaceutical composition comprising the cell in a subject (Sahin et al, pg. 103, claim 38).
Regarding claim 27, Sahin et al teach the cancer can be lymphoma, gastric cancer, and pancreatic cancer (Sahin et al, pg. 72, paragraph 3 and pg. 73, paragraph 4).
Regarding claim 40, Sahin et al teach the T- cells can be derived from PBMCs (Sahin et al, pg. 70, paragraph 5).
Claim(s) 3 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of Application No 18047750 in view of Sahin et al (WO2016180782, published 11/17/2016), as applied to claims 1, 2, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40, and further in view of Soto et al (WO03082919, published 10/09/2003).
The invention of the conflicting claims and Sahin et al does not recite a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprises instant SEQ ID NO: 24. This deficiency is remedied by Soto et al.
The teachings of Soto et al are detailed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the invention of the conflicting claims and Sahin et al with the teachings of Soto et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the OX40L synergistic domain comprise instant SEQ ID NO: 24. One of ordinary skill in the art would have been motivated to do so, because as indicated above, Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Soto et al, one of ordinary skill in the art would have been motivated to include an OX40L synergistic domain comprising instant SEQ ID NO: 24. As such one of ordinary skill in the art would have been motivated to modify the invention of the conflicting claims and Sahin et al, which teaches the fusion protein comprising a CAR and an OX40L synergistic domain, to further include an OX40L synergistic domain comprising instant SEQ ID NO: 24, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an OX40L synergistic domain, is effective in treating cancer. The invention of the conflicting claims, Sahin et al, and Soto et al meets the limitations of claims 3 and 20.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of Application No 18159887 in view of Sahin et al (WO2016180782, published 11/17/2016), as applied to claims 1, 2, 6-7, 9-12, 14, 16, 18, 21-23, 25-28, 34, and 40, and further in view of Brulliard et al (EP2080812, published 07/22/2009).
The instant claims and the conflicting claims both recite a fusion protein comprising a CAR and costimulatory domains. However, the conflicting claims do not recite a fusion protein comprising a CAR and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprises instant SEQ ID NO: 25. This deficiency is remedied by Brulliard et al.
The teachings of Brulliard et al are discussed above and incorporated herein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Sahin et al with those of Brulliard et al to arrive at a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR wherein the CCR7 synergistic domain comprise instant SEQ ID NO: 25. One of ordinary skill in the art would have been motivated to do so, because Sahin et al teach a fusion protein comprising a CAR targeting CLDN18.2 and a synergistic domain that can improve the tumor cell killing capacity of the CAR. Furthermore based upon the teachings of Brulliard et al, one of ordinary skill in the art would have been motivated to include an CCR7 synergistic domain comprising instant SEQ ID NO: 25. As such one of ordinary skill in the art would have been motivated to modify the invention of the conflicting claims and Sahin et al, which teaches the fusion protein comprising a CAR and synergistic domain, to further include an CCR7 synergistic domain comprising CCR7, because there would have been a reasonable expectation that the resultant invention, which comprises a CAR targeting CLDN18.2 comprising an CCR7 synergistic domain, is effective in treating cancer. The invention of the conflicting claims, Sahin et al and Brulliard et al meets the limitations of claims 4-5.
Conclusion
No claim is allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642