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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/05/2026 has been entered.
Claims 1-13, 15-18, 20-23, 28, 34, 36-39, 41, and 48-56 have been cancelled. Claims 24-26 have been withdrawn. Claims 30 and 40 have been amended. Claims 59-61 are new.
Claims 14, 19, 27, 29-33, 35, 40, 42-47, and 57-61 are under examination.
2. The rejection of claim 40 under 35 U.S.C. 112(d) is withdrawn in response to the amendment to delete the recitation of ICOS set forth by SEQ ID NO: 40.
Claim Rejections - 35 USC § 112(d)
3. 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.
4. Claim 30 is 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “Th17 non-polarized cell” in claim 30 is used by the claim to mean that the CD4+ T-cell is at the same time “non-polarized and a Th17 cell”, while the accepted meaning of a Th17 cell is “a polarized CD4+ T-cell having the Th17 phenotype”. The term is indefinite because the specification does not clearly redefine the term.
For examination purposes, the claim is reasonably interpreted as being drawn to a non-polarized CD4+ T-cell.
Claim Rejections - 35 USC § 103
5. 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 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.
6. Claims 14, 15, 19, 27, 30-33, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. (PGPUB 2005/0113564), in view of all Martin-Orozco et al. (Immunity, 2009, 31: 787-798), Stephan et al. (Nat. Med., 2007, 13: 1440-1449), June et al. (WO 13/126733), and Fukuda et al. (PNAS, 2005, 102: 15213-15218).
Campana et al. teach a composition for cancer therapy comprising genetically-engineered CD8+ T-cells comprising a CAR containing an extracellular antigen binding domain, the CD8[Symbol font/0x61] transmembrane (TM) domain, and an intracellular domain comprising the CD3zeta and 4-1BB (CAR-BBz); the antigen binding domain is an anti-CD19 scFv (claims 14, 19, 32, and 33); the genetically-engineered CD8+ T-cells are obtained by a method comprising providing CD8+ T-cells and introducing into the CD8+ T-cells a nucleic acid encoding the CAR (claims 43 and 44) (see [0012]-[0013]; [0045]; [0047]; [0068]; [0075]-[0079]; [0088]; [0111]; [0115]).
Campana et al. do not teach Th17-polarized CD4+ cells (claims 14, 31, 43, and 44). However, further adding Th17 cells is suggested by the prior art. For example, Martin-Orozco et al. teach that Th17 cells enhance the activation, recruitment, and proliferation (i.e., persistence) of tumor specific CD8+ T-cells necessary for the antitumor effect (see Abstract; paragraph bridging p. 788 and 789; p. 790, paragraph bridging columns 1 and 2; p. 792; p. 793, column 1, first paragraph). Martin-Orozco et al. teach that Th17 and CD8 T-cells directed against tumor antigens could be used together to enhance anti-cancer immunity in cancer patients (see paragraph bridging p. 795 and 796). Based on these teachings, one of skill in the art would have found obvious to modify the composition of Campana et al. by further including genetically engineered Th17 cells comprising the CAR-BBz of Campana et al. to achieve the predictable result of obtaining a composition exhibiting enhanced antitumor activity.
While the CAR-BBz of Campana et al. has the 4-1BB costimulatory domain, Campana et al. teach that 4-1BB costimulation in CD4+ cells is not as efficient as in CD8+ T-cells (see [0115]). June et al. teach that Th17 cells having the ICOS costimulatory domain exhibit enhanced function, persistence, and anti-tumor activity as compared to the Th17 cells having the 4-1BB costimulatory domain; June et al. also teach using ICOS TM to obtain Th17 CARs (claim 14) (see p. 2, lines 7-10; p. 5, lines 11-17; p. 9, lines 1-11 and 18-24; p. 22, lines 15-24; p. 44, lines 10-16; p. 64, lines 1-10; paragraph bridging p. 65 and 66). Thus, modifying Campana et al. and Martin-Orozco et al. by replacing the CD8[Symbol font/0x61] TM and 4-1BB costimulatory domains with the ICOS TM and costimulatory domains would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition with enhanced therapeutic potential. By doing so, one of skill in the art would have obtained a CARCD4+ having CD3zeta as the primary intracellular signaling domain and ICOS as the co-stimulatory domain (CAR-ICOSz) (claims 14 and 43). Since June et al. does not teach that the ICOS domain comprises a mutation, one of skill in the art would have reasonably concluded that June et al. teach the wild-type ICOS and would have found obvious to use the wild-type ICOS as the co-stimulatory signaling domain to obtain the Th17 cells.
Campana et al, Martin-Orozco et al., and June et al. do not teach a second CARCD8+ having a different intracellular signaling domain (claims 14, 32, 33, and 43). Stephan et al. teach that 4-1BB and CD28 co-stimulatory pathways act in synergy with respect to their anti-tumoral activity when independently and concomitantly activated in CD8+ T-cells (see Abstract; p. 1441, Fig. 1; paragraph bridging p. 1441 and 1442; paragraph bridging p. 1442 and 1443; paragraph bridging p. 1446 and 1447). Based on these teachings, one of skill in the art would have found obvious to modify the CD8+ T-cells of Campana et al, Martin-Orozco et al., and June et al. by further introducing a CD19 CAR comprising CD3zeta and CD28 as the intracellular signaling domain with the reasonable expectation that doing so would result in a composition exhibiting synergistic anti-tumoral activity (claims 27 and 32). By doing so, one of skill in the art would have obtained a CARCD8+ having a first CAR comprising CD3zeta/4-1BB as the intracellular domain and second CAR comprising CD3zeta/CD28 as the intracellular domain (claim 14).
With respect to claim 30, using non-polarized CD4+ T-cells may be patentable if it produces an unexpected result over using Th17 cells taught by the prior art. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case there is no evidence of record indicating that using non-polarized CD4+ T-cells leads to unexpected results over using Th17 cells.
With respect to claim 42, kits containing instructions for transfection of cells with non-viral vectors containing nucleic acids have been used before the invention was made. One would have been motivated to assemble a kit, i.e., put the reagents in a box containing instructions how to use the reagents, because they are convenient to use and save time.
With respect to claims 45-47, the cited prior art suggests clinical trials with autologous CAR-T cells (see Campana et al., [0118]-[0119]; see June et al., p. 3, lines 26-33; p. 57, lines 3-7; p. 79, lines 1-9). Thus, formulating the composition of Campana et al., Martin-Orozco et al., Stephan et al., and June et al. with a pharmaceutically acceptable carrier (claim 19) and administering it to a subject affected by cancer would have been obvious to one of skill in the art with the reasonable expectation that doing so would treat the cancer in the subject.
While the cited prior art does not teach that ICOS costimulatory domain is set forth by SEQ ID NO: 46 (claim 14), the only difference between the wild type ICOS and SEQ ID NO: 46 is the Y to F mutation (disclosed as ICOS(FMFM) in the specification, see p. 213, Example 7; see the Sequence Alignment of record). Using the ICOS set forth by SEQ ID NO: 46 to obtain the CARCD4+ may be patentable if it produces an unexpected result over the wild type ICOS taught by the prior art. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case there is no evidence of record indicating that using SEQ ID NO: 46 leads to unexpected results over wild type ICOS.
Furthermore, the ICOS(FMFM) set forth by SEQ ID NO: 46 was taught by the prior art. For example, Fukuda et al. teach that activation of PI3 kinase (PI3K) by ICOS stimulation contributes to T-cell malignancy as diagnosed by multilobulated nucleus formation. Fukuda et al. teach that using the Y180F ICOS mutant (or FMFM mutant) dramatically reduces the frequency of multilobulated nucleus formation upon ICOS stimulation (see Abstract; p. 15213, column 2, second full paragraph; p. 15215, column 2, last paragraph; p. 15216, Fig. 4). Thus, replacing wild type ICOS with the Y180F mutant would have been obvious to one of skill in the art, with the reasonable expectation that doing so would reduce the progression to malignancy of the administered CAR-ICOSz Th cells.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
7. Claims 14, 15, 19, 27, 30-33, 35, 40, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. taken with all Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al., in further view of Powell et al. (WO 13/063419)
The teachings of Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. are applied as above for claims 14, 15, 19, 27, 30-33, and 42-47. Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. do not teach and anti-mesothelin scFv (claims 33, 35, and 40). However, anti-mesothelin scFv (such as ss1) were used in the prior art to obtain CARs. For example, Powell et al. teach that T-cells comprising an anti-mesothelin CAR containing the ss1 scFV (i.e., set forth by SEQ ID NO: 80, see the specification, p. 67), the CD8[Symbol font/0x61] TM, CD3zeta and 4-1BB are useful to treat mesothelin-expressing cancers (p. 2-3; p. 11, lines 7-13). Modifying the composition of Campana et al, Martin-Orozco et al., Stephan et al., June et al, and Fukuda et al. by replacing their anti-CD19 scFv with an anti-mesothelin scFV such as ss1 would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable to treat mesothelin-expressing cancers.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. Claims 14, 15, 19, 27, 29-33, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. taken with all Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al., in further view of Moeller et al. (Blood, 2005, 106: 2995-3003).
The teachings of Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. are applied as above for claims 14, 15, 19, 27, 30-33, and 42-47. Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. do not teach a specific Th1: CD8+ ratio (claim 29). Moeller et al. teach varying the ratio to assess the minimum number of CD4 cells required to achieve total tumor regression (Abstract; p. 2996, column 2, third full paragraph; p. 2998, column 2, second paragraph; p. 3002, column 2, last paragraph). Thus, varying the ratio would have been obvious to one of skill in the art to achieve the predictable result of determining the minimum number of Th17 cells required for the efficient killing of tumor cells.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
9. Claims 14, 15, 19, 27, 30-33, 40, 42-47, 57, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. taken with all Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al., in further view of Prosser et al. (Mol. Immunol., 2012, 51: 263-272).
The teachings of Campana et al, Martin-Orozco et al., Stephan et al., June et al. , and Fukuda et al. are applied as above for claims 14, 15, 19, 27, 30-33, and 42-47. Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. do not teach a PD1 CAR (claims 57 and 58). Prosser et al. teach that using a costimulatory chimeric receptor having the PD1 ECD fused to CD28 transmembrane and cytoplasmic domains overcoming T-cell exhaustion and results in efficient costimulation. Prosser et al. suggest expressing the chimeric receptor together with a CAR for enhanced effect (see Abstract; p. 271, paragraph bridging columns 1 and 2). Based on these teachings, one of skill in the art would have found obvious to replace the anti-CD19 scFv of either CAR with the PD1 ECD with a reasonable expectation that doing so would results in a composition with enhanced therapeutic effect. By doing so, one of skill in the art would have obtained a PD1 CAR comprising the PD1 ECD, CD8[Symbol font/0x61] TM domain, and an intracellular domain comprising the CD3zeta stimulatory and 4-1BB costimulatory domains. As evidenced by the sequence search of record, SEQ ID NO: 27 (claim 58) comprises the PD1 ECD, CD8[Symbol font/0x61] TM domain, and an intracellular domain comprising the CD3zeta stimulatory and 4-1BB costimulatory domains. While the PD1 CAR taught by the cited prior art may not have a sequence identical to SEQ ID NO: 27, the essential components (i.e., PD1 ECD, CD8[Symbol font/0x61] TM domain, CD3zeta stimulatory and 4-1BB costimulatory domains) are taught by the combination of the cited prior art. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence on the record that the PD1 CAR set forth by SEQ ID NO: 27 exhibits unexpected property over the PD1 CAR taught by prior art.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
10. Claims 14, 15, 19, 27, 30-33, 40, 42-47, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. taken with all Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al., in further view of Paulos et al. (Science Translational Medicine, 2000, 27: 1-13).
The teachings of Campana et al, Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. are applied as above for claims 14, 15, 19, 27, 30-33, and 42-47. Campana et al, Martin-Orozco et al., Stephan et al., June et al, and Fukuda et al. do not specifically teach that the CAR-ICOSz Th17 cells enhance the persistence of CD8+ T-cells for at least 33 days (claim 59). Paulos et al. show that CAR-ICOS Th17 cells exhibit enhanced persistence in vivo, enhance the in vivo persistence of CD8+ T-cells for at least 43 days, and enhance antitumor activity (see p. 9, column 2, first paragraph; p. 10, Fig. 7). June et al. teach that administering CAR-ICOSz Th17 in combination with CAR CD8+ T-cells results in complete remission at day 50 (see paragraph bridging p. 65 and 66; Fig. 7A). Based on these teachings, one of skill in the art would have reasonably concluded that the administration of CAR-ICOSz Th17 cells would enhance the in vivo persistence of the CD8+ T-cells cells for at least 43 days.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
11. Claims 14, 15, 19, 27, 30-33, 42-47, 60, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al. taken with all Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al., in further view of Yao et al. (New Engl. J. Med., 2011, 364: 514-523).
The teachings of Campana et al., Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. are applied as above for claims 14, 15, 19, 27, 30-33, and 42-47. Campana et al., Martin-Orozco et al., Stephan et al., June et al., and Fukuda et al. do not teach RAD001 (claims 60 and 61). Yao et al. teach using RAD001 to treat cancer (see p. 514; p.515, column 1). Thus, further adding RAD001 to the pharmaceutical composition of Campana et al., Martin-Orozco et al., Stephan et al., June et al., Fukuda et al. would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in a composition suitable to treat cancer. MPEP 2144.06 I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
12. The applicant argues that, as demonstrated by the specification, using SERQ ID NO: 46 leads to unexpected results over wild type ICOS.
This is not found persuasive. As demonstrated by Fig. 11B in the specification, there is no significant difference between the mutated ICOS set forth by SEQ ID NO: 46 and the wild type ICOS with respect to the anti-tumoral effect; by day 35, the wild type and the mutated ICOS exhibited the same anti-tumoral activity. The specification also discloses that there is no difference with respect to the tumor persistence of CD4+ and CD8+ T-cells (see p. 213, last paragraph; Fig. 11C-D).
Furthermore, the Y180F ICOS mutant set forth by SEQ ID NO: 46 was taught by the prior art; the prior art also provides the motivation to replace the wild type ICOS with the Y180F mutant.
The argument of unexpected results is not found persuasive. That enhanced persistence would be dependent on the CAR used to redirect the Th17 cells was expected from the teachings in the prior art. June provides evidence that CD4+ CAR-ICOS Th17 cells exhibit enhanced persistence and antitumor activity. Paulos provides evidence that both CD4+ T-cells and Th17 cells redirected with CAR-ICOS exhibit enhanced persistence and also enhance the persistence of CD8+ T-cells and antitumor activity (see p. 9, column 2, first paragraph; p. 10, Fig. 7). Fig. 7 in Paulos shows that CAR-ICOS Th17 cells exhibit superior activity compared to the non-polarized CD4+ T-cells.
For these reasons, the arguments addressing Martin-Orozco are not found persuasive. Martin-Orozco, June, and Paulos together provide evidence that Th17 cells exhibit the same properties regardless of whether they are activated via a TCR or a CAR.
The argument of lack of motivation to combine and reasonable expectation of success are not found persuasive because they are just arguments not supported by any evidence.
The applicant refers to Exhibits 1 and 2; these Exhibits were not provided.
13. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633