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 .
1. Claims 1-13, 15-18, 20-23, 28, 34, 36-39, 41, and 48-56 have been cancelled. Claims 24-26 have been withdrawn. Claim 30 has been amended.
Claims 14, 19, 27, 29-33, 35, 40, 42-47, and 57-61 are under examination.
2. The rejection of claim 30 under 35 U.S.C. 112(b) is withdrawn in response to the amendment deleting the term “Th17” from the claim.
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 14, 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 expressing a CAR having
the ICOS costimulatory domain exhibit enhanced function, persistence, and anti-tumor activity as compared to the Th17 cells expressing a CAR 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 as 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 on 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.
5. Claims 14, 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, 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.
6. Claims 14, 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, 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.
7. Claims 14, 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, 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.
8. Claims 14, 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, 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 Th17 cells costimulated with ICOS exhibit enhanced persistence in vivo; they also enhance the in vivo persistence of CD8+ T-cells (for at least 43 days) and 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.
9. Claims 14, 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, 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
10. The applicant argues that the teaching of TCR-directed T-cells in Martin-Orozco does not provide the motivation for extrapolation to CAR-directed T-cells, nor does Martin-Orozco provide the reasonable expectation of success in doing so. The applicant argues that the examiner did not provide references establishing that TH17 cells exhibit the same properties regardless of whether they are activated via a TCR or a CAR.
These arguments are not found persuasive because they are not supported by the evidence of record. Firstly, Martin-Orozco clearly provides the motivation. Secondly, Martin-Orozco does not have to provide a reasonable expectation of success. The reasonable expectation of success is provided by June. The portions cited by the applicant from Exhibits 1 and 2 do not provide any evidence to the contrary (it is again noted that Exhibits 1 and 2 were not provided).
Martin-Orozco teaches that Th17 cells enhance the activation, recruitment, and proliferation/persistence of tumor specific CD8+ T-cells. Thus, Martin-Orozco provides the motivation to modify Campana by including Th17 cells. While Martin-Orozco does not specifically teach ICOS, both Campana and June provide the motivation to use CAR-ICOS Th17 cells. June also provides evidence that CAR-ICOS Th17 cells exhibit enhanced persistence and antitumor activity compared to CAR-4-1BB Th17 cells. Thus, June provides the reasonable expectation of success.
Paulos was only cited for addressing the limitations of claim 59, not for providing the motivation to combine. The applicant is right in pointing out that the Paulos does not teach CAR-ICOS Th17 cells. However, Paulos teaches that the CAR-4-1BB Th17 cells costimulated with ICOS (i.e., via their TCR) exhibit enhanced in vivo persistence and also promote the enhanced in vivo persistence of CD8+ T-cells. Thus, the combined teachings of June and Paulos indicate that ICOS signaling in Th17 cells results in the same properties regardless of whether these cells express TCR or CAR-ICOS.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
For the reasons above, the argument that Paulos teaches away is not found persuasive. There is no teaching to this effect in Paulos or the prior art of record.
With respect to the argument that June does not trach CD8+ T-cells expressing different CARs as recited in claim 14, it is noted that none of the references has to teach every claim limitation.
The applicant argues that, due to the differences between TCRs and CARs, Stephan’s results are not extrapolatable with a reasonable expectation of success.
This argument is not found persuasive because it is just an argument not supported by any evidence. Stephan teaches that the independent and concomitant activation of 4-1BB and CD28 co-stimulatory pathways in the same CD8+ T-cell results in synergistic anti-tumoral activity. One of skill in the art would have reasonably concluded that co-expressing a 4-1BB CAR and a CD28 CAR recognizing the same tumor antigen in a CD8+ T-cell would provide independent and concomitant synergistic activation of the 4-1BB and CD28 pathways via a single signal from the tumor cells, without the need for a second signal from cells expressing the 4-1BB and CD28 ligands. MPEP 2141.03 states:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
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The "hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
The applicant argues that June teaches away from using two CARs. The applicant argues that June’s disclosure would have led to using a CAR ICOS/4-1BB in the CD4+ T-cell (i.e., Th17 cell).
However, the claims require two CARs in a CD8+ T-cell, not a Th17 cell.
The passage indicated by the applicant only relates to Th17 cells (p. 66, line 12 through p. 67, line 2). Thus, the passage is not material to the effect of 4-1BB and CD28 when activated independently and concomitantly in the same CD8+ T-cell. There is nothing in June teaching away from the independent and concomitant stimulation of 4-1BB CAR and a CD28 in the same CD8+ T-cell, as motivated by Stephan.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
11. 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 ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ILEANA POPA/ Primary Examiner, Art Unit 1633
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