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 1-67, 75, 76, 80, 82, 84, 85, and 89-96 have been cancelled. Claim 68 has been amended.
Claims 68-74, 77-79, 81, 83, 86-88, and 97 are pending and under examination.
2. The objection to claim 68 is withdrawn in response to applicant’s arguments.
Claim Objections
3. Claim 68 is objected to because of the recitation “obtaining an activated T-cell” in the last line. Correction to “obtaining the activated T-cell” is required.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 68-74, 77, 83, 86-88, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Pease (PGPUB 2012/0141537), in view of all Davenport et al. (PNAS, 2015, 115: E2068-E2076), Edes et al. (Mol. Ther., May 2016, 24: S201-S202), and Ebert et al. (Mol. Immunol., 2005, 42: 799-809), as evidenced by Tubo et al. (Cell, 2013, 153: 785-796).
Pease teaches in vivo activating the naïve self-reactive CD8+ T-cells in a subject having cancer, to focus the autoimmune cellular responses against cancer; the subject could be a human and activation occurs by administering an adenovirus encoding a modified MHC class I polypeptide having one or more amino acid changes from the wild-type (i.e., allogeneic), to generate primed self-reactive CD8+ T-cells capable of lysing the cancer cells expressing the self-antigen; administration could be subcutaneous (claims 68-70, 77, and 86) owever, activating (see Abstract; [0003]; [0005]-[0006]; [0009]; [0020]; [0038]-[0041]; [0043]; [0045]; [0048]; [0057]; [0072]). As evidenced by Tubo et al., each naïve T-cell comprises a different native TCR (see p. 785, column 1). Thus, by administering the allogeneic MHC class I polypeptide, Pease produces a polyclonal response of activated CD8+ T-cells, each comprising a different native TCR (claims 68 and 88).
Pease does not teach further administering a nucleic acid encoding a tumor-specific CAR (claims 68, 71, 72, and 87). Davenport et al. teach that dual-specific T-cells expressing a TCR recognizing an MHC class I antigen present on cancer cells and a CAR recognizing a different antigen present on the same cancer cells are capable of serially killing the targets tumor cells; Davenport et al. teach that the dual-specific T-cells could be tuned to the desired response depending on the disease status, resulting in a more rapid serial killing (via the CAR; when the initial disease burden is high) or a slower but more protracted killing (via the TCR; for tumor relapse) (see Abstract; paragraph bridging p. E2068 and E2069; p. E2069, column 1, first full paragraph; p. E2073, column 1, last paragraph and column 2; p. E2074, column 1, first paragraph and paragraph bridging columns 1 and 2). Furthermore, Edes et al. teach that the CD8+ T-cells could be transduced in vivo by intravenously administering a CD8-targeted retroviral vector encoding the desired heterologous antigen receptor (see Abstract 506). Based on these teachings, one of skill in the art would have found obvious to modify Pease by further administering a CD8-targeted retroviral vector encoding a CAR recognizing a different antigen present on the tumor cells expressing the self-antigen, with the reasonable expectation that doing so would generate CD8+ T-cells suitable to treat the cancer in the human subject, where the CD8+ T-cells are capable of eradicating large tumor burden as well as controlling residual cancer (claims 73, 74, and 83).
Pease, Davenport et al., and Edes et al. teach administering the CAR-encoding retroviral vector intravenously, not into a lymph node (LN) (claim 68). However, the prior art teaches that the naïve T-cells circulate between the blood and LNs in search for antigen-presenting DCs (see Ebert et al., Abstract). One of skill in the art would have reasonably concluded that, similar to intravenous administration, direct administration to a LN would also result in the transduction of naïve CD8+ T-cells. Using direct administration to a LN would have been obvious to one of skill in the art to achieve the predictable result of activating the naïve self-reactive CD8+ T-cells.
It is noted that administering the adenoviral encoding the modified MHC class I polypeptide as taught by Pease would have produced a polyclonal response and would have activated more than 2.5% of the CD8+ T-cells in the LNs of the subject (including the LN used to further administer the CAR-encoding retroviral vector) because all that is required to achieve this is to administer the MHC class I-encoding adenovirus before administering the CAR-encoding retroviral vector (claim 68). The claims do not require more than this and the specification does not teach more than this.
Pease, Davenport et al., Edes et al., and Ebert et al. do not teach that the MHC class I polypeptide has the amino acid sequence set forth by SEQ ID NO: 3 (claim 97). However, 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 that specifically using the polypeptide set forth by SEQ ID NO: 3 leads to unexpected results.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 68-74, 77, 78, 81, 83, 86, 88, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Pease taken with all Davenport et al., Edes et al., and Ebert et al., as evidenced by Tubo et al., in further view of Yang et al. (Nat. Biotechnol., 2008, 26: 326-334).
The teachings of Pease, Davenport et al., Edes et al., and Ebert et al. are applied as above for claims 68-74, 77, 83, 86, 88, and 97. Pease, Davenport et al., Edes et al., and Ebert et al. teach administering the adenovirus subcutaneously, not intradermally (claim 78). Yang et al. teach that subcutaneous administration of viral encoding tumor antigens results in dendritic cells (DCs) transduction and their migration to lymph nodes (LNs) to activate the resident naïve CD8+ T-cells to effect anti-tumor activity (see Abstract; p. 326, column 1, last paragraph; paragraph bridging p. 328 and 329; p. 332, column 2). Yang et al. teach that DCs are resident in the dermis (see p. 332, column 2, second paragraph). One of skill in the art would have found obvious to replace the subcutaneous injection of the modified MHC class I polypeptide-encoding adenovirus with intradermal injection, to achieve the predictable result of activating the naïve self-reactive tumor-specific CD8+ T-cells.
With respect to claim 81, Yang et al. teach that retroviruses and LVs are capable of transducing the same cell type (see p. 326, column 1, second paragraph) and thus, one of skill in the art would have reasonably concluded that an LV could be used instead of the retrovirus to transduce the CD8+ T-cells in vivo. Replacing the retrovirus with an LV would have been obvious to one of skill in the art to achieve the predictable result of obtaining genetically engineered CD8+ T-cells expressing the tumor-specific CAR.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
7. Claims 68-74, 77, 79, 83, 86, 88, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Pease taken with all Davenport et al., Edes et al., Ebert et al., and Ebert et al., as evidenced by Tubo et al., in further view of Sixt et al. (Immunity, 2005, 22: 19-29).
The teachings of Pease, Davenport et al., Edes et al., and Ebert et al. are applied as above for claims 68-74, 77, 83, 86, 88, and 97. Pease, Davenport et al., Edes et al., and Ebert et al. do not teach administering the adenovirus to a LNs (claim 79). Sixt et al. teach that LNs comprise resident DCs (see Abstract). One of skill in the art would have found obvious to administer the MHC class I-encoding adenovirus to the same LN to transduce the resident DCs with the reasonable expectation that the transduced resident DCs would activate the LN resident naïve CD8+ T-cells.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
8. The arguments addressing Davenport individually are not found persuasive because the reference does not have to teach or suggest every claim limitation. The fact that Davenport does not teach generating the T-cells in vivo is not evidence of non-obviousness. 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).
Pease already generates activated self-reactive CD8+ T-cells in vivo (via the administration of an adenovirus encoding an allogeneic MHC class I antigen); these cells already express a TCR recognizing the self-antigen (MHC class I antigen) and lyse the cancer cells expressing the self-antigen. Thus, Pease already practices the first method step of claim 68, i.e., administering the virus encoding the allogeneic MHC class I antigen.
Davenport teaches the advantages of using dual T-cells (expressing a TCR recognizing an MHC class I antigen on cancer cells and a CAR recognizing a different antigen on the same cancer cells) for cancer therapy. Based on Davenport, one of skill in the art would have found obvious to modify Pease by further administering a CAR-encoding vector to generate dual self-reactive CD8+ T-cells in vivo. By doing so, one of skill in the art would have practiced the second step of claim 68, i.e., administering the CAR-encoding nucleic acid.
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 argument that there would be no reason to activate the cells in Edes as they are already activated is not material to the rejection because the rejection is not based on and does not state activating the cells in Edes. Similar considerations apply to the argument that there is no teaching or suggestion for changing the administration order in Edes.
Edes was only cited for teaching that CARs could be introduced into CD8+ T-cells in vivo by using a CAR-encoding retroviral vector targeted to CD8+ T-cells.
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
9. 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.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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