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 .
Response to Amendment
The rejection of claims 143, 145, 147, 148 and dependent claim 146 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the removal of the broad term “solid tumor” in claim 143, addition of the term “additional” in claims 145-148, and further defining the target antigen in claim 148 as a VEGF inhibitor.
Specification
The disclosure is objected to because of the following informalities: The specification recites SEQ ID NO: 13, 111 and 122 in Table 1. These are sequences of fewer than 4 amino acids or fewer than 10 nucleotides; however, the actual sequences do not appear in the Sequence Listing but are represented by "000" in accordance with ST.26 sequence filing. As a result, those SEQ ID NOs must be replaced with the actual amino acid sequence (see instant Table 1).
Claim Objections
Claim 142 is objected to because of the following informalities: The claim recites SEQ ID NO:13, which is a sequence of fewer than 4 amino acids and shown as “000” in the Sequence Listing (filed under ST.26). It must be replaced with the actual amino acid sequence WAS.
Appropriate correction is required.
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.
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Claims 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49, 51-61 and 63-80 of U.S. Patent No. US 10,851,165 B2 (‘165) in view of Champiat et al. (J. Thorac. Oncol. 9(2):144-153, Feb. 2014, cited in the IDS filed 12/18/2024) and Port et al. (Front. Oncol. 4:63, 11 pages, doi.org/10.3389/fonc.2014.00064, 14 April 2014, cited in the IDS filed 12/18/2024) for the reasons set forth in the previous Office action and as recast here to better address Applicant’s arguments.
The instant claims and patented claims are both drawn to a method of treating cancer comprising administering an antibody that binds human PD-L1 and has the sequence set forth in claims 1, sections (a)-(d), and 66-68 of ‘165, which are the same as in instant claims 142 and 152-154. IgGs and sequences thereof for the antibody are set forth in claims 70-71 of ‘165 and instant claims 156-157. The binding domain may be an Fab, Fv or scFv (claim 69 of `165 and instant claim 155). Properties of the antibody and its form as a humanized, monospecific or bispecific antibody are in claims 72 and 73 of ‘165 and instant claims 158-159. A bispecific antibody molecule comprising the claimed PD-L1-binding site and a second antigen binding site which binds PD-1 are claimed (claim 73-74 of ‘165 and instant claim 159-160). Types of cancer, including hematological (e.g., lymphoma), renal cell carcinoma, melanoma, lung (specifically NSCLC), triple negative breast cancer, glioblastoma, hepatocellular carcinoma and MIS-high cancer are set forth in claims 2-18 of ‘165 and instant claims 143-155. An additional therapeutic of claims 20-21 of ‘165 are the same as instant claims 146-147. Claims 23-49, 51-53 and 55-60 of ‘165 further define the additional therapeutic and are the same as or encompass those of instant claims 148-149. Claim 52 of ‘165 specifically recites a cancer vaccine (see instant claim 148). The dose of the anti-PD-L1 antibody is about 1-30 mg/kg (claims 63-64 of ‘165 and instant claim 150) and administration is once every 1, 2, 3 or 4 weeks (claim 65 of ‘165 and instant claim 151). The patent does not claim treatment including an AKT inhibitor.
Champiat et al. teaches treatment of non-small-cell lung cancer (NSCLC) by immune checkpoint blockers, including those targeting PD-1 or PD-L1 (p. 144, col. 2, second paragraph). It is reported that PD-L1 is expressed by many cancer types as well as in approximately 50% of NSCLCs. “Indeed, one important mechanism for tumor cells to escape the immune system is by overexpressing PD-1 ligands on their surface.” (p. 145, col. 2, second paragraph). Monoclonal antibodies targeting PD-1 or PD-L1 have shown “significant clinical activity against several tumor types,” as recorded in Table 1, which lists the clinical trials for the antibodies (p. 145, last paragraph and Table 1). The anticancer agent, erlotinib, an EGFR tyrosine kinase inhibitor, significantly downregulates Akt signaling (p. 147, col. 2, fourth paragraph). Also, it has been shown that activation of P13K/Akt pathway in glioma, breast and prostate cancers can lead to increased PD-L1 expression, while in vitro cancer cell line PD-L1 expression was downregulated with P13k/Akt inhibitor treatment (p. 148, col. 1). “There is a strong rationale to combine immune checkpoints with a number of therapeutics.” This includes for treatment of melanoma and NSCLC (p. 149, col. 1, second paragraph). Also, two cancer vaccines for NSCLC are in phase III trials (p. 149, paragraph bridging cols. 1-2). It is discussed that (p. 150, first paragraph):
A major reason for combination is that it may help to eliminate drug-resistant clones. As previously described, NSCLC patients treated by targeted therapies like erlotinib, gefitinib, or bevacizumab ultimately develop drug resistance leading to tumor growth. Drug resistance is often owed to downstream activation of alternative pathways and nevertheless, some of these alternative signaling can potentially lead to upregulation of immune checkpoints at the surface of the drug-resistant cell. Therefore, combination of a targeted drug with an immune checkpoint blocker can be possibly used to extend efficacy against drug-resistant mutants and to improve duration of response.
There is also a suggestion that blocking immune checkpoints at different levels may have a synergistic effect (e.g., Fig. 1 legend and p. 144, col. 2, third paragraph).
Porta et al. teaches targeting the PI3K/Akt/mTOR signaling pathway for cancer treatment. It is discussed that activation of the P13K/Akt/mTOR pathway in cancer appears to be crucial for cancer growth and cell survival, leading “to a competitive growth advantage, metastatic competence, angiogenesis, and therapy resistance.” (p. 1, col. 1, second and fourth paragraphs) Akt/PKB can inactivate proapoptotic factors, and has been linked to increased resistance of prostate cancer cells to TRAIL-mediated apoptosis. It is reported that compounds targeting the Akt ATP binding site, PH domain, LINK and other protein substrates site of Akt have been made, and some are in preclinical or clinical trials (Table 3 and p. 6, end of col. 1). Inhibitors of mTOR, a molecule downstream in the AKT pathway that depends on mitogen-drive signaling through P13K/Akt (though it can also be activated through the Ras/MEK/ERK pathway), rapamycin or prodrug thereof, have been approved for treatment of advanced renal cell carcinoma (RCC) and mantle cell lymphoma (Fig. 1 and p. 3, col. 1, third full paragraph, and col. 2, second paragraph). Everolimus is also a mTOR inhibitor that has been approved for treatment of advanced RCC (p. 4, col. 1, fourth full paragraph). It is concluded, “Novel agents targeting P13K/Akt/mTOR promise further improvement of the results achieved so far through higher selectivity and potency, as well as to combinability with other therapeutic strategies.”
It would have been obvious to the artisan of ordinary skill to have included for the treatment of cancer a combination of anti-PD-L1 antibody, i.e., one of the claimed antibodies, and an AKT inhibitor. Porta et al. taught that the Akt pathway is critical for cancer cell survival and that targeting the pathway with combination treatments is promising. Champiat et al. teaches that Akt pathway activation in a number of cancers increases expression of PD-L1, an anti-cancer target, on the surface of cancer cells, while inhibition has been shown to decrease PD-L1 expression on cancer cells. Further, Champiat et al. states that drug resistance of cancers may be caused by upregulation of immune checkpoints on drug-resistant cells, and a targeted drug in addition to an immune checkpoint blocker, e.g., an anti-PD-L1 antibody, may improve duration of response to the blocker. As a result, it would have been desirable to have combined inhibition of PD-L1 using an antibody thereto with an Akt inhibitor to decrease PD-L1 expression on cancer cells and inhibit cancer cell survival, for which the prior art provides a reasonable expectation of success, and to potentially inhibit drug-resistance to an immune checkpoint blocker.
Applicant argues (p. 15 of REMARKS) that combining Champiat and Porta do not provide motivation for the skilled artisan to modify the ‘165 patent to include an AKT inhibitor. Neither reference suggests any additive or synergistic effects between an anti-PD-L1 antibody and AKT inhibitor. The only relationship between the combined agents is that activation of Akt correlates with increased expression of PD-L1 and inhibition of Akt decreases expression of PD-L1. No reason is provided “why a skilled artisan would be motivated to use both inhibiting agents when inhibition of Akt itself has the desired checkpoint inhibition effect (i.e., decreased PD-L1).” (emphasis by Applicant) Therefore, the skilled artisan would not have inferred a benefit by combining the two drugs, so there would have been no motivation for their combined use. The arguments have been fully considered but are not persuasive. An artisan of ordinary skill would have been motivated to have combined two treatments which had both been shown to be effective for the treatment of cancer but worked through different mechanisms and had a reasonable expectation of success based on the known performance of each alone. Further, Applicant has not shown that or provided a preponderance of evidence supporting that the combination of an anti-PD-L1 antibody, particularly one claimed, and an AKT inhibitor produces unexpected results related to the treatment of a cancer. Champiat et al. clearly states there is a strong rationale to combine immune checkpoints with other cancer therapies to, for example, “optimize different aspects of the immune response:…” (p. 149, col. 1, second and third paragraphs) Also (ibid at (p. 150, first paragraph), “Therefore, combination of a targeted drug with an immune checkpoint blocker can be possibly used to extend efficacy against drug-resistant mutants and to improve duration of response.” Champiat et al. provides clear suggestion and motivation to combine therapeutic agents for treatment of cancer, principally immune checkpoint blockers with other agents such as PI3k/Akt inhibitors. Porta et al. also supports the use of Akt inhibitors in cancer therapy to reduce the action of Akt in cancer growth and cell survival and in inhibition of proapoptotic proteins. There would have been a reasonable expectation of success in the treatment of cancer with the combination beyond that of only the PD-L1 antibody because of the additional activities that Akt has which affect cancer cells, e.g., increasing PD-L1 expression and cancer cell growth and survival, as discussed by the prior art. The rejection is maintained.
Conclusion
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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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
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