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 .
Claims Status
The amendments and remarks filed 10/08/2025 are acknowledged.
Claims 1-2, 4-8, 10-12, 14-18, and 20-21 are pending.
Claims 1, 10-11, and 14-16 are amended.
Claims 3, 9, 13, 19, and 22 are canceled.
Claims 7, 18, and 20-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/05/2025.
Claims 1-2, 4-6, 8, 10-12, and 14-17 read on the elected species and are therefore under examination.
Withdrawn
The objections to the drawings are withdrawn. Applicant has amended the specification and submitted replacement drawings to overcome the objections.
The objections to claims 14-16 are withdrawn. Applicant has amended the claims to overcome the objections.
The rejections of claims 1-6 and 8 under 35 U.S.C. 112(a) are withdrawn. Applicant has amended claim 1 to overcome the rejections.
The rejections of claims 1-6 and 8 under 35 U.S.C. 112(b) are withdrawn. Applicant has amended claim 1 to overcome the rejections.
The rejection of claim 13 under 35 U.S.C. 112(d) are withdrawn. Applicant has canceled the claim to overcome the rejection.
The rejections of claims 1-2, 5-6, 8-11, and 17 under 35 U.S.C. 102 are withdrawn. Applicant has amended claim 1 to overcome the rejections.
Maintained Rejections
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4-6, 8, 10-11, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Woessner (WO 2016062722; 09/05/2024 PTO-892) in view of Moleculin Biotech, 2018 (04/10/2025 PTO-892).
Regarding claims 1-2, 4, 10 and 17, Woessner teaches a method of treating cancer (disease; proliferative disease) with an immunomodulator, such as an immune checkpoint inhibitor, and an antisense compound targeted to STAT3 (transcription inhibitor) in a subject in need thereof [page 3, lines 8-10], and that the type of cancer that the combination treatment is proposed for includes breast cancer, pancreatic cancer, and lymphoma [page 4, lines 9-14]. Woessner further teaches that the patient with cancer is administered (i) at least one immunomodulatory agent (immune checkpoint inhibitor) and (ii) an antisense compound targeted to STAT3 (transcription inhibitor) in pharmaceutically effective amounts [page 39, lines 24-26].
However, Woessner does not teach that the STAT3 inhibitor is a α,β-unsaturated cyanocarboxamide or WP1732.
Moleculin Biotech teaches WP1732 (transcription inhibitor, α,β-unsaturated cyanocarboxamide), an immune-stimulating STAT3 inhibitor, that targets pancreatic cancer (disease) [page 1, third paragraph], and that WP1732 has the ability to inhibit activated STAT3, which is widely considered a key transcription factor involved in the development and progression of tumors [page 2, second paragraph]. Moleculin Biotech further teaches that WP1732 has demonstrated significantly different organ distribution in animal models [page 2, second paragraph], is suited for intravenous administration [page 2, third paragraph], and preclinical testing has shown its properties make it a promising candidate for treating pancreatic cancer [page 2, seventh paragraph].
Applicant states at paragraph 18 of the instant specification that WP1066, WP1732, and other α,β-unsaturated cyanocarboxamide-containing compounds have a potent anti-tumor effect, thus implying that WP1732 is a α,β-unsaturated cyanocarboxamide. Absent evidence to the contrary, the Examiner is interpreting WP1732 as being a α,β-unsaturated cyanocarboxamide, as set forth in instant claim 3.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Woessner and to have substituted the STAT3 inhibitor of Woessner to be the STAT3 inhibitor (i.e. WP1732) of Moleculin Biotech. One would have been motivated to make this modification because Moleculin Biotech teaches that WP1732 inhibits STAT3, which is widely considered a key transcription factor involved in the development and progression of tumors, and has shown to be a promising candidate for treating pancreatic cancer. Further, it would have been obvious to make this modification because Woessner and Moleculin Biotech both teach STAT3 inhibitors for the treatment of pancreatic cancer, and it is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)).
Claim 5 is included in this rejection because Woessner teaches that the immunomodulator can include an anti-PD-L1 antibody, an anti-PD1 antibody, and an anti-CTLA-4 antibody [page 3, lines 10-12].
Claim 6 is included in this rejection because Woessner teaches that the anti-PD1 antibody can be pembrolizumab [page 3, lines 31-32 – page 4, line 1].
Claim 8 is included in this rejection because Woessner teaches that the anti-CTLA-4 antibody can be ipilimumab [page 3, lines 31-32 – page 4, line 1].
Claim 11 is included in this rejection because Woessner teaches that the method of treating cancer can decrease or retard cancer tumor growth (i.e. inhibits the survival or proliferation of cancer cells) [page 43, lines 24-25].
Claims 1-2, 4-6, 8, 10-12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Woessner (WO 2016062722; 09/05/2024 PTO-892) in view of Moleculin Biotech, 2018 (04/10/2025 PTO-892), as applied to claims 1-2, 4-6, 8, 10-11, and 17 above, and further in view of Skelton et al., 2017 (04/10/2025 PTO-892).
The teachings of Woessner and Moleculin Biotech are above. Further, Woessner teaches that treatment with the STAT3 inhibitor resulted in an increase in tumor infiltrating CD45+ cells [page 49, lines 23-30] and also teaches enhanced antitumor activity of combination treatment vs. single agents, and that treatment with the STAT3 inhibitor enhances the activity of immune checkpoint inhibitors [page 53, 1-4]. Woessner further teaches that the combination activity results in an increase in antitumor immune infiltrates in the tumor, which enables enhanced inhibition of tumor growth when immune checkpoints are blocked by treatment with therapeutics targeting PD-L1 and CTLA-4 [page 53, lines 4-8].
However, Woessner and Moleculin Biotech do not specifically teach that the patient has previously failed to respond to the administration of an immune checkpoint inhibitor.
Regarding claim 12, Skelton teaches that a combination approach to immunotherapy is needed to overcome resistance to immune checkpoint inhibitors as pancreatic ductal adenocarcinoma (PDAC) does not respond to single-agent checkpoint inhibitors [see Abstract]. Skelton also teaches that anti-CTLA-4 and anti-PD-1 antibodies can work through a complementary mechanism [page 60, left column, fourth paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have treated a patient with pancreatic cancer that has previously failed to respond to the administration of an immune checkpoint inhibitor with the method taught by Woessner and Moleculin Biotech. One would have been motivated to treat this patient population with the method taught by Woessner and Moleculin Biotech because Skelton teaches that a combination approach to immunotherapy is needed to overcome resistance to immune checkpoint inhibitors as pancreatic ductal adenocarcinoma (PDAC) does not respond to single-agent checkpoint inhibitors, and Woessner teaches that the combination treatment results in an increase in antitumor immune infiltrates in the tumor, which enables enhanced inhibition of tumor growth when immune checkpoints are blocked by treatment with therapeutics targeting PD-L1 and CTLA-4. Thus, since Skelton teaches that PDAC does not respond to single-agent checkpoint inhibitors, one skilled in the art could reasonably assume that a patient with pancreatic cancer would have failed to respond to the administration of an immune checkpoint inhibitor, but that there would be a reasonable expectation of success in treating the patient with the method (i.e. combination therapy) taught by Woessner and Moleculin Biotech.
Claims 1-2, 4-6, 8, 10-11, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Woessner (WO 2016062722; 09/05/2024 PTO-892) in view of Moleculin Biotech, 2018 (04/10/2025 PTO-892), as applied to claims 1-2, 4-6, 8, 10-11, and 17 above, and further in view of Funakoshi et al., 2004 (04/10/2025 PTO-892).
The teachings of Woessner and Moleculin Biotech are above.
However, Woessner and Moleculin Biotech do not specifically teach further administering an anti-cancer therapy, wherein the anti-cancer therapy is chemotherapy, and wherein the chemotherapy is irinotecan.
Regarding claims 14-16, Funakoshi teaches administering irinotecan (CPT-11) to patients with metastatic pancreatic cancer with ten patients showing a partial response (PR) with a median survival rate of 7.3 months [see Abstract]. Funakoshi concludes that CPT-11 is effective for metastatic pancreatic cancer [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating pancreatic cancer, as taught by Woessner and Moleculin Biotech, to further comprise administering irinotecan, as taught by Funakoshi. One would have been motivated to make this modification because Funakoshi teaches that irinotecan is an effective treatment for pancreatic cancer. This follows the logic of MPEP 2144.06 which 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). Therefore, it would have been obvious to combine the separate, known compositions for the same purpose of treating pancreatic cancer.
Response to Arguments
On pages 10-12 of the remarks, Applicant argues that Woessner teaches away from the administration of small molecule inhibitors of STAT3, pointing to Figure 6 of Woessner that demonstrated the addition of AZ-JAK1 to anti-PD-L1 antibody or anti-CTLA-4 antibody antagonized the antitumor activity of the antibodies, resulting in tumor growth rates, and arguing that Woessner teaches that the combination activity of STAT3 antisense oligonucleotides plus anti-PD-L1 antibody treatment cannot be replicated and is in fact antagonized by other approaches to inhibition of JAK/STAT. This is not found persuasive because firstly, the AZ-JAK1 is a JAK1 inhibitor, not a STAT3 inhibitor, and while JAK1 and STAT3 work together in the JAK-STAT signaling pathway, the AZ-JAK1 inhibitor is targeting JAK1 and not STAT3 as instantly claimed. Secondly, this is a misinterpretation of the teachings of Woessner. Woessner clearly indicates that targeting STAT3 enhances antitumor activity of antibodies targeting PD-L1 [see Example 3]. Woessner is stating that this enhanced antitumor activity is from the specific inhibition of STAT3 and these results cannot be replicated by inhibiting a different target in the JAK/STAT pathway, which is demonstrated by the JAK1 inhibitor example. Thus, based on the teachings of Woessner, one of skill in the art would specifically target STAT3 instead of another target of the JAK/STAT pathway.
On page 13 of the remarks, Applicant argues that Moleculin does not use the α,β-unsaturated cyanocarboxamide WP1732 in combination with an immune checkpoint inhibitor, and as such, Moleculin does not teach any advantages of WP1732 in combination with an immune checkpoint inhibitor over other types of STAT3 inhibitors in the treatment of proliferative disease. This is not found persuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On pages 13-14 of the remarks, Applicant argues surprising and unexpected results of synergistic effects of the combination for WP1066 or WP1732 with anti-PD-1/CTLA-4 antibodies, pointing to Examples 1 and 2 and Figure 1A of the instant specification. The arguments of alleged unexpected, synergistic results are not persuasive. Regarding Figure 1A which displays the results of Example 1, while these results are potentially persuasive suggesting that the combination of WP1066 and an CTLA-4/PD-1 antibody is unexpectedly better than WP1066 or the CTLA-4/PD-1 antibody alone, these results are not commensurate in scope because again, the claims are directed to the broad genus of any α, β-unsaturated cyanocarboxamide and any immune checkpoint inhibitor, and not specifically to WP1066 and the CTLA-4/PD-1 antibody used in Example 1. Regarding Figure 2A, which displays the results of Example 2, these results are not commensurate in scope because the claims are directed to a broad genus of any α,β-unsaturated cyanocarboxamide and any immune checkpoint inhibitor, and not specifically to WP1732 and the CTLA-4/PD-1 antibody used in Example 2. Further, even if the claims were commensurate in scope,
the results in Example 2 demonstrate additive effects, not unexpected synergistic effects. Example 2 teaches about a 30% survival at about 2.5 days post implantation with each of the WP1732 alone and the CTLA4/PD1 antibody alone, but teaches a 30% survival at about 4.5 days post implantation with the combination of the WP1732 and CTLA4/PD1 antibody. A person of ordinary skill in the art would expect that when two individual therapeutics that each have a 30% survival at about 2.5 days post implantation would result in an additive effect of 30% survival at about 4.5 days post implantation. On page 14 of the remarks, Applicant argues that the synergistic effect of α,β-unsaturated cyanocarboxamide combined with CTLA-4/PD-1 antibodies could not have been predicted from Woessner or Moleculin, or their combination, since Woessner teaches only the benefit of using a STAT3 ASO as a mechanism of inhibition, and Moleculin does not teach combinations with immune checkpoint inhibitors. This is not found persuasive because to reiterate, the alleged unexpected results are not commensurate in scope with the claims and further, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675