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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 12, 2026 has been entered.
Claim Status
Claims 1-3, 19-27, 53-55, 57, and new claims 59-60 are under consideration in this office action.
New Objections/Rejections Necessitated by Amendment
Claim Objections
Claim 27 is objected to because of the following informalities: claim 28 incorrectly recites “PD-1 pathway monotherapy”; this phrase should read “PD-1 pathway inhibitor monotherapy”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 19-20, 22-24, 26-27, 53 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.
Claims 19 and 53 recite the limitation "the recombinant fusion protein”. There is insufficient antecedent basis for this limitation in the claim.
Claim 20 recites the limitation "the CD25 component”. There is insufficient antecedent basis for this limitation in the claim.
Claims 22-24 and 26-27 recite the limitation “the cytotoxic fusion monotherapy”. These claims are dependent from claim 1, which does not include a monotherapy limitation. There is insufficient antecedent basis for this limitation in the claim.
Claims 22, 24, and 26 recite the limitation “the PD1-pathway inhibitor monotherapy”; claim 27 recites the limitation “the PD-1 pathway monotherapy”. There is insufficient antecedent basis for these limitations in the claims.
Claims 57 and 60 are included in this rejection for failing to cure the indefiniteness of the base claim.
Claim Rejections - 35 USC § 103
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.
Claims 1-2, 5-6, 11, 19-27, 53-58 and new claims 59-60 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019173478A2, published September 12, 2019 (“Bishai”; IDS from December 30, 2021) in view of US 2019/0367607 A1, published December 5, 2019 (”Tedder”; PTO-892 from 12/18/2023) and Varga et al, published online December 3, 2018 (instant PTO-892).
Instant claims 1 and 53 are directed to a method of treating a subject with uterine corpus cancer, cervical cancer, or ovarian cancer, wherein the subject has been previously treated with a PD-1 pathway inhibitor, comprised of intravenously administering a composition comprising a monomeric cytotoxic fusion protein diphtheria toxin fragment A and B and human IL-2 of SEQ ID NO: 1 (herein referred to as “cytotoxic fusion protein”) at 6-12 mg/kg/day and intravenously administering the PD-1 pathway inhibitor pembrolizumab at 200-500 mg.
Bishai teaches a recombinant cytotoxic protein (i.e. denileukin diftitox) comprised of the sequences for diphtheria toxin fragments A and B and the sequence for human IL-2 (pg 1, ln 13-15), as in the cytotoxic fusion protein of instant claims 1 and 53. Bishai teaches a process to produce a C. diphtheriae-derived analogue of E. coli derived denileukin diftitox in which the protein is secreted in fully soluble form and is monomeric (pg 43, ln 4-6). E. coli-derived denileukin diftitox (Bishai SEQ ID NO: 10), which is identical to instant SEQ ID NO: 1, and C. diphtheriae-derived denileukin diftitox (Bishai SEQ ID NO: 13) have polypeptide sequences that differ by one amino acid; the E. coli-derived protein has an N-terminal methionine residue, which is absent in the C. diphtheriae protein (pg 3, ln 3-7). This methionine is removed as a result of cleavage of the signal sequence (pg 38, ln 5-7). As these two variants of denileukin diftitox are structurally similar and functionally identical, it would have been obvious to one of ordinary skill in the art to substitute one for the other. One would do so with a reasonable expectation of success, because there is no evidence of criticality for the N-terminal methionine in the sequence of E. coli derived denileukin diftitox. Thus, Bishai teaches the cytotoxic fusion protein of SEQ ID NO: 1 of instant claim 1.
SEQ ID NO: 58 of Bishai consists of C diphtheriae-derived denileukin diftitox (i.e. Bishai SEQ ID NO: 13) and a six histidine tail for affinity purification. The formulation for SEQ ID NO: 58 is >97% pure (see Fig 23), as required by instant claims 1 and 53-54.
Bishai teaches a dual sequential therapy comprised of administration of cytotoxic fusion protein followed by administration of an inhibitor of PD-1 for the treatment of cancer (pg 72, ln 10-15), as in instant claim 1. In a preferred embodiment, the checkpoint inhibitor of Bishai is the anti-PD-L1 antibody pembrolizumab (pg 10, ln 9-14), as in instant claims 1 and 53. Bishai teaches that PD-1 blockade enhances anti-tumor responses to produce durable clinical responses in some patients; for those who do not respond to these inhibitors, combinatorial drug regimens may be required to improve clinical outcomes (pg 3, ln 15-20; pg 67, ln 6-17). Thus, Bishai teaches the limitation wherein the subject exhibits resistance to treatment with PD-1 inhibitor therapy prior to administration of the monomeric cytotoxic fusion protein and the PD-1 pathway inhibitor, as in instant claims 1, 53 and new claims 59-60
The compositions of Bishai are suitable for administration for intravenous administration (pg 94, ln 24-25), as in instant claims 1 and 53.
Bishai teaches that the subject is human (pg 32, ln 20-22), as in instant claim 2.
Bishai teaches that Ontak alone has clinical efficacy for the treatment of ovarian carcinoma (pg 65, ln 14-22), as in amended claims 1 and 53.
Treatment with the method comprising cytotoxic fusion of protein and inhibitor of PD-1 pathway of Bishai depletes cells expressing CD25 (see Figure 31) and induces cell death of tumors (see Figure 32), as in instant claim 20.
Bishai teaches that the dose of the fusion protein may be about 10 mg/kg or about 50 mg/kg and any range derivable therein (pg 88-89), as in the limitation of claims 56 and 58 wherein the fusion protein is administered at a dose of up to 12 mg/kg/day.
Given that Bishai teaches the cytotoxic fusion protein for the treatment of cancer, it would have been obvious to the ordinary artisan to use a composition comprising the cytotoxic fusion protein of Bishai of SEQ ID NO: 58, which is at least 95% monomeric protein, and the PD-1 pathway inhibitor pembrolizumab to treat a subject with cancer. Although SEQ ID NO: 58 is not identical to instant SEQ ID NO: 1, the burden is upon the applicant to demonstrate that the cytotoxic fusion protein of Bishai is different from the instantly claimed protein, such that Bishai’s cytotoxic fusion protein cannot have the intended use/functionality, thereby establishing patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ2d 1922(PTO Bd. Pat. App. & Int. 1989).
Bishai does not teach a dose for the PD-1 pathway inhibitor pembrolizumab, as required by claims 1 and 53, or sequential administration of PD-1 pathway inhibitor followed by cytotoxic fusion protein, as required by claims 19 and 53.
Tedder teaches a method for enhancing anti-tumor response by combining the cytotoxic fusion protein (i.e. denileukin diftitox) with a PD-1 inhibitor [0086]. An exemplary anti-PD-L1 inhibitor taught by Tedder is pembrolizumab, which may be administered about 0.5 mg/kg to about 5 mg/kg [0063], as in instant claims 1 and 53. Weight based dosing can be converted to a flat dose using a conversion factor of 80, as the median body weight for adults is approximately 80 kg, as evidenced by Walpole et al (PTO-892 from 3/10/2025). The weight-based dose of Tedder of 0.5 mg/kg to 5 mg/kg, when converted to a flat dose, is 40-400 mg, which overlaps with the 200-500 mg dose range of pembrolizumab in the limitations of claims 1, 53, 55, and 57.
Claims 21-27 are directed to expected results with combination therapy comprising a cytotoxic fusion protein and PD-1 pathway inhibitor, where the treatment is effective to prolong survival compared to PD-1 pathway inhibitor monotherapy or cytotoxic fusion protein monotherapy. Bishai in view of Tedder teaches the combination therapy of pembrolizumab and cytotoxic fusion protein of the instant claims. Therefore, it would be expected, absent any evidence to the contrary, that using the dual sequential therapy of Bishai would inhibit the growth and/or proliferation of cancer cells (as in claims 21-22) and prolong the survival of the subject (as in claims 23-27), because the antibodies and method steps of treatment of Bishai are the same as the instant claims. The results of claims 21-27 would have been predicted because the therapeutic components and method are taught by Bishai in view of Tedder. Since the cytotoxic fusion protein and pembrolizumab compositions satisfy all structural limitations set forth in the claims, it necessarily follows that the antibody carrier inherently possesses the functionality and the ability to serve the intended use recited in the claims, absent objective evidence to the contrary.
Bishai does not teach administration of a PD-1 pathway inhibitor before administering the cytotoxic fusion protein or simultaneously with the cytotoxic fusion protein. Indeed, Bishai discourages use of this dosing strategy. This is because treatment with cytotoxic fusion protein is associated with the killing of effector T cells and Tregs and treatment with PD-1 pathway inhibitors increases effector T cell activity; thus, treatment with cytotoxic fusion protein with or after PD-1 pathway inhibitor treatment would be expected to decrease the tumor inhibitory activity of the PD-1 pathway inhibitor (pg 71, ln 14-19). Accordingly, cytotoxic fusion protein administration preceded by PD-1 inhibitor treatment would be expected to have decreased tumor-inhibitory activity compared to PD-1 inhibitor treatment alone or treatment with sequential dual therapy wherein cytotoxic fusion protein treatment precedes checkpoint inhibitor therapy, as in Bishai (pg 71, ln 14-19).
Tedder, however, teaches a method for enhancing anti-tumor response by combining the cytotoxic fusion protein (i.e. denileukin diftitox) with a PD-1 inhibitor [0086]. As seen in figure 14C of Tedder, coadministration of the cytotoxic fusion protein denileukin diftitox with PD-1 inhibitor significantly decreased tumor volume when the two agents were administered simultaneously compared to vehicle control, denileukin diftitox (i.e. Ontak) alone, and PD-1 inhibitor alone in a murine model of carcinoma [0027]. This experiment demonstrates that the simultaneous administration of cytotoxic fusion protein and PD-1 inhibitor is efficacious in the treatment of carcinoma, as in claim 53.
Regarding claims 19 and 53, when considered in view of the findings of Tedder, efficacy of the administration protocol wherein PD-1 inhibitor is administered first followed by cytotoxic fusion protein is not wholly unexpected. Despite the misgivings of Bishai regarding simultaneous or prior administration of PD-1 pathway inhibitor with cytotoxic fusion protein, Tedder has clearly demonstrated that simultaneous administration is efficacious.
Therefore, it would have been obvious to one of ordinary skill in the art to administer the cytotoxic fusion protein and PD-1 inhibitor of Bishai simultaneously with or prior to cytotoxic fusion protein. One would have been motivated to administer them simultaneously or PD-1 pathway inhibitor prior to cytotoxic fusion protein because Tedder had already demonstrated that this combination was associated with significant reduction in tumor volume, more so than PD-1 inhibitor alone (see Figure 14C).
Although Bishai teaches a method of treating ovarian cancer with the cytotoxic fusion protein, Bishai in view of Tedder does not teach a method of treating ovarian cancer comprising administration of the cytotoxic fusion protein and the anti-PD-L1 antibody pembrolizumab.
Varga et al teaches that pembrolizumab has antitumor activity in patients with advanced PD-L1-positive ovarian cancer. Varga et al teach a dose of 10 mg/kg every 2 weeks (pg 247, column 1, para 1). This weight-based dose and the fixed-dose of 200 mg every 3 weeks of pembrolizumab exhibit no difference in efficacy, and these doses are comparable (pg 247, columns 1-2); Varga teaches the dose of 200 mg of instant claims 1, 53, 55, and 57.
Given that Bishai in view of Tedder teach a method of treating cancer comprising the claimed cytotoxic fusion protein and the PD-1 pathway inhibitor pembrolizumab, and further given that Bishai teaches a method of treating ovarian cancer with the cytotoxic fusion protein and Varga teaches a method of treating ovarian cancer with pembrolizumab, it would have been obvious to one of ordinary skill in the art that a combination therapy comprising cytotoxic fusion protein and pembrolizumab could be successfully used for the treatment of subjects with ovarian cancer. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalence for the same purpose: "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 they having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Accordingly, the cumulative reference teachings render obvious the claimed method.
Response to Arguments
Applicant's arguments filed February 12, 2026 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the teachings of Cheung have been considered but are moot because the new ground of rejection does not rely on any teaching or matter of Cheung specifically challenged in the argument.
After revisiting the Bishai reference, the examiner finds that there is support in Bishai for the treatment of a subject that is not completely responsive to anti-PD-1 antibody therapy alone. A new reference, Varga et al, has been added to address the new limitation directed to uterine corpus cancer, cervical cancer, or ovarian cancer.
Conclusion
No claims are allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675