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 .
Summary
Receipt of Applicant’s Remarks/Amendments and Restriction/Elections filed on 01/06/2026 and Remarks filed on 7/30/2026 are acknowledged.
Claims 1-14, 16-23, 27-31, 34, 38-43, 45-49, 51, 52, and 56 are pending.
Claims 15, 24-26, 32-33, 35-37, 44, 50, 53-55 are cancelled.
Claims 2-14, 16-23, 27, 29-31, 34, 38-43, 45-49, 51, 56 have been amended.
Election/Restrictions
Applicant elects Group I with traverse, claims 1-13, 16, 23, 23, 28-31, 34, 38-42, 45, 51 and 52.
Claims 14, 17-20, 27, 43, 46-49 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The election is made FINAL.
Claims 1-13, 16, 22-23, 28-31, 34, 38-42, 45, 51 and 52 are pending and under examination in this application. This is a new ground of rejection necessitated by the newly cited Utku and Hennenfent references, which were not of record in the prior Office Action. This is a new non-final Office Action.
Priority
The current application filed on 02/21/2023 is a 371 of PCT/EP2021/073034 filed 08/19/2021, which in turn claims priority to patent application GB2012954.0 and GB2012956.5 filed on 08/19/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/05/2026, 10/25/2024 and 05/22/2023 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-13, 16, 22, 23, 28-31, 34, 38-42, 45, 51 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Utku (WO 2011/127948 A1 in view of Spira (KR 20200014947A), in view of Liu (US 20090118354A1) and further in view of Hennenfent “Novel formulations of taxanes: a review. Old wine in a new bottle?”.
Utku teaches analogues of etoposide for the treatment of patients having a tumor, and also relates to an in vitro method of selecting a respective patient for treatment with an analogue of etoposide (abstract).
Spira teaches lyophilized pharmaceutical preparation comprising a cytotoxic dipeptide (melphalan flufenamide) and one or more excipient (s) selected from the group consisting of polysorbate, polyethylene glycol and benzyl alcohol (¶ 0001a).
Liu teaches liquid pharmaceutical formulation for parenteral administration comprising docetaxel or a pharmaceutically acceptable salt thereof, one or more glycols, and a pharmaceutically acceptable nonaqueous solvent system, wherein the formulation has a pH meter reading in the range of from 2.5 to 7 (abstract).
Hennenfent teaches an overview of novel formulations of taxanes, their mechanisms of action, pharmacokinetics, dose and administration, adverse effects, clinical efficacy and due to their poor solubility profiles, the necessary inclusion of surfactant vehicles (Cremophor EL and polysorbate 80) have long comprised as the standard solvent system for paclitaxel and docetaxel (abstract).
Regarding claim 1, Utku discloses a liquid pharmaceutical formulation of etoposide toniribate (referred to therein as CAP7.1, a compound of Formula I where X = O, n = 1, R1 = R2 = H, p. 6), comprising a nonionic surfactant (polyethoxylated castor oil) and ethanol in a 50:50 ratio (“Formulation of CAP7.1,” Example 10: “CAP7.1 is presented in 3 mg strengths as a solution for intravenous infusion. The active ingredient is solubilised in 20 ml polyethoxylated castor oil (e.g. Cremophor EL®) and ethanol (50:50) in glass vials before dilution into sterile sodium chloride (0.9%) for infusion.”).
Utku does not expressly disclose polysorbate as the nonionic surfactant, instead disclosing polyethoxylated castor oil (Cremophor EL). However, Hennenfent establishes that Cremophor EL and polysorbate 80 are art-recognized, functionally interchangeable nonionic surfactants used to solubilize poorly water-soluble antineoplastic small molecules for intravenous administration, each long-established as “the standard solvent system” for one of a pair of structurally related taxanes (paclitaxel and docetaxel, respectively) (p. 735), and further establishes that Cremophor EL is associated with “clinically relevant acute hypersensitivity reactions” (p. 735). Spira independently teaches polysorbate 80 as a solubilizing surfactant, in a working range of 10-50%, in a liquid parenteral formulation of a structurally analogous poorly water-soluble cytotoxic small molecule (page 3, ¶ 7). It would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the polysorbate 80 of Spira for the Cremophor EL of Utku’s CAP7.1 formulation, with a reasonable expectation of success, because Hennenfent establishes the two are art-recognized equivalents performing the identical solubilizing function for the same class of compound in the same route of administration, and because doing so would reduce the risk of hypersensitivity reaction, a recognized and documented advantage. See MPEP 2144.06(II) (art-recognized equivalents used for the same purpose need only be disclosed in the prior art to support a finding of obviousness).
The resulting combination discloses a liquid pharmaceutical formulation comprising etoposide toniribate, a polysorbate, and ethanol, as recited in claim 1.
Regarding claims 2-11, directed to concentration ranges of the recited components, Spira (page 3, ¶ 7) and Liu (¶ 0129, Examples 1-9) disclose overlapping concentration ranges for polysorbate and ethanol in comparable cytotoxic small-molecule IV formulations. Where the claimed ranges overlap the ranges disclosed in the prior art, a prima facie case of obviousness exists. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Selection of a workable concentration within the overlapping, art-disclosed ranges is a matter of routine optimization within the level of ordinary skill.
Regarding claims 12, 13, and 34, directed to pH ranges, Liu expressly identifies pH as a variable affecting the solubility and/or stability of a poorly water-soluble cytotoxic small molecule formulated in an ethanol/surfactant vehicle for intravenous use (¶¶ 0032-0038, disclosing and preferring a pH range of 2.5-7, more preferably 3-7, most preferably 4-6). This constitutes express recognition of pH as a result-effective variable for the relevant class of formulation, satisfying the predicate required by In re Antonie, 559 F.2d 618 (C.C.P.A. 1977). Because the claimed pH ranges fall within and overlap Liu’s disclosed ranges, discovery of an optimum value within this established range is obvious. In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955); In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).
Regarding claims 16 and 45, directed to an infusion solution or kit comprising the formulation of claim 1 and a diluent, Utku’s Example 10 itself teaches dilution of the CAP7.1 concentrate with sterile 0.9% sodium chloride to prepare the infusion solution. Liu additionally teaches water for injection and 5% glucose as art-recognized, interchangeable intravenous diluents for a comparable cytotoxic formulation (¶ 0084). Selection among these art-recognized diluent options is obvious.
Regarding claims 22, 23, 51, and 52, directed to kit embodiments further comprising benzyl alcohol and/or an ethanol/water diluent mixture, Spira teaches benzyl alcohol and an ethanol/water diluent system in a kit embodiment for a comparable cytotoxic formulation (page 12, ¶¶ 1, 16), and Liu independently teaches benzyl alcohol as a preservative in the same class of formulation (¶¶ 0037, 0039, 0105). Combining these art-recognized, function-appropriate components with the base formulation of claim 1/16 is obvious for the reasons discussed above.
Regarding claim 28 (independent), the combination of Utku, Spira, and Liu renders obvious a liquid pharmaceutical formulation comprising etoposide toniribate, PEG, a polysorbate, ethanol, and benzyl alcohol, for the same reasons discussed with respect to claim 1, with the further combination of PEG 300 and benzyl alcohol as taught by Spira, which discloses these excipients together with polysorbate in a single formulation for a comparable cytotoxic small molecule (page 4, ¶ 7 and last paragraph). Each of PEG 300, polysorbate, and benzyl alcohol is combined performing its known function (co-solubilizer, primary solubilizing surfactant, and preservative, respectively), and combining prior art elements according to known methods to yield predictable results is obvious. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Regarding claims 29-31, directed to concentration ranges, see the analysis of claims 2-11 above; Spira (page 4, ¶ 7) and Liu (¶ 0129) disclose overlapping ranges for the corresponding components.
Regarding claim 38, directed to citric acid, Spira (page 6, ¶ 17) and Liu (¶¶ 0037, 0039, 0105) each teach citric acid as a pH-adjusting agent in the same class of formulation. Its inclusion is obvious for the reasons discussed with respect to claims 12, 13, and 34.
Regarding claims 39-42, directed to dehydrated/anhydrous ethanol, Liu teaches ethanol as a solvent/co-solvent in the claimed formulation class (¶ 0108). Selection of dehydrated (low water content) ethanol as opposed to standard-grade ethanol is a matter of routine purity selection within the level of ordinary skill, particularly where water content is understood to affect the stability of a formulation already recognized (via Liu) as sensitive to aqueous conditions; no unexpected result has been shown for this purity selection.
Response to Arguments
Applicant’s remarks filed 07/30/2026 have been fully considered but are moot in view of the new ground of rejection necessitated by the newly cited Utku and Hennenfent references.
Regarding Point I (references fail to teach etoposide toniribate): Persuasive as to Aitani, Spira, and Liu individually as previously combined — that rejection has accordingly been withdrawn. It is not persuasive as to the new rejection: Utku expressly teaches etoposide toniribate (CAP7.1) as a liquid formulation for intravenous administration, solubilized in an ethanol-containing vehicle and diluted for infusion (Ex. 10). Applicant’s argument that formulations developed for etoposide are not presumptively applicable to etoposide toniribate is acknowledged and is precisely why the rejection no longer relies on an etoposide reference for the API — Utku is a reference to etoposide toniribate itself.
Regarding Point II (no reason to combine references directed to different pharmaceutical systems): Not persuasive as applied to the new combination. Utku, Spira, and Liu are not directed to different active ingredients requiring cross-API extrapolation — Utku supplies the claimed API in an ethanol/nonionic-surfactant IV vehicle, and Spira/Liu are directed to the same general class of poorly water-soluble cytotoxic small molecules formulated in the same solvent family (ethanol, polysorbate, PEG, benzyl alcohol) for the same route of administration (IV infusion, following dilution). The rejection identifies an explicit, documented reason (Hennenfent) for substituting Utku’s surfactant, rather than relying on generic overlap of disclosed elements or hindsight.
Regarding Point III (result-effective variables not established): Not persuasive in view of Liu, which expressly identifies pH as a variable governing the stability/solubility of a structurally and functionally analogous poorly water-soluble cytotoxic small molecule formulated in an ethanol/surfactant vehicle for IV use (Liu ¶¶ 0032-0038). This satisfies the “recognized as result-effective” predicate of In re Antonie; optimization of the claimed pH range, which falls within Liu’s disclosed and preferred ranges, is accordingly obvious under In re Aller.
Regarding Point IV (inherency legally insufficient): Moot. The new rejection does not rely on inherency for the pH limitation; it relies on Liu’s express teaching, as discussed above.
Regarding Point V (unexpected results/advantages not addressed by the art): Not persuasive on the present record. Applicant has not provided a showing, commensurate in scope with the claims, comparing the claimed formulations against the closest prior art — which is now Utku’s Cremophor/ethanol CAP7.1 formulation (Ex. 10), not “conventional formulations” generally. Should Applicant provide such a comparative showing against Utku specifically, it will be fully considered.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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