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 .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/CN2021/116194, filed 09/02/2021, which claims the priority benefit of CHINA Application No. 202010910072.5, filed 09/02/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/28/2022, 03/14/2023, 11/15/2023, 03/19/2024, 09/13/2024, and 12/18/2024 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claims 1-8, 10-11 and 14 are pending in this application. Claims 1 and 11 have been amended. Claim 14, is withdrawn from further consideration for covering non-elected species or inventions from the 05/09/2025 office action. Claims 9, 12-13 and 15-22 have been canceled by applicant, without prejudice or disclaimer. Claims 1-8, and 10-11 are currently under examination.
Applicant’s arguments, filed 12/17/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 09/24/2025 Office Action and modified in order to address the most recent amendments.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-8, and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ashley (U.S. Patent 6,893,859 B2) in view of Bahrami (U.S. Pub. 2019/0194278 Al) and further in view of Felton (Essentials of Pharmaceutics).
The instant claims are directed to a solid oral formulation comprising utidelone as
an active ingredient and a hydrophilic pharmaceutically acceptable excipient is a micro pellet capsule or tablet comprises 2-10% or 30-70% (w/w) of pharmaceutical excipients and 20-60% (w/w), and a sustained-release pharmaceutical excipient, and optionally a surfactant.
Ashley et al. teach methods of use and formulation of epothilone compound
derivatives of formula I for treatment of a disease or condition characterized by cellular
hyperproliferation, including cancer (Abstract). Ashley also teaches an embodiment of formula I as 10, 11-dehydroepothilone D (col 2, lines 52-67). Ashley also discloses contemplation of alternative stereochemistry of disclosed compounds "[u]nless stereochemistry is specifically indicated, all stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof" (col. 13, lines 6-9). Ashley discloses "[a] composition of the present invention generally comprises a compound of the present invention and a pharmaceutically acceptable carrier. The inventive compound may be in free form or where appropriate as pharmaceutically acceptable derivatives such as prodrugs, and salts and esters of the inventive compound. The composition may be in any suitable form such as solid, semisolid, or liquid form." and that the active ingredient may be compounded non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, and stabilizing agents may be used (col. 34, lines 30-56). Ashley also teaches the composition of the invention comprises a compound of formula I and a pharmaceutically acceptable carrier including polyethoxylated castor oil which is typically used as a surfactant and be in a solid form as tablets or capsules (col. 37, lines 29-34). Ashley also teaches that the inventive compound of formula I may be formulated as microcapsules or nanoparticles by adjusting the ratio of surface area to volume to facilitate oral administration (col. 35, lines 1-10). Ashley also discloses "[t]he term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated" (col. 13, lines 54-60). Ashley discloses that active ingredients and carrier materials used to produce a single dose will vary depending on the subject being treated and the method of administration, and cites an example in which a formulation is diluted between 2-30 fold (col. 36 lines 8-17). Ashley also discloses that the amount of compound in a composition is in a range of 50-95% or more by weight of the components of the composition (col. 16, lines 9-14). Ashley also teaches in example 35, a method to prevent toxicity in a patient wherein a pretreatment regiment of corticosteroids can be used to prevent anaphylaxis in patients when using compositions comprising polyethoxylated castor oil (Cremophor®), (col. 83, lines 43-51 ). Ashley also discloses naturally occurring epothilones, including epothilone D, can have its structure modified through semi synthesis or produced by de novo synthesis for use as anti-cancer agents (col. 2, lines 18-39).
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10, 11-dehydroepothilone D
(epothilone D)
However, Ashley et al. fail to disclose the specific 10, 11-dehydroepothilone D
(epothilone D) analog known as utidelone.
Bahrami et al. teach utidelone as a preferred epothilone [0138] Bahrami also teaches that an epothilone is a chemotherapeutic agent [0134]. Bahrami also teaches treatment of cancer in a subject comprising co-administering a therapeutically effective amount of a chemotherapeutic and/or immunotherapeutic agent to subject in need thereof [0133]. Bahrami also discloses the use of the poloxamer Kolliphor® as a nonionic emulsifier [0121 ]. Bahrami teaches an example in which tablets or capsules are optionally formulated as slow-release tablets/capsules [0125].
Felton et al. teach high molecular weight (high viscosity grade) nonionic cellulose ethers, and more specifically, hydroxypropyl methylcellulose (HPMC, also referred to as hypromellose). "The popularity of HPMC can be attributed to its flexibility to obtain desired drug release profiles, cost-effectiveness, and broad safety and regulatory acceptance" (pg. 628, col 2, 3rd para.).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to combine Ashley's disclosure of a solid composition of 10, 11-dehydroepothilone D (epothilone D), polyethoxylated castor oil in formulated as microcapsules or nanoparticles for oral administration with Bahrami's teaching of a chemotherapeutic agent of utidelone (a stereoisomer of epothilone D), and poloxamers into a slow release tablet because the combination of the teachings with Felton's disclosure of hypromellose because doing so would enhance the solubility and bioavailability of utidelone which would eliminate the reliance of other methods of administration such as being restricted to intravenous injections which can be prone to adverse reactions from certain excipients such as Polyethoxylated castor oil.
It is noted that the limitation of a tablet prepared by micro pellet compression, wherein the micro pellets are pellet cores coated, with a coating layer comprising the active ingredient and said pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises a hydrophilic pharmaceutical excipient a sustained-release pharmaceutical excipient, and optionally a surfactant, and wherein the ratio of the active ingredient to the pharmaceutically acceptable excipient is in the range of 1:1 to 1:30 is a product-by-process claim. See MPEP 2113 and MPEP 2144.05
The term "amorphous" in claims 13 and 22 is being interpreted to mean a noncrystalline form based on the instant specification (p.6, lines 26-27).
A person of ordinary skill in the art would have been motivated to combine the teachings of Ashley, Bahrami and Felton because administering utidelone in an oral composition and pharmaceutical excipients would preferably reduce potential toxicity in patients rather than administration using intravenous methods which may use excipients such as Polyethoxylated castor oil and would require use of a pretreatment corticosteroid to reduce potential reactions including anaphylaxis. Following the teachings of Ashley, Bahrami and Felton, a person of ordinary skill in the art would have had a reasonable expectation of success in arriving at an oral formulation of utidelone and a pharmaceutical excipient to provide the instantly claimed composition. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, based on the current record.
Response to Arguments and Declaration
Applicant's arguments and declaration filed 12/17/2025 have been fully considered but they are not persuasive.
Applicant argues the pending claims are not obvious over the cited references, at least because none of the cited references disclose a formulation comprising utidelone, as an active ingredient, is present in an amorphous or molecular form in a solid formulation, nor do they suggest that a compound having utidelone in an amorphous or molecular form in a solid formulation exhibits unexpected technical effects (e.g., improved stability, solubility, and bioavailability).
As disclosed above in the previous office action dated 09/24/2025, Bahrami et al. teach utidelone as a preferred epothilone [0138]. Furthermore, Bahrami teaches utidelone as a preferred compound as an active ingredient in [0103] following [0099] which states “For instance, the further active ingredient of the pharmaceutical composition can be a chemotherapeutic agent selected from the group consisting of”. The use of utidelone as an active pharmaceutical ingredient would have been obvious from the disclosures of Bahrami.
In response to applicant's declaration and argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., compound having utidelone in an amorphous or molecular form in a solid formulation exhibits unexpected technical effects (e.g., improved stability, solubility, and bioavailability)) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, Ashley (U.S. PAT. 6,893,859 B2) discloses an inventive compound may be formulated as microcapsules and nanoparticles and that an inventive compound may also be formulated using other methods that have been previously used for low solubility drugs. For example, the compounds may form emulsions, liposomes as drug delivery vehicles are well known in the art. Ashley also provides Example 15 as an illustrative protocol for making liposomes containing 10,11-dehydroepothilone D. Ashley also discloses a method formulating an inventive compound using polymers such as polymers such as biopolymers or biocompatible (synthetic or naturally occurring) polymers and conjugating a compound of the present invention to a polymer that enhances aqueous solubility or conjugated to a monoclonal antibody (Col. 35-36).
Applicants are reminded that the burden to demonstrate unexpected results which are commensurate in scope belongs to Applicants. MPEP 716.02(b). Applicants have not demonstrated that the results presented are both unexpected and commensurate in scope with the instant claims. As such, they have not met the burden placed upon them. Accordingly, the argument is unpersuasive and the obviousness rejection is maintained.
Conclusion
All claims are rejected, no claims are allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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