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 is acknowledged. Claims 1-56 are pending.
Claims 15, 24-26, 32-33, 35-37, 44, 50, 53-55 have been have been cancelled.
Claims 2-14, 16-23, 27, 29-31, 34, 38-43, 44-49, 51, 56 have been amended.
Election/Restrictions
Applicant elects Group I with traverse, claims 1-13, 16, 28-31, 34, 38-42 and 45.
Claims 14, 17-23, 27, 43, 46-49, 51, 52, and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Response to traversal
Upon review of the traversal filed 1/06/2026, the remarks are found persuasive, thus claims 22-23 and 51-52 directed to a kit, will be included in the examination.
Claims 1-13, 16, 22-23, 28-31, 34, 38-42, 45, 51 and 52 are pending and under examination in this application.
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 GB 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 Aitani (JP 2004346023A) in view of Spira (KR 202000114947A) and further in view of Liu (US 20090118354A1).
Aitani teaches local therapeutic agent for prostate cancer comprising ethanol, etoposide, a kit for local treatment of prostate cancer (page 1, ¶ Local treatment for prostate cancer), and the injectable preparation or a solution preparation can be prepared using the anticancer agents etoposide, camptothecins (irinotecan hydrochloride, nogitecan hydrochloride, etc.), doxorubicins (doxorubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, idarubicin hydrochloride, daunorubicin hydrochloride, pirarubicin hydrochloride, amrubicin hydrochloride), Cisplatins (cisplatin, carboplatin, nedaplatin, etc.), taxanes (paclitaxel, docetaxel, etc.), vinca alkaloids (vincristine sulfate, vindesine sulfate, pinolerubin tartrate, etc.), bleomycins (bleomycin hydrochloride, pepromycin sulfate, etc.) , Fluorouracils (fluorouracil, tegafur, gemcitabine hydrochloride, fludarabine phosphate, etc.), or a pharmacologically acceptable salt thereof, various pharmaceutical additives, carriers, stabilizer, preservatives, soothing agents, emulsifiers used as necessary, and Aitani discloses the content of the API anti-cancer drug can be varied over a wide range depending on the preparation form and the like, and is generally 0.01 to 70% (weight), 0.1 to 50 % (weight) and the dose of the API anti-cancer drug or a pharmaceutically salt thereof varies depending on the size and symptoms of the tumor, but etoposide is about 10 to 500mg/day per adult (page 2, top to mid of page). Moreover, Aitani discloses solvent polyethylene glycol (PEG) 400, Tween (polysorbate) 80, etc. and phycological saline (100 µL) with etoposide (20mg/ml) intravenous formulation (page 2, mid to end of page). Notably, Aitani discloses that an advantage of using ethanol as a solvent for an anti-cancer agent is that when the solvent infiltrates inside the tumor, the anti-cancer agent is spread together (page 1, top to mid portion of page). Therefore, it would have been obvious to a person having ordinary skill in the art to be motivated in using ethanol with an anti-cancer agent in a formulation.
Regarding claims 1-13, 16, 22, 23, 28-31, 34, 39-42, 45, 51 and 52, as noted above, Aitani teaches the subject matter, limitations and structural features in the claims (etoposide, polysorbate and ethanol). The claimed variations in the concentrations of etoposide, polysorbate 80, ethanol, and pH represents routine optimization of known result-effective variables. Aitani teaches the use of each component for the same purpose (anti-cancer), and adjusting their relative amounts to achieve desired solubility, stability, and injectability would have been well within the ordinary skill of a person having ordinary skill in the art. The recitation of multiple examples with differing concentrations merely reflects routine experimentation and does not render the claimed composition non-obvious. The dosage strength is inherently adjustable, especially in cancer treatment and formulations, and Aitani teaches that multiple concentrations can be applied to etoposide, polysorbate 80 and ethanol, and selecting a particular mg/ml value is a clinical and formulation optimization that would undoubtably be obvious to a PHOSITA. The polysorbate 80 amount depends on solubility needs, and increasing or decreasing surfactant to maintain solubility is known, thus no new function emerges at specific claimed values, also the co-solvent level is routinely tuned, and a PHOSITA would expect to vary amount of ethanol percentages. The benzyl alcohol concentration is used within known preservative ranges, adjusted to meet antimicrobial effectiveness and safety, and the citric acid concentration is driven by desired pH, adjusted as needed to reach stability window which merely correlates to pH target. The recited pH range of 3.5-7.8 is fairly broad, encompassing nearly all pharmaceutically acceptable injectable pH values. See MPEP 2144.05 --1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105... is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d...
Moreover, in any aqueous or hydro alcoholic injectable (intravenous) solution, the formulation would necessarily have a pH level and failure to specifically disclose a pH does not mean that pH was absent, it simply means that the pH was not expressly measured or reported. The pH range of 3.7 and 5.0 to 7.8 would be considered a variable in IV anti-cancer formulations, especially for etoposide formulations. A PHOSITA would understand that an IV anti-cancer formulations must be; chemically stable, physically compatible, tolerable upon injection and these constraints would necessarily limit pH to a workable range, and etoposide is known to be poorly water soluble, stability is known to depend on acidic to near-neutral pH. Thus, anti-cancer formulations using ethanol, polysorbate 80, and acids can naturally be adjusted to fall into the claimed ranges of 3.7 and 5.0 to 7.8. Therefore, Aitani’s anti-cancer formulation would necessarily possesses a pH, and the pH would expectedly fall within a range suitable for intravenous administration of a drug stability.
Aitani fails to specifically teach water for injection, benzyl alcohol, citric acid and dehydrated ethanol.
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).
Regarding claims 1-13, 16, 22-23, 28-31, 34, 38-42, 45, 51 and 52, Spira teaches lyophilized pharmaceutical formulations, pharmaceutical compositions or kits provided herein may comprise only melphalan flufenamide or a pharmaceutically acceptable salt thereof as an anti-tumor agent, and melphalan flufenamide may also be combined with one or more anti-tumor agent, for example, other anti-tumor agents such as etoposide or other therapeutically effective substances (page 13, last ¶ to page 14, 1st ¶). Moreover, Spira discloses kits or pharmaceutical compositions for use as a medicament, that relates to a lyophilized pharmaceutical agent, kit or medicament for use in the treatment and/or prophylaxis of cancer such as ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer and/or any other solid or hematological cancer relate to a pharmaceutical composition (page 14, ¶ 4). Moreover, Spira discloses sufficient solubility in physiologically acceptable solutions, polysorbates, Benzyl alcohol, propylene glycol (page 2, ¶ 3, ¶ 6, and ¶ 11), and in some embodiments, 10% to 50% polysorbate 80 is used (page 3, ¶ 7), and in one embodiment, the excipient may be selected from polysorbate 80, PEG 400, Benzyl alcohol, PEG 300 (page 4, ¶ 7 and last ¶).
Regarding claim 38, Spira teaches citric acid (page 6, ¶ 17).
Regarding claims 22, 23, 51 and 52 Spira teaches benzyl alcohol, and a mixture of ethanol and water (page 12, ¶ 1), water for injection (WFI) (page 12, ¶ 16). It would have been obvious for a PHOSITA to include these excipients in a kit.
Spira fails to specifically disclose pH, 0.9% NaCl solution and 5% glucose solution.
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).
Regarding claims 1-13, 16, 28-31, 34, 39 and 40-42, Liu teaches anti-cancer liquid pharmaceutical formulations comprising additives of ethanol, glucose, propylene glycol, benzyl alcohol, sodium chloride (¶ 0013). Moreover, Liu discloses 13% ethanol in water for injection (¶ 0007), and citric acid, PEG 300 and polysorbate 80 (¶ 0129, Examples 1-9). Moreover, Liu disclose polyethylene glycols are widely used in a variety of pharmaceutical formulations including parenteral, topical, ophthalmic, oral, and rectal preparations. Polyethylene glycols are stable, hydrophilic Substances that are essentially non-irritant to the skin. Although they do not readily penetrate the skin, polyethylene glycols are water soluble and as such are easily removed from the skin by washing; they are therefore useful as ointment bases. Solid grades are generally employed in topical ointments with the consistency of the base being adjusted by the addition of liquid grades of poly ethylene glycol (¶ 0103), and ethanol is commonly used as a solvent, anti-microbial preservative, disinfectant and penetration enhancer and ethanol and aqueous ethanol solutions of various concentrations are widely used in pharmaceutical formulations and cosmetics. Although ethanol is primarily used as a solvent it is also employed in Solutions as an antimicrobial preservative (¶ 0108).
Regarding claims 12, 13 and 34, Liu teaches pH meter reading in the range of from 2.5 to 7 (¶ 0032). Moreover, Liu discloses a person skilled in the art will know that pH is a measure of free H+ ions in a solution. For example, free H+ will exist in alcohol systems which contain acids. The pH may be measured by placing a pH meter directly into the liquid formulation, such pH meter having been calibrated for the appropriate pH range with standard aqueous buffers. Persons skilled in the art will know of other methods which may be used to measure pH. Such a person will further know that, while the pH meter reading obtained for a substantially non aqueous formulation may not be a true reflection of the actual H+ ion concentration in the solution, it may nonetheless give
a meaningful and reproducible measurement that indicates the relative acidity/basicity of the solution as is the case for the docetaxel formulations disclosed herein. Preferably, the pH meter reading is in the range from 3 to 7, more preferably 3 to 6. Most preferably, the pH meter reading is in the range of from 4 to 6. These ranges are for measurements made at room temperature (20 to 25°C.). A person skilled in the art will
know that the pH meter reading will vary depending on the temperature (¶ 0034), and
The pH of a formulation comprising 10 mg docetaxel, 260 mg polysorbate 80, 0.23 ml ethanol and PEG 300 to one ml had a pH reading of 8.2. Polysorbate 80 on its own
had a pH reading of 8 (¶ 0035), and a person skilled in the art will recognize that the pH
meter reading of the formulations according to the invention can be achieved by acidifying the formulation itself, or by adjustment of the pH of any of the components of the formulation, for example by purification of the surfactant to remove basic contaminants or acidification of any one of the components prior to the mixing of the formulation (¶ 0036), and a person skilled in the art will know that the amount
of pharmaceutically acceptable acid used will be limited by the particular acid's solubility in the pharmaceutically acceptable nonaqueous solvent system. The amount of acid
required will also be further determined by the relative strength of the acid (¶ 0038).
Regarding claim 38, Liu teaches citric acid in the range of from 1.6 to 6 mg/ml) (¶ 0037 and ¶ 0039) and citric acid, as either the monohydrate or anhydrous material, is widely used in pharmaceutical formulations and food products primarily to adjust the pH of solutions (¶ 0105).
Regarding claims 16, 22, 23, 45, 51 and 52, Liu teaches water for injection, 5% glucose solution, and 0.9% NaCl saline (¶ 0084).
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to arrive at the claimed liquid pharmaceutical formulation comprising etoposide, polysorbate, ethanol, PEG, Benzyl alcohol, citric acid, and a pH within about 3.7 and pH of about 5 - 7.8 for the following reasons: 1) the combined teachings of Aitani in view of Spira and further in view of Liu teaches same anti-cancer formulation framework of liquid injectable etoposide formulations comprising etoposide (anti-cancer agent), PEG 300 as a solubilizing vehicle, polysorbate 80 as a nonionic surfactant, ethanol as a co-solvent or diluent, benzyl alcohol as a preservative and optional co-solvent, and citric acid as pH-adjusting agent. These components are disclosed for the same purpose (solubilizing and stabilizing etoposide for IV administration) and are known to be compatible with one another. Thus, the claimed formulation differs from the teachings of Aitani, Spira and Liu only in routine variations of solvent purity, excipient concentrations, and pH selection.
2) It would have been obvious to a PHOSITA that in combining these components, would yield predictable results. The PEG 300, polysorbate 80, and ethanol are routinely combined to solubilize poorly water-soluble drugs like etoposide. Benzyl alcohol is considered a standard preservative in multi-dose injectable formulations and was already known to be compatible with etoposide. Citric acid is a conventional pH-adjusting agent for injectable drugs. Therefore, a PHOSITA would reasonably expect that combining these excipients would maintain solubility, stability, and injectability, as explicitly taught in Aitani, Spira and Liu.
3) Despite where Aitani, Spira and Liu does not expressly recite the specified claimed pH, every liquid injectable formulation necessarily possesses a pH. Moreover, pH is a known result-effective variable in pharmaceutical formulation. A PHOSITA would routinely adjust pH to ensure chemical stability, solubility, and IV compatibility, and the claimed pH range of about 3.7 to about 5 - 7.8 falls within the expected and acceptable range for injectable anti-cancer formulations. Additionally, the claimed pH range is broad, overlaps what a PHOSITA would routinely select and this pH range represents routine optimization.
Regarding the dehydrated ethanol, the ethanol taught in Aitani, Spira and Liu renders the use of dehydrated (anhydrous) ethanol, which is an obvious variant because dehydrated ethanol is chemically the same substance as ethanol, differing only in water content. The selection of ethanol purity is a routine formulation choice, often made to reduce water content, improve solubility of hydrophobic drugs, enhance stability, and thus choosing dehydrated ethanol constitutes a predictable variation of a known excipient. Moreover, the recitation of different concentrations of etoposide, PEG 300, polysorbate 80, ethanol, benzyl alcohol, and citric acid across multiple embodiments reflects routine experimentation and optimization. These concentrations are result-effective variables that a PHOSITA would adjust as a matter of ordinary skill to achieve desired formulation properties.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615