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 Amendments and Arguments filed on 12/12/2025 is acknowledged.
Claims 1-15 are pending.
Claims 1, 5, 6, and 13-15 are amended.
Claims 2 and 3 are cancelled.
Claims 1, 4-15 are pending and are under examination in the application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/23/2025 and 05/09/2023 is 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 Objections
In view of amended claims 1, 14 and 15, the objections is hereby withdrawn.
Claim Rejections - 35 USC § 112
In view of amended claims 5, 13, 14 and 15, the rejections are hereby withdrawn.
Modified 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.
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, 4-15 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (WO 2019/144117 A1) in view of Nanoemulsion: Concepts, development and applications in drug delivery (hereinafter the referenced is referred as Singh) and further in view of Ulm et al. (US 2006/0148776 A1) (hereinafter the reference is referred as Ulm), both Singh and Ulm cited in IDS filed 05/09/2023.
Zheng teaches compositions that induce the degradation of the Bcl-2 family proteins and their method of use in the treatment of various cancers (¶ 0003) directed to compounds of anti-apoptosis Bcl-2 protein degraders comprising formula (I) in (¶ 0024-0037):
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in an embodiment, the below compound (¶ 0037) is explicitly displayed on page 37.
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Comprising a variety of vehicles are suitable for delivering a composition, for example, nanoparticles, liposomes, microemulsions, micelles, dendrimers and other phospholipid containing systems and methods of incorporating compositions into delivery vehicles are known in the art (¶ 0058). Furthermore, Zheng discloses
Regarding claims 1, as noted above, Zheng teaches compounds comprising formula (I), and in an embodiment, the composition may be delivered to a cell as a microemulsion comprising an aqueous solution, a surfactant, and “oil”, wherein the “oil” is the supercritical fluid phase, and the surfactant rests at the oil-water interface (¶ 0066). Furthermore, Zheng discloses as will be appreciated by a skilled artisan, microemulsions can and will have a multitude of different microscopic structures including sphere, rod, or disc shaped aggregates, and in one embodiment, the structure may be micelles, which are the simplest microemulsion structures that are generally spherical or cylindrical objects, wherein micelles are like drops of oil in water, and reverse micelles are like drops of water in oil, and in an alternative embodiment, the microemulsion structure is the lamellae. It comprises consecutive layers of water and oil separated by layers of surfactant. The "oil" of microemulsions optimally comprises phospholipids (¶ 0066). Therefore, the limitation of formula (I), dispersed medium, and dispersing medium, emulsion (microemulsion) are taught.
Regarding claims 4-7, Zheng teaches pharmaceutical compositions for effective administration are deliberately designed to be appropriate for the selected mode of administration, and pharmaceutically acceptable excipients, for example, compatible dispersing agents, buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents and the like are used as appropriate (¶ 0096), and preparation may be an aqueous or an oil-based solution comprising an antioxidant, for example ascorbic acid or sodium bisulfite (¶ 0055), a chelating agent ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate; and/or an agent for the adjustment of tonicity such as sodium chloride, dextrose, or a polyalcohol such as mannitol or sorbitol, and the pH of the aqueous solution may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide, wherein Oil-based solutions or suspensions may further comprise sesame, peanut, olive oil, or mineral oil (¶ 0055), emulsifying and/or suspending agents (¶ 0054) and polyethylene glycol (PEG) (¶ 0049, 0062).
Regarding claim 8, Zheng teaches pH modifying agent may be sodium carbonate sodium bicarbonate, citric acid or phosphoric acid (¶ 0044).
Regarding claims 9 and 10, Zheng teaches oil-in-water or a water-in-oil base (¶ 0057), and the solvent may be an organic solvent or an inorganic solvent or a combinations thereof (¶ 0063), as well as diluents of ethanol, glycerin, and combinations thereof (¶ 0054). Furthermore, Zheng teaches parenteral administration (including subcutaneous, intradermal, intravenous, intramuscular, and intraperitoneal), the preparation may be an aqueous or an oil-based solution, and aqueous solutions may be include a sterile diluent such as water, saline solution, a pharmaceutically acceptable polyol such as glycerol, propylene glycol, or other synthetic solvents (¶ 0055). Thus the limitations of dispersed medium is a water miscible organic solvent and the dispersing medium is water, a water miscible solvent, or a mixture of two or more of water, a water miscible solvent are taught.
Zheng fails to specifically teach nanoemulsion and lecithin.
Singh teaches nanoemulsion are biphasic dispersion of two immiscible liquids: either water in oil (W/O) or oil in water (O/W) droplets stabilized by an amphiphilic surfactant, and these come across as ultrafine dispersions whose differential drug loading; viscoelastic as well as visual properties can cater to a wide range of functionalities including drug delivery (abstract). Moreover, Singh discloses, however there is still relatively narrow insight regarding development, manufacturing, fabrication and manipulation of nano-emulsions which primarily stems from the fact that conventional aspects of emulsion formation and stabilization only partially apply to nanoemulsion, and attempt to explore varying intricacies, excipients, manufacturing techniques and their underlying principles, production conditions, structural dynamics, prevalent destabilization mechanisms, and drug delivery applications of nano-emulsions to spike interest of those contemplating a foray in this field (abstract). Moreover, Singh discloses applications of nanoemulsion directed to deliver drugs with lower bioavailability and/or narrow therapeutic indices, for example, nanoemulsion using vitamin E and TPGS to co-deliver hydrophilic and hydrophobic cytotoxics, 5-fluoroucacil and paclitaxel, to overcome drug resistance in human epidermal carcinoma cell line KB-
8-5, and a vitamin E derivatized nanoemulsion carrying paclitaxel has been developed to tackle intrinsic or acquired drug resistance in ovarian carcinoma by inhibiting P-gp and altering levels of apoptotic and anti-apoptotic proteins, Bax and Bcl-2 (page 41, right column, ¶ 1).
Regarding claim 1, Singh discloses ultrafine dispersions whose differential drug loading and tailoring methods for nano-emulsions can be categorized into high- energy or low-energy or a combination of low and high energy, and sequence of excipient and bioactive addition has a bearing on the final outcome, wherein a lipophilic drug is dispersed directly or with assistance of an organic solvent in the oil phase, whereas hydrophilic drugs go into the aqueous phase, and other excipients are drafted in as per requirement, and the most important criterion in manufacturing nanoemulsion is obtainment of desired droplet size with monomodal distribution, which ensures uniformity of properties and provides a good starting point for further fabrication (page 32, ¶ 3.4. Manufacturing nano-emulsions). Moreover, Singh discloses a partially digested nanoemulsion droplet, or in cases where the oil is lipase resistant, an intact droplet might also be solubilized in a mixed micelle (page 39, Fig. 9).
Singh fails to specifically teach the dispersed medium is long chain triglyceride, a medium chain triglyceride, or a short chain triglyceride.
Ulm teaches drug formulations having emulsifying agents and both medium and long chain triglycerides, and some embodiments, the long chain triglycerides negate or lessen deleterious central nervous system effects that are caused by medium chain triglycerides (abstract). Moreover, Ulm discloses emulsions comprising an oil phase and an aqueous phase are widely known in the art as carriers of therapeutically active ingredients or as sources of parenteral nutrition, and emulsions can exist as either oil-in-water or water-in oil forms, and the therapeutic ingredient is particularly soluble in the oil phase the oil-in-water type is in some embodiments (¶ 0055). Furthermore, Ulm teaches simple emulsions are thermodynamically unstable systems from which the oil and aqueous phases separate (coalescence of oil droplets), and incorporation of emulsifying agent(s) into the emulsion is critical to reduce the process of coalescence to
insignificant levels (¶ 0055).
Regarding claims 4-8, Ulm teaches emulsion (¶ 0055), the surfactant/emulsifying agent is lecithin (¶ 0047), osmotic agent glycerol, sugars, sugar alcohols (¶ 0052), EDTA disodium, dihydrate (¶ 0074, 0077), and to prevent or minimize oxidative degradation or lipid peroxidation, antioxidants, e.g., alpha-tocopherol and butylated hydroxytoluene, and preservatives, for example edentate may be included in addition to, or as an alternative to, oxygen deprivation (e.g., formulation in the presence of inert gases such as nitrogen and argon, and/or the use of light resistant containers) (¶ 0056). Furthermore, Ulm teaches buffer solution, for example Hank’s solution, Ringer’s solution, or physiological saline buffer, as each are well-known in the art (¶ 0067).
Regarding claims 9 and 11, Ulm teaches pharmaceutical composition comprising a pharmacologically active compound, e.g., an ansamycin such as 17-AAG, in combi nation with an emulsifying agent (e.g., phospholipids such as found in lecithin) and oil, wherein the oil may contain long chain triglycerides and the composition can also contain medium chain triglycerides, and the emulsifying agent and oil together constitute a lipid phase (¶ 0013).
Regarding claim 10, Ulm teaches the surfactant/emulsifying agent is typically present in a concentration of about 0.5-25% w/v based on the amount of the water and/or other components into which the surfactant is dissolved (¶ 0047). Furthermore, Ulm teaches ethanol is added in an amount approximately 50x the drug weight and the solution sonicated in a water bath to disperse the drug (¶ 0075), and the pharmaceutical composition of claim 1 that is an oil in water emulsion having a lipid phase and an aqueous phase, and wherein said lipid phase comprises 5-30% by weight of the total (claims 6, 8).
Regarding claim 12, Ulm teaches formulation of 17-allylamino-geldanamycin (17-AAG) is a synthetic analog of geldanamycin (GDM), wherein both molecules belong to a broad class of antibiotic molecules known as ansamycins (¶ 0004) and (17-AAG) are thought to exert anti-cancerous effects by tight binding of the N-terminus ATP-binding pocket of HSP90 (¶ 0006). Furthermore, Ulm teaches in some embodiments, the compound (17-AAG) drug in an amount of 0.5mg/ml to 4 mg/ml or 0.05 % w/w to 0.4% w/w relative to the total formulation weight (¶ 0021), particularly, in one embodiment, comprises components of 2 mg/ml (17-AAG), 6.6 % lecithin, 7.5 % sucrose, and water (¶ 0022). This example differs from instant formulation as it does not contain instant formula of compound (I), however the limitations of percentages of components of the amounts of the compound, lecithin and sugar overlaps with instant ranges and the long chain and medium chain triglyceride can be 0 % as recited in the claim. A person having ordinary skill in the art would have been able to convert w/w to w/v relative to the total formulation volume used.
Regarding claims 13-15, Ulm teaches variation of processes comprising of adding long chain triglycerides for the compound (17-AAG) at 1 % w/w, a source of long chain triglycerides (soya oil) 16 % w/w, mixed with Miglyol 812N (a source of medium chain triglycerides) at 50.0 % w/w, and an emulsifying agent (Phospholipon 90G (PL90G)) at 33.03 % w/w, and 9.375 % w/w sucrose, and EDTA 0.0063 % w/w (¶ 0084, Example 6). Furthermore, Ulm discloses formulation 1 and formulation 2 with different amounts of (17-AAG), a source of long chain triglycerides (soya oil), Miglyol 812N (a source of medium chain triglycerides), lecithin, sucrose, sodium edetate, and water (¶ 0085) and further exemplary examples 1-9 are representative of various aspects of embodiments and one skilled in the art would have been able to adapt, carry out or modify the objects and obtain the ends and advantages within the spirit and scope of the invention (¶ 0096). Therefore, it would have been obvious to a person having ordinary skill in the art to optimize the percentages of the components in order to prevent or minimize oxidative degradation with proper amount of antioxidant (e.g., inert gases, EDTA) and achieve desired emulsification of the emulsion with surfactant/emulsifying agent (e.g., lecithin, PEG), osmotic agent (e.g., a sugar, glycerol), and stability with pH modifying agent (e.g., citric acid, phosphoric acid or a buffer solution).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate the Bcl-2 proteins degraders for cancer treatment of compounds as taught by Zheng and incorporate the instant compound I of Zheng into a nanoemulsion to improve drug delivery, stability, and across wide range of dispersions and drug loading capability as taught by Singh and further optimize the similar components of long chain triglyceride, medium chain triglyceride, lecithin, sugar, sucrose, EDTA, PL90G as taught by Ulm in order to successfully achieve the desired nanoemulsion with compound I with similar properties. A person having ordinary skill in the art would have been motivated to combine the teachings of Zheng’s compound I and micelles and further improve the formulation by incorporating into nanoemulsion formulation of Singh to achieve better drug delivery.
One would have been motivated to do so because the combined teaching of Zheng, Singh and Ulm discloses compounds directed to instant formula (I) and variations and components involved in nanoemulsion formulations for drug delivery.
One of ordinary skill in the art would have been motivated to do this because the combination references are drawn to the identical instant molecular structure of compound (I) and nanoemulsion, concepts, development and applications in drug delivery.
One of ordinary skill in the art would have found it obvious to apply the different amounts and percentages of surfactant, emulsifying agent, osmotic adjusting agent, an antioxidant, a stabilizer, a pH modification agent, an inorganic salt or a buffering agent in order to improve the desired nanoemulsion formulation and use as taught by Zheng in view of Singh and further in view of Ulm.
From the combine teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
It is obvious to combine prior art elements according to the known methods to yield predictable results. Please see MPEP 2141 (III)(A)-(G). Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “ Obvious to try ” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP § 214 3 for a discussion of the rationales listed above along with examples illustrating how the cited rationales may be used to support a finding of obviousness. See also MPEP § 2144 - § 2144.09 for additional guidance regarding support for obviousness determinations.
Response to Arguments
Applicant's arguments filed 12/12/2025 have been fully considered but they are not persuasive. Applicant amended claim 1 to specify a nanoemulsion formulation and argues that cited prior art of record only teaches microemulsion, micelles, and emulsions and differs in concepts, manufacturing, fabrication and manipulation of nano emulsions and that conventional aspects of emulsion formation and stabilization only partially apply to nano emulsions.
Examiner respectfully disagrees. The prior art of record, alone and/or in combination teaches all the limitations, features, characteristics, properties and components in the claimed nanoemulsion formulation. One of ordinary skill in the art would have found it obvious to combine the teachings in the cited references in order to improve the desired nanoemulsion formulation and one would have been motivated to do so because the combined teachings of Zheng, Singh and Ulm discloses compounds directed to instant formula (I), variations and components involved in nanoemulsion formulations for drug delivery.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615