DETAILED ACTION
Status of the Claims
Claims 1-13 are pending in the instant application. Claims 7-13 have been withdrawn based upon Restriction/Election as discussed below. Claims 1-6 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant's election without traverse of Group I drawn to methods of making currently claims 1-6 in the reply filed on 09/09/2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Claims 7-13 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Priority
The instant Application was filed on 08/16/2024, and claims priority to CN 202410134061.0 filed 01/31/2024, a certified copy made of record as electronically retrieved on 10/13/2024.
The U.S. effective filing date has been determined to be 08/16/2024, the filing date of the instant application. Applicant's claim for a priority date of, 01/31/2024, is acknowledged, however no English translation of the priority document CN 202410134061.0 has been provided such that the examiner can verify written description support therein. Accordingly, priority to this document cannot be afforded at this time.
Information Disclosure Statement
No Information Disclosure Statements have been filed in the instant application. Applicants are reminded of their duty to disclose patents and publications relevant to the patentability of the instant claims. Applicant is reminded of the requirements of 37 CFR 1.56 and Li Second Family Limited Partnership v. Toshiba Corp., 56 USPQ2d 1681 (Fed. Cir. 2000); accord McKesson Information Solutions, Inc. v. Bridge Medical, Inc. 487 F.3d 897, 913. (Fed.Cir.2007).
Claim Objections
Claim 1 is objected to because of the following informalities: in step 2 the claim recites “placing the transparent glass bottle after the water bath ultrasonic treatment on a magnetic stirrer and stirring for 20 minutes”, wherein the phrase “after the water bath ultrasonic treatment should be offset with commas - “placing the transparent glass bottle, after the water bath ultrasonic treatment, on a magnetic stirrer and stirring for 20 minutes”. Additionally, in step 4, line 1, the claim recites “step 3in” which should be “step 3 in”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
Scope of the Claimed Invention:
Applicant claims a preparation method for an oil-in-water nanoemulsion material, comprising the following steps: (1) first, adding a predetermined amount of hydrophobic small molecule substance, an oil, and a surfactant to a transparent glass bottle, and the fixing the transparent glass bottle in an ultrasonic cleaner and performing a water bath ultrasonic treatment for 20 min; (2) placing the transparent glass bottle after the water bath ultrasonic treatment on a magnetic stirrer and stirring for 20 min, then, under a condition of a continuous stirring, adding an aqueous phase dropwise into the transparent glass bottle using a peristaltic pump, and continuously stirring for 30 minutes after completing an addition of the aqueous phase, wherein the aqueous phase is phosphate buffered saline (PBS); (3) putting a predetermined amount of water into a beaker, and then placing the beaker on a magnetic stirrer whit a heating device, heating the water in the beaker to 60°C in advance and maintaining a constant temperature, at this time, placing the transparent class bottle in the beaker with the water, and continuously stirring an emulsion in the transparent glass bottle for 20 min at 60°C; and (4) quickly placing the transparent bottle processed by step (3) in an ice water bath for a cooling, after lowering a temperature to 5°C, preparing and obtaining an oil-in-water nanoemulsion loaded with the hydrophobic small molecule substance, and finally, storing the oil-in-water emulsion in a 4°C refrigerator (instant claim 1). Applicant claims the preparation method for an oil-in-water nanoemulsion material according to claim 1, wherein calculated by mass percentage, proportions of the hydrophobic small molecule substance, the oil, the surfactant, and aqueous phase are 1%, 6%, 4%, and 89%, respectively (instant claim 2).
Disclosure of the Prior Art:
Ostertag et al. (“Low-energy formation of edible nanoemulsions: Factors influencing droplet size produced by emulsion phase inversion,” 2012, ELSEVIER; Journal of Colloid and Interface Science, Vol. 388, pp. 95–102) teaches factors influencing droplet size in nanoemulsions formed by low-energy methods (title), and particularly that: “A number of low energy approaches used to prepare oil-in-water nanoemulsions rely on inducing a phase inversion from a W/O to a O/W system, e.g., phase inversion temperature (PIT), phase inversion composition (PIC), and emulsion inversion point (EPI) methods. These approaches can be further categorized according to their underlying physicochemical principle as either transitional or catastrophic phase inversion methods (Fig. 1).” (p. 96, col. 2, lines 5-12; Figure 1).
Ostertag et al. teaches the influence of the surfactant-to-oil ratio on particle size, and particularly that: “At low surfactant concentrations (SOR from 0.1 to 0.65) the droplets formed were relatively large (d32 from 0.5 to 50 μm), but at higher values (SOR from 0.65 to 2.5) emulsions were produced with relatively small droplets (d32 from 0.16 to 0.10 μm).” (p. 98, col. 1, §4.1).
Ostertag et al. teaches the influence of oil type on particle size, and particularly that: “We found that the smallest droplets could be produced using medium chain triglycerides (MCT), and then using flavor oils (orange oil and limonene). Only relatively large droplets (d32 > 0.6 μm) could be formed using mineral oil or long chain triglyceride oils (such as olive, grape seed, sesame, peanut and canola oils).” (pp. 98-99, §4.2).
Ostertag et al. teaches the influence of the surfactant type on particle size, and particularly that: The nature of the surfactant(s) used to form the emulsions clearly had a major impact on the size of the droplets produced using the emulsion phase inversion method (Figs. 6 and 7).” (p. 99, §4.3).
Ostertag et al. teaches the influence of initial surfactant location on the particle size, and particularly that: “Our results clearly show that the initial location of the surfactant has a major impact on the particle size distribution and mean particle diameter (Figs. 8 and 9). The higher the fraction of the surfactant that was initially present in the organic phase, the smaller the droplets produced.” (p. 100, §4.4).
NICOLOSI (US 2011/0206739 A1) teaches compositions and methods of forming nanoemulsions containing an active component in combination with a lipophilic component such as oil, hydrophilic components such as water, and one or more surfactants capable of causing a temperature-dependent phase inversion (title, abstract). NICOLOSI teaches the general procedure in Figure 1, including combining the oil with the active component(s), adding surfactant to the oil/active, adding water to form O/W emulsion, heating O/W emulsion above surfactant PIT to form W/O emulsion, and rapid cooling to form O/W nanoemulsion.
NICOLOSI teaches that: “The compositions can include oil, water, and a surfactant capable of temperature-dependent phase inversion between the oil and water phases, such as a nonionic polyethoxylated surfactant. Such compositions can be used to form nanoemulsions by temperature-dependent phase inversion of the surfactant. As described herein, nanoemulsions formed by temperature-dependent phase inversion of a surfactant are also termed self-assembled nanoemulsions ("SANE").” ([0008]).
NICOLOSI discloses that: “In addition, some embodiments of the invention are based on the discovery that SANE compositions do not form when certain active components are added to compositions of certain lipophilic components, hydrophilic components and surfactants that otherwise form a stable SANE composition in the absence of the additional active component. In particular, some embodiments are based, in part, on the discovery that certain active components ( e.g., dacarbazine, gemcitabine or coumarin), do not form stable SANE compositions from a rice bran oil lipophilic component in combination with a polyethylene glycol 660 hydroxystearate surfactant (e.g., Solutol® HS15), while other active components (e.g., paclitaxel, tocotrienols, or coumarin) are able to form SANE compositions with these components. Furthermore, other embodiments of the invention are based in part on the discovery that certain active components ( e.g., lutein, tocotrienols), do not form stable SANE compositions from a rice bran oil lipophilic component in combination with a C20 ethoxylated monoglyceride surfactant (e.g., EMG-20).” ([0011]). NICOLOSI discloses examples of suitable active components ([0017]), examples of suitable surfactants ([0080]-[0081]), examples of suitable oils ([0082]). NICOLOSI discloses specific Examples including specific combinations of oil, surfactants and water to form “blank nanoemulsion” (Example 1), in specific amounts (Example 1, Table 1). And teaches Example of SANE compositions including the active component coumarin (Example 2), curcumin (Example 3), 5-Fluorouracil (Example 4), Dacarbazine (Example 5), Paclitaxel (Example 6), and tocopherols (Example 7).
PATHAK (US 2012/0052126 A1) teaches nanoemulsions including antioxidants and other health-promoting compounds (title, abstract), and particularly “In an embodiment, an emulsion is prepared that includes an oil phase, and a water phase. The oil phase includes oil, an emulsifying agent, and one or more antioxidants. The water phase includes water. Optionally, in some embodiments, the water phase includes a preservative, and a stabilizing agent.” ([0015]). And that: “In some embodiments, the oil is unsaturated oil, such as, for example, soybean oil, olive oil, safflower oil, canola oil, or a combination of two or more of those. Alternatively, the oil is an antioxidant, such as, for example, vitamin E or vitamin A.” ([0016]). And further that: “In general, the emulsifying agent is a phospholipid, a natural emulsifying agent from a vegetable source, a natural emulsifying agent from animal source, a polymeric emulsifying agent, a semi-synthetic polysaccharide, a synthetic emulsifying agent, an anionic surfactant, a cationic surfactant, a non-ionic surfactant, a finely divided solid, or a combination of two or more of the above. In some embodiments, the emulsifying agent is one of, or a combination of, those chosen from the group tragacanth, acacia, agar, chondrus, pectin, lecithin, lanolin, cholesterol, methyl cellulose, sodium carboxylmethyl cellulose, hydroxylpropyl cellulose, cetrimide, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, propylene glycol monosteatrate, polyoxyl stearate, bentonite, aluminum magnesium stearate, attapulgite, colloidal anhydrous silica, and hectorite. The agents described and taught herein, which are used as emulsifying agents, preservatives, and stabilizers, are available for purchase from a number of commercial sources.” ([0017]).
PATHAK teaches Examples including Base Formulations I-III ([0031]), and Examples 1-6 ([0034]-[0035]), and Additional Samples ([0036]-[0039]).
GUERRERO-RIVERA (US 2018/0185282 A1) teaches curcumin-loaded nanoemulsions, and particularly oil-in-water nanoemulsions that include curcumin dissolved in at least one miscible solvent and encapsulated in an oil core comprising a stabilizer (title, abstract), and particularly that: “In one aspect of the invention, an oil-in-water curcumin nanoemulsion includes curcumin dissolved in at least one miscible solvent and encapsulated in an oil core, wherein the oil core also comprises a stabilizer, wherein the oil core forms an organic phase which is dispersed in an aqueous solvent, and wherein the oil core is selected from a pharmaceutically acceptable oil. […] The pharmaceutically acceptable oil is selected from the group consisting of soybean oil, ethyl oleate, ethyl butyrate, ethyl caprylate, Miglyol 812, mineral oil, liquid paraffin, medium-chain triglyceride oil, grapeseed oil, and combinations thereof. […] The stabilizer in the oil core is selected from the group consisting of an ionic surfactant, Epikuron 145 V, lecithin, agar, carrageenan, gellan, gelatin, guar gum, sodium alginate, xanthan gum, and combinations thereof.” ([0011]). GUERRERO-RIVERA teaches specific Examples of curcumin loaded nanoemulsions ([0058]-[0065]).
Disclosure of the Instant Application:
The instant Specification discloses that: “The present disclosure relates to a preparation method and an application for an oil-in-water nanoemulsion material, which belongs to the technical field of nanoemulsion material.” (p. 1, [0002]).
The instant Specification discloses that: “Nanoemulsion (NE) refers to a thermodynamic stable and isotropic dispersion system with a transparent or translucent appearance and particle size of 1-100 nm formed by two immiscible solutions under the action of the surfactant or cosurfactant. According to its structure, the nanoemulsion can be divided into water in oil type (W/O), oil in water type (O/W) and bicontinuous phase type (W/O/W or O/W/O). Its structural type depends on the proportion and properties of each phase, and under certain conditions, they can be converted into each other.” (p. 1, [0003]). And that: “In the traditional preparation methods of the nanoemulsion, high-energy or low-energy methods are usually used for preparation. The high-energy method uses specialized mechanical equipment (such as sonar, ultrasound, microfluidics, and high-pressure valve homogenizers), to form small droplets with nanometer size, which is suitable for the preparation of the nanoemulsion using a small amount of surfactant and oil. However, the use of large equipment in the high-energy method can cause problems such as high costs and significant damage to bioactive chemicals. The low-energy method mainly relies on the combination of surfactant-oil-water to spontaneously form small droplets with nanometer size under appropriate environment or conditions. The low-energy method usually includes a phase inversion composition method (PIC), a phase inversion temperature method (PIT) and spontaneous emulsification, which has the advantages of lower cost and less damage to bioactive chemicals. However, the types of surfactant and oils that can be utilized in the preparation of the nanoemulsion by the low-energy method are limited, it is usually necessary to use a large number of surfactant to form the nanoemulsion with nanometer size, which is inefficient, at the same time, the presence of a large number of surfactant may have serious biosafety problems.” (p. 2, [0005]).
The instant Specification discloses that: “In order to solve the above technical problems, the present disclosure provides a preparation method and an application for an oil-in-water nanoemulsion material, and the preparation method has the advantages of simple operation, low energy consumption, small damage to the activity of hydrophobic small molecular substances, and can effectively promote the emulsification effect of oil phase and water phase, effectively improve the Ostwald ripening phenomenon in solution, uniformly disperse solid particles, improve the stability of emulsion, and realize the application of hydrophobic bioactive substances in biomedicine.” (p. 2, [0006]).
The instant Specification discloses the step of instant claim 1 (p. 2, [0007] through [0011]), the proportional amounts of hydrophobic small molecule substance, oil, surfactant and aqueous phase (PBS) as recited in claim 2 (p. 3, [0012]), the species of the hydrophobic small molecule substances are isoliquiritigenin, curcumin, myricetin, apigenin or naringenin (claim 3; p. 3, [0013]). As well as the subject matter of instant claims 4-6 (p. 3, [0014] through [0016]).
The instant Specification discloses that: “Due to the adoption of the above technical solutions, the present disclosure has the following advantages: the present disclosure is a new method combining sonication-phase inversion composition-phase inversion temperature, S-PIC-T method, i.e., the combined application of the sonication, the phase inversion composition method and the phase inversion temperature develops a new type nano-preparation with small droplet size, high loading hydrophobic small molecule substances, and stable physical and chemical properties. Therefore, in the present disclosure, the sonication in the high-energy method is combined with PIC and PIT in the low-energy method, because the sonication does not produce high heat, the amount of surfactant is reduced, and the size of emulsion droplets is reduced while the energy consumption is low, while PIC and PIT reduce production costs and protect the biological activity of hydrophobic bioactive substances, which not only improves the preparation efficiency of oil-in-water nanoemulsion carriers, shortens the preparation time, but also further enhances its application in the fields of chemistry, pharmacy, and cosmetics under the premise of protecting the biological activity of hydrophobic substances.
The instant Specification discloses that: “FIG 1A is a loading rate effect diagram of the oil-in-water nanoemulsion of the present disclosure; FIG. 1B is a loading rate effect diagram of isoliquiritigenin microemulsion; FIG. IC is a loading rate effect diagram of iRGD-modified isoliquiritigenin hybrid nanoparticles; FIG. ID is a loading rate effect diagram of TPGS-modified isoliquiritigenin liposomes;” (p. 4, [0020] through [0023]). The examiner notes that Figures 1A through 1D are pictures of samples in clear containers an not diagrams.
The instant Specification discloses that: FIG. 2 shows an electron microscopy image of the oil-in-water nanoemulsion loaded with isoliquiritigenin of the present disclosure; FIG. 3 shows a particle size distribution diagram of the oil-in-water nanoemulsion loaded with isoliquiritigenin of the disclosure measured by nanoparticle size analyzer; FIG. 4 is an effect diagram of the oil-in-water nanoemulsion of the present disclosure in anti-breast cancer experiments in vivo and in vitro; FIG. 5 shows an electron microscope image of the oil-in-water nanoemulsion of the present disclosure after co-culture with mouse breast cancer 4Tl cells; FIG. 6 shows a tumor growth curve diagram in mice in vivo after treatment with the oil-in-water nanoemulsion of the present disclosure; and FIG. 7 shows an appearance diagram of tumors extracted from mice after treatment with the oil-in-water nanoemulsion of the present disclosure.” (p. 4, [0024] through [0029]).
The instant Specification discloses that: “Through the combined application of the high-energy method and the low-energy method, the nanoemulsion with small droplet size, stable physical and chemical properties, and high hydrophobic small molecule loading were prepared.” (p. 6, [0042]).
The instant Specification discloses that: “In order to verify the loading effect of the oil-in-water nanoemulsion A of the present disclosure, isoliquiritigenin microemulsion Dl, iRGD-modified isoliquiritigenin hybrid nanoparticle D2 and TPGS-modified isoliquiritigenin liposome D3 were compared with the oil-in-water isoliquiritigenin nanoemulsion A of the present disclosure. Referring to FIGS. lA-lD, the oil-in-water nanoemulsion A of the present disclosure had a uniform loading effect on isoliquiritigenin, while the loading effect of isoliquiritigenin microemulsion Dl, iRGD-modified isoliquiritigenin hybrid nanoparticle D2 and TPGS-modified isoliquiritigenin liposome D3 on isoliquiritigenin had poor uniform; and meanwhile, referring to FIG. 2, the oil-in-water nanoemulsion A of the present disclosure exhibited a narrower small-size droplet distribution. Referring to Table 1, from Table 1, it might be seen the encapsulation rate and concentration of four types of nanoemulsion on isoliquiritigenin, wherein, the encapsulation rate and concentration of the oil-in-water nanoemulsion A of the present disclosure were the highest.” (pp. 6-7, [0043]; Table 1).
The instant Specification does not disclose any oil(s), any (co)surfactant(s)/emulsifier(s) which are specifically required elements of any nanoemulsion(s).
Discussion:
Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111, (Fed. Cir. 1991), states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claim indicates that these claims are drawn to a genus, i.e., preparation method(s) for oil-in-water nanoemulsion material.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
Possession is analyzed for each claim drawn to a species and thereafter for each claim drawn to a genus. In the instant case, there are a vast number of species of oils and a vast number of species of (co)surfactant(s)/emulsifier(s) within the genus of nanoemulsions produced by the claimed method(s). And the instant Specification discloses zero species of oils and zero species of (co)surfactant(s)/emulsifier(s) disclosed that are within the scope of the claimed genus, i.e. preparation method(s) for oil-in-water nanoemulsion material. The present claims encompasses numerous species that are not described whatsoever. While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005).
Applicant has disclosed method(s) of making oil-in-water nanoemulsions with specific steps without properly describing a single species of oil(s) or a single species of (co)surfactant(s)/emulsifier(s), and few hydrophobic small molecule (active agents) each of which are critical to the claimed process of making an oil-in-water nanoemulsion. Given that the species of oil(s) and surfactant(s) are critical to the process of making and no species are described in the as-filed Application, the claims are properly rejected for as failing to comply with the written description requirement as the claims containing subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an Enablement rejection.
Scope of the Claimed Invention:
The scope of the claimed invention is discussed above.
Disclosure of the Prior Art:
The disclosure of the prior art is discussed above. The examiner particularly notes that no prior art references have been found that describe methods of making oil-in-water nanoemulsions without any species of oil(s) and/or (co)surfactant(s)/emulsifier(s) described therein.
Disclosure of the Instant Application:
The disclosure of the instant Application is discussed above.
Discussion:
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d1400 (Fed. Cir. 1988). Among these factors are: 1) scope or breadth of the claims; 2) nature of the invention; 3) relative level of skill possessed by one of ordinary skill in the art; 4) state of, or the amount of knowledge in, the prior art; 5) level or degree of predictability, or a lack thereof, in the art; 6) amount of guidance or direction provided by the inventor; 7) presence or absence of working examples; and 8) quantity of experimentation required to make and use the claimed invention based upon the content of the supporting disclosure.
Scope or breadth of the claims
The scope of the claims is narrow in terms of the process steps but broad in terms of the critical constituent ingredients in the oil-in-water nanoemulsions the process is directed at producing. Particularly, the scope of hydrophobic small molecule substances vast encompassing nearly infinite number of species, the scope of (co)surfactant(s)/emulsifier(s) is vast encompassing at least thousands of species, and the scope of oil is vast encompassing at least thousands of species.
Nature of the Invention
The nature of the invention is directed to specific method(s) of making nanoemulsions incorporating a first step 1 of combining a hydrophobic small molecule substance with an oil and surfactant, which includes mixtures of surfactants and oils, by sonication (in an ultrasonic water bath). A second step of dropwise adding the aqueous phase (water/PBS) under mixing, which is described as the phase inversion composition (PIC) method; and steps 3-4 encompassing heating the mixed emulsion to 60 °C for 20 minutes, and quickly cooling in an ice water bath to obtain the resulting oil-in-water nanoemulsion.
Relative level of skill possessed by one of ordinary skill in the art
The level of skill in the art pertaining to nanoemulsions is relatively considered a mid-level requiring, for example, a 4-6 year degree in science to understand and produce.
State of, or the amount of knowledge in, the prior art
The level of knowledge is also considered mid-level, while nanoemulsions are well-known including methods of making the same, scientific investigations continue on new methods, particularly low-energy methods of making nanoemulsions.
Level or degree of predictability, or lack there of, in the art
The level of predictability is mid-level including various different low-energy methods of making nanoemulsions in the prior art.
Amount of guidance or direction provided by the inventor
The inventors provide guidance to the specific method steps but no guidance as to what specific oil(s) should or should not be utilized and what specific (co)surfactant(s)/emulsifier(s) should or should not be utilized. The guidance toward species of “hydrophobic small molecule substances” is limited to those of instant claim 3 - isoliquiritigenin, curcumin, myricetin, apigenin and/or naringenin (5-species).
Presence or absence of working examples
The Specification appears to include Examples, however, the description of the Examples is inadequate for one of ordinary skill in the art to reproduce from the disclosed Examples. Particularly Examples include oil-in-water nanoemulsion A (according to the present invention), D1-D3 (comparative examples), without any species of oil(s) or (co)surfactant(s)/emulsifier(s) or aqueous phase(s) described.
Quantity of experimentation required to make and use the invention
The amount of experimentation to produce the claimed oil-in-water nanoemulsion material(s) would be an undue level of experimentation to select from the vast number of species of oil(s) and (co)surfactant(s)/emulsifier(s) to use in the instantly claimed method(s) for making oil-in-water nanoemulsion material(s).
In conclusion, claims 1-6 are rejected in light of the lack of guidance provided by the inventor to any species of oil(s) and (co)surfactant(s)/emulsifier(s) usable in the claimed method(s) for preparation of an oil-in-water nanoemulsion material.
To emphasize this point the Examiner points Applicants to "Genentech, 108 F.3d at 1366 and Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966)" which states,
"a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
Claim Rejections - 35 USC § 112(b)
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.
Claim 4 is 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 pre-AIA the applicant regards as the invention.
Claim 4 s rejected as being indefinite because the claim recites “tin paper” in line 3, where it is unclear what “tin paper” is meant to be. Appropriate clarification is required.
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.
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.
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 1-3, 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Isoliquiritigenin Nanoemulsion Preparation by Combined Sonication and Phase-Inversion Composition Method: In Vitro Anticancer Activities,” 2022, MDPI; Bioengineering, Vol. 8, No. 382, pp. 1-19) in view of YUE (CN 103315958 A; published 09/25/2013; Machine translation relied on herein); Hong et al. (“Orthogonal Optimization, Characterization, and In Vitro Anticancer Activity Evaluation of a Hydrogen Peroxide-Responsive and Oxygen-Reserving Nanoemulsion for Hypoxic Tumor Photodynamic Therapy,” 2023, MDPI; Cancers, Vol. 15, No. 1576, pp. 1-23); and Yu et al. (“Highly Stable Concentrated Nanoemulsions by the Phase Inversion Composition Method at Elevated Temperatures,” 2012, ACS Publications; Langmuir, Vol. 28, pp. 1457-14552).
Applicants Claims
Applicant claims are discussed above.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Wang et al. teaches Isoliquiritigenin Nanoemulsion Preparation by Combined Sonication and Phase-Inversion Composition Method (title, see whole document). Wang et al. teaches that: “Isoliquiritigenin (ILQ) has a number of biological activities such as antitumor and anti-inflammatory effects. However, biomedical applications of ILQ are impeded by its poor aqueous solubility. Therefore, in this research, we prepared a novel ILQ-loaded nanoemulsion, i.e., ILQ-NE, which consisted of Labrafil® M 1944 CS (oil), Cremophor® EL (surfactant), ILQ, and phosphate buffered saline, by employing a combined sonication (high-energy) and phase-inversion composition (low-energy) method (denoted as the SPIC method). The ILQ-NE increased the ILQ solubility ~1000 times more than its intrinsic solubility. It contained spherical droplets with a mean diameter of 44.10 ±0.28 nm and a narrow size distribution. The ILQ loading capacity was 4%. The droplet size of ILQ-NE remained unchanged during storage at 4 °C for 56 days. Nanoemulsion encapsulation effectively prevented ILQ from degradation under ultraviolet light irradiation […].” (abstract)(instant claim 3, the hydrophobic small molecule is isoliquiritigenin - ILQ).
Wang et al. discloses that: “Unless otherwise stated, the nanoemulsion was produced as follows. First, a vial containing the organic phase consisting of oil (Labrafil® M 1944 CS, 0.18 g), a surfactant (Cremophor® EL, 0.12 g), and ILQ (24 mg) was partially immersed in the water and sonicated for 20 min (750 r min-1) using an ultrasonic cleaning machine (SB-4200D, Xinzhi Biotechnology Co., […].” (p. 3, last paragraph)(instant claim 1 step 1; instant claim 6, “power of the ultrasonic cleaner is 40 KHz”). And “Afterwards, the vial was put on a multipoint magnetic stirrer […] and stirred for 20 min (750 r min-1). Then, the aqueous phase (2.7 mL PBS, pH 7.4) was added into the organic phase dropwise with a 1 mL injector while it was under constant stirring (750 r min-1) at a rate of 1 drop per second. After the addition of the aqueous phase, stirring was continued for 30 min. The preparation process was carried out at room temperature.” (p. 4, 1st paragraph)(instant claim 1, step 2; instant claim 5; instant claim 6, mixing speed in step 2 is 750 rpm).
Regarding the relative amounts of the hydrophobic small molecule substance, the oil, the surfactant, and the aqueous phase recited in instant claim 2, (1%, 6%, 4% and 89%, respectively), Wang et al. discloses 24 mg ILQ, 180 mg oil (0.18 g), 120 mg surfactant (0.12 g), combined with 2.7 mL phosphate buffer (PBS), which is approximately 0.51%:3.83%:2.5%:93.1%, respectively where the density of PBS is taken as 1.62 mg/mL. The amounts are not the same as claimed but are merely close (MPEP §2144.05(I) - Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.)(instant claim 2).
Wang et al. discloses that: “To investigate the effect of ultrasonic depth, i.e., the height of the water in the ultrasonic cleaning machine, on the formation of small droplets using the SPIC method, small vials containing organic phases were partially (1.5 cm was under water) placed into the water, and the height of the water in the ultrasonic cleaning machine was varied.” (p. 7, last paragraph)(instant claim 4, “a bottle body of the transparent glass enters 1.5 cm below the liquid level.”). Wang et al. utilizes transparent glass bottles (Figures 3b, 4b, 5b and 6b)(instant claim – “transparent glass bottle”).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Wang et al. is that Wang et al. does not expressly teach the claimed combined PIC (step 2) and PIT (step 3) method.
YUE teaches “a benzene alkene pidotimod nano emulsion and preparation method thereof, adopting compound regulating HLB value surfactant to 13 to 14 degrees centigrade, and can be regulated to a specific HLB value, the obtained nano emulsion grain size range is 10 ~ 50nm, uniform particles, and with increasing drug and stronger stability,” (abstract). And that: “[0015] The invention also provides a preparation method of alkene benzene pidotimod nano milk, it adopts the PIT method combined with the PIC preparation.” (p. 4, [0015]). And that: “the preparation method provided by the invention, selecting mixing temperature is 60 to 80 degrees centigrade.” (p. 4, [0016]). And further that: “the loading amount of nano emulsion prepared by the surfactant of the invention is two times of the existing technology,” (p. 5, [0021]).
Hong et al. teaches that: “ In this context, herein we designed and prepared a multifunctional nanoemulsion system, aiming at integrating the merits of the in situ oxygen generation strategy and oxygen delivery strategy. This multifunctional nanoemulsion system contains catalase, a synthetic triterpenoid the methyl ester of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), photosensitizer IR780, and perfluoropolyether. It is named the catalase-CDDO-Me-IR780- perfluoropolyether nanoemulsion, and abbreviated as CCIPN. […] To prepare CCIPN, we used a sonication-phase inversion composition–sonication (S-PIC-S) method that we developed by advancing our previous sonication and phase-inversion composition (SPIC) method. The S-PIC-S method could further reduce the production droplet size while retaining the advantage of environment-sensitive substance (herein, IR780) protection.” (p. 2, last paragraph through p. 3, line 4). Hong et al. teaches that: “The water phase (3.6 mL PBS, pH 7.4 containing 16 mg CAT) was then titrated into the mixture with a peristaltic pump ([…]) when the mixture was continuously agitated at 750 r min-1. The rotation speed of the peristaltic pump was set as 22.0 rpm, and the titration rate was approximately one drop every 3 s.” (p. 3, last paragraph, lines 11-15)(instant claim 6 – “a speed of the peristaltic pump is 22 rpm.”).
Yu et al. teaches that: “For the low-energy method, the chemical energy stored in the components is used by changing the spontaneous curvature of the surfactants. For nonionic surfactant systems, this can be achieved by changing the temperature at constant composition, i.e., phase inversion temperature, PIT method, or changing the composition at constant temperature, i.e., phase inversion composition, PIC method. The PIC method has a great potential for scale-up applications because of the ease of formation and relatively low energy costs. A phase transition is produced by stepwise addition of water to a mixture of the surfactant and oil for the formation of oil-in-water (O/W) nanoemulsions. This process is well-known for the emulsification of short-chain alkanes prepared at 25 °C. However, the Ostwald ripening, i.e., the oil diffusion in the aqueous phase, causes nanoemulsions to break down in relatively short time periods, which is the main limitation for developing practical applications.” (p. 14547, 2nd paragraph). And that: “Generally speaking, the production of monodisperse nanoemulsions with small droplet size and high kinetic stability is attractive for both a theoretical and practical point of view. In our previous work, the liquid paraffin-in-water nanoemulsions were prepared via the PIC method at low temperature. The emulsion droplet diameter grows slowly and remains less than 300 nm after 5 months of storage at room temperature. Afterward, nanoemulsions were prepared via the PIT method using a more viscous paraffin oil. The size distribution has not changed more than 6 months. In this report we present a complete study on the formation and stability of nanoemulsions made via the PIC method using the viscous paraffin oil. This study explored the influence of emulsification temperature, HLB value, and droplet volume fraction. These results demonstrate that the PIC method at elevated temperature is of great significance in nanoemulsion formation and long-term stability.” (p. 14547, 3rd paragraph).
Yu et al. teaches the effect of emulsification temperature on emulsion droplet size and interfacial tension (Figure 1), particularly that: “The droplet diameter of the nanoemulsions as a function of the preparation temperature is shown in Figure 1. Droplet diameter decreases from 10.3 μm to 51 nm with the increase of emulsification temperature at a constant composition (O/S = 1:1, φ = 0.1). Macroemulsions with high polydispersities were obtained when the emulsions were prepared at 20 or 30 °C. The droplet size and polydispersity decrease dramatically with the increase of emulsification temperature from 20 to 70 °C and remain unchanged with a further increase in the temperature. Figure 1 also shows the
curve of interfacial tension, which is similar to that of droplet size. This means that nanoemulsions cannot be obtained at low temperature due to the relatively high interfacial tension and the high viscous resistance of the oil phase. With the increase of preparation temperature, the interfacial tension decreases and the amount of surfactant molecules adsorbed at the O/W interface increases gradually. At elevated temperatures (≥70 °C), the surfactant adsorption reaches saturation.” (p. 14548, col. 1, last paragraph through col. 1, 1st paragraph; Figure 1).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a method for making an nanoemulsion comprising an active agent such as isoliquiritigenin (ILQ) including a step of sonication of the oil/surfactant phase and a phase-inversion composition (PIC) step for forming an nanoemulsion, as suggested by Wang et al., and further to include a phase-inversion temperature (PIT) step, as suggested by YUE, for the production of smaller nanoemulsion droplet sizes, increased drug loading, and increased stability as suggested by YUE and Yu et al., and to utilize a peristaltic pump at 22 rpm as suggested by Hong et al. for the introduction of the aqueous phase into the oil phase.
From the 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. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al.; YUE; Hong et al. and Yu et al., as applied to claims 1-3, 5 and 6 above, and further in view of Dokovic et al. (“Curcumin Loaded PEGylated Nanoemulsions Designed for Maintained Antioxidant Effects and Improved Bioavailability: A Pilot Study on Rats,” 2021, MDPI; International Journal of Molecular Sciences, Vol. 22, No. 7991, pp. 1-27).
Applicants Claims
Applicant claims are discussed above.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Wang et al. teaches Isoliquiritigenin Nanoemulsion Preparation by Combined Sonication and Phase-Inversion Composition Method, as discussed above and incorporated herein by reference.
YUE teaches a benzene alkene pidotimod nano emulsion and preparation method thereof, including combining the PIC and PIT methods, as discussed above and incorporated herein by reference.
Hong et al. teaches a preparation method for a multifunctional nanoemulsion system including introduction of the aqueous phase into the organic phase using a peristaltic pump, as discussed above and incorporated herein by reference.
Yu et al. teaches nanoemulsions prepared by the PIC method at elevated temperatures, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Wang et al. is that Wang et al. does not expressly teach the claimed “wrapping the transparent glass bottle in tin paper” (instant claim 4). The examiner is interpreting “tin paper” to encompass aluminum foil.
Dokovic et al. teaches curcumin loaded nanoemulsions (see whole document), and particularly that “The tubing was placed in a flask containing 200 mL of dissolution medium and covered with aluminum foil in order to prevent the evaporation of ethanol and avoid the light degradation of curcumin.” (p. 21, §3.11, lines 7-9).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a method for making an nanoemulsion comprising an active agent such as isoliquiritigenin (ILQ) including a step of sonication of the oil/surfactant phase and a phase-inversion composition (PIC) step for forming an nanoemulsion, as discussed above, and further to utilize aluminum foil (tin paper) to cover the transparent glass vial, as suggested by Dokovic et al., to protect the active agent from light degradation prior to formation of the nanoemulsion which is taught by Wang et al. to protect from UV degradation - “Nanoemulsion encapsulation effectively prevented ILQ from degradation under ultraviolet light irradiation” (abstract, lines 9-10).
From the 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. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 1-6 are pending and have been examined on the merits. Claims 1-6 are rejected under 35 U.S.C. 112(a)(written description, and separately, enablement); claim 4 is rejected under 35 U.S.C. 112(b); and claims 1-6 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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