Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/17/25 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Receipt of amendment and response dated 9/25/25 is acknowledged.
Claims 69, 70, 72 and 77-79 have been canceled.
Claims 81-84 have been withdrawn from consideration as being non-elected.
Claims 65-68, 71, 73-76, 80 and 85-90 have been considered examination.
The following Double patenting rejection has been maintained:
Double Patenting
Claims 65-67, 71, 74-75, 80, 85, 87 and 88 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,729,674.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are directed to a method of preparing nanoparticulates genistein combining with a pharmaceutically acceptable suspension medium, the pharmaceutically acceptable suspension medium comprising an aqueous carrier, nanomilling the combination of genistein and the suspension to produce nanoparticulates genistein. The dependent claims of the above patent recite polyvinylpyrrolidone as the water-soluble polymer and hence meet instant claimed water soluble polymer. The patented claims recite a specific method of preparing genistein nanoparticulates i.e., nanomilling, which is within the broad genus of a method claimed in the instant claims, including milling of instant dependent claims, and thus the claimed product. Patented claims recite 250mg/ml to 500 mg/ml amount of genistein, which includes 300 mg/ml. Patented claims include a nonionic surfactant and hence meet instant claim 65. While the patented claims fail to claim packaging step of claim 71, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to package the genistein nanosuspension of the patented claims depending on the final formulation i.e., injection formulation, oral formulation etc., in order to effectively administer the composition, in a bottle or a measured container.
Patented claims recite the concentration of genistein (250mg/ml to 500 mg/ml) that is also claimed in the instant application. Claim 15 of the patent recites a range of 5-15% w/w water soluble polymer. Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention to choose the optimum amount of PVP with 250mg/ml to 500 mg/ml genistein, so as to arrive at the claimed ratio of at least 6:1 and prepare a suitable suspension formulation.
Claim 65-68, 71, 73-76, 80 and 85-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,729,674, as applied to claims 65-67, 71, 74-75, 80, 85, 87 and 88 and in view of US 2009/0035336 to Vollhardt et al., and US 2006/0264497 to Zeligs et al.
The patented claims do not recite a sweetening agent of claim 73, a syringe (claim 76), buffering agent (claim 86), capsule formulation (claim 68), and buffered saline (claim 86).
Vollhardt teaches stable and nanoparticle compositions comprising high concentrations of genistein in a carrier, for cosmetic, pharmaceutical, food or feed purposes (abstract, [0017]. The nanoparticulate genistein of Vollhardt has an average particle size of 0.05-3 microns [0036] and particularly 0.05-0.5 microns (50 nm-500 nm), which meets the instant claimed value of D(0.5) of 50 microns or less and no particle measures greater than 2 microns. Vollhardt teaches several genistein dispersions having D(v 0.1) and D(v 0.5) sizes (ex: tables 1-VIII). Vollhardt teaches preparing suspensions of genistein [0034] employing carriers such as hydroxypropyl methylcellulose, gums, cellulose derivatives etc. [0030, 0032] or starch, sorbitol, maltose, alginate, gum etc., which are also described in the instant specification as water soluble polymers [0031] and suggest a genistein to carrier ratio of 10:1. For the process of preparing the genistein, Vollhardt teaches that the isoflavone nanoparticles are prepared by high pressure homogenization process, particularly subject to agitated bead mill [0025, 0028 and 0102], spray drying or freeze drying [col. 6, l 20-25]. For the claimed packaging step, Vollhardt teaches that genistein nanoparticles are useful in preparing cosmetic, pharmaceutical compositions, feed or food stuff. Further, Vollhardt teaches solid dispersions of patented claims in the form of various oral formulations such as tablets, capsules etc., [0090]; as well as injectable formulations [0095]. Example 8 further teaches methylparaben, ethylparaben that meet the instant preservatives.
Zeligs reference has been relied upon to show that a sweetening agent is conventionally used in oral composition comprising genistein as an active agent. Zeligs teaches oral mucosal compositions comprising diindolylmethane-based (DIM-based) or DIM-related indole, alone or in combination with other anti-inflammatory compounds (abstract, 0114-0115). The composition is in the form of capsules, tablets, gels, etc (abstract). Zeligs teaches genistein as one of the phytoestrogens. The composition is in the form of tablets, capsules, drink mix, food etc (0036), in the form of spray dried solid dispersions [0130-0133], comprising polymers such as such as polyvinylpyrrolidone, hydroxypropyl methylcellulose etc [0141-0142]. Zeligs further teach lyophilized powders comprising active agents [col. 23, l 54-col. 24, l 18). Zeligs teaches inclusion of suitable pharmaceutical additives such as abrasive agents, gelling agent, humectant, sweetening agent, buffering agents etc [0185 and 0190]. Zeligs further teaches buffers such as sodium citrate, sodium carbonate, sodium bicarbonate etc [0197]. Example 6 of Zeligs teaches a composition comprising genistein and DIM as active agent, and further include fructose (which meet instant sweetening agent).
Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to prepare suspensions of genistein of patented claims, and further modify to include the instant claimed buffers, polysorbate, and preservatives such as methylparaben; and further prepare the composition as an oral or injectable compositions, because Vollhardt teaches genistein suspension formulation are suitable for oral administration as well as injectable formulations, and suggests employing the instant claimed excipients. Both Vollhardt and Zeligs references are analogous to the patented claims i.e., drawn to genistein suspensions and teach spray drying (Vollhardt), lyophilization (Vollhardt and Zeligs), for stabilization of the active agent. Zeligs further employ additional excipients and additives such as buffering agents, fructose as sweetening agent in the said composition. One of an ordinary skill would have been motivated to modify because one would have recognized that genistein can be prepared as oral formulations such as capsule or tablet (as suggested by Vollhardt) and Zeligs teaches that it is routine to employ buffering agents and sweetening agents.
Claims 65-66, 71, 74-75, and 85-88 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 9,308,167. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 9308167 patent are directed to a method of preparing nanoparticulates genistein combining with a pharmaceutically acceptable suspension medium, the pharmaceutically acceptable suspension medium comprising an aqueous carrier, nanomilling the combination of genistein and the suspension to produce nanoparticulates genistein. The dependent claims of the above patent recite polyvinylpyrrolidone as the water-soluble polymer and hence meet instant claimed water soluble polymer. The patented claims recite a specific method of preparing genistein nanoparticulates i.e., nanomilling, which is within the broad genus of a method claimed in the instant claims, including milling of instant dependent claims, and thus the claimed product.
Patented claims recite the concentration of genistein (250mg/ml to 500 mg/ml) that is also claimed in the instant application. Claim 12 of the patent recites a range of 5-15% w/w water soluble polymer. Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention to choose the optimum amount of PVP with 250mg/ml to 500 mg/ml genistein, so as to arrive at the claimed ratio of at least 6:1 and prepare a suitable suspension formulation. Patented claims recite polysorbate and hence meet instant claimed surfactant and polysorbate (claims 87 and 88).
Further, the patented claims recite the instant claimed buffer (claim 86). While the patented claims fail to claim packaging step of claim 71, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to package the genistein nanosuspension of the patented claims depending on the final formulation i.e., injection formulation, oral formulation etc., in order to effectively administer the composition.
Claims 65-68, 71, 73-76, 80 and 85-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 9,308,167, as applied to claims 65-66, 71, 74-75, and 85-89, and further in view of US 2009/0035336 to Vollhardt et al. and US 2006/0264497 to Zeligs et al.
The patented claims recite 65-66, 71, 74-75, and 85-88 but do not recite the packaging of claims 67-68, sweetening agent of claim 73, syringe of claim 76, and the preservative of claims 88 and 90.
The teachings of Vollhardt and Zeligs have been discussed above and incorporated herewith.
Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to prepare suspensions of genistein of patented claims, and further modify to include the instant sweeteners and preservatives such as methylparaben; and further prepare the composition as an oral or injectable compositions, because Vollhardt teaches genistein suspension formulation are suitable for oral administration as well as injectable formulations, and suggests employing the instant claimed excipients. Zeligs further employ additional excipients and additives such as buffering agents, fructose as sweetening agent in the said composition. Both Vollhardt and Zeligs references are analogous to the patented claims i.e., drawn to genistein suspensions and teach spray drying (Vollhardt), lyophilization (Vollhardt and Zeligs), for stabilization of the active agent. Hence, one of an ordinary skill would have been motivated to modify because one would have recognized that genistein can be prepared as oral formulations such as capsule or tablet (as suggested by Vollhardt) and Zeligs teaches that it is routine to employ a sweetening agent.
Response to Arguments
Applicant’s arguments dated 9/25/25, have been considered.
In response to the Double patenting rejections, Applicants request that the rejections over US 10729674 and US 9308167 be held in abeyance. Applicants have not provided arguments regarding the merits of the rejections. Accordingly, the rejections have been maintained.
The following rejection of record has been maintained:
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 65-68, 71, 73-76, 80 and 85-90 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Motlekar et al in view of WO 2008/086400 to Doney et al (Doney), US 2009/0035336 to Vollhardt et al., and US 2006/0264497 to Zeligs et al.
Motlekar teaches preparation and characterization of genistein containing polyethylene glycol (PEG) microparticles, for enhanced dissolution profile (abstract). Motlekar teaches that the microparticles are prepared by solvent evaporation. Motlekar teaches that several methods have been employed to improve the solubility of poorly water-soluble drugs and include micronization, nanosuspension formulation, complexation, solubilization using surfactants, formation micelles, and self-micro-emulsifying drug delivery systems. Motlekar teaches solid dispersions of genistein prepared by using emulsion-solvent evaporation improves the solubility of genistein (p 2071, col. 1). Fig.6 shows the effect of genistein to polymer ratio of 1:40 on the dissolution of the drug. The method of preparing microparticles of genistein and PEG is described on page 2072 (col.1). Table II shows the effect of molecular weight of PEG on the percent dissolution of PEG. Instant claim 65 does not specify the water-soluble polymer and therefore PEG of Motlekar reads on instant polymer. Motlekar teaches microparticles. Motlekar teaches a 1:1 mixture of genistein and PEG. Further, even though Motlekar teaches 16 mg genistein and 100-1500 mg of PEG (page 2072).
Motlekar does not teach the instant claim limitation “wherein the weight ratio of nanoparticulate genistein to polyvinylpyrrolidone in the suspension is at least about 6:1”. Instead, Motlekar teaches a higher ratio of genistein to polyvinylpyrrolidone.
Doney teaches a sirtuin-activating compounds (SAC) of enhanced solubility and bioavailability, wherein the composition includes a mixture comprising at least one SAC, a solubility-enhancing polymer (SAP) and a solvent and removing the solvent to form amorphous SAC (abstract). For the SAC, Doney teaches flavonoids [002], and in particular, the flavonoids have genistein [004]. Doney teaches that SACs such as flavonoids have poor water solubility and require increased aqueous solubility and bioavailability [0007], wherein a mixture is prepared by blending SACs with a solubility enhancing polymer, employing a solvent, which is further spray dried to produce the SAC in an amorphous state ([0010-0012]). Further, Doney teaches that the solid dispersion is dispersed evenly throughout the other component or components, and the dispersion includes particles have a size of less than 1 micron [0025], and hence overlap with the claimed nanoparticulate sizes. For Doney teaches several methods of preparing the amorphous compounds by dissolving in a solvent. Doney also teaches evaporating the solvent and further spray dying particles.
For the solubility-enhancing polymer, Doney teaches polyvinylpyrrolidone [0034 & 0039].
For the claimed ratio of genistein: PVP of at least 6:1, Doney teaches that the active ingredient (SAC) is employed in an amount of up to 80%, depending on the dose of the active and the weight ratio of SAC: polymer from 95% SAC:5% polymer or 5% SAC:95% polymer [0041]. Even though, Doney teaches a more particular ratio of 70% SAC:30% polymer or more particularly, 60% SAC : 40% polymer, it would have been obvious for one of an ordinary skill in the art before the effective filing date of the instant invention to modify the composition of Motlekar i.e., substitute PEG with PVP, in particular a ratio of genistein:PVP and further optimize the ratio of genistein:PVP, so as to arrive at the claimed ratio of genistein : PVP of at least 6:1, and further optimize the amount of genistein so as to arrive at the claimed concentration, depending on the desired dose and concentration of genistein.
In this regard, Vollhardt reference discussed below also teaches a genistein to water soluble carrier polymer ratio of 10:1.
Vollhardt teaches stable and nanoparticle compositions comprising high concentrations of genistein in a carrier, for cosmetic, pharmaceutical, food or feed purposes (abstract, [0017]. The nanoparticulate genistein of Vollhardt has an average particle size of 0.05-3 microns [0036] and particularly 0.05-0.5 microns (50 nm-500 nm), which meets the instant claimed value of D(0.5) of 50 microns or less and no particle measures greater than 2 microns. Vollhardt teaches several genistein dispersions having D(v 0.1) and D(v 0.5) sizes (ex: tables 1-VIII). Vollhardt teaches preparing suspensions of genistein [0034] employing carriers such as hydroxypropyl methylcellulose, gums, cellulose derivatives etc. [0030, 0032] or starch, sorbitol, maltose, alginate, gum etc., which are also described in the instant specification as water soluble polymers [0031] and suggest a genistein to carrier ratio of 10:1. For the process of preparing the genistein, Vollhardt teaches that the isoflavone nanoparticles are prepared by high pressure homogenization process, particularly subject to agitated bead mill [0025, 0028 and 0102], spray drying or freeze drying [col. 6, l 20-25]. For the claimed packaging step, Vollhardt teaches that genistein nanoparticles are useful in preparing cosmetic, pharmaceutical compositions, feed or food stuff.
Therefore, one of an ordinary skill in the art would have been motivated to do so because Doney teaches a range of the active:polymer depending on the desired dose of the active agent and further suggest teaches PVP increases solubility of [0034, 0040, 0072, 0085 and examples 2-5]. Therefore, one of an ordinary skill in the art would have optimized the ratios so as to result in increased solubility of genistein and bioavailability.
Doney does not teach nonionic surfactant, aqueous carrier, preservatives and sweeteners of instant claims.
Further, Vollhardt teaches solid dispersions in the form of various oral formulations such as tablets, capsules etc., [0090]; as well as injectable formulations [0095]. Example 8 further teaches methylparaben, ethylparaben that meet the instant preservatives.
Zeligs reference has been relied upon to show that a sweetening agent is conventionally used in oral composition comprising genistein as an active agent. Zeligs teaches oral mucosal compositions comprising diindolylmethane-based (DIM-based) or DIM-related indole, alone or in combination with other anti-inflammatory compounds (abstract, 0114-0115). The composition is in the form of capsules, tablets, gels, etc (abstract). Zeligs teaches genistein as one of the phytoestrogens. The composition is in the form of tablets, capsules, drink mix, food etc (0036), in the form of spray dried solid dispersions [0130-0133], comprising polymers such as such as polyvinylpyrrolidone, hydroxypropyl methylcellulose etc [0141-0142]. Zeligs further teach lyophilized powders comprising active agents [col. 23, l 54-col. 24, l 18). Zeligs teaches inclusion of suitable pharmaceutical additives such as abrasive agents, gelling agent, humectant, sweetening agent, buffering agents etc [0185 and 0190]. Zeligs further teaches buffers such as sodium citrate, sodium carbonate, sodium bicarbonate etc [0197]. Example 6 of Zeligs teaches a composition comprising genistein and DIM as active agent, and further include fructose (which meet instant sweetening agent).
Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to prepare genistein compositions of Motlekar modified by Doney and Vollhardt, and further modify to include claimed surfactants (polysorbate), buffers, and preservatives such as methylparaben; and prepare the composition as an oral or injectable compositions, because Vollhardt teaches genistein suspension formulation are suitable for oral administration as well as injectable formulations, and suggests employing the instant claimed excipients. Zeligs further employ additional excipients and additives such as buffering agents, fructose as sweetening agent in the said composition. Both Vollhardt and Zeligs references are drawn to genistein suspensions and teach spray drying (Vollhardt), lyophilization (Vollhardt and Zeligs), for stabilization of the active agent. Hence, one of an ordinary skill would have been motivated to modify because one would have recognized that genistein can be prepared as oral formulations such as capsule or tablet (as suggested by Vollhardt) and Zeligs teaches that it is routine to employ buffering agents and sweetening agents.
Response to Arguments
Applicant's arguments filed 9/25/25 have been fully considered but they are not persuasive.
Applicants argue that claims 65 and 75 each set forth a method of making a stable aqueous genistein formulation consisting essentially of nanoparticulate genistein, polyvinylpyrrolidone (PVP), a nonionic surfactant, and an aqueous carrier, wherein the suspension contains at least about 300 mg/ml genistein, and wherein the weight ratio of nanoparticulate genistein to PVP in the suspension is at least about 6:1, whereas Moetlekar fails to disclose, inter alia, a suspension of genistein and PVP in an aqueous carrier. It is argued that Doney describes a process of formulating an amorphous solid dispersion of a SAC that involves pairing a solubility-enhancing polymer with a specific solvent/non-solvent blend, and teaches as a requirement that “the solvent possesses a lower boiling point than the non-solvent.” [0034]. It is argued that the solid dispersion is created by spray-drying a mixture of the SAC, the polymer, and the solvent/non-solvent blend under pressure and/or temperature conditions selected to remove the solvent from said mixture, thus resulting removing solvent with non-solvent remaining. It is argued that one of an ordinary skill in the art would have been motivated to employ solvent/non-solvent system of Doney in the composition of Moetlekar, which would neither yield nor guide a skilled person to a method of making a stable aqueous genistein formulation “consisting essentially” of nanoparticulate genistein, PVP, a nonionic surfactant, and an aqueous carrier as set forth in the claims. It is argued that Vollhardt and Zeligs fail to remedy the deficiencies of Motlekar both alone and in combination with Doney.
Applicants’ arguments are not found persuasive because the transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of "consisting essentially of," applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of the claimed invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd. Pat. App. & Inter. 1989). In the instant case, Applicants have not provided any evidence to show that the solvent/non-solvent of Doney affects the instant composition. Moreover, the present rejection relies on Doney only for the ratio of genistein:polymer. The rejection relies on Vollhardt for aqueous carrier. Applicants have not argued the merits of Vollhardt and Zeligs. Accordingly, the rejection has been maintained.
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.
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/LAKSHMI S CHANNAVAJJALA/Primary Examiner, Art Unit 1611