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 .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 29 December 2025 are acknowledged and have been fully considered. Claims 1-24, 26-31 and 34 are pending. Claims 1-24, 26-31 and 34 are under consideration in the instant office action. Claims 25 and 32-33 are canceled.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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 1-24, 26-31 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over MOURI et al. (WO2015/059193, previously cited) in view of Singh et al. (AAPS PharmSciTech, Vol. 16, No. 2, April 2015, previously cited), Hayek et al. (WO 2013/086015, IDS reference, previously cited), Sahoo et al. (Designed Monomers and Polymers 14 (2011) 95–108, previously cited), Baker (US 2013/0058983, previously cited), and McCartt et al. (US 2006/0127429, previously cited).
Applicants’ claims
Applicant claims a method of delivering an active agent to a non-sterile open wound site.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
MOURI et al. teach a new organogel formulation, comprising lecithin, water, ethanol and acylglycerols. Said organogel formulation can be used for therapeutical purposes, both per se and as matrix for a pharmaceutically or veterinary active agent. Said organogel formulation can also be used in the treatment of dermatological affections or as a matrix for cosmetic or personal care substances (see abstract). MOURI et al. teach in claim 1
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The organogel formulation according to claim 1, wherein the organogel further comprises at least one sterol, preferably sitosterol (see claim 2). The organogel formulation according to claim 1 or 2, comprising: from 5 to 23 wt water, from 0.01 to 9.5 wt% ethanol, from 25 to 50 wt lecithin, and from 30 to 49 wt acylglycerols, relative to the total weight of the organogel (see claim 3). An organogel formulation as defined in anyone of claims 1 to 8, for use in improving and/or accelerating cicatrisation of a wound, a burn, an inflammation and/or a bedsore (see claim 12).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Mouri et al. do not specifically teach sorbitan monostearate as the organogelator and linoleic acid. These deficiencies are cured by the teachings of Singh et al.
Singh et al. teach the current study explains the development of sorbitan monostearate and sesame oil-based organogels for topical drug delivery. The organogels were prepared by dissolving sorbitan monostearate in sesame oil (70°C). Metronidazole was used as a model antimicrobial. The formulations were characterized using phase contrast microscopy, infrared spectroscopy, viscosity, mechanical test, and differential scanning calorimetry. Phase contrast microscopy showed the presence of needle-shaped crystals in the organogel matrix. The length of the crystals increased with the increase in the sorbitan monostearate concentration. XRD studies confirmed the amorphous nature of the organogels. Viscosity study demonstrated shear thinning behavior of the organogels. The viscosity and the mechanical properties of the organogels increased linearly with the increase in the sorbitan monostearate concentration. Stress relaxation study confirmed the viscoelastic nature of the organogels. The organogels were biocompatible. Metronidazole-loaded organogels were examined for their controlled release applications. The release of the drug followed zero-order release kinetics. The drug-loaded organogels showed almost similar antimicrobial activity against Escherichia coli when compared to the commercially available Metrogyl® gel. In gist, it can be proposed that the developed organogels had sufficient properties to be used for controlled delivery of drugs (see abstract). Sesame oil is obtained from the ripe seeds of Sesamum indicum L. Sesame seeds contain the highest oil (44–58%) among the primary edible oils along with proteins (18–25%) and carbohydrates (13.5%) (15). Sesame oil has been used extensively for pharmaceutical and cosmetic applications due to its antiseptic, disinfectant, antiinflammatory, antitubercular, antiviral, antibacterial, and antioxidant properties. The major components of sesame oil (sesamin, sesamolin, and sesamol) provide stability against oxidative deterioration of the formulations. Sesame oil has the highest antioxidant content among the primary edible oils. It also contains abundant fatty acids such as oleic acid (43%), linoleic acid (35%), palmitic acid (11%), and stearic acid (7%) (see page 294). The required quantity of sorbitan monostearate was dissolved in sesame oil (70°C, 500 RPM). The stirring was continued for 15 min under similar experimental condition to obtain a homogenous transparent mixture. The optimization of the composition of the organogel was done by varying the concentration of sorbitan monostearate from 5% w/w to 22% w/w. The minimum gelator (SMS) concentration required for inducing gelation is called the critical gelator concentration (CGC). The compositions tested for the gel formation are shown in Table I. The hot mixture when cooled to room temperature forms organogel at the sorbitan monostearate concentration ≥CGC. The formulations which did not show flow on inversion were selected as the representative samples for further characterization. The organogels were examined for their organoleptic properties like odor, color, texture, pH, oil leakage, phase separation, and tendency to flow (25). Metronidazole was added to the organogels as a model antimicrobial drug at a concentration of 1% w/w. The drugloaded organogels were prepared in a similar way. The drug was uniformly dispersed in sesame oil before adding sorbitan monostearate.
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Sorbitan monostearate–sesame oil-based organogels were prepared and characterized thoroughly by investigating various molecular, mechanical, and thermal properties. The micrographs of the organogels showed the presence of needle-shaped crystal structures of sorbitan monostearate. The organogels were stable, smooth, and biocompatible. They were amorphous in nature and showed a non-Newtonian shear thinning flow behavior. The stability (long-term and thermal) and the mechanical properties (viscosity and firmness) increased with the increase in the organogelator (sorbitan monostearate) concentration. The metronidazole-loaded organogels showed diffusion-mediated release of drug from the organogel matrix. The antimicrobial assay showed a good inhibitory action of the drug-loaded organogels against E. coli. The critical gelator concentration of sorbitan monostearate was 15% w/w, which was much lower as compared to the reported literatures. The developed organogels showed a controlled release of metronidazole (46%–64% w/w) compared to the previously reported sorbitan monostearate-based organogels. Hence, the developed organogels can be considered as probable matrices for a controlled release of the antimicrobials for topical application (see conclusion).
Mouri et al. do not specifically teach the composition forming an organogel drug depot and wherein the organogel drug depot is delivered to the open wound site by injection from a syringe through a percutaneous needle or cannula. Furthermore Mouri et al. is silent with respect to the limitation reciting wherein the step of compounding and the step of delivering are performed contemporaneously specifically the fact that the organogel is formed first and applied to the wound site. These deficiencies are cured by the teachings of Hayke et al. and Sahoo et al.
Hayek et al. teach Serial-solvent biomaterials are described. Embodiments include materials made in an organic solvent that are stripped of the solvent and used in a patient, where they imbibe water and form a hydrogel. These materials are useful for, among other things, delivering therapeutic agents, tissue augmentation, and radiological marking (see abstract). A process of making a medical material comprising forming an organogel around a powder of a water soluble biologic, with the powder being dispersed in the organogel (see abstract). A biomaterial made by a process of any of claims 1-31 (see claim 32). Hayek et al. teach Figure 1A depicts an embodiment of this process, which is started with protein particles 100 that have been prepared by conventional means to preserve protein secondary and, if present, tertiary or quaternary structure. These are combined with precursors 102, 104, into organic solvent 106. The mixture is processed to achieve the desired shape of the biomaterial, e.g., by casting 108, as rod 110, as particles and/or spheres 1 12, and molded shapes 114. The solvent is stripped out of the shapes and the materials will form hydrogels when exposed to water. The entire process, until the point where the xerogel is actually used with a patient, may be performed in an absence of water and/or in an absence of hydrophobic materials. Fig. IB depicts a micro structure of a biomaterial 120 made by this process. The structure is representative of the material across the process of its manufacture and use: organogel, xerogel, and then hydrogel. The crosslinked matrix is made of precursors 124 that have been covalently reacted with each other. Particles 124 of a water soluble biologic are dispersed within the matrix. The matrix is a continuous phase and the particles are spread out inside it and are the discontinuous phase, also referred to as the dispersed phase. The examiner takes the position that Hayek et al. teach forming the organogel before applying it to tissue.
Sahoo et al. teach an organogel, a viscoelastic system, can be regarded as a semi-solid preparation which has an immobilized external apolar phase. The apolar phase is immobilized within spaces of the three-dimensional network structure formed due to the physical interactions amongst the self-assembling structures of compounds regarded as gelators. In general, organogels are thermodynamically stable in nature and have been explored as matrices for the delivery of bioactive agents. In the current paper, attempts have been made to understand the properties of organogels, various types of organogelators and some applications of the organogels in controlled delivery (see abstract). In general, sorbitan monostearate organogels have a very short half-life at the injection site. This may be attributed to the diffusion of water molecules within the gelled structure, which results in the subsequent disruption of the networked structure due to the emulsification of the gel surface. The same group has also reported the development of a sorbitan-monostearate-based organogel which has shown sustained delivery of a model antigen and radiolabelled bovine serum albumin after intra-muscular administration of the same in mice. The results indicated the probable use of the formulation as depot (see page 104).
Mouri et al. do not specifically teach applying the antimicrobial agents listed in claims 22-23 containing organogels to open wound. These deficiencies are cured by the teachings of Baker et al.
Baker et al. teach Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural surfaces that contain bacterial biofilm, including unexpected synergy or enhancing effects between bismuth-thiol (BT) compounds and certain antibiotics, to provide formulations including antiseptic formulations (see abstract). In another embodiment of the present invention there is provided an antiseptic composition for treating a natural surface that contains bacterial biofilm, comprising at least one of (1) a composition that comprises (a) at least one BT composition that comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 .mu.m to about 5 .mu.m; and (b) at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, (2) a composition that comprises (a) at least one BT composition that comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 microns to about 5 microns; and (b) at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline, tobramycin, clindamicin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and (3) the composition of (2) wherein the aminoglycoside antibiotic is selected from amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin (paragraph 37). A microparticulate BT compound may also be used for preventing or treating caries and/or inflammation (i.e., reducing the likelihood of occurrence or recurrence of caries and/or inflammation, respectively) by administering the microparticulate BT compound to the surface of the teeth. A composition comprising a microparticulate BT compound may be a mucoadhesive composition that is applied to the surface of a tooth and/or gum or oral mucous membrane may be in any form that adheres to some extent to a surface or that delivers a pharmaceutically effective amount of the active ingredient(s) to the desired surface. A microparticulate BT compound can also be formulated to release slowly from the composition applied to the tooth. For example, the composition may be a gel (e.g., a hydrogel, thiomer, aerogel, or organogel) or liquid. An organogel may comprise an organic solvent, lipoic acid, vegetable oil, or mineral oil. Such gel or liquid coating formulations may be applied interior or exterior to an amalgam or composite or other restorative composition. A slow-release composition may deliver a pharmaceutically effective amount of microparticulate BT compound for 1, 2, 3, 4, 5, 6, or 7 (a week) days or for 2, 3, 4, 5, 6, 7 weeks, or 1, 2, 3, 4, 5, or 6 months. Such compositions can be prepared by a person skilled in the art using any number of methods known in the art (paragraph 132). The presently disclosed invention embodiments relate to compositions and methods for the treatment of microbial infections. In particular, the present embodiments relate to improved treatments for managing bacterial infections in epithelial tissues, including in wounds such as chronic wounds and acute wounds, and in clinical, personal healthcare, and other contexts, including treatment of bacterial biofilms and other conditions (paragraph 3). According to certain contemplated embodiments topical administration may comprise direct application into an open wound. For instance, an open fracture or other open wound may include a break in the skin that may expose additional underlying tissues to the external environment in a manner that renders them susceptible to microbial infection. Such a situation is not uncommon in certain types of acute traumatic military wounds, including, for example, Type III (severe) open fractures. In accord with these and related embodiments, topical administration may be by direct contact of the herein described BT composition with such damaged skin and/or another epithelial surface and/or with other tissues, such as, for instance, connective tissues including muscle, ligaments, tendons, bones, circulatory tissues such as blood vessels, associated nerve tissues, and any other organs that may be exposed in such open wounds. Examples of other tissues that may be exposed, and hence for which such direct contact is contemplated, include kidney, bladder, liver, pancreas, and any other tissue or organ that may be so detrimentally exposed to opportunistic infection in relation to an open wound (see paragraph 194).
Mouri et al. does not specifically teach local anesthetic as the active agents. These deficiencies are cured by the teachings of McCartt et al.
McCartt et al. teach a method for anesthetizing skin prior to a dermatologic laser procedure, the method comprising applying to the skin of a patient a composition comprising at least one anesthetic agent admixed in a lecithin organogel base (see claim 1). The invention also provides a composition for topical anesthesia prior to laser application to the skin of a human subject, the composition comprising about 15 to about 25 percent (w/w) benzocaine, about 5 to about 15 percent (w/w) lidocaine, and about 1 to about 10 percent (w/w) tetracaine in a lecithin organogel base. The lecithin organogel may be a pluronic lecithin organogel. In one embodiment, the composition comprises about 20 percent (w/w) benzocaine, about 10 percent (w/w) lidocaine, and about 4 percent (w/w) tetracaine in about 66 percent lecithin organogel (see paragraph 9). One hundred grams of a 20% benzocaine, 10% lidocaine, 4% tetracaine topical analgesic composition were prepared by admixing twenty grams of 20% benzocaine, 10 grams of 10% lidocaine, and 4 grams of 4% tetracaine. Butylated hydroxytoluene NF (BHT) (0.1 gram of 0.1%) was triturated in a glass mortar and pestle to reduce particle size. Polysorbate 80 was added to wet the BHT. Pluronic lecithin organogel was added as a lipoderm base to the benzocaine, lidocaine, tetracaine mixture with trituration, then the BHT/Polysorbate 80 was added. The entire composition was then mixed in an ointment mill (paragraph 29).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by using sorbitan monostearate as the organogelator and linoleic acid as the solvent because Singh et al. teach the current study explains the development of sorbitan monostearate and sesame oil-based organogels for topical drug delivery. The organogels were prepared by dissolving sorbitan monostearate in sesame oil (70°C). Metronidazole was used as a model antimicrobial. The formulations were characterized using phase contrast microscopy, infrared spectroscopy, viscosity, mechanical test, and differential scanning calorimetry. Phase contrast microscopy showed the presence of needle-shaped crystals in the organogel matrix. The length of the crystals increased with the increase in the sorbitan monostearate concentration. XRD studies confirmed the amorphous nature of the organogels. Viscosity study demonstrated shear thinning behavior of the organogels. The viscosity and the mechanical properties of the organogels increased linearly with the increase in the sorbitan monostearate concentration. Stress relaxation study confirmed the viscoelastic nature of the organogels. The organogels were biocompatible. Metronidazole-loaded organogels were examined for their controlled release applications. The release of the drug followed zero-order release kinetics. The drug-loaded organogels showed almost similar antimicrobial activity against Escherichia coli when compared to the commercially available Metrogyl® gel. In gist, it can be proposed that the developed organogels had sufficient properties to be used for controlled delivery of drugs (see abstract). Sesame oil is obtained from the ripe seeds of Sesamum indicum L. Sesame seeds contain the highest oil (44–58%) among the primary edible oils along with proteins (18–25%) and carbohydrates (13.5%) (15). Sesame oil has been used extensively for pharmaceutical and cosmetic applications due to its antiseptic, disinfectant, antiinflammatory, antitubercular, antiviral, antibacterial, and antioxidant properties. The major components of sesame oil (sesamin, sesamolin, and sesamol) provide stability against oxidative deterioration of the formulations. Sesame oil has the highest antioxidant content among the primary edible oils. It also contains abundant fatty acids such as oleic acid (43%), linoleic acid (35%), palmitic acid (11%), and stearic acid (7%) (see page 294). The required quantity of sorbitan monostearate was dissolved in sesame oil (70°C, 500 RPM). The stirring was continued for 15 min under similar experimental condition to obtain a homogenous transparent mixture. The optimization of the composition of the organogel was done by varying the concentration of sorbitan monostearate from 5% w/w to 22% w/w. The minimum gelator (SMS) concentration required for inducing gelation is called the critical gelator concentration (CGC). The compositions tested for the gel formation are shown in Table I. The hot mixture when cooled to room temperature forms organogel at the sorbitan monostearate concentration ≥CGC. The formulations which did not show flow on inversion were selected as the representative samples for further characterization. The organogels were examined for their organoleptic properties like odor, color, texture, pH, oil leakage, phase separation, and tendency to flow (25). Metronidazole was added to the organogels as a model antimicrobial drug at a concentration of 1% w/w. The drugloaded organogels were prepared in a similar way. The drug was uniformly dispersed in sesame oil before adding sorbitan monostearate.
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Sorbitan monostearate–sesame oil-based organogels were prepared and characterized thoroughly by investigating various molecular, mechanical, and thermal properties. The micrographs of the organogels showed the presence of needle-shaped crystal structures of sorbitan monostearate. One of ordinary skill in the art would have been motivated to utilize sorbitan monostearate and lineolic acicd based organogels because Singh et al. teach that this organogels were stable, smooth, and biocompatible. They were amorphous in nature and showed a non-Newtonian shear thinning flow behavior. The stability (long-term and thermal) and the mechanical properties (viscosity and firmness) increased with the increase in the organogelator (sorbitan monostearate) concentration. The metronidazole-loaded organogels showed diffusion-mediated release of drug from the organogel matrix. The antimicrobial assay showed a good inhibitory action of the drug-loaded organogels against E. coli. The critical gelator concentration of sorbitan monostearate was 15% w/w, which was much lower as compared to the reported literatures. The developed organogels showed a controlled release of metronidazole (46%–64% w/w) compared to the previously reported sorbitan monostearate-based organogels. Hence, the developed organogels can be considered as probable matrices for a controlled release of the antimicrobials for topical application (see conclusion). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Singh et al. because both references teach organogels made from oils and fatty acids. In the case where the claimed range of amounts of ingredients and their particle size "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are teach in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
It would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by applying the biocompatible organogel contemporaneously because Hayek et al. teach serial-solvent biomaterials are described. Embodiments include materials made in an organic solvent that are stripped of the solvent and used in a patient, where they imbibe water and form a hydrogel. These materials are useful for, among other things, delivering therapeutic agents, tissue augmentation, and radiological marking (see abstract). A process of making a medical material comprising forming an organogel around a powder of a water soluble biologic, with the powder being dispersed in the organogel (see abstract). One of ordinary skill in the art would have been motivated to utilize a premade organogel because Hayek et al. teach a biomaterial made by a process of any of claims 1-31 (see claim 32). Hayek et al. teach Figure 1A depicts an embodiment of this process, which is started with protein particles 100 that have been prepared by conventional means to preserve protein secondary and, if present, tertiary or quaternary structure. These are combined with precursors 102, 104, into organic solvent 106. The mixture is processed to achieve the desired shape of the biomaterial, e.g., by casting 108, as rod 110, as particles and/or spheres 1 12, and molded shapes 114. The solvent is stripped out of the shapes and the materials will form hydrogels when exposed to water. The entire process, until the point where the xerogel is actually used with a patient, may be performed in an absence of water and/or in an absence of hydrophobic materials. Fig. IB depicts a micro structure of a biomaterial 120 made by this process. The structure is representative of the material across the process of its manufacture and use: organogel, xerogel, and then hydrogel. The crosslinked matrix is made of precursors 124 that have been covalently reacted with each other. Particles 124 of a water soluble biologic are dispersed within the matrix. The matrix is a continuous phase and the particles are spread out inside it and are the discontinuous phase, also referred to as the dispersed phase. The examiner takes the position that Hayek et al. teach forming the organogel before applying it to tissue. With regard to the term "contemporaneously" applicant's specification defines it as within 2 hours or less once the organogel is prepared as a biomaterial as demonstrated by Hayke et al. it is within the purview of one ordinary skill in the art to quickly utilize the organogel on a wound site or on a surgical site to achieve the most efficient therapeutic value and avoid any structural instability of the organogel. The contemporaneous utilization is not meaningfully distinguishing over Hayek et al. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Hayke et al. because both references teach organogels biocompatible materials for tissue treatment.
It would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by forming an organogel drug depot that is injectable because Sahoo et al. teach an organogel, a viscoelastic system, can be regarded as a semi-solid preparation which has an immobilized external apolar phase. The apolar phase is immobilized within spaces of the three-dimensional network structure formed due to the physical interactions amongst the self-assembling structures of compounds regarded as gelators. In general, organogels are thermodynamically stable in nature and have been explored as matrices for the delivery of bioactive agents. In the current paper, attempts have been made to understand the properties of organogels, various types of organogelators and some applications of the organogels in controlled delivery (see abstract). In general, sorbitan monostearate organogels have a very short half-life at the injection site. This may be attributed to the diffusion of water molecules within the gelled structure, which results in the subsequent disruption of the networked structure due to the emulsification of the gel surface. One of ordinary skill in the art would have been motivated to do so because Sahoo et al. teach that the development of a sorbitan-monostearate-based organogel which has shown sustained delivery of a model antigen and radiolabelled bovine serum albumin after intra-muscular administration of the same in mice. The results indicated the probable use of the formulation as depot (see page 104). With regard to the limitations of instant claims 2-4 one of ordinary skill in the art would want to utilize the drug containing organogel depot as quickly as possible because Sahoo et al. teach that in general, sorbitan monostearate organogels have a very short half-life at the injection site (see page 104). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Sahoo et al. because both references teach organogels made from oils and fatty acids.
It would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by applying the antimicrobial agents listed in claims 22-23 containing organogels to open wound because Baker et al. teach Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural surfaces that contain bacterial biofilm, including unexpected synergy or enhancing effects between bismuth-thiol (BT) compounds and certain antibiotics, to provide formulations including antiseptic formulations (see abstract). In another embodiment of the present invention there is provided an antiseptic composition for treating a natural surface that contains bacterial biofilm, comprising at least one of (1) a composition that comprises (a) at least one BT composition that comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 .mu.m to about 5 .mu.m; and (b) at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, (2) a composition that comprises (a) at least one BT composition that comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 microns to about 5 microns; and (b) at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline, tobramycin, clindamicin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and (3) the composition of (2) wherein the aminoglycoside antibiotic is selected from amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin (paragraph 37). A microparticulate BT compound may also be used for preventing or treating caries and/or inflammation (i.e., reducing the likelihood of occurrence or recurrence of caries and/or inflammation, respectively) by administering the microparticulate BT compound to the surface of the teeth. A composition comprising a microparticulate BT compound may be a mucoadhesive composition that is applied to the surface of a tooth and/or gum or oral mucous membrane may be in any form that adheres to some extent to a surface or that delivers a pharmaceutically effective amount of the active ingredient(s) to the desired surface. A microparticulate BT compound can also be formulated to release slowly from the composition applied to the tooth. For example, the composition may be a gel (e.g., a hydrogel, thiomer, aerogel, or organogel) or liquid. An organogel may comprise an organic solvent, lipoic acid, vegetable oil, or mineral oil. Such gel or liquid coating formulations may be applied interior or exterior to an amalgam or composite or other restorative composition. A slow-release composition may deliver a pharmaceutically effective amount of microparticulate BT compound for 1, 2, 3, 4, 5, 6, or 7 (a week) days or for 2, 3, 4, 5, 6, 7 weeks, or 1, 2, 3, 4, 5, or 6 months. Such compositions can be prepared by a person skilled in the art using any number of methods known in the art (paragraph 132). The presently disclosed invention embodiments relate to compositions and methods for the treatment of microbial infections. In particular, the present embodiments relate to improved treatments for managing bacterial infections in epithelial tissues, including in wounds such as chronic wounds and acute wounds, and in clinical, personal healthcare, and other contexts, including treatment of bacterial biofilms and other conditions (paragraph 3). According to certain contemplated embodiments topical administration may comprise direct application into an open wound. For instance, an open fracture or other open wound may include a break in the skin that may expose additional underlying tissues to the external environment in a manner that renders them susceptible to microbial infection. Such a situation is not uncommon in certain types of acute traumatic military wounds, including, for example, Type III (severe) open fractures. One of ordinary skill in the art would have been motivated to include the antibiotics in organogels and deliver them direct to the wound site because Baker et al. teach that topical administration may be by direct contact of the herein described BT composition with such damaged skin and/or another epithelial surface and/or with other tissues, such as, for instance, connective tissues including muscle, ligaments, tendons, bones, circulatory tissues such as blood vessels, associated nerve tissues, and any other organs that may be exposed in such open wounds. Examples of other tissues that may be exposed, and hence for which such direct contact is contemplated, include kidney, bladder, liver, pancreas, and any other tissue or organ that may be so detrimentally exposed to opportunistic infection in relation to an open wound (see paragraph 194). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Baker et al. because both references teach organogels for the delivery of active agents.
It would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by incorporating local anesthetic as the active agent in the organogel because McCartt et al. teach a method for anesthetizing skin prior to a dermatologic laser procedure, the method comprising applying to the skin of a patient a composition comprising at least one anesthetic agent admixed in a lecithin organogel base (see claim 1). The invention also provides a composition for topical anesthesia prior to laser application to the skin of a human subject, the composition comprising about 15 to about 25 percent (w/w) benzocaine, about 5 to about 15 percent (w/w) lidocaine, and about 1 to about 10 percent (w/w) tetracaine in a lecithin organogel base. The lecithin organogel may be a pluronic lecithin organogel. In one embodiment, the composition comprises about 20 percent (w/w) benzocaine, about 10 percent (w/w) lidocaine, and about 4 percent (w/w) tetracaine in about 66 percent lecithin organogel (see paragraph 9). One hundred grams of a 20% benzocaine, 10% lidocaine, 4% tetracaine topical analgesic composition were prepared by admixing twenty grams of 20% benzocaine, 10 grams of 10% lidocaine, and 4 grams of 4% tetracaine. Butylated hydroxytoluene NF (BHT) (0.1 gram of 0.1%) was triturated in a glass mortar and pestle to reduce particle size. Polysorbate 80 was added to wet the BHT. Pluronic lecithin organogel was added as a lipoderm base to the benzocaine, lidocaine, tetracaine mixture with trituration, then the BHT/Polysorbate 80 was added. The entire composition was then mixed in an ointment mill (paragraph 29). One of ordinary skill in the art would have been motivated to incorporate local anesthetic to utilize the drugs for numbing and decreasing pain. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and McCartt et al. because both references teach organogels for the delivery of active agents.
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(a).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 29 December 2025 have been fully considered but they are not persuasive.
Applicant argues that the posited combination of references does not demonstrate that it would have been obvious to perform a claimed method that includes the steps of delivering a formed organogel drug depot to a non-sterile open wound site, wherein at the time of delivery underlying fascia, muscle, bone, or internal organs are exposed at the open wound site, and the open wound site is exposed to a non-sterile environment, wherein the step of compounding and the step of delivering are performed contemporaneously. Applicant argues Applicant's disclosure sets forth a clear distinction between organogels and hydrogels (see, e.g., specification at paragraphs [0150]-[0154]), and, as specified in claim 1, the present claims are not directed to any delivery of hydrogels (or xerogels). Hayek discloses organogels only as precursors to the formation of xerogel particles (which are then used to form a hydrogel) - see, e.g., Hayek at page 3, lines 12-14; page 5, lines 16-28; page 6, lines 22-29; page 7, lines 1-4 - and does not disclose or suggest delivery of organogels that release an active agent therefrom.
This is not found persuasive because the primary reference Mouri et al. clearly teach the utilization of organogels for the delivery of active agents on a wound. MOURI et al. teach a new organogel formulation, comprising lecithin, water, ethanol and acylglycerols. Said organogel formulation can be used for therapeutical purposes, both per se and as matrix for a pharmaceutically or veterinary active agent. Said organogel formulation can also be used in the treatment of dermatological affections or as a matrix for cosmetic or personal care substances (see abstract). MOURI et al. teach in claim 1
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The organogel formulation according to claim 1, wherein the organogel further comprises at least one sterol, preferably sitosterol (see claim 2). The organogel formulation according to claim 1 or 2, comprising: from 5 to 23 wt water, from 0.01 to 9.5 wt% ethanol, from 25 to 50 wt lecithin, and from 30 to 49 wt acylglycerols, relative to the total weight of the organogel (see claim 3). An organogel formulation as defined in anyone of claims 1 to 8, for use in improving and/or accelerating cicatrisation of a wound, a burn, an inflammation and/or a bedsore (see claim 12). Hayek et al. is merely added to demonstrate that organogels can be premade before utilization on a tissue site. The examiner maintains that it would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by applying the biocompatible organogel contemporaneously because Hayek et al. teach serial-solvent biomaterials are described. Embodiments include materials made in an organic solvent that are stripped of the solvent and used in a patient, where they imbibe water and form a hydrogel. These materials are useful for, among other things, delivering therapeutic agents, tissue augmentation, and radiological marking (see abstract). A process of making a medical material comprising forming an organogel around a powder of a water soluble biologic, with the powder being dispersed in the organogel (see abstract). One of ordinary skill in the art would have been motivated to utilize a premade organogel because Hayek et al. teach a biomaterial made by a process of any of claims 1-31 (see claim 32). Hayek et al. teach Figure 1A depicts an embodiment of this process, which is started with protein particles 100 that have been prepared by conventional means to preserve protein secondary and, if present, tertiary or quaternary structure. These are combined with precursors 102, 104, into organic solvent 106. The mixture is processed to achieve the desired shape of the biomaterial, e.g., by casting 108, as rod 110, as particles and/or spheres 1 12, and molded shapes 114. The solvent is stripped out of the shapes and the materials will form hydrogels when exposed to water. The entire process, until the point where the xerogel is actually used with a patient, may be performed in an absence of water and/or in an absence of hydrophobic materials. Fig. IB depicts a micro structure of a biomaterial 120 made by this process. The structure is representative of the material across the process of its manufacture and use: organogel, xerogel, and then hydrogel. The crosslinked matrix is made of precursors 124 that have been covalently reacted with each other. Particles 124 of a water soluble biologic are dispersed within the matrix. The matrix is a continuous phase and the particles are spread out inside it and are the discontinuous phase, also referred to as the dispersed phase. The examiner takes the position that Hayek et al. teach forming the organogel before applying it to tissue. With regard to the term "contemporaneously" applicant's specification defines it as within 2 hours or less once the organogel is prepared as a biomaterial as demonstrated by Hayke et al. it is within the purview of one ordinary skill in the art to quickly utilize the organogel on a wound site or on a surgical site to achieve the most efficient therapeutic value and avoid any structural instability of the organogel. The contemporaneous utilization is not meaningfully distinguishing over Hayek et al. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Hayke et al. because both references teach organogels biocompatible materials for tissue treatment. Additionally, it would have been prima facie obvious to a person of ordinary skill in the art at the time the present invention was filed to modify the teachings of Mouri et al. by forming an organogel drug depot that is injectable because Sahoo et al. teach an organogel, a viscoelastic system, can be regarded as a semi-solid preparation which has an immobilized external apolar phase. The apolar phase is immobilized within spaces of the three-dimensional network structure formed due to the physical interactions amongst the self-assembling structures of compounds regarded as gelators. In general, organogels are thermodynamically stable in nature and have been explored as matrices for the delivery of bioactive agents. In the current paper, attempts have been made to understand the properties of organogels, various types of organogelators and some applications of the organogels in controlled delivery (see abstract). In general, sorbitan monostearate organogels have a very short half-life at the injection site. This may be attributed to the diffusion of water molecules within the gelled structure, which results in the subsequent disruption of the networked structure due to the emulsification of the gel surface. One of ordinary skill in the art would have been motivated to do so because Sahoo et al. teach that the development of a sorbitan-monostearate-based organogel which has shown sustained delivery of a model antigen and radiolabelled bovine serum albumin after intra-muscular administration of the same in mice. The results indicated the probable use of the formulation as depot (see page 104). With regard to the limitations of instant claims 2-4 one of ordinary skill in the art would want to utilize the drug containing organogel depot as quickly as possible because Sahoo et al. teach that in general, sorbitan monostearate organogels have a very short half-life at the injection site (see page 104). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Mouri et al. and Sahoo et al. because both references teach organogels made from oils and fatty acids.
Applicant further argues additionally, although Baker is cited by the Office for the proposition that it would have been obvious to apply organogels to an open wound as defined in Applicant's claims, this contention on the part of the Office does not derive from a proper interpretation of the cited prior art. Baker concerns particulate bismuth-thiol compounds for the treatment of microbial infections in clinical infectious diseases and conditions in personal healthcare (see, e.g., paragraph [0029]), and for treating tissues and/or surfaces that contain bacterial biofilms or bacteria related to biofilm formation (paragraph [0030]). Baker only mentions organogels passingly, and only in the specific context of its proposed use as a mucoadhesive formulation for application to a tooth (see paragraph [0132]).
This is not found persuasive because Baker is included in the rejection for its teachings of the antibiotics. Applying to a wound site aspect is covered by Mouri et al., Hayek, et al., and Sahoo et al. as described above.
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.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619
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