DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after August 14, 2023, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 08/14/2023 in the matter of Application N° 18/233,564. Said documents are entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after August 14, 2023, is being examined under the first inventor to file provisions of the AIA .
Thus, claims 1, 3-9, 11-18, and 20 represent all claims currently under consideration. Claims 2, 10 and 19 are cancelled.
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 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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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, 3-9, 11-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wenk et al. (WO2009077399A1) in view of Vanderhoff et al. (WO1999031167A1), and Longin et al. (WO2006056204A1), and Jiangwei et al. (CN111840638A), and Josef Friedrich (WO2017036597A1).
Wink et al. teach the process of making crosslinked hyaluronic acid microbeads and the microbeads that are produced involves the following steps: (a) supplying an aqueous alkaline solution that contains hyaluronic acid or a salt of it; (b) creating microdroplets of the appropriate size from the mixture of step (a) in an organic or oil phase to create a water-in-oil or water-in-organic emulsion, where the amount of oil phase used ranges from 20 to less than 50% by weight depending on the sum of the oil phase and water; (C) adding a solution that contains a crosslinking agent to the emulsion, allowing the reaction between the hyaluronic acid and the crosslinking agent to produce crosslinked hyaluronic acid microbead (See abstract). Hyaluronic acid or a salt of it can be combined with an alkaline aqueous solution to create an aqueous alkaline solution. A base, usually an inorganic base, more preferably an alkali metal hydroxide, and most especially sodium hydroxide, can be added to water or a solution containing water to create an aqueous alkaline solution (See pg.11, paragraph 6).
Wink et el. teach that providing an initial period of stirring during and/or immediately after combining the solution comprising the crosslinking agent with the hyaluronic acid (HA) solution step (c) facilitates satisfactory gel formation. Accordingly, the crosslinking agent solution is added while stirring, preferably under vigorous stirring conditions. Wink et al. further indicate that the crosslinking agent solution may be added over a time period ranging from approximately 1 to 80 minutes, preferably while stirring, followed by continued stirring for an additional period of approximately 1 to 180 minutes after completion of the addition. In a further embodiment, the reaction mixture of step (c) is maintained at room temperature for a short duration following completion of the crosslinking reaction while continuing to stir the mixture. In contrast, wink et al. do not disclose stirring the bead mixture at room temperature for a duration of 24 hours (See page 13, fourth paragraph, and page 14, second paragraph).
Regarding claim 8, Vanderhoff et al. teach the process utilized to create the sodium alginate microspheres was also employed to create the hyaluronic acid microspheres. To achieve the required droplets, the hyaluronic acid solution was first emulsified in toluene after ammonium hydroxide was added to bring the pH up to 10-11. Following the addition of the XAMA-7 crosslinking agent, acetic acid was used to lower the pH to 8-9. After 4 or 24 hours of crosslinking at room temperature, the isopropanol dehydrating agent was applied. To create a single phase devoid of microspheres, the top layer of the sample was removed and cleaned with methanol. The high molecular weight of the hyaluronic acid and the 1.75 or 2.0 hyaluronic acid/XAMA-7 ratio were blamed for the inability to form microspheres. An immobue gel was produced with a hyaluronic acid content of 3.5%. when span 60 emulsifier was added to a 1.5% hyaluronic acid solution, the solution became sufficiently viscous to form inverse droplets in toluene (See paragraph 216).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the instant effective filing date to incorporate the composition and conditions of Vanderhoff et al., to the process of Wink et al. in order to improve bead formation and stability, as Vanderhoff demonstrates that such crosslinking and pH adjustments are effective for preparing polysaccharide-based microspheres. A person of ordinary skill in the art would have had a reasonable expectation of success in combining these teachings, since both references are directed to forming crosslinked polysaccharide microbeads using comparable emulsion-based techniques.
Regarding claim 3, Longin teach comparing the cross-linked gels made using the invention’s method to the conventional DVS crosslinked HA-hydrogels, the former exhibit greater uniformity and texture. Using a syringe to inject the gels produced by the instant innovation method is simpler.
Longin et al. teach a method of creating a hydrogel with hyaluronic acid or its salt crosslinked with divinylsulfone (DVS) is the first aspect of the invention. This technique includes the following steps:
(a) supplying an alkaline solution of hyaluronic acid or its salt;
(b) Incorporating DVS into step (a)’s solution, whereupon the DVS and hyaluronic acid, or its salt, crosslink to create a gel;
(c) when the gel from step (b) is treated with a buffer, it expands and creates a hydrogel made of hyaluronic acid or a salt of it that has been crosslinked with DVS. Second, the invention relates to a hydrogel made of hyaluronic acid or a salt of it that has been crosslinked with divinylsulfone (DVS). This hydrogel is sufficiently homogeneous to be injected from a 1 ml syringe through a 27G ½ needle over a distance of 55 mm at a speed of 12.5 mm/min with a stable injection force, both after the first 40 seconds of the injection and until the syringe is empty (See pg. 3, lines 8-25).
Regarding claims 4, 5, and 11, Jiangwei et al. teach in order to prepare a crosslinked hyaluronic acid filler for injection, the invention offers a method that involves adding a crosslinking agent prior to emulsification and using a low-temperature control reverse phase emulsification crosslinking technology. The filler contains crosslinked hyaluronic acid microspheres.
The following procedures are used to prepare crosslinked hyaluronic acid microspheres for injection as part of the preparation method:
Combining water, alkali, a crosslinking agent, and hyaluronic acid or its salt at a low temperature, then evenly spreading the mixture to create a water phase;
Combining the water phase with an emulsifier containing oil phase and completely emulsifying to create an emulsion;
To obtain the crosslinked hyaluronic acid microspheres, the emulsion is crosslinked at a crosslinking temperature, the oil phase is removed after crosslinking, and post-treatment is carried out (See paragraph 1, Disclosure of invention, and claim 1).
In addition to the phase of creating the crosslinked hyaluronic acid microspheres, the filler preparation process includes the subsequent steps:
(a). producing hyaluronic acid gel by dissolving hyaluronic acid or its salt in water;
(b). to create the crosslinked hyaluronic acid filling agent for injection, add the crosslinked hyaluronic acid microspheres or the crosslinked hyaluronic acid microspheres and other useful ingredients to the hyaluronic acid gel made in step (a), stirring evenly, subpackage, and dry.
The invention prepares the crosslinked hyaluronic acid microspheres by low-temperature control inverse emulsification crosslinking technology. The content of hyaluronic acid or salt thereof, the dosage of the cross-linking agent, the shearing speed during emulsification, the proportion of water phase and oil phase and other conditions can be adjusted to ensure that the particle size of the microspheres meets the requirements (See paragraph 2, Disclosure of invention, and claim 2).
Additionally, in step (1), the aqueous phase is prepared at a low temperature, which lowers the reaction rate and inhibits or diminishes the hyaluronic acid’s cross-linking. The temperature is ideally regulated to prevent the formation of huge, hard gel lumps in the aqueous phase (See paragraph 3, Disclosure of invention).
Furthermore, the components may be added as an aqueous solution or as a pure product, and the sequence in which they are mixed during the aqueous phase production is arbitrary. In order to facilitate uniform contact between the cross-linking agent and the hyaluronic acid or its salt, improve cross-linking efficiency and uniformity, and decrease the likelihood of cross-linking a water phase at low temperatures, it is preferable to mix the cross-linking agent and hyaluronic acid or its salt uniformly in water before adding the alkali (See paragraph 4, Disclosure of invention).
The emulsifier level in the oil phase is 2-10 wt%, and the water phase to oil phase volume ratio is 1:5-20 (See claim 6). The oil phase comprises an emulsifier and an oil phase matrix. The emulsifier’s hydrophilic-hydrophobic balancing value is 3-9. The oil phase matrix includes mineral oil, vegetable oil, silicone oil, dodecane, n-octane, or cyclohexane (See claim 7). Adding gel 2 into 400mL of n-octane containing 2wt% Span80, emulsifying with high-shear dispersion emulsifying homogenizer at 20000rpm for 10min, standing to remove air bubbles after uniform emulsification. And controlling the temperature of the emulsified liquid after emulsification to be 30 ℃, and stirring for 12 hours for crosslinking. After the crosslinking was completed, the oil phase was removed by centrifugation, and washed twice with ethanol and distilled water in this order (See example 1, numbers 2, 3, and 4).
Regarding claim 6, Jiangwei et al. teach microspheres are created following the completion of crosslinking and are acquired by additional post-treatment. There are several ways to perform the work-up that have been documented in the previous art, such as centrifugation, washing, drying, etc. the following post-processing technique is used in one embodiment of the present invention: following the completion of crosslinking, the oil phase is removed by centrifugation and similar techniques, and the microspheres are then washed with an organic solvent to remove the oil phase from their surfaces. Thereafter, the microspheres are washed with water to remove the organic solvent from their surfaces and the alkali liquor within them. The microspheres are then dried by vacuum drying after being dehydrated and precipitated with ethanol (See paragraph 14, Disclosure of invention).
Regarding claim 7, Wenk et al. teach the process of creating crosslinked hyaluronic acid microbeads and the microbeads themselves involves the following steps: (a) supplying an aqueous alkaline solution containing hyaluronic acid or it’s salt; (b) creating microdroplets of the appropriate size from the blended solution of step (a) in an organic or oil phase to create a water-in-oil or water-in-organic emulsion, where the amount of oil phase used ranges from 20 to less than 50% by weight depending on the sum of the oil phase and water; (C) adding a solution containing a crosslinking agent to the emulsion, whereby the reaction between the hyaluronic acid and the crosslinking agent occurs to produce crosslinked hyaluronic acid microbeads. Increasing the dispersion of the crosslinked hyaluronic acid microbeads produced in step (C) is optional (See abstract, and claim 1). wherein the crosslinking agent is comprised in the mixed solution of step (c) in a weight ratio of between 1 :1 and 100:1 of hyaluronic acid or a salt thereof: crosslinking agent (dry weight) (See claim 6).
Regarding claim 8, Jiangwei et al. teach the crosslinked sodium hyaluronate microspheres made by adding the same quantity of crosslinking agent as in example 1 during the emulsification process exhibit a fast expansion rate and a low degree of crosslinking, as demonstrated by comparative example 1. The cross-linking reaction is produced in the uniform mixing process, the subsequent stirring and dispersing process is influenced, and the resulting cross-linked sodium hyaluronate microspheres have large particle size, large particle size distribution, and non-concentrated particles. Thus, is in contrast to comparative example 2, where the sodium hyaluronate, the cross-linking agent and the alkali solution are mixed at room temperature (See paragraph 43, Description).
Regarding claim 9, Vanderhoff teach Dissolve 15.00 g NaOH in 500 ml distilled and deionized water. Solution I: Mix 0.5 g hyaluronic acid with 25 ml of Solution A in a 50 ml test tube. Solution B: Mix 9.0 g Sorbitan monostearate (Span-60) in 150 ml toluene in a 500 ml glass bottle. Solution II: Add 10 ml ethylene glycol diglycidyl ether (EGDGE), or other diepoxide type crosslinking agent, to Solution B (See Example 29, paragraph 1).
Organic solution: 150 mL toluene + 9 mL Sorbitan Triooleate (SPAN 85) Reaction: Add 25 mL Ethylene glycol diglycidyl ether (EGDGE) to aqueous solution when sodium hyaluronate was completely dissolved in aqueous solution in a reactor placed in waterbath at 70°C. Organic solution was added after EGDGE dissolved in aqueous solution. The reactor was cooled down to room temperature 30 min after addition of organic solution. Add 75 mL EGDGE and continue stirring overnight (See Example 29, paragraph 9).
wetting the powdered polymer at 75-85 degrees Celsius and then adding the remaining water while cooling and stirring allowed the methyl cellulose to dissolve. Chilling the solution to below 10 degrees Celsius increased its clarity. Following the standard procedure, 16 g of 1% aqueous methyl cellulose, 0.1 g of hexamethoxyhnethyl melamine (CYMEL 300), 0.0128 g of P-toluene sulfonic acid catalyst, and heated for 20 minutes at 50 degrees Celsius. When heated, instead, for 30 minutes at 60°C, a large mass of crosslinked polymer was formed. This crosslinking reaction was carried out in the emulsion (See example 28, paragraph 30).
Friedrich teaches in one embodiment, the procedure is described as follows: in step a) the diluted alkaline solution is fed from a second container 20 to the first container 10, specifically through a filter 31; the interior of the first and second containers 10, 20, have temperatures between 3 and 50 degrees Celsius; and/or the diluted alkaline solution is made in the second container 20; and/or the diluted alkaline solution, prior to the feeding to the first container 10, has a temperature, which deviates from the temperature of the cooling medium in the jacket of the container by 2 °C at the most; and/or the diluted alkaline solution is fed by means of reducing a container volume of the second container 20, or by means of applying pressure; and/or the diluted alkaline solution is passed through a particle filter 31 ; and/or a fed amount of the diluted alkaline solution is determined by means of weighing means 81 of the first and/or second container 10, 20, and a provided amount of the hyaluronic acid is fed directly into container 10; and/or after feeding the hyaluronic acid into the first container 10, a stirrer 71 is operated, in particular time- and/or process-depending and/or with high speed until the hyaluronic acid is completely dissolved, preferably homogeneously dissolved (See 00153)
in one embodiment, in step a), the temperature inside the first container is between 2 and 35 degrees Celsius, or 3 and 25 degrees Celsius, specifically between 4 and 21 degrees Celsius, either before or during the feeding of the diluted alkaline solution and/or after, whereby a decrease of the temperature to about 4 °C is advantageous for longer dissolution periods. In one embodiment, the interior of the first container is tempered to said temperature, in particular by means of operated or controlled heating and/or cooling of the first container (See 0034). In one embodiment, the device consists of a control device, specifically a programmable control device, that can perform a method described herein, including at least one of the disclosed steps a) to f), entirely or substantially automatically. In one configuration the control device is signaled to the stirrer’s drives, piston shifting actuators, the positioning unit for positioning the stirrer/stirrers and/or pistons, devices for temperature measurement for determining temperatures and controlling in the interior of the container via the facility of heating and cooling, and/or weighing means, in order to control same, respectively to obtain measurement data from same (See 00108). The device further comprises cooling elements and/or heating elements for tempering the first and second container 10, 20 as well as a vacuum system for degassing gels ready to be filled up in the first container 10 and/or the mobile storage container (See 00131).
Regarding claim 12, Jiangwei et al. teach the invention uses a reverse phase emulsification method, in which the water phase is added to the oil phase for emulsification. The oil phase is made up of an oil phase matrix and an emulsifier, the latter of which can be chosen from among the emulsifiers disclosed in the prior art, such as those with a hydrophilic-hydrophobic balance value of 3-9, and the latter of which can be chosen from among those that can coat the water phase to form tiny droplets, such as vegetable, mineral, silicone, and the like (See paragraph 20, and claim 7). Further, the emulsifier may be sorbitan monooleate (Span 80), or the like. Further, in the oil phase, the content of the emulsifier is 2 to 10 wt%. The volume ratio of the water phase to the oil phase is 1: 5-20 (See paragraph 21, claim 6, and claim 8).
Regarding claim 13, Wenk et al. teach for instance, the optional step d) may be a separation or neutralization step. Water, water and acid, water and a buffer, particularly water and phosphate buffer, water and saline buffer, or water and a phosphate buffer and saline buffer may be used to neutralize the crosslinked microbeads either immediately or after they have separated from the dispersion. The optional step (d) ideally consists of using an acid or buffer to neutralize the crosslinked microbeads pH. In step d) the invention, a variety of buffers and acids have been envisioned as appropriate for the swelling and neutralizing of the crosslinked microbeads, as is well known to the skilled individual. Preferably, the acids or acid solutions utilized come from the group of fatty acids that are liquid at 25 degrees Celsius, particularly lactic, oleic, or isostearic acids. Using aqueous solutions of acids that include 75-95% by weight, ideally 80-90% by weight of water-soluble acid, such as lactic acid, may be beneficial. Preferably the crosslinked microbeads are contacted with a liquid, especially an aqueous acid solution or an aqueous buffer with a pH value in the range of from 2.0 to 10.0, preferably in the range of from 5.0 to 9.5. If the neutralization is done without separation of the microbeads, it is advantageous not to use mineral acids for neutralization because such acids might result in the destruction of the emulsion/dispersion (See pg. 16, paragraphs 1 and 2). The crosslinked microbeads have a pH value between 7 and 9.5, ideally between 8.5 and 9.5, and ideally around 9. This is achieved by selecting a preferred, appropriate buffer with a pH value. It is estimated that the pH of the dispersion (the liquid comprising the microbeads) is essentially the same as the pH value of the microbeads. The pH of the microbeads can therefore be easily determined by well-known methods, e.g. putting pH paper or a pH electrode of a pH meter into the dispersion. It is preferred that the buffer in the method of the first aspect comprises a phosphate buffer and/or a saline buffer (See pg. 16, paragraph 3).
Regarding claims 14, 15, and 18, Wenk et al. teach there are several known functions for HA in the body. As a mechanical support for the cells of several tissues, including the skin, tendons, muscles, and cartilage, it is crucial to the biological organism. Important biological functions like lubrication and tissue moisturization are mediated by HA. Numerous physiological processes, including adhesion, development, cell motility, cancer, angiogenesis, and wound healing, are also thought to be impacted by it. Due to the unique physical and biological properties of HA (including viscoelasticity, biocompatibility, biodegradability), HA is employed in a wide range of current and developing applications within cosmetics, ophthalmology, rheumatology, drug delivery, wound healing and tissue engineering. The use of HA in some of these applications is limited by the fact that HA is soluble in water at room temperature, i.e. about 20°C, it is rapidly degraded by hyaluronidase in the body, and it is difficult to process into biomaterials. Crosslinking of HA has therefore been introduced in order to improve the physical and mechanical properties of HA and its in vivo residence time (See pg. 3, paragraph 1). The ideal temperature range for the reaction between hyaluronic acid or its salt and the crosslinking agent, divinylsulfone, is between zero and one hundred degrees Celsius; ten to fifty degrees Celsius is even better; and twenty to thirty degrees Celsius is even better. After mixing the liquids, the current inventors concluded that a heating phase was advantageous. The technique of the first aspect, which involves heating the mixed solution of step (C) to a temperature between 20 and 100 degrees Celsius, is therefore a preferred embodiment of the invention, preferably in the range of 25°C - 80°C, more preferably in the range of 30°C - 60°C, and most preferably in the range of 35°C - 55°C, and wherein the temperature maintained in this range for a period of at least 5 minutes, preferably at least 10 minutes, 20 minutes, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or most preferably at least 180 minutes after mixing the solutions; preferably without stirring (See pg. 15, paragraph 1). In a preferred embodiment of the method of the invention, the reaction mixture of step (c) is maintained after the reaction has taken place for a period of at least 5 minutes, preferably at least 10 minutes, 20 minutes, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or most preferably at least 180 minutes, at a temperature in the range of 0°C - 40°С, preferably in the range of 10°C - 30°с (See pg. 15, paragraph 2).
Regarding claims 16, 17, and 20, Wenk et al. teach an aqueous polymer solution consisting of a water soluble polymer chosen from hyaluronic acid, carrageenans, proteins, glycoproteins, peptidoglycans, proteoglycans, or combinations thereof, and an aqueous medium, is added to an oil base containing a water in oil emulsifying agent to create a crosslinked water soluble polymer particle preparation with particles smaller than 212 µm in diameter and at least 80% of spherical, agitating the mixture to form an emulsion containing polymer droplets, and crosslinking the polymer droplets in situ by a crosslinking agent resulting in the formation of crosslinked polymer particles. For the production of hyaluronic acid microspheres, the crosslinking agent is added directly to an emulsion of aqueous hyaluronic acid in toluene (See pg. 4, paragraph 1). The preparation of hyaluronic acid-based submicron hydrogel particles using isooctane as oil phase. For preparing the emulsion 0.54 ml of aqueous hyaluronic acid solution was added to 15 ml of isooctane, resulting in a weight ratio of aqueous phase to oil phase is higher than 10 to 1 (See pg. 4 paragraph 2). Apart from the previously stated soluble chemical, insoluble pigments, which are finely dispersed metal oxides and salts, can also be used for this purpose. Examples of these include zinc oxide, titanium dioxide, iron oxide, and zinc stearate. In this context, the particles should have an average diameter of less than 100 nm, e.g. between 5 and 50 nm and in particular between 15 and 30 nm. They can have a spherical shape, but those particles which have an ellipsoid shape or a shape which deviates otherwise from the spherical can also be employed. Micronized organic pigments, such as, for example, 2,2'-methylene-bis-{6-(2Hbenzotriazole-2-yl)-4-(1,1,3,3-tetramethylbutyl) phenol} having a particle size of < 200 nm, which is obtainable e.g. as a 50 % strength aqueous dispersion, are a relatively novel class of light protection filters (See pg.’s. 23-24).
Response to Arguments
Applicant's arguments filed October 24, 2025 have been fully considered but they are not persuasive. Applicant argues that the prior art fails to teach or suggest (i) suspending cross-linked HA beads in an HA solution and (ii) cross-linking HA beads such that they dissolve in vivo in 20 minutes upon contact with hyaluronidase. These arguments are not persuasive for the reasons set forth below.
Wenk et al. teach that hyaluronic acid is widely used as a biomaterial due to its viscoelasticity, biocompatibility, and biodegradability, and that HA functions as a mechanical support and lubricating medium in biological tissues. Wenk et al. further teach that HA is employed in cosmetic, drug delivery, wound healing, and tissue engineering, applications, where HA is processed into biomaterials with tailored physical properties through cross-linking. Given these teachings, it would have been obvious to one of ordinary skill in the art at the time of the invention to suspend cross-linked HA particles or beads within an HA matrix in order to achieve a filler having desirable viscoelastic and mechanical properties. Suspending particulate HA within an HA carrier merely represents the predictable use of HA as both a structural matrix and a delivery medium, consistent with Wenk et al.’s disclosure of HA as a mechanical support and viscoelastic biomaterial. Moreover, the use of HA as both a continuous phase and a dispersed phase does not constitute a structural distinction over the prior art, but rather reflects routine formulation optimization of known HA materials for injectable or filler-type applications.
Wenk et al. expressly teach that cross-linking of hyaluronic acid is introduced to improve physical and mechanical properties and to increase in vivo residence time due to HA’s rapid degradation by hyaluronidase. Wenk et al. further teach that the degree of cross-linking can be controlled through reaction conditions, including temperature, reaction time, and cross-linking agents such as divinylsulfone.
Accordingly, it would have been obvious to one of ordinary skill in the art to provide HA materials having different levels of cross-linking to tailor degradation rate and mechanical properties, including providing HA beads having a higher degree of cross-linking than a surrounding HA matrix. Selecting different cross-linking levels for different HA components represents routine optimization of known parameters to achieve predictable results, namely increased structural integrity of beads relative to the surrounding HA.
Applicant further argues that the prior art does not teach HA beads adapted to dissolve in vivo in 20 minutes upon contact with hyaluronidase. However, Wenk et al. explicitly teach that unmodified HA is rapidly degraded by hyaluronidase in vivo and that cross-linking is employed to modulate degradation rate and residence time. Thus, the rate of degradation of HA in the presence of hyaluronidase is a known, predictable result of the degree of cross-linking. The recited dissolution time of “20 minutes” represents an optimization of a result-effective variable (degree of cross-linking ) and does not confer patentable weight absent evidence of unexpected results. No evidence has been provided demonstrating that dissolution within 20 minutes yields a surprising or non-obvious technical effect relative to known HA degradation behavior. Further, the claim does not recite any specific cross-linking chemistry or structural limitation that would distinguish over HA materials whose degradation rate is inherently controlled by known cross-linking techniques taught by Wenk et al.
In view of the foregoing, Wenk et al. teach or render obvious the claimed filler comprising hyaluronic acid with controlled cross-linking, including the use of cross-linked HA beads suspended in an HA matrix, wherein degradation in vivo is governed by known interaction with hyaluronidase. The claimed subject matter represents the predictable use of prior art elements according to their established functions and involves routine optimization of known parameters.
Conclusion
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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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615