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 .
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)
or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application, filed on 09/21/2023, claims domestic benefit to U.S. provisional application no. 63/408,718, filed on 09/21/2022.
Status of Claims/Application
Claims 1 – 20, filed on 09/21/2023, are currently pending and are examined on the merits herein. No preliminary amendment was submitted.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 depends on claim 1 and states the limitation “wherein the composition comprises 10-50 mg/ml biodegradable poly (alpha-hydroxy acid) polymer”. Claim 1 already states the same limitation in component (c) of the composition recited. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 14, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0333596 (PTO-892) in view of US 2021/0308332 (PTO-892).
US’596 teaches injectable dermal filler compositions in the form of a gel, comprising hyaluronic acid (HA), carboxymethyl cellulose (CMC) and, optionally, microparticles such as calcium hydroxyapatite (CaHAP) microparticles. The injectable dermal filler compositions have improved rheological properties while at the same time have low extrusion forces. US’596 teaches a method for preparing such injectable dermal filler compositions and their use for cosmetic and therapeutic purposes (pg. 1, col. 1, [0001]).
US’596 teaches an injectable dermal filler composition in the form of a gel, comprising crosslinked (e.g., BDDE crosslinked) hyaluronic acid (HA) and carboxymethyl cellulose (CMC) (pg. 1, col. 2, [0010]). US’596 teaches that the hyaluronic acid is present in the composition in a concentration of preferably 0.1% to 5.0% or 0.2% to 4.5% or 0.3% to 4.0% or 0.4% to 4.0% or 0.5% to 4.0% or 0.7% to 4.0% or 1.0% to 4.0%, more preferably 0.5% to 3.0% or 1.0% to 3.0% or 1.5% to 3.0% or 2.0% to 3.0%, most preferably 1.0% to 2.5% or 2.0% to 2.5% weight/volume, and the crosslinked HA forms a “matrix”, the term “matrix” is intended to mean a network of polysaccharides, either crosslinked or non-crosslinked, in the form of a solution or gel (pg. 3, col. 1, [0039]). US’596 teaches that the injectable dermal filler composition is crosslinked with BDDE (1,4-butanediol diglycidyl ether) (pg. 3, col. 2, [0045]). US’596 teaches that the injectable dermal filler composition further comprises resorbable biocompatible microparticles. The term “microparticles” generally relates to substantially rounded or spherical particles, wherein the microparticles preferably have a mean diameter of 5 μm to 500 μm, more preferably 10 μm to 200 μm, particularly preferably 15 μm to 100 μm or 20 μm to 75 μm, and most preferably 25 μm to 45 μm (pg. 4, col. 1, [0049]). The microparticles are preferably present in the composition in a concentration of 0.5% to 50% or 1.0% to 50%, more preferably 1.0% to 40%, particularly preferable 5.0% to 35%, in particular 15.0% to 30% or 20% to 25%, and most preferable 25.0% to 35% volume/volume (pg. 4, col. 1, [0050]). US’596 teaches that the resorbable biocompatible microparticles may consist of calcium phosphate-based materials, alumina-based materials, a biodegradable natural polysaccharide or a derivate thereof, or a biodegradable polyester, polyorthoester or polyanhydride synthetic polymer (pg. 4, col. 1, [0051]). The biodegradable polyester, polyorthoester or polyanhydride synthetic polymer may be a homopolymer or copolymer of glycolide, lactide, caprolactone, and p-dioxanone, or is trimethylene carbonate, or a poly(hydroxybutyrate) or poly(hydroxyvalerate) polymer. Preferably, the biodegradable polyester, polyorthoester or polyanhydride synthetic polymer is selected from poly-ε-caprolactone, polyglycolides, polylactides, polydioxanone, poly(lactic-co-glycolic acid), poly(glycolide-co-caprolactone), and poly (glycolide-co-trimethylene carbonate), and is most preferred poly-ε-caprolactone or polydioxanone (pg. 4, col. 2, [0054]). US’596 teaches that the injectable dermal filler composition may include crosslinked and/or non-crosslinked polymers other than the crosslinked HA and CMC. In particular, the injectable dermal filler composition may further comprise 0.001% to 15%, in particular 1% to 10% volume/volume non-crosslinked hyaluronic acid (pg. 4, col. 2, [0058]). US’596 teaches that other crosslinked or non-crosslinked polymers, such as chondroitin sulfate, keratan, keratan sulfate, heparin, heparin sulfate, cellulose and its derivatives, chitosan, carrageenan, xanthan, and alginate, or one of their salts, may also be included in the injectable dermal filler composition in low amounts (e.g., less than 10%, usually less than 5% or less than 1% volume/volume) (pg. 4, col. 2, [0059]). US’596 teaches the method for preparing an injectable dermal filler composition, comprising the following steps: (a) providing a crosslinked hyaluronic acid gel, (b) providing a carboxymethyl cellulose gel, (c) mixing the crosslinked hyaluronic acid gel and the carboxymethyl cellulose gel, and the microparticles may be suspended in the carboxymethyl cellulose gel provided in step (b) or, alternatively, the microparticles may be mixed together with the crosslinked hyaluronic acid gel and the carboxymethyl cellulose gel in step (c). Also, the microparticles may be added to the mixture obtained in step (c) (pg. 5, col. 1 and 2, [0068] to [0072]). US’596 teaches that the composition is preferably administered for treating a cosmetic condition, such as the treatment of wrinkles or lines of the skin (e.g., facial lines and facial wrinkles), glabellar lines, nasolabial folds, chin folds, marionette lines, buccal commissures, perioral wrinkles, crow's feet, cutaneous depressions, scars, temples, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, perioral region, infraorbital region, facial asymmetries, jawlines, and chin (pg. 5, col. 2, [0079]). US’596 exemplifies the preparation and purification of the crosslinked HA (MHA gel) in an alkaline solution consisting of NaOH and BDDE in Example 1 (pg. 6, col. 2, [0088] – [0090]). US’596 teaches that a composition comprising of the MHA gel (which is a result of crosslinking, and purifying the resultant crosslinked HA, and this MHA gel is equivalent to the crosslinked glycosaminoglycan hydrogel of the instant claims), free HA as lubricant, and microparticles in Example 7, Preparation of a HA/CaHAP Gel with 10% (v/v) Free HA as Lubrication Phase (Comparative Gel) (pg. 7, col. 2, [0103]).
The teaching of US’596 differ from the instantly claimed invention in that it does not teach the exact concentrations of the three components of the instantly claimed composition (crosslinked HA 0.1% to 5.0% weight/volume compared to 10 -45 mg/ml of the instant claim 1, free HA 0.001% to 15%, in particular 1% to 10% volume/volume compared to 20 % - 50% by weight of the crosslinked GAG hydrogel of the instant claim 1, microparticles are in a concentration of 0.5% to 50% or 1.0% to 50%, more preferably 1.0% to 40%, particularly preferable 5.0% to 35%, in particular 15.0% to 30% or 20% to 25%, and most preferable 25.0% to 35% volume/volume compared to 10 – 50 mg/ml of the instant claim 1).
Further, the teachings of US’596 differ from the instantly claimed invention in that US’596 does not teach the crosslinked glycosaminoglycan hydrogel’s particle size, and the poly (alpha-hydroxy acid) polymer’s particle size as recited in instant claim 8, and US’596 does not teach that the crosslinked glycosaminoglycan is crosslinked by (i) a non-carbohydrate-based di- or multinucleofile crosslinker or (ii) a carbohydrate based di- or multinucleofile crosslinker, wherein the non-carbohydrate-based di- or multinucleofile crosslinker is hexamethylenediamine (HMDA) or the carbohydrate based di- or multinucleofile crosslinker is diaminotrehalose (DATH) as recited in instant claims 12 and 13, and US’596 does not teach the use of the composition for improving skin quality in a subject as recited in instant claim 19.
US’332 teaches compositions comprising hydrogels and solid particles and their use, methods for manufacturing of a composition comprising solid particles encapsulated within crosslinked polysaccharide molecules forming hydrogel particles, and use of the composition as a dermal filler (pg. 1, col. 1, [0002]). US’332 teaches a method of manufacturing a composition comprising a crosslinked glycosaminoglycan hydrogel comprising solid particles embedded in the hydrogel, the method comprising: (a) mixing in a water suspension at a pH between 5 and 9 the following: (i) glycosaminoglycan molecules comprising one or more carboxyl groups, (ii) water insoluble solid particles, (iii) a di- or multinucleophilic functional crosslinker, and (iv) a coupling agent, thereby activating the glycosaminoglycan molecules with the coupling agent; (b) crosslinking the activated glycosaminoglycan molecules; and (c) embedding the solid particles in the crosslinked glycosaminoglycan molecules to form a composition comprising a glycosaminoglycan hydrogel embedded with the solid particles (pg. 1, col. 2, [0009]). US’332 teaches that the method further comprises dividing the composition into smaller fractions by providing particles of the composition, having an average size in the range of 0.01-5 mm, preferably 0.1-0.8 mm. The hydrogel comprising the polymer particles is physically divided into pieces that are small enough to enable filling into syringes and extrusion through a needle (pg. 7, col. 1, [0073]). US’332 teaches that the polysaccharide concentration (crosslinked and/or non-crosslinked) in the final product may be in the range of 5-50 mg/mL, such as 10-30 mg/mL, and the amount of solid particles in the final product may be in the range of 0.01-10% by weight, such as 0.1-5% (pg. 7, col. 1, [0074]). US’332 teaches that the solid polymer particles may be solid synthetic aliphatic polyester particles or co-polymers of the same, preferably selected from the group consisting of polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or co-polymers of the same, preferably poly-L-lactic acid (PLLA). The solid polymer particles are typically biodegradable and prone to degradation in acidic or basic pH, such as PLA, PLLA, PCL, or PGA (pg. 10, col. 1, [0108]), and the average size of the solid polymer particles range from 0.5-100 μm in diameter, such as 5-100 μm. In some aspects, the average size of the solid polymer particles range from 0.5 to 100 μm, 1 to 100 μm, 5 to 100 μm, 10 to 100 μm, 25 to 100 μm, 50 to 100 μm, 0.5 to 50 μm, 1 to 50 μm, 5 to 50 μm, 10 to 50 μm, 25 to 50 μm, 0.5 to 25 μm, 1 to 25 μm, 5 to 25 μm, 10 to 25 μm, 0.5 to 10 μm, 1 to 10 μm, 5 to 10 μm, 0.5 to 5 μm, or 1 to 5 μm (pg. 10, col. 1, [0109]). US’332 teaches that the crosslinker consists of the two or more functional groups and the spacer. Crosslinking can be achieved using a non-carbohydrate based di- or multinucleophilic crosslinker, for example hexamethylenediamine (HMDA), or a carbohydrate based di- or multinucleophilic crosslinker, for example diaminotrehalose (DATH) together with a glycosaminoglycan. The crosslinkers used typically comprise a diamino structure/derivative, e.g. comprise two or more primary amines and is devoid of carboxylic groups. The diamino structures may be aliphatic/aromatic diamino structures, peptide structures, such as lysine, or diamino carbohydrates, which may be selected from the group comprising diamino trehalose, diamino hyaluronic acid tetrasaccharide, diamino hyaluronic acid hexasaccharide, diamino lactose, diamino maltose, diamino sucrose, chitobiose, and diamino raffinose (pg. 10, col. 2, [0115]). US’332 teaches that the crosslinker itself contributes to maintained or increased properties of the hydrogel, for example when crosslinking with a structure that correlates to hyaluronic acid (e.g., diamino hyaluronic acid tetrasaccharide) or when crosslinking with a structure with high water retention properties (e.g., trehalose) (pg. 11, col. 1, [0117]). US’332 teaches that the injectable hydrogel composition may advantageously be used for the transport or administration and slow or controlled release of various pharmaceutical or cosmetic substances. The sterilized injectable hydrogel composition may be employed in medical as well as non-medical, e.g. purely cosmetic, procedures by injection of the composition into soft tissues of a patient or subject. The compositions may be useful in, e.g., soft tissue augmentation, for example filling of wrinkles, by hyaluronic acid gel injection. The compositions may be useful in a cosmetic treatment, referred to herein as skin revitalization, whereby small quantities of a hyaluronic acid composition are injected into the dermis at a number of injection sites distributed over an area of the skin to be treated, resulting in improved skin tone and skin elasticity. Skin revitalization is a simple procedure and health risks associated with the procedure are very low (pg. 14, col. 1, [0154]).
It would have been obvious to one of ordinary skill in the art, before the effective
filing date of the instantly claimed invention to combine US’332 with US’596, to optimize the amount of each component of the instant claim 1, as each component is taught by US’596, and US’332 teaches that the polysaccharide concentration (crosslinked and/or non-crosslinked) in the final product may be in the range of 5-50 mg/mL, such as 10-30 mg/mL, and the amount of solid particles in the final product may be in the range of 0.01-10% by weight, such as 0.1-5% (pg. 7, col. 1, [0074]), to arrive at a hydrogel comprising of the instantly claimed composition. MPEP 2144.05 states: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed 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 further would have been obvious to one of ordinary skill in the art at the time
the invention was made to optimize the amount of each component. One would have been motivated to do so in order to arrive at a composition with desirable rheological properties. There would be a reasonable expectation of success since the prior art teaches a range that could guide the experimentation for the instantly claimed range. It is noted that MPEP 2144.05 states: "In the case where the claimed ranges "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); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d
1362, 1365-66 (Fed. Cir. 1997).
Regarding claims 2 – 4, the same case of prima facie obviousness exists as stated above.
Regarding claim 5, US’596 teaches the MHA gel, which is a crosslinked HA.
Regarding claim 6, US’596 teaches free HA.
Regarding claim 7, US’596 teaches that the resorbable biocompatible microparticles may consist of the biodegradable polyester, polyorthoester or polyanhydride synthetic polymer may be a homopolymer or copolymer of glycolide, lactide, caprolactone, and p-dioxanone, or is trimethylene carbonate, or a poly(hydroxybutyrate) or poly(hydroxyvalerate) polymer, and US’332 teaches poly (alpha-hydroxy acid) polymer particles.
Regarding claim 8, it would have been prima facie obvious to combine US’596 with US’332 before the effective filing date of the claimed invention to provide hydrogel with reduced particle size for ease of application through a syringe to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because US’332 teaches particles having an average size in the range of 0.01 – 5 mm are small enough to enable filling into syringes and extrusion through a needle (pg. 7, col. 1, [0073]) and the average size of the solid polymer particles range from 0.5-100 μm in diameter, such as 5-100 μm, including narrower ranges such as 25 to 50 μm (pg. 10, col. 1, [0109]).
Regarding claims 9 – 11 and 14, US’596 teaches that the injectable dermal filler composition is crosslinked with BDDE (1,4-butanediol diglycidyl ether) (pg. 3, col. 2, [0045]).
Regarding claims 12 and 13, it would have been prima facie obvious to combine US’596 with US’332 before the effective filing date of the claimed invention to crosslink the glycosaminoglycan by using a non-carbohydrate based di- or multinucleophilic crosslinker, for example hexamethylenediamine (HMDA), or a carbohydrate based di- or multinucleophilic crosslinker, for example diaminotrehalose (DATH) together with a glycosaminoglycan, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because US’332 teaches that the crosslinker itself contributes to maintained or increased properties of the hydrogel, for example when crosslinking with a structure that correlates to hyaluronic acid (e.g., diamino hyaluronic acid tetrasaccharide) or when crosslinking with a structure with high water retention properties (e.g., trehalose) (pg. 11, col. 1, [0117]).
Regarding claim 19, it would have been prima facie obvious to combine US’596 with US’332 before the effective filing date of the claimed invention to use the composition for skin quality enhancement in a subject to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because US’332 teaches that the injectable hydrogel composition may advantageously be used for the transport or administration and slow or controlled release of various pharmaceutical or cosmetic substances resulting in improved skin tone and skin elasticity, and skin revitalization is a simple procedure and health risks associated with the procedure are very low (pg. 14, col. 1, [0154]).
Claims 15 – 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0333596 (PTO-892) in view of US 2021/0155763 (PTO-892).
US’596 teaches injectable dermal filler compositions in the form of a gel, comprising hyaluronic acid (HA), carboxymethyl cellulose (CMC) and, optionally, microparticles such as calcium hydroxyapatite (CaHAP) microparticles. The injectable dermal filler compositions have improved rheological properties while at the same time have low extrusion forces. US’596 teaches a method for preparing such injectable dermal filler compositions and their use for cosmetic and therapeutic purposes (pg. 1, col. 1, [0001]).
US’596 exemplifies the preparation and purification of the crosslinked HA (MHA gel) in an alkaline solution consisting of NaOH and BDDE in Example 1, and the resulting gel (the “MHA gel”) was then used to prepare the MHAG (without CaHAP) and the MHAI (with CaHAP) gel formulations (pg. 6, col. 2, [0088] – [0092]). US’596 in Example 3 teaches the Preparation of a HA Gel with 15% (v/v) Free HA as Lubrication Phase (Comparative Gel), which comprises of the following steps. A solution “LB2” was prepared by dissolving 1.131 g of lidocaine HCl in 72.743 g of phosphate buffer. Then, 1.170 g of sodium hyaluronate (2.5-3.0 MDa) were added. After complete dissolution, 33.005 g of glycerin were added. The mixture was then stirred at a moderate speed for 1 hour and 30 minutes and kept at 5° C. before use. A HA gel with 15% (v/v) free HA lubricant was prepared by mixing 106.721 g of LB2 with 387.357 g of the MHAG gel prepared in Example 1. A moderate mixing was maintained for 2 hours. After degassing, the mixture was transferred in 1 ml syringes and sterilized at 127° C. for 4 min (pg. 7, col. 1, [0095],[0096]). US’596 in Example 7 teaches the Preparation of a HA/CaHAP Gel with 10% (v/v) Free HA as Lubrication Phase (Comparative Gel), which comprises of the following steps. A solution “LB6” was prepared in the same manner as for LB2, except that the following materials and quantities were used: 208.548 g of glycerin, 3.108 g of sodium hyaluronate, and 188.581 g of phosphate buffer. A HA/CaHAP gel with 10% (v/v) free HA lubricant was prepared by mixing 156.781 g of the MHAG gel prepared in Example 1 with 63.32 g of LB6 and 2120 μL of lidocaine solution (2 g of lidocaine in 2 g phosphate buffer). Then, 280.02 g of CaHAP (25 μm to 45 μm) were added and mixed moderately for 1.5 hours. After degassing, 1 ml syringes were filled and sterilized at 121° C. for 20 min (pg. 7, col. 2, [0103], [0104]). US’596 teaches after degassing under vacuum, 1 ml syringes were filled and sterilized at 121° C. for 20 minutes (pg. 7, col. 1, [0098]).
The teachings of US’596 differ from the instantly claimed invention in that US’596 does not teach 2% - 4% v/v NaOH for crosslinking the glycosaminoglycan, filtering the crosslinked glycosaminoglycan hydrogel, precipitating and washing the crosslinked glycosaminoglycan hydrogel using ethanol.
US’763 teaches a process for manufacturing a cross-linked hyaluronic acid (HA) gel product comprising the steps of: (a) preparing an aqueous mixture of HA and a cross-linking agent selected from multiepoxides and diepoxides; wherein the HA is dissolved in an aqueous solution containing 1-10% (w/w) inorganic hydroxide; and wherein the dissolved HA constitutes more than 10% (w/w) of the final mixture; and (b) subjecting the aqueous mixture to cross-linking conditions to allow the dissolved HA to react with the cross-linking agent so as to obtain a cross-linked HA gel product (Abstract). US’763 teaches that the preferred inorganic hydroxide is NaOH. The resulting aqueous solution is preferably comprising more than 1%, such as 1.5% or more, such as 2% or more, such as more than 2.00%, such as 2.1% or more, such as 2.5% or more (w/w) inorganic hydroxide. Importantly, the resulting aqueous solution is at the same time comprising 10% or less, such as 8% or less, such as 6% or less, such as 5% or less, such as 4% or less (w/w) inorganic hydroxide. Preferred ranges of inorganic hydroxide in the solution are e.g. 1.5-8%, such as 1.5-6% (w/w); such as 2-4% (w/w) inorganic hydroxide, especially more than 2.00%, such as 2.1% or more (w/w) inorganic hydroxide which provides strong and firm HA gel products (pg. 3, col. 1, [0044]). US’763 teaches that it has been experimentally observed that stronger gels can be obtained using more than 2.00%, such as 2.1% or more, such as 2.5% or more or even 4% or more (w/w) inorganic hydroxide in combination with a dissolved HA concentration of 20% or more, or 25% or more (w/w) of the final mixture (pg. 3, col. 2, [0046]). US’763 teaches that the manufacturing process involves a step of isolating the cross-linked HA product, e.g. by filtration, dialysis or precipitation in a precipitating medium to remove cross-linking agent which has not been incorporated into the HA gel product (pg. 4, col. 1, [0057]. US’763 teaches that it is particularly preferred to include a step of precipitating the HA gel product after the cross-linking step has been terminated to wash away residual (soluble) cross-linking agent which has not been incorporated into the product (pg. 4, col. 1 [0058]). US’763 teaches that the useful precipitation media include pentane, hexane, cyclohexane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetamide, diethyl ether, tetrahydrofurane, acetonitrile, methyl ethyl ketone, acetone, lower alkyl alcohols, e.g. methanol, ethanol, propanol, isopropanol and butanol. A preferred group of precipitation media is the lower alkyl alcohols. The term lower alkyl alcohol includes primary, secondary and tertiary alkyl alcohols having from one to six carbon atoms, i.e. C1-6 alkyl alcohols. Specific examples of lower alkyl alcohols include methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol. Preferred lower alkyl alcohols are methanol and ethanol, in particular ethanol, due to price, availability and easy handling (pg. 4, col. 1, [0059]). US’763 teaches that the manufacturing process involves a further step of sterilizing the cross-linked HA product, e.g. by autoclaving, radiation, heating etc., so as to obtain a sterile cross-linked HA product (pg. 4, col. 1, [0060]). US’ 763 teaches the product can be manufactured in various shapes, such as a particle, a fibre, a string, a strand, a net, a film, a disc or a bead. It is preferred that the shape has an extension of less than 5 mm, preferably less than 1 mm, and larger than 0.5 mm or even larger than 0.8 mm when the HA substrate is in swollen form in physiological saline. A preferred shape is particles or beads having a size of 0.1-5 mm, such as 0.5-1 mm, when fully swollen in physiological saline (pg. 4, col. 2, [0066]). US’763 teaches that the desired shape and size can be achieved by subjecting the gel to mechanical disruption, such as mincing, mashing or passing the swollen or partly swollen gel through a filter or mesh with suitable pore size. The resulting gel particles or pieces are dispersed in a physiological salt solution, resulting in a gel dispersion or slurry with particles of desired size and shape. Depending on the shape, the size of a gel structure may be determined in any suitable way, such as by laser diffraction, microscopy, filtration, etc., and is decided by the longest distance between two ends of the particle. For spherical structures, the diameter equals the size for this purpose (pg. 4, col. 2, [0067]). US’763 exemplifies the HA gel in which an aliquot of the gel was precipitated and washed in EtOH and then dried in a vacuum chamber. The gel powder was rehydrated in a buffer solution to 20 mg/g HA. The amount of free BDDE derivatives in the solution (i.e. not coupled to the gel) was determined using LC-MS prior to and after the precipitation step, which showed that an additional precipitation and washing in ethanol is highly effective to reduce undesirable soluble BDDE derivatives which are not covalently coupled to the gel product (pg. 8, col. 1, [0112],[0114]).
It would have been prima facie obvious to combine US’596 with US’763 before the effective filing date of the claimed invention to prepare effectively crosslinked glycosaminoglycan hydrogel under optimal alkaline conditions, by filtering the crosslinked glycosaminoglycan hydrogel to obtain particles of desired size, further precipitating and washing the crosslinked glycosaminoglycan using ethanol to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because US’763 teaches that it has been experimentally observed that stronger gels can be obtained using more than 2.00%, such as 2.1% or more, such as 2.5% or more or even 4% or more (w/w) inorganic hydroxide in combination with a dissolved HA concentration of 20% or more, or 25% or more (w/w) of the final mixture (pg. 3, col. 2, [0046]), a preferred shape is particles or beads having a size of 0.1-5 mm which could be achieved by passing the swollen or partly swollen gel through a filter or mesh with suitable pore size (pg. 4, col. 2, [0067]), and an additional precipitation and washing in ethanol is highly effective to reduce undesirable soluble BDDE derivatives which are not covalently coupled to the gel product (pg. 8, col. 1, [0112],[0114]).
Conclusion
Claims 1 – 20 are rejected. No claims are allowed.
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/JANAKI ANANTH MAHADEVAN/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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